Biology subjects

Evans, W. R.

Publications and source records attributed to Evans, W. R..

3 recordsLinked to original sources

bioRxiv2026

Striatal cholinergic and dopaminergic driven astrocyte Ca2+ activity is disrupted in Parkinsonian mice

Brain neuromodulatory systems exert powerful effects on local neuronal circuit function and behavior. In addition to classical actions directly on neurons, growing evidence indicates that neuromodulators also recruit Ca2+-dependent astrocyte mechanisms to regulate synaptic plasticity and network function. The dorsal striatum integrates cortical and thalamic inputs under strong dopamine (DA) and acetylcholine (ACh) neuromodulatory control. To what extent the circuit and behavioral effects of striatal ACh and DA depend on astrocyte Ca2+ activity remains unclear. We show that locomotion elicits robust DA, ACh, and astrocyte Ca2+ activity in the dorsolateral striatum (DLS). DA and ACh release exhibits a negative correlation on a fast time scale but shows a positive correlation during continuous locomotion as slower astrocyte Ca2+ activity builds. Higher ACh and DA release is associated with higher astrocyte events, suggesting that both neurotransmitters drive astrocyte activity. In agreement, pharmacological blockade of muscarinic ACh or D1/D2 DA receptors decreases locomotion-evoked astrocyte Ca2+. Closed-loop optogenetic inhibition of striatal cholinergic interneurons (CINs) during locomotion reduces astrocyte Ca2+ activity, demonstrating a causal contribution of ACh release to astrocyte activity. Locomotion related ACh release was severely compromised in a mouse model of Parkinsons disease (PD), with the dual loss of DA and ACh attenuating astrocyte Ca2+ activity. Facilitating astrocyte cholinergic signaling via chemogenetics improved both calcium activity and motor deficits in our recent work. Thus, the pathophysiology of PD in part involves attenuated astrocyte Ca2+ signaling, placing these non-neuronal cells as a prime underexplored therapeutic target for PD.

neuroscience↗

bioRxiv2024

Functional activation of dorsal striatum astrocytes improves movement deficits in hemi-parkinsonian mice

Parkinsons disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal inputs, which causes striatal network dysfunction and leads to pronounced motor deficits. Recent evidence highlights astrocytes as a potential local source of striatal network modulation. However, it remains unknown how dopamine loss affects striatal astrocyte activity and whether astrocyte activity regulates behavioral deficits in PD. We addressed these questions by performing astrocyte-specific calcium recordings and manipulations using in vivo fiber photometry and chemogenetics. We find that locomotion elicits astrocyte calcium activity over a slower timescale than neurons. Unilateral dopamine depletion reduced locomotion-related astrocyte responses. Chemogenetic activation facilitated astrocyte activity, and improved asymmetrical motor deficits and open field exploratory behavior in dopamine lesioned mice. Together, our results establish a novel role for functional striatal astrocyte signaling in modulating motor function in PD and highlight non-neuronal targets for potential PD therapeutics.

neuroscience↗

bioRxiv2023

Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinsons disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.

neuroscience↗