Cholinergic Contribution to Circuits Guiding Behavioral Responses to Stressors

Project Summary The relationship between chronic stress and human anxiety disorders and depression is clear from epidemiological and clinical studies. Stress induces the release of neuromodulators that coordinate adaptive behavioral responses, but sustained activation of stress pathways results in dysregulation of circuits that can bias behavior toward maladaptive behavioral ensembles. Further, it is not clear why some individuals are susceptible to long term behavioral changes induced by stress and others are not. Acetylcholine (ACh) is released in response to stressful stimuli in multiple brain areas that govern behavioral responses to stressors. ACh signaling is important for adaptive behaviors, but also facilitates stress-related learning and hypervigilance and promotes stress-related avoidance. We have identified receptor subtypes that mediate effects of ACh in the amygdala, hippocampus and prefrontal cortex in response to stressors, and have begun to identify mechanisms that may modulate transitions to maladaptive behavioral ensembles. In the studies proposed here we will study the role of ACh in 1) acute, and 2) experience-dependent behavioral responses to stressors, and 3) test a novel hypothesis that prolonged ACh signaling may alter the balance in attention/encoding of aversive vs. appetitive stimuli. A negative cognitive bias is commonly observed in patients with anxiety disorders, depression or post-traumatic stress disorder; therefore, discovering a role for ACh in modulation of stress and reward encoding could result in novel directions for therapeutic development based on cholinergic mechanisms.