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Neuron and Glia Numbers in the Basolateral Nucleus of the Amygdala From Preweaning Through Old Age in Male and Female Rats: A Stereological Study
Abstract
The rat basolateral nucleus of the amygdala continues to develop connectivity with the frontal cortex through the periadolescent period and even into young adulthood. Although neuronal loss in the prefrontal cortex has been found during the periadolescent period, prior literature has not examined whether neuron number in the basolateral amygdala is stable through this period. In addition, aging of the rat basolateral nucleus is accompanied by significant increases in the dendritic tree of its principal neurons, but whether this occurs in the context of neuronal death has not been previously explored. In the present study, a stereological examination of neuron and glia numbers in the rat basolateral amygdalar nucleus was undertaken in male and female hooded rats at four ages across the lifespan. Our findings indicate 1) a significant decrease in the number of neurons and glia in the basolateral nucleus between adolescence and adulthood; and 2) the number of glia, as well as the volume of the basolateral nucleus, increases between adulthood and old age, whereas neuron number remains stable. These findings provide an important cellular context for interpretation of the neurochemical and other alterations documented in developmental and age-related literature on the rat basolateral amygdala, and underline the substantial development of this brain area during adolescence, as well as its comparative preservation during aging.
... In humans, the maximum volume of the amygdala is reached between 9 and 11 years of age (Uematsu et al., 2012). In rats, the amygdala undergoes a significant increase and subsequent decrease in volume between P7-P25 and P25-P45 respectively, before stabilizing in adulthood (Kraszpulski et al., 2006;Rubinow and Juraska, 2009). Across species, this high growth rate seems to coincide with a pre-adolescent period (Chareyron et al., 2012). ...
... Across species, this high growth rate seems to coincide with a pre-adolescent period (Chareyron et al., 2012). However, slight increases in amygdala volume have been observed between P90 and postnatal month 22 (Rubinow and Juraska, 2009). These volumetric changes are accompanied by increases in dendritic spine density and length between P20 and P35 (Koss et al., 2014;Zehr et al., 2006). ...
... These volumetric changes are accompanied by increases in dendritic spine density and length between P20 and P35 (Koss et al., 2014;Zehr et al., 2006). Dendritic pruning during adolescence refines these over-produced networks, as seen in the rat and Syrian hamster [Mesocricetus auratus; (Rubinow and Juraska, 2009;Zehr et al., 2006)]. ...
In this paper, our goal is to explore what is known about the role of social touch during development. We first address the neural substrates of social touch and the role of tactile experience in neural development. We discuss natural variation in early exposure to social touch, followed by a discussion on experimental manipulations of social touch during development and "natural experiments", such as early institutionalization. We then consider the role of other developmental and experiential variables that predict social touch in adults. Throughout, we propose and consider new theoretical models of the role of social touch during development on later behavior and neurobiology.
... However, insufficiently studied aspects, according to the analysis of neuromorphologic studies, are peculiarities of microscopical structure of the spinal ganglia of small animals, including the domestic dog. Furthermore, the literature contains controversial data on neuron organization of the spinal ganglia in the the normal condition and regarding age (Rubinow & Juraska, 2009). Also, such research concerning the structure of the spinal ganglia of dogs has been seen to be fragmentary in character. ...
... Moreover, on the basis of the analysis of morphometric data of various populations of nerve cells of the spinal ganglia of different segmentary levels, we should note the heterochrony of the parameters of volume of cell perikarya, their nuclei and therefore nuclear-cytoplasmic ratio. In our opinion, such changes occur due to the fact that the spinal ganglia of different location level innervate different structures -act as receptors of the skin, the movement apparatus, while the other ganglia act as receptors of the internal organs, etc, i.e. the structures of different levels of morphofunctional activity (Rubinow & Juraska, 2009;Nazarchuk, 2010;Stepanchuk, 2020). Therefore, morphometric analysis of the populations in the spinal ganglia revealed high parameters of the volumes of neuronal perikarya and nuclei in the segments of the cervical and lumbar enlargements which take part in the innervation of accordingly the muscles of thoracic and pelvic limbs. ...
The spinal ganglia, which perform the function of the first link on the afferent impulses’ way from the receptors to the central nervous system, recognize internal and external irritations, and are the first to transform them into a nervous impulse. As the representatives of the peripheral nervous system, they are some of the main objects of the studies in contemporary neuromorphology. Based on the results of anatomic, neurohistological, histochemical, morphometric and statistical methods of the studies, we conducted a complex survey, revealing the morphology of spinal ganglia of different segmental levels in the domestic dog. In particular, we determined the differences in the microscopic structure and morphometric parameters of cervical, thoracic, lumbar and sacral spinal ganglia and the ganglia of the cervical and lumbar enlargements in mature domestic dogs. The study showed that the spinal ganglia of domestic dogs can have different skeletotopy, different shape and sizes due to their species peculiarity. Also, the surveyed animals, according to the results of our studies, had the cervical and thoracic spinal ganglia of oval, while the lumbar and sacral – spindle-like shapes. According to the results of morphometry, the area of the spinal ganglia in lengthwise section differed: the smallest area belonged to the thoracic, the largest to the sacral spinal ganglia. The density of neuronal arrangement per 0.1 mm2 of the area of the spinal ganglia correlated with their sizes: the highest parameter was identified for the thoracic spinal ganglia, the lowest – for the sacral. The conducted studies revealed that histo- and cyto-structure of the spinal ganglia is characteristic of notable differentiation of the nervous cells of small sizes. Therefore, we differentiated neurons of the spinal ganglia into large, medium and small. The highest quantity of large neurons was found in the sacral ganglia, and largest amount of medium-sized neurons – in the ganglia of the lumbar enlargement. In other ganglia, small neurons dominated. Correspondingly, different nuclear-cytoplasmic ratio in these neurons was determined, indicating different extent of morphofunctional condition of nervous cells. We determined content of localization and separation of nucleic acids in histostructure of the spinal cord at the tissue and cellular levels.
... Concurrent with these changes in BLA spine density are fluctuations in amygdalar volume and the total number of cells within the amygdala. The volume of the lateral, basal, and central nuclei of the amygdala increases from Postnatal Day (P)7 to 35 in rats [39,40] (see Appendix A for a guide to postnatal development in rodents in postnatal days). Thereafter, amygdala volume decreases across adolescence to similar levels as in adulthood by P45 [39]. ...
... Thereafter, amygdala volume decreases across adolescence to similar levels as in adulthood by P45 [39]. The decrease in amygdala volume across adolescence is likely due to small decreases in neuron number ( [40] but see [39]) and reduced arborisation. It is interesting to note that volumetric analyses of amygdala development in humans appear to parallel the pattern of increasing amygdala volume from preadolescence to early adolescence reported in rats but not the later decreases across adolescence. ...
Anxiety disorders that develop in adolescence represent a significant burden and are particularly challenging to treat, due in no small part to the high occurrence of relapse in this age group following exposure therapy. This pattern of persistent fear is preserved across species; relative to those younger and older, adolescents consistently show poorer extinction, a key process underpinning exposure therapy. This suggests that the neural processes underlying fear extinction are temporarily but profoundly compromised during adolescence. The formation, retrieval, and modification of fear- and extinction-associated memories are regulated by a forebrain network consisting of the prefrontal cortex (PFC), the amygdala, and the hippocampus. These regions undergo robust maturational changes in early life, with unique alterations in structure and function occurring throughout adolescence. In this review, we focus primarily on two of these regions—the PFC and the amygdala—and discuss how changes in plasticity, synaptic transmission, inhibition/excitation, and connectivity (including modulation by hippocampal afferents to the PFC) may contribute to transient deficits in extinction retention. We end with a brief consideration of how exposure to stress during this adolescent window of vulnerability can permanently disrupt neurodevelopment, leading to lasting impairments in pathways of emotional regulation.
... Considering the relatively few behavioral studies examining male and female subjects prior to or during puberty, recent studies investigating the neuronal properties of the basolateral amygdala and prefrontal cortex in male and female rats indicate developmental and/or sexspecific changes in these brain regions emerge prior to puberty and continue into adulthood (Rubinow and Juraska 2009;Koss et al. 2014;Willing and Juraska 2015). Moreover, the septalhippocampal cholinergic system implicated in contextual processing emerges earlier in female than male rats and continues to differentiate into adulthood (Loy and Sheldon 1987). ...
... In male rats, PFC neuron numbers do not significantly change from P25 toward adulthood (Willing and Juraska 2015). Conversely, the number of neurons within the basolateral amygdala, a vital region for the association and maintenance of fear decreases from P35 to P90 in females, but not in males (Rubinow and Juraska 2009). In the present study, this coincides with a developmental attenuation of context fear specific to female rats. ...
Development and sex differentiation impart an organizational influence on the neuroanatomy and behavior of mammalian species. Prior studies suggest that brain regions associated with fear motivated defensive behavior undergo a protracted and sex-dependent development. Outside of adult animals, evidence for developmental sex differences in conditioned fear is sparse. Here, we examined in male and female Long-Evans rats how developmental age and sex affect the long-term retention and generalization of Pavlovian fear responses. Experiments 1 and 2 describe under increasing levels of aversive learning (three and five trials) the long-term retrieval of cued and context fear in preadolescent (P24 and P33), periadolescent (P37), and adult (P60 and P90) rats. Experiments 3 and 4 examined contextual processing under minimal aversive learning (1 trial) procedures in infant (P19, P21), preadolescent (P24), and adult (P60) rats. Here, we found that male and female rats display a divergent developmental trajectory in the expression of context-mediated freezing, such that context fear expression in males tends to increase toward adulthood, while females displayed an opposite pattern of decreasing context fear expression toward adulthood. Longer (14 d) retention intervals produced an overall heightened context fear expression relative to shorter (1 d) retention intervals an observation consistent with fear incubation. Male, but not Female rats showed increasing generalization of context fear across development. Collectively, these findings provide an initial demonstration that sexual differentiation of contextual fear conditioning emerges prior to puberty and follows a distinct developmental trajectory toward adulthood that strikingly parallels sex differences in the etiology and epidemiology of anxiety and trauma- and stressor-related disorders.
... where "ΣQ − " was the total number of the cells in the CA1 and DG coming into focus throughout scanning the height of the disector; "ΣP", the total number of counting frames in most fields; "h", the height of the disector; "a/f", the frame area; "t", the mean section thickness calculated in every sampled field using the microcator; and "BA", the block advance of the microtome set at 40 µm (Rubinow and Juraska 2009). ...
The present study aimed to investigate the combination effects of hypothermia (HT) and intranasal insulin (INS) on structural changes of the hippocampus and cognitive impairments in the traumatic brain injury (TBI) rat model. The rats were divided randomly into the following five groups (n = 10): Sham, TBI, TBI with HT treatment for 3 h (TBI + HT), TBI with INS (ten microliters of insulin) treatment daily for 7 days (TBI + INS), and TBI with combining HT and INS (TBI + HT + INS). At the end of the 7th day, the open field and the Morris water maze tests were done for evaluation of anxiety-like behavior and memory performance. Then, after sacrificing, the brain was removed for stereological study. TBI led to an increase in the total volume of hippocampal subfields CA1 and DG and a decrease in the total number of neurons and non-neuronal cells in both sub-regions, which was associated with anxiety-like behavior and memory impairment. Although, the combination of HT and INS prevented the increased hippocampal volume and cell loss and improved behavioral performances in the TBI group. Our study suggests that the combined treatment of HT and INS could prevent increased hippocampal volume and cell loss in CA1 and DG sub-regions and consequently improve anxiety-like behaviors and memory impairment following TBI.
... Our data allow us to infer that the age-associated reduction in the density of NPYpositive interneurons detected in the present study is not due to cell death because it was found that the intracerebroventricular administration of NGF to aged rats restores their number to normal adult values. This observation is in line with previous data showing that the number of neurons in the basolateral nucleus of the amygdala does not differ between rats at 3 months of age and at 19-22 months of age [73]. Thus, it is very probable that the age-associated reduction in the NPY expression in the BLA may just reflect a decrease in the synthesis and, subsequently, in the NPY expression to levels below immunocytochemistry detectability. ...
The basolateral amygdala (BLA) contains interneurons that express neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), both of which are involved in the regulation of functions and behaviors that undergo deterioration with aging. There is considerable evidence that, in some brain areas, the expression of NPY and VIP might be modulated by acetylcholine. Importantly, the BLA is one of the brain regions that has one of the densest cholinergic innervations, which arise mainly from the basal forebrain cholinergic neurons. These cholinergic neurons depend on nerve growth factor (NGF) for their survival, connectivity, and function. Thus, in this study, we sought to determine if aging alters the densities of NPY- and VIP-positive neurons and cholinergic varicosities in the BLA and, in the affirmative, if those changes might rely on insufficient trophic support provided by NGF. The number of NPY-positive neurons was significantly reduced in aged rats, whereas the number of VIP-immunoreactive neurons was unaltered. The decreased NPY expression was fully reversed by the infusion of NGF in the lateral ventricle. The density of cholinergic varicosities was similar in adult and old rats. On the other hand, the density of cholinergic varicosities is significantly higher in old rats treated with NGF than in adult and old rats. Our results indicate a dissimilar resistance of different populations of BLA interneurons to aging. Furthermore, the present data also show that the BLA cholinergic innervation is particularly resistant to aging effects. Finally, our results also show that the reduced NPY expression in the BLA of aged rats can be related to changes in the NGF neurotrophic support.
... the basolateral amygdala (Bla) has been shown to play an essential role in assigning associative value to sensory inputs associated with salient outcomes, and therefrom permitting the expression of the conditioned fear (e.g., Johansen et al., 2011). in rats of both sexes, the lengths, complexities, and densities of Bla neurons increase substantially between postnatal day 20 (P20) to P35, reaching adult levels soon thereafter, though these effects are also related to onset of puberty (Koss et al., 2014;spear, 2000). still, most Bla cellular refinement processes do not occur until late adolescence (Rubinow & Juraska, 2009). as such, one interpretation of our acquisition data is that alcohol experience produces development-dependent disruptions of Bla maturation and processing. ...
Alcohol use during adolescence coincides with elevated risks of stress-related impairment in adults, particularly via disrupted developmental trajectories of vulnerable corticolimbic and mesolimbic systems involved in fear processing. Prior work has investigated the impact of binge-like alcohol consumption on adult fear and stress, but less is known about whether voluntarily consumed alcohol imparts differential effects based on adolescence phases and biological sex. Here, adolescent male and female Long Evans rats were granted daily access to alcohol (15%) during either early (Early-EtOH; P25-45) or late adolescence (Late-EtOH; P45-55) using a modified drinking-in-the-dark design. Upon adulthood (P75-80), rats were exposed to a three-context (ABC) fear renewal procedure. We found that male and female Early-EtOH rats showed faster acquisition of fear but less freezing during early phases of extinction and throughout fear renewal. In the extinction period specifically, Early-EtOH rats showed normal levels of freezing in the presence of fear-associated cues, but abnormally low freezing immediately after cue offset, suggesting a key disruption in contextual processing and/or novelty seeking brought by early adolescent binge consumption. While the effects of alcohol were most pronounced in the Early-EtOH rats (particularly in females), Late-EtOH rats displayed some changes in fear behavior including slower fear acquisition, faster extinction, and reduced renewal compared with controls, but primarily in males. Our results suggest that early adolescence in males and females and, to a lesser extent, late adolescence in males is a particularly vulnerable period wherein alcohol use can promote stress-related dysfunction in adulthood. Furthermore, our results provide multiple bases for future research focused on developmental correlates of alcohol mediated disruption in the brain.
