[Show abstract][Hide abstract] ABSTRACT: Stress plays a substantial role in shaping behavior and brain function, often with lasting effects. How these lasting effects occur in the context of a fixed postmitotic neuronal genome has been an enduring question for the field. Synaptic plasticity and neurogenesis have provided some of the answers to this question, and more recently epigenetic mechanisms have come to the fore. The explo-ration of epigenetic mechanisms recently led us to discover that a single acute stress can regulate the expression of retrotransposons in the rat hippocampus via an epigenetic mechanism. We propose that this response may represent a genomic stress response aimed at maintaining genomic and transcriptional stability in vulnerable brain regions such as the hippocampus. This finding and those of other researchers have made clear that retrotransposons and the genomic plasticity they permit play a significant role in brain func-tion during stress and disease. These observations also raise the possibility that the transposome might have adaptive functions at the level of both evolution and the individual organism. hippocampus | retrotransposon | histone marks | brain | genomic stress response T he brain is the central organ of stress and adaptation to stressors because it not only perceives what is threatening or potentially threatening and initiates behavioral and physiological responses to those challenges but also is a target of the stressful experiences and the hormones and other mediators of the stress response (1–4). The neural and hormonal mediators of the stress response affect most of the body's organ systems, and prolonged or severe stressors can have prolonged physiologic and behav-ioral sequelae that can extend throughout the lifespan and be-yond, to leave its imprint on our offspring (2, 5, 6). Short-term activation of stress mediators can be beneficial to cope with challenges, but long-term activation is accompanied by cumula-tive, potentially detrimental effects referred to, with increasing severity, as "allostatic load and overload" (3, 7, 8) Thus, although the brain is the conductor of this neuroendocrine orchestra, it is also shaped in many ways by its music, with both adaptive and pathogenic results (1, 2, 9). Stress has a well-established influence on brain structure, function, and behavior; however "stress" is not a unitary phe-nomenon, nor are its effects upon individuals entirely predictable. The effects of stress upon an individual are dictated by a number of factors: stress duration, severity, controllability, age, and sex have clearly delineated roles in determining the impact of a par-ticular stressor on an individual (10, 11). An individual's stress history also seems to play an important role in the capacity to resist future stress exposures. Surprisingly, at least from the clas-sical Darwinian perspective, the stress history of parents is a sig-nificant factor in the resilience of their offspring (12). The desire to understand how environmental stress transduces its effects into lasting changes on physiology and behavior, which can vary even among genetically identical individuals, has led scientists to hy-pothesize that epigenetic factors might provide an explanatory mechanism (1, 13, 14). The introduction of next-generation se-quencing technologies to the exploration of epigenetics and stress neurobiology has led to greater attention to the possibility that the largely unexplored genomic space represented by retrotrans-posons might also have functional significance for brain function and stress susceptibility (15–17).
Proceedings of the National Academy of Sciences 11/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prenatal brain develops under the influence of an ever-changing hormonal milieu that includes endogenous fetal gonadal and adrenal hormones; placental and maternal hormones; and exogenous substances with hormonal activity that can cross the placental barrier. This review discusses the influences of endogenous fetal and maternal hormones on normal brain development, and potential consequences of pathophysiological hormonal perturbations to the developing brain, with particular reference to autism. We also consider the effects of hormonal pharmaceuticals used for assisted reproduction, the maintenance of pregnancy, the prevention of congenital adrenal hypertrophy, and hormonal contraceptives continued into an unanticipated pregnancy, among others. These treatments, while in some instances life-saving, may have unintended consequences on the developing fetuses. Additional concern is raised by fetal exposures to endocrine-disrupting chemicals (EDCs) encountered universally by pregnant women from food/water containers, contaminated food, household chemicals, and other sources. What are the potential outcomes of prenatal steroid perturbations on neurodevelopmental and behavioral disorders, including autism spectrum disorders? Our purposes here are: (i.) to summarize some consequences of steroid exposures during pregnancy for the development of brain and behavior in the offspring; (ii.) to summarize what is known about the relationships between exposures and behavior, including autism spectrum disorders; (iii.) to discuss the molecular underpinnings of such effects, especially molecular epigenetic mechanisms of prenatal steroid manipulations, a field that may explain effects of direct exposures, and even transgenerational effects; and (iv.) for all of these, to add cautionary notes about their interpretation in the name of scientific rigor.
