Sunday, May 4, 2025
5/4/2025
Mechanisms of operant reward seeking in prefrontal somatostatin-expressing interneurons - Project summary Substance use disorder (SUD) is a debilitating disorder characterized by severe alterations in the neural circuits of reward. Among others, the gamma aminobutyric acid (GABA) system is a critical component of the pathology of SUDs. While historically studied in the context of alcohol use, the GABAergic system is now gaining more attention for its roles in mediating the rewarding properties of other drug types (such as opioids) and natural rewards. However, in comparison to other systems like dopamine, our understanding of the GABAergic mecha- nisms of reward seeking is far less complete. Like the fields of reward and addiction, a vast majority of studies of fear memory, which is where our previous work was situated, generally cast GABAergic neurons aside as simple gain modulators and instead focus on glutamatergic neurons as the main memory substrate. As a result, much less is known about whether and how GABAergic neurons themselves encode aversive memory. We pioneered this area and revealed that a population of somatostatin-expressing interneurons (SST-INs) in the prelimbic (PL) region of the rodent medial prefrontal cortex is a prominent substrate of fear memory. We also identified a second orthogonal PL SST-IN population which is activated by a single intraperitoneal morphine injection that drives positive valence. While these results hint towards a role for PL SST-INs in reward, the mech- anisms that underlie this function are unknown. Moreover, how PL SST-INs may differentially regulate different reward behaviors, such as natural and drug reward seeking, is unstudied. We will address these gaps by pursu- ing three Aims. 1. Reveal the in vivo dynamics, behavioral contributions, and map the circuits of PL SST-INs that drive natural and drug reward seeking. We will perform Miniscope imaging of PL SST-INs across natural and drug reward seeking to reveal when and how they are activated in self-administration tasks. Next, we will perform intersectional activity-dependent neural tagging and in vivo optogenetics to determine the specific contributions of tagged neurons to natural and drug reward seeking behaviors. Last, we will use nested optogenetics-based neural tagging to reveal the organization and brain-wide projections of PL projection neurons disinhibited by natural and drug reward-tagged SST-INs. 2. Determine the circuit plasticity mechanisms of operant natural and drug reward seeking in PL SST-INs. By using intersectional activity-dependent neural tagging and optogenetics- assisted brain slice physiology, we will reveal the synaptic and intrinsic plasticity mechanisms as well as the specific microcircuit alterations related to natural and drug reward seeking in SST-INs. 3. Reveal the transcrip- tional profiles of PL SST-INs driving operant natural and drug reward seeking. We will isolate nuclei from PL SST-INs tagged in response to natural and drug reward seeking and subject them to single-nucleus RNA-seq. Comparisons will be made between natural and drug reward-tagged as well as non-tagged PL SST-INs to reveal reward-specific transcriptional programs. Overall, results from this work will provide important fundamental in- sight to the mechanisms of natural and drug reward seeking in PL SST-INs.
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