... ;https://doi.org/10.1101https://doi.org/10. /2023 adolescence (Rubinow and Juraska, 2009). As such, one interpretation of our acquisition data is that alcohol experience produces development-dependent disruptions of BLA maturation and processing. ...
Alcohol use during adolescence coincides with elevated risks of stress-related impairment in adults, particularly via disrupted developmental trajectories of vulnerable corticolimbic and mesolimbic systems involved in fear processing. Prior work has investigated the impact of binge-like alcohol consumption on adult fear and stress, but less is known about whether voluntarily consumed alcohol imparts differential effects based on adolescence phases and biological sex. Here, adolescent male and female Long Evans rats were granted daily access to alcohol (15%) during either early (Early-EtOH; P25-45) or late adolescence (Late-EtOH; P45-55) using a modified drinking-in-the-dark design. Upon adulthood (P75-80), rats were exposed to a three-context (ABC) fear renewal procedure. We found that male and female Early-EtOH rats showed faster acquisition of fear but less freezing during early phases of extinction and throughout fear renewal. In the extinction period specifically, Early-EtOH rats showed normal levels of freezing in the presence of fear-associated cues, but abnormally low freezing immediately after cue offset, suggesting a key disruption in contextual processing and/or novelty seeking brought by early adolescent binge consumption. While the effects of alcohol were most pronounced in the Early-EtOH rats (particularly in females), Late-EtOH rats displayed some changes in fear behavior including slower fear acquisition, faster extinction, and reduced renewal compared with controls, but primarily in males. Our results suggest that early adolescence in males and females and, to a lesser extent, late adolescence in males is a particularly vulnerable period wherein alcohol use can promote stress-related dysfunction in adulthood. Furthermore, our results provide multiple bases for future research focused on developmental correlates of alcohol mediated disruption in the brain.
... Цьому сприяло накопичення даних у таких галузях, як нейробіологія, фізіологія, клітинна біологія та нейроморфологія. Працями ряду вітчизняних (Kovaleva, 1985;Nazarchuk, 2009;Goralskyi et al., 2016;Ostrovskyi, 2019;Sokulskyi et al., 2021) та зарубіжних (Pannese et al., 1999;Khorooshi et al., 2001;Rubinow & Juraska, 2009;Rodríguez-Bodero & Encinas-Pérez, 2022) нейрогістологів встановлено, що нервова тканина відрізняється вираженою неоднорідністю клітинного складу, водночас гліальні клітини значно переважають у кількісному плані нервові, займають увесь об'єм нервової тканини між судинами та нейронами. За нашими даними, показник щільності гліальних клітин на умовну одиницю площі є найвищим у спинномозкових вузлах річкового коропа порівняно з іншими представниками хребетних тварин, а найнижчим -у ставкової жаби. ...
An important issue of modern neuromorphology of animals is the study of spinal cord nodes, which play an important role as primary centers on the way to transmit sensory information from receptors to the central nervous system, providing appropriate reactions to the action of certain factors. The scientific article uses material that is a fragment of the research work of the department of normal and pathological morphology, hygiene and expertise “Development, morphology and histochemistry of animal organs in normal and pathological conditions”, state registration number – 0120U100796. Using anatomical, morphological, neurohistological and statistical methods of research, the histomorphology of spinal cord nodes in a comparative anatomical series of vertebrates: bony fish, amphibians, reptiles, which differ in motor activity and their place of existence in a certain environment, was clarified in the work. It has been established that in the process of phylogenesis, a certain structural and morphofunctional reorganization of the spinal nodes occurs. They differ in shape and size. Adaptation to various living conditions of animals was formed on the basis of changes in the density and size of neurons, their morphological structures, an increase in the total number of gliocytes and glial cells, and polymorphism in the degree of chromatophilia. Thus, according to neurohistological studies, it has been noted that the neurons of the spinal cord nodes of cold-blooded animals (pond frog, pond lizard) are characterized by a functional degree of relative polymorphism – chromatophilia. With the total impregnation of the spinal cord nodes with silver nitrate according to the Bolshovsky-Gross method, different intensity of staining of nerve cells is found in all the studied animals: light, light-dark and dark. It was found that the neurocytes of all groups of vertebrates differ in the volume of the perikaryon, the nucleus and the nuclear-cytoplasmic ratio, which is related to the peculiarities of species and age-related neuromorphology, the morpho-functional state of the nervous system and the type of higher nervous activity. Nissl staining of histopreparations of spinal nodes of poikilothermic animals showed that the neuroplasm of nerve cells of spinal nodes contains deep basophilic substances in the form of small grains of varying density. In carp neurons, the basophilic substance is concentrated on the periphery of the dust-like neuroplasm. Nuclear chromatin is more pronounced in the pond frog than in the carp, the depths of which are much larger. It should be noted that the highest degree of development of the protein-synthesizing apparatus is characteristic of the neurocytes of the spinal nodes of the swift lizard, compared to the previously studied vertebrates. The obtained research results have not only important general biological significance, which complements and expands modern scientific ideas about certain regularities of morpho-functional rearrangements of spinal cord nodes in a comparative anatomical series, but also serve to develop new material and substantiate the morpho-functional assessment of species morphological differences of the nervous system of poikilothermic vertebrates, adapted to different conditions of existence in the environment.
... Where "ΣQ − " was the total number of the nuclei in the CA1 and DG within the sampling boxes; "ΣP", the total number of counting frames; "t", the mean thickness of sections calculated by the microcater; and "BA", the block advance set at 50 µm [31]. The total volume of CA1 and DG was estimated by the Cavalieri method [29] mentioned above. ...
Valproate (VPA) as a histone deacetylase (HDAC) inhibitor has shown neuroprotective effects in neurodegenerative diseases. This study evaluated whether VPA treatment ameliorated the synaptic plasticity dysfunction, hippocampal neuronal loss, and spatial memory deficits induced by cerebral ischemia in the middle cerebral artery occlusion (MCAO) model. Thirty-two male Sprague-Dawley rats were randomly divided into 4 groups control, sham, cerebral ischemia+vehicle (MCAO+V), and MCAO+VPA. The right common carotid artery was occluded for 1 hour. VPA (300 mg/kg) or vehicles were injected intraperitoneally on days 0,1,2 and 3 of the reperfusion. After 7 days of reperfusion the Morris water maze, passive avoidance, and open field tests were performed. Hippocampal synaptic plasticity in the CA1 area was recorded by field potential recording. We used the term neuronal Input-Output (I/O) function and paired-pulse ratio (PPR) to refer to basal synaptic transmission and presynaptic neurotransmitter release probability respectively. After that, the brains were removed for assaying stereological parameters of the CA1 neurons. Our results showed the VPA administration significantly reduced the total infarct volume, improved MCAO-induced spatial learning -memory, fear memory, and anxiety compared to the MCAO+V group. In addition, the field potential recording showed that VPA significantly ameliorated the impaired the long- term potentiation (LTP) induced by MCAO, without any effects on basal synaptic transmission and neurotransmitter release probability. Therefore, it seems that a decrease in total infarct volume and induction of long-term potentiation via postsynaptic mechanisms is responsible for improving MCAO-induced cognitive impairment.
... Development of the prefrontal cortex is highly protracted, particularly in the context of affective regulation, continuing into the early 20s in humans (15). In contrast, the amygdala exhibits peaks in structural development in both humans (16) and rodents (17,18) during adolescence. Moreover, greater functional activation of the amygdala in response to fearassociated stimuli has been observed during adolescence relative to adults (19). ...
Significant advances have been made in recent years regarding the developmental trajectories of brain circuits and networks, revealing links between brain structure and function. Emerging evidence highlights the importance of developmental trajectories in determining early psychiatric outcomes. However, efforts to encourage cross talk between basic developmental neuroscience and clinical practice are limited. Here, we focus on the potential advantage of considering features of neural circuit development when optimizing treatments for adolescent patient populations. Drawing on characteristics of adolescent neurodevelopment, we highlight two examples, safety cues and incentives, that leverage insights from neural circuit development and may have great promise for augmenting existing behavioral treatments for anxiety disorders during adolescence. This commentary seeks to serve as a framework to maximize the translational potential of basic research in developmental populations for strengthening psychiatric treatments. In turn, input from clinical practice including the identification of age-specific clinically relevant phenotypes will continue to guide future basic research in the same neural circuits to better reflect clinical practices. Encouraging reciprocal communication to bridge the gap between basic developmental neuroscience research and clinical implementation is an important step toward advancing both research and practice in this domain.
... These state-dependent effects of sex hormones may mediate the observed sex differences in oxidative stressassociated CNS disorders. Cortex (rat) 1:1 [116] Striatum (mouse) 1:17 [117] Female bias: MD [110,111,113] Male bias: PD, SZ, ASD Basal ganglia (human) 1:2 [118] Female bias: MD, [110,111,113,114] Male bias: PD, SZ, ASD Substantia nigra pars compacta (mouse) 1:9 [119] Female bias:- [110,120] Male bias: PD, SZ Thalamus (human) 17:1 [121] Female bias: MD [111,113,122] Male bias: PD, SZ Hippocampus overall (mouse) 1:1 [117] Female bias: AD, MD, ANX, Male bias: PD, SZ, ASD [109][110][111][112][113][114] CA1 (mouse) 1:2 [117] CA3 (mouse) 1:3 [117] Locus coeruleus (human) 27:1 [123] Female bias: AD, MD [110-112, 124, 125] Male bias: PD, ANX Amygdala basolateral (rat) 1:7 [117,126] Female bias: AD, MD, ANX, [110,112,114,127] Male bias: PD, ASD Spinal cord (rat) 1:6 [128] Female bias:- [110] Male bias: PD Cerebellum (mouse) Cerebellum (human) Female bias:- [110,114] Male bias: PD, ASD AD Alzheimer's disease, PD Parkinson's disease, MD major depression, ANX anxiety disorders, SZ schizophrenia, ASD autism spectrum disorders ...
Background:
The role of sex hormones on cellular function is unclear. Studies show androgens and estrogens are protective in the CNS, whereas other studies found no effects or damaging effects. Furthermore, sex differences have been observed in multiple oxidative stress-associated CNS disorders, such as Alzheimer's disease, depression, and Parkinson's disease. The goal of this study is to examine the relationship between sex hormones (i.e., androgens and estrogens) and oxidative stress on cell viability.
Methods:
N27 and PC12 neuronal and C6 glial phenotypic cell lines were used. N27 cells are female rat derived, whereas PC12 cells and C6 cells are male rat derived. These cells express estrogen receptors and the membrane-associated androgen receptor variant, AR45, but not the full-length androgen receptor. N27, PC12, and C6 cells were exposed to sex hormones either before or after an oxidative stressor to examine neuroprotective and neurotoxic properties, respectively. Estrogen receptor and androgen receptor inhibitors were used to determine the mechanisms mediating hormone-oxidative stress interactions on cell viability. Since the presence of AR45 in the human brain tissue was unknown, we examined the postmortem brain tissue from men and women for AR45 protein expression.
Results:
Neither androgens nor estrogens were protective against subsequent oxidative stress insults in glial cells. However, these hormones exhibited neuroprotective properties in neuronal N27 and PC12 cells via the estrogen receptor. Interestingly, a window of opportunity exists for sex hormone neuroprotection, wherein temporary hormone deprivation blocked neuroprotection by sex hormones. However, if sex hormones are applied following an oxidative stressor, they exacerbated oxidative stress-induced cell loss in neuronal and glial cells.
Conclusions:
Sex hormone action on cell viability is dependent on the cellular environment. In healthy neuronal cells, sex hormones are protective against oxidative stress insults via the estrogen receptor, regardless of sex chromosome complement (XX, XY). However, in unhealthy (e.g., high oxidative stress) cells, sex hormones exacerbated oxidative stress-induced cell loss, regardless of cell type or sex chromosome complement. The non-genomic AR45 receptor, which is present in humans, mediated androgen's damaging effects, but it is unknown which receptor mediated estrogen's damaging effects. These differential effects of sex hormones that are dependent on the cellular environment, receptor profile, and cell type may mediate the observed sex differences in oxidative stress-associated CNS disorders.
... Similar to humans, male rodents have larger medial amygdala volume across both adolescence and adulthood [58]. In the basolateral amygdala, which is involved in emotional learning, females undergo more extensive neuronal loss across development, but volumes are similar by adulthood [33,59]. Table 1 summarizes relevant findings from animal and human studies. ...
Purpose of Review
It is well established that adolescence is a period of time during which experimentation with substances escalates, while neurobiological changes simultaneously leave adolescents increasingly vulnerable to the development of substance use disorders (SUDs). This review sought to summarize the literature on sex differences in neurobiological risk for substance use and SUDs among adolescents. Findings from previous reviews are discussed and supplemented with evidence from recent research.
Recent Findings
We synthesize literature from human and animal studies and highlight sex differences in development, structure, and function in three primary brain regions linked to SUD risk: the prefrontal cortex, ventral striatum, and amygdala. Evidence from both human and animal studies suggests sex-divergent paths in risk for substance use and addiction: an internalizing path in females and an externalizing path in males.
Summary
While much work is still needed to clarify sex-dependent neurobiological changes that contribute to differences in addiction risk, prefrontal and striatal findings have emerged in both animal and human studies. Continued efforts are needed in order to shed light on mechanisms of risk and, eventually, sex-tailored interventions.
... Specifically, the adolescent period is defined as a time in development in which neural structures and systems are going through a period of reduction and refinement (Casey, Getz, & Galvan, 2008;Uhlhaas & Singer, 2011). This is the case for several brain regions and neurotransmitter receptors implicated in extinction retention, such as the PFC, amygdala, hippocampus, and NMDA receptors (Andersen & Teicher, 2004;Baker & Richardson, 2017;Casey, 2015;Davis, 2011;Ferguson & Gao, 2015;Giedd et al., 1999;Rubinow & Juraska, 2009;Steinberg, 2005). Brain regions are particularly sensitive to stress while they are still developing and undergoing reduction and refinement in synaptic communication (Saul, Helmreich, Callahan, & Fudge, 2014;Saul et al., 2012). ...
Adolescence is noted as a time of "storm and stress." In this developmental stage both rodents and humans exhibit an impairment in the extinction of learned fear; however, this impairment can be alleviated, at least in rodents, by increasing the amount of extinction training given or by administering the partial NMDA receptor agonist D-Cycloserine. In the present study we explored whether the benefits of these treatments would be reduced by chronic exogenous corticosterone (a commonly studied stress-related hormone). In 2 experiments, adolescent rats were given pairings of a white noise and shock (acquisition) and then given extinction training (white noise presented alone). In Experiment 1, adolescents exhibited impaired extinction retention even after 2 days of extinction training if they had been exposed to corticosterone in adolescence but not if the exposure occurred when they were juveniles. In Experiment 2, exposure to exogenous corticosterone in adolescence, but not during the juvenile period, reduced the efficacy of the pharmacological adjunct D-Cycloserine at enhancing extinction retention after 1 day of extinction training. Taken together, the results support the idea that adolescence is a time of particular susceptibility to elevated levels of the stress hormone corticosterone. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
... In addition, in SG of cold-blooded, instead of the unipolar sensitive neurons, which are characteristic for SG invertebrates are pseudounipolar with T-shaped apophysis pronounced, resulting in greater speed of conduction of excitation without the involvement of the cell body. By works of row national (Goralskiy at al., 2016;Kovaleva, 1985) and foreign (Pannese et al., 1999;Khorooshi et al., 2001;Rubinow, Juraska, 2009) neurohistologists it was determined, that neural tissue is characterized by marked heterogenity of cellular composition, meanwhile, glial cells greatly predominate quantitatively over the nervous, occupy the entire volume of the nervous tissue between blood vessels and neurons. According to our data, the density of glial cells per unit of area is highest in spinal ganglia of river carp in comparison with other representatives of vertebrates, and the lowest -the pond frogs. ...
