Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli

Early-life ketamine exposure attenuates the preference for ethanol in adolescent Sprague-Dawley rats

Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces quick and effective antidepressant results in depressed juvenile and adult individuals. The long-term consequences of using ketamine in juvenile populations are not well known, particularly as it affects vulnerability to drugs of abuse later in life, given that ketamine is also a drug of abuse. Thus, the current study examined whether early-life ketamine administration produces long-term changes in the sensitivity to the rewarding effects of ethanol, as measured using the conditioned place preference (CPP) paradigm. On postnatal day (PD) 21, juvenile male and female rats were pretreated with ketamine (0.0 or 20 mg/kg) for 10 consecutive days (i.e., PD 21-30) and then evaluated for ethanol-induced CPP (0.0, 0.125, 0.5, or 2.0 g/kg) from PD 32 - 39. Results revealed that early-life ketamine administration attenuated the rewarding properties of ethanol in male rats, as ketamine pretreated rats failed to exhibit ethanol-induced CPP at any dose compared to saline pretreated rats, which showed an increased preference towards the ethanol-paired compartment in a dose-dependent manner. In females, ethanol-induced CPP was generally less robust compared to males, but ketamine pretreatment resulted in a rightward shift in the dose-response curve, given that ketamine pretreated rats needed a higher dose of ethanol compared to saline pretreated rats to exhibit ethanol-induced CPP. When considered together, the findings suggest that early use of ketamine does not appear to enhance the vulnerability to ethanol later in life, but in contrast, it may attenuate the rewarding effects of ethanol.18 month embargo; published online: 30 April 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice

Social stress, including bullying during adolescence, is a risk factor for common psychopathologies such as depression. To investigate the neural mechanisms associated with juvenile social stress-induced mood-related endophenotypes, we examined the behavioral, morphological, and biochemical effects of the social defeat stress model of depression on hippocampal dendritic spines within the CA1 stratum radiatum. Adolescent (postnatal day 35) male C57BL/6 mice were subjected to defeat episodes for 10 consecutive days. Twenty-four h later, separate groups of mice were tested on the social interaction and tail suspension tests. Hippocampi were then dissected and Western blots were conducted to quantify protein levels for various markers important for synaptic plasticity including protein kinase M zeta (PKMζ), protein kinase C zeta (PKCζ), the dopamine-1 (D1) receptor, tyrosine hydroxylase (TH), and the dopamine transporter (DAT). Furthermore, we examined the presence of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor subunit GluA2 as well as colocalization with the post-synaptic density 95 (PSD95) protein, within different spine subtypes (filopodia, stubby, long-thin, mushroom) using an immunohistochemistry and Golgi-Cox staining technique. The results revealed that social defeat induced a depression-like behavioral profile, as inferred from decreased social interaction levels, increased immobility on the tail suspension test, and decreases in body weight. Whole hippocampal immunoblots revealed decreases in GluA2, with a concomitant increase in DAT and TH levels in the stressed group. Spine morphology analyses further showed that defeated mice displayed a significant decrease in stubby spines, and an increase in long-thin spines within the CA1 stratum radiatum. Further evaluation of GluA2/PSD95 containing-spines demonstrated a decrease of these markers within long-thin and mushroom spine types. Together, these results indicate that juvenile social stress induces GluA2- and dopamine-associated dysregulation in the hippocampus – a neurobiological mechanism potentially underlying the development of mood-related syndromes as a consequence of adolescent bullying

Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance.

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors