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Tactile stimulation during development alters behaviour and neuroanatomical organization of normal rats
Abstract
The purpose of this study was to examine the anatomical and behavioural sequelae in the normal brain associated with tactile stimulation treatment during development. Using a split litter design, male and female rats were randomly assigned to either the tactile stimulation group (tactile stimulation for 15 min, three times/day, from postnatal day 3 to 21), or the no-tactile stimulation group. In adulthood, the rats were tested on the Whishaw tray reaching task, activity box, novel object recognition, and elevated plus maze. Following behavioural testing, rats were sacrificed for Golgi-Cox analysis. Dendritic length, dendritic branching, and spine density were analyzed in two areas of the prefrontal cortex (mPFC and OFC) and spine density in the amygdala. Tactile stimulation significantly altered rat behaviour on the novel object recognition task and Whishaw tray reaching task, but failed to have an effect on behaviour in the elevated plus maze or activity box. Importantly, tactile stimulation dramatically altered dendritic morphology in the prefrontal cortex and amygdala of both male and female rats. Tactile stimulation significantly increased dendritic branching, dendritic length, and spine density in all brain regions examined. These findings demonstrate that similar to early adversity, positive experiences early in development can dramatically alter neuroplasticity.
... The outcomes of these studies show that an increase in tactile stimulations in initial development periods forms absence seizure-modifying effects in WAG/Rij rats. Application of TS mimics maternal licking and grooming behavior in rats, which is a sensory stimulation method to the skin [14]. Studies show that TS therapy stimulates maturation in rat pups and in human infants [15]. ...
... Evidence has shown that TS during initial periods of development enables to reorganize dendritic organization in various brain regions and induces behavioural benefits in adult age [16]. Given during early developmental periods, TS improves anxietylike behaviors and prevents preference to addictive drugs and depression-like behaviors [14]. When given in adult rats, however, TS shows beneficial influence on the brain function, preventing cortical lesion and increasing neurotrophin and dendritic length [17]. ...
... Early life is a critical period for development of the central nervous system when plasticity levels are high and brain is extremely susceptible to environmental factors. Environmental stimuli during the early developmental period may influence the brain's functional maturation and its long-term integrity [14,20,[35][36][37]. Richards et al. (2012) showed that TS early in life increased spine density, dendritic branching, and dendritic length in prefrontal cortex and amygdala of rats [14]. ...
Objective:
The aim of our study is to examine the effects of neonatal tactile stimulations on the brain structures that previously defined as the focus of epilepsy in the Wistar-Albino-Glaxo from Rijswijk (WAG/Rij) rat brain with genetic absence epilepsy.
Methods:
In the present research, morphology and density of dendritic spines were analyzed in layer V pyramidal neurons of the somatosensory cortex (SoCx) of WAG/Rij rats (nonstimulated control, tactile-stimulated, and maternal separated rats) and healthy Wistar (nonepileptic) rats. To achieve this, a Golgi-Cox method was used.
Results:
Dendritic spine number in layer V of the SoCx has been detected significantly higher in adult WAG/Rij rats at postnatal day 150 in comparison to nonepileptic adult control Wistar rats (p < 0.001). Moreover, quantitative analyses of dendrite structure in adult WAG/Rij rats showed a decrease in dendrite spine density of pyramidal neurons of SoCx which occurred in early neonatal exposure to maternal separation (MS) and tactile stimulation (TS) (p < 0.001).
Conclusions:
Our findings provide the first evidence that tactile stimulations during the early postnatal period have a long-term impact on dendrite structure in WAG/Rij rat's brain and demonstrate that neonatal tactile stimulation can regulate dendritic spines in layer V in pyramidal neurons of SoCx in epileptic brains.
... The outcomes of these studies show that an increase in tactile stimulations in initial development periods forms absence seizure-modifying effects in WAG/Rij rats. Application of TS mimics maternal licking and grooming behavior in rats, which is a sensory stimulation method to the skin [12]. Studies show that TS therapy stimulates maturation in rat pups and in human infants [13]. ...
... Evidence has shown that TS during initial periods of development enables to reorganize dendritic organization in various brain regions and induces behavioural benefits in adult age [14]. Given during early developmental periods, TS improves anxiety-like behaviors, prevents preference to addictive drugs and depression-like behaviors [12]. When given in adult rats, however, TS shows beneficial influence on the brain function, preventing cortical lesion and increasing neurotrophin and dendritic length [15]. ...
... Studies showed that TS, which is an enriching positive experience that mimics maternal licking and grooming, has the potential to affect the neuroanatomic organization of the brain Richards et al., (2012) showed that TS early in life increased spine density, dendritic branching, and dendritic length in prefrontal cortex and amigdala of rats [12]. In another study, TS treatment, by increasing dendritic complexity, length and synaptic contact in all cortical areas and amygdala, reversed neuroanatomical alterations caused by prenatal valproic acid exposure in rats [31]. ...
Objective: The aim of our study is to examine the effects of neonatal tactile stimulatons on the brain structures that previously defined as the focus of epilepsy in the Wistar-Albino-Glaxo from Rijswijk (WAG/Rij) rat brain with genetic absence epilepsy.
Methods: In the present research, morphology and density of dendritic spines were analyzed in the somatosensory cortex (SoCx) of WAG/Rij rats (non stimulated control, tactile-stimulated and maternal separated rats) and healthy Wistar (non-epileptic) rats. To achieve this, a Golgi-Cox method was used.
Results: Dendritic spine number in layer V of the SoCx has been detected significantly higher in adult WAG/Rij rats at post natal day 150 in comparison to non-epileptic adult control Wistar rats (p<0,001). Moreover, quantitative analyses of dendrite structure in adult WAG/Rij rats showed a decrease in dendrite spine density of pyramidal neurons of SoCx which occurred in early neonatal exposure to maternal separation (MS) and tactile stimulation (TS) (p<0,001).
Conclusions: Our findings provide the first evidence that tactile stimulations during the early postnatal period have a long-term impact on dendrite structure in WAG/Rij rat’s brain and suggest a reduction in dendrite spine density is linked to absence seizure reduction.
... The outcomes of these studies show that an increase in tactile stimulations in initial development periods forms absence seizure-modifying effects in WAG/Rij rats. Application of TS mimics maternal licking and grooming behavior in rats, which is a sensory stimulation method to the skin [12]. Studies show that TS therapy stimulates maturation in rat pups and in human infants [13]. ...
... Evidence has shown that TS during initial periods of development enables to reorganize dendritic organization in various brain regions and induces behavioural benefits in adult age [14]. Given during early developmental periods, TS improves anxiety-like behaviors, prevents preference to addictive drugs and depression-like behaviors [12]. When given in adult rats, however, TS shows beneficial influence on the brain function, preventing cortical lesion and increasing neurotrophin and dendritic length [15]. ...
... It has been suggested that possible mechanisms that underlie the neural and behavioural effects of TS include endocrine function alterations, increased production of neurotrophic factors (insulin-like growth factor, brain-derived neurotrophic factor, and fibroblast growth factor-2) and altered gene methylation [12]. ...
Objective: The aim of our study is to examine the effects of neonatal tactile stimulatons on the brain structures that previously defined as the focus of epilepsy in the Wistar-Albino-Glaxo from Rijswijk (WAG/Rij) rat brain with genetic absence epilepsy.
Methods: In the present research, morphology and density of dendritic spines were analyzed in the somatosensory cortex (SoCx) of WAG/Rij rats (non stimulated control, tactile-stimulated and maternal separated rats) and healthy Wistar (non-epileptic) rats. To achieve this, a Golgi-Cox method was used.
Results: Dendritic spine number in layer V of the SoCx has been detected significantly higher in adult WAG/Rij rats at post natal day 150 in comparison to non-epileptic adult control Wistar rats (p<0,001). Moreover, quantitative analyses of dendrite structure in adult WAG/Rij rats showed a decrease in dendrite spine density of pyramidal neurons of SoCx which occurred in early neonatal exposure to maternal separation (MS) and tactile stimulation (TS) (p<0,001).
Conclusions: Our findings provide the first evidence that tactile stimulations during the early postnatal period have a long-term impact on dendrite structure in WAG/Rij rat’s brain and suggest a reduction in dendrite spine density is linked to absence seizure reduction.
... The outcomes of these studies show that an increase in tactile stimulations in initial development periods forms absence seizure-modifying effects in WAG/Rij rats. Application of TS mimics maternal licking and grooming behavior in rats, which is a sensory stimulation method to the skin [12]. Studies show that TS therapy stimulates maturation in rat pups and in human infants [13]. ...
... Evidence has shown that TS during initial periods of development enables to reorganize dendritic organization in various brain regions and induces behavioural bene ts in adult age [14]. Given during early developmental periods, TS improves anxiety-like behaviors, prevents preference to addictive drugs and depression-like behaviors [12]. When given in adult rats, however, TS shows bene cial in uence on the brain function, preventing cortical lesion and increasing neurotrophin and dendritic length [15]. ...
... Studies showed that TS, which is an enriching positive experience that mimics maternal licking and grooming, has the potential to affect the neuroanatomic organization of the brain [12,16,31,32,33]. Richards et al., (2012) showed that TS early in life increased spine density, dendritic branching, and dendritic length in prefrontal cortex and amigdala of rats [12]. ...
Background
In previous studies, it has been shown that in early developmental period, the high level of tactile stimulations prevent absence epilepsy development and comorbid depression in Wistar-Albino-Glaxo from Rijswijk (WAG/Rij) rats with absence epilepsy. The aim of our study is to examine the effects of neonatal tactile stimulatons on the brain structures that previously defined as the focus of epilepsy in the rat brain with genetic absence epilepsy.
Results
In the present research, morphology and density of dendritic spines were analyzed in the somatosensory cortex (SoCx) in WAG/Rij rats with absence epilepsy, sensory experienced WAG/Rij rats (tactile-stimulated and maternal separated) and healthy Wistar (non-epileptic) rats. To achieve this, a Golgi-Cox method was used. Dendritic spine number in layer V of the SoCx has been detected significantly higher in adult WAG/Rij rats at post natal day 150 in comparison to non-epileptic adult control Wistar rats (p < 0,001). Moreover, quantitative analyses of dendrite structure in adult WAG/Rij rats showed a decrease in dendrite spine density of pyramidal neurons of SoCx which occurred in early neonatal exposure to maternal separation (MS) and tactile stimulation (TS) (p < 0,001).
Conclusions
Our findings provide the first evidence that tactile stimulations during the early postnatal period have a long-term impact on dendrite structure in WAG/Rij rat’s brain and suggest a reduction in dendrite spine density is linked to absence seizure reduction.
... Neonatal TS enriches the experience and improves maturation of newborn animals, positively influencing behaviors and neuroendocrine systems in pups (Boufleur et al., 2012(Boufleur et al., , 2013Antoniazzi et al., 2014). Others showed that neonatal TS increases neurogenesis and neuroplasticity, improves anxietylike behaviors and prevents depression-like behaviors (Richards et al., 2012;Freitas et al., 2015;Roversi et al., 2019). Recent reports have shown that when TS is applied both during the initial periods of development and in adult rats, neurotrophins such as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF-2) increase in different brain areas. ...
... Maternal care in rats includes, besides nursing, two primary behavior types: (i) LG (a form of sensory manipulation to the skin) of pups and (ii) NABN (non-nutritive contacts with pups) (Richards et al., 2012). It has been shown that LG behavior of mother rats can be mimicked by TS. ...