The paper presents the results of research and studied the morphology of spinal ganglia in representatives of different classes of vertebrates: bony fish, amphibians, reptiles, birds and mammals, differing by level of organization, locomotion, habitat. It is revealed that certain structural and morphofunctional restructuring of spinal ganglia is carried out in the process of phylogenesis. Adaptation to different conditions of existence was accompanied by a change in the number of parameters of the spinal ganglia: density and size of neurocytes, increasing of the total number of gliocytes and perineuronal glial cells, polymorphism of neurocytes to the degree of chromatophily.
... Varying the cell count from 1,000 up to 27,000, we found that the 455 standard deviation of the LFP scaled with density following N 0.67 . Since cell density in 456 rats is reported to range from 2.5×10 4 to 2×10 5 /mm 3 (Tuunanen and Pitkanen, 2000;457 Salm et al., 2004;Pego et al., 2008;Rubinow and Juraska, 2009;Chareyron et al., 458 2011), while the model density is 9,840 neurons/mm 3 (27,000 neurons, 1.4mm x 1.4mm 459 x 1.4mm), the LFP correction factor would correspondingly range from 1.9 to 7.5 460 ...
The basolateral nucleus of the amygdala (BL) is thought to support numerous emotional behaviors through specific microcircuits. These are often thought to be comprised of feedforward networks of principal cells and interneurons. Neither well understood nor often considered are recurrent and feedback connections, which likely engender oscillatory dynamics within BL. Indeed, oscillations in the gamma frequency range (40-100 Hz) are known to occur in the BL, and yet their origin and effect on local circuits remains unknown. To address this, we constructed a biophysically and anatomically detailed model of the rat BL and its local field potential based on the physiological and anatomical literature, along with in vivo and in vitro data we collected on the activities of neurons within the rat BL. Remarkably, the model produced intermittent gamma oscillations (~50-70 Hz) whose properties matched those recorded in vivo, including their entrainment of spiking. BL gamma-band oscillations were generated by the intrinsic circuitry, depending upon reciprocal interactions between principal cells and fast-spiking interneurons, while connections within these cell types affected the rhythm’s frequency. The model allowed us to conduct experimentally impossible tests to characterize the synaptic and spatial properties of gamma. The entrainment of individual neurons to gamma depended on the number of afferent connections they received, and gamma bursts were spatially restricted in the BL. Importantly, the gamma rhythm synchronized principal cells and mediated competition between ensembles. Together, these results indicate that the recurrent connectivity of BL expands its computational and communication repertoire.
... Another region with high expression of HIGD1A at P8 was the amygdala, one of the regions in the brain where a delayed development has been described in rodents as well as in humans (Rubinow and Juraska 2009). Furthermore, a very strong and singular pattern of expression was observed in many nuclei of the brainstem. ...
HIGD1A (hypoxia-induced gene domain protein-1a), a mitochondrial inner membrane protein present in various cell types, has been mainly associated with anti-apoptotic processes in response to stressors. Our previous findings have shown that Higd1a mRNA is widely expressed across the central nervous system (CNS), exhibiting an increasing expression in the spinal cord from postnatal day 1 (P1) to 15 (P15) and changes in the distribution pattern from P1 to P90. During the first weeks of postnatal life, the great plasticity of the CNS is accompanied by cell death/survival decisions. So we first describe HIGD1A expression throughout the brain during early postnatal life in female and male pups. Secondly, based on the fact that in some areas this process is influenced by the sex of individuals, we explore HIGD1A expression in the sexual dimorphic nucleus (SDN) of the medial preoptic area, a region that is several folds larger in male than in female rats, partly due to sex differences in the process of apoptosis during this period. Immunohistochemical analysis revealed that HIGD1A is widely but unevenly expressed throughout the brain. Quantitative Western blot analysis of the parietal cortex, diencephalon, and spinal cord from both sexes at P1, P5, P8, and P15 showed that the expression of this protein is predominantly high and changes with age but not sex. Similarly, in the sexual dimorphic nucleus, the expression of HIGD1A varied according to age, but we were not able to detect significant differences in its expression according to sex. Altogether, these results suggest that HIGD1A protein is expressed in several areas of the central nervous system following a pattern that quantitatively changes with age but does not seem to change according to sex.
... We are confident regarding the measurement of the thickness of the sections used in the current study, since our computer-aided analysis system is equipped with a Focus Encoder providing 0.1 μm resolution measurements of the actual position of the microscope stage in the z-axis, and does not rely on the pre-defined settings of the motorized stage. The average section thickness measured in the current study is similar to what we previously found during the completion of stereological studies of the rat and monkey amygdala, which have supported the reliability and generalizability of our normative data (Chareyron et al., 2011) and that were very close to those reported by other laboratories (Berdel, Morys, & Maciejewska, 1997;Carlo, Stefanacci, Semendeferi, & Stevens, 2010;Cooke, Stokas, & Woolley, 2007;Rubinow & Juraska, 2009). In our study, the disector height (5 μm) represented 37.5% of the averaged section thickness, the counting frame was 40 μm × 40 μm and we used different scan grids for individual layers (Table 1). ...
The entorhinal cortex is a prominent structure of the medial temporal lobe, which plays a pivotal role in the interaction between the neocortex and the hippocampal formation in support of declarative and spatial memory functions. We implemented design‐based stereological techniques to provide estimates of neuron numbers, neuronal soma size, and volume of different layers and subdivisions of the entorhinal cortex in adult rhesus monkeys (Macaca mulatta; 5‐9 years of age). These data corroborate the structural differences between different subdivisions of the entorhinal cortex, which were shown in previous connectional and cytoarchitectonic studies. In particular, differences in the number of neurons contributing to distinct afferent and efferent hippocampal pathways suggest not only that different types of information may be more or less segregated between caudal and rostral subdivisions, but also, and perhaps most importantly, that the nature of the interaction between the entorhinal cortex and the rest of the hippocampal formation may vary between different subdivisions. We compare our quantitative data in monkeys with previously published stereological data for the rat and human, in order to provide a perspective on the relative development and structural organization of the main subdivisions of the entorhinal cortex in two model organisms widely used to decipher the basic functional principles of the human medial temporal lobe memory system. Altogether, these data provide fundamental information on the number of functional units that comprise the entorhinal‐hippocampal circuits and should be considered in order to build realistic models of the medial temporal lobe memory system.
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... Similar developmentally regulated changes have been observed in rodents during their adolescent period, which has been argued to range from as early as postnatal day (P) 28 to at least P60 based on social, cognitive, hormonal, and neurophysiological changes that parallel markers of human adolescence (Tirelli et al. 2003;Spear 2011). For example, during rodent adolescence there are significant increases in connectivity between the basolateral amygdala and medial prefrontal cortex (Cunningham et al. 2002(Cunningham et al. , 2008, changes in the density of monoamine transporters (Moll et al. 2000;Bradshaw et al. 2016), increases in prefrontal cortex dopamine innervation (Kalsbeek et al. 1988), decreases in medial prefrontal cortex neuron number (Markham et al. 2007;Willing and Juraska 2015), and reorganization of the amygdala (Rubinow and Juraska 2009;Koss et al. 2014). ...
RATIONALE: Adolescence is a period of considerable development of brain and behavior and is the time during which most drug use is initiated. OBJECTIVE: Age-dependent differences in motivated behaviors may be one of the factors that contribute to heightened vulnerability to developing substance use disorders, so we sought to compare age differences in methamphetamine (METH) and saccharin seeking. METHODS: Beginning during adolescence or adulthood, male and female Sprague-Dawley rats were trained to self-administer 0.1% saccharin (via liquid dipper cup) or intravenous METH at one of three doses (0.02, 0.05, 0.08 mg/kg/inf) under increasing fixed ratios schedules of reinforcement. Subsequently, responding for METH (0.02, 0.05, 0.08 or 0.1 mg/kg/inf) under progressive ratio response requirements was assessed in rats that acquired METH self-administration at the highest dose (0.08 mg/kg/inf). RESULTS: We found that adult-onset rats acquired METH self-administration more readily and exhibited higher motivation compared to adolescent-onset rats, although there were no differences in METH intake during acquisition. Adult rats also acquired saccharin self-administration more readily, but in contrast to METH, there were age and sex differences in saccharin intake driven by high levels of responding in adult females. CONCLUSIONS: These findings challenge the prevailing notion that adolescents are hypersensitive to reward and instead raise questions about the potential role of methodological factors on which rodent studies often differ.
... Пріоритетним напрямом у вирішенні цієї проблеми є всебічне комплексне дослідження нервової системи тварин (Rubinow and Marisa, 2009;Horalskyi et al., 2016). Особливий інтерес до нервової системи викликаний її різноманітними функціями та властивостями: сприйняттям і проведенням нервових імпульсів, трансформацією, генерацією, зберіганням різних видів енергії та інформацій зовнішнього середовища, а також її здатністю до збудження й гальмування, до процесів синтетичного і аналітичного порядку, трофічної функції (Zherebcov, 1991). ...
У статті за використання анатомічних, гістологічних, нейрогістологічних та морфометричних методів досліджень викладено особливості макро- та мікроскопічної будови мозочка статевозрілої великої рогатої худоби (ВРХ). За результатами досліджень мозочок великої рогатої худоби характеризується загальними принципами його структурної організації та морфотопографії, проте відрізняється органометричними показниками. Так, за даними органометрії досліджень встановлено, що абсолютна маса мозочка великої рогатої худоби становить 72,59 ± 0,94 г, відносна – 0,02 ± 0,002%, його довжина складає 42,1 ± 0,36 мм, ширина – 55,3 ± 0,41, висота – 43,5 ± 0,44 мм. Сіра речовина мозочка розміщена поверхнево і формує його кору, біла міститься у центрі. У сірій речовині мозочка розрізняють три шари клітин: молекулярний (зовнішній), гангліонарний (середній) і зернистий (внутрішній), які мають різну товщину та характеризуються неоднаковою популяцією нейронів. Молекулярний шар кори мозочка найбільш поверхневий. Він містить невеликі нейрони – кошикові та зірчасті. Гангліонарний шар кори мозочка представлений надзвичайно великими клітинами Пуркіньє, розміщеними в один ряд на незначній відстані одна від одної. Їх нейроплазма містить виражені глибки базофільної зернистості, що свідчить про інтенсивний розвиток у них білоксинтезувального апарату, який знаходиться у вигляді дрібної або крупнішої зернистості, рівномірно заповнюючи майже всю нейроплазму. Зернистий шар мозочка складається з великої кількості нейронів: клітин-зерен та зірчастих клітин Гольджі, яких є два види (короткоаксонні та довгоаксонні). За результатами проведених цитоморфометричних досліджень середній показник об’єму нейронів клітин Пуркіньє мозочка у великої рогатої худоби становить 6581,62 ± 688,7 мкм3, показники об’єму ядра клітин Пуркіньє – 484,48 ± 94,5 мкм3. Виходячи із середніх показників об’єму перикаріона нервових клітин та їх ядер, ядерно-цитоплазматичне відношення відповідно становить 0,079 ± 0,002. У результаті проведених нами морфометричних досліджень архітектонічних шарів у порівняльному аспекті встановлено, що найбільша товщина кори мозочка ВРХ властива його молекулярному шару – 413,01 ± 10,84 мкм (53,2%), дещо менша вона у зернистому – 313,60 ± 13,84 мкм (40,4%) і найменша у гангліонарному – 49,03 ± 1,94 мкм (6,32%). Загальна товщина кори мозочка у великої рогатої худоби складає 775,64 ± 26,62 мкм.
... Discrimination learning depends on intact corticostriatal circuits [56,57] and reversal learning relies on the OFC [58,59], suggesting that METH self-administration in adolescent-onset females disrupted corticostriatal and OFC-sensitive functions. The putative deficits in adolescent-onset females is consistent with age-and sex-dependent differences in the development of corticostriatal circuits, reflecting research demonstrating that development of these circuits is ongoing during adolescence [60][61][62][63][64][65] and this process is different in males and females [61,63,65]. That the reversal deficit was only observed early in training is consistent with other studies showing transient amphetamine-induced deficits in PFC-sensitive tasks [17,52,53]. ...
Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age- and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HT2CR localization in the orbitofrontal cortex (OFC) in an age- and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT2C receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT2C receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT2C receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT2CR co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.
... We observed many bcl-2+ or DCX+ cells directly contacting immunoreactive fibers that extend dorsally into the basal nucleus, suggesting a substrate for immature neuronal migration from the paralaminar region into the amygdala (Fig. 2). It is important to note that regardless of the mechanism driving mature neuron increase in primates, similar age effects have not been observed in rats, and the presence of the paralaminar nucleus is debated in this species (34,35). Thus, this developmental pattern may be unique to, or more extensive in, primates. ...
Significance
We demonstrate that the number of mature neurons in the human amygdala increases from childhood into adulthood. This trajectory may be due to the incorporation of immature neurons from the paralaminar nucleus in the ventral amygdala. In contrast, individuals with autism spectrum disorder (ASD) show an initial excess of mature neurons followed by a decline into adulthood. Our results suggest a degenerative component in ASD and highlight the need for a more comprehensive understanding of the protracted cellular development of the human amygdala for multiple psychiatric disorders.
... For instance, the PFC volume declines in adolescence in humans (Sowell et al., 2001(Sowell et al., , 1999 as well as in rats (van Eden et al., 1990). Similarly, the BLA volume decreases between PND 35 and PND 90 in rats (Rubinow and Juraska, 2009). Interestingly, there is a continual growth in the density of the fibers connecting the mPFC and the amygdala into early adulthood (Cunningham et al., 2002;Cunningham et al., 2007). ...
Background:
Post-traumatic stress disorder (PTSD) and obesity are highly prevalent in adolescents. Emerging findings from our laboratory and others are consistent with the novel hypothesis that obese individuals may be predisposed to developing PTSD. Given that aberrant fear responses are pivotal in the pathogenesis of PTSD, the objective of this study was to determine the impact of an obesogenic Western-like high-fat diet (WD) on neural substrates associated with fear.
Methods:
Adolescent Lewis rats (n = 72) were fed with either the experimental WD (41.4% kcal from fat) or the control diet. The fear-potentiated startle paradigm was used to determine sustained and phasic fear responses. Diffusion tensor imaging metrics and T2 relaxation times were used to determine the structural integrity of the fear circuitry including the medial prefrontal cortex (mPFC) and the basolateral complex of the amygdala (BLA).
