Neurochemical and Electrophysiological Characterization of Target-specific Neuronal Populations in the Dorsal Raphe Nucleus and Their Susceptibility to Chronic Corticosterone as a Model of Depression

摘要

Serotonin (5-HT) neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many homeostatic physiological processes and neuropsychiatric disorders. Heterogeneity among DR 5-HT neurons with respect to their anatomical relationships, neurochemical profiles, and electrophysiological properties is well-recognized, but only recently have studies begun aligning such phenotypic variations with specific brain functions. The goal of this work was to link DR neurons to the operation of cognitive and emotional circuitry or sensory processing networks by characterizing cells according to their neurotransmitter expression, electrophysiological profiles, and efferent connectivity; specifically, neurons projecting to the medial prefrontal cortex (mPFC, a region involved in cognition and mood regulation) or the lateral geniculate nucleus (LGN), a visual sensory relay. A further goal was to determine whether serotonergic regulation of cognitive/emotional function might be selectively impacted by a glucocorticoid-excess model of rodent depression; therefore, we examined the effect of chronic corticosterone (CORT) administration on the electrophysiology of these target-specific neuronal populations. Following retrograde tracer injection in mPFC or LGN (and once-daily subcutaneous injections of CORT at 40 mg/kg for 21 days in a subset of animals), rat brainstem sections containing the DR were immunohistochemically stained for 5-HT and co-transmitters or used for whole-cell patch clamp recordings. We found that neuronal nitric oxide synthase was expressed in a significantly greater proportion of neurons projecting to mPFC than to LGN (60% vs 22%)---a neurochemical bias consistent with the emerging role of nitric oxide in stress responses and depression. Additionally, only mPFC-projecting neurons displayed CORT-induced hypo-excitability, suggesting that protracted exposure to excess glucocorticoids may preferentially reduce 5-HT output in the mPFC. In summary, these data indicate that subsets of DR 5-HT neurons, defined by efferent connectivity and co-transmitter expression, respond selectively to elevated CORT levels and may account for functionally-specific differences in 5-HT transmission under normal conditions and in neuropsychiatric disease states. Based upon these initial findings we propose that the observed hypo-excitability in DR-mPFC projecting cells may underlie the cognitive deficits and emotional disturbances characteristic of depression and that functional enhancement of these cells may correlate with positive therapeutic responses to serotonergic antidepressants.