Substance use disorders (SUD) are characterized by pathological behavioral engagement with rewarding stimuli
despite negative outcomes. There has been a concerted effort to identify the neural correlates of reward receipt,
as well as the systems-level processes that govern chronic cannabis use disorders, a growing problem in the
US. There remains a lack of mechanistic understanding of the intrinsic neurobiology which underlies behavioral
engagement, a fundamental process in drug seeking behavior. As such, the primary goal of this pathway to
independence proposal will be to receive in depth neuroscience training, facilitating new skills in a series of
cutting-edge approaches which will provide a deeper understanding of the underpinnings of neuromodulatory
regulation of engagement in reward-seeking behaviors, and how these mechanisms are altered with chronic
cannabinoid use. The Nucleus Accumbens(NAc) represents an important reward network hub known to regulate
reward engagement and the reinforcing properties of drugs of abuse. The NAc receives dense innervation from
the Paraventricular Thalamus(PVT), which receives visceromotor and interoceptive inputs from the
hypothalamus and hindbrain, and projects widely across the forebrain to regulate a variety of motivated
behaviors. 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(NTS) is selectively expressed in the anterior PVT and our preliminary data
demonstrates that these neurons send excitatory projections to the NAc, which are enriched with the cannabinoid
1 receptor(CB1R) and tightly regulated via endogenous cannabinoid(eCB) signaling. In this proposal, we first aim
to understand how eCB modulation of aPVT projections to the NAc regulates behavioral engagement. Our
preliminary experiments demonstrate that aPVT projections to the NAc are inhibited during behavioral
engagement and excited upon disengagement, in both rewarding and aversive contexts. In tandem with our
electrophysiology data demonstrating retrograde eCB inhibition of PVT terminals, we will determine when and
how eCBs are released in vivo to modulate aPVT input to ultimately affect behavioral engagement. Our second
aim will be to determine how the activity of projection defined NAc neurons is causally linked to eCB
production and reward seeking behavior. In this aim, we will use 1-photon imaging to record the activity of
specific aPVT-NAc projection ensembles. We will multiplex this high-resolution neural data with novel machine
learning behavioral tracking algorithms to directly correlate neural activity with discrete aspects of reward seeking
behaviors. Finally, in the R00 portion of this grant, I will expand the scope of this study to other aPVT output
regions to determine how the aPVT regulates cannabinoid seeking behaviors through divergent efferent
projections across the forebrain. The training received under this proposal will facilitate my transition to
heading my own independent academic research laboratory focused on decoding neuromodulation in SUD.