Acute stress has been shown to aid in the development of anxiety-like symptoms as well as lead to specific anxiety disorders such as post-traumatic stress disorder (PTSD). The cellular and molecular mechanisms underlying development of depressive and anxiety disorders remain largely unknown. One approach to studying the pathogenesis of these disorders is to examine how the brain controls the physiological and behavioral response to acute stress. Upon exposure to an acutely stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis is activated, resulting in a rapid increase in plasma glucocorticoid (GC) levels. The acute stress system also encompasses the sympathomedullary component, which induces the secretion of adrenalin from the adrenal medulla, leading to physiological changes including an increase in body temperature and heart rate as well as the classical fright, fight or flight responses. A key brain structure that exerts powerful negative regulation on the stress-response system by inhibiting the HPA axis is the hippocampus. While critical for the animal's short-term survival, stress responses can become harmful if uncontrolled, leading to maladaptive coping mechanisms. It has been proposed that these maladaptive coping mechanisms contribute to development of depressive- and anxiety-like disorders. Interestingly, acute stress also enables a form of stress-induced synaptic plasticity called long-term depression (LTD) in the adult hippocampus. In contrast to the well-studied role of long-term potentiation (LTP) in learning and memory, the biological functions of hippocampal LTD, especially in the adult, remain obscure. Recent findings have suggested that LTD may be a cellular mechanism to ensure adequate or proper behavioral responses to environmental changes. In the present study, we hypothesized that acute, stress-enabled hippocampal LTD might be a necessary coping mechanism aiding the recovery from acutely stressful and/or traumatic situations. The p75 neurotrophin receptor (p75NTR) is a candidate for participating in LTD and mediating responses to acute stress. The p75NTR is a pan-neurotrophin receptor that is activated by all members of the neurotrophin family. Neurotrophins play important roles in neuronal development, synaptic plasticity, learning and memory, and mediating long-term stress responses in the brain. We found that transgenic mice lacking the p75NTR do not exhibit stress-induced LTD. We also found that the p75NTR mutants show increased levels of anxiety-like behavior. In the adult brain, p75NTR is primarily expressed in basal forebrain cholinergic neurons (BFCN), which are the major source of cholinergic innervation to the hippocampus. Inhibiting cholinergic transmission with the muscarinic antagonist scopolamine also blocked stress-enabled LTD in the hippocampus, and also led to increased anxiety-like behavior. We then 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. These findings suggest novel molecular targets and neurotransmitter pathways responsible for elaboration of the stress response, which if further developed could have potential therapeutic importance in anxiety disorders.
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