A highly opioid responsive VTA projection to the dorsal endopiriform nucleus.

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SUMMARY The dorsal endopiriform nucleus (DEn) is a highly conserved structure found in mammalian brains that is developmentally related to the claustrum and has been linked to the claustrum's role as the “seat of consciousness”. The DEn is connected to more limbic regions than the claustrum, has a very dense projection to infralimbic cortex, and receives strong inputs from sensory cortices especially olfactory and gustatory regions. While the DEn's role in behavior remains largely unknown beyond contributing to the generation of seizure activity, it has long been known to have extremely high levels of mu, delta, and kappa opioid receptor (MOR, DOR, and KOR) protein and mRNA. In preliminary studies we discovered a mostly non-dopaminergic ventral tegmental area (VTA) projection to the DEn; these neurons show a significantly stronger hyperpolarization in response to the MOR agonist DAMGO than any other VTA projection we have investigated. This is an exciting find because opioid reward, including intra-VTA opioid reward, is dopamine independent in opioid naïve animals. Thus, this non-dopaminergic, MOR sensitive projection may contribute to this opioid reward. Since the DEn receives inputs from a variety of sensory cortices, this is also a potential site of direct interaction between reinforcement encoding from the VTA and sensory cue information. Here we propose to anatomically map the VTA innervation of the DEn, characterize the VTA  DEn synaptic connectivity including its MOR sensitivity, and test whether selective modulation of this circuit connection produces reward or promotes learning or salience signaling. Together these studies will lay the groundwork for understanding a previously unstudied but highly opioid sensitive output of the VTA to an opioid receptor enriched brain region situated to integrate information from across cerebral cortex.