... It should be emphasized that BDNF is involved in the maturation of inhibitory GABAergic synapses (Henneberger et al., 2002;Yamada et al., 2003;Berghuis et al., 2004;Zhu et al., 2019), as well as that maturation and functioning of excitatory and inhibitory transmission is also modulated differently by BDNF (Gottmann et al., 2009;Meis et al., 2019). Moreover, it has been shown that early NTS treatment leads to increase in the skin and the brain production of FGF-2 (Richards et al., 2012). Studies suggested that increased FGF-2 following TS contribute to brain plasticity in animals (Comeau et al., 2007;Gibb et al., 2010;Richards et al., 2012). ...
Recent studies suggest that development of absence epilepsy and comorbid depression might be prevented by increased maternal care of the offspring, in which tactile stimulation induced by licking/grooming and non-nutritive contact seem to be crucial. In this study, we aimed to evaluate the effect of neonatal tactile stimulations (NTS) on absence epilepsy and depression-like behaviors in adulthood. Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat pups with a genetic predisposition to absence epilepsy were divided into tactile stimulation (TS) group, deep touch pressure (DTP) group, maternal separation (MS) group or control group. Between postnatal day 3 and 21, manipulations (TS, DTP, and MS) were carried out for 15 min and three times a day. Animals were submitted to locomotor activity, sucrose consumption test (SCT) and forced swimming test (FST) at five months of age. At the age of six months, the electroencephalogram (EEG) recordings were conducted in order to quantify the spike-wave discharges (SWDs), which is the hallmark of absence epilepsy. The TS and DTP groups showed less and shorter SWDs in later life in comparison to maternally separated and control rats. SWDs’ number and total duration were significantly reduced in TS and DTP groups whereas mean duration of SWDs was reduced only in DTP group (p < 0.05). TS and DTP also decreased depression-like behaviors measured by SCT and FST in adult animals. In the SCT, number of approaches was significantly higher in TS and DTP groups than the maternally separated and control rats. In the FST, while the immobility latency of TS and DTP groups was significantly higher, only TS group showed significantly decreased immobility and increased swimming time. The results showed that NTS decreases both the number and length of SWDs and the depression-like behaviors in WAG/Rij rats probably by increasing arousal level and causing alterations in the level of some neurotrophic factors as well as in functions of the neural plasticity in the developing rat’s brain.
... Testing was performed as described (Richards et al., 2012) and occurred 2 weeks after exposure. NOR for temporal order memory was run in three separate trials starting 1 h apart on filming day. ...
... Testing was performed as previously described (Richards et al., 2012). Activity was measured 2 weeks after irradiation. ...
... All statistical analyses were carried out using SPSS 16.0 (Richards et al., 2012). Each rat was used as a unit of analysis. ...
Irradiated cells can signal damage and distress to both close and distant neighbors that have not been directly exposed to the radiation (naïve bystanders). While studies have shown that such bystander effects occur in the shielded brain of animals upon body irradiation, their mechanism remains unexplored. Observed effects may be caused by some blood-borne factors; however they may also be explained, at least in part, by very small direct doses received by the brain that result from scatter or leakage. In order to establish the roles of low doses of scatter irradiation in the brain response, we developed a new model for scatter irradiation analysis whereby one rat was irradiated directly at the liver and the second rat was placed adjacent to the first and received a scatter dose to its body and brain. This work focuses specifically on the response of the latter rat brain to the low scatter irradiation dose. Here, we provide the first experimental evidence that very low, clinically relevant doses of scatter irradiation alter gene expression, induce changes in dendritic morphology, and lead to behavioral deficits in exposed animals. The results showed that exposure to radiation doses as low as 0.115 cGy caused changes in gene expression and reduced spine density, dendritic complexity, and dendritic length in the prefrontal cortex tissues of females, but not males. In the hippocampus, radiation altered neuroanatomical organization in males, but not in females. Moreover, low dose radiation caused behavioral deficits in the exposed animals. This is the first study to show that low dose scatter irradiation influences the brain and behavior in a sex-specific way.
... Similarly, when Muhammad et al. (2011) gave infant rats tactile stimulation with a fine brush 15 min per day from birth until weaning they found an attenuated response to amphetamine in adulthood. They chose tactile stimulation because like drugs and complex housing, tactile stimulation produces large changes in dendritic organization in multiple cerebral regions (e.g., Richards et al., 2012). The found a marked attenuation of the effects of amphetamine given in adulthood. ...
... This is often the case but not always. For example we have shown that tactile stimulation in early development has a profound effect on neural organization and behavior (e.g., Richards et al., 2012) so we anticipated that tactile stimulation might be a good treatment for brain injury, which it is (see Richards et al., 2012, below). What we had not expected, however, was that the synaptic changes in normal and brain-injured animals would be qualitatively different and that different injuries would respond with quite different changes. ...
... A second type of effective experience in changing neural circuitry is tactile stimulation (e.g., Richards et al., 2012). Both adult and infant rats benefit from tactile stimulation using light touch with a fine brush several times daily for 15 min for 2-3 weeks after the brain injury. ...
A fundamental property of the brain is its capacity to change with a wide variety of experiences, including injury. Although there are spontaneous reparative changes following injury, these changes are rarely sufficient to support significant functional recovery. Research on the basic principles of brain plasticity is leading to new approaches to treating the injured brain. We review factors that affect synaptic organization in the normal brain, evidence of spontaneous neuroplasticity after injury, and the evidence that factors including postinjury experience, pharmacotherapy, and cell-based therapies, can form the basis of rehabilitation strategies after brain injuries early in life and in adulthood.
... These results suggest that postnatal tactile stimulation might increase spatial learning and the ability to recall the stored information. The performance in the tactile stimulated animals has been attributed to the increase in the arborization and dendrite length as a result of postnatal stimulation (Richards et al., 2012). It has been proposed that structural changes due to stimulation are associated with the increase in the expression of synaptic proteins such as synaptophysin, spinophilin, and GluR2 (AMPA-receptor subunit), which are implicated in the formation of new dendritic synapses and spines (Kozorovitskiy et al., 2005). ...
... This has been attributed to the increase in the number of glucocorticoid receptors in the hippocampus and prefrontal cortex (Avishai-Eliner et al., 2001;Meaney and Aitken, 1985;Meaney et al., 1988). Furthermore, increase in dendritic arborization, length and spine density in the cerebral regions involved in the HPA axis regulation could explain these results (Richards et al., 2012). ...
... First, they require no training, external motivation, or reward enabling us to monitor signs of implantation sites and resorbed embryos within a short time after weaning. Second, their ability to show the effects of stress on rodents' behaviour has been previously well documented [36][37][38][39] . The NOR test, which assesses recognition memory, is widely used for investigating a wide range of cognitive, memory, and neuropsychological functions 30,40,41 . ...
... Time spent with each object was only calculated during the second session. If the nose of the mouse was within 1 cm of the object, it was considered to be in contact with an object 38,39 . The ratio of time spent with the old compared to the new object was calculated by subtracting times spent with 'old' from the new object divided by the total time spent for exploration 100 . ...
Stress during gestation has harmful effects on pregnancy outcome and can lead to spontaneous abortion. Few studies, however, have addressed the impact of gestational stress, particularly auditory stress, on behavioural performance and pregnancy outcome in mice. This study aimed to examine the effect of two types of gestational stress on uterus receptivity and behavioural performance. Pregnant C57BL/6 mice were randomly assigned to either auditory or physical stress conditions or a control condition from gestational days 12–16. The auditory stress regimen used loud 3000 Hz tone, while the physical stressor consisted of restraint and exposure to an elevated platform. Three behavioural tests were performed in the dams after weaning. Uterine receptivity was investigated by counting the number of sites of implantation and fetal resorption. Also, the offspring survival rates during the early postnatal period were calculated. Auditory stress caused an increase in anxiety-like behaviour, reduced time spent exploring new object/environment, and reduced balance when compared to the physical stress and control groups. Auditory stress also caused higher rates of resorbed embryos and reduction of litter size. Our results suggest that the adverse effect of noise stress is stronger than physical stress for both uterus receptivity and behavioural performance of the dams.
... These results suggest that postnatal tactile stimulation might increase spatial learning and the ability to recall the stored information. The performance in the tactile stimulated animals has been attributed to the increase in the arborization and dendrite length as a result of postnatal stimulation (Richards et al., 2012). It has been proposed that structural changes due to stimulation are associated with the increase in the expression of synaptic proteins such as synaptophysin, spinophilin, and GluR2 (AMPA-receptor subunit), which are implicated in the formation of new dendritic synapses and spines (Kozorovitskiy et al., 2005). ...
... This has been attributed to the increase in the number of glucocorticoid receptors in the hippocampus and prefrontal cortex (Avishai-Eliner et al., 2001;Meaney and Aitken, 1985;Meaney et al., 1988). Furthermore, increase in dendritic arborization, length and spine density in the cerebral regions involved in the HPA axis regulation could explain these results (Richards et al., 2012). ...
Neurogenesis in the dentate gyrus (DG) of the hippocampus is increased by spatial learning and postnatal stimulation. Conversely, prenatal stress (PS) produces a decrease in the proliferation of hippocampal granular cells. This work evaluated the effect of postnatal tactile stimulation (PTS), when applied from birth to adulthood, on cognitive performance and hippocampal neurogenesis (survival and differentiation) in PS female and male rats. The response of the adrenal axis to training in the Morris water maze (MWM) was also analyzed. PS was provided during gestational days 15 through 21. Hippocampal neurogenesis and cognitive performance in the MWM were assessed at an age of three months. Results showed that escape latencies of both female and male PS rats were longer compared to those of their controls (CON). DG cell survival increased in the PS female rats. Corticosterone concentrations were significantly higher in the male and female PS rats after MWM training. PTS improved escape latencies and increased the number of new neurons in the DG of PS animals, and their corticosterone concentrations were similar to those in CON. In CON, PTS diminished DG cell survival but increased differentiation and reduces latency in the MWM. These results show that long-term PTS in PS animals might prevent learning deficits in adults through increase in the number of DG new cells and decrease of the reactivity of the adrenal axis to MWM training.
... During this time window, the nervous system becomes extremely plastic and highly sensitive to environmental changes that may modify these developmental cellular processes. Therefore, it is essential to avoid negative or traumatic experiences and to be exposed to positive stimuli in early life (Kolb and Whishaw 1998;Landi et al. 2007a, b;Gibb et al. 2010;Richards et al. 2012). ...
... In stimulated rats, important morphological changes, such as the higher number of blood vessels, fewer damaged myelin fibers, and densely packed fibers, were found when we investigated the cytoarchitecture of the developing optic nerve, indicating the acceleration of optic nerve maturation. These characteristics might be explained by the increased release of factors such as IGF (Guzzetta et al. 2009) and fibroblast growth factor 2 (FGF-2) (Gibb et al. 2010;Richards et al. 2012) in response to tactile stimulation, as previously demonstrated. However, the increase in myelinated fibers might be explained with other mechanisms in addition to the increased growth factor release. ...
This study was designed to investigate the progressive effect of tactile stimulation in the cytoarchitecture of the optic nerve of normal rats during early postnatal development. We used 36 male pups which were randomly assigned to either the tactile-stimulated group (TS—stimulation for 3 min, once a day, from postnatal day (P) 1 to 32) or the non-tactile-stimulated (NTS) group. Morphological analysis were performed to evaluate the alterations caused by tactile stimulation, and morphometric analysis were carried out to determine whether the observed changes in optic nerve cytoarchitecture were significantly different between groups and at three different ages (P18, P22, and P32), thereby covering the entire progression of development of the optic nerve from its start to its completion. The rats of both groups presented similar increase in body weight. The morphometric analysis revealed no difference in the astrocyte density between age-matched groups; however, the oligodendrocyte density of TS group was higher compared to the NTS at P22, and P32, but not at P18. The optic nerve of TS group showed an increase of blood vessels and a reduction of damage fiber density when compared to the age-matched pups of NTS. Taken together, these findings support the view that tactile stimulation, an enriching experience, can positively affects the neuroanatomy of the brain, modifying its cellular components by progressive morphological and morphometric changes.
