Investigating the Role of GABAergic Interneurons in the Dorsomedial Striatum in Goal-Directed Behavior

Project Summary: Goal-directed behaviors aim to maximize rewards in changing environments. Abnormalities in goal-directed behavior are a feature of a range of neuropsychiatric diseases and are functionally impairing. The dorsomedial striatum (DMS) is critical for the execution of goal-directed behavior. Within the DMS, the role of sparse GABAergic interneurons in behavior is of increasing interest. Parvalbumin-positive (PV+) fast-spiking interneurons (FSIs) exhibit sensory-guided choice- and action initiation-related activity, while somatostatin- positive (SST+) low-threshold spiking interneurons (LTSIs) exhibit novel reward-related activity that decays throughout operant learning. However, the role of FSIs and LTSIs in value-based goal-directed behavior is not known. Both subtypes receive cortical inputs that guide value-based choice and signal unexpected outcomes. FSIs are soma-targeting, allowing them to directly control principal neuron spiking and optimize ensemble recruitment, while LTSIs are dendritic-targeting, allowing them to modulate excitability of principal neurons in response to cortical inputs. Using this framework as a starting point would suggest striatal FSIs mediate updating of actions by silencing previously active SPN ensembles, while LTSIs may facilitate reward-history integration by decreasing SPN excitability and attenuating sensitivity to incoming cortical information biasing choice. LTSIs additionally exert inhibition onto midbrain dopaminergic afferents to the DMS, which play a role in the modulation of motor vigor. My preliminary data demonstrate that LTSIs exhibit unexpected outcome-related activity, and that constitutive inhibition of LTSIs increases motor vigor. I therefore hypothesize that DMS FSIs exhibit pre-choice activity to refine action selection and inhibit competing actions, especially as contingencies change. Conversely, I hypothesize that DMS LTSI activity is higher in the setting of unexpected rewards, and thus helps constrain vigor and facilitate integration of evidence when contingencies change. To test these hypotheses, I have developed a head-fixed two-alternative forced choice behavioral paradigm in mice that assays the effect of varying relative reward values, reward probabilities, and net reward environment on value-based goal-directed choice and motor vigor. With this task, I aim to elucidate FSI and LTSI activity patterns during value-based behavior using fiber photometry and 1-photon miniscope recordings, and causally manipulate their activity using optogenetics. These findings will contribute to a growing evidence base on the role of striatal microcircuitry in striatal function and goal-directed behavior, with potential translational relevance suggested by evidence implicating striatal interneurons in a range of neuropsychiatric disease presentations.