Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

• Published in: The European journal of neuroscience 2019-07, Vol.50 (1), p.1712-1726
• Main Authors: Prouty, Eric W., Chandler, Daniel J., Gao, Wen‐Jun, Waterhouse, Barry D.
• Format: Article
• Language: English
• Subjects: Action potential; Animals; Cognitive ability; Cortex (somatosensory); Corticosterone; Corticosterone - administration & dosage; Corticosterone - pharmacology; Depression - metabolism; Dorsal raphe nucleus; Dorsal Raphe Nucleus - drug effects; Dorsal Raphe Nucleus - metabolism; Excitability; Excitatory postsynaptic potentials; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Firing rate; Forebrain; Geniculate Bodies - drug effects; Geniculate Bodies - metabolism; Glucocorticoids; Glucocorticoids - metabolism; Lateral geniculate nucleus; Male; Mental depression; Mental disorders; Nerve Net - drug effects; Nerve Net - metabolism; Neuroanatomical Tract-Tracing Techniques; Neurons; Patch-Clamp Techniques; Phenotypic variations; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Raphe nuclei; Rats; Rats, Sprague-Dawley; retrograde tracing; Serotonergic Neurons - drug effects; Serotonergic Neurons - metabolism; Serotonin; Serotonin - metabolism; Sprague‐Dawley rat; Visual cortex; Visual pathways; Visual Pathways - drug effects; Visual Pathways - metabolism; whole‐cell patch clamp electrophysiology
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14355

Glucocorticoid hormones and serotonin (5‐HT) are strongly associated with the development and treatment of depression, respectively. Glucocorticoids regulate the function of serotonergic neurons in the dorsal raphe nucleus (DR), which are the major source of 5‐HT to the forebrain. DR 5‐HT neurons are electrophysiologically heterogeneous, though whether this phenotypic variation aligns with specific brain functions or neuropsychiatric disease states is largely unknown. The goal of this work was to determine if chronic exogenous glucocorticoid administration differentially affects the electrophysiological profile of DR neurons implicated in the regulation of emotion versus visual sensation by comparing properties of cells projecting to medial prefrontal cortex (mPFC) versus lateral geniculate nucleus (LGN). Following retrograde tracer injection into mPFC or LGN, male Sprague‐Dawley rats received daily injections of corticosterone (CORT) for 21 days, after which whole‐cell patch clamp recordings were made from retrogradely labeled DR neurons. CORT‐treatment significantly increased the action potential half‐width of LGN‐projecting DR neurons, but did not significantly affect the firing frequency or excitatory postsynaptic currents of these cells. CORT‐treatment significantly reduced the input resistance, evoked firing frequency, and spontaneous excitatory postsynaptic current frequency of mPFC‐projecting DR neurons, indicating a concurrent reduction of both intrinsic excitability and excitatory drive. Our results suggest that the serotonergic regulation of cognitive and emotional networks in the mPFC may be more sensitive to the effects of glucocorticoid excess than visual sensory circuits in the LGN and that reduced 5‐HT transmission in the mPFC may underlie the association between glucocorticoid excess and depression. Following chronic corticosterone injections, only dorsal raphe (DR) neurons projecting to the medial prefrontal cortex (mPFC) displayed intrinsic and synaptic electrophysiological responses indicative of hypoactivity, which suggests mPFC serotonin levels may be particularly sensitive to glucocorticoid excess. We propose that hypoactivity of DR‐mPFC cells may result in deficient serotonergic modulation of mPFC functions such as emotional regulation and thereby contribute to depressive symptoms.