Neurophysiological biomarkers in preclinical assays of risk propensity

PROJECT SUMMARY: Individual humans and animals can lie anywhere along a continuum of high to low risk- taking propensity. Several neuropsychiatric conditions are characterized by extremes of risk-taking propensity. For example, patients with pathological anxiety or anorexia nervosa show high risk aversion, while patients

with gambling disorder, or substance use disorder exhibit low risk aversion. Both high and low risk-taking propensity are thought to drive and maintain maladaptive behavior in these disorders. Therefore, novel pharmacological agents that shift risk-taking propensity closer to population mean values could provide novel

treatments for these disorders. Although risky decision-making paradigms exist for humans and animals, behavioral assays that also elicit robust and translationally relevant neurophysiological markers are lacking. Here, we propose to optimize, pharmacologically test, and mechanistically probe a novel in vivo behavioral and

neurophysiological assay to be used for translational studies and for screening for novel drugs to treat psychiatric conditions associated with high or low aversion to risk. Recent work in wild-type rats suggests that the activity of dopamine receptor 2 expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens

core (NAcC) encodes prior outcomes and predicts future choices during a risky decision-making operant task. First, we will manipulate operant task parameters to establish that the task fully captures both extremes of risk- taking propensity, and also measures constructs underlying risky decision-making, including reward and loss

sensitivity, motivation, and goal-directed versus habitual responding. We will also identify neurophysiological markers of risky versus safe choices during the task using fiber photometry and whole brain local field potentials (LFP). We predict that during the decision period immediately preceding safe or risky lever selection,

increases in both NAcC D2-MSN activity and theta oscillations within a corticostriatal circuit including the NAcC/ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC), will precede safe choices. In contrast, we predict that decreases in NAcC D2-MSN activity and theta activity within this

corticostriatal circuit will precede risky choices. Theta activity within corticostriatal brain regions will provide a non-invasive and translationally relevant neurophysiological marker of risk-propensity, while NAcC D2-MSN activity will provide a marker of risk-propensity for drug screening using animals. Second, we will test whether

drugs with known effects on risky decision-making in humans produce the same effects on the behavior of rats in the optimized paradigm. We will assess the effects of the dopamine D2/D3 agonist pramipexole, which increases problem gambling in Parkinson’s Disease, and the D2/D3 antagonist sulpiride, which increases risk

aversion in humans. We will also determine drug effects on NAcC D2-MSN activity and corticostriatal theta. Third, we will use intra-NAcC drug infusions and optogenetics to test whether changes in NAcC D2-MSN activity during the decision period of the operant task plays a causal role in safe versus risky decision-making.