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

National Institute Of Mental Health

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Abstract

Mood and anxiety disorders are common psychiatric disorders that affect patients chronically and can adversely complicate the prognosis of other medical conditions. As stressful life events are often associated with the development of depressive- and anxiety-like behaviors, both disorders have been described as stress-related. Stress, particularly when chronic, can aggravate and increase susceptibility for developing depression, but does not seem to confer the disorder per se. In contrast, 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 depressive and anxiety disorders remain largely unknown. Clinically, these disorders show high rates of co-morbidity and both respond to antidepressant therapy, but the extent to which they share underlying mechanisms is unclear. [unreadable] One approach to studying the pathogenesis of these disorders is to examine how the brain controls the physiological and behavioral response to acute and chronic stressors. 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 critical brain structure that exerts powerful negative regulation on the stress-response system by inhibiting the HPA axis is the hippocampus, which receives and processes information to determine what is stressful and whether or not the body needs to mount an appropriate, adaptive response. While critical for the animal's short-term survival, these stress responses can become harmful if uncontrolled, leading to maladaptation that results in an elevated HPA response. This can ultimately lead to damage and atrophy of neurons in the hippocampus as well as development of depressive- and anxiety-like phenotypes. [unreadable] Interestingly, acute stress also enables long-term depression (LTD) in the adult hippocampus, which, unlike the juvenile hippocampus, does not express LTD under normal conditions. 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 studies have begun to provide some clues. Blockade of LTD in the nucleus accumbens (NAc) dampens amphetamine-induced behavioral sensitization. Also, in the hippocampus, genetic manipulation that impairs LTD is correlated with behavioral inflexibility. These findings suggest 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 to aid the organism in its recovery effort. We attempted to develop strategies that selectively block stress-enabled hippocampal LTD. One such strategy was to take advantage of p75NTR knockout (KO) mice, which have recently been shown to exhibit no LTD in the adolescent hippocampus. Surprisingly, the p75NTR mutants behave anxiously under stressful conditions, without any signs of depression. In the adult brain, p75NTR is primarily expressed in basal forebrain cholinergic neurons (BFCN), which have a major cholinergic projection to the hippocampus via the medial septum. Inhibition of the cholinergic transmission by the muscarinic antagonist scopolamine also blocked stress-enabled LTD, leading to anxiety. A final strategy is to block LTD directly using a specific peptide that prevents AMPA receptor endocytosis. Systemic injection of the peptide inhibitor exacerbated anxiety-like behavior after the animal was exposed to an acute stressor. Thus, anxiety- and depressive-like behaviors can be separated mechanistically, and p75NTR-cholinergic transmission-LTD might be a major pathway that the brain uses to manage stress-induced anxiety.