[Show abstract][Hide abstract] ABSTRACT: Reproduction is an energy-expensive process that relies on indicators of energy availability to adjust its proper functioning. The adipokine leptin provides one such metabolic signal, with leptin receptor-expressing neurons at sites widespread within the CNS, including regions associated with the neuroendocrine reproductive axis. One substantial population lies within the hypothalamic ventral premammillary nucleus (PMv), a region itself linked to reproductive control, which may provide a strategic site for the integration of energy availability, sensory and gonadal cues. Here we review our current understanding of leptin and PMv regulation of reproduction, including emerging details about intracellular mechanisms of leptin action at this site.
Journal of Chemical Neuroanatomy 08/2014; · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: •There are many sex differences in physiology, including in the brain.•There are many sex differences in psychiatric and neurological disorders.•This Special Issue highlights etiologies of sex differences in brain disorders.•We hope this SI will lead to more research of sex differences in brain disorders.
Frontiers in Neuroendocrinology 08/2014; · 7.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report that mice with closed-head multiple traumatic brain injury (TBI) show a decrease in the motoric aspects of generalized arousal, as measured by automated, quantitative behavioral assays. Further, we found that temporally-patterned deep brain stimulation (DBS) can increase generalized arousal and spontaneous motor activity in this mouse model of TBI. This arousal increase is input-pattern-dependent, as changing the temporal pattern of DBS can modulate its effect on motor activity. Finally, an extensive examination of mouse behavioral capacities, looking for deficits in this model of TBI, suggest that the strongest effects of TBI in this model are found in the initiation of any kind of movement.
Behavioural Brain Research 07/2014; · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is not clear how, after a large perturbation, the brain explores the vast space of potential neuronal activity states to recover those compatible with consciousness. Here, we analyze recovery from pharmacologically induced coma to show that neuronal activity en route to consciousness is confined to a low-dimensional subspace. In this subspace, neuronal activity forms discrete metastable states persistent on the scale of minutes. The network of transitions that links these metastable states is structured such that some states form hubs that connect groups of otherwise disconnected states. Although many paths through the network are possible, to ultimately enter the activity state compatible with consciousness, the brain must first pass through these hubs in an orderly fashion. This organization of metastable states, along with dramatic dimensionality reduction, significantly simplifies the task of sampling the parameter space to recover the state consistent with wakefulness on a physiologically relevant timescale.
Proceedings of the National Academy of Sciences 06/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Anabolic-androgenic steroids (AASs) are abused primarily in the context of intense exercise and for the purposes of increasing muscle mass as opposed to drug-induced euphoria. AASs also modulate the HPA axis and may increase the reinforcing value of exercise through changes to stress hormone and endorphin release. To test this hypothesis, 26 adult males drawn from a larger study on AAS use completed a progressive ratio task designed to examine the reinforcing value of exercise relative to financial reinforcer.
Sixteen experienced and current users (8 on-cycle, 8 off-cycle) and 10 controls matched on quantity x frequency of exercise, age, and education abstained from exercise for 24 hours prior to testing and provided 24-hour cortisol, plasma cortisol, ACTH, β-endorphin samples, and measures of mood, compulsive exercise, and body image.
Between group differences indicated that on-cycle AAS users had the highest β-endorphin levels, lowest cortisol levels, higher ACTH levels than controls. Conversely, off-cycle AAS users had the highest cortisol and ACTH levels, but the lowest β-endorphin levels. Exercise value was positively correlated with β-endorphin and symptoms of AAS dependence.
The HPA response to AASs may explain why AASs are reinforcing in humans and exercise may play a key role in the development of AAS dependence.
