Brain, behavior, and physiological changes associated with predator stress-An animal model for trauma exposure in adult and neonatal rats.

The use of predators and predator odor as stressors is an important and ecologically relevant model for studying the impact of behavioral responses to threat. Here we summarize neural substrates and behavioral changes in rats resulting from predator exposure. We briefly define the impact predator exposure has on neural targets throughout development (neonatal, juvenile, and adulthood). These findings allow us to conceptualize the impact of predator exposure in the brain, which in turn may have broader implications for human disorders such as PTSD. Importantly, inclusion of sex as a biological variable yields distinct results that may indicate neural substrates impacted by predator exposure differ based on sex.

Leveraging individual power to improve racial equity in academia.

Academia in the United States continues to grapple with its longstanding history of racial discrimination and its active perpetuation of racial disparities. To this end, universities and academic societies must grow in ways that reduce racial minoritization and foster racial equity. What are the effective and long-lasting approaches we as academics should prioritize to promote racial equity in our academic communities? To address this, the authors held a diversity, equity, and inclusion (DEI) panel during the Society for Behavioral Neuroendocrinology 2022 annual meeting, and in the following commentary synthesize the panelists' recommendations for fostering racial equity in the US academic community.

DNA topoisomerase Top3ß is impacted by early life stress in the developing female and male rat brain.

DNA topoisomerases are essential for preserving genomic integrity. DNA topoisomerases induce breakage of DNA to facilitate replication and transcription by relaxing DNA and relieving supercoiling. Aberrant expression and deletions of topoisomerases are associated with psychiatric disorders such as schizophrenia and autism. Our study investigated the effects of early life stress (ELS) on three topoisomerases, Top1, Top3α, and Top3ß in the developing rat brain. Newborn rats were exposed to a predator odor stress on postnatal days 1, 2, and 3; brain tissue was collected either 30 min after the last stressor on postnatal day 3 or during the juvenile period. We found that exposure to predator odor resulted in a decrease in Top3ß expression levels in the neonatal male amygdala and in the juvenile prefrontal cortex of males and females. These data suggest that developing males and females respond differently to predator odor-induced stress. As ELS results in lower Top3ß levels, these data suggest that ELS experienced during development may have consequences for genomic structural integrity and increased mental health risk.

Sex differences in anxiety and depression: circuits and mechanisms.

Epidemiological sex differences in anxiety disorders and major depression are well characterized. Yet the circuits and mechanisms that contribute to these differences are understudied, because preclinical studies have historically excluded female rodents. This oversight is beginning to be addressed, and recent studies that include male and female rodents are identifying sex differences in neurobiological processes that underlie features of these disorders, including conflict anxiety, fear processing, arousal, social avoidance, learned helplessness and anhedonia. These findings allow us to conceptualize various types of sex differences in the brain, which in turn have broader implications for considering sex as a biological variable. Importantly, comparing the sexes could aid in the discovery of novel therapeutics.

Early life stress during the neonatal period alters social play and Line1 during the juvenile stage of development.

Early life stress (ELS) has been shown to have a significant impact on typical brain development and the manifestation of psychological disorders through epigenetic modifications that alter gene expression. Line1, a retrotransposon associated with genetic diversity, has been linked with various psychological disorders that are associated with ELS. Our previous work demonstrated altered Line1 DNA copy number in the neonatal period following stressful experiences; we therefore chose to investigate whether early life stress altered Line1 retrotransposition persists into the juvenile period of development. Our study uses a neonatal predator odor exposure (POE) paradigm to model ELS in rats. We examined Line1 using qPCR to assess Line1 expression levels and DNA copy number in the male and female juvenile amygdala, hippocampus and prefrontal cortex-areas chosen for their association with affective disorders and stress. We report a sex difference in Line1 levels within the juvenile amygdala. We also find that ELS significantly increases Line1 DNA copy number within the juvenile amygdala which correlates with reduced juvenile social play levels, suggesting the possibility that Line1 may influence juvenile social development.

Early life stress increases Line1 within the developing brain in a sex-dependent manner.

