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

Abstract

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

Suppression of adult cytogenesis in the rat brain leads to sex‐differentiated disruption of the HPA axis activity

“…The hippocampus sends direct synaptic output to regions within the HPA axis, namely the BLA and the bed nucleus of the stria terminalis (BNST). BNST, which is sex‐dimorphic in adulthood, integrates inputs from various sources, including mPFC, hippocampus, BLA and central amygdala (CeA), and helps in modulating neuroendocrine and behavioural responses, including anxiety‐like behaviour 82–86 . Despite not described to be sex‐dimorphic under basal conditions, BLA is hypertrophic specifically in females upon cytogenesis ablation, in this study.…”

Threat imminence dictates the role of the bed nucleus of the stria terminalis in contextual fear

“…Thus, delayed or unpredictable onset of aversive events may be a critical feature that recruits the BNST to anxiety-related behaviors, as well as for fear and drug relapse in the aftermath of unpredictable stressors (Goode et al, 2018;Harris and Winder, 2018;Mantsch et al, 2016;Miles et al, 2018;Stamatakis et al, 2014;Vranjkovic et al, 2017). Nonetheless, the BNST is an intricate, sexually dimorphic and heterogeneous structure, with diverse functions (Avery et al, 2014;Crestani et al, 2013;Daniel and Rainnie, 2016;Flavin and Winder, 2013;Hammack et al, 2012Hammack et al, , 2010Hammack et al, , 2009Kash, 2012;Kash et al, 2015;Radley and Johnson, 2018;Waraczynski, 2016)-more work is needed to fully characterize its complex neural responses and contributions to aversive stimuli [ (Acca et al, 2017;Duvarci et al, 2009;Haufler et al, 2013;Jennings et al, 2013;Luyck et al, 2018, Marcinkiewcz et al, 2019, 2016Martinon et al, 2019;Moaddab and Dabrowska, 2017); also, see (Bjomi et al, 2019)]. Our findings relied on local pharmacological inactivation of this complex circuitry; other drugs or cell-type specific manipulations may reveal unique roles of BNST circuits in aversive learning and memory.…”

Constitutive 5-HT2C receptor knock-out facilitates fear extinction through altered activity of a dorsal raphe-bed nucleus of the stria terminalis pathway

“…5-HT2CR activation in turn engages a BNST microcircuit that inhibits anxiolytic projections to the ventral tegmental area and lateral hypothalamus to increase anxiety (17). In contrast, anxiolytic 5-HT actions in the BNST are attributed to 5-HT2CR desensitization (6) and enhanced 5-HT1AR activation, favoring anxiolytic outputs (63,64). Additionally, plasticity changes in 5-HT1AR signaling following contextual fear conditioning is thought to buffer the animal's system against excessive activation (63).…”