Histamine H3 Receptor Function Biases Excitatory Gain in the Nucleus Accumbens

Abstract

Background: Histamine (HA), a wake-promoting monoamine implicated in stress-related arousal states, is synthesized in histidine decarboxylase-expressing hypothalamic neurons of the tuberomammillary nucleus. Histidine decarboxylase-containing varicosities diffusely innervate striatal and mesolimbic networks, including the nucleus accumbens (NAc). The 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: Using 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 H₃ receptor-dependent long-term depression that requires G_βγ-directed Akt-GSK3β signaling. Furthermore, HA asymmetrically regulates glutamatergic transmission from the prefrontal cortex and mediodorsal thalamus, with inputs from the prefrontal cortex undergoing robust HA-induced long-term depression. Finally, we report that acute immobilization stress attenuates this long-term depression by recruiting endogenous H₃ receptor signaling in the NAc at glutamatergic synapses onto D1(+)-MSNs.

Conclusions: Stress-evoked HA signaling in the NAc recruits H₃ 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.

Keywords: Glutamatergic transmission; Histamine; Histamine H3 receptor; Nucleus accumbens; Stress; Synaptic plasticity.