REGULATION OF SEPTOHIPPOCAMPAL PATHWAY

Yale University, New Haven CT

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Abstract

Mood disorders are often precipitated/worsened by stress, which decreases hippocampal neurogenesis, causes atrophy and decreases- derived neurotrophic factor (BDNF) mRNA. These effects may partly be mediated via an excess of glucocorticoids (GC) possibly due to decreased hippocampal hypothalamic-pituitary-adrenal (HOA) axis feedback. Anti-depressants up-regulated hippocampal (BDNF) aqnd neurogenesis. Functionally, hippocampal disruption may contribute to cognitive deficits in stress-related disorders. Available evidence suggests that, similar to cognitive functions, hippocampal BDNF and HPA axis feedback are highly dependent on the septohippocampal pathway which provides the hippocampus with almost its entire ACh. Thus, rats with selective loss of septohippocampal cholinergic neurons are not only cognitively impaired, but have higher basal corticosterone (CORT) and higher CORT levels for a longer period after restrain stress. Muscarinic receptor antagonists mimic this effect, suggesting that hippocampal cognition, HPA axis feed back and BDNF are under a septohippocampal muscarinic tone. In turn, retrograde-transported hippocampal BDNF provides essential trophic support to the septohippocampal cholinergic neurons. Behavioral, neurochemical and molecular studies have demonstrated that septohippocampal cholinergic functions decline rapidly with stress. In our preliminary studies, conducted using electrophysiological recordings in rat brain slices, we have found that muscarinic tones, which reflects the availability of ACH that is synthesized by septohippocampal cholinergic neurons, is significantly reduced both in stressed rats as well as in BDNF null-mutant mice. Therefore, we hypothesize that 1) stress reduces septohippocampal functions by reducing the availability of ACh; 2) the decreased muscarinic tone impairs the hippocampal cognition and HPA axis feedback, and reduces BDNF and neurogenesis; 3) the reduced BDNF and elevated CORT further exacerbate cholinergic functions. Mechanistically, we hypothesize that 1) the effects of stress are mediated via septal GC receptors and/or CRF1 receptors; 2) GC and/or CRF enhance breakdown of available ACh by transcriptional activation of AChE; 3) antidepressants, by up-regulating hippocampal BDNF and enhancing monoamine levels, restore septohippocampal functions. The above hypothesis will be tested using electrophysiological recordings in septohippocampal neurons in conjunction with immunocytochemical and in situ hybridization techniques. The proposed research will provide fresh insights into the mechanisms underlying stress-induced changes in brain functions and possibly treatment of associated cognitive deficits.