Mechanisms governing the reactivation-dependent destabilization of memories and their role in extinction. Flavell, Charlotte R. Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior. Ploense, Kyle L.
Activation of BDNF signaling prevents the return of fear in female mice. The amygdala and medial prefrontal cortex: partners in the fear circuit. Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaptation. On the potential role of active DNA demethylation in establishing epigenetic states associated with neural plasticity and memory. The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Barry, Guy, Briggs, J.
Wei, Wei, Coelho, Carlos M. Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders. The brain-specific microRNA miRb regulates the formation of fear-extinction memory.
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MicroRNA regulation of neural plasticity and memory. Bredy, Timothy W. Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders. Dudley, Kevin J. Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p Marek, Roger, Coelho, Carlos M. How the epigenome contributes to the development of psychiatric disorders. Paternal deprivation during infancy results in dendrite- and time-specific changes of dendritic development and spine formation in the orbitofrontal cortex of the biparental rodent Octodon degus.
Social modulation of associative fear learning by pheromone communication. The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Timothy, Bredy and Barad, Mark The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Effect of resource availability on biparental care, and offspring neural and behavioral development in the California mouse Peromyscus californicus.
Behavioural epigenetics and psychiatric disorders. Bredy, Timothy Behavioural epigenetics and psychiatric disorders. Maternal programming of defensive responses through sustained effects on gene expression. Activity-dependent RNA methylation in learning and memory. Widagdo, J. A deciding factor in this early environment for laboratory rats and mice is the sex ratio of the litter. Usually the sex ratio in utero and following birth are similar, but this does not mean that each period has an equivalent contribution to behavior.
There is abundant evidence that the prenatal environment the sex of fetal neighbors and the postnatal period the nature and quantity of maternal care affect the adult behavioral phenotype Ryan and Vandenbergh, ; Fleming et al. However, in none of these studies have these two periods prenatal and postnatal been disassociated.
Specifically, research demonstrating that the intrauterine sex ratio influences adult behavior has not controlled for sex ratio of the litter postnatally. Similarly, research demonstrating litter sex ratio influences on maternal behavior has not taken into account the prenatal sex ratio of the pregnant mother. Thus, it is not known the extent to which the former prenatal affects the latter postnatal , or vice versa. It is possible to re-assemble the litter at birth and in that manner deconstruct this usually continuous process into its component life phases.
When this is done we find the surprising finding that neither intrauterine position or maternal behavior have significant effects on the performance and attractiveness of males in adulthood deMederios et al. Rather, it is the sex ratio of the litter postnatally that has the greatest effect on sexuality. That is, regardless of prenatal sex ratio, males raised in female-biased 2 males: 6 females litters exhibit less mounting compared to males raised in litters of equal sex ratio 4 males: 4 females or in male-biased 6 males: 2 females litters.
Further, males from female-biased litters are less attractive to sexually receptive females. These differences are not erased by sexual experience, suggesting that the effects of the sibling environment are permanent. Surprisingly, these males compensate for their lower attractiveness by being more efficient copulators. For example, in the case of mice and rats lacking functional copies of gene s , the ratio of the various genotypes within the litter is as important as litter sex ratio.
Typically, researchers using KO mice do not control for the early social environment of their experimental animals. However, this early social environment has a powerful effect on shaping the adult behavioral and neural phenotypes. Both HTZ and KO individuals lack a functional copy of this important sex steroid receptor and research has revealed the role of this gene in differentiation of morphology and physiology, as well as distinct behavioral phenotypes Ogawa and Pfaff, ; Rissman et al. The question becomes, to what extent are the behavioral phenotypes due to the absence of the gene versus the sex and genotype ratios in the litter in which the individual develops.
It is possible to reconstitute litters soon after birth to control for these two factors Crews et al. Using this approach recent work has revealed that in both males and females the Sex and Genotype of siblings affect aggressive behaviors as well as patterns of metabolic activity in limbic nuclei later in adulthood. For example, WT females spend significantly more time in social contact in a Resident-Intruder test compared to KO females when raised in same-sex, same-genotype litters Crews et al.
