Investigating the role of the lateral septum-ventral tegmental area projection in shaping reward learning

The desire and ability to appropriately seek out rewards is crucial to the survival of most species. Several psychiatric disorders, including major depressive disorder and substance use disorder, are characterized by dysfunctional reward seeking. Identifying neural circuit mechanisms that support reward seeking behaviors will ultimately lead to new treatments for these disorders. One region that has previously been implicated in reward seeking is the lateral septum (LS). However, the mechanism by which the LS modulates reward seeking behavior is unknown. One potential mechanism is through the connection between the LS and ventral tegmental area (VTA). Dopamine neurons in the VTA encode a reward prediction error (RPE) to represent the difference between the expected and actual reward received. This RPE signal determines whether a reward is worth seeking or not, with positive RPE values driving learning reward associations and negative RPE signals driving extinction. There have been multiple hypotheses as to the origin of the RPE signal in VTA dopamine neurons, but whether the signal is locally generated or largely inherited from elsewhere in the brain remains debated. This raises the possibility that upstream regions could significantly contribute to or shape RPE in the VTA, such as the LS. The LS directly innervates the VTA and has been shown to be reward responsive, which suitably positions it as a possible candidate to modulate reward-related behaviors by influencing the RPE signal. This proposal aims to identify whether the LS modulates reward seeking via its projection to the VTA, and specifically how the LS contributes to the generation and modulation of the RPE signal in VTA dopamine neurons. In Aim 1, I will perform cellular resolution calcium imaging of the LS-VTA population while the animal engages with a series of operant assays designed to elicit an error signal. I predict that LS-VTA neurons, like the non-specific LS neurons, have a differential response to rewarded trials and unrewarded trials when the expected reward is omitted. In Aim 2, I will implement projection-specific, closed-loop optogenetic inhibition of LS-VTA neurons while simultaneously performing population-level calcium imaging of dopamine neuron activity to examine the causal role of the LS-VTA population in shaping the VTA RPE signal and in extinction of a learned behavior. These results will determine the extent to which LS-VTA neurons causally contribute both to the RPE signal and reward seeking behavior. Furthermore, the findings of this proposal could aid in identifying novel mechanisms to target in the treatment of several psychiatric disorders and substance use disorders. Project Number: 1F31MH142027-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Sonia Karkare | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $50,114 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F02A-D (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11386180