Disinhibition of mesolimbic dopamine circuit by the lateral hypothalamus regulates pain sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABA-ergic inputs from the lateral hypothalamus to the ventral tegmental area (LH GABA →VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathological pain. We demonstrated that optogenetic manipulation of the LH GABA →VTA projection bi-directionally regulated pain sensation in naïve male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathological pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by Complete Freund's Adjuvant. Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABA-ergic neurons and VTA GABA-ergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABA-ergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LH GABA →VTA projection. Furthermore, repeated activation of the LH GABA →VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LH GABA →VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LH GABA →VTA projection regulated pain sensation by targeting local GABA-ergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release. Significance Statement The mesolimbic dopamine (DA) system its brain-derived neurotropic factor (BDNF) signaling has been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends the different afferent fibers into and strongly influences function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA-VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of LH and the mesolimbic DA system in physiological and pathological pain.