Sex Differences in Synaptic Plasticity: Hormones and Beyond

Notable sex-differences exist between neural structures that regulate sexually dimorphic behaviors such as reproduction and parenting. While anatomical differences have been well-characterized, advancements in neuroimaging and pharmacology techniques have allowed researchers to identify differences between males and females down to the level of the synapse. Disparate mechanisms at the synaptic level contribute to sex-specific neuroplasticity that is reflected in sex-dependent behaviors. Many of these synaptic differences are driven by the endocrine system and its impact on molecular signaling and physiology. While sex-dependent modifications exist at baseline, further differences emerge in response to stimuli such as stressors. While some of these mechanisms are unifying between sexes, they often have directly opposing consequences in males and females. This variability is tied to gonadal steroids and their interactions with intra- and extra-cellular signaling mechanisms. This review article focuses on the various mechanisms by which sex can alter synaptic plasticity, both directly and indirectly, through steroid hormones such as estrogen and testosterone. That sex can drive neuroplasticity throughout the brain, highlights the importance of understanding sex-dependent neural mechanisms of the changing brain to enhance interpretation of results regarding males and females. As mood and stress responsivity are characterized by significant sex-differences, understanding the molecular mechanisms that may be altering structure and function can improve our understanding of these behavioral and mental characteristics

Chronic Adolescent Stress Alters GR-FKBP5 Interactions in the Hippocampus of Adult Female Rats

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures

Enduring Effects of Paternal Deprivation in California Mice (Peromyscus californicus): Behavioral Dysfunction and Sex-Dependent Alterations in Hippocampal New Cell Survival

Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Early-life experiences with caregivers can significantly affect offspring development in human and non-human animals. While much of our knowledge of parent-offspring relationships stem from mother-offspring interactions, increasing evidence suggests interactions with the father are equally as important and can prevent social, behavioral, and neurological impairments that may appear early in life and have enduring consequences in adulthood. In the present study, we utilized the monogamous and biparental California mouse (Peromyscus californicus). California mouse fathers provide extensive offspring care and are essential for offspring survival. Non-sibling virgin male and female mice were randomly assigned to one of two experimental groups following the birth of their first litter: (1) biparental care: mate pairs remained with their offspring until weaning; or (2) paternal deprivation (PD): paternal males were permanently removed from their home cage on postnatal day (PND) 1. We assessed neonatal mortality rates, body weight, survival of adult born cells in the dentate gyrus of the hippocampus, and anxiety-like and passive stress-coping behaviors in male and female young adult offspring. While all biparentally-reared mice survived to weaning, PD resulted in a ~35% reduction in survival of offspring. Despite this reduction in survival to weaning, biparentally-reared and PD mice did not differ in body weight at weaning or into young adulthood. A sex-dependent effect of PD was observed on new cell survival in the dentate gyrus of the hippocampus, such that PD reduced cell survival in female, but not male, mice. While PD did not alter classic measures of anxiety-like behavior during the elevated plus maze task, exploratory behavior was reduced in PD mice. This observation was irrespective of sex. Additionally, PD increased some passive stresscoping behaviors (i.e., percent time spent immobile) during the forced swim task—an effect that was also not sex-dependent. Together, these findings demonstrate that, in a species where paternal care is not only important for offspring survival, PD can also contribute to altered structural and functional neuroplasticity of the hippocampus. The mechanisms contributing to the observed sex-dependent alterations in new cell survival in the dentate gyrus should be further investigated

Separation increases passive stress-coping behaviors during forced swim and alters hippocampal dendritic morphology in California mice.