Results:
The rats that consumed the WD exhibited attenuated fear learning and fear extinction. These behavioral impairments were associated with oversaturation of the fear circuitry and astrogliosis. The BLA T2 relaxation times were significantly decreased in the WD rats relative to the controls. We found elevated fractional anisotropy in the mPFC of the rats that consumed the WD. We show that consumption of a WD may lead to long-lasting damage to components of the fear circuitry.
Conclusions:
Our findings demonstrate that consumption of an obesogenic diet during adolescence has a profound impact in the maturation of the fear neurocircuitry. The implications of this research are significant as they identify potential biomarkers of risk for psychopathology in the growing obese population.
... Stereological quantifications of the human amygdala found 3,240,000 (± 520,000) neurons in BLA and 360,000 (± 80,000) in CeA (Shumann and Amaral 2006). The total number of BLA neurons was 130,000 in rat and 100,000 in rabbit (Rubinow and Juraska 2009;Jagalska-Majewska et al. 2003). Hence, the present neuronal population in mink amygdala is small compared to other smallbrained mammals. ...
Conspecifics vary consistently in their behavioural responses towards environment stimuli such as exposure to novel objects; ethologists often refer to this variability as animal personality. The neurological mechanisms underlying animal personality traits remain largely unknown, but linking the individual variation in emotional expression to brain structural and neurochemical factors is attracting renewed interest. While considerable research has focused on hormonal and neurotransmitter effects on behavioural responses, less is known about how individual variation in the number of specific neuron populations contributes to individual variation in behaviour. The basolateral amygdala (BLA) and the central nuclei of the amygdala (CeA) mediate emotional processing by regulating behavioural responses of animals in a potentially threatening situation. As such, these structures are good candidates for evaluating the relationship between neuronal populations and behavioural traits. We now show that individual American mink (Neovison vison) reacting more boldly towards novelty have more neurons in the BLA than do their more timid conspecifics, suggesting that a developmental pattern of the number of amygdala neurons can influence behavioural traits of an adult animal. Furthermore, post hoc correlations revealed that individuals performing with higher arousal, as reflected by their frequency of startle behaviour, have more CeA neurons. Our results support a direct link between the number of neurons in amygdala regions and aspects of animal personality.
... Similar developmentally regulated changes have been observed in rodents during their adolescent period, which has been argued to range from as early as postnatal day (P) 28 to at least P60 based on social, cognitive, hormonal, and neurophysiological changes that parallel markers of human adolescence (Tirelli et al. 2003;Spear 2011). For example, during rodent adolescence there are significant increases in connectivity between the basolateral amygdala and medial prefrontal cortex (Cunningham et al. 2002(Cunningham et al. , 2008, changes in the density of monoamine transporters (Moll et al. 2000;Bradshaw et al. 2016), increases in prefrontal cortex dopamine innervation (Kalsbeek et al. 1988), decreases in medial prefrontal cortex neuron number (Markham et al. 2007;Willing and Juraska 2015), and reorganization of the amygdala (Rubinow and Juraska 2009;Koss et al. 2014). ...
Rationale:
Adolescence is a period of considerable development of brain and behavior and is the time during which most drug use is initiated.
Objective:
Age-dependent differences in motivated behaviors may be one of the factors that contribute to heightened vulnerability to developing substance use disorders, so we sought to compare age differences in methamphetamine (METH) and saccharin seeking.
Methods:
Beginning during adolescence or adulthood, male and female Sprague-Dawley rats were trained to self-administer 0.1% saccharin (via liquid dipper cup) or intravenous METH at one of three doses (0.02, 0.05, 0.08 mg/kg/inf) under increasing fixed ratio schedules of reinforcement. Subsequently, responding for METH (0.02, 0.05, 0.08, or 0.1 mg/kg/inf) under progressive ratio response requirements was assessed in rats that acquired METH self-administration at the highest dose (0.08 mg/kg/inf).
Results:
We found that adult-onset rats acquired METH self-administration more readily and exhibited higher motivation compared to adolescent-onset rats, although there were no differences in METH intake during acquisition. Adult rats also acquired saccharin self-administration more readily, but in contrast to METH, there were age and sex differences in saccharin intake driven by high levels of responding in adult females.
Conclusions:
These findings challenge the prevailing notion that adolescents are hypersensitive to reward and instead raise questions about the potential role of methodological factors on which rodent studies often differ.
... " is the frame area, "t" is the mean section thick- ness measured in every sampled field using the microcator (20 µm on average), and "BA" is the block advance of the microtome (Rubinow and Juraska, 2009). ...
Sleep Deprivation (SD) is known to result in a range of neurological consequences in chronically-afflicted subjects. Curcumin, a natural substance, has neuroprotective properties. This study aimed to evaluate the effects of curcumin on the medial Prefrontal Cortex (mPFC) of SD rats. Male rats were arbitrarily assigned to nine groups, including control, curcumin (100 mg/kg/day), olive oil, SD, SD+curcumin, SD+olive oil, grid, grid+curcumin, and grid+olive oil groups. SD was induced by a multiplatform box containing water. After a period of 21 days, the learning and memory of the rats were tested in an eight-arm radial maze. Afterwards, their brains were evaluated using stereological methods. Concomitant treatment of curcumin during SD caused fewer errors during evaluation of the working and reference memory errors in the acquisition and retention phases. The overall volume of the mPFC, Infralimbic Cortex (ILC), Prelimbic Cortex (PLC), Anterior Cingulate Cortex (ACC) and the total number of neurons and glial cells reduced by 20%-40% on average in the SD animals in comparison to the control group. This indicated atrophic changes and cell loss in these areas (p < 0.01). The dendrites’ length and the number of spines per dendrite also reduced by 35%-55% in the SD rats compared to the ones in the control group (p < 0.01). Yet, treatment of the SD animals with curcumin prevented the atrophic changes of the mPFC, cell loss, and dendritic changes (p < 0.05). SD induced structural changes in the mPFC and memory impairment in the rats. However, curcumin could protect their PFC. © 2017, Leibniz Research Centre for Working Environment and Human Factors. All rights reserved.
... The boundaries of the areas of interest were defined in accordance with Paxinos and Watson rat atlas (Paxinos and Watson, 2005). Volume of the dentate gyrus (DG), entire hippocampus and basolateral amygdala (BLA) was estimated as described earlier (Rubinow and Juraska, 2009;Veena et al., 2009a;Mahati et al., 2016) by drawing contours across the aforementioned areas and were calculated using unbiased stereology using Stereo Investigator software (MBF Bioscience, Microbrightfield, Inc., USA). The process was repeated on every 6th section and analysis was done on both the hemispheres separately by adding them together. ...
Severe and prolonged stress is the main environmental factor that precipitates depression, anxiety and cognitive dysfunctions. On the other hand, exposure to environmental enrichment (EE) has been shown to induce progressive plasticity in the brain and improve learning and memory in various neurological and psychiatric disorders. It is not known whether exposure to enriched environment could ameliorate chronic immobilisation stress-induced cognitive deficits and altered molecular markers. Hence, in the present study we aimed to evaluate the effect of enriched environment on chronic immobilisation stress (CIS) associated changes in spatial learning and memory, behavioural measures of anxiety, depression and molecular markers as well as structural alterations. Male Wistar rats were subjected to chronic immobilisation stress for 2 h/day/10 days followed by 2 weeks of exposure to EE. CIS resulted in weight loss, anhedonia, increased immobility, spatial learning and memory impairment, enhanced anxiety, and reduced expression of BDNF, VEGF, GFAP and glucocorticoid receptors (GR) in discrete brain regions. Interestingly, stressed rats exposed to enrichment ameliorated behavioural depression, spatial learning and memory impairment and reduced anxiety behaviour. In addition, EE restored BDNF, VEGF, GFAP and GR expression and normalized hypotrophy of dentate gyrus and hippocampus in CIS rats. In contrast, EE did not restore hypertrophy of the amygdalar complex. Thus, EE ameliorates stress-induced cognitive deficits by modulating the neurotrophic factors, astrocytes and glucocorticoid receptors in the hippocampus, frontal cortex and amygdala.
... Specifically, the basolateral amygdala (BLA), primarily comprised of glutamatergic pyramidal neurons and various GABAergic interneuron populations, has been shown to be critical in initiating and regulating anxiety-like behaviors (Janak and Tye, 2015;LeDoux, 2000). While development of the BLA glutamate and GABA systems appear to fully mature by early adolescence in rodents (~postnatal day (P) 28) (Ehrlich et al., 2012(Ehrlich et al., , 2013, studies have shown that the number of neurons decrease in the BLA after adolescence (Rubinow and Juraska, 2009), consistent with age-dependent reductions in cell proliferation in this structure (Saul et al., 2014). BLA excitability, primarily driven by glutamatergic pyramidal neuron activity, is positively associated with increased anxiety-like responses (Wang et al., 2011) and elevations in BLA GABAergic activity can robustly suppress anxiety-like behaviors (Bueno et al., 2005;Lack et al., 2007). ...
Anxiety disorders are one of the most common and debilitating mental illnesses worldwide. Growing evidence indicates an age-dependent rise in the incidence of anxiety disorders from adolescence through adulthood, suggestive of underlying neurodevelopmental mechanisms. Kappa opioid receptors (KORs) are known to contribute to the development and expression of anxiety; however, the functional role of KORs in the basolateral amygdala (BLA), a brain structure critical in mediating anxiety, particularly across ontogeny, are unknown. Using whole-cell patch-clamp electrophysiology in acute brain slices from adolescent (postnatal day (P) 30–45) and adult (P60+) male Sprague-Dawley rats, we found that KOR activation increased the frequency of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in the adolescent BLA, without an effect in the adult BLA or on sIPSC amplitude at either age. The KOR effect was blocked by the KOR antagonist, nor-BNI, which alone did not alter GABA transmission at either age, and the effect of the KOR agonist was TTX-sensitive. Additionally, KOR activation did not alter glutamatergic transmission in the BLA at either age. In contrast, U69593 inhibited sIPSC frequency in the central amygdala (CeA) at both ages, without altering sIPSC amplitude. Western blot analysis of KOR expression indicated that KOR levels were not different between the two ages in either the BLA or CeA. This is the first study to provide compelling evidence for a novel and unique neuromodulatory switch in one of the primary brain regions involved in initiating and mediating anxiety that may contribute to the ontogenic rise in anxiety disorders.
... In adult animals stress resulted in impaired extinction and plasticity in the form of longterm potentiation in the mPFC (Maroun and Richter-Levin 2003;Rocher et al. 2004;Markham et al. 2007;Schayek and Maroun 2015), whereas in juvenile animals, a similar stressor was associated with enhanced extinction and enhanced mPFC plasticity (Schayek and Maroun 2015). The BLA, similarly to the mPFC, undergoes changes in juvenile rats (Markham et al. 2007;Rubinow and Juraska 2009). These results may suggest that the interaction between the mPFC and the BLA is different in juvenile and adult animals. ...
The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (PI3K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear and extinction in juvenile animals and whether these mechanisms are distinctive from those in adult animals. In the present study, we examined (1) changes in phosphorylation of Akt in the BLA and mPFC after fear conditioning and extinction in juvenile and adult rats and (2) the effect of BLA and mPFC localized inhibition of the PI3K following acquisition and extinction of contextual fear memory. Our results show that Akt phosphorylation is increased following acquisition of contextual fear learning in the BLA but not in the mPFC in adult and juvenile rats. Extinction learning was not associated with changes in Akt phosphorylation. Although there were no differences in the pattern of phosphorylation of Akt either in adult or juvenile rats, microinjection of the PI3K inhibitor, LY294002, into the BLA or mPFC elicited differential effects on fear memory acquisition and extinction, depending on the site and timing of the microinjection, as well as on the age of the animal. These results suggest that PI3K/Akt has a differential role in formation, retrieval, and extinction of contextual fear memory in juvenile and adult animals, and point to developmental differences between adult and juvenile rats in mechanisms of extinction.
... Learning and expression of fear behaviors requires several neural structures embedded in a network, including the amygdala, hippocampus and medial prefrontal cortex (mPFC). These brain regions and connectivity between them continue to undergo functional maturation during adolescence (Giedd, 2004;Goddings et al., 2014;Koss et al., 2014;Mills et al., 2014;Rubinow & Juraska, 2009;Saul et al., 2013;Smith et al., 2015;Wierenga et al., 2014). The amygdala, located in the medial temporal lobe, is necessary for acquisition of fear as well as the organization of its expression (Davis et al., 2010;Debiec & LeDoux, 2009;LeDoux, 2000;Perusini & Fanselow, 2015;Quinn & Fanselow, 2006). ...
Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions.
In rodents, the first weeks of postnatal life feature remarkable changes in fear memory acquisition, retention, extinction, and discrimination. Early development is also marked by profound changes in brain circuits underlying fear memory processing, with heightened sensitivity to environmental influences and stress, providing a powerful model to study the intersection between brain structure, function, and the impacts of stress. Nevertheless, difficulties related to breeding and housing young rodents, preweaning manipulations, and potential increased variability within that population pose considerable challenges to developmental fear research. Here we discuss several factors that may promote variability in studies examining fear conditioning in young rodents and provide recommendations to increase replicability. We focus primarily on experimental conditions, design, and analysis of rodent fear data, with an emphasis on mouse studies. The convergence of anatomical, synaptic, physiological, and behavioral changes during early life may increase variability, but careful practice and transparency in reporting may improve rigor and consensus in the field. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC.
Using anatomical, histological, neurohistological and morphological research methods, the histomorphology of spinal cord nodes in a comparative anatomical series of vertebrates: bony fishes, amphibians, reptiles, birds and mammals, which differ in their motor activity and their place of existence in a certain environment, was clarified in the work. It has been established that in the process of phylogenesis, a certain structural and morphofunctional reorganization of the spinal nodes occurs. They differ in shape and size. Adaptation to various living conditions of animals was formed on the basis of changes in the density and size of neurocytes, an increase in the total number of gliocytes and perineuralneglia cells, and polymorphism in the degree of chromatophilia. Thus, according to neurohistological studies, it has been noted that the neurons of the spinal cord nodes of cold-blooded animals (pond frog, pond lizard) are characterized by a functional degree of relative polymorphism – chromatophilia. Impregnation of spinal cord nodes with silver nitrate in all studied animals revealed different intensity of staining of nerve cells (light, light-dark, dark), which is related to the specifics of species and age-related neuromorphology, the morpho-functional state of the nervous system and the type of higher nervous activity. An important issue of modern neuromorphology of animals is the study of spinal cord nodes, which play an important role as primary centers on the way to transmit sensory information from receptors to the central nervous system, providing appropriate reactions to the action of certain factors. The scientific article uses material that is a fragment of the research work of the adjacent departments "Development, morphology and histochemistry of animal organs in normal and pathological conditions", state registration number – 0120U100796. The obtained results of the research have an important general biological significance, which complements and expands the idea of certain regularities of spinal nodes, which relate to their structural organization and comparative characteristics at the cellular and tissue levels in vertebrate animals of various species.
Significant changes in emotional and cognitive functioning, as well as an increase in stress-related psychiatric disorders like anxiety and depression, are all related to adolescent growth. Additionally, the brain is undergoing tremendous maturation at this period, as evidenced by structural changes in numerous limbic and cortical regions. Although the adolescent-related alterations in these regions have been well-described by numerous exquisite human neuroimaging studies, surprisingly less is known about these changes in non-human animals.
