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. 2022 Aug;70(8):1554-1580.
doi: 10.1002/glia.24168. Epub 2022 Mar 17.

A perspective on astrocyte regulation of neural circuit function and animal behavior

Johannes Hirrlinger  1   2 , Axel Nimmerjahn  3
Affiliations

A perspective on astrocyte regulation of neural circuit function and animal behavior

Johannes Hirrlinger et al. Glia. 2022 Aug.

Abstract

Studies over the past two decades have demonstrated that astrocytes are tightly associated with neurons and play pivotal roles in neural circuit development, operation, and adaptation in health and disease. Nevertheless, precisely how astrocytes integrate diverse neuronal signals, modulate neural circuit structure and function at multiple temporal and spatial scales, and influence animal behavior or disease through aberrant excitation and molecular output remains unclear. This Perspective discusses how new and state-of-the-art approaches, including fluorescence indicators, opto- and chemogenetic actuators, genetic targeting tools, quantitative behavioral assays, and computational methods, might help resolve these longstanding questions. It also addresses complicating factors in interpreting astrocytes' role in neural circuit regulation and animal behavior, such as their heterogeneity, metabolism, and inter-glial communication. Research on these questions should provide a deeper mechanistic understanding of astrocyte-neuron assemblies' role in neural circuit function, complex behaviors, and disease.

Keywords: actuator; astrocytes; behavior; computational approaches; genetic targeting; indicator; neural circuit.

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Figures

FIGURE 1
FIGURE 1
Astrocytes regulate and are controlled by neural circuits and animal behavior. Animal behavior activates a subset of local excitatory, inhibitory, and projection neurons, leading to the release of diverse molecular signals. Astrocytes are thought to spatially and temporally integrate these time-varying signals in their environment, with calcium and/or PKA playing central roles in this process. Signal integration also involves intermediate signals, such as reactive oxygen species (ROS), IP3, cAMP, and IRBIT. Astrocyte excitation, in turn, is thought to modulate neural circuit function (e.g., network state, excitation-inhibition balance, synaptic strength, or number) through different mechanisms (e.g., extracellular ion regulation, neuroactive factor release, perisynaptic process structure) and on various timescales (second to minutes) (see also Figures 2–3). Abbreviations: Ado, adenosine; cAMP, cyclic adenosine monophosphate; Glu, glutamate; IP3, inositol-trisphosphate; IRBIT, IP3 receptor-binding protein released with IP3; PKA, protein kinase A
FIGURE 2
FIGURE 2
Astrocytes regulate neural circuits on various timescales. Astrocyte transients (e.g., calcium, cAMP) tend to be slow (sub-seconds to minutes), resulting from molecular signal integration in their environment. Similarly, astrocyte modulation of neural circuit function (e.g., through regulation of extracellular ion homeostasis, neuroactive factor release, or metabolic support) typically occurs on the seconds to minutes timescale, whereas morphological and gene expression-dependent changes (e.g., perisynaptic process structure, myelin regulation) influence neural circuit plasticity and function on the minutes to days or even longer timescale. Notably, the spatiotemporal dynamics of astrocytes’ functional signals, their spatial arrangement, gene expression, and coupling suggest that these cells serve complementary roles to neurons (see text for more details). Abbreviations: cAMP, cyclic adenosine monophosphate; GPCR, G-protein coupled receptor; LTD, long-term depression; LTP, long-term potentiation
FIGURE 3
FIGURE 3
Astrocytes regulate neural circuits directly and indirectly. Astrocytes can modulate neural circuit function directly through different mechanisms (see Figure 1). Microglia have also been shown to control neuronal synapse number and activity on various timescales. Similarly, oligodendrocytes can regulate neurons’ axonal properties (e.g., conduction velocity) in an activity- and behavior-dependent manner. Astrocytes bidirectionally communicate with and regulate both microglia and oligodendrocytes (e.g., through diffusible messengers and physical interactions), allowing them to influence neural circuits indirectly and in a spatially and temporally distinct manner than their direct routes
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