Prefrontal amygdala interactions in fear conditioning

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Pursuit of reward and avoidance of threat are two major behavioral motivators. Failure to balance these motivations results in maladaptive decisions and may underlie various pathological conditions. The sustained threat construct of the NIMH Research Domain Criteria (RDoC) includes avoidance, conflict detection, and perseverative behaviors. Sustained threat reactions interfere with the pursuit of rewarding activities that can decrease social interactions and trigger depression. Little is known about how decisions guide behavior during approach-avoidance conflict. The first phase of this MERIT shifted our focus from Pavlovian fear conditioning to active avoidance, exploring how prefrontal-amygdala-striatal circuits express and extinguish active avoidance. For the second MERIT phase, we have developed a new task that maximizes approach-avoidance conflict within a timed cue encounter that pits active avoidance against the pursuit of food. The new approach-avoidance conflict task has revealed three distinct behavioral phenotypes: 1) food-preferring rats that pursue food throughout the tone with little or no avoidance; 2) avoidance-preferring rats which avoid throughout the tone with little or no food-seeking; and 3) timers which seek food early in the tone and avoid later, thereby maximizing both access to food and safety. We will capitalize on these unique behavioral phenotypes to characterize the circuits mediating approach- avoidance decisions, using electrophysiological, immunohistochemical, and optogenetic methods. We will use both male and female rats in all our aims. Aim 1 will use immunohistochemistry combined with electrophysiology and fiber photometry to identify the circuits involved in conflict decision making. Aim 2 will test the circuits identified in Aim 1 with optogenetic manipulations. Aim 3 will assess the power of this task to identify new multi-dimensional behavioral phenotypes integrating conflict strategies with anxiety and social interactions. This research program will enable us to characterize decision-making circuits underlying different strategies for resolving approach-avoidance conflict. RELEVANCE (See instructions): Failure to balance pursuit of reward and avoidance of threat results in maladaptive decisions and pathological conditions including anxiety and depression. Using a novel rodent task that maximizes approach-avoidance conflict, we will characterize the circuits mediating approach-avoidance decisions using electrophysiological, immunohistochemical, and optogenetic methods. This research program will enable us to characterize circuits for resolving approach-avoidance conflict.