... Testing was performed as described [45] and occurred two weeks after exposure. In brief, an NOR for temporal order memory was run in three separate trials, each starting one hour apart, on filming day. ...
... All statistical analyses were carried out using SPSS 16.0 [45]. Each rat was used as a unit of analysis. ...
Radiation therapy can not only produce effects on targeted organs, but can also influence shielded bystander organs, such as the brain in targeted liver irradiation. The brain is sensitive to radiation exposure, and irradiation causes significant neuro-cognitive deficits, including deficits in attention, concentration, memory, and executive and visuospatial functions. The mechanisms of their occurrence are not understood, although they may be related to the bystander effects.
We analyzed the induction, mechanisms, and behavioural repercussions of bystander effects in the brain upon liver irradiation in a well-established rat model.
Here, we show for the first time that bystander effects occur in the prefrontal cortex and hippocampus regions upon liver irradiation, where they manifest as altered gene expression and somewhat increased levels of γH2AX. We also report that bystander effects in the brain are associated with neuroanatomical and behavioural changes, and are more pronounced in females than in males.
... Interestingly, animal studies have shown TS to be an effective measure of protection against cortical injury [43,44] and anxiety [45]. TS has also been shown to stimulate maturation in preterm and newborn animals [46,47], and even alter the behavioral and neuroanatomical organization in non-brain injured rats [48]. Given the abundance of literature reinforcing TS as positive enriching experience, it is plausible that such an experience may offer preventative or remedial intervention in animal models of autism. ...
... Twelve dams and twelve male Long-Evans rats were utilized in this study. The control animals were a subset of a larger study conducted by Richards et al. [48] and the same data was utilized. All procedures among the VPA and control animals -from gestation to adult behavioral testing -were identical and conducted during the same time period, to ensure no significant effect of time or any observable behavioral differences. ...
... Although there are many reported and utilized techniques for the examination of negative early experiences on brain maturation, such as perinatal stress 1,2 , sensory deprivation 3 , and drug toxicity 4 , there are very few methodologies employed to examine the effects of positive experiences in this time period. Aside from environmental enrichment, tactile stimulation is one of a few brain enhancing treatments with demonstrated effects 5 . Tactile stimulation is a method of sensory stimulation to the skin that mimics the maternal rat behavior, licking and grooming. ...
... Testing was performed as described elsewhere (Richards, Mychasiuk, Kolb, & Gibb, 2012) and occurred two weeks after exposure. In brief, an NOR for temporal order memory was run in three separate trials, each starting one hour apart, on filming day. ...
Purpose:
In recent years, much effort has been focused on developing new strategies for the prevention and mitigation of adverse radiation effects on healthy tissues and organs, including the brain. The brain is very sensitive to radiation effects, albeit as it is highly plastic. Hence, deleterious radiation effects may be potentially reversible. Because radiation exposure affects dendritic space, reduces the brain's ability to produce new neurons, and alters behavior, mitigation efforts should focus on restoring these parameters. To that effect, environmental enrichment through complex housing (CH) and exercise may provide a plausible avenue for exploration of protection from brain irradiation. CH is a much broader concept than exercise alone, and constitutes exposure of animals to positive physical and social stimulation that is superior to their routine housing and care conditions. We hypothesized that CHs may lessen harmful neuroanatomical and behavioural effects of low dose radiation exposure.
Methods:
We analyzed and compared cerebral morphology in animals exposed to low dose head, bystander (liver), and scatter irradiation on rats housed in either the environmental enrichment condos or standard housing.
Results:
Enriched condo conditions ameliorated radiation-induced neuroanatomical changes. Moreover, irradiated animals that were kept in enriched CH condos displayed fewer radiation-induced behavioural deficits than those housed in standard conditions.
Conclusions:
Animal model-based environmental enrichment strategies, such as CH, are excellent surrogate models for occupational and exercise therapy in humans, and consequently have significant translational possibility. Our study may thus serve as a roadmap for the development of new, easy, safe and cost-effective methods to prevent and mitigate low-dose radiation effects on the brain.
... For most gregarious mammals, social interactions begin immediately after birth, through contact with the mother and littermates, thereby providing a critical source of stimulation required for development. In rodents, stimulation from maternal grooming and licking shapes the development of a number of speciestypical behaviors in later life [1][2][3][4][5][6][7]. ...
Early life social interactions in gregarious mammals provide an important source of stimulation required for the development of species-typical behaviors. In the present study, complete deprivation of maternal and littermate contact through artificial rearing was used to examine the role of early social stimulation on copulatory behavior and the ejaculate in adult rats. We found that artificially reared naïve male rats were sexually motivated; nevertheless, they did not acquire the level of sexual experience that typically occurs during copulatory training. Disrupted expression of sexual experience of artificially reared rats was demonstrated by an inconsistent pattern of ejaculatory behavior across training tests. Artificial tactile stimulation applied during isolation prevented this disruption and rats achieved ejaculation in most copulatory tests. Despite the irregularity of ejaculatory behavior in isolated rats, their sperm count and seminal plug were similar to control maternally reared (sexually experienced) and artificially-reared rats that received tactile stimulation. These results suggest that tactile sensory information provided by the mother and/or littermates to the offspring is crucial for the development of copulatory behavior. The absence of social and/or tactile stimulation during early life compromises the ability of male rats to gain sexual experience in adulthood.
... Rats that experience less LG show suppressed synaptic plasticity and intrinsic excitability in the dorsal hippocampus, and heightened plasticity and excitability in the ventral hippocampus; these changes are related to anxiety-like behaviors (Nguyen et al., 2015). Conversely, early tactile stimulation in rodents triggers dendritic changes that increase the connectivity of the prefrontal cortex and amygdala, differences which are linked to heightened performance on learning tasks (Richards et al., 2012). Though comparable studies have not yet been conducted in humans, in general, parent-infant synchronous interactions have been identified as a key factor in the formation of reward circuitry (Feldman, 2017). ...
Though rarely included in studies of parent–infant interactions, affectionate touch plays a unique and vital role in infant development. Previous studies in human and rodent models have established that early and consistent affectionate touch from a caregiver confers wide-ranging and holistic benefits for infant psychosocial and neurophysiological development. We begin with an introduction to the neurophysiological pathways for the positive effects of touch. Then, we provide a brief review of how affectionate touch tunes the development of infant somatosensory, autonomic (stress regulation), and immune systems. Affective touch also plays a foundational role in the establishment of social affiliative bonds and early psychosocial behavior. These touch-related bonding effects are known to be mediated primarily by the oxytocin system, but touch also activates mesocorticolimbic dopamine and endogenous opioid systems which aid the development of social cognitive processes such as social learning and reward processing. We conclude by proposing a unique role for affectionate touch as an essential pathway to establishing and maintaining parent-infant interactional synchrony at behavioral and neural levels. The limitations of the current understanding of affectionate touch in infant development point to fruitful avenues for future research.
... Neonatal TS is a procedure applied during developmental periods mimicking nonspecific maternal stimulation such as licking and grooming of pups. It has emerged as an efficient tool to improve the behavior by altering brain organization and enhancing hippocampus neurogenesis (Guerrero et al., 2016) and neuroplasticity (Richards et al., 2012). TS decreases anxiety-like behaviors (Río-Alamos et al., 2015), and prevents the negative effects of stress (Boufleur et al., 2013) and the development of depressive-like behaviors (Freitas et al., 2015). ...
The serotonin transporter (SERT) gene, especially the short allele of the human serotonin transporter linked polymorphic region (5-HTTLPR), has been associated with the development of stress-related neuropsychiatric disorders. In line, exposure to early life stress in SERT knockout animals contributes to anxiety- and depression-like behavior. However, there is a lack of investigation of how early-life exposure to beneficial stimuli, such as tactile stimulation (TS), affects later life behavior in these animals. In this study, we investigated the effect of TS on social, anxiety, and anhedonic behavior in heterozygous SERT knockouts rats and wild-type controls and its impact on gene expression in the basolateral amygdala. Heterozygous SERT+/– rats were submitted to TS during postnatal days 8–14, for 10 min per day. In adulthood, rats were assessed for social and affective behavior. Besides, brain-derived neurotrophic factor (Bdnf) gene expression and its isoforms, components of glutamatergic and GABAergic systems as well as glucocorticoid-responsive genes were measured in the basolateral amygdala. We found that exposure to neonatal TS improved social and affective behavior in SERT+/– animals compared to naïve SERT+/– animals and was normalized to the level of naïve SERT+/+ animals. At the molecular level, we observed that TS per se affected Bdnf, the glucocorticoid-responsive genes Nr4a1, Gadd45β, the co-chaperone Fkbp5 as well as glutamatergic and GABAergic gene expression markers including the enzyme Gad67, the vesicular GABA transporter, and the vesicular glutamate transporter genes. Our results suggest that exposure of SERT+/– rats to neonatal TS can normalize their phenotype in adulthood and that TS per se alters the expression of plasticity and stress-related genes in the basolateral amygdala. These findings demonstrate the potential effect of a supportive stimulus in SERT rodents, which are more susceptible to develop psychiatric disorders.
... However, it is largely unknown how early sensory development affects the maturation of the limbic system. Several studies have shown that sensory experience is important for synaptic pruning during PFC development (Schanberg and Field, 1987;Richards et al., 2012). For example, raising rodents in a tactile-enriched environment from birth on increases the prefrontal spine density and improves the performance in PFC-dependent tasks at adulthood. ...
The emergence of cross-modal learning capabilities requires the interaction of neural areas accounting for sensory and cognitive processing. Convergence of multiple sensory inputs is observed in low-level sensory cortices including primary somatosensory (S1), visual (V1), and auditory cortex (A1), as well as in high-level areas such as prefrontal cortex (PFC). Evidence shows that local neural activity and functional connectivity between sensory cortices participate in cross-modal processing. However, little is known about the functional interplay between neural areas underlying sensory and cognitive processing required for cross-modal learning capabilities across life. Here we review our current knowledge on the interdependence of low- and high-level cortices for the emergence of cross-modal processing in rodents. First, we summarize the mechanisms underlying the integration of multiple senses and how cross-modal processing in primary sensory cortices might be modified by top-down modulation of the PFC. Second, we examine the critical factors and developmental mechanisms that account for the interaction between neuronal networks involved in sensory and cognitive processing. Finally, we discuss the applicability and relevance of cross-modal processing for brain-inspired intelligent robotics. An in-depth understanding of the factors and mechanisms controlling cross-modal processing might inspire the refinement of robotic systems by better mimicking neural computations.
... In adult and old rats, early postnatal handling has been shown to reduce anxiety, decrease levels of prolactin and corticosterone following stress, prevent age-related loss of hippocampal CA1 and CA3 pyramidal cells and deterioration of working memory and recognition memory (Boufleur et al., 2013;Fenoglio et al., 2005;Ferré et al., 1995;Meaney et al., 1988;Meerlo et al., 1999;Stamatakis et al., 2008;Valée et al., 1999;Viau et al., 1993). The above mentioned neonatal handling mediated memory improvement was accompanied by increase in dendritic length and dendritic spine density in the cortex (Richards et al., 2012). Positive effect of early postnatal handling has been shown on prenatal stress, alcohol exposure and malnutrition in experimental rats (Raineki et al., 2014). ...
