Compulsive gambling can destroy lives, yet its underlying causes remain mysterious. One enticing clue as to the neural basis of the impulse to gamble comes from Parkinson's Disease. When treated with dopamine D2/D3 receptor agonists, Parkinson's patients are 20-fold more likely to develop pathological gambling as compared to the general population. The goal of this project is to investigate how D2/D3 receptor signaling impacts reward processing in the context of gambling behavior. Although many regions of the brain express D2 or D3 receptors, I have found, through targeted pharmacology and immunohistochemistry for the immediate early gene cFos, that the primary site of action for pramipexole, a D2/D3 agonist frequently associated with pathological gambling behavior in Parkinson's patients, is the nucleus accumbens (NAc). The NAc receives a large direct projection from the ventral tegmental area (VTA), the region of the human and rodent brain that contains the primary population of dopamine neurons. Because D2-like receptors have a high affinity for dopamine, it is thought that D2/D3 receptors in the NAc are typically agonized by the tonic low levels of dopamine released by the VTA, but may sense the pauses in dopamine neuron firing that occur with unexpected negative events. In this way, they may encode the negative aspect of reward prediction error. The goal of the experiments proposed here is to utilize in-vivo behaving electrophysiology and optogenetic techniques to test the hypothesis that D2/D3 agonism diminishes encoding of negative reward prediction errors leading to increased risk-seeking in the context of gambling behavior. Furthermore, these experiments are aimed at establishing a causal role for D2R-expressing neurons in the NAc in this behavioral change, with an eye towards potential therapeutics for complulsive gambling involving manipulation of D2R-expressing NAc neuron activity.
Impulse---control disorders have a devastating effect on the lives of individual sufferers and a substantial impact on the United States economy. The National Institutes on Drug Abuse estimates that the costs of drug abuse alone exceed $600 billion annually. This research will explore the mechanisms by which dopamine signaling impacts these risk-seeking behaviors, particularly in the context of pathological gambling.
|Zalocusky, Kelly A; Ramakrishnan, Charu; Lerner, Talia N et al. (2016) Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making. Nature 531:642-6|
|Ferenczi, Emily A; Zalocusky, Kelly A; Liston, Conor et al. (2016) Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science 351:aac9698|
|Lerner, Talia N; Shilyansky, Carrie; Davidson, Thomas J et al. (2015) Intact-Brain Analyses Reveal Distinct Information Carried by SNc Dopamine Subcircuits. Cell 162:635-47|