Further, it appears that female WT siblings are able to compensate for this deficit, just as KO siblings cause a deficit in WT females. The neural networks that subserve sociosexual behavior vary in different ways. Second, the type of sibling sex as well as genotype influences the neural network exhibited in adulthood. The relative effects of sex independent of genotype, and of genotype independent of sex, are striking. Taken together, these findings indicate that in studies with genetically modified mice, the litter composition during the preweaning period must be considered as it can effect the development of behavior and the neural network responsible for the regulation of emotional behaviors.
Finally, developmental psychobiologists and behavioral endocrinologists traditionally have focused on the sexual differentiation of behavior, virtually ignoring the problem of individual differences Crews, , This in part is due to the organisms studied most typically inbred birds and mammals and, as a consequence, the perspective engendered is that variation is categorical male vs.
However, sex and sexuality are conceptually distinct but often confused; gonadal sex is a discrete character that categorizes the individual, whereas sexuality is a suite of continuously variable traits that is unique to each individual.
Sexuality therefore resides in the brain, not in the gonads, and the sexual differentiation of mating behaviors, their underlying mechanisms, and the relation to individual variation involves more than just the type of gonad and pattern of circulating sex steroid hormones. Mammals and birds have sex chromosomes, and, as a consequence, genetic sex and gonadal sex hormones are inextricably linked. The very nature of genotypic sex determination GSD makes it difficult to distinguish non-genomic yet heritable epigenetic factors from genetic contributions to sexuality.
Consider, for example, aggressive and sexual behaviors displayed by both sexes, but at different frequencies and often in different contexts and situations. To what extent are differences observed between adult males and females due to their differences in sex chromosomes, differences in the nature and pattern of past and present endocrine history, differences in environmental influences or sex-typical experiences? Examples exist for all of these. Although research with transgenic mice suggests that the sex-specific gene SRY may play a role in behaviors, these effects are not robust and it is doubtful that in wild species they play a role in sexually dimorphic behaviors.
The leopard gecko has temperature-dependent sex determination TSD and thus does not have the complications arising from genotypic sex determination. In this species high and low incubation temperatures produce only females while intermediate incubation temperatures produce different sex ratios. Despite this temperature determination of sex, there is continuous within-sex variation in both sexes that with few exceptions overlap. Incubation temperature accounts for much of the within-sex variation observed in the morphology, growth, endocrine physiology, and aggressive and sexual behavior of the adult Crews, ; Crews and Groothuis, ; Crews et al.
Temperature during embryogenesis is one type of experience. Another type is sexual experience during adulthood. How might experiences early in life interact with experiences later in life to affect sexual behavior and their underlying neural circuits? One indication is seen in mate preference Putz and Crews, Sexually experienced Tf and Tm males both show strong preferences in a Y-maze apparatus to females or their odors, but the type of female they choose depends upon their incubation history.
Among females, Tm females are less attractive to males than are Tf females and also exhibit male-typical patterns of aggression.
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For neurobehavioral studies, cytochrome oxidase CO histochemistry is a particularly useful tool for studies of the effects of significant life-history events. The abundance and activity of CO activity in a brain area is a measure of the metabolic capacity of that brain region. In other words, the CO abundance not only reflects the metabolic history of an area but also determines the amount of ATP available in a neuron, constraining the amount of activity a neuron can sustain Sakata et al. Incubation temperature also influences the metabolic capacity of specific forebrain nuclei, in adult leopard geckos Coomber et al.
Sexual experience in females has a different effects depending upon the individuals incubation temperature Crews et al. Although outside the scope of this essay, an often unappreciated distinction is that of experience versus age. An individual ages as it gains experience, but it is possible for an animal to age without acquiring certain experience; for example, a socially subordinate male may never have breeding experience. There is clear evidence that age and experience have separate, and at times, opposing effects on behavioral and neural phenotypes Crews et al.