Handling is a form of experience which can result in physiological changes depending on the period of postnatal age when performed. There is a lot of evidence about the positive effect of neonatal handling, but a lack dealing with handling of adult rats. Behavioral changes and memory deficits are present in dementia-like disorders. In the present work, we tested whether 6 weeks lasting handling of young adult rats could revert memory impairment induced by trimethyltin (TMT) (7.5 mg/kg, intraperitoneally). Testing rats in Morris water maze revealed significant effect of TMT as well significant effect of handling. We observed improvement of spatial memory also between healthy, non-degenerated rats as well as degenerated rats, represented by shorter latency onto the platform. In our paper, we report beneficial effect of handling on spatial memory that is in compliance with published works about beneficial effect of cognitive therapy and training in patients with early stage of Alzheimer's disease and dementia.
... During the rat's nursing period, the mother-litter bonds are relevant for newborn development and to maintain the maternal care activity for pup survival and breeding. Thus, the lactating mother provides important olfactory, tactile, thermal, and vestibular stimulation to the pups through body and anogenital licking, retrieving, whisking, and manipulation, which are significantly reduced in early underfed lactating dams, causing long-term behavioral, anatomical, and neurochemical deficits for the progeny [28] [29] [30]. Journal of Behavioral and Brain Science During lactation, neonatally underfed F1 young interact poorly with their F0 mothers and littermates, and the somatosensory cues of the mother decrease significantly [31] [32]. ...
... Similar result was obtained for the later brain damage in animal model studies, i.e., for tactile stimulation, where the stimulation was done by using light touch with a fine brush several times daily for 15 min for 2-3 weeks after the brain injury. [35,37,38] Pharmacotherapeutic agents, especially psychostimulants, which boosts neural plasticity are emerging these days. Although their effectiveness is limited by lesion size, location, and route of administration, amphetamine and nicotine have showed harnessing effect on neuronal plasticity in laboratory animal studies. ...
... Growing evidence from experimental studies has suggested that non-pharmacological treatments, including physical exercise and environmental enrichment, can exert neuroprotective effects and improve depression-like symptoms by changing the BDNF and the glucocorticoid signaling [31,32]. In line with this, tactile stimulation (TS) constitutes a simple procedure that can modify the brain organization by increasing neurogenesis [33] and neuroplasticity [34] in the hippocampus, improving anxiety-like behaviors [35], and preventing preference to addictive drugs [36,37] and depression-like behaviors [38] when applied during initial periods of development. Experimental studies also showed TS beneficial influence on the brain function, when applied in adult rats, preventing cortical lesion [39], and increasing neurotrophins and dendritic length [40]. ...
Depression is a common psychiatric disease which pharmacological treatment relieves symptoms, but still far from ideal. Tactile stimulation (TS) has shown beneficial influences in neuropsychiatric disorders, but the mechanism of action is not clear. Here, we evaluated the TS influence when applied on adult female rats previously exposed to a reserpine-induced depression-like animal model. Immediately after reserpine model (1 mg/kg/mL, 1×/day, for 3 days), female Wistar rats were submitted to TS (15 min, 3×/day, for 8 days) or not (unhandled). Imipramine (10 mg/kg/mL) was used as positive control. After behavioral assessments, animals were euthanized to collect plasma and prefrontal cortex (PFC). Behavioral observations in the forced swimming test, splash test, and sucrose preference confirmed the reserpine-induced depression-like behavior, which was reversed by TS. Our findings showed that reserpine increased plasma levels of adrenocorticotropic hormone and corticosterone, decreased brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B, and increased proBDNF immunoreactivity in the PFC, which were also reversed by TS. Moreover, TS reestablished glial fibrillary acidic protein and glucocorticoid receptor levels, decreased by reserpine in PFC, while glial cell line–derived neurotrophic factor was increased by TS per se. Our outcomes are showing that TS applied in adulthood exerts a beneficial influence in depression-like behaviors, modulating the HPA axis and regulating neurotrophic factors more effectively than imipramine. Based on this, our proposal is that TS, in the long term, could be considered a new therapeutic strategy for neuropsychiatric disorders improvement in adult life, which may represent an interesting contribution to conventional pharmacological treatment.
... The brain size, cortical thickness, complexity in dendritic branching, and spine density of animals exposed to an enriched environment are highly increased, as are the cognitive abilities (85)(86)(87)(88)(89)(90). Furthermore, light tactile stimulation for the first 10-15 d of postnatal neurodevelopment results in significant changes in nervous system and behavior that are beneficial (91,92). These changes are permanent, which is consistent with experiments performed by Mychasiuk et al. (93), indicating that enriched environment leads to a significant decrease in gene methylation in the frontal cortex and hippocampus, suggesting that early experiences result in epigenetic changes. ...
Attention deficit hyperactivity disorder (ADHD) is now among the most commonly diagnosed chronic psychological dysfunctions of childhood. By varying estimates, it has increased by 30% in the past 20 years. Environmental factors that might explain this increase have been explored. One such factor may be audiovisual media exposure during early childhood. Observational studies in humans have linked exposure to fast-paced television in the first 3 years of life with subsequent attentional deficits in later childhood. Although longitudinal and well controlled, the observational nature of these studies precludes definitive conclusions regarding a causal relationship. As experimental studies in humans are neither ethical nor practical, mouse models of excessive sensory stimulation (ESS) during childhood, akin to the enrichment studies that have previously shown benefits of stimulation in rodents, have been developed. Experimental studies using this model have corroborated that ESS leads to cognitive and behavioral deficits, some of which may be potentially detrimental. Given the ubiquity of media during childhood, these findings in humansand rodents perhaps have important implications for public health.
... De esta manera, los lamidos/acicalamiento proporcionados por madres cuidadoras durante la primera semana de vida, han reportado aumentar la expresión de marcadores de sinaptogénesis, sinaptofisina y N-CAM, en la adultez (Liu et al.). De manera similar, la estimulación táctil aplicada durante el periodo lactacional induce crecimiento de dendritas y de espinas dendríticas en áreas límbicas de la corteza prefrontal (Richards et al., 2012). En consecuencia, es posible hipotetizar que el estrés prenatal induce mecanismos que produce de atrofia celular, incrementando la densidad neuronal de la placa hipocampal; y, la estimulación táctil/kinestésica por su parte tendría efectos beneficiosos sobre el crecimiento y maduración de la placa hipocampal, que reducirían la densidad neuronal. ...
This investigation was undertaken in order to know whether the postnatal tactile/kinesthetic stimulation is effective in reversing the Prenatal Stress, in the cytoarchitecture of the CA3 region of the hippocampus, in female pups. 12 pups of female rats from the Sprague-Dawley strain were distributed to Control Group (GC), the Prenatal Maternal Stress by restriction group (EP) and Prenatal Maternal Stress with postnatal tactile/ kinesthetic stimulation Group (EP-ETK). The Prenatal Maternal Stress in female pups increased neuronal density in CA3b and CA3c areas (p<0.001). When compared to Prenatal Maternal Stress, pups prenatal stress who received early tactile/kinesthetic stimulation showed a decrease in neuronal density in CA3b and CA3c areas (p < 0,001). Postnatal tactile/kinesthetic stimulation was shown to successfully reverse the Prenatal Maternal Stress effects by decreasing neuronal density in CA3b and CA3c hippocampal areas.
... The time spent with each object was only calculated during the second session. If the nose of the mouse was within 1 cm of the object, it was considered to be in contact with an object 6,82,98 . The ratio of time spent with the old compared to the new object was calculated by subtracting times spent with old from the new object divided by the total time spent for exploration 99 . ...
Noise stress is a common environmental pollutant whose adverse effect on offspring performance has been less studied. This study was novel in terms of using “noise” as a prenatal stress compared with physical stress to explore the effect of stress during gestation on HPA axis activation, cognitive performance, and motor coordination, as well as in investigating the effect of behavioral assessments on the corticosterone (CORT) levels. Three groups of C57BL/6 mice with a gestational history of either noise stress (NS), physical stress (PS), or no stress were examined in several behavioral tests. Plasma CORT level was significantly higher before starting the behavioral tests in NS group than the two other groups. It was significantly increased after the behavioral tests in both prenatal stressed groups relative to the controls. Stress caused anxiety-like behavior and reduced learning and memory performance in both stressed groups compared to the controls, as well as decreased motor coordination in the NS group relative to the other groups. The findings suggested that: prenatal NS severely changes the HPA axis; both prenatal stressors, and particularly NS, negatively impair the offspring’s cognitive and motor performance; and, they also cause a strong susceptibility to interpret environmental experiences as stressful conditions.
... When mother leaves the litter, or is separated from the pups, they frequently emit ultrasonic calls at 30-50 kHz, and the dam retrieves them to the nest, calming and reducing the distress response (Oswalt and Meier, 1975;Okabe et al., 2013;Yoshida et al., 2013). Thus, early lactation is a fundamental stage of the dam's lifespan; through an intense mother-litter interaction, the dam sustains the litter by nursing, promoting its physical development, and exposing it to early learning experiences that influence their brain growth and function, as well as the affective responses that may be expressed as adaptive responses in later stages of life (Moriceau and Sullivan, 2006;Richards et al., 2012). ...
The expression of different behavioral components in the adult rat depends on a number of early influences, including age, hormones, manipulations of sensory cues, and perinatal undernutrition, all of which impact the development of brain areas underlying adaptive processes, maternal behavior, and the response to novelty. The current study investigates the effects of pre- and neonatal undernutrition on various components of maternal behavior of dams exposed to the challenge of an unfamiliar home cage on days 4, 8, and 12 of lactation. Food restriction was initiated from gestational day (G) G6 to G19 when dams received 50-70% of the normal balanced diet, followed by 100% from G20 to G21. After birth, pups were underfed by alternating every 12 h between two lactating dams, one of which, had ligated nipples. Weaning was at 25 days of age followed by an ad libitum diet until postpartum day 90, when females were mated, and subsequently tested for maternal behavior in an unfamiliar cage. The results indicated that in early underfed mothers the frequency of handling wood shavings and of, approaching, licking, crouching, and grasping pups for retrieval was significantly reduced. Moreover, self-grooming increased substantially in the underfed dams, but the frequency of rearing was reduced. Additionally, the body weight of pups nursed by early underfed dams was significantly lower than that of control pups. These findings suggest a relation between early food restriction and the deficient maternal care observed when these dams were challenged by exposure to an unfamiliar home cage.
... juga analisa Golgi-Cox untuk menganalisa panjang dendrit, percabangan dendrit di prefrontal cortex dan densitas tulang di amygdala setelah dilakukan stimulasi taktil, ternyata hasilnya adalah panjang dendrit, percabangan dendrit dan densitas tulang meningkat disemua area pemeriksaan. Hal ini menandakan pengalaman dini pada awal perkembangan dapat mengubah plastisitas neural31 ...
... Previous studies revealed that malnourished rats achieved some prophy- laxis by exposure to an enriched environment (Soares et al., 2013;De Oliveira Soares et al., 2014;Barbosa et al., 2016;Soares et al., 2015). There is now an abundance of literature reinforcing the fact that tactile stimulation (TS) treatment is a positive enriching experience (Kolb and Gibb, 2007;Imanaka et al., 2008;Gibb et al., 2010;Kolb and Gibb, 2010;Richards et al., 2012;Freitas et al., 2015; Horiquini- Barbosa and Lachat, 2016). This work includes studies showing that tactile stimulation accelerates visual development both in rat pups and in human infants (Guzzetta et al., 2009), as well as our initial findings showing that optic nerve development is accelerated in rats that were exposed to neonatal TS (Horiquini- Barbosa and Lachat, 2016). ...