Aluminum (Al) is known to induce neurotoxicity in both humans and rodents. Recent evidence has indicated that the toxicity of Al Oxide (Al2O3) nanoparticles (Al-NP), one of the most abundantly used engineered nanoparticles, is far greater than that of Al itself. To date, however, no information is available regarding the effect of Al-NP on the stereological parameters of hippocampus. In particular, no stereological studies have evaluated the effect of Al-NP on hippocampal CA1, dentate gyrus volume, and number of pyramidal and granular cells. Thus, the present study aimed to take a multidimensional approach to assess the concomitant cognitive, stereological, and apoptotic changes induced by a five-day Al-NP ingestion (10 mg/kg/day) in mice. The results demonstrated that the five-day Al-NP ingestion elicited a reduced preference to explore a novel object in the novel object recognition test (a hippocampal-dependent task). Perhaps contributing to this memory deficit, Al-NP induced additional alterations in the hippocampus of male NMRI mice in terms of (1) hippocampal volume (decreased the volume of the whole hippocampus, CA1, and dentate gyrus regions), (2) cell number (decreased the number of CA1 pyramidal neurons and dentate gyrus granular cells), and (3) increased cleaved caspase-3 in the whole hippocampus. These results provided new mechanistic insight to understand the impairing effect of AL-NP on the hippocampal function and structure.
The ability to decide adaptively between immediate vs. delayed gratification (intertemporal choice) is critical for well-being and is associated with a range of factors that influence quality of life. In contrast to young adults, many older adults show enhanced preference for delayed gratification; however, the neural mechanisms underlying this age difference in intertemporal choice are largely un-studied. Changes in signaling through GABAB receptors (GABABRs) mediate several age-associated differences in cognitive processes linked to intertemporal choice. The current study used a rat model to determine how GABABRs in two brain regions known to regulate intertemporal choice (prelimbic cortex; PrL and basolateral amygdala; BLA) contribute to age differences in this form of decision making in male rats. As in humans, aged rats showed enhanced preference for large, delayed over small, immediate rewards during performance in an intertemporal choice task in operant test chambers. Activation of PrL GABABRs via microinfusion of the agonist baclofen increased choice of large, delayed rewards in young adult rats but did not influence choice in aged rats. Conversely, infusion of baclofen into the BLA strongly reduced choice of large, delayed rewards in both young adult and aged rats. Aged rats further showed a significant reduction in expression of GABABR1 subunit isoforms in the prefrontal cortex, a discovery that is consonant with the null effect of intra-PrL baclofen on intertemporal choice in aged rats. In contrast, expression of GABABR subunits was generally conserved with age in the BLA. Jointly, these findings elucidate a role for GABABRs in intertemporal choice and identify fundamental features of brain maturation and aging that mediate an improved ability to delay gratification.
The links between early life stress (ELS) and the emergence of psychopathology such as increased anxiety and depression are now well established, although the specific neurobiological and developmental mechanisms that translate ELS into poor health outcomes are still unclear. The consequences of ELS are complex because they depend on the form and severity of early stress, duration, and age of exposure as well as co-occurrence with other forms of physical or psychological trauma. The long term effects of ELS on the corticolimbic circuit underlying emotional and social behavior are particularly salient because ELS occurs during critical developmental periods in the establishment of this circuit, its local balance of inhibition:excitation and its connections with other neuronal pathways. Using examples drawn from the human and rodent literature, we review some of the consequences of ELS on the development of the corticolimbic circuit and how it might impact fear regulation in a sex- and hemispheric-dependent manner in both humans and rodents. We explore the effects of ELS on local inhibitory neurons and the formation of perineuronal nets (PNNs) that terminate critical periods of plasticity and promote the formation of stable local networks. Overall, the bulk of ELS studies report transient and/or long lasting alterations in both glutamatergic circuits and local inhibitory interneurons (INs) and their associated PNNs. Since the activity of INs plays a key role in the maturation of cortical regions and the formation of local field potentials, alterations in these INs triggered by ELS might critically participate in the development of psychiatric disorders in adulthood, including impaired fear extinction and anxiety behavior.
The lateral (LA) and basolateral (BL) nuclei of the amygdala regulate emotional behaviors. Despite their dissimilar extrinsic connectivity, they are often combined, perhaps because their cellular composition is similar to that of the cerebral cortex, including excitatory principal cells reciprocally connected with fast-spiking interneurons (FSIs). In the cortex, this microcircuitry produces gamma oscillations that support information processing and behavior. We tested whether this was similarly the case in the rat (males) LA and BL using extracellular recordings, biophysical modeling, and behavioral conditioning. During periods of environmental assessment, both nuclei exhibited gamma oscillations that stopped upon initiation of active behaviors. Yet, BL exhibited more robust spontaneous gamma oscillations than LA. The greater propensity of BL to generate gamma resulted from several microcircuit differences, especially the proportion of FSIs and their interconnections with principal cells. Furthermore, gamma in BL but not LA regulated the efficacy of excitatory synaptic transmission between connected neurons. Together, these results suggest fundamental differences in how LA and BL operate. Most likely, gamma in LA is externally driven, whereas in BL it can also arise spontaneously to support ruminative processing and the evaluation of complex situations.
In recent years, a growing body of research has shown sex differences in the prevalence and symptomatology of psychopathologies, such as depression, anxiety, and fear-related disorders, all of which show high incidence rates in early life. This has highlighted the importance of including female subjects in animal studies, as well as delineating sex differences in neural processing across development. Of particular interest is the corticolimbic system, comprising the hippocampus, amygdala, and medial prefrontal cortex. In rodents, these corticolimbic regions undergo dynamic changes in early life, and disruption to their normative development is believed to underlie the age and sex-dependent effects of stress on affective processing. In this review, we consolidate research on sex differences in the hippocampus, amygdala, and medial prefrontal cortex across early development. First, we briefly introduce current principles on sexual differentiation of the rodent brain. We then showcase corticolimbic regional sex differences in volume, morphology, synaptic organization, cell proliferation, microglia, and GABAergic signaling, and explain how these differences are influenced by perinatal and pubertal gonadal hormones. In compiling this research, we outline evidence of what and when sex differences emerge in the developing corticolimbic system, and illustrate how temporal dynamics of its maturational trajectory may differ in male and female rodents. This will help provide insight into potential neural mechanisms underlying sex-specific critical windows for stress susceptibility and behavioral emergence.
Aging affects different parts of the brain structure and function. These changes are associated with several age-related emotional alterations like anxiety that is regulated by the amygdala and medial prefrontal cortex (mPFC). Thus, this study aimed to explore the effects of aging on the morphology changes in these regions. Twenty male Wistar rats were assigned to young and old groups. The anxiety level was evaluated by Elevated plus-maze. Then, their brains were removed, fixed, cut, and stained with Cresyl Violet or Golgi-Cox. In addition to the estimation of stereological parameters, dendrite complexity, and spatial distribution of the neurons in the mPFC and amygdala were evaluated. Aging increased the medial amygdala volume and its total number of neurons, but it did not have a significant effect on these parameters in the mPFC. Furthermore, the size of the neurons in the mPFC increased, whereas the total length of the dendrite and its complexity significantly decreased with aging in this structure and increased in the amygdala. Although aging did not significantly change the dendritic spine density in both regions, old rats showed a more mature spine in the mPFC and more anxiety-like behavior. In conclusion, the increase of anxiety in the old individuals could be attributed to structural changes in the morphology of the dendrite and neuron and its spatial distribution in the mPFC and amygdala. The findings of this study partly support this hypothesis.
Across species, aging is associated with an increased ability to choose delayed over immediate gratification. These experiments used young and aged rats to test the role of the basolateral amygdala (BLA) in intertemporal decision making. An optogenetic approach was used to inactivate the BLA in young and aged rats at discrete time points during choices between levers that yielded a small, immediate vs. a large, delayed food reward. BLA inactivation just prior to decisions attenuated impulsive choice in both young and aged rats. In contrast, inactivation during receipt of the small, immediate reward increased impulsive choice in young rats but had no effect in aged rats. BLA inactivation during the delay or intertrial interval had no effect at either age. These data demonstrate that the BLA plays multiple, temporally distinct roles during intertemporal choice, and show that the contribution of BLA to choice behavior changes across the lifespan.
Cambridge Core - Psychiatry - Concussion and Traumatic Encephalopathy - edited by Jeff Victoroff
Concussion and Traumatic Encephalopathy - edited by Jeff Victoroff February 2019
Aging is associated with an increased ability to delay gratification. Moreover, even when matched for performance, young and aged subjects recruit distinct brain circuitry to complete complex cognitive tasks. Experiments herein used an optogenetic approach to test whether altered recruitment of the basolateral amygdala (BLA), a brain region implicated in valuation of reward-cost contingencies, contributes to age-dependent changes in intertemporal decision making. BLA inactivation while rats deliberated prior to choices between options that yielded either small, immediate or large, delayed rewards rendered both young and aged rats less impulsive. In contrast, BLA inactivation after choices were made (during evaluation of choice outcomes) rendered young rats more impulsive but had no effect in aged rats. These data define multiple, temporally-discrete roles for BLA circuits in intertemporal decision making and implicate altered recruitment of BLA in the elevated preference for delayed rewards that is characteristic of advanced age.
Impact Statement
Basolateral amygdala (BLA) performs multiple, temporally-discrete functions during intertemporal decision making. Differential engagement of BLA contributes to the enhanced ability to delay gratification that is characteristic of advanced ages.
Previous research has shown a relationship between alcohol exposure and conditioned fear, but the nature of this relationship remains unclear. We determined whether chronic intermittent access to alcohol during adolescence and early adulthood would alter or be associated with the level of conditioned fear to an auditory cue in male Long Evans rats. Rats received 6 weeks of chronic intermittent access to 20% alcohol or water from PND 26-66 and began behavioral testing 10 days later. We found no evidence that voluntary alcohol consumption altered fear. However, we found that rats that consumed more alcohol had lower fear, as measured with conditioned suppression of lever-pressing and conditioned freezing to an auditory cue. We have previously shown that higher levels of alcohol consumption are correlated with faster instrumental extinction learning. Therefore, we determined whether instrumental extinction would be directly associated with conditioned fear in rats never given alcohol access. As predicted, we found that rats that exhibited faster instrumental extinction also exhibited lower conditioned fear, as measured with conditioned suppression of lever-pressing and conditioned freezing. Our results suggest that at least part of the relationship between alcohol consumption levels and fear learning differences may be due to pre-existing individual differences. In addition, our finding that conditioned fear and instrumental extinction abilities (both separately associated with alcohol consumption levels) are associated with each other suggests that alcohol consumption levels may be a marker that can distinguish two separate phenotypes that encompass a wide variety of learning traits.
The advantages of using design-based stereology in the collection of quantitative data, have been highlighted, in numerous publications, since the description of the disector method by Sterio (1984). This review article discusses the importance of total number derived with the disector method, as a key variable that must continue to be used to understand the rodent brain and that such data can be used to develop quantitative networks of the brain. The review article will highlight the huge impact total number has had on our understanding of the rodent brain and it will suggest that neuroscientists need to be aware of the increasing number of studies where density, not total number, is the quantitative measure used. It will emphasize that density can result in data that is misleading, most often in an unknown direction, and that we run the risk of this type of data being accepted into the collective neuroscience knowledge database. It will also suggest that design-based stereology using the disector method, can be used alongside recent developments in electron microscopy, such as serial block-face scanning electron microscopy (SEM), to obtain total number data very efficiently at the ultrastructural level. Throughout the article total number is discussed as a key parameter in understanding the micro-networks of the rodent brain as they can be represented as both anatomical and quantitative networks.
The basolateral amygdala (BLA) controls numerous behaviors, like anxiety and reward seeking, via the activity of glutamatergic principal neurons. These BLA neurons receive excitatory inputs primarily via two major anatomical pathways - the external capsule (EC), which contains afferents from lateral cortical structures, and the stria terminalis (ST), containing synapses from more midline brain structures. Chronic intermittent ethanol (CIE) exposure/withdrawal produces distinct alterations in these pathways. Specifically, 10 days of CIE (via vapor inhalation) increases presynaptic function at ST synapses and postsynaptic function at EC synapses. Given that 10-day CIE/withdrawal also increases anxiety-like behavior, we sought to examine the development of these alterations at these inputs using an exposure time-course in both male and female rats. Specifically, using 3, 7, and 10 days CIE exposure, we found that all three durations increase anxiety-like behavior in the elevated plus maze. At BLA synapses, increased presynaptic function at ST inputs required shorter exposure durations relative to post-synaptic alterations at EC inputs in both sexes. But, synaptic alterations in females required longer ethanol exposures compared to males. These data suggest that presynaptic alteration at ST-BLA afferents is an early neuroadaptation during repeated ethanol exposures. And, the similar patterns of presynaptic-then-postsynaptic facilitation across the sexes suggest the former may be required for the latter. These cooperative interactions may contribute to the increased anxiety-like behavior that is observed following CIE-induced withdrawal and may provide novel therapeutic targets to reverse withdrawal-induced anxiety.
Suboptimal maternal care is a form of chronic early-life stress (ELS) and a risk factor for mental illness and behavioral impairments throughout the life span. The amygdala, particularly the basolateral amygdala (BLA), exhibits exquisite sensitivity to ELS and could promote dysregulation of stress reactivity and anxiety-related disorders. While ELS has profound impacts on the adult or adolescent amygdala, less is known regarding the sensitivity of the preweaning BLA to ELS. We employed a naturalistic rodent model of chronic ELS that limits the amount of bedding/nesting material (LB) available to the mother between postnatal day (PND) 1-9 and examined the morphological and functional effects in the preweaning BLA on PND10 and 18-22. BLA neurons displayed dendritic hypertrophy and increased spine numbers in male, but not female, LB pups already by PND10 and BLA volume tended to increase after LB exposure in preweaning rats, suggesting an accelerated and long-lasting recruitment of the amygdala. Morphological changes seen in male LB pups were paralleled with increased evoked synaptic responses recorded from BLA neurons in vitro, suggesting enhanced excitatory inputs to these neurons. Interestingly, morphological and functional changes in the preweaning BLA were not associated with basal hypercorticosteronemia or enhanced stress responsiveness in LB pups, perhaps due to a differential sensitivity of the neuroendocrine stress axis to the effects of LB exposure. Early changes in the synaptic organization and excitability of the neonatal amygdala might contribute to the increased anxiety-like and fear behavior observed in adulthood, specifically in male offspring.
During adolescence, the increased susceptibility to stress-related dysfunctions (e.g., anxiety, drug use, obesity) may be influenced by changes in the hormonal stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. We have previously reported that restraint stress leads to significantly prolonged HPA responses in pre-adolescent compared to adult rats. Further, pre-adolescent animals exposed to restraint show greater levels of neural activation than adults in the paraventricular nucleus of the hypothalamus (PVN), a key nucleus integrating information from brain regions that coordinate HPA responses. Here, we examined the potential contribution of the noradrenergic A2 region of the nucleus of the solitary tract (NST) as a contributor to these age-dependent shifts in HPA reactivity. Specifically, we used double-labeled immunohistochemistry for FOS and dopamine-β-hydroxylase (DβH) to measure cellular activation and noradrenergic cells, respectively, before or after restraint stress in pre-adolescent (30 days old) and adult (70 days old) male rats. We also measured the density of DβH-immunoreactive fibers in the PVN as an index of noradrenergic inputs to this area. We found that pre-adolescent animals have a greater number of DβH-positive cells in the A2 region compared to adults, yet the number and percentage of double-labeled DβH/FOS cells were similar between these two ages. We found no differences between the ages in the staining intensity of DβH-immunoreactive fibers in the PVN. These data indicate there are adolescent-related changes in the number of noradrenergic cells in the A2 region, but no clear association between the increased stress reactivity prior to pubertal maturation and activation of A2 noradrenergic afferents to the PVN.
