Vardy, A. S. | bioRxiv Science

bioRxiv2026

Sex-specific control of feeding and defensive behaviors by MC3R neurons in the bed nuclei of the stria terminalis

The bed nuclei of the stria terminalis (BST) is a nuclear complex that coordinates neuroendocrine, autonomic, and behavioral responses associated with maintaining homeostasis. Here, we demonstrate that melanocortin 3 receptor (MC3R) neurons in the BST (BSTMC3R) play a key role in modulating feeding behaviors and responses to stressful events. BSTMC3R neurons are primarily GABAergic and colocalize with neuropeptides known to regulate feeding and affective behaviors. Chemogenetic activation of BSTMC3R neurons causes reduced feeding, particularly in males. BSTMC3R neurons are also robustly activated by stress and can control responses to stress and defensive behaviors in both sexes. Whole-brain monosynaptic rabies tracing identified multiple sexually dimorphic inputs to BSTMC3R neurons that may contribute to observed functional sexual dimorphisms. Altogether, these data reveal that BSTMC3R neurons participate in sexually dimorphic circuits that influence feeding and defensive behaviors, responses to stress, and may represent a potential therapeutic target for stress- and eating-related disorders.

neuroscience↗

bioRxiv2024

BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice

Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), and Crh+ neurons in this region are thought to play a key role in chronic ethanol-induced increases in volitional ethanol intake. This role has been hypothesized to be driven by emergent BNST-dependent negative affective behaviors. Indeed, we report here that in female mice undergoing a home cage chronic drinking forced abstinence model (CDFA), excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Excitatory NMDA receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. We find that knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in dBNST or specifically in dBNST Crh+ neurons. Finally, to determine the impact of GluN2D expression on negative affective behaviors, open field, elevated zero maze, and forced swim tasks were used to measure anxiety- and depressive-like behaviors in constitutive and conditional BNST GluN2D knockout mice. Surprisingly, we find that deletion of GluN2D fails to alter negative affect in ethanol-naive female mice. Together, these data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking behaviors but not abstinence from ethanol, highlighting potential sex differences and behavioral specificity in the context of AUD behaviors. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.

neuroscience↗