The role of β2-nicotinic acetylcholine receptors in striatal microcircuits and striatum-dependent behaviors

The basal ganglia are essential for regulating movement, motivation, and cognitive flexibility by integrating excitatory, inhibitory, and modulatory signals. Within this network, the striatum serves as the principal input nucleus, where convergent cortical, thalamic, and midbrain inputs are integrated to guide adaptive behavior. Among striatal neurons, cholinergic interneurons (CINs) play a pivotal role in shaping network dynamics through the release of acetylcholine (ACh), which regulates presynaptic glutamate release at corticostriatal and thalamostriatal synapses and engages local inhibitory microcircuits to coordinate striatal output.This dissertation investigates how β₂-containing nicotinic acetylcholine receptors (β₂-NRs) regulate inhibitory and dopaminergic signaling within striatal microcircuits and how their dysfunction impacts behavior. Although β₂-NRs are expressed on both striatal interneurons and dopaminergic terminals, their cell type–specific contributions to striatal computation have remained poorly understood. Using a combination of cell type–specific conditional knockouts, optogenetic activation of CINs, fast-scan cyclic voltammetry, and ex vivo electrophysiology, this work delineates distinct roles for β₂-NRs in two fundamental inhibitory circuits: CIN-induced feedforward inhibition of spiny projection neurons (SPNs) and feedback inhibition within the cholinergic network.Conditional deletion of β₂-NRs from striatal interneurons (β₂-INs) markedly reduced CIN-induced feedforward inhibition of SPNs, demonstrating that β₂-NR activation on GABAergic interneurons is essential for rapid cholinergic control of striatal output. This work further reveals that CIN-induced dopamine release modulates this inhibitory pathway, establishing a direct link between local cholinergic signaling and dopaminergic regulation of striatal inhibition. In contrast, β₂-IN deletion did not affect feedback inhibition among CINs, whereas deletion of β₂-NRs from striatal afferents abolished feedback inhibitory responses entirely, indicating that an unidentified β₂-NR–expressing GABAergic afferent contributes to the coordination of cholinergic network activity.Behaviorally, β₂-IN deletion impaired cognitive flexibility in a reversal learning task, selectively increasing perseverative behavior without disrupting instrumental learning or goal directed control, implicating nicotinic signaling in adaptive action switching. Preliminary data further showed that deletion of β₂-NRs from nigrostriatal dopaminergic terminals did not alter effort-based decision-making, suggesting that β₂-dependent modulation of dopamine release is not required for normal effort valuation.Together, these findings identify CIN-induced feedforward inhibition as a key circuit mechanism linking β₂-NR–dependent cholinergic and dopaminergic signaling to adaptive behavioral control, providing new insight into how acetylcholine dynamically shapes striatal computation in health and disease.