A growing body of evidence suggests that the hypothalamic neuropeptide oxytocin (OT), aside from its central role in the regulation of social behavior, reduces fear and anxiety. The functional and opposing interactions of the medial prefrontal cortex (mPFC) and the amygdala in regulation of fear provide a unique experimental setting to examine the effects of OT on fear and extinction. Recent evidence suggests that in the adult animal OT can play a dual role in the regulation of fear leading to contrasting effects on fear depending on the manipulated brain region and the time of manipulations. The OT system is one of the systems that undergoes major changes throughout development, however, its role in regulating fear in young animals has not been widely explored. We recently showed that the mechanisms of extinction, and specifically engagement of the mPFC in extinction, are not identical in adult and juvenile animals. Thus, the purpose of this study was to elucidate the effects of OT on fear and extinction in juvenile animals. To that end, we determine extinction, by measuring freezing at different time points, following microinjection of the OT agonist, TGOT, into the mPFC, the basolateral and the central nuclei of the amygdala (BLA and CeA, respectively). The results show that whereas TGOT microinjections into the IL-mPFC did not affect extinction, microinjections into the amygdala were mainly associated with enhanced fear and impaired extinction. These results further emphasize the differences between adult and juvenile brains.
In this chapter, we present a developmentally sensitive diathesis–stress model of psychopathology—triple network allostasis—the core components of which are the canonical large-scale networks of the brain. In doing so, we highlight the role of the brain in diathesis–stress processes through the integration of two major theoretical advances, the introduction of allostasis in stress research and recognition of the central role of large-scale neural networks in psychopathology. We incorporate these approaches into our life span model of modulated allostasis to produce an allostatic diathesis–stress model based on the large-scale functional architecture of the brain. Through the concept of dynamic diathesis, we link life span development, current contextual risk and resources, prior life experience, and stress physiology into a working diathesis–stress model that predicts mental state, psychopathology onset, and future mental health. Predictions from this model are testable and evidence from the extant literature is reviewed.
Recent brain research has revealed structural differences in the hypothalamus in relation to biological sex and sexual orientation. Differences in size and cell number of various nuclei in the hypothalamus for homosexual versus heterosexual men have recently been reported in two studies. We have found that a cluster of cells in the preoptic area of the human hypothalamus contains about twice as many cells in young adult men as in women. We have called this cluster the sexually dimorphic nucleus (SDN). The magnitude of the difference is the SDN depends on age. In other human research, two other hypothalamic nuclei (interstitial nuclei of the anterior hypothalamus [INAH] 2 and 3) and part of the bed nucleus of the stria terminalis (BST) have been reported to be sexually dimorphic in the human. Sexual differentiation to the human brain takes place much later than originally claimed. At birth the SDN contains only some 20% of the cells found at 2 to 4 years of age. The cell number rapidly increases in boys and girls at the same rate until 2 to 4 years of age. After that age period, a decrease in cell number takes place in girls, but not in boys. This causes the sexual differentiation of the SDN. This postnatal period of hypothalamic differentiation indicates that, in addition to genetic factors, a multitude of environmental and psychosocial factors may have profound influence on the sexual differentiation of the brain. No difference in SDN cell number was observed between homosexual and heterosexual men. This finding refutes Dörner's hypothesis that homosexual males have a "female" hypothalamus. However, in a sample of brains of homosexual men we did find that an area of the hypothalamus called the suprachiasmatic nucleus (SCN) contains twice as many cells as the SCN of a heterosexual group. A recent report by LeVay claims that another nucleus, INAH-3, is more than twice as large in heterosexual as in homosexual men, whereas Allen and Gorski found that the anterior commissure was larger in homosexual men than in heterosexual men or women. Preliminary research on male-to-female transsexuals is also discussed. The functional implications of these findings in determining adult sexual orientation are as yet far from clear.
There are significant age and sex effects in cognitive ability and brain disease. However, sex differences in aging of human brain areas associated with nonreproductive behavior have not been extensively studied. We hypothesized that there would be significant sex differences in aging of brain areas that subserve speech, visuospatial, and memory function.
We investigated sex differences in the effect of aging on human brain morphometry by means of volumetric magnetic resonance imaging and on regional cerebral metabolism for glucose by positron emission tomography. In the magnetic resonance imaging study, we examined 69 healthy right-handed subjects (34 women and 35 men), divided into young (age range, 20 to 35 years) and old (60 to 85 years) groups. In the positron emission tomography study, we investigated 120 healthy right-handed subjects (65 women and 55 men) aged 21 to 91 years.
In the magnetic resonance imaging study, age-related volume loss was significantly greater in men than women in whole brain and frontal and temporal lobes, whereas it was greater in women than men in hippocampus and parietal lobes. In the positron emission tomography study, significant sex differences existed in the effect of age on regional brain metabolism, and asymmetry of metabolism, in the temporal and parietal lobes, Broca's area, thalamus, and hippocampus.
We found significant sex differences in aging of brain areas that are essential to higher cognitive functioning. Thus, our findings may explain some of the age-sex differences in human cognition and response to brain injury and disease.
Pediatric neuroimaging studies1, 2, 3, 4, 5, up to now exclusively cross sectional, identify linear decreases in cortical gray matter and increases in white matter across ages 4 to 20. In this large-scale longitudinal pediatric neuroimaging study, we confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20.
We spatially and temporally mapped brain maturation between adolescence and young adulthood using a whole-brain, voxel-by-voxel statistical analysis of high-resolution structural magnetic resonance images (MRI). The pattern of brain maturation during these years was distinct from earlier development, and was localized to large regions of dorsal, medial and orbital frontal cortex and lenticular nuclei, with relatively little change in any other location. This spatial and temporal pattern agrees with convergent findings from post-mortem studies of brain development and the continued development over this age range of cognitive functions attributed to frontal structures.
The projection from the basolateral nucleus of the amygdala (BLA) conveys information about the affective significance of sensory stimuli to the medial prefrontal cortex (mPFC). By using an anterogracle tract-tracing procedure combined with immunocytochemistry and correlated light/ electron microscopical examination, labeled BLA afferents to layers 2-6 of the rat mPFC are shown to establish asymmetrical synaptic contacts, not only with dendritic spines (approximately 95.7% of targets innervated), but also with the aspiny dendritic shafts and somata of multipolar parvalbumin immunopositive (PV+) neurons. A population of PV- dendritic shafts was also innervated. Labeled BLA synaptic input to identified PV+ structures occurred in layers 2-6 of mPFC. The results indicate that labeled BLA afferents predominantly contact the spiny processes of presumed pyramidal cells and also provide a direct and specific innervation to a sub-population of local circuit neurons in mPFC containing PV. Since PV+ cells include two significant classes of fastspiking GABAergic inhibitory interneuron (basket and axo-axonic cells), these novel observations indicate that the amygdalocortical pathway in the rat has the ability to directly influence functionally strategic 'feed-forward' inhibitory mechanisms at the first stage of processing amygdalocortical information. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.
The recent cloning of a second estrogen receptor (ER) provided a new tool to investigate and clarify how estrogens are capable of communicating with the brain and influence gene expression and neural function. The purpose of the present study was to define the neuroanatomical organization of each receptor subtype using a side-by-side approach and to characterize the cellular population(s) expressing the ERβ transcript in the endocrine hypothalamus using immunohistochemistry combined with in situ hybridization. Axonal transport inhibition was accomplished to cause neuropeptide accumulation into the cytoplasm and thus facilitate the detection of all positive luteinizing hormone-releasing hormone (LHRH), corticotropin-releasing factor (CRF), vasopressin (AVP), oxytocin (OT), gastrin-related peptide (GRP), and enkephalin (ENK) neurons. The genes encoding either ERα or -β were expressed in numerous limbic-associated structures, and fine differences were found in terms of intensity and positive signal. Such phenomenon is best represented by the bed nucleus of the stria terminalis (BnST) and preoptic area/anterior hypothalamus, where the expression pattern of both transcripts differed across subnuclei. The novel ER was also found to be expressed quite exclusively in other hypothalamic nuclei, including the supraoptic (SON) and selective compartments (magnocellular and autonomic divisions) of the paraventricular nucleus (PVN). A high percentage of the ERβ-expressing neurons located in the ventro- and dorsomedial PVN are of OT type; 40% of the OT-ir cells forming the medial magnocellular and ventromedial parvocellular PVN showed a clear hybridization signal for ERβ mRNA, whereas a lower percentage (15–20%) of OT neurons were positive in the caudal parvocellular PVN and no double-labeled cells were found in the rostral PVN and other regions of the brain with the exception of the SON. Very few AVP-ir neurons expressing ERβ transcript were found throughout the rat brain, although the medial PVN displayed some scattered double-labeled cells (<5%). Quite interestingly, the large majority of the ERβ-positive cells in the caudal PVN were colocalized within CRF-ir perikarya. Indeed, more than 60–80% of the CRF-containing cells located in the caudolateral division of the parvocellular PVN exhibited a positive hybridization signal for ERβ mRNA, whereas very few (<5%) neuroendocrine CRF-ir parvocellular neurons of the medial PVN expressed the gene encoding ERβ. A small percentage of ERβ-expressing cells in the dorsocaudal and ventromedial zones of the parvocellular PVN were also ENK positive. The ventral zone of the medial parvocellular PVN also displayed GRP-ir neurons, but no convincing hybridization signal for ERβ was detected in this neuronal population. Finally, as previously described for the gene encoding the classic ER, LHRH neurons of both intact and colchicine-pretreated animals did not express the novel estrogen receptor. This study shows a differential pattern of expression of both receptors in the brain of intact rats and that ERβ is expressed at various levels in distinct neuropeptidergic populations, including OT, CRF, and ENK. The influence of estrogen in mediating genomic and neuronal responses may therefore take place within these specific cellular groups in the brains of cycling as well as intact male mammals. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 357–378, 1998
Examined the effects of excitatory amino acid lesions of the nucleus basalis magnocellularis in 34 young (3-mo-old), adult (9-mo-old), and aged (21-mo-old) male rats on the expression of conditioned freezing to an environmental context and to a discrete CS (a tone) in a Pavlovian fear-conditioning task. Lesions caused by injections of N-methyl-D-aspartate (NMDA) resulted in reductions in the levels of conditioned freezing to the context in each age group, while freezing levels displayed during the presentation of the tone were unaffected. Results suggest that the nucleus basalis plays a role in the expression of conditioned fear to environmental context and in the behavioral changes associated with the normal aging process. Also, the vulnerability of these cells to excitotoxic damage, and the resulting behavioral deficit, increase with age. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The volume of the temporal lobe, superior temporal gyrus, amygdala, and hippocampus was quantified from magnetic images of the brains of 99 healthy children and adolescents aged 4–18 years. Variability in volume was high for all structures examined. When adjusted for a 9% larger total cerebral volume in males, there were no significant volume differences between sexes. However, sex-specific maturational changes were noted in the volumes of medial temporal structures, with the left amygdala increasing significantly only in males and with the right hippocampus increasing significantly only in females. Right-greater-than-left laterality effects were found for temporal lobe, superior temporal gyrus, amygdala, and hippocampal volumes. These results are consistent with previous preclinical and human studies that have indicated hormonal responsivity of these structures and extend quantitative morphologic findings from the adult literature. In addition to highlighting the need for large samples and sex-matched controls in pediatric neuroimaging studies, the information from this understudied age group may be of use in evaluating developmental hypotheses of neuropsychiatric disorders. © 1996 Wiley-Liss, Inc.†
The most prominent sites of vasopressin (VP) production in the rat brain are the paraventricular nucleus, the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis (BST), and the medial amygdaloid nucleus (MA). Recently a number of new sites have been suggested, including the hippocampus, the diagonal band of Broca, and the choroid plexus. This chapter shows how differential regulation of these VP systems can be exploited to identify the contributions of individual VP systems to the various central functions in which VP has been implicated. It will focus on the development, anatomy, and function of the sexually dimorphic VP projections of the BST and MAThis system contains more cells and has denser projections in males than in females. This system is also extremely responsive to gonadal steroids as it only produces VP in the presence of gonadal steroids. It has been implicated in sexually dimorphic functions such as aggressive behavior as well as in non-sexually dimorphic functions such as social recognition memory. Using comparative studies done in prairie voles as an example, this chapter makes the case that the VP projections of the BST and MA may simultaneously generate sex differences in some brain functions and behaviors and prevent them in others.
Voxel-based-morphometry (VBM) is a whole-brain, unbiased technique for characterizing regional cerebral volume and tissue concentration differences in structural magnetic resonance images. We describe an optimized method of VBM to examine the effects of age on grey and white matter and CSF in 465 normal adults. Global grey matter volume decreased linearly with age, with a significantly steeper decline in males. Local areas of accelerated loss were observed bilaterally in the insula, superior parietal gyri, central sulci, and cingulate sulci. Areas exhibiting little or no age effect (relative preservation) were noted in the amygdala, hippocampi, and entorhinal cortex. Global white matter did not decline with age, but local areas of relative accelerated loss and preservation were seen. There was no interaction of age with sex for regionally specific effects. These results corroborate previous reports and indicate that VBM is a useful technique for studying structural brain correlates of ageing through life in humans.
Frontal lobe dysfunction is thought to be involved in schizophrenia and age-associated cognitive decline. Frontal lobe volume changes have been investigated in these conditions using MRI, but results have been inconsistent. Few volumetric MRI protocols exist that divide the pre-frontal cortex into its sub-regions. In the present article, we describe a new method, which allows assessment of the superior, middle and inferior frontal gyrus, as well as the orbitofrontal and cingulate regions. The method uses multiple planes to help guide the anatomical decisions and combines this with a geometric approach utilizing readily apparent anatomical landmarks. Using this protocol, the frontal lobe volumes in young healthy subjects were contrasted with those of young schizophrenic patients and elderly healthy subjects (nine male subjects per group). The results showed that the method could be reproduced with high reliability (ricc≥0.88–0.99). Schizophrenic as well as old subjects had specific significant reductions in the superior frontal gyrus and orbitofrontal regions compared with the young group. However, old and schizophrenic subjects did not differ from each another. No volume differences were observed in the other three regions assessed. Whether or not these volume reductions reflect a common pathological process remains to be investigated in future studies.