Drug and Alcohol Dependence 06/2014; · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Research suggests a causal link between estrogens and mood. Here, we began by examining the effects of estradiol (E2) on rat innate and conditioned defensive behaviors in response to cat odor. Second, we utilized whole-cell patch clamp electrophysiological techniques to assess noradrenergic effects on neurons within the dorsal premammillary nucleus of the hypothalamus (PMd), a nucleus implicated in fear reactivity, and their regulation by E2. Our results show that E2 increased general arousal and modified innate defensive reactivity to cat odor. When ovariectomized females treated with E2 as opposed to oil were exposed to cat odor, they showed elevations in risk assessment and reductions in freezing, indicating a shift from passive to active coping. In addition, animals previously exposed to cat odor showed clear cue + context conditioning 24 h later. However, although E2 persisted in its effects on general arousal in the conditioning task, its effects on fear disappeared. In the patch clamp experiments noradrenergic compounds that typically induce fear clearly excited PMd neurons, producing depolarizations and action potentials. E2 treatment shifted some excitatory effects of noradrenergic agonists to inhibitory, possibly by differentially affecting α- and β-adrenoreceptors. In summary, our results implicate E2 in general arousal and fear reactivity, and suggest these may be governed by changes in noradrenergic responsivity in the PMd. These effects of E2 may have ethological relevance, serving to promote mate seeking even in contexts of ambiguous threat and shed light on the involvement of estrogen in mood and its associated disorders.
European Journal of Neuroscience 05/2014; · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The male predominance of autism spectrum disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD's etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.
Frontiers in Neuroendocrinology 04/2014; · 7.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This theoretical paper proposes that underlying the concept of libido is a primitive set of brain mechanisms responsible for the generalized arousal of the central nervous system and the activation of all behavioral responses. Having given the concept of “generalized CNS arousal” an operational definition, we write an equation that describes how specific motivational needs are integrated with generalized arousal to produce an overall state of the CNS sufficient for potentiating behavioral responses. Factor analysis of behavioral data with mice suggests that among all CNS arousal-related influences, generalized arousal contributes about a third of the variance. Many neuroanatomical, neurophysiological, and genomic mechanisms for arousal are reviewed here. Highlighted are large reticular formation neurons in the medullary medulla whose axons bifurcating rostrally and caudally equip them to contribute, respectively, both to cerebral cortical arousal and to autonomic arousal. Their rapid responses would cause sudden changes in CNS state associated with, for example, states of panic. Consequences of the actions of generalized arousal networks include increased alertness and attention that serve all cognitive functions and all emotional expression. Specifically with respect to psychoanalytic concepts, these networks provide the psychic energy necessary for the expression of libido.
Neuropsychoanalysis: An Interdisciplinary Journal for Psychoanalysis and the Neurosciences. 01/2014; 9(2):173-181.
[Show abstract][Hide abstract] ABSTRACT: The male predominance of autism spectrum disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD’s etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.
Frontiers in Neuroendocrinology 01/2014; · 7.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ER), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E, initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17ß-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a Gaq coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ERa phospho-deficient mutants, that E2-BSA mediated phosphorylation of ERa is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain.
