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?

Abstract

The diverse cell-types of the basal forebrain control sleep-wake states, cortical activity and reward processing. Large, slow-firing, cholinergic neurons suppress cortical delta activity and promote cortical plasticity in response to reinforcers. Large, fast-firing, cortically-projecting GABAergic neurons promote wakefulness and fast cortical activity. In particular, parvalbumin/GABAergic neurons promote neocortical gamma band activity. Conversely, excitation of slower-firing somatostatin/GABAergic neurons promotes sleep through inhibition of cortically-projecting neurons. Activation of glutamatergic neurons promotes wakefulness, likely by exciting other cortically-projecting neurons. Similarly, cholinergic neurons indirectly promote wakefulness by excitation of wake-promoting, cortically-projecting GABAergic neurons and/or inhibition of sleep-promoting somatostatin/GABAergic neurons. Both glia and neurons increase the levels of adenosine during prolonged wakefulness. Adenosine presynaptically inhibits glutamatergic inputs to wake-promoting cholinergic and GABAergic/parvalbumin neurons, promoting sleep.

Figure 1

The basal forebrain (BF) is a large, heterogeneous structure located adjacent to the ventral surface of the forebrain. It is typically defined by the presence of cholinergic projection neurons [8] although as we discuss here, GABAergic and glutamatergic neurons play important functional roles. Rostral BF regions (MS, vDB) contain neurons which project to the hippocampus and associated archaecortical regions. This review is mainly focused on intermediate BF subregions with neurons projecting to neocortex, including MCPO, HDB, VP and SI as well as caudally-located cholinergic and GABAergic projection neurons in the nucleus basalis (a term often used interchangeably with basal forebrain in the human literature) located within the boundaries of the globus pallidus (GP). This figure was adapted with permission from figures previously published in “The mouse brain in stereotaxic coordinates” (ISBN: 9780123910578) by George Paxinos & Keith Franklin (2008) 3rd ed. New York, Academic Press (Copyright Elsevier). Abbreviations: aca: anterior part of anterior commissure; acp: posterior part of anterior commissure; CPu: caudate putamen; D3V: dorsal 3^rd ventricle; f: fornix; GP: globus pallidus; HDB: horizontal limb of the diagonal band; ic: internal capsule; LV: lateral ventricle; MCPO: magnocellular preoptic nucleus; MS: medial septum; SI: substantia innominata; vDB: ventral limb of the diagonal band; VP: ventral pallidum. Scale bar=1mm.

Figure 2. Basal forebrain neuronal subtypes and their discharge properties across sleep-wake states

Blue represents the well-known cholinergic (ChAT+) population representing ~10–20 % of all BF neurons, depending on the subregion [8]. Green represents the GABAergic (GAD67+) population, the largest group of BF neurons, ~5 times the number of cholinergic neurons [19]. Orange represents the smaller glutamatergic population (mainly vGluT2+ with small numbers of vGluT1+ and vGluT3+ neurons; [30]). A few vGluT3 neurons are cholinergic (grey/blue box) and project to the amygdala [15]. The black frame represents cortically-projecting neuronal subtypes, including most cholinergic neurons, three different types of GABAergic neurons and glutamatergic (vGluT2) neurons. Cortically-projecting neurons are active during wakefulness and/or REM-sleep in association with cortical fast-activity [7,18,50,51]. GABAergic PV neurons are wake/REM active [7,22]. They represent ~7 % of all BF GABA neurons but ~25 % of large (>20 μm, likely cortically-projecting neurons) [6]. GABAergic Kv2.2+ neurons represent ~60 % of all BF GABAergic neurons in HDB and MCPO [28], including large putative cortically-projecting neurons. Nk3R+ neurons represent a third group of cortically-projecting GABAergic neurons [29]. Other subgroups of GABAergic neurons containing SOM, NPY, nNOS and calretinin project caudally and/or locally within BF [7,8,11,29]. Some SOM and NPY neurons are likely to be sleep-active [7,50,51]. The discharge of vGluT2 neurons is weakly modulated by behavioral state [7]. They discharge faster during wakefulness and REM sleep. The calcium binding proteins Calb and Calret are expressed in subsets of glutamatergic as well as GABAergic neurons. Calb+/vGluT2+ neurons may be cortically projecting whereas calretinin neurons are not [20]. Abbreviations: Calb: calbindin; Calret: calretinin; ChAT: Choline acetyltransferase; GAD: glutamic acid decarboxylase; Kv: voltage-gated delayed-rectifier potassium channel; Nk3R: Neurokinin B receptors, type 3; nNOS+: neuronal nitric oxide synthase; NPY: neuropeptide Y; PV: parvalbumin; REM: rapid eye movement; SOM: somatostatin; vGluT1/2/3: vesicular glutamate transporter type 1/2/3.

Figure 3. Models of the basal forebrain (BF) circuits controlling sleep-wake behavior

Solid lines with arrowheads indicate excitatory effects on the target neurons. The black dashed lines indicate a weak excitatory effect. Lines with flat ends indicate inhibitory effects. A. BF circuits promoting wakefulness, cortical activation and adaptive responses to behaviorally-relevant stimuli. Current data indicates that GABAergic projections neurons are the most important for promoting wakefulness. An important subset of these neurons containing parvalbumin (PV) regulates cortical gamma band activity. Cholinergic (ChAT+) and glutamatergic (vGluT2+) neurons promote wakefulness and cortical activation indirectly via excitatory effects on GABAergic/parvalbumin (GAD67+/PV) neurons, as well as via their direct cortical projections. Cholinergic neurons promote cortical plasticity in response to reinforcers. B. BF circuitry involved in sleep promotion. During prolonged wakefulness (i.e. sleep deprivation) there is accumulation of extracellular adenosine due to direct release from neurons as well as breakdown from the neurotransmitter/gliotransmitter, ATP. Adenosine inhibits BF cholinergic and GABAergic projection neurons by inhibiting their glutamatergic inputs via A1 receptors [47,48], thereby promoting a homeostatic sleep response. Activation of a subset of GABAergic neurons containing somatostatin may facilitate spontaneous transitions into non-REM sleep by direct postsynaptic inhibition of wake-promoting cholinergic and GABAergic neurons. Abbreviations: ATP: adenosine triphosphate; choline acetyltransferase; GAD: glutamic acid decarboxylase; mAChR: muscarinic acetylcholine receptors; nAChR: nicotinic acetylcholine receptor; NREM: non-rapid-eye-movement; PV: parvalbumin; SOM: somatostatin; vGluT2: vesicular glutamate transporter type 2.