... 3 Therefore, it is essential that the environmental stimuli be provided in the initial weeks after birth. 4,5 Environmental enrichment (EE) is a type of stimulation that can alter the levels of some neurotransmitters and result in morphologic alterations in the central nervous system (CNS). This experimental model has been widely used to investigate the influence of early experiences during brain development. ...
... In the last few years various handling routines enriched environments, and chronic tactile stimulation or body massage have been used with salutary effects on functional neuronal rehabilitation following several types of brain damage including that due to early nutritional deficiencies [25,30,31]. Thus, neonatal tactile stimulation increases the neurogenesis, and the number of dendrites and spines in the hippocampus, amygdala, and the cerebral cortex [32,33]. However, little is known about the effects of the chronic body massage and whether it can restore normal morphology after neuronal alterations associated with the perinatal undernutrition, particularly in the brainstem structures underlying the basic ultrasound vocalization in the rat. ...
... One powerful sensory experience for the developing brain is tactile stimulation (e.g., Field, 2003;Guzzetta et al., 2009). Although few studies have examined the effect on prefrontal cortex, Richards et al. (2012) showed that early tactile stimulation (15 min of light stimulation with a soft brush, 3 times daily for 14 days) improves motor and cognitive functions in adulthood as well as increasing dendritic length and spine density across many forebrain structures, including in both mPFC and OFC. We are unaware of similar studies on adult rats, although Gibb et al. (2010) reported increased dendritic length in the forelimb region of the motor cortex of animals receiving tactile stimulation in adulthood. ...
We review the plastic changes of the prefrontal cortex of the rat in response to a wide range of experiences including sensory and motor experience, gonadal hormones, psychoactive drugs, learning tasks, stress, social experience, metaplastic experiences, and brain injury. Our focus is on synaptic changes (dendritic morphology and spine density) in pyramidal neurons and the relationship to behavioral changes. The most general conclusion we can reach is that the prefrontal cortex is extremely plastic and that the medial and orbital prefrontal regions frequently respond very differently to the same experience in the same brain and the rules that govern prefrontal plasticity appear to differ for those of other cortical regions.
... In California mice (Peromyscus californicus)‚ paternal grooming promotes the development of novel object recognition (Bredy et al. 2004) and a recent study showed that paternal licking is critical to the survival and physical and behavioral development of young rodents in prairie voles (Microtus ochrogaster) (Betty McGuire et al. 2014). Artificial licking-like tactile stimulation provided to rat pups reduces behavioral indices of anxiety, improves social learning and increases curiosity and problem solving abilities (Gonzalez et al. 2001;Richards et al. 2012) and when provided to mandarin voles it increases body weight, sociability and novel object recognition and decreases anxiety-like behavior (Wei et al. 2013). Paternal licking and grooming is an important measure of overall paternal behavior and it confirms that using it to distinguish males that provide high-quality and low-quality paternal care is appropriate. ...
In monogamous mammals paternal care plays an important role in the neural and behavioral development of offspring. However, the neuroendocrine mechanisms underlying paternal behavior remain poorly understood. Here, we investigate the association between natural variation in paternal responsiveness and central levels of oxytocin (OT) and estrogen receptor alpha (ERα). We used the frequency of licking and grooming behavior to distinguish low paternal responsiveness and high paternal responsiveness in virgin mandarin voles (Microtus mandarinus). Males that engaged in high paternal behavior had elevated levels of OT immunoreactive neurons in the paraventricular nuclei of the hypothalamus and supraoptic nuclei of the hypothalamus compared with males that displayed low paternal behavior. Likewise, males of high paternal responsiveness had more ERα immunoreactive neurons in the medial preoptic area, bed nucleus of the stria terminalis, arcuate nucleus of the hypothalamus and medial amygdaloid nucleus compared to low responsive males. The level of ERα immunoreactive neurons in the ventromedial hypothalamic nucleus was lower in highly paternal males compared to less paternal males. These results suggest that natural variation in paternal responsiveness may be directly related to variation in central OT and ERα.
... The newborn human infant is almost continuously exposed to mechanical skin stimulation, whether it is through maternal contact, wrapping or spontaneous twitching and there is increasing evidence that this tactile input plays an important role in the growth and development of the brain (1,2). Furthermore, the excessive handling and skin breaking procedures experienced by preterm infants in neonatal intensive care are correlated with delayed cortical development (3). ...
AimDespite the importance of neonatal skin stimulation, little is known about activation of the newborn human infant brain by sensory stimulation of the skin. We carried out functional magnetic resonance imaging (fMRI) to assess the feasibility of measuring brain activation to a range of mechanical stimuli applied to the skin of neonatal infants.Methods
We studied 19 term infants with a mean age of 13 days. Brain activation was measured in response to brushing, von Frey hair (vFh) punctate stimulation and, in one case, non-tissue damaging pinprick stimulation of the plantar surface of the foot. Initial whole brain analysis was followed by region of interest analysis of specific brain areas.ResultsDistinct patterns of functional brain activation were evoked by brush and vFh punctate stimulation, which were reduced, but still present, under chloral hydrate sedation. Brain activation increased with increasing stimulus intensity. The feasibility of using pinprick stimulation in fMRI studies was established in one unsedated healthy full term infant.Conclusion
Distinct brain activity patterns can be measured in response to different modalities and intensities of skin sensory stimulation in term infants. This indicates the potential for fMRI studies in exploring tactile and nociceptive processing in the infant brain.This article is protected by copyright. All rights reserved.
... So far, we do not know the exact molecular mechanism involved in the beneficial effects of TS on the addiction parameters, as observed in this study, but some hypotheses described in the literature can be considered here: i) Neonatal handling has shown beneficial changes in the functionality of the hypothalamic–pituitary–adrenal (HPA) axis (Levine, 1957) and so, their adaptation to novel and/or stressful stimuli can be significantly increased (Meaney et al., 1991); ii) experimental studies showed that neonatal handling can increase the glucocorticoid receptor density in different brain areas (O'Donnell et al., 1994; Stamatakis et al., 2008 ), indicating that the HPA axis feedback to glucocorticoids can be enhanced, affording better response against stressful situations (Pham et al., 1997 ). Thus, TS may be considered a form of prevention against HPA axis imbalance caused by common stress situations later in life; iii) an increased production of the fibroblast growth factor-2 (FGF-2) in both skin and brain was associated with TS (Richards et al., 2012), which would likely contribute to higher cortical plasticity, playing a key role for TS effects; iv) as TS animals show less signs of withdrawal, the lower CPP in these animals could be explained by development of resistance to an AMPH withdrawal-induced CPP. While behavioral changes have been related to emotional stress (Boufleur et al., 2013) and increased monoamine metabolism, AMPH administration is also related to increased generation of reactive species (RS) from increased release of monoamines, which are available for oxidation (Brown and Yamamoto, 2003; Gluck et al., 2001; Frey et al., 2006). ...
Alzheimer's disease (AD) is associated with cerebral plaques and tangles, reduced synapse number, and shrinkage in several brain areas and these morphological effects are associated with the onset of compromised cognitive, motor, and anxiety-like behaviours. The appearance of both anatomical and behavioural symptoms is worsened by stress. The focus of this study was to examine the effect of neonatal tactile stimulation on AD-like behavioural and neurological symptoms on APP NL-G-F/NL-G-F mice, a mouse model of AD, who have been gestationally stressed. Our findings indicate that neonatal tactile stimulation improves cognition, motor skills, and anxiety-like symptoms in both gestationally stressed and non-stressed adult APP mice and that these alterations are associated with reduced Aβ plaque formation. Thus, tactile stimulation appears to be a promising non-invasive preventative strategy for slowing the onset of dementia in aging animals.
After large neocortical lesions, such as hemidecortication, children can show significant motor and cognitive impairments. It thus is of considerable interest to identify treatments that might enhance long-term functional outcome. We have previously shown that tactile stimulation enhances recovery from perinatal focal cortical lesions in rats, so the goal of the present experiment was to explore the effectiveness of postlesion tactile stimulation in reducing functional deficits associated with neonatal hemidecortication. Rats were given hemidecortications on postnatal day 10 (P10). Half of the group was then exposed to a daily tactile stimulation treatment for 15minutes, three times a day for eleven days following the surgery. All groups were then tested on a number of behavioural tasks (Morris water task, skilled reaching, forelimb placing during spontaneous vertical exploration, and a sunflower seed opening task) beginning at P 120. The brains of the male animals were prepared for Golgi-Cox staining and subsequent analysis of dendritic arborisation and spine density. There were two main findings in this experiment: 1) Tactile stimulation improved cognitive ability and some motor performance after P 10 hemidecortication; and, 2) Tactile stimulation altered cortical organization after P10 hemidecortication. Tactile stimulation may provide an important noninvasive therapy after hemispherectomy in children.
This review discusses the long-term effects of early-life environment on epileptogenesis, epilepsy, and neuropsychiatric comorbidities with an emphasis on the absence epilepsy. The WAG/Rij rat strain is a well-validated genetic model of absence epilepsy with mild depression-like (dysthymia) comorbidity. Although pathologic phenotype in WAG/Rij rats is genetically determined, convincing evidence presented in this review suggests that the absence epilepsy and depression-like comorbidity in WAG/Rij rats may be governed by early-life events, such as prenatal drug exposure, early-life stress, neonatal maternal separation, neonatal handling, maternal care, environmental enrichment, neonatal sensory impairments, neonatal tactile stimulation, and maternal diet. The data, as presented here, indicate that some early environmental events can promote and accelerate the development of absence seizures and their neuropsychiatric comorbidities, while others may exert anti-epileptogenic and disease-modifying effects. The early environment can lead to phenotypic alterations in offspring due to epigenetic modifications of gene expression, which may have maladaptive consequences or represent a therapeutic value. Targeting DNA methylation with a maternal methyl-enriched diet during the perinatal period appears to be a new preventive epigenetic anti-absence therapy. A number of caveats related to the maternal methyl-enriched diet and prospects for future research are discussed.
Alzheimer's Disease (AD) is one of the largest health crises in the world. There are limited pharmaceutical interventions to treat AD, however, and most of the treatment options are not for cure or prevention, but rather to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation on AD-like symptoms and pathology in APP NL-G-F/NL-G-F mice, a mouse model of AD. The results show that tactile stimulation reduces the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviours and these improvements in behavior are associated with reduced AD pathology in APP mice. Thus, tactile stimulation appears to be a promising non-invasive strategy for slowing the onset of dementia in aging animals. This article is protected by copyright. All rights reserved.
The developing brain is especially sensitive to perturbations such as hypoxia-ischemia (HI) or surgical ablation in the perinatal period. We first review and contrast the effects perinatal HI and surgical perturbation in laboratory rats. The developing brain is also very responsive to a wide range of other experiences that can induce remarkable neural plasticity in both the normal and perinatally injured brain. We next review the factors that influence this plasticity in both the normal and perinatal injured. We consider treatments that stimulate cerebral and behavioural plasticity, especially in the motor systems. The goal is to draw attention to possible treatments that could be translated from perinatal surgical ablation to the HI model and eventually to the clinic.
