Dopaminergic regulation of striatal ensembles during cognitive performance: Implications for Parkinson's disease

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Abstract Patients with Parkinson's disease suffer from debilitating motor and cognitive impairments. These symptoms are largely driven by the striatal dopamine depletion caused by the disease. In healthy individuals, striatal dopamine modulates distinct pools of medium striatal spiny neurons (MSNs) that express either D1 or D2 receptors. D1 and D2 MSNs project to different downstream structures and play dissociable roles in movement. However, how D1 and D2 MSNs mediate higher-order cognitive functions is unclear. This proposal will target this knowledge gap by investigating how D1 and D2 MSNs mediate performance during timing tasks. During timing tasks, subjects are presented with a cue that informs them to make a motor response after a certain interval of time elapses (e.g., press a button after 6 seconds passes). Timing tasks recruit several cognitive functions (e.g., working-memory, attention, and decision- making). Furthermore, timing is heavily dependent on the striatum, sensitive to dopaminergic manipulations, and disrupted in both Parkinson's patients and animal models of this disease. In Aim 1, we will evaluate how striatal dopamine modulates D1 and D2 MSN activity during timing tasks. Specifically, during timing tasks, many MSNs progressively increase or decrease their firing rates linearly across time. This `ramping' activity is critical for performance and appears to progress until a `threshold' level of activity is reached, at which point a decision to respond is made. Blocking striatal D1 or D2 receptors delays when decisions are made during timing tasks. Furthermore, the types of decisions that are impacted by D1 or D2 blockade are dissociable. We will combine focal pharmacology, cell-type specific optogenetics, and electrophysiology to test the hypothesis that dopamine tunes the threshold activity level of D1 and D2 ramping MSNs. In Aim 2, we will test the hypothesis that local connectivity between D1 and D2 MSNs within the striatum is critical for timing performance. Specifically, blocking striatal D2 receptors substantially impairs timing behavior. Surprisingly, inactivating the downstream structures of D2 MSNs does not impact timing performance. Therefore, we will test the hypothesis that D2 MSNs mediate timing via lateral inhibition to D1 MSNs within the striatum, rather than through their downstream output. Specifically, we will disrupt D2 MSN activity while simultaneously blocking the downstream output of D2 MSNs with optogenetics. If D2 MSNs mediate timing via lateral inhibition within the striatum, manipulating D2 MSN activity within the striatum should still exert an effect, even when their downstream output is blocked.