Individuals within monogamous species form bonds that may buffer against the negative effects of stress on physiology and behavior. In some species, involuntary termination of the mother-offspring bond results in increased symptoms of negative affect in the mother, suggesting that the parent-offspring bond may be equally as important as the pair bond. To our knowledge, the extent to which affect in paternal rodents is altered by involuntary termination of the father-offspring bond is currently unknown. Here, we investigated to what extent separation and paternal experience alters passive stress-coping behaviors and dendritic morphology in hippocampal subfields of California mice (Peromyscus californicus). Irrespective of paternal experience, separated mice displayed shorter latencies to the first bout of immobility, longer durations of immobility, and more bouts of immobility than control (non-separated) mice. This effect of separation was exacerbated by paternal experience in some measures of behavioral despair-separation from offspring further decreased the latency to immobility and increased bouts of immobility. In the dentate gyrus, separation reduced dendritic spine density regardless of paternal experience. Increased spine density was observed on CA1 basal, but not apical, dendrites following paternal experience. Regardless of offspring presence, fatherhood was associated with reduced apical dendritic spine density in area CA3 of the hippocampus. Separation enhanced complexity of both basal and apical dendrites in CA1, while fatherhood reduced dendritic complexity in this region. Our data suggest that forced dissolution of the pair bond induces passive stress-coping behaviors and contributes to region-specific alterations in hippocampal structure in California mouse males

Effects of apomorphine on mating behavior, flank marking and aggression in male hamsters

In male rats, the dopamine agonist apomorphine (APO) generally facilitates copulatory behavior. However, disruptive effects of high APO doses have been reported. These have been interpreted in diverse ways, as products of a dopaminergic system that inhibits sexual behavior or as consequences of APO\u27s stimulation of competing responses. To test the generality of these effects, we observed APO\u27s impact on copulatory behavior in male hamsters. Several effects were observed, all attributable to a relatively high dose and involving the disruption of male behavior. More unexpectedly, APO treatment caused males to attack estrous stimulus females in the course of these tests. To clarify these effects, we observed the effects of APO on flank marking, a type of scent marking closely allied to aggression and dominance in hamsters. Treatment reliably decreased the latency of marking. It also increased the rate of marking when appropriate measures were taken to prevent this effect from being obscured by drug-induced cheek pouching. Together, these results confirm and extend APO\u27s well-known ability to increase aggression. Further, they suggest that APO-induced aggression can intrude into other contexts so as to disrupt, or possibly facilitate, other forms of social behavior

Enduring Effects of Paternal Deprivation in California Mice (Peromyscus californicus): Behavioral Dysfunction and Sex-Dependent Alterations in Hippocampal New Cell Survival

Early-life experiences with caregivers can significantly affect offspring development in human and non-human animals. While much of our knowledge of parent-offspring relationships stem from mother-offspring interactions, increasing evidence suggests interactions with the father are equally as important and can prevent social, behavioral, and neurological impairments that may appear early in life and have enduring consequences in adulthood. In the present study, we utilized the monogamous and biparental California mouse (Peromyscus californicus). California mouse fathers provide extensive offspring care and are essential for offspring survival. Non-sibling virgin male and female mice were randomly assigned to one of two experimental groups following the birth of their first litter: (1) biparental care: mate pairs remained with their offspring until weaning; or (2) paternal deprivation (PD): paternal males were permanently removed from their home cage on postnatal day (PND) 1. We assessed neonatal mortality rates, body weight, survival of adult born cells in the dentate gyrus of the hippocampus, and anxiety-like and passive stress-coping behaviors in male and female young adult offspring. While all biparentally-reared mice survived to weaning, PD resulted in a ~35% reduction in survival of offspring. Despite this reduction in survival to weaning, biparentally-reared and PD mice did not differ in body weight at weaning or into young adulthood. A sex-dependent effect of PD was observed on new cell survival in the dentate gyrus of the hippocampus, such that PD reduced cell survival in female, but not male, mice. While PD did not alter classic measures of anxiety-like behavior during the elevated plus maze task, exploratory behavior was reduced in PD mice. This observation was irrespective of sex. Additionally, PD increased some passive stress-coping behaviors (i.e., percent time spent immobile) during the forced swim task—an effect that was also not sex-dependent. Together, these findings demonstrate that, in a species where paternal care is not only important for offspring survival, PD can also contribute to altered structural and functional neuroplasticity of the hippocampus. The mechanisms contributing to the observed sex-dependent alterations in new cell survival in the dentate gyrus should be further investigated