Alterations in somatosensory (touch and pain) behaviors are highly prevalent among people with autism spectrum disorders (ASDs). However, the neural mechanisms underlying abnormal touch and pain-related behaviors in ASDs and how altered somatosensory reactivity might contribute to ASD pathogenesis has not been well studied. Here, we provide a brief review of somatosensory alterations observed in people with ASDs and recent evidence from animal models that implicates peripheral neurons as a locus of dysfunction for somatosensory abnormalities in ASDs. Lastly, we describe current efforts to understand how altered peripheral sensory neuron dysfunction may impact brain development and complex behaviors in ASD models, and whether targeting peripheral somatosensory neurons to improve their function might also improve related ASD phenotypes.
Iron is the most common micronutrient deficiency in the world and it is most prevalent in young children, exposing their developing brain to inadequate iron levels. The damage related to neuroanatomical parameters is not reversed after iron treatment. However, evidence suggest that tactile stimulation (TS) may offer great therapeutic efficacy in cases of nutritional disorders postnatally, since the brain is remarkably responsive to its interaction with the environment. Recently, we shown that neonatal iron deficient rats achieved some remedial effect by exposing them to TS treatment early in life, reinforcing the fact that the TS approach is a positive enriching experience, therefore, here we ask whether exposure to TS treatment, could also be employed to prevent fine structural changes in the fibers from optic nerve of rats maintained on an iron-deficient diet during brain development. To elucidate the protective effect of tactile stimulation, our methods resulted in 10859 analyzed fibers, divided into small and large fibers. We found that iron deficiency led to a decreased axon, fiber and myelin size of small fibers, however, TS completely reversed the iron-decifiency-induced alteration on those fiber measurements. Large fibers were disproportionately affected by iron deficiency and there was no remediating effect due to tactile stimulation treatment. The present study adds new information regarding different alterations between small and large fibers due to diet and TS, which suggest a size-based selectivity. These results emphasize the concept that compromised brain development can be mitigated at an early age by environmental factors, such as tactile stimulation.
In the last decade much progress has been made in research using animal models of developmental psychopathology. The field has moved from the demonstration of long-term impacts of early adversity on behavioral and physiological development and the role of genetic risks for vulnerability, to including transgenerational transmission of stress-induced phenotypes through epigenetic modifications. Additional and critical paradigm shifts have also taken place, including increased focus on ecologically and ethologically valid animal models, research on resilience, the adolescent transition as a period of brain and behavioral reorganization, and sex differences. In this chapter we review recent literature using rodent and nonhuman primate animal models that examines the biological mechanisms through which the early environment programs neurobehavioral, cognitive, and physiological development. We discuss the evolutionary role of this plasticity on behavioral development, as it has an adaptive value in changing environments. Because of maternal care's critical role in early environment, we focus on models that study the effects of mother–infant relationship disruption and dissect the mechanisms by which maternal care regulates the development of brain circuits that control emotional and social behaviors of relevance for developmental psychopathology. Finally, we discuss developmental sensitive/critical periods as windows of opportunity for plastic adaptation of developing organisms to the environment that, if taken too far—as in the case of early traumatic experiences such as childhood maltreatment—lead to maladaptive developmental trajectories (psychopathology, pathophysiology). Animal models of early life adversity are paramount to understand the basic mechanisms and principles that translate early experience into developmental outcomes in our own species.
Recent studies have shown that tactile stimulation (TS) in pups is able to prevent and/or minimize fear, anxiety behaviors, and addiction to psychostimulant drugs in adult rats. In these studies, animals have been exposed to handling from postnatal day (PND) 1 to 21. The present study was designed to precisely establish which period of preweaning development has a greater influence of TS on neuronal development. After birth, male pups were exposed to TS from PND1 to 7, PND8 to 14, and PND15 to 21. In adulthood, the different periods of postnatal TS were assessed through behavioral, biochemical and molecular assessments. Animals that received TS from PND8-14 showed lower anxiety-like symptoms, as observed by decreased anxiety index in elevated plus maze. This same TS period was able to improve rats' working memory by increasing the percentage of alternation rate in Y-maze, and induce better ability to cope with stressful situations, as showed in the defensive burying test by a reduced time of burying behavior. On the other hand, animals receiving TS in the first week of life showed longest cumulative burying time, which is directly related to increased anxiety-like behavior. Moreover, TS from PND8-14 showed lower corticosterone levels and better oxidative status, as observed by decreased lipid peroxidation and increased catalase activity in the hippocampus. Brain-derived neurotrophic factor (BDNF) immunocontent was increased in the hippocampus of animals receiving TS from PND8-14, while glucocorticoid receptors immunocontent was decreased in both TS1-7 and TS15-21, but not TS8-14. To the best of our knowledge, this study is the first to show TS can be more efficient if applied over a focused period of neonatal development (PND8-14) and this beneficial influence can be reflected on reduced emotionality and increased ability to address stressful situations in adulthood. This article is protected by copyright. All rights reserved.
It is well known that events which occur in early life exert a significant influence on brain development, what can be reflected throughout adulthood. This study was carried out in order to assess the influence of neonatal tactile stimulation (TS) on behavioral and morphological responses related to depression-like and anxiety-like behaviors, assessed following the administration of sertraline (SERT), a selective serotonin re-uptake inhibitor (SSRI). Male pups were submitted to daily TS, from postnatal day 8 (PND8) to postnatal day 14 (PND14), for 10 min every day. On PND50, adult animals were submitted to forced swimming training (15. min). On PND51, half of each experimental group (UH and TS) received a single sub-therapeutic dose of sertraline (SER, 0.3. mg/kg body weight, i.p.) or its vehicle (C, control group). Thirty minutes after injection, depression-like behaviors were quantified in forced swimming test (FST, for 5 min). On the following day, anxiety-like behaviors were assessed in elevated plus maze (EPM), followed by biochemical assessments. TS per se increased swimming time, decreasing immobility time in FST. Besides, TS per se was able to increase frequency of head dipping and time spent in the open arms of EPM, resulting in decreased anxiety index. In addition, groups exposed to TS showed decreased plasma levels of corticosterone per se. Interestingly, while TS exposure significantly potentiated the antidepressant activity of a subtherapeutic dose of SERT, this drug was able to exacerbate TS-induced anxiolytic activity, as observed in FST and EPM, respectively. Decreased plasma levels of both corticosterone and cortisol in animals exposed to TS and treated with SERT are able to confirm the interesting interaction between this neonatal handling and the antidepressant drug. From our results, we conclude that neonatal TS is able to exert beneficial influence on the ability to cope with stressful situations in adulthood, preventing depression and favorably modulating the action of antidepressant drugs.
Objectives:
This study aimed to compare the effects of environmental enrichment in nourished (on a diet containing 16% protein) and malnourished (on a diet containing 6% protein) rats during the critical period of brain development, specifically focusing on the optic nerve.
Methods:
By means of morphologic and morphometric assessment of the optic nerve, we analyzed the changes caused by diet and stimulation (environmental enrichment) on postnatal day 35, a time point ideal for such morphological analysis since developmental processes are considered complete at this age.
Results:
Malnourished animals presented low body and brain weights and high body-to-brain weight ratio compared to well-nourished rats. Furthermore, malnourished animals showed morphological changes in the optic nerve such as edema and vacuolization characterized by increased interstitial space. The malnourished-stimulated group presented lesions characteristic of early protein malnutrition but were milder than lesions exhibited by malnourished-non-stimulated group. The morphometric analysis revealed no difference in glial cell density between groups, but there was significantly higher blood vessel density in the stimulated rats, independent of their nutritional condition.
Discussion:
Our data indicate that protein malnutrition imposed during the critical period of brain development alters the cytoarchitecture of the optic nerve. In addition, we affirm that a 1-hour exposure to an enriched environment everyday was sufficient for tissue preservation in rats maintained on a low-protein diet. This protective effect might be related to angiogenesis, as confirmed by the increased vascular density observed in morphometric analyses.
Prenatal stress (PS) can produce profound and long-lasting perturbations of individual adaptive capacities, which in turn can result in an increased proneness to behavioural disorders. Indeed, in PS rats there is evidence of impaired social play behaviour, disturbances in a variety of circadian rhythms, enhanced anxiety and increased hypothalamic-pituitary-adrenal (HPA) axis reactivity. This study was designed to experimentally investigate the degree of reversibility of PS-induced disturbances of social play and HPA reactivity by assessing the effect of the enrichment of the physical environment on PS rats during periadolescence. PS subjects showed a reduced expression of social play behaviour and a prolonged corticosterone secretion in response to restraint stress, but both these effects were markedly reversed following environmental enrichment. Interestingly, the enrichment procedure increased social behaviour but had no effect on corticosterone secretion in nonstressed animals, indicating a differential impact of the postnatal environment as a function of prenatal background. As a whole, results clearly indicate that rats prenatally exposed to stress can benefit during periadolescence from the modulatory effects of an enriched environment. Moreover, they confirm that PS may well represent a suitable animal model for the design and testing of new therapeutic strategies for behavioural disorders produced by early insults.
Sensitive Periods in Sensory-System Development: Experience-expectant Information Storage Experience-dependent Information Storage in Later Development and Adulthood Some Cautionary Notes Brain Adaptation to Experience: an Update
In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.
The birth of neurons, their migration to appropriate positions in the brain, and their establishment of the proper synaptic contacts happen predominately during the prenatal period. Environmental stressors during gestation can exert a major impact on brain development and thereby contribute to the pathogenesis of neuropsychiatric illnesses, such as depression and psychotic disorders including schizophrenia.
The objectives here are to present recent preclinical studies of the impact of prenatal exposure to gestational stressors on the developing fetal brain and discuss their relevance to the neurobiological basis of mental illness. The focus is on maternal immune activation, psychological stresses, and malnutrition, due to the abundant clinical literature supporting their role in the etiology of neuropsychiatric illnesses.
Prenatal maternal immune activation, viral infection, unpredictable psychological stress, and malnutrition all appear to foster the development of behavioral abnormalities in exposed offspring that may be relevant to the symptom domains of schizophrenia and psychosis, including sensorimotor gating, information processing, cognition, social function, and subcortical hyperdopaminergia. Depression-related phenotypes, such as learned helplessness or anxiety, are also observed in some model systems. These changes appear to be mediated by the presence of proinflammatory cytokines and/or corticosteroids in the fetal compartment that alter the development the neuroanatomical substrates involved in these behaviors.
Prenatal exposure to environmental stressors alters the trajectory of brain development and can be used to generate animal preparations that may be informative in understanding the pathophysiological processes involved in several human neuropsychiatric disorders.
Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1.
Developmentally regulated plasticity of vision has generally been associated with "sensitive" or "critical" periods in juvenile life, wherein visual deprivation leads to loss of visual function. Here we report an enabling form of visual plasticity that commences in infant rats from eye opening, in which daily threshold testing of optokinetic tracking, amid otherwise normal visual experience, stimulates enduring, visual cortex-dependent enhancement (>60%) of the spatial frequency threshold for tracking. The perceptual ability to use spatial frequency in discriminating between moving visual stimuli is also improved by the testing experience. The capacity for inducing enhancement is transitory and effectively limited to infancy; however, enhanced responses are not consolidated and maintained unless in-kind testing experience continues uninterrupted into juvenile life. The data show that selective visual experience from infancy can alone enable visual function. They also indicate that plasticity associated with visual deprivation may not be the only cause of developmental visual dysfunction, because we found that experientially inducing enhancement in late infancy, without subsequent reinforcement of the experience in early juvenile life, can lead to enduring loss of function.
