![]() ![]() ![]() Batini subsequently showed that the chronic EEG desynchrony/behavioral insomnia in the pretrigeminal preparation was not dependent upon sensory inflow from the auditory or visual systems. The first experimental evidence to suggest that the brainstem might participate in sleep control came from work by Batini who showed that transection of the brainstem just rostral to the origin of the trigeminal roots (i.e., the “pretrigeminal” preparation) produced chronic EEG activation. ![]() In this review, we will describe the seminal historical work that first inspired the hypothesis of a brainstem sleep system, and then move to more recent findings that have identified specific cells and pathways by which the brainstem may control SWS and, finally, we will discuss current knowledge gaps and thoughts on future experimental directions. Taken together, it is perhaps not surprising that until the recent advent of molecular–genetic tools, which enabled selective and reversible interrogation of cell populations, a considerable void existed in the literature regarding brainstem sleep systems. Fourth, the rodent brainstemis located deep in the skull, below the cerebellum and is therefore far less accessible than the forebrain. Third, there is extensive interdigidation of excitatory(glutamate) and inhibitory (GABA) neurons in the cellular brainstem, rendering the interpretation of nonselective experimental ablation, stimulation or inhibition experiments challenging. Second, experimental approaches that proved fruitful in the forebrain, such as excitotoxic lesions, did not prove as successful in the brainstem, often, instead, resulting in subject death. First, there is history: the seminal clinico-anatomic studies by von Economo established that relatively discrete inflammatory lesions within the anterior hypothalamus/POA could produce a chronic state of insomnia, setting the stage for decades of focused experimental work on the anterior hypothalamus/POA. This rather conspicuous temporal gap in identifying and characterizing brainstem sleep-promoting circuitry was likely a consequence of several issues. Considerable convergent evidence has, in fact, identified a particularly important role for VLPO neurons in the sleep process, including: 1) VLPO neurons show a dramatic increase in firing during SWS 2) cell-body specific lesions of the VLPO produce a sustained and dramatic decrease (∼40-50%) in SWS in rodents and 3) chemo- and opto-genetic activation of VLPO neurons produces sleep (C.B.Saper, perscomm).Īs indicated, transection studies - reaching back over 60 years - as well as more recent human imaging studies have inferred the existence of a brainstem “sleep system” but, until recently, a brainstem “homolog” of the POA or VLPO remained elusive. These sleep-active VLPO and MnPO neurons are largely GABAergic and project to, and hence presumably inhibit, multiple arousal-regulatory centers. Within the POA region both the ventrolateral (VLPO) and median preoptic (MnPO) nuclei contain high-density clusters of sleep-active neurons. With respect to the forebrain “sleep system”, the preoptic area (POA) plays an important, if indispensable, role in the initiation and maintenance of SWS. For instance, early postnatal midbrain transections in kittens revealed the ability of the forebrain and brainstem to drive, albeit often in temporal dissociation, electrocortical and behavioral rhythms, respectively, of sleep. Previous lesion, transection and stimulation work has suggested not only redundancy in sleep-promoting circuitry but also, and rather remarkably, that the forebrain and brainstem can independently regulate sleep. The circuit and synaptic bases by which sub-cortical cell populations regulate behavioral and EEG SWS is complex and remains incompletely understood. And while these models provide varying levels of explanatory power for “whole brain sleep”, we will emphasize in this review the circuit-based model, as this model assumes that delimited nodes of sub-cortical neurons differentially and specifically contribute to the initiation and maintenance of slow-wave-sleep and its electroencephalographic (EEG) correlate. To the former, there exist several conceptual models for how the brain achieves sleep, spanning humoral, local network, distributed network and circuit-based theories. Yet, the ‘how’ and ‘why’ of sleep remain among the most enduring mysteries in the neurosciences. Sufficient quality and quantity of sleep is the sine qua non for optimal physiologic, neurocognitive and psychologic function. ![]()
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