Stress-induced plasticity of the autonomic ganglion neurons innervating the urogenital system
스트레스에 의한 비뇨생식계를 지배하는 자율신경의 가소성/
Dept. of Medicine/박사
Stress is defined as a state of threatened homeostasis, following exposure to extrinsic or intrinsic adverse forces (stressors). In order to re-establish the disturbed equilibrium against an imposed stressor, a repertoire of physiologic and behavioral responses is rapidly mobilized, constituting the adaptive stress response. Hallmarks of the adaptive stress response are the activation of the autonomic nervous system and hypothalamo-pituitary-adrenal (HPA) axis. Stress is known to alter neural, endocrine, immune and cardiovascular functions. To date, studies on stress-induced neural plasticity have focused on the central nervous system, but not the peripheral nervous system. Several studies suggest that stress can impact on the urogenital functions including voiding and erectile reflexes although neural mechanisms underlying this are poorly understood. Thus, the present study was designed to address whether stress can alter synaptic transmission as well as excitability of autonomic major pelvic ganglion (MPG) neurons innervating the urogenital system. In this regard, male Sprague-Dawley rats were immobilized daily for 2 hr in restraint cages. After 7 days, serum level of corticosterone was measured and MPG neurons were enzymatically dissociated for patch-clamp study. Real-time PCR analysis revealed that IMO stress did not alter expression of nicotinic acetylcholine receptor 3 and 4 subunits which mediate cholinergic synaptic transmission in MPG. In consistent with this, Ach-induced currents were not affected by IMO stress. As reported previously, MPG contains both sympathetic and parasympathetic neurons. The sympathetic and parasympathetic neurons show tonic and phasic firing patterns in response to prolonged current injections, respectively. IMO stress significantly reduced spike firing frequency in tonic MPG neurons by increasing afterhyperpolarization (AHP) duration. The effects of IMO stress on spike firing were prevented by adrenalectomy (ADX). RT-PCR analysis showed that STREX, a stress-sensitive splicing variant of large-conductance Ca2+-activated K+ channel (BK) was up-regulated in the MPG neurons of IMO rats. In addition, IMO stress also enhanced expression of SK2 and SK3, small conductance Ca2+-activated K+ channels (BK) isoforms which determine AHP duration and thereby spike firing frequency. Previousl studies have shown that tonic MPG neurons have been found to express T-type Ca2+ channels which are responsible for low-threshold spike firing. IMO stress reduced Ni2+- and mibefradil-sensitive low-threshold spike firing by down-regulation of T-type calcium channel 1H isoform in tonic MPG neurons. Down-regulation of T-type Ca2+ channels was reproduced in corticosterone-treated MPG neurons, indicating that corticosterone is a mediator of the altered gene expression. Finally, IMO stress was also found to down-regulate voltage-gated Na+ channels. Taken together, these data suggest that IMO stress reduces the excitability of autonomic neurons by altering expression of Na+, T-type Ca2+, BK, and SK channels, which might affect functions of target organs such as the bladder, the penis, etc. I studied for the first time effects of short-term stress on functional plasticity of autonomic ganglion neurons. More importantly, I suggest the molecular and cellular mechanisms underlying the stress-induced autonomic plasticity.