Review
doi: 10.3389/fneur.2015.00135. eCollection 2015.Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal
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- PMID:26124745
- PMCID: PMC4463930
- DOI: 10.3389/fneur.2015.00135
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Review
Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal
Ritchie E Brown et al. Front Neurol..
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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.
Keywords: EEG; arousal; gamma rhythm; hypnotics; theta rhythm; wakefulness.
Figures
GAD67-GFP knock-in mice delineate the location of GABAergic neurons involved in cortical arousal and sleep-wake control (24, 25, 28, 34). The location of select nuclei described in this review is illustrated, moving in a caudal to rostral direction through the mouse brain(A–H). Numbers in the bottom right corner indicate the location of these coronal sections with respect to Bregma (in mm). Green (GFP) fluorescence is present in cell bodies and fibers of GABAergic neurons.(A) Nucleus incertus (NI) GABAergic neurons involved in theta-rhythm generation are located near the midline of the central gray, above the medial longitudinal fasciculus (mlf), and ventromedial to the densely packed GABAergic neurons in the dorsal tegmental nucleus of Gudden (DTg). DTg neurons are involved in signaling head direction and project to the lateral mammillary body.(B) Ventral tegmental nucleus of Gudden (VTg) GABAergic neurons are clustered ventral to the mlf and the dorsal raphe (DR) nucleus. They innervate glutamatergic neurons in the medial mammillary body (see Figure 2).(C) GABAergic cell bodies and fibers delineate the substantia nigra pars reticulata (SNr), located lateral to the medial lemniscus (ml) and medial reticular nucleus (mRt). SNr GABAergic neurons represent the main output of the basal ganglia in rodents and tonically inhibit the motor thalamus and the centromedian-parafascicular nucleus (CM-Pf).(D) Tuberomammillary (TMN) histamine neurons located lateral to the lateral mammillary nucleus (LM) also express GABAergic markers and may release GABA.(E) Thalamic reticular nucleus (TRN) GABAergic neurons surround and inhibit almost all thalamic relay nuclei. More ventrally and medially are the zona incerta (ZI) GABAergic neurons, which project to higher-order thalamic nuclei and the neocortex. The internal capsule (ic) separates these nuclei from GABAergic neurons in the globus pallidus (GP).(F) The master circadian pacemakers in the suprachiasmatic nucleus (SCN) of the hypothalamus are GABAergic. 3V = 3rd ventricle.(G) Caudal/intermediate nuclei of the basal forebrain contain many large-sized GABAergic neurons which project to the neocortex and regulate gamma oscillations and wakefulness. acp, anterior commissure, posterior part; HDB, horizontal limb of the diagonal band; MCPO, magnocellular preoptic nucleus; SI, substantia innominata; VP, ventral pallidum.(H) Rostral nuclei of the basal forebrain, the medial septum (MS), and vertical limb of the diagonal band (VDB) contain GABAergic septohippocampal neurons regulating hippocampal theta and gamma rhythms. Scale bars:(A,B,D,F) 0.25 mm;(C,G,H) 0.5 mm;(E) 0.75 mm.
Brainstem GABAergic projection neurons in the nucleus incertus (NI) and ventral tegmental nucleus of Gudden (VTg) regulate theta (4–8 Hz) rhythms important for spatial navigation and memory formation.(A) NI GABAergic/relaxin-3 positive neurons receive input from neighboring pontine nucleus oralis (PnO) reticular neurons which increase their activity during active wakefulness and REM sleep. They project to and synchronize the activity of theta-rhythm related neurons in the supramammillary nucleus (SUM), medial septum (MS), and hippocampus. They receive return projections from a different population of septal GABAergic neurons.(B) VTg GABAergic projection neurons generate theta rhythmic activity through interactions with medial mammillary body glutamatergic neurons (MMB). MMB neurons transmit rhythmic theta-frequency activity to the anterior thalamus (AT) and through the rest of the Papez circuit. These two theta-generating circuits participate in synchronizing the activity of neurons involved in spatial navigation and memory by linking neurons representing information about the environment with those representing information about the position of the animal (51).
GABAergic neurons and inputs to the ventral tegmental area (VTA) are involved in the control of reward and reward-related arousal.(A) VTA GABAergic projection neurons innervate the prefrontal cortex (PFC) and nucleus accumbens (NAcc). They increase their discharge in association with arousal and in anticipation of reward. VTA neurons projecting to PFC target both principal neurons and cortical GABAergic interneurons. VTA GABAergic neurons projecting to the NAcc receive input from PFC and specifically target 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.
Basal forebrain (BF) GABAergic neurons are excited by wake promoting neuromodulators and promote gamma rhythms in the cortex via projections to cortical GABAergic interneurons. At least three, largely separate, populations of BF GABAergic neurons express the calcium-binding protein, parvalbumin (PV), the neurokinin-3 receptor (NK3R), and the potassium channel Kv2.2. BF GABAergic neurons can also be subdivided according to the amplitude and kinetics of their hyperpolarization-activated cation currents (H-currents). GABA/PV neurons in caudal/intermediate parts of the BF appear to be important in regulating cortical gamma oscillations through their synchronization of cortical PV interneurons. Rostral BF GABA/PV neurons (not shown) regulate hippocampal theta and gamma oscillations. The functions of the NK3R and Kv2.2. subpopulations are less well-understood but they also appear to be wake-promoting. Cortical and hippocampal projections of identified BF GABAergic or PV fibers preferentially appose GABAergic interneurons, including fast-spiking, somatic targeting PV interneurons, and dendrite-targeting somatostatin (SOM) interneurons. Return projections from the cortex target cortically projecting BF PV neurons and possibly other GABAergic subpopulations but avoid cholinergic neurons.
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