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Sex differences in vasopressin 1a receptor regulation of social communication within the lateral habenula and dorsal raphe of mice.

ABSTRACT: The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication in diverse taxa, often through its actions on the V1a receptor (V1aR) and in a sex-different and steroid-dependent way. One source of sex-different brain AVP is the steroid-sensitive and sexually-dimorphic AVP neurons in the bed nucleus of the stria terminalis (BNST), a cell population that regulates social behavior in a sex-dependent manner. Potential targets of these BNST-AVP cells include the lateral habenula (LHb) and dorsal raphe (DR), areas known to be important for social behavior, yet few studies have investigated AVP action within these regions. Consequently, to test if V1aR action in the LHb or DR controls social behavior in a sexually dimorphic manner, we administered a highly-specific V1aR antagonist (or saline vehicle) in the LHb or DR of C57BL/6 male and female mice and tested its effects on social investigation, social communication (urine marking, ultrasonic vocalizations), and territorial aggression. V1aR antagonism of the LHb or DR decreased male urine marking toward unfamiliar males, but not toward unfamiliar females. Additionally, V1aR blockade of the LHb decreased ultrasonic vocalizations generated in the presence of females. Social investigation, locomotion and aggressive behavior were not altered by V1aR antagonism in either area. Blocking V1aR in the LHb or DR of females had no effect, indicating V1aR action in the DR and LHb drives sex differences in social communication.

SUBMITTER: Rigney N

PROVIDER: S-EPMC7249673 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn/KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABAAR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABAAR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

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Sex differences in vasopressin 1a receptor regulation of social communication within the lateral habenula and dorsal raphe of mice.

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