1.1. Sexual dimorphism of human brain anatomy has not been well-studied between 4 and 18 years of age, a time of emerging sex differences in behavior and the sexually specific hormonal changes of adrenarche (the predominantly androgenic augmentation of adrenal cortex function occurring at approximately age 8) and puberty.2.2. To assess sex differences in brain structures during this developmental period volumes of the cerebrum, lateral ventricles, caudate, putamen, globus pallidus temporal lobe, amygdala, and hippocampus, and midsagittal area measurements of the corpus callosum were quantified from brain magnetic resonance images of 121 healthy children and adolescent and examined in relation to age and sex.3.3. Males had a 9% larger cerebral volume. When adjusted for cerebral volume by ANCOVA only the basal ganglia demonstrated sex differences in mean volume with the caudate being relatively larger in females and the globus pallidus being relatively larger in males. The lateral ventricles demonstrated a prominent sex difference in brain maturation with robust increases in size in males only. A piecewise-linear model revealed a significant change in the linear regression slope of lateral ventricular volume in males after age 11 that was not shared by females at that or other ages.4.4. Amygdala and hippocampal volume increased for both sexes but with the amygdala increasing significantly more in males than females and hippocampal volume increasing more in females.5.5. These sexually dimorphic patterns of brain development may be related to the observed sex differences in age of onset, prevalence, and symptomatology seen in nearly all neuropsychiatrie disorders of childhood.
The rat basolateral amygdala shows neuroanatomical sex differences, continuing development after puberty and aging-related alterations. Implications for amygdala-dependent memory processes were explored here by testing male and female hooded rats in adolescence, adulthood and old age on the food-conditioned place preference task. While aged rats were unimpaired, adolescents failed to learn the task. This finding may be related to ongoing development of the basolateral amygdala and related memory systems during the adolescent period.
The cytoarchitectonic structure and divisions of the amygdaloid complex are described in the rat and cat, with special reference to the axonal connections of each of the amygdaloid nuclei, and to interspecies variations and similarities. Several intra-amygdaloid connections are also described, based on autoradiographic experiments with small injections of 3H-amino acids into the individual nuclei. Although it has probably not been possible to determine all of the intra-amygdaloid projections from these experiments, the connections which have been shown are very specific. The lateral nucleus projects to the basomedial nucleus, the lateral part of the central nucleus, and the periamygdaloid cortex, while the basolateral nucleus projects only to itself, the medial part of the central nucleus, and the nucleus of the lateral olfactory tract. The basomedial nucleus projects to the cellular layer of the medial nucleus and the amygdalo-hippocampal area, while the molecular layer of these structures and of the posterior cortical nucleus, receives projections from the periamygdaloid cortex or from the endopiriform cortex. There are also interconnections between the medial and posterior cortical nuclei, and commissural connections between the posterior cortical nuclei of the two sides.
Projections asre described from the basolateral, lateral and anterior cortical nuclei of the amygdaloid complex, and from the prepiriform cortex, to several discrete areas of the cerebral cortex in the rat and cat and to th mediodorsasl thalamic nucleus in the rat. These projections are very well-defined in their origin, and in their area and laminar pattern of termination.
The basolateral amygdaloid nucleus can be divided into anterior and posterior divisions, based on cytoarchitectonic and connectional distinctions. In both the rat and cat the posterior division projects to the prelimbic area (area32) and the infralimbic area (area 25) on the medial surface of the hemisphere. The anterior division projects more lightly to these areas, but also sends fibers to the dorsal and posterior agrangular insular areas and the perirhinal area on the lateral surface. Furtheremore, in the cat the perirhinal area is divided into two areas(area 35 and 36) and the anterior division projects to both of these and also to a ventral part of the grangular insular area; this last area is adjacent to, but separate from the auditory insular area and the second cortical taste area. In most of these areas, the fibers from the basolateral nucleus terminate predominantly in two bands: one in the deep part of layer I and layer II, and a heavier band in layer V (in the rat) or layers V and VI (in the cat).
The lateral amygdaloid nucleus projects heavily to the perirhinal area, and also to the posterior agranular insular area. These fibers terminate predominantly in the midle layers of the cortex, although the cellular lamination in these two areas is relatively indistinct. The anterior cortical amygdaloid nucleus and the prepiriform cortex both project to th infralimbic area and the ventral agranular insular area, and the anterior cortical nucleus also projects to the posterior agranular area and the perirhinal area. In all of these areas, the fibers from these olfactory-relasted structures terminate in the middle of layer I.
In the rat, the two divisions of the basolateral nucleus also project to the medial segment of the mediodorsasl thalamic nucleus, with the anterior division projecting mainly to the posterior part of this segment and the posterior division to the anterior part. The endopiriform nucleus, deep to the prepiriform cortex, projects to the central segment of the mediodorsasl nucleus, since little or no projection could be demonstrated from the prepiriform cortex itself. Projections to the mediodorsal nucleus have not been found in the cat.
Sex differences are described in subregions of two nuclei of the rat brain: the medical nucleus of the amygdala (MA) and the bed nucleus of the stria terminalis (BNST). The volume of the posterodorsal region of the medial nucleus of the amygdala (MApd) is approximately 85% greater and the volume of the encapsulated region of the bed nucleus of the stria terminalis (BNSTenc) is approximately 97% greater in males than in females. The MApd and BNSTenc are distinct subregions of the MA and BNST. They exhibit intense uptake of gonadal hormones and are anatomically connected to each other and to other sexually dimorphic nuclei. The MA and BNST in general are involved in regulation of several sexually dimorphic functions, including aggression, sexual behavior, gonadotropin secretion and integration of olfactory information. Precise localization of sex differences in subregions of the MA and BNST, such as the MApd and BNSTenc, may facilitate understanding of the neural basis of such functions.
We have previously shown that the thickness of the binocular area of the primary visual cortex is sexually dimorphic in rats. In the present study, sex differences in the number of neurons in this cortical area were examined in nine littermate pairs of 90-day-old Long-Evans hooded rats. Cytoarchitectonic characteristics were used to define the binocular visual cortex, and its volume was estimated through three-dimensional reconstruction of serial coronal sections for each hemisphere. Neuronal and glial density as well as neuronal soma size were estimated from semithin sections through a stereological technique, the disector, in the same animals that were used to estimate volume. The volume of the binocular area was 19% greater in males than in females. While there were no sex differences in soma size or in neuronal density, the differences in the volume of the binocular area resulted in significant sex differences (male greater than female) in the number of neurons overall and in every layer, except layer IV. Glial density was not different between the sexes, but the total number of glial cells was higher in males than in females. These results demonstrate that the binocular visual cortex of the rat is sexually dimorphic in its volume and much of the difference is due to sex differences in the number of neurons and glial cells.
Seventy-six healthy adults underwent magnetic resonance imaging (1.5 T) to investigate the effects of age on regional cerebral volumes and on the frequency and severity of cortical atrophy, lateral ventricular enlargement, and subcortical hyperintensity. Increasing age was associated with (1) decreasing volumes of the cerebral hemispheres (0.23% per year), the frontal lobes (0.55% per year), the temporal lobes (0.28% per year), and the amygdala-hippocampal complex (0.30% per year); (2) increasing volumes of the third ventricle (2.8% per year) and the lateral ventricles (3.2% per year); and (3) increasing odds of cortical atrophy (8.9% per year), lateral ventricular enlargement (7.7% per year), and subcortical hyperintensity in the deep white matter (6.3% per year) and the pons (8.1% per year). Many elderly subjects did not exhibit cortical atrophy or lateral ventricular enlargement, however, indicating that such changes are not inevitable consequences of advancing age. These data should provide a useful clinical context within which to interpret changes in regional brain size associated with "abnormal" aging.
The thalamic innervation of the rat basolateral amygdaloid complex was studied with a combination of light- and electron microscopic techniques using anterogradely transported Phaseolus vulgaris-leucoagglutinin (PHA-L) as well as combined degeneration and single-section Golgi impregnation for the identification of thalamo-amygdaloid synaptic relations. The results indicated that the basolateral amygdaloid nucleus corresponds in several features to a cortical structure. Like all cortical areas, the basolateral amygdaloid nucleus is reciprocally related to other cortical regions as well as to the thalamus.
A three-dimensional counting rule and its integral test system, the disector, for obtaining unbiased estimates of the number of arbitrary particles in a specimen is presented. Used in combination with ordinary and recently developed stereological methods unbiased estimates of various mean particle sizes and the variance of particle volume are obtainable on sets of two parallel sections with a known separation. The same principle allows the unbiased estimation of the distribution of individual particle volumes in sets of serial sections.
This study describes the morphology of neurons from the basolateral (ABL), central (ACE), and medial (AM) nuclei of the amygdaloid complex in neonatally undernourished (U) and control (C) Wistar strain rats. The cells were impregnated with the Golgi-Cox technique and studied at the ages of 12, 20, and 40 days postnatally. In the U-pups the neurons of the three nuclei displayed a reduced somatic area compared to that of the C-group on Days 12 and 20. However, at 40 days, this difference diminished due to a reduction in the somatic area of the C-group. The dendritic area also appeared reduced on Days 12 and 20 in the U-group, but on Day 40 it reached control values. The neurons from ABL and ACE suffered a significant decrease in the number of dendritic branches due to undernutrition, but the AM nucleus did not show this change. The data suggest different vulnerability of these amygdaloid nuclei to neonatal undernutrition. The findings also suggest that the abnormal emotional response characteristic of perinatal undernourished rats could have a morphological cause.
The distribution of androgen receptor immunoreactive-neurons, mapped with the PG21 anti-androgen receptor antibody, was compared in male rat brains with the distribution of Fos-immunoreactive neurons induced by mating. In gonadally intact, but not in castrated male rats, substantial numbers of androgen receptor-containing neurons were present in a variety of forebrain and midbrain regions. The PG21 antibody apparently had a higher affinity for occupied than for non-occupied androgen receptors. Androgen receptor-immunoreactive regions included the medial preoptic area and other forebrain areas previously identified as containing androgen receptors, the dorsal and ventral periaqueductal gray, and a midbrain region that included the lateral part of the central tegmental field, part of the caudal zona incerta, the subparafascicular nucleus of the thalamus and the peripeduncular nucleus. Fos-expressive neurons were essentially absent in non-mated males but were present in the brains of rats which mated to ejaculation. All brain regions in which androgen receptor-immunoreactive neurons were counted also expressed Fos immunoreactivity after mating, and there was considerable overlap between the distributions of androgen receptor- and Fos-immunoreactive neurons. In a second experiment, we used immunofluorescent techniques to document the intraneuronal co-localization of Fos with androgen receptor immunoreactivity in the medial preoptic area, medial amygdala, and central tegmental field. In these regions mating-induced Fos immunofluorescence was exclusively localized in androgen receptor-immunofluorescent neurons. However, not all androgen receptor neurons were Fos expressive, suggesting that only some androgen-sensitive neurons were activated during mating. These results are consonant with the view that hormone actions on forebrain and midbrain structures influence the neuronal activity correlated with mating.
Development and maturation of the basolateral complex of the amygdaloid body were studied in fetal and postnatal rat brains. In cresyl violet-stained sections the basolateral complex was distinguishable at the 17th prenatal day. On about the 14th postnatal day, it showed all the features of the adult structure. The acetylcholinesterase activity appeared in neuropil of the basolateral complex on the seventh postnatal day; it increased slowly up to the 60th day. After that age, the acetylcholinesterase activity was stable in all parts of the basolateral complex and corresponded to its cytoarchitectonic differentiation. Our results suggest that the process of maturation of the amygdaloid basolateral complex, being related to the ingrowing of the cholinergic fibers from the basal forebrain, lasts at least up to the end of the second month of postnatal life.
Density of dopamine D1 and D2 family receptors was assessed using autoradiography in male and female rats from 25 to 120 days of age, focusing on transitions through puberty into full adulthood. Males had greater overproduction (approximately 4.6-fold) and elimination of striatal D1 and D2 receptors than females, though their adult densities were very similar. Males had more extensive overproduction of D1 receptors in nucleus accumbens and sustained a greater density into adulthood (57.8 +/- 21.2%). These results have implications for understanding gender differences in the prevalence of clinical disorders associated with dopamine.
In the early eighties we found sex differences in the vomeronasal organ (VNO) and hypothesized that the vomeronasal system (VNS), a complex neural network involved in the control of reproductive behavior, might be sexually dimorphic. At that time sex differences had already been described for some structures that receive VNO input, such as the medial amygdala, the medial preoptic area, the ventromedial hypothalamic nucleus, and the ventral region of the premammillary nucleus. Since then, we have shown sex differences in the accessory olfactory bulb (AOB), the bed nucleus of the accessory olfactory tract (BAOT), and the bed nucleus of the stria terminalis (BST). When new VNS connections were found, all of them ended in nuclei that present sex differences. In general, sex differences in the olfactory system show two morphological patterns: one in which males present greater morphological measures than females, and just the opposite. To explain the morphometric measures of males in the latter, it has been hypothesized that androgens serve as inhibitors. Our work on the involvement of the GABA(A) receptor in the development of AOB and maternal behavior sex differences also suggests that neonatal changes in neuronal membrane permeability to the ion Cl- differences. This might be the first animal model to help us to understand the situation in which human genetic and gonadal sex do not agree with brain and behavioral sex. Finally, we stress that sex differences in the VNS constitute a neurofunctional model for understanding sex differences in reproductive behaviors.
Neuronal changes in the amygdala basolateral complex were studied during development and maturation in fetal and postnatal rat brains using morphometrical methods. Forty brains of animals of various ages were fixed in formalin, frozen and cut into 25 microm thick sections and stained with cresyl violet or haematoxylin and eosin (H&E). In cresyl violet preparations, the complex appeared for the first time on embryonic day (E)17 and was composed of two homogeneous nuclei lateral and basolateral. On about the seventh postnatal day, each of these nuclei was divided into two parts the first one into the dorsolateral and ventromedial and the second one into the anterior and posterior. Morphometric investigations showed a different increase of the neuronal and nuclear size in various parts of the basolateral complex up to postnatal day (P)14; after that time these parameters did not change significantly. The neuronal density and the total number of neurons stabilized at P7 in all parts of this complex, except for the dorsolateral part of the lateral nucleus in which a 30% decrease of the total number of cells was observed. From P14, in all nuclei under study, the total number of neurons did not change significantly.
The recent cloning of a second estrogen receptor (ER) provided a new tool to investigate and clarify how estrogens are capable of communicating with the brain and influence gene expression and neural function. The purpose of the present study was to define the neuroanatomical organization of each receptor subtype using a side-by-side approach and to characterize the cellular population (s) expressing the ERbeta transcript in the endocrine hypothalamus using immunohistochemistry combined with in situ hybridization. Axonal transport inhibition was accomplished to cause neuropeptide accumulation into the cytoplasm and thus facilitate the detection of all positive luteinizing hormone-releasing hormone (LHRH), corticotropin-releasing factor (CRF), vasopressin (AVP), oxytocin (OT), gastrin-related peptide (GRP), and enkephalin (ENK) neurons. The genes encoding either ERalpha or -beta were expressed in numerous limbic-associated structures, and fine differences were found in terms of intensity and positive signal. Such phenomenon is best represented by the bed nucleus of the stria terminalis (BnST) and preoptic area/anterior hypothalamus, where the expression pattern of both transcripts differed across subnuclei. The novel ER was also found to be expressed quite exclusively in other hypothalamic nuclei, including the supraoptic (SON) and selective compartments (magnocellular and autonomic divisions) of the paraventricular nucleus (PVN). A high percentage of the ERbeta-expressing neurons located in the ventro- and dorsomedial PVN are of OT type; 40% of the OT-ir cells forming the medial magnocellular and ventromedial parvocellular PVN showed a clear hybridization signal for ERbeta mRNA, whereas a lower percentage (15-20%) of OT neurons were positive in the caudal parvocellular PVN and no double-labeled cells were found in the rostral PVN and other regions of the brain with the exception of the SON. Very few AVP-ir neurons expressing ERbeta transcript were found throughout the rat brain, although the medial PVN displayed some scattered double-labeled cells (<5%). Quite interestingly, the large majority of the ERbeta-positive cells in the caudal PVN were colocalized within CRF-ir perikarya. Indeed, more than 60-80% of the CRF-containing cells located in the caudolateral division of the parvocellular PVN exhibited a positive hybridization signal for ERbeta mRNA, whereas very few (<5%) neuroendocrine CRF-ir parvocellular neurons of the medial PVN expressed the gene encoding ERbeta. A small percentage of ERbeta-expressing cells in the dorsocaudal and ventromedial zones of the parvocellular PVN were also ENK positive. The ventral zone of the medial parvocellular PVN also displayed GRP-ir neurons, but no convincing hybridization signal for ERbeta was detected in this neuronal population. Finally, as previously described for the gene encoding the classic ER, LHRH neurons of both intact and colchicine-pretreated animals did not express the novel estrogen receptor. This study shows a differential pattern of expression of both receptors in the brain of intact rats and that ERbeta is expressed at various levels in distinct neuropeptidergic populations, including OT, CRF, and ENK. The influence of estrogen in mediating genomic and neuronal responses may therefore take place within these specific cellular groups in the brains of cycling as well as intact male mammals.
