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BACKGROUND: Histamine (HA), a wake-promoting monoamine implicated in stress-related arousal states, is synthesized in histidine decarboxylase (HDC)-expressing hypothalamic neurons of the tuberomammillary nucleus (TMN). HDC-containing varicosities diffusely innervate striatal and mesolimbic networks, including the nucleus accumbens (NAc). The nucleus accumbens (NAc) integrates diverse monoaminergic inputs to coordinate motivated behavior. While the NAc expresses various HA receptor subtypes, mechanisms by which HA modulates NAc circuit dynamics are undefined. METHODS: Utilizing male D1tdTomato transgenic reporter mice, whole-cell patch clamp electrophysiology, and input-specific optogenetics, we employed a targeted pharmacological approach to interrogate synaptic mechanisms recruited by HA signaling at glutamatergic synapses in the NAc. We incorporated an immobilization stress protocol to assess whether acute stress engages these mechanisms at glutamatergic synapses onto D1 receptor-expressing [D1(+)] medium spiny neurons (MSNs) in the NAc core. RESULTS: HA negatively regulates excitatory gain onto D1(+)-MSNs via presynaptic H(3) receptor-dependent long-term depression (LTD) that requires G(βγ)-directed Akt-GSK3β signaling. Furthermore, HA asymmetrically regulates glutamatergic transmission from the prefrontal cortex (PFC) and mediodorsal thalamus (MDT), with inputs from the PFC undergoing robust HA-induced LTD. Finally, we report that acute immobilization stress attenuates this LTD by recruiting endogenous H(3)R signaling in the NAc at glutamatergic synapses onto D1(+)-MSNs. CONCLUSION: Stress-evoked HA signaling in the NAc recruits H(3) heteroreceptor signaling to shift thalamocortical input onto D1(+)-MSNs in the NAc. Our findings provide novel insight into an understudied neuromodulatory system within the NAc and implicate HA in stress-associated physiological states. |
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