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Regulation of Neural Circuits and Behavior by Microglia

Microglia are the primary immune cells of the central nervous system and contribute to inflammatory injury and tissue repair in neurological disorders. In addition, studies have identified the role of homeostatic microglia in regulating neuronal activity, interacting with synapses, modulating neural circuits, and regulating behavior.

Creative Biolabs provides microglia-related services, including modeling, assays, research tools, etc.

Services What We Do Advantages
Microglia Differentiation Service Our service process, based on stem cell technologies, utilizes iPSCs as a fundamental resource, which are treated with a cocktail of factors to direct their differentiation into microglial cells. The process of differentiation is carefully monitored to ensure the generation of pure, functional microglia.
  • Fully customizable
  • Extensive experience
  • Simplified cell collection procedure
Neuronal Activity Monitor Services Creative Biolabs has a reputation as an industry-leading provider of basic neuroscience assays. We specialize in neuroscience and have built a comprehensive technology platform. Neuronal activity monitoring service is one of the proven services offered by our platform.
  • Advanced technology
  • High-quality facilities
  • Professional experts
Viral Vector for Neural Circuitry Research We develop a variety of viral vectors for cell labeling. By using specific promoters and viral vectors, neuronal labeling and manipulation at the cellular and subcellular levels can be achieved.
  • Higher safety
  • Higher precision
  • Low immunogenicity
  • Contains marker genes
  • Can be used both in vivo and in vitro

Microglia dynamically survey the central nervous system through highly active processes. As the primary immune cells of the CNS, microglia contribute to inflammatory damage and repair during disease onset and progression. But their role goes beyond immune function in disease. Microglia also play a key role in sensing and regulating neuronal activity. In the healthy brain, homeostatic microglia physically interact with various neuronal compartments (e.g., neuronal cytosol, axon initial segments, Longfellow's nodes, and synapses) to shape neural architecture and regulate neuronal activity.

Microglia Sense and Regulate Neuronal Activity through Synaptic Interactions

U-shaped pattern of microglial cell responses in sensory and regulatory neuronal activity. (Zhao, Shunyi, Anthony D. Umpierre, and Long-Jun Wu, 2024)Fig. 1 U-shaped pattern of microglial cell responses in sensory and regulatory neuronal activity.1

  • When neuronal activity is increased, microglia exhibit a high degree of protrusive interactions with active neurons. These interactions are characterized by protrusion lengthening, protrusion convergence, protrusion pockets, and faster movement speeds, causing an increase in contact time, which can rescue neurons from excitotoxicity.
    • The underlying mechanism involves the microglial P2Y12 receptor, which brings microglial protrusions in close proximity to overactive ATP-releasing neurons.
    • In addition, the presence of CD39 and CD73 extracellular enzymes on microglia membranes permits rapid hydrolysis of adenosine by ATP, thereby reducing neuronal firing via adenosine receptors.
  • When neurons are underactive, microglia lengthen their protrusions and increase their kinetics.
    • This response is modulated by alterations in neuronal norepinephrine (NE) signaling, which acts exclusively on microglial β2-adrenergic receptors, during the transition from basal to hypoactive states.

These findings demonstrate a dynamic interaction between microglia and neuronal activity, highlighting the U-shaped pattern of microglia sensing neuronal activity. Although microglia respond to neuronal over- and under-activity by different mechanisms, in general, microglia are able to maintain dynamic equilibrium in the brain by interacting with neuronal dynamic processes to achieve homeostasis of neural activity.

Microglia Regulate Neural Circuits and Behavior

Given the close interactions between microglia and neurons, it is not surprising that microglia may contribute to adult neural networks and related behaviors. Using methods such as microglia ablation and microglia conditional knockout, studies in animal models have shown that microglia are able to modulate learning and memory, sleep, anxiety-like behaviors, obsessive-compulsive behaviors, and alcohol consumption.

Based on this, several studies have applied optogenetic and chemogenetic tools to reveal the exact function of microglia electrophilic (channel) and metabolic (G protein-coupled receptors, GPCRs) signaling in fine-tuning and modulating neural circuits.

Microglia Manipulation How to Do
Optogenetic manipulation Optogenetic approaches have been used to understand the role of microglial chemotaxis signals in microglia protrusion chemotaxis and neuronal network function. Recent studies have shown that photogenic activation of microglia can enhance neural activity and induce behavioral changes.
  • Photogenetic activation of ReaChR, a red-shifted ChR variant, depolarizes spinal microglia and increases neuronal activity.
  • The modern optogenetic toolbox also includes light-gated proton pumps, K+ channels, and Cl- channels. The function of the light-activated proton pump, archaeorhodopsin (ARCHT), was also tested in microglia.
Current studies using microglial cell optogenetics have demonstrated that alterations in microglial ionophilic signaling have profound effects on neural activity and behavior. Integrating optogenetics into the larger toolkit for studying microglial cell function will allow researchers to understand how microglial ionophilic signaling affects neural circuits and reveal the complex role of microglia in behavior.
Chemical genetic manipulation To further understand the microglial GPCR signaling pathway, recent studies have applied a chemogenetic platform to manipulate the microglial GPCR signaling pathway. This chemogenetic manipulation technique has the potential to mimic the known functions of endogenous microglial GPCRs and explore previously unknown signaling pathways activated by microglial GPCRs.

Different Microglia Functions in Neuronal Circuits

Region-specific neuronal responses to microglia manipulation highlight the role of microglia spatial heterogeneity in the modulation of local neural networks. Furthermore, optogenetic and chemogenetic manipulation of microglia suggests that different intracellular signaling pathways in microglia explain different behavioral outcomes, revealing region-specific changes in neural activity and behavior. The mechanisms by which microglia regulate neuronal circuits in different regions of the CNS deserve further investigation.

  • The spatial heterogeneity of microglia may be involved in region-specific neuronal modulation. Ongoing studies of microglia spatial heterogeneity and how microglia regulate local circuits will deepen the understanding of microglia function in health and disease.
  • Neuronal heterogeneity may influence the outcome of microglia-mediated neuromodulation. Microglia may regulate different neural circuits in different ways.
  • The response of microglia is influenced by the microenvironment within the local neural circuit.
  • Microglia interact with different types of neurons whose axon terminals exhibit spatial differences.

Exploring how microglia interact with specific neuronal populations in different brain regions may provide new insights into the differential roles of microglia in the maintenance of intra-neuronal homeostasis, synaptic plasticity and behavioral regulation.

The current understanding of how these interactions between microglia and neurons affect neuronal function remains limited. Addressing these questions could benefit from a combination of membrane clamp technology, transcriptome analysis, and multiphoton imaging. At Creative Biolabs, we are committed to helping researchers distinguish between different types of microglia-neuron interactions, monitor changes in microglia membrane potential during these interactions, and understand their molecular profiles.

Reference

  1. Zhao, Shunyi, Anthony D. Umpierre, and Long-Jun Wu. "Tuning neural circuits and behaviors by microglia in the adult brain." Trends in Neurosciences (2024).

For Research Use Only. Not For Clinical Use.