Neurotensinergic-eCB modulation of reward and aversion via a PVT-NAc circuit

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PROJECT SUMMARY The Nucleus Accumbens (NAc) represents an integral functional component of the mesocorticolimbic pathway, canonically known as the “reward” pathway. Decades of pharmacological studies have demonstrated that nearly all drugs of abuse elicit dopamine release within the NAc, altering innate systems for reward processing both acutely and over chronic time scales. Long-term abuse and addiction to drugs is conceptualized as being driven in part by these maladaptive changes in reward and aversion processing alongside a desire to avoid the dysphoric effects of drug withdrawal or stress. Therefore, a comprehensive neuropharmacological understanding of the mechanisms that govern reward and aversion are crucial towards advancing new pharmacological targets for drug addiction. Primary NAc output neurons, medium spiny neurons (MSNs), have little spontaneous activity, and instead rely more heavily on extrinsic excitatory input from brain regions such as the basolateral amygdala (BLA), paraventricular thalamus (PVT), and prefrontal cortex (PFC). The PVT, a relatively understudied brain region, has similarly been shown to play an integral role in regulating behavioral responses to rewarding and aversive stimuli. It has been recently shown that PVT-NAc circuit activity regulates the behavioral effects of opiate withdrawal, sucrose seeking/consumption, and behavioral responses to painful stimuli. The PVT is a highly heterogenous structure, and recent studies examining the PVT-NAc circuit have shown conflicting results, partially driven by a lack of genetic and anatomical specificity within the PVT. The neuromodulatory peptide neurotensin is selectively expressed in the anterior PVT and our preliminary data demonstrates that these neurons send excitatory projections to the NAc. This peptide, while less characterized than many other neuropeptidergic signaling systems, has been shown to regulate the behavioral responses to drugs of abuse and dopamine release in the NAc. The first aim of this proposal is to determine the pharmacological mechanism by which neurotensinergic input from the PVT regulates NAc activity. Prior studies have shown NTS signaling in the striatum mobilizes endogenous cannabinoid (eCB) production, which has similarly been implicated in regulating reward and aversion. Our preliminary data supports that eCBs regulate PVT input to the NAc. In this aim, we will determine the functional interaction between NTS and eCBs in regulating the activity of the excitatory PVT-NAc circuit. Our second aim will be to determine the functional role of NTS-eCB modulation of PVT NTS-NAc excitatory projections in regulating reward and aversion. Using state of the art in vivo photometric techniques, we will determine how rewarding and aversive stimuli modulate neural activity and NTS/eCB release within the PVT-NAc circuit. We will further use in vivo optogenetic techniques combined with pharmacology to test the necessity and sufficiency of PVT-NAc activity in driving behavioral responses to rewarding and aversive stimuli. These data will facilitate a better understanding of the innate mechanisms regulating reward and aversion opening up potential new pharmacological treatments for substance abuse.