Long-interspersing element 1 (Line1)-a retrotransposon that comprises ~17% of the human genome and ~24% of the rat genome -is aberrantly expressed in psychiatric disorders such as schizophrenia, bipolar disorder, and Rett syndrome, suggesting it may play an important role in neurodevelopment. Retrotransposons such as Line1 have the ability to self-replicate via reverse transcription and can subsequently be reinserted throughout the genome, potentially increasing genetic diversity. We sought to understand whether early life stress (ELS), a known risk factor for the development of later psychiatric disorders in humans, would affect Line1 expression and DNA copy number. Our study uses a neonatal predator odor exposure (POE) paradigm to model ELS in rats. We found sex- and region-specific increases in both Line1 Open Reading Frame 1 (ORF1) and ORF2 mRNA following POE-induced stress. Interestingly, ELS increased Line1 DNA copy number within the male hippocampus. These data suggest the possibility that early life stress can mobilize Line1 in a sex- and region-specific manner, resulting in genomic heterogeneity between cells in the brain suggesting that some cells may have a different genetic makeup than others resulting in genomic heterogeneity.

Early life stress alters opioid receptor mRNA levels within the nucleus accumbens in a sex-dependent manner.

Early life stress (ELS) strongly impacts mental health, but little is known about its interaction with biological sex and postnatal development to influence risk and resilience to psychopathologies. A number of psychiatric disorders, such as social anhedonia and drug addiction, involve dysfunctional opioid signaling; moreover, there is evidence for differential central opioid function in males vs. females. The present study examined opioid receptor gene expression in the nucleus accumbens (NAc) and amygdala of male and female rats subjected to a neonatal predator odor exposure (POE) paradigm to model ELS. Brain tissue was collected at two developmental time points: neonatal and juvenile. Results showed that, following the neonatal POE experience, opioid receptor mRNA levels in the NAc were differentially regulated at the neonatal and juvenile time points. POE downregulated neonatal mu- and kappa-opioid receptor mRNA levels in neonatal females, but upregulated mu- and delta-opioid receptor mRNA levels in juvenile females. Intriguingly, POE had no significant effect on NAc opioid receptor mRNA levels in males at either time point, indicating that the impact of POE on opioid system development is sex-dependent. Finally, POE failed to alter amygdalar opioid receptor gene expression in either sex at either time-point. The spatiotemporally- and sex-specific impact of ELS within the developing brain may confer differential risk or resilience for males and females to develop atypical opioid-regulated behaviors associated with conditions such as depression and addiction.

Binge Drinking and Intergenerational Implications: Parental Preconception Alcohol Impacts Offspring Development in Rats.

Preconception behaviors and experiences of mothers and fathers can affect future offspring. Recently, our laboratory showed that alcohol-naive offspring of parents who were exposed to repeated binge alcohol during adolescence showed altered DNA methylation patterns in the hypothalamus, a brain region involved in regulation of pubertal development, stress, and behavior. These observations have potentially far-reaching consequences for human health, as more than 4.6 million Americans under the age of 21 years report engaging in the rapid intoxication behavior of binge-pattern alcohol (EtOH) drinking. Therefore, we tested the hypothesis that offspring of binge EtOH‒exposed parents would have altered hypothalamic function manifested phenotypically as improper pubertal development, impaired socialization, and dysregulated stress response. In addition, we tested the hypothesis that parental EtOH exposure would confer adaptive protection from the negative effects of EtOH when offspring were themselves exposed to EtOH. Rats received EtOH via oral gavage once daily for 6 days at both early [postnatal day (PND) 37] and late puberty (PND 67). Animals were paired (EtOH-EtOH, vehicle-vehicle) for mating 24 hours after the last EtOH dose. After weaning, offspring were randomized to vehicle treatment to assess changes in normal development or to EtOH treatment to assess the effect of parental EtOH exposure on offspring response to this treatment. We found that offspring had smaller body weights and displayed fewer play behaviors when parents had been exposed to EtOH before conception. In addition, offspring showed a reduction in pubertal development markers that could indicate that parental preconception EtOH exposure confers maladaptive epigenetic traits in first-generation offspring.

N6-methyladenine is an epigenetic marker of mammalian early life stress.

Recent evidence described 6-methyladenine (6 mA) as a novel epigenetic regulator in a variety of multicellular species, including rodents; however, its capacity to influence gene expression in the mammalian brain remains unknown. We examined if 6 mA is present and regulated by early life stress associated with predator odor exposure (POE) within the developing rat amygdala. Our results provide evidence that 6 mA is present in the mammalian brain, is altered within the Htr2a gene promoter by early life stress and biological sex, and increased 6 mA is associated with gene repression. These data suggest that methylation of adenosine within mammalian DNA may be used as an additional epigenetic biomarker for investigating the development of stress-induced neuropathology.