Abstract
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Recent technological advances have illuminated the role of GABAergic neurons in control of cortical arousal and sleep. Sleep-promoting GABAergic neurons in the preoptic hypothalamus are well-known. Less well-appreciated are GABAergic projection neurons in the brainstem, midbrain, hypothalamus, and basal forebrain, which paradoxically promote arousal and fast electroencephalographic (EEG) rhythms. Thus, GABA is not purely a sleep-promoting neurotransmitter. GABAergic projection neurons in the brainstem nucleus incertus and ventral tegmental nucleus of Gudden promote theta (4–8 Hz) rhythms. Ventral tegmental area GABAergic neurons, neighboring midbrain dopamine neurons, project to the frontal cortex and nucleus accumbens. They discharge faster during cortical arousal and regulate reward. Thalamic reticular nucleus GABAergic neurons initiate sleep spindles in non-REM sleep. In addition, however, during wakefulness, they tonically regulate the activity of thalamocortical neurons. Other GABAergic inputs to the thalamus arising in the globus pallidus pars interna, substantia nigra pars reticulata, zona incerta, and basal forebrain regulate motor activity, arousal, attention, and sensory transmission. Several subpopulations of cortically projecting GABAergic neurons in the basal forebrain project to the thalamus and neocortex and preferentially promote cortical gamma-band (30–80 Hz) activity and wakefulness. Unlike sleep-active GABAergic neurons, these ascending GABAergic neurons are fast-firing neurons which disinhibit and synchronize the activity of their forebrain targets, promoting the fast EEG rhythms typical of conscious states. They are prominent targets of GABAergic hypnotic agents. Understanding the properties of ascending GABAergic neurons may lead to novel treatments for diseases involving disorders of cortical activation and wakefulness.
Highlights
Our current understanding of the brain and the mechanisms involved in switching between different behavioral states is based on the investigational tools available to researchers
NAcc cholinergic interneurons, which regulate plasticity of medium spiny neurons (MSN). (B) The activity of dopaminergic VTA neurons which encode unexpected rewards and project to NAcc and PFC is under the control of local GABAergic interneurons and GABAergic inputs from the rostromedial tegmental nucleus (RMTg)
RMTg and local VTA GABAergic neurons are excited by lateral habenula (LHb) glutamatergic neurons which encode expected rewards or the absence of rewards, based on inputs from the basal ganglia
Summary
Our current understanding of the brain and the mechanisms involved in switching between different behavioral states is based on the investigational tools available to researchers. In the last two decades, rapid advances in technology have allowed us for the first time to selectively identify and manipulate the activity of GABAergic neurons involved in control of the sleep-wake cycle. Extracellular unit recordings in vivo are essential for establishing the normal firing patterns of GABAergic neurons and correlating them with the electroencephalographic (EEG) activity and behavior They have a limited ability to reveal the underlying cellular mechanisms, i.e., the ion channels and neurotransmitter receptors which are the targets of most pharmacological agents used clinically to modulate brain activity. The development of mice expressing the bacterial enzyme Cre recombinase under the control of the GAD, vesicular GABA transporter (vGAT), or PV promoters further advanced our knowledge concerning the role of GABAergic neurons Use of these mice allowed selective optogenetic [33] and designer receptor exclusively targeted by designer drugs (DREADD). We begin in the brainstem and continue rostrally along the dorsal and ventral pathways of the ascending reticular activating system (ARAS), which include the thalamus and BF as their final nodes
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