Effects of NPY on Hippocampal Circuit Function

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Neuropeptide Y (NPY) has robust anxiolytic (anti-anxiety) properties and is thought to be a stress resilience factor. Clinical and pre-clinical studies have shown that NPY signaling regulates stress-dependent behavior in both humans and rodents. Our knowledge of the mechanisms by which NPY affects synaptic and circuit function to alter behavior is incomplete. NPY has been implicated in a wide variety of anxiety disorders, including post- traumatic stress disorder (PTSD). Low levels of NPY have been measured in patients with PTSD and in animals exposed to traumatic stress. Modulation of NPY has been proposed as a potential therapy for PTSD and other anxiety disorders. The hippocampus has been implicated in anxiety disorders including PTSD, which can be considered maladaptive forms of learning. NPY and its receptors are found at high levels in hippocampus, and direct injections of NPY into hippocampus attenuate avoidance behavior in rodents. Importantly, the levels of NPY in hippocampus are reduced in rodents exposed to traumatic stress. The mechanism underlying this decrease is not known. However, the reduction in NPY expression by traumatic stress is important, because injection of NPY into hippocampus alleviates behavioral symptoms. In the previous funding period, we showed that traumatic stress causes the loss of NPY release in the temporammonic pathway in the CA1 region of hippocampus, a pathway that is important for memory consolidation and fear learning. In this funding period, we will determine the effects of NPY release in the TA pathway on hippocampal circuit function and behavior, investigate the mechanisms of decreased NPY release caused by traumatic stress, and test whether enhancing release of NPY in the TA pathway can rescue the behavioral effects of traumatic stress. These studies could lead to new therapeutic strategies to alleviate anxiety symptoms in PTSD patients.