Role of the p75NTR, LTD and the cholinergic system in mediating coping mechanism

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

The cellular and molecular mechanisms underlying development of stress-related anxiety disorders remain largely unknown. Exposure to psychogenic stress contributes to the development of anxiety disorders, including post-traumatic stress disorder (PTSD). One approach to studying the pathogenesis of these disorders is to examine how the brain controls and responds to stress in animal models. Studies show that stress responses are critical for the animal's short-term survival, but they can become harmful if uncontrolled, leading to maladaptive coping mechanisms and altered brain physiology, chemistry, and anatomy. These studies were designed to better understand the roles of the p75 neurotrophin receptor (p75NTR) and long-term depression (LTD), a form of synaptic plasticity, in mediating development of anxiety and the stress response. These studies focused on 1) the physiological effects of loss of p75NTR in hippocampal physiology and the relationship to cholinergic signaling and 2) how disruption of these processes affects development of anxiety-like behavior and the response to acute stress. In the adult brain, p75NTR is primarily expressed in basal forebrain cholinergic neurons, which are the major source of cholinergic innervation to the hippocampus. Exposure to acute psychological stress enables a form of synaptic plasticity called long-term depression (LTD) in the adult hippocampus. The biological functions of hippocampal LTD, especially in the adult, remain obscure. Recent findings have suggested that LTD may mediate behavioral flexibility by ensuring adaptive responses to environmental changes. We found that transgenic mice lacking the p75NTR do not exhibit stress-induced long-term depression. We also found that the p75NTR-null mice show increased levels of anxiety-like behavior. Inhibiting cholinergic transmission with the muscarinic antagonist scopolamine also blocked stress-enabled LTD in the hippocampus, leading to increased anxiety-like behavior. We confirmed that these behavioral effects were related to a deficiency in stress-enabled LTD by blocking LTD directly using a specific peptide inhibitor and examining anxiety-like behavior. As expected, administration of the peptide inhibitor reduced stress-induced LTD and exacerbated anxiety-like behavior. Our studies provide an excellent foundation for further exploration of how stress-enabled LTD regulates mood in response to acute stress.