Cholinergic Circuit Control of Postnatal Neurogenesis

Abstract

New neuron addition via continued neurogenesis in the postnatal/adult mammalian brain presents a distinct form of nervous system plasticity. During embryonic development, precise temporal and spatial patterns of neurogenesis are necessary to create the nervous system architecture. Similar between embryonic and postnatal stages, neurogenic proliferation is regulated by neural stem cell (NSC)-intrinsic mechanisms layered upon cues from their local microenvironmental niche. Following developmental assembly, it remains relatively unclear what may be the key driving forces that sustain continued production of neurons in the postnatal/adult brain. Recent experimental evidence suggests that patterned activity from specific neural circuits can also directly govern postnatal/adult neurogenesis. Here, we review experimental findings that revealed cholinergic modulation, and how patterns of neuronal activity and acetylcholine release may differentially or synergistically activate downstream signaling in NSCs. Higher-order excitatory and inhibitory inputs regulating cholinergic neuron firing, and their implications in neurogenesis control are also considered.

Figure 1.

Cholinergic projections and neurogenic niches in the postnatal mouse brain. (A) Sagital section view showing major cholinergic nuclei and their known projections. Nuclei of the nucleus basalis group include: nucleus basalis of Meynert and magnocellularis (B); horizontal diagonal band of Broca (HDB); substantia innominate (SI). Nuclei of the medial septal group include: medial septal nucleus (MS) and vertical diagonal band (VDB). Nuclei of the pontine cholinergic group include: laterodorsal tegmental nuclei (LDT) and pedunculopontine tegmental nuclei (PPT). Other notable cholinergic neuron groups are found in: medial habenular nucleus (mHAB); striatum (St); and subependymal zone (SEZ). Major cholinergic neuron/nuclei projection targets include: basal ganglia (BG); cerebellum (CB); cortex (Ctx); dorsal raphae nucleus (DR); hippocampus (Hip); interpeduncular nucleus (IPN); lateral hypothalamus (LH); olfactory bulb (OB); pons (P); pontine reticular nucleus (PRN); substancia nigra (SN); thalamus (Th); and tectum (T). Neurogenic niches (LV and SGZ) are expanded in panels below. (B) Coronal section view of the SGZ neurogenic niche in the dentate gyrus (DG). Blue fibers indicate innervating projections from medial septal cholinergic neurons. Neurogenic cell types: astrocyte-like precursor (Type 1), transiently proliferating progenitor (Type 2), neuroblast, immature granule cell (GC), and mature GC. GLC = granule cell layer; ML = molecular layer of the DG. (C) Coronal view of the LV neurogenic niche, showing subep-ChAT neurons as well as neighboring striatal cholinergic neurons (St-ChAT). Neurogenic cell types include: (NSC) neural stem cell, Mash1⁺ transiently proliferating progenitor (TPP), and neuroblasts.

Figure 2.

ACh release and receptor activation dynamics to convey neuronal activity patterns. (A) Schematic representation of ACh released directly onto a receptive zone, with a high density of nAChR and mAChR receptors. In such specialized contacts (neuronal synapse as an example), ACh upon release is quickly degraded by extracellular acetylcholinesterase. Nicotinic currents are typically rapid and fast-inactivating, while muscarinic currents are longer lasting. (B) Multiple neuronal activations can cause released ACh to spillover and activate nAChRs/mAChRs away from the immediate receptive zone. This leads to prolonged nicotinic and muscarinic currents in the responding cell. (C) Volume release of ACh stimulates larger fields of receptors at low concentrations. Cholinergic currents evoked by volume release may be small and prolonged. (D) Diagram of nAChR resting, activation, and desensitization cycle (cycle time = t, receptor subtype specific). Depending on the timing of cholinergic neuron inter-stimulus intervals (ISI), the resulting patterns of ACh release will enhance nAChR desensitization when ISI< t, or promote nAChR recovery for reactivation when ISI > t, resulting in distinct nicotinic activation dynamics in the receiving cell. AChE = acetylcholinesterase.

Figure 3.

Subependymal cholinergic neuron bridging SEZ niche/neurogenesis to neural circuit-level control. Schematic representation of subep-ChAT neuron (green) providing ACh to modulate adult SEZ neural stem cells (NSC) production of new neuroblasts, which then migrate and assemble into neuroblast chains. Dashed lines represent putative excitatory (+, blue) or inhibitory (−, red) inputs onto subep-ChAT neuron dendrites. LV = lateral ventricle.

Figure 4.

Example functional connectivity of a subgroup of CNS cholinergic neurons. Striatal cholinergic neurons (TANs) receive glutamatergic inputs from both cortex and intralaminar thalamus, as well as dopaminergic modulation from the substantia nigra pars compacta (SNc). Medium spiny neurons (MSNs), projection neurons in the striatum, express either type 1 or type 2 dopamine receptors (D1 or D2, respectively). Following thalamic stimulation, TANs generate a burst-pause pattern of activity that transiently and presynaptically inhibits thalamic and cortical excitation of D1 and D2 striatal MSNs through muscarinic receptor subtype M2 signaling. It also initiates a sustained, muscarinic receptor subtype M1-mediated facilitation of dendritic responsiveness in D2 MSNs: resulting in a bias of cortical and thalamic excitation toward D2 expressing, striatopallidal MSNs for the duration of the pause in TAN activity. The pause is dependent on dopaminergic signaling onto TANs. Functionally, thalamic excitation of TANs is thought to provide a window in which excitation of D2-expressing MSNs is enhanced, allowing for preferential recruitment of the striatopallidal pathway. Such wiring diagrams may serve as useful models to study subep-ChAT neuron connectivity. Distinct neuronal cell types and projection patterns are represented in different colors for clarity.