Histamine H3 Receptor Function Biases Excitatory Gain in the Nucleus Accumbens
| Autor: | Kevin M. Manz, Brad A. Grueter, Carrie A. Grueter, Jennifer C. Becker |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Chemistry Nucleus accumbens Heteroreceptor Medium spiny neuron 03 medical and health sciences Glutamatergic 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Monoamine neurotransmitter Synaptic plasticity medicine Histamine H3 receptor Tuberomammillary nucleus Neuroscience 030217 neurology & neurosurgery Biological Psychiatry |
| Zdroj: | Biological Psychiatry. 89:588-599 |
| ISSN: | 0006-3223 |
| Popis: | 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 Gβγ-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. |
| Databáze: | OpenAIRE |
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