Physiology and information processing of the OCD circuit

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Project Summary (P2). The control of adaptive behavior, at its most fundamental level, relies on appropriately weighting the rewards and aversive outcomes, and deciding when to take a risk to maximize reward, and when to play it safe. Malfunctions in these processes are associated with psychiatric disorders and maladaptive behavioral states, such Obsessive-Compulsive Disorder (OCD) and anxiety. But despite their importance in everyday decision making and clinical settings, little is known about how aversive outcomes influence value- based decision making. In particular, in non-human primates, the closest animal model to humans, the neuronal mechanisms of how the brain evaluates and anticipates aversive events is poorly understood. P2 will (1) assess how the brain controls decision making under the risk and uncertainty of aversive outcomes in non- human primates and (2) in collaboration with other projects in the Conte Center, will utilize this information to shed light on the circuit mechanisms of, and novel therapies for, OCD and related pathologies. Aim 1 will utilize functionally targeted in-vivo anterograde tracing to identify regions within vlPFC, insula, and other regions that receive inputs from an area in ACC that has been functionally implicated in processing value and uncertainty of aversive outcomes. In the same animals, we will perform electrophysiological examinations of newly identified brain regions and assess whether and how they contribute to the processing of valuation, uncertainty, and receipt of aversive reinforcements. With P1, we will understand the relationship between functional properties of the OCD related brain areas and their anatomic connectivity. With P3-P5, we will relate single neuron data in non-human primates to ongoing therapy development and circuit mapping efforts in humans. Aim 2. will utilize a combination of computational and experimental methods to assess how the neural encoding of information about aversive reinforcements could give rise to OCD-like maladaptive behavior under aversive-outcome uncertainty. This Aim will utilize the probabilistic approach-avoidance task (PAAT), that we developed with P3, to determine the mental algorithms involved in aversive decision making under uncertainty and derive their neural underpinnings in the ACC-vlPFC-insula circuit. It will then disrupt the neural activity in identified sub regions of the circuit to obtain causal evidence for their contributions to specific aspects of behavioral control in PAAT. The unprecedented precision of single neuron recordings in this Aim will inform the interpretation of imaging data in other Projects. Furthermore, a wide range of direct manipulation methods for mediating OCD-related circuitry will be explored to facilitate the development of novel treatments for OCD in P5. In sum, these Center-integrated Aims represent crucial steps for our understanding of the neurobiology of OCD and more generally will broaden our understanding of the mechanisms of decision making. Particularly, in collaboration with other projects of the Center, they will shed light on how brain areas known to be crucially involved in OCD mediate our everyday decision making.