Behaviorally consequential astrocytic regulation of neural circuits

Abstract

Astrocytes are a large and diverse population of morphologically complex cells that exist throughout nervous systems of multiple species. Progress over the last two decades has shown that astrocytes mediate developmental, physiological, and pathological processes. However, a long-standing open question is how astrocytes regulate neural circuits in ways that are behaviorally consequential. In this regard, we summarize recent studies using Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, and Mus musculus. The data reveal diverse astrocyte mechanisms operating in seconds or much longer timescales within neural circuits and shaping multiple behavioral outputs. We also refer to human diseases that have a known primary astrocytic basis. We suggest that including astrocytes in mechanistic, theoretical, and computational studies of neural circuits provides new perspectives to understand behavior, its regulation, and its disease-related manifestations.

Keywords: Caenorhabditis elegans; Danio rerio; Drosophila melanogaster; Mus musculus; astrocyte; behavior; genetic disorders; glia; microcircuit; neuronal circuit.

Figure 1:. Phenotypes and functions of astrocytes from different species discussed herein.

The schematics illustrate the locations of CNS (gray), neuropil (purple) and astrocytes (green) in nematode (A), fruit fly (B), zebrafish (C), mouse (D), and human (E) at the level of organism, CNS and circuit. Dot plots summarize that 16 well-defined cellular phenotypes/functions of astrocytes are either found in astrocytes (green), found in other type(s) of glia (blue), not known or currently being explored (light green), or not found in glia (white) in the relevant organism indicated. Some human astrocytes project long, unbranched processes that cross cortical laminae (asterisk).

Figure 2:. Neural circuit and behavioral functions of astrocyte-like cells in nematode, fruit fly and zebrafish.

(A) Nematode CEPsh glia are required for normal sleep and locomotion. Left: The oscillatory activity of AVE neuron correlates with head retraction of worm and regulates locomotion. ALA neurons are active during sleep and synaptically inhibit AVE. The working model from ablation experiments suggests that CEPsh glia tune the ALA-AVE synapse in proper behavioral state transition from wakefulness to sleep. Right: AVA neurons are a major class of interneuron driving backward locomotion. CEPsh glia uptake glutamate (Glu) from synaptic cleft at excitatory synapses onto AVA. Deletion of glutamate transporter GLT-1 from CEPsh glia results in spillover of Glu from the synapses, activating presynaptic mGluR5 to cause repetitive excitation of AVA and reversal in worm locomotion. (B) Fly astrocytes regulate sleep and sensory-driven behavior. Left: Drosophila TNFα homologue Eiger (EGR), expressed in fly astrocyte-like cells (green), acts on Wengen a receptor of EGR on neurons to regulate normal sleep. An astrocyte-enriched small secreted immunoglobulin (Ig)-domain protein Noktochor (NKT) exhibit reduction and fragmentation in night sleep, but not in day sleep. Right: upon sensory stimuli, the Tdc2-expressing neurons release neuromodulator tyramine (Tyr) or octopamine (Oct), the invertebrate analogues of norepinephrine, to increase Ca²⁺ in fly astrocytes in ventral nerve cord. Waterwitch (Wtrw)/TRP channel also produce Ca²⁺ in the same type of astrocytes. The astrocyte Ca²⁺ signaling inhibits dopaminergic neuron firing via ATP/adenosine and is required for olfactory-driven chemotaxis and touch-induced startle responses. (C) Fish radial astroglia play causal roles in behavioral passivity triggered by futility. When fish recognize an accumulated unsuccessful attempt, noradrenergic neurons in norepinephrine cluster of the medulla oblongata (NE-MO) become active and released NE activates α1-adenoceptor (AR) in radial astroglia. The radial astroglia Ca²⁺ signaling in turn enhances activity of GABAergic neurons in the lateral hindbrain to cause behavioral passivity.

Figure 3.. Summary illustrating acute astrocytic regulation of neuronal circuits and behaviors relevant to different regions of the mouse brain.

Schematic of a sagittal section of a mouse brain where various regions and nuclei as well as associated behaviors that were shown to be regulated by acute astrocytic mechanisms are depicted. Ob, olfactory bulb; Cx, cerebral cortex; M1, primary motor cortex; Lv, lateral ventricle; Cc, corpus callosum; dSt, dorsal striatum; NAc, nucleus accumbens; Hip, hippocampus; Th, thalamus; LHb, lateral habenula; Hy, hypothalamus; ARC, arcuate nucleus; SCN, suprachiasmatic nucleus; CeM, central amygdala; VTA, ventral tegmental area; DVC, dorsal vagal complex. Note: in the text we also consider sleep, but this is not illustrated here because it involves multiple brain nuclei. Furthermore, the cartoon does not include studies where behavioral alterations result over longer periods such as following the deletion of a critical gene within astrocytes or during development and aging.