The Overlooked Role of Cerebellar Glia in Regulating Aggression

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The cerebellum, long recognized for its involvement in motor coordination and learning, is now gaining attention for its intricate connections to non-motor functions such as emotion and social cognition. Recent research has shed light on the association between the cerebellum and various neuropsychiatric disorders, including autism spectrum disorders and schizophrenia.

Notably, studies have highlighted the involvement of the cerebellar vermis in human aggression, opening up avenues for understanding the neural mechanisms underlying aggressive behavior.

Cerebellar Circuitry and Aggression

The heightened activity of Purkinje cells (PCs) in the cerebellum plays a pivotal role in regulating aggression. PCs, as GABAergic inhibitory neurons, inhibit the activity of deep cerebellar nuclei (DCN), leading to a complex interplay within the cerebellar circuitry. Recent discoveries have unveiled an excitatory synaptic connection from the DCN to the ventral tegmental area (VTA), establishing a negative correlation between PC activity and VTA activity.

Given the crucial role of dopamine-releasing neurons in the VTA in controlling social behaviors, including aggression, this circuitry provides a potential neural pathway for the modulation of aggressive behavior.

Optogenetics studies directly manipulating PC activity have demonstrated a direct link between cerebellar function and aggression. Increases and decreases in PC activity have been shown to correspond to the reduction and enhancement of aggressive behavior, respectively, emphasizing the role of the cerebellum in shaping social interactions.

Cerebellar Glia and Social Behavior

While the cerebellum’s neuronal circuitry has been a focal point in understanding aggression, the role of glial cells, particularly Bergmann glia cells (BGs), has been largely overlooked. BGs, a subtype of glial cells in the cerebellum, exhibit a unique morphological relationship with PCs, completely encasing almost every synaptic contact. This close interaction suggests an intimate neuron-glia functional relationship in the cerebellum.

Recent studies have demonstrated that microglia in the cerebellum trigger plasticity of the intrinsic excitability of the cerebellum in response to inflammation, influencing the average spiking level of PCs and, consequently, setting the tone for social behavior. This underappreciated role of glia in regulating cerebellar function adds a new layer of complexity to our understanding of the neural mechanisms underlying aggression.

Neuron-Glia Interaction in the Cerebellum

In the cerebellum, both neuron-to-glia and glia-to-neuron interaction pathways have been identified. PC activity is not only regulated by traditional inputs from excitatory parallel/climbing fiber pathways and inhibitory stellate/basket cell activity but also by gliotransmitter release and ionic regulation by BGs. This bidirectional communication highlights the intricate interplay between neurons and glial cells in shaping cerebellar function.

Implications and Future Directions

Building on these findings, the hypothesis emerges that BGs in the vermis of the cerebellum play a crucial role in setting the tone for aggression. The study presented here aims to bridge the gap in our understanding of the cerebellum’s involvement in social behavior, emphasizing the potential significance of glia and vascular responses in modulating aggression and regulating the inclination to violent behavior.

Discussion

In this study, we employed the resident-intruder model to investigate aggression, inducing combat behavior in mice. Despite the traditional use of this model where the resident is typically the aggressor, our experimental conditions allowed for a more nuanced exploration as the roles of aggressor and victim were not fixed. This approach increased general tension and aggression in both animals, offering a unique perspective on cerebellar reactions during combat breakup.

Analyzing cerebellar reactions during combat breakup presented challenges due to rapidly alternating offensive and defensive behaviors. The fluctuation in cerebellar glial Ca2+ levels, considered a potential indicator of the internal mood of the recorded mouse, posed difficulties in correlating with observable behavior. To address this, we manually selected isolated instances of apparent offensive or passive modes through frame-by-frame visual inspection. Acknowledging the limitations of this approach, future studies may benefit from the development of algorithms, possibly utilizing deep learning software, to objectively categorize aggressive behavior with a higher frame rate.

Transgenic mice expressing fluorescent sensor proteins specifically in astrocytes, including cerebellar Bergmann glia cells (BGs), were instrumental in our study. The optical fiber implantation into the cerebellar vermis allowed for in vivo fiber photometry, capturing glial cytosolic Ca2+ and pH, as well as local brain blood volume (BBV) fluctuations during spontaneous combats. Our findings revealed distinct patterns of local field potential (LFP) changes upon combat breakup, which could be replicated through photoactivation of channelrhodopsin-2 (ChR2) expressed in glia.

The sustained increase in cerebellar glial cytosolic Ca2+ observed during combat breakup could be attributed to the activation of Ca2+-permeable AMPA receptors, purinergic receptors, or other receptors. This increase in Ca2+ might induce gliotransmitter release, such as glutamate, potentially influencing the excitability of Purkinje cells (PCs). The resulting enhancement in PC excitability could lead to the inhibition of deep cerebellar nuclei (DCN), subsequently reducing the excitatory projection from DCN to the ventral tegmental area (VTA) and resulting in decreased aggression.

While our study predominantly focused on Ca2+, fluctuations in glial cytosolic pH were also estimated. The potential impact of cytosolic pH on neuronal activity, coupled with the demonstrated capability of glial pH to fluctuate under non-pathological conditions, suggests a complex interplay between glial activity and aggression. ChR2-induced acidification triggering gliotransmitter release may influence cerebellar neuronal activity, adding another layer to the regulatory mechanisms governing aggression.

Despite the experimental complexities limiting a straightforward correlation analysis, the accumulation of significant data may pave the way for predicting aggressive behavior based on cerebellar brain environmental fluctuations. Identifying a causal relationship between glial activity and aggression holds therapeutic promise, potentially enabling interventions aimed at regulating the cerebellar brain environment to address excessive aggression and violent behavior.

This study underscores the intricate nature of the cerebellar contribution to social behavior and sets the stage for future research to unravel the complexities of neural mechanisms underlying aggression.


reference link : https://www.sciencedirect.com/science/article/pii/S0168010223002031?via%3Dihub#sec0005

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