Highlights d Visual deprivation prevents vDSGC dendrite orientation toward the ventral axis d Ventral direction tuning is maintained despite altered dendritic orientation d Inhibition-independent DS tuning is reduced in visually deprived vDSGCs d Spatially offset, null direction inhibition is maintained in visually deprived vDSGCs

Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.

Mu opioid receptor (MOR) agonists are the most effective analgesics, but their use risks respiratory depression and addiction. The epithalamic lateral habenula (LHb) is a critical site that signals aversive states, often via indirect inhibition of reward circuitry, and MORs are highly expressed in the LHb. We found that the LHb is a potent site for MOR-agonist analgesia. Strikingly, LHb MOR activation generates negative reinforcement but is not rewarding in the absence of noxious input. While the LHb receives inputs from multiple sites, we found that inputs from the lateral preoptic area of the hypothalamus (LPO) are excited by noxious stimulation, express MOR mRNA, and are preferentially targeted by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state relieved by LHb MOR activation. Therefore targeting this MOR sensitive forebrain circuit can relieve pain yet lower the risk of misuse by pain free individuals.

Mu opioid receptor (MOR) agonists are the most effective analgesics, but their use risks respiratory depression and addiction. The epithalamic lateral habenula (LHb) is a critical site that signals aversive states, often via indirect inhibition of reward circuitry, and MORs are highly expressed in the LHb. We found that the LHb is a potent site for both MOR-agonist analgesia. Strikingly, LHb MOR activation generates negative reinforcement but is not rewarding in the absence of noxious input. While the LHb receives inputs from multiple sites, we found that inputs from the lateral preoptic area of the hypothalamus (LPO) are excited by noxious stimulation, express MOR mRNA, and are preferentially targeted by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state relieved by LHb MOR activation. Therefore targeting this MOR sensitive forebrain circuit can relieve pain yet lower the risk of misuse by pain free individuals.

Changes in dendritic morphology in response to activity have long been thought to be a critical component of how neural circuits develop to properly encode sensory information. Here we report the impact of dark-rearing on the dendritic morphology and function of a retinal ganglion cell type, a ventral-preferring direction-selective ganglion cell (vDSGC). vDSGCs have asymmetric dendrites oriented along their preferred direction. We found that, at eye opening, vDSGC dendrites are not yet ventrally oriented, and that, surprisingly, dark-rearing prevents ventral orientation of vDSGC dendrites. Despite their dramatic change in dendritic morphology, vDSGCs in dark-reared mice maintain ventral directional preference. Direction selective tuning in dark-reared mice is mediated by asymmetric inhibition, as observed in vDSGCs of normally reared animals. Hence, we postulate that dendritic form follows proper circuit function, where dendritic orientation is refined over the course of development and is dependent on structured visual experience following eye opening.