For example, CO activity is higher in the anterior hypothalamus of males, in the ventromedial hypothalamus of both males and females from the Tm incubation temperature, and in the preoptic area of females from both incubation temperatures. These differences were not paralleled by differences in circulating levels of sex hormones; only plasma androgen levels differed as a function of experience in males. These data suggest that the volume and metabolic capacity of specific brain regions change as animals age and gain sociosexual experience, but the nature and degree of change depends upon prenatal events.
Michael Skinner and colleagues have developed a rat model in which the male germline bears a permanent epigenetic imprint, thereby creating a truly transgenerational epigenetic phenotype Anway and Skinner, ; Anway et al. Exposing gestating Sprague-Dawley female rat to the endocrine disrupting pesticide methoxychlor or the fungicide vinclozolin during the period of embryonic sex determination reprograms the germline in a sex-specific manner.
This modification is evident in every generation without further exposure to the chemical for five generations the number of generations studied to date. As noted above, the F3 generation is the first generation that the body burden from the exposure is completely absent and any effects cannot be attributed to the chemical exposure. Remarkably, males in each generation show accelerated onset of adult diseases such as cancer, prostate disease, kidney disease and immune defects; these diseases develop spontaneously at about days of age in normal males, but in the transgenerationally modified males, they begin to be observed around days of age.
The appearance of a series of new imprinted-like genes that transgenerationally transmits this altered epigenome to promote disease phenotypes appear not only in the sperm epigenome but also in the brain epigenome Anway et al. Using the Vinclozolin model system we have established the behavior of individuals is also epigenetically modified.
Females discriminate and prefer male descendants of the line that were not exposed to the chemical, whereas similarly epigenetically imprinted males do not exhibit such a preference Crews et al. Specifically, in a partner preference test, F3 generation females of both the Vinclozolin- and Control-lineages discriminate and prefer males who do not have a history of exposure; males do not exhibit such a preference.
Odor preference tests rule out possible differences in the odor discrimination ability of epigenetically modified animals; males and females of both lineages explore odors of the opposite sex much more than familiar self odors or novel odors of the same sex, and all animals explore novel odors of the same sex more than own odors. It is seems intuitive that Germline-Dependent and Context-Dependent epigenetic modifications would interact, and thereby underlie the individual variation observed in traits.
That is, events in past generations heritability influence how an individual responds to events in their own life history experience. The possible combinations are detailed in Table 1. Skinner and I have been investigating the effects of chronic restraint stress on brain and behavior using the Vinclozolin model system described above. Specifically the hypothesis is that chronic stress during adolescence interacts either additively or synergistically with the transgenerational epigenetic imprint. Four types of scenarios are depicted. The first does not exist in nature or in the laboratory.
An example of Life History 2 would be studies of the effects of selection natural, sexual, or artificial for a particular trait. Life History 3 would be studies in which individuals are exposed to a challenge s during its life history. This is characteristic of most experimental studies of behavior today. Life History 4 is believed to reflect how real life operates, but the extent to which the heredity and experience interact is rarely studied experimentally. Initially we have focused on a well-studied trait, body weight gain through life. Figure 1 illustrates that there is no difference in body weight between Vinclozolin- and Control-lineage males at birth or at weaning, but Vinclozolin-lineage males become heavier.
This difference is greatest in non-stressed animals. Chronic restraint stress has an immediate effect on body weight regardless of lineage. Following restraint stress the rate of change is increased in stressed animals regardless of lineage. This finding is consistent with other studies showing that chronic restraint stress can have a long-lasting effect on traits e. Effects of germline-dependent and context-dependent epigenetic modifications on body weight in F3 Sprague-Dawley rats whose grandmothers had been treated with either Vinclozolin-Lineage or Vehicle-Lineage while pregnant.
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