Sex-Dependent Modulation of Anxiety and Fear by 5-HT_1A Receptors in the Bed Nucleus of the Stria Terminalis

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_2CR) 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 significantly alter behavior under basal conditions, but can act as a molecular brake that buffer against excessive activation of aversive circuits in more threatening contexts.