The Journal of steroid biochemistry and molecular biology 10/2013; · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Expression of the primary female sex behaviour, lordosis, in laboratory animals depends on oestrogen-induced expression of progesterone receptor (PgR) within a defined cell group in the ventrolateral portion of the ventromedial nucleus of the hypothalamus (VMH). The minimal latency from oestradiol administration to lordosis is 18 hours. During that time, ligand-bound oestrogen receptors (ER), members of a nuclear receptor superfamily, recruit transcriptional coregulators, which induce covalent modifications of histone proteins thus leading to transcriptional activation or repression of target genes. The aim of this study was to investigate early molecular epigenetic events underlying oestrogen-regulated transcriptional activation of the Pgr gene in the VMH of female mice. Oestradiol (E2) administration induced rapid and transient global histone modifications in the VMH of ovariectomised female mice. Histone H3 N-terminus phosphorylation (H3S10phK14Ac), acetylation (H3Ac) and methylation (H3K4me3) exhibited distinct temporal patterns facilitative to the induction of transcription; and a transcriptional repressive (H3K9me3) modification showed a different temporal pattern. Collectively these should create a permissive environment for the transcriptional activity necessary for lordosis, within 3-6 hours after E2-treatment. In the VMH, changes in the H3Ac and H3K4me3 levels of histone H3 were also detected at the promoter region of Pgr gene within the same time window, but were delayed in the preoptic area. Moreover, examination of histone modifications associated with the promoter of another ER-target gene, oxytocin receptor (Oxtr), revealed gene- and brain-region specific effects of E2 treatment. In the VMH of female mice, E2-treatment resulted in the recruitment of ERα to the oestrogen-response-elements-containing putative enhancer site of Pgr gene ~200kb upstream of the transcription start site (TSS), but failed to increase ERα association with the more proximal promoter region. Finally, E2 administration led to significant changes in the mRNA expression of several ER coregulators in a brain-region dependent manner. Taken together, these data indicate that in the hypothalamus and preoptic area of female mice, early responses to E2-treatment involve highly specific changes in chromatin structure, dependent on cell group, gene, histone modification studied, promoter/enhancer site and time following E2. This article is protected by copyright. All rights reserved.
Journal of Neuroendocrinology 08/2013; · 3.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The endocannabinoid (eCB) system regulates emotion, stress, memory and cognition through the CB1 receptor. In order to test the role of CB1 signaling in social anxiety and memory, we utilized a genetic knockout (KO) and a pharmacological approach. Specifically, we assessed the effects of a constitutive KO of CB1 receptors (CB1 KOs) and systemic administration of a CB1 antagonist (AM251; 5 mg/kg) on social anxiety in a social investigation paradigm and social memory in a social discrimination test. Results showed that when compared to wildtypes (WT) and vehicle-treated animals, CB1 KOs and WT animals that received an acute dose of AM251 displayed anxiety-like behaviors toward a novel male conspecific. When compared to WT animals, KOs showed both active and passive defensive coping behaviors; i.e. elevated avoidance, freezing and risk-assessment behaviors, all consistent with an anxiety-like profile. Animals that received acute doses of AM251 also showed an anxiety-like profile when compared to vehicle treated animals, yet did not show an active coping strategy i.e. changes in risk-assessment behaviors. In the social discrimination test, CB1 KOs and animals that received the CB1 antagonist showed enhanced levels of social memory relative to their respective controls. These results clearly implicate CB1 receptors in the regulation of social anxiety, memory and arousal. The elevated arousal/ anxiety resulting from either total CB1 deletion or an acute CB1 blockade may promote enhanced social discrimination/memory. These findings may emphasize the role of the eCB system in anxiety and memory to affect social behavior.
Genes Brain and Behavior 05/2013; · 3.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thyroid hormones influence both neuronal development and anxiety via the thyroid hormone receptors (TRs). The TRs are encoded by two different genes, TRα and TRβ. The loss of TRα1 is implicated in increased anxiety in males, possibly via a hippocampal increase in GABAergic activity. We compared both social behaviors and two underlying and related non-social behaviors, state anxiety and responses to acoustic and tactile startle in the gonadally intact TRα1 knockout (α1KO) and TRβ (βKO) male mice to their wild-type counterparts. For the first time, we show an opposing effect of the two TR isoforms, TRα1 and TRβ, in the regulation of state anxiety, with α1 knockout animals (α1KO) showing higher levels of anxiety and βKO males showing less anxiety compared to respective wild-type mice. At odds with the increased anxiety in non-social environments, α1KO males also show lower levels of responsiveness to acoustic and tactile startle stimuli. Consistent with the data that T4 is inhibitory to lordosis in female mice, we show subtly increased sex behavior in α1KO male mice. These behaviors support the idea that TRα1 could be inhibitory to ERα driven transcription that ultimately impacts ERα driven behaviors such as lordosis. The behavioral phenotypes point to novel roles for the TRs, particularly in non-social behaviors such as state anxiety and startle.
