Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal

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.

The menagerie of the basal forebrain: how many (neural) species are there, what do they look like, how do they behave and who talks to whom?

“…At least three types of large, cortically-projecting BF GABAergic neurons exist [27]. One functionally important subgroup (~25 % of large GABAergic neurons and ~7 % of all GABAergic neurons) [6], involved in the control of cortical gamma band oscillations [22], contains the calcium binding protein, parvalbumin (PV) [6,20].…”

“…They have very narrow action potentials and extremely high maximal discharge rates, like cortical PV interneurons [6]. Unlike cortical PV interneurons however, they exhibit prominent H-currents, a depolarized membrane potential and different pharmacology [2,6,27]. A second, large population (60 %) of BF GABAergic neurons located in HDB and MCPO expresses a particular type of delayed rectifier potassium channels (Kv2.2) [28].…”

Developmental ethanol exposure-induced sleep fragmentation predicts adult cognitive impairment

“…This induced change in excitation/inhibition balance could modify both plasticity and function of forebrain circuits underlying cognition and emotion (Hensch, 2005, Sadrian et al, 2013). However, GABAergic neurons are also important for sleep-related oscillations and switching between sleep states (Hermanstyne et al, 2010, Halassa et al, 2011, Abel et al, 2013, Qiu et al, 2014, Brown and McKenna, 2015, Xu et al, 2015), and impaired function of GABAergic neurons impairs sleep (Kalume et al, 2015). If developmental EtOH exposure impairs GABAergic neuron function and/or reduces GABAergic cell number in subcortical areas known to regulate sleep, this may be an important link between early ethanol and sleep, as well as a potential therapeutic target.…”

“…In both healthy and pathological populations, sleep deprivation and fragmentation are associated with impaired cognitive function, attention and emotional regulation (Durmer and Dinges, 2005, Abel et al, 2013, Basner et al, 2013). Sleep onset and transitions between sleep states are controlled by a variety of sub-cortical nuclei, including regions of thalamus, hypothalamus and brainstem (Jones, 2005, Abel et al, 2013), and GABAergic neurons in these regions play a crucial role in sleep regulation (Brown and McKenna, 2015). Commonly used hypnotics target GABAergic receptors (Manfridi et al, 2001, Walsh et al, 2007, Brickley and Mody, 2012), and insomnia and sleep fragmentation have been associated with impaired GABAergic neuron function in these regions (Lundahl et al, 2007, Kalume et al, 2015).…”

Intrinsic membrane properties and cholinergic modulation of mouse basal forebrain glutamatergic neurons in vitro

“…The basal forebrain (BF) is a subcortical brain region involved in the control of sleep-wake cycles, cortical activation, attention and reward processing (Brown et al, 2012; Zaborszky et al, 2012; Brown and McKenna, 2015; Lin et al, 2015). BF integrity and function is impaired in diverse neuropsychiatric conditions such as coma (Edlow et al, 2013), dementia (Whitehouse et al, 1982) and narcolepsy (Nishino et al, 1995; Reid et al, 1998).…”