Dorsal striatal circuit mechanisms contributing to astrocyte modulation of alcohol-related behaviors

Ardinger, C.; Kalelkar, A.; Madden, M.; Gunda, A.; Patel, A.; Xanthos, G.; Mahboob, M.; Khawaja, A.; Collie-Beard, N.; Bocarsly, M.; Huda, R.

doi:10.64898/2026.06.01.729412

bioRxiv · 10.64898/2026.06.01.729412

Dorsal striatal circuit mechanisms contributing to astrocyte modulation of alcohol-related behaviors

Ardinger, C.·Kalelkar, A.·Madden, M.·Gunda, A.·Patel, A.·Xanthos, G.·Mahboob, M.·Khawaja, A.·Collie-Beard, N.·Bocarsly, M.·Huda, R.

View original source ↗Export metadata ↓

Abstract

BackgroundThe dorsolateral striatum (DLS) is a key site for coordinating the alcohol-induced stimulant response, a behavioral marker predictive of future alcohol use disorder. Although ethanol (EtOH) affects all brain cells, little is known about the contribution of non-neuronal DLS cell types to EtOH-induced stimulation. MethodsWe used ex vivo two photon calcium imaging, in vivo fiber photometry of astrocyte and neuronal GCaMP, and astrocyte-specific manipulations in mice to determine DLS astrocyte contributions to EtOH-induced stimulation and voluntary EtOH drinking behavior. Using fiber photometry of GRAB-ACh sensors and cell-type specific chemogenetics, we also assessed the role of cholinergic signaling in observed astrocyte EtOH effects. ResultsAs expected, intraperitoneal EtOH injections (0.5-2g/kg) evoked a stimulant response, evidenced by increased locomotion compared to saline. In parallel, EtOH dose-dependently decreased astrocyte calcium activity but had minimal effects on direct and indirect pathway neuronal activity. Mimicking this reduction with astrocyte-specific expression of CalEX, a calcium extruding pump, facilitated EtOH stimulation compared to mice expressing a control fluorophore. Hence, EtOH