Role and Origin of the GABAergic Innervation of Dorsal Raphe Serotonergic Neurons

Abstract

Extracellular electrophysiological recordings in freely moving cats have shown that serotonergic neurons from the dorsal raphe nucleus (DRN) fire tonically during wakefulness, decrease their activity during slow wave sleep (SWS), and are nearly quiescent during paradoxical sleep (PS). The mechanisms at the origin of the modulation of activity of these neurons are still unknown. Here, we show in the unanesthetized rat that the iontophoretic application of the GABA(A) antagonist bicuculline on dorsal raphe serotonergic neurons induces a tonic discharge during SWS and PS and an increase of discharge rate during quiet waking. These data strongly suggest that an increase of a GABAergic inhibitory tone present during wakefulness is responsible for the decrease of activity of the dorsal raphe serotonergic cells during slow wave and paradoxical sleep. In addition, by combining retrograde tracing with cholera toxin B subunit and glutamic acid decarboxylase immunohistochemistry, we demonstrate that the GABAergic innervation of the dorsal raphe nucleus arises from multiple distant sources and not only from interneurons as classically accepted. Among these afferents, GABAergic neurons located in the lateral preoptic area and the pontine ventral periaqueductal gray including the DRN itself could be responsible for the reduction of activity of the serotonergic neurons of the dorsal raphe nucleus during slow wave and paradoxical sleep, respectively.

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

“…GALR1 in the vPAG could be expressed in GABA interneurons, which are known to inhibit 5-HT neurons directly (116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127). Moreover, some 5-HT neurons in the rat and mouse lateral wings are GABA/GAD + (70,117,(128)(129)(130)(131), and thus probably corelease GABA and 5-HT.…”

Preoptic Area Neurons and the Homeostatic Regulation of Rapid Eye Movement Sleep

“…It is well accepted that inhibition of serotonergic cells in the dorsal raphe nucleus (DRN) and noradrenergic neurons in the locus ceruleus (LC) is a necessary prerequisite for REM sleep generation. These monoaminergic cells are active during waking, decrease activity during non-REM sleep, and become inactive during REM sleep (Heym et al, 1982;Fornal et al, 1985;Sakai, 1986;Reiner and McGeer, 1987;Yamuy et al, 1995Yamuy et al, , 1998Thakkar et al, 1998;Gervasoni et al, 2000). Evidence suggests that the quiescence of these cells during REM sleep is attributable to GABA-mediated inhibition (Levine and Jacobs, 1992;Wang et al, 1992;Siegel, 1996, 1997a,b;Gervasoni et al, 2000).…”

“…Both regions project to monoaminergic and orexinergic neurons (Gritti et al, 1994;Zardetto-Smith and Johnson, 1995;Sherin et al, 1998;Steininger et al, 2001;Thompson and Swanson, 2003) that exhibit suppression of discharge during REM sleep (McGinty and Harper, 1976;Aston-Jones and Bloom, 1981;Heym et al, 1982;Sakai, 1986Sakai, , 1988. Some evidence suggests that the quiescence of these cells during REM sleep is attributable to GABA-mediated inhibition (Nitz and Siegel, 1997a,b;Gervasoni et al, 2000). Therefore, activation of MnPN and vlPOA GABAergic cells could be involved in the inhibition of arousal systems (Saper et al, 2001; and promote REM sleep.…”

Expression of 5-HT7 receptor mRNA in the hamster brain: Effect of aging and association with calbindin-D28K expression

“…Furthermore, the relatively low levels of expression of 5-HT 7 receptor mRNA observed in the DRN (and MRN) suggest that some of the 5-HT 7 receptor protein identified in these regions by binding studies or functional studies may be located on afferent terminals of nerve fibers originating in other brain regions. Some of the brain regions that have been demonstrated to be afferent to the DRN in the rat, such as the bed nucleus of the stria terminalis, the medial preoptic nucleus, the anterior hypothalamic area, the ventral pontine periaqueductal gray, the cingulate cortex, and the paraventricular thalamic nucleus (Peyron et al, 1998;Gervasoni et al, 2000;Brown et al, 2002;Lee et al, 2005), exhibited 5-HT 7 receptor mRNA expression in the hamster brain, although other afferent regions, such as the lateral preoptic area, lateral hypothalamic area, lateral habenula, perifornical nucleus, posterior hypothalamic area, and medial tuberal nucleus, did not show 5-HT 7 receptor mRNA signal in this study. Of the DRN-afferent regions that expressed 5-HT 7 receptor mRNA, only two, the cingulate cortex and the paraventricular thalamic nucleus, exhibited age-related decreases in expression of this mRNA.…”

“…This study investigated whether aging is associated with changes in 5-HT 7 receptor mRNA expression in the DRN, and other circadian substrates, e.g., the suprachiasmatic nucleus (SCN), the intergeniculate leaftlet (IGL), and the median raphe (MRN). Additionally, brain regions afferent to the DRN were measured, including the cingulate cortex, bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala, anterior hypothalamus, anterior paraventricular thalamic nucleus, zona incerta, and lateral periaqueductal gray (LPAG) (Gervasoni et al, 2000;Rampon et al, 1999). Finally, the dentate gyrus (DG) and fields CA1, CA2, and CA3 of the hippocampus were also studied.…”