Hormones and Behavior 04/2013; · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We recently reported that acute stress causes a substantial upregulation of the epigenetic mark, Histone H3 Lysine 9 Trimethyl (H3K9me3) in the rat hippocampus within an hour of acute stress exposure. To determine the function of this change we used ChIP-sequencing to determine where this silencing mark was being localized. We found that it showed a strong bias toward localization at more active classes of retrotransposable elements and away from genes. Further, we showed that the change was functional in that it reduced transcription of some of these elements (notably the endogenous retrovirus IAP and the B2 SINE). In this commentary we examine these results, which appear to describe a selective genomic stress response and relate it to human health and disease, particularly stress related maladies such as Post-traumatic Stress Disorder, which have recently been shown to have both epigenetic elements in their causation as well as differences in epigenetic marking of retrotransposons in human patients.
[Show abstract][Hide abstract] ABSTRACT: The hippocampus is a highly plastic brain region particularly susceptible to the effects of environmental stress; it also
shows dynamic changes in epigenetic marks in response to stress and learning. We have previously shown that, in the rat, acute
(30 min) restraint stress induces a substantial, regionally specific, increase in hippocampal levels of the repressive histone
H3 lysine 9 trimethylation (H3K9me3). Because of the large magnitude of this effect and the fact that stress can induce the
expression of endogenous retroviruses and transposable elements in many systems, we hypothesized that the H3K9me3 response
was targeted to these elements as a means of containing potential genomic instability. We used ChIP coupled with next generation
sequencing (ChIP-Seq) to determine the genomic localization of the H3K9me3 response. Although there was a general increase
in this response across the genome, our results validated this hypothesis by demonstrating that stress increases H3K9me3 enrichment
at transposable element loci and, using RT-PCR, we demonstrate that this effect represses expression of intracisternal-A particle
endogenous retrovirus elements and B2 short interspersed elements, but it does not appear to have a repressive effect on long
interspersed element RNA. In addition, we present data showing that the histone H3K9-specific methyltransferases Suv39h2 is up-regulated by acute stress in the hippocampus, and that this may explain the hippocampal specificity we observe. These
results are a unique demonstration of the regulatory effect of environmental stress, via an epigenetic mark, on the vast genomic
terra incognita represented by transposable elements.
Proceedings of the National Academy of Sciences 10/2012; 109(43):17657-17662. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The medial preoptic area has been shown to be intricately involved in many behaviors, including locomotion, sexual behavior, maternal care, and aggression. The gene encoding estrogen receptor-α (ERα) protein is expressed in preoptic area neurons, and a very dense immunoreactive field of ERα is found in the preoptic region. ERα knockout animals show deficits in maternal care and sexual behavior and fail to exhibit increases in these behaviors in response to systemic estradiol treatment. In the present study, we used viral-vector mediated RNA interference to silence ERα expression specifically in the preoptic area of female mice and measured a variety of behaviors, including social and sexual aggression, maternal care, and arousal activity. Suppression of ERα in the preoptic area almost completely abolished maternal care, significantly increasing the latency to pup retrieval and significantly reducing the time the moms spent nursing and licking the pups. Strikingly, maternal aggression toward a male intruder was not different between control and preoptic ERα-silenced mice, demonstrating the remarkably specific role of ERα in these neurons. Reduction of ERα expression in preoptic neurons significantly decreased sexual behavior in female mice and increased aggression toward both sexual partners and male intruders in a seminatural environment. Estrogen-dependent increases in arousal, measured by home cage activity, were not mediated by ERα expression in the preoptic neurons we targeted, as ERα-suppressed mice had increases similar to control mice. Thus, we have established that a specific gene in a specific group of neurons is required for a crucially important natural behavior.
Proceedings of the National Academy of Sciences 09/2012; 109(40):16324-9. · 9.81 Impact Factor