This article considers how experience can influence the developing and mature brain and proposes a new categorization scheme based upon the type of information stored and the brain mechanisms that appear to be involved in storing it. In this scheme, experience-expectant information storage refers to incorporation of environmental information that is ubiquitous in the environment and common to all species members, such as the basic elements of pattern perception. Experience-expectant processes appear to have evolved as a neural preparation for incorporating specific information: in many sensory systems, synaptic connections between nerve cells are overproduced, and a subsequent selection process occurs in which aspects of sensory experience determine the pattern of connections that remains. Experience-dependent information storage refers to incorporation of environmental information that is idiosyncratic, or unique to the individual, such as learning about one's specific physical environment or vocabulary. The neural basis of experience-dependent processes appears to involve active formation of new synaptic connections in response to the events providing the information to be stored. Although these processes probably do not occur entirely independently of one another in development, the categories offer a new view more in accord with neural mechanisms than were terms like "critical" or "sensitive period."
The adrenal glucocorticoids and catecholamines comprise a frontline of defense for mammalian species under conditions which threaten homeostasis (conditions commonly referred to as stress). Glucocorticoids represent the end product of the hypothalamic-pituitary-adrenal (HPA) axis and along with the catecholamines serve to mobilize the production and distribution of energy substrates during stress. The increased secretion of pituitary-adrenal hormones in response to stress is stimulated by the release of corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) from neurons in the nucleus paraventricularis. In this way, a neural signal associated with the stressor is transduced into a set of endocrine and sympathetic responses. The development of the HPA response to stressful stimuli is altered by early environmental events. Animals exposed to short periods of infantile stimulation or handling show decreased HPA responsivity to stress, whereas maternal separation, physical trauma and endotoxin administration enhance HPA responsivity to stress. In all cases, these effects persist throughout the life of the animal and are accompanied by increased hypothalamic levels of the mRNAs for CRH and often AVP. The inhibitory regulation of the synthesis for these ACTH releasing factors is achieved, in part, through a negative feedback loop whereby circulating glucocorticoids act at various neural sites to decrease CRH and AVP gene expression. Such inhibitory effects are initiated via an interaction between the adrenal steroid and an intracellular receptor (either the mineralocorticoid or glucocorticoid receptor). We have found that these early environmental manipulations regulate glucocorticoid receptor gene expression in the hippocampus and frontal cortex, regions that have been strongly implicated as sites for negative-feedback regulation of CRH and AVP synthesis. When the differences in glucocorticoid receptor density are transiently reversed, so too are those in HPA responses to stress. Taken together, our findings indicate that the early postnatal environment alters the differentiation of hippocampal neurons. This effect involves an altered rate of glucocorticoid receptor gene expression, resulting in changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and AVP in hypothalamic neurons. Changes in CRH and AVP levels, in turn, determine the responsivity of the axis to subsequent stressors; increased releasing factor production is associated with increased HPA responses to stress. Thus, the early environment can contribute substantially to the development of stable individual differences in HPA responsivity to stressful stimuli. These data provide examples of early environmental programming of neural systems. One major objective of our research is to understand how such programming occurs within the brain.
The mothers of infant rats show individual differences in the frequency of licking/grooming and arched-back nursing (LG-ABN) of pups that contribute to the development of individual differences in behavioral responses to stress. As adults, the offspring of mothers that exhibited high levels of LG-ABN showed substantially reduced behavioral fearfulness in response to novelty compared with the offspring of low LG-ABN mothers. In addition, the adult offspring of the high LG-ABN mothers showed significantly (i) increased central benzodiazepine receptor density in the central, lateral, and basolateral nuclei of the amygdala as well as in the locus ceruleus, (ii) increased alpha2 adrenoreceptor density in the locus ceruleus, and (iii) decreased corticotropin-releasing hormone (CRH) receptor density in the locus ceruleus. The expression of fear and anxiety is regulated by a neural circuitry that includes the activation of ascending noradrenergic projections from the locus ceruleus to the forebrain structures. Considering the importance of the amygdala, notably the anxiogenic influence of CRH projections from the amygdala to the locus ceruleus, as well as the anxiolytic actions of benzodiazepines, for the expression of behavioral responses to stress, these findings suggest that maternal care during infancy serves to "program" behavioral responses to stress in the offspring by altering the development of the neural systems that mediate fearfulness.
The present study investigated the roles of the perirhinal cortex, medial prefrontal cortex, and intrahemispheric interactions between them in recognition and temporal order memory for objects. Experiment 1 assessed the effects of bilateral microinfusions of the sodium channel blocker lidocaine into either the anterior perirhinal or medial prefrontal cortex immediately before memory testing in a familiarity discrimination task and a recency discrimination task, both of which involved spontaneous exploration of objects. Inactivation of the perirhinal cortex disrupted performance in both tasks, whereas inactivation of the medial prefrontal cortex disrupted performance in the recency, but not the familiarity, discrimination task. In a second experiment, the importance of intrahemispheric interactions between these structures in temporal order memory were assessed by comparing the effects of unilateral inactivation of either structure alone with those of crossed unilateral inactivation of both structures on the recency discrimination task. Crossed unilateral inactivation of both structures produced a significant impairment, whereas inactivation of either structure alone produced little or no impairment. Collectively, these findings suggest that the perirhinal cortex, but not the medial prefrontal cortex, contributes to retrieval of information necessary for long-term object recognition, whereas both structures, via intrahemispheric interactions between them, contribute to retrieval of information necessary for long-term object temporal order memory. These data are consistent with models in which attributed information is stored in posterior cortical sites and supports lower-order mnemonic functions (e.g., recognition memory) but can also be retrieved and further processed via interactions with the prefrontal cortex to support higher-order mnemonic functions (e.g., temporal order memory).
Both chronic stress in adulthood and episodes of stress in the early postnatal period have been shown to interfere with neuronal development in limbic prefrontal cortical regions. The present study in rats showed for the first time that the development of layer II/III pyramidal neurons in the dorsal anterior cingulate (ACd) and orbitofrontal cortex (OFC) is significantly affected in offspring of mothers exposed to stress during pregnancy. In prenatally stressed (PS) male rat pups the ACd and OFC showed significantly lower spine densities on the apical dendrite (ACd, -20%; OFC, -25%), on basal dendrites reduced spine densities where found only in the OFC (-20% in PS males). Moreover, in both cortical areas a significant reduction of dendritic length was observed in PS males compared to control offspring, which was confined to the apical dendrites (ACd, -30%, OFC, -26%). Sholl analysis revealed that these alterations were accompanied by a significantly reduced complexity of the dendritic trees in both cortical regions. PS females displayed reductions of dendritic spine densities in the ACd and OFC on both the basal (ACd, -21%; OFC, -20%) and apical dendrites (ACd, -21%; OFC, -21%), however, in contrast to the findings in PS males, no dendritic atrophy was detected in the PS females. These findings demonstrate that gestational stress leads to significant alterations of prefrontal neuronal structure in the offspring of the stressed mothers in a sex-specific manner.
Environmental enrichment has been shown to have profound effects on the healthy adult brain and as a remedial tool for brains compromised by injury, disease, or negative experience. Based upon these findings and evidence from the prenatal stress literature, we ventured an exploratory study to examine the effects of parental enrichment on offspring development. Using Long Evans rats, paternal enrichment was achieved by housing sires in enriched environments for 28 days prior to mating with a control female. For the maternal enrichment paradigm, female rats were also housed in enriched environments for 28 days (7 days prior to conception and for the duration of pregnancy). Increased size, multiple levels for exploration, an abundance of stimulating toys, and numerous cagemates for social interaction were characteristic of the enriched environments. Offspring were assessed using two early behavioral tests and then sacrificed at postnatal day 21 (P21). Brain tissue from the frontal cortex and hippocampus was harvested for global DNA methylation analysis. Parental enrichment, preconceptionally and prena-tally, altered offspring behavior on the negative geotaxis task and openfield exploratory behavior task. Paternal enrichment significantly decreased offspring brain weight at P21. Additionally, both environmental enrichment paradigms significantly decreased global methylation levels in the hippocampus and frontal cortex of male and female offspring. This study demonstrates that positive prenatal experiences; preconceptionally in fathers and prenatally in mothers, have the ability to significantly alter offspring developmental trajectories.
it would be difficult to disentangle all of the factors that could contribute to variability in the gross size of the human corpus callosum, but it is not surprising that the cortical anatomy of the human is variable / even in the rat (a species with a "simpler" cortex that most would agree could be less plastic in response to the environment than the human cortex), the anatomy of the cerebral cortex varies not only with gender but also with the complexity of the rearing environment
both gender and environmentally induced alterations in cortical structure in the rat are examined here (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The experience of peer play during the juvenile phase in rats is known to be important for the devel-opment of adult social competence. Adult social competence is also compromised by damage to the orbitofrontal cortex (OFC), an area known to be involved in social behavior. We therefore hypothesized that the functioning of the OFC in social behavior is facilitated through the experience of peer play dur-ing the juvenile period. Further, because the OFC and medial prefrontal cortex (mPFC) are known to be reciprocally responsive to a variety of manipulations, we suspected that the functioning of the mPFC is also responsive to the experience of peer play during development. Female Long-Evans rats were raised in conditions that varied with respect to the experience of peer play, and Golgi techniques were used to examine the neuronal morphology of the OFC and mPFC. The results indicated that the neurons of the OFC responded to the number of peers present, not whether those peers engaged in play or not, whereas the neurons of the mPFC responded specifically to the experience of play.
Environmental enrichment has been shown to have profound effects on the healthy adult brain and as a remedial tool for brains compromised by injury, disease, or negative experience. Based upon these findings and evidence from the prenatal stress literature, we ventured an exploratory study to examine the effects of parental enrichment on offspring development. Using Long Evans rats, paternal enrichment was achieved by housing sires in enriched environments for 28 days prior to mating with a control female. For the maternal enrichment paradigm, female rats were also housed in enriched environments for 28 days (7 days prior to conception and for the duration of pregnancy). Increased size, multiple levels for exploration, an abundance of stimulating toys, and numerous cagemates for social interaction were characteristic of the enriched environments. Offspring were assessed using two early behavioral tests and then sacrificed at postnatal day 21 (P21). Brain tissue from the frontal cortex and hippocampus was harvested for global DNA methylation analysis. Parental enrichment, preconceptionally and prenatally, altered offspring behavior on the negative geotaxis task and openfield exploratory behavior task. Paternal enrichment significantly decreased offspring brain weight at P21. Additionally, both environmental enrichment paradigms significantly decreased global methylation levels in the hippocampus and frontal cortex of male and female offspring. This study demonstrates that positive prenatal experiences; preconceptionally in fathers and prenatally in mothers, have the ability to significantly alter offspring developmental trajectories.
This is the second of a 2-part series to provide an overview of our current level of knowledge related to nonpharmacological strategies to diminish the pain associated with commonly performed procedures in the NICU. In our first article we discussed the prevalence of repeated pain exposure in the NICU and the importance of nonpharmacological strategies specifically containment or facilitated tucking, swaddling, positioning, nonnutritive sucking, and sweet solutions. These strategies are generally nurse-driven and we believe their importance has been underutilized. In this article we will emphasize the importance of maternal presence as a mediator for pain relief. The efficacy of breastfeeding, maternal skin-to-skin care (often referred to as kangaroo care), and multisensorial stimulation such as auditory and olfactory recognition will be the primary focus of our discussion. In addition, although primarily mother-driven, these strategies are ultimately nurse-enabled, thus the importance of this connection cannot be under appreciated with respect to successful implementation in the NICU.
