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Serotonergic neurons are spontaneously active with slow regular discharge during alert behavior and decreased activity during sleep. Sleep-related inhibition of serotonergic neurons is mediated by GABAergic inputs that originate in hypothalamic and brainstem sleep centers. During alert behavior, tonic release of GABA contributes to feedback and feedforward inhibitory circuits that, together with serotonin autoreceptors, prevent excess stimulation of serotonergic neurons. Glutamatergic inputs to the raphe originate in the brainstem, several hypothalamic nuclei and cerebral cortex. Although glutamate receptor agonists strongly stimulate serotonergic neuronal discharge, the physiological significance of glutamatergic inputs is not well established. In the dorsal raphe nucleus (DRN), more glutamatergic fibers terminate on GABAergic than serotonergic neurons. Moreover, GABA normally restrains the excitatory influence of glutamatergic inputs to serotonergic neurons in the DRN. Peptidergic neurons modulate the activity of GABAergic and glutamatergic interneurons that synapse with serotonergic neurons in the DRN. These neuropeptides, for example CRF, endogenous opioids and Substance P, are implicated in responses to environmental challenges. Thus, stress can indirectly influence the activity of serotonergic neurons. In the raphe, GABAergic and glutamatergic interneurons may serve as a final common pathway for integrating information about environmental challenges and inputs from hypothalamic and brainstem centers that control the usual sleep-related inhibition of serotonergic neurons. Neuropeptides might thereby promote alert behavior to appropriately cope with stress. However, persistent peptidergic-induced changes in the strength of GABAergic and glutamatergic inputs to serotonergic neurons could contribute to insomnia, anxiety and major psychiatric disorders such as depression and schizophrenia. [ABSTRACT FROM AUTHOR]

The primary circadian pacemaker resides within the suprachiasmatic nucleus (SCN) in the hypothalamus, and controls the circadian rhythms of virtually all mammalian behaviors and physiological processes, including sleep and wakefulness. Serotonergic neurons in the midbrain dorsal (DRN) and median (MRN) raphe nuclei have been suggested to play an important role in behavioral state control. These neurons also show circadian rhythmicity in their activity, and may be an important target of the SCN circadian signal for organizing circadian sleep-wake rhythms. There are, however, no direct efferent projections from the SCN to the DRN or the MRN, suggesting that most of the SCN neuronal output may be conveyed indirectly. In this review, we first provide an overview of the anatomical evidence for the indirect neuronal pathways from the SCN to the DRN and MRN via several hypothalamic nuclei, namely, the medial preoptic area, subparaventricular zone, and dorsomedial hypothalamic nucleus. We discuss functional evidence to suggest that the SCN may influence the regulation of sleep-wake states by sending its circadian signal through these indirect pathways to the raphe nuclei. We then consider the feedback projections from the DRN and MRN to the SCN, and discuss functional evidence to suggest that these projections carry feedback information to the SCN regarding the vigilance state of the animal. We hypothesize that the reciprocal interactions between the circadian and sleep-wake regulatory systems may ensure a stable yet adaptive rhythmicity of daily sleepwake cycles. [ABSTRACT FROM AUTHOR]