Young adult, middle-aged, and old male F-344 rats were assessed for their hippocampal ability. This was accomplished by examining the animals on two different paradigms, each incorporating a simultaneous measure of hippocampal-dependent and -independent processing. The animals were fear conditioned and then tested for retention of the conditioning context and tone. This was followed by an 8-arm radial maze task which combined spatial working and cued reference memory elements. The two paradigms are compared in terms of task demands, potential confounds, and validity for aging studies. The results indicate that the performance of the animals on the two tasks is correlated. Age-related deficits limited to the hippocampal aspects of the above tasks were found, with no deficits found in the analogous but hippocampus-independent aspects of these tasks.
The distribution of GABA-immunoreactive neurons in the rat amygdala was determined by immunohistochemical methods. Sex differences in the number of GABA-immunoreactive cell bodies were observed in the medial, central, cortical and basolateral amygdaloid nuclei. Females had more numerous GABA-expressing neurons than males (P < 0.01). Castration of neonatal males had controversial effects on this sex difference in the different parts of the amygdaloid complex. In the cortical and basolateral amygdala castrated males showed a female pattern of GABA-expression. In the central amygdala no effect of castration on the number of GABA-immunoreactive cells was found. In the medial amygdaloid nucleus numbers of GABAergic neurons in castrated males differed both from intact males and females. The results of the present study suggest that the expression of GABA in the neurons of the amygdala is under complicated gonadal hormone regulation.
The most prominent sites of vasopressin (VP) production in the rat brain are the paraventricular nucleus, the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis (BST), and the medial amygdaloid nucleus (MA). Recently a number of new sites have been suggested, including the hippocampus, the diagonal band of Broca, and the choroid plexus. This chapter shows how differential regulation of these VP systems can be exploited to identify the contributions of individual VP systems to the various central functions in which VP has been implicated. It will focus on the development, anatomy, and function of the sexually dimorphic VP projections of the BST and MA. This system contains more cells and has denser projections in males than in females. This system is also extremely responsive to gonadal steroids as it only produces VP in the presence of gonadal steroids. It has been implicated in sexually dimorphic functions such as aggressive behavior as well as in non-sexually dimorphic functions such as social recognition memory. Using comparative studies done in prairie voles as an example, this chapter makes the case that the VP projections of the BST and MA may simultaneously generate sex differences in some brain functions and behaviors and prevent them in others.
Several investigators have defined normal age-specific values for the medial temporal lobe structures in neurologically normal elderly subjects, but, to our knowledge, no one has reported those values for a large sample of healthy volunteers. The purpose of our study was to define normal age-specific values for the hippocampal formation, the amygdala, and the temporal horn of the lateral ventricle by age group, ranging from 40 to 90 years, in order to generate a guideline for the quantitative MR diagnosis and differential diagnosis for early Alzheimer disease.
MR-based volumetric measurements of the hippocampal formation, the amygdala, and the temporal horn, standardized by total intracranial volume, were obtained from oblique coronal and sagittal T1-weighted MR images in 619 healthy volunteers and two cadaveric specimens.
Differences in standardized volumes of the hippocampal formation, the amygdala, and the temporal horn were significant among the 61- to 70-year-old, 71- to 80-year-old, and 81- to 90-year-old groups, and were not significant between the 40- to 50-year-old and 51- to 60-year-old groups. We found no significant differences in side or sex among the age groups for any of the structures.
Differences in the mean value and in the 95% normal range of standardized volumes of the hippocampal formation, the amygdala, and the temporal horn correspond to differences in age among healthy subjects; therefore, age should be considered a factor in correlative research, especially in that involving patients in the early stages of Alzheimer disease.
The medial amygdala (MeA) has receptors for gonadal hormones and is a sexually dimorphic area in rats. The aims of the present work were (1) to look at sex differences and the effect of gonadal hormone withdrawal in males castrated as offspring or at adulthood on neuronal soma area in the anterior and posterior MeA and (2) to study the dendritic branching and the density of dendritic spines in neurons from the MeA of intact males and females. Animals were adult rats, for which the single-section Golgi method was used. Stellate and bitufted cells were found in the MeA. Comparing data among groups, no significant difference in cell body area was found. Dendrites divide sparingly and have very different lengths, and a statistical difference (p < 0.001, males higher than females) in the spine density in the anterior MeA, but not in the posterior MeA, was found. These results suggest that castration does not alter the somal area in males submitted to gonadectomy during the early postnatal period or at adulthood. In addition, the already described sex difference in this nucleus may be more related to the neuropil than the neuronal somal area, which may be relevant for the function of the MeA.
Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correlated with both depression severity and "stressed" plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala-driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli. Antidepressant drugs may compensate for this dysfunction by inhibiting pathological limbic activity.
To successfully negotiate the developmental transition between youth and adulthood, adolescents must maneuver this often stressful period while acquiring skills necessary for independence. Certain behavioral features, including age-related increases in social behavior and risk-taking/novelty-seeking, are common among adolescents of diverse mammalian species and may aid in this process. Reduced positive incentive values from stimuli may lead adolescents to pursue new appetitive reinforcers through drug use and other risk-taking behaviors, with their relative insensitivity to drugs supporting comparatively greater per occasion use. Pubertal increases in gonadal hormones are a hallmark of adolescence, although there is little evidence for a simple association of these hormones with behavioral change during adolescence. Prominent developmental transformations are seen in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems. Developmental changes in these stressor-sensitive regions, which are critical for attributing incentive salience to drugs and other stimuli, likely contribute to the unique characteristics of adolescence.
Parvalbumin and calbindin‐D28k are calcium‐binding proteins, which are considered to be markers for certain populations of GABAergic neurons. Their correct development in the basolateral amygdaloid complex is critical for the proper emotional functioning in adult live of human and animals. Therefore, in this paper we describe the pattern of the morphological differentiation and distribution of immunoreactive elements of the parvalbumin and calbindin‐D28k in this complex on the basis of immunohistochemically stained material obtained from embryonic (E20) and postnatal (P0–P90) rat brains.
Calbindin‐D28k appeared early in the development, already in the prenatal life. At this time immunopositive reaction was visible only in cell bodies. However, during development the population of immunopositive neurons was divided into four types: (1) polygonal; (2) piriform‐like; (3) bipolar; and (4) pyramidal‐like. Two weeks after birth calbindin‐D28k immunoreactivity also appeared in neuropil. First, there were visible calbindin‐D28k positive fibers and granules that encircled unstained cell bodies and formed basket‐like structures. Subsequently, these granules appeared along proximal parts of unstained dendrites forming, so called ‘cartridges’. The distribution of calbindin‐D28k positive cells during postnatal life was rather homogenous throughout whole basolateral complex. Intensity of calbindin‐D28k immunoreactivity reached mature level on the 21st day after birth.
The maturation pattern of parvalbumin immunopositive elements followed the same sequence as calbindin‐D28k, but it started much later — since the 17th day after birth and reached mature appearance on the 30th day of life. Contrary to calbindin‐D28k, parvalbumin was not homogeneously distributed in the basolateral complex. Originally, parvalbumin was restricted to the magnocellular part of basolateral nucleus but it was finally expressed also in the parvicellular part of basolateral nucleus and the dorsolateral part of lateral nucleus.
The differences in development of these two calcium‐binding proteins indicate that parvalbumin and calbindin‐D28k play diverse roles during development and maturation of the basolateral amygdala.
Corticotropin-releasing factor (CRF) coordinates the mammalian response to stress. In the amygdala, the CRF system appears to be responsible, at least in part, for the behavioral responses resulting from stress. Associated with amygdalar CRF is a 37 kDa binding protein (CRF-BP) which may also play a role in regulating stressful stimuli. Aging has been shown to be associated with abnormal neuroendocrine stress systems and little is known with regards to how amygdalar stress systems change with aging. In our study, we have assessed levels of amygdalar CRF and CRF-BP mRNA in Fischer 344 rats of 4, 12 or 24 months of age following 14 days of hourly restraint. Prior to sacrifice, rats were also tested for anxiety-like behaviors on the elevated plus maze. After behavioral testing, rats were perfused with 4% paraformaldehyde and the brains were processed for in situ hybridization. Twenty micron sections were hybridized with a CRF as well as a CRF-BP riboprobe. Following hybridization, tissue sections were oppossed to X-ray film and relative amounts of mRNA in the amygdala were quantitated. Levels of CRF mRNA in the amygdala of 12 and 24 month-old rats following chronic restraint were significantly lower relative to rats which were handled for 14 days. There were no significant differences in amygdalar CRF gene expression between stressed and handled 4 month-old rats. At 12 and 24 months of age but not 4 months, there were also significant effects of restraint associated with decreases in amygdalar CRF-BP gene expression. Furthermore, there were reciprocal decreases in anxiety-like behaviors in the 12 and 24 month-old rats which were significant; the changes in anxiety-like behaviors between restrained vs. handled 4 month-old rats were not significantly different. The decreased gene expression of CRF in the amygdala in concert with decreased anxiety-like behaviors following restraint is consistent with the known behavioral effects of exogenously applied intra-amygdalar CRF. The changes in amygdalar CRF-BP observed may be secondary to the known regulatory effects that CRF exhibits on its binding-protein. These studies have relevance to better understanding the molecular basis of aging related changes in neuroendocrine stress systems.
Two experiments were conducted to examine contextual information processing in adult (7 months) and aged (22 months) Wistar rats. In Experiment 1, rats were tested for contextual fear conditioning when exposed to six series, one per day, of ten pairings of a tone (CS) with a foot-shock (US) delivered in one of a two-compartment apparatus. Conditioned fear was estimated by recording: (1) the amount of freezing in the shock compartment; and (2) the time spent avoiding the shock compartment. Results show that, after only one series of ten CS-US pairings, all rats showed freezing in the shock compartment, with aged rats exhibiting the stronger response. Adult rats also avoided the shock compartment during place preference tests in contrast to aged rats, that spent an equivalent time - with an intense freezing reaction - in both the shock and the safe compartments. After 60 CS-US pairings, contextual freezing in the shock compartment decreased in both groups, but, contrary to adults, aged rats were still not avoiding that compartment. In Experiment 2, radial maze performance was studied under distinct quantitative extra-maze cueing conditions (poor versus rich) and successive context shifts. Compared to adults, aged rats were impaired when trained initially under poor cueing conditions. No group difference was evident when rats were transferred to a context involving more cues (rich cueing conditions), but age-related impairments re-emerged when rats were returned to the original poor cueing conditions. Thus, the fact that performance deficits in a given task were restricted to certain testing procedures suggests that aging affects more the utilization than the processing of contextual information.
It has been demonstrated that the posteromedial cortical amygdaloid nucleus (PMCo), is sexually dimorphic. It is shown (Experiment 1) that male orchidectomy on the day of birth (D1) decreases the volume and number of neurons of the PMCo, while a single injection of propionate testosterone to the female on D1 masculinizes the PMCo in this gender. Since male gonadectomy on D1 (Experiment 2) is counteracted by a single injection of estradiol benzoate in males it has been suggested that the masculinization of the PMCo is due to the aromatization of testosterone to estradiol in this structure. These findings support the hypothesis that the development of sex differences in structures that belong to the vomeronasal system are due to the aromatization of testosterone to estradiol shortly after birth.
It is hypothesized that adolescent development involves a redistribution of cerebral functions from lower subcortical structures to higher regions of the prefrontal cortex to provide greater self-control over emotional behavior. We further hypothesized that this redistribution is likely to be moderated by sex-specific hormonal changes. To examine developmental sex differences in affective processing, 19 children and adolescents underwent fMRI while viewing photographs of faces expressing fear. Males and females differed in the pattern of their amygdala vs prefrontal activation during adolescent maturation. With age, females showed a progressive increase in prefrontal relative to amygdala activation in the left hemisphere, whereas males failed to show a significant age related difference. There appear to be sex differences in the functional maturation of affect-related prefrontal-amygdala circuits during adolescence.
Brain development during childhood and adolescence is characterized by both progressive myelination and regressive pruning processes. However, sex differences in brain maturation remain poorly understood. Magnetic resonance imaging was used to examine the relationships between age and sex with cerebral gray and white matter volumes and corpus callosal areas in 118 healthy children and adolescents (61 males and 57 females), aged 6-17 years. Gender groups were similar on measures of age, handedness, socioeconomic status and Full Scale IQ. Significant age-related reductions in cerebral gray and increases in white matter volumes and corpus callosal areas were evident, while intracranial and cerebral volumes did not change significantly. Significant sex by age interactions were seen for cerebral gray and white matter volumes and corpus callosal areas. Specifically, males had more prominent age-related gray matter decreases and white matter volume and corpus callosal area increases compared with females. While these data are from a cross-sectional sample and need to be replicated in a longitudinal study, the findings suggest that there are age-related sex differences in brain maturational processes. The study of age-related sex differences in cerebral pruning and myelination may aid in understanding the mechanism of several developmental neuropsychiatric disorders.
Normal volunteers, aged 30 to 99 years, were studied with MRI. Age was related to estimated volumes of: gray matter, white matter, and CSF of the cerebrum and cerebellum; gray matter, white matter, white matter abnormality, and CSF within each cerebral lobe; and gray matter of eight subcortical structures. The results were: 1) Age-related losses in the hippocampus were significantly accelerated relative to gray matter losses elsewhere in the brain. 2) Among the cerebral lobes, the frontal lobes were disproportionately affected by cortical volume loss and increased white matter abnormality. 3) Loss of cerebral and cerebellar white matter occurred later than, but was ultimately greater than, loss of gray matter. It is estimated that between the ages of 30 and 90 volume loss averages 14% in the cerebral cortex, 35% in the hippocampus, and 26% in the cerebral white matter. Separate analyses were conducted in which genetic risk associated with the Apolipoprotein E epsilon4 allele was either overrepresented or underrepresented among elderly participants. Accelerated loss of hippocampal volume was observed with both analyses and thus does not appear to be due to the presence of at-risk subjects. MR signal alterations in the tissues of older individuals pose challenges to the validity of current methods of tissue segmentation, and should be considered in the interpretation of the results.