The current study used stereological techniques in combination with Golg-Cox methods to examine the neuroanatomical alterations in the prefrontal cortex and hippocampus of developing offspring exposed to gestational stress. Morphological changes in dendritic branching, length, and spine density, were examined at weaning along with changes in actual numbers of neurons. Using this information we generated a gross estimation of synaptic connectivity. The results showed region-specific and sex-dependent alterations to neuroanatomy in response to prenatal stress. The two regions of the prefrontal cortex, medial prefrontal, and orbital prefrontal cortices, exhibited sexually dimorphic, opposite changes, in synaptic connectivity in response to the same experience. Both male and female offspring demonstrated a loss of neuron number and estimated synapse number in the hippocampus despite exhibiting increased spine density. The results from this study suggest that prenatal stress alters normal development and the organization of neuronal circuits in both neocortex and hippocampus early in development and thus likely influences the course of later experience-dependent synaptic changes.
Neonates who are born preterm and are admitted to neonatal intensive care units endure frequent procedures that may be painful. Nonpharmacological interventions that have been studied to relieve their pain may be categorized in 2 main groups according to their nature: interventions that focus on creating a favorable environment and offering pleasant sensorial stimuli and interventions that are centered on maternal care. These interventions may be considered within the philosophy of developmental care, since they are aimed at adjusting the environment to the needs of the neonate and involve family-centered care. In this article, the first of a 2-part series, we will synthesize the evidence from experimental studies of interventions that focus on the environment and on tactile and gustatory stimulation. The mechanisms suggested by researchers as possible explanations for the efficacy of these interventions are pointed, and the implications for procedural pain management in neonatal care are drawn.
Although the critical role of maternal care on the development of brain and behaviour of the offspring has been extensively studied, knowledge about the importance of paternal care is comparatively scarce. In biparental species, paternal care significantly contributes to a stimulating socio-emotional family environment, which most likely also includes protection from stressful events. In the biparental caviomorph rodent Octodon degus, we analysed the impact of paternal care on the development of neurones in prefrontal-limbic brain regions, which express corticotrophin-releasing factor (CRF). CRF is a polypeptidergic hormone that is expressed and released by a neuronal subpopulation in the brain, and which not only is essential for regulating stress and emotionality, but also is critically involved in cognitive functions. At weaning age [postnatal day (P)21], paternal deprivation resulted in an elevated density of CRF-containing neurones in the orbitofrontal cortex and in the basolateral amygdala of male degus, whereas a reduced density of CRF-expressing neurones was measured in the dentate gyrus and stratum pyramidale of the hippocampal CA1 region at this age. With the exception of the CA1 region, the deprivation-induced changes were no longer evident in adulthood (P90), which suggests a transient change that, in later life, might be normalised by other socio-emotional experience. The central amygdala, characterised by dense clusters of CRF-immunopositive neuropil, and the precentral medial, anterior cingulate, infralimbic and prelimbic cortices, were not affected by paternal deprivation. Taken together, this is the first evidence that paternal care interferes with the developmental expression pattern of CRF-expressing interneurones in an age- and region-specific manner.
Maternal stress during gestation in humans and experimental animals can result in emotional and cognitive dysfunction in the offspring. To facilitate our understanding of the underlying neuronal changes induced by prenatal stress (PNS), the dendritic and synaptic development was analyzed in three-dimensionally reconstructed Golgi-impregnated neurons in the hippocampal formation of offspring from pregnant dams which were stressed from day 15-20 by varied stressors. The analysis was focused on prepubertal rats and on the comparison of stress vulnerabilities in male and female offspring. In the hippocampal CA1 region PNS increased spine density on pyramidal neurons only in males, which thereby reached the levels observed in control females. On granular neurons of the dentate gyrus, PNS altered spine-density, dendritic length and dendritic complexity in opposite directions in males and females. In the CA3 area, PNS resulted in shorter and less complex dendrites in both sexes compared with unstressed controls. Another aim was to assess whether neonatal environmental interventions, such as handling (H) during the first 10 postnatal days, can reverse PNS-induced neuronal changes. We show here for the first time that H can "reverse" or prevent PNS-induced changes in spine density and dendritic length and complexity in a sex-, region- and dendrite-specific manner. These findings indicate that the sex-specific changes of neuronal and synaptic features in the hippocampal formation may represent a neuronal substrate of the stress-induced behavioral alterations and that these changes can be partly "normalized" by neonatal interventions.
A method for impregnating the whole rat brain with Golgi-Cox stain and sectioning with the vibratome is described. The method is simple, inexpensive and provides good resolution of dendrites and spines.
Maternal stress experience is associated with neurodevelopmental disorders including schizophrenia and autism. Recent studies have examined mechanisms by which changes in the maternal milieu may be transmitted to the developing embryo and potentially translated into programming of the epigenome. Animal models of prenatal stress have identified important sex- and temporal-specific effects on offspring stress responsivity. As dysregulation of stress pathways is a common feature in most neuropsychiatric diseases, molecular and epigenetic analyses at the maternal-embryo interface, especially in the placenta, may provide unique insight into identifying much-needed predictive biomarkers. In addition, as most neurodevelopmental disorders present with a sex bias, examination of sex differences in the inheritance of phenotypic outcomes may pinpoint gene targets and specific windows of vulnerability in neurodevelopment, which have been disrupted. This review discusses the association and possible contributing mechanisms of prenatal stress in programming offspring stress pathway dysregulation and the importance of sex.
Based on the findings of postnatal tactile stimulation (TS), a favorable experience in rats, the present study examined the influence of prenatal TS on juvenile behavior, adult amphetamine (AMPH) sensitization, and structural alteration in the prefrontal cortex (PFC) and the striatum. Female rats received TS through a baby hair brush throughout pregnancy, and the pups born were tested for open field locomotion, elevated plus maze (EPM), novel object recognition (NOR), and play fighting behaviors. Development and persistence of drug-induced behavioral sensitization in adults were tested by repeated AMPH administration and a challenge, respectively. Structural plasticity in the brain was assessed from the prefrontal cortical thickness and striatum size from serial coronal sections. The results indicate that TS females showed enhanced exploration in the open field. TS decreased the frequency of playful attacks whereas the response to face or evade an attack was not affected. Anxiety-like behavior and cognitive performance were not influenced by TS. AMPH administration resulted in gradual increase in locomotor activity (i.e., behavioral sensitization) that persisted at least for 2 weeks. However, both male and female TS rats exhibited attenuated AMPH sensitization compared to sex-matched controls. Furthermore, the drug-associated alteration in the prefrontal cortical thickness and striatum size observed in controls were prevented by TS experience. In summary, TS during prenatal development modified juvenile behavior, attenuated drug-induced behavioral sensitization in adulthood, and reorganized brain regions implicated in drug addiction.
Adolescence is a transitional period between childhood and adulthood that encompasses vast changes within brain systems that parallel some, but not all, behavioral changes. Elevations in emotional reactivity and reward processing follow an inverted U shape in terms of onset and remission, with the peak occurring during adolescence. However, cognitive processing follows a more linear course of development. This review will focus on changes within key structures and will highlight the relationships between brain changes and behavior, with evidence spanning from functional magnetic resonance imaging (fMRI) in humans to molecular studies of receptor and signaling factors in animals. Adolescent changes in neuronal substrates will be used to understand how typical and atypical behaviors arise during adolescence. We draw upon clinical and preclinical studies to provide a neural framework for defining adolescence and its role in the transition to adulthood.
This study investigated the effect of postnatal tactile stimulation (TS) on juvenile behavior, adult amphetamine (AMPH) sensitization, and the interaction of TS and AMPH on prefrontal cortical (PFC) thickness and striatum size. Pups received TS by stroking daily with a feather duster from birth till weaning and were tested, as juveniles, in behavioral tasks including open field locomotion, elevated maze, novel object recognition, and play fighting behavior. Development and persistence of drug-induced behavioral sensitization was tested by chronic AMPH administration and challenge, respectively. PFC thickness and striatum size were assessed from serial brain sections. The findings showed that TS rats spent less time with novel objects on first exposure but open field locomotion and elevated plus maze tasks were not affected substantially. TS reduced the frequency of play fighting and enhanced evasion in response to a playful attack, but only in males. The probability of complete rotation defense, leading to a supine posture during play, was reduced in both sexes. AMPH administration resulted in gradual increase in behavioral sensitization that persisted at least for 2 weeks. However, TS rats exhibited attenuated AMPH sensitization compared to sex-matched controls. Neuroanatomically, AMPH reduced the PFC thickness in control females but enlarged the posterior striatum in control males. TS experience blocked these effects. In summary, TS during development modulated the response to novel objects and altered social behaviors and attenuated AMPH-induced behavioral sensitization by preventing drug-induced structural alteration in the PFC and the striatum, brain regions implicated in drug abuse.
Cocaine exposure during pregnancy can impact brain development and have long-term behavioral consequences. The present study examined the lasting consequences of prenatal cocaine (PN-COC) exposure on the performance of cognitive tasks and dendritic spine density in adult male and female rats. From gestational day 8 to 20, dams were treated daily with 30 mg/kg (ip) of cocaine HCl or saline. At 62 days of age, offspring were tested consecutively for anxiety, locomotion, visual memory and spatial memory. PN-COC exposure significantly increased anxiety in both sexes. Object recognition (OR) and placement (OP) tasks were used to assess cognitive function. Behavioral tests consisted of an exploration trial (T1) and a recognition trial (T2) that were separated by an inter-trial delay of varying lengths. Male PN-COC subjects displayed significantly less time investigating new objects or object locations during T2 in both OR and OP tasks. By contrast, female PN-COC subjects exhibited impairments only in OR and only at the longest inter-trial delay interval. In addition, gestational cocaine increased dendritic spine density in the prefrontal cortex and nucleus accumbens in both genders, but only females had increased spine density in the CA1 region of the hippocampus. These data reveal that in-utero exposure to cocaine results in enduring alterations in anxiety, cognitive function and spine density in adulthood. Moreover, cognitive deficits were more profound in males than in females.
The influences of complex housing, T-maze, and Grice box training on dendritic morphology of the prefrontal cortex (PFC) and primary somatosensory (Par 1) were investigated in the rat. Golgi-Cox analyses demonstrated that all learning paradigms produced alterations in PFC connectivity, albeit differently. Furthermore, the effects of experience on dendritic morphology varied by region, hemisphere, and lamina and often resulted in opposing changes within each. For example, complex housing produced a time-dependent decrease in the dendritic fields of layer (L) V neurons in region 3 of the cingulate cortex (Cg3) in the medial PFC (mPFC) neurons and increases in LIII of the dorsal agranular insular (AID) region of the orbitofrontal cortex. In contrast, T-maze training produced increases in Cg3 LV and decreases in AID LIII spine density. Of interest, the influence of experience was not reflected equally between hemispheres. For example, T-maze training produced an increase in Cg3 LV and AID LIII branch order and length in the right hemisphere, and an increase in Cg3 LIII branch order in the left hemisphere. Additionally, correlation analysis of task performance and dendritic morphology indicated an opposing influence of experience within the different laminae of the Cg3. For example, whereas, performance was negatively correlated with Cg3 LV dendritic branch order/length, there was a positive correlation with Cg3 LIII dendrites. Complex housing induced changes in the Par 1were also time -dependent but were only apparent after a prolonged period of exposure. In addition to demonstrating learning-specific modifications in dendritic connectivity within the PFC, the results illustrate varying patterns of change that likely reflect task-dependent requirements on the PFC.