Serotonin (5-hydroxytryptamine; 5-HT) coordinates behavioral responses to stress through a variety of presynaptic and postsynaptic receptors distributed across functionally diverse neuronal networks in the central nervous system. Efferent 5-HT projections from the dorsal raphe nucleus (DRN) to the bed nucleus of the stria terminalis (BNST) are generally thought to enhance anxiety and aversive learning by activating 5-HT 2C receptor (5-HT 2C R) signaling in the BNST, although an opposing role for postsynaptic 5-HT 1A receptors has recently been suggested. In the present study, we sought to delineate a role for postsynaptic 5-HT 1A receptors in the BNST in aversive behaviors using a conditional knockdown of the 5-HT 1A receptor. Both males and females were tested to dissect out sex-specific effects. We found that male mice have significantly reduced fear memory recall relative to female mice and inactivation of 5-HT 1A receptor in the BNST increases contextual fear conditioning in male mice so that they resemble the females. This coincided with an increase in neuronal excitability in males, suggesting that 5-HT 1A receptor deletion may enhance contextual fear recall by disinhibiting fear memory circuits in the BNST. Interestingly, 5-HT 1A receptor knockdown did not significantly alter anxiety-like behavior in male or female mice, which is in agreement with previous findings that anxiety and fear are modulated by dissociable circuits in the BNST. Overall, these results suggest that BNST 5-HT 1A receptors do not

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Adolescent alcohol use can permanently alter brain function and lead to poor health outcomes in adulthood. Emerging evidence suggests that alcohol use predispose to pain disorders or exacerbate existing pain conditions, but the neural mechanisms are currently unknown. Here we report that mice exposed to adolescent intermittent access to ethanol (AIE) exhibit increased pain sensitivity and depressive-like behaviors that persist after alcohol cessation and are accompanied by elevated CD68 expression in microglia and reduced numbers of serotonin (5-HT)-expressing neurons in the dorsal raphe nucleus (DRN). 5-HT expression was also reduced in the thalamus, anterior cingulate cortex (ACC) and amygdala as well as the lumbar dorsal horn of the spinal cord. We then found that chronic minocycline administration after AIE alleviated hyperalgesia and social deficits, while chemogenetic activation of microglia in the DRN of Cx3cr1-cre-GFP mice reproduced the effects of AIE on pain and social interaction. Taken together, these results indicate that microglial activation in the DRN may be a primary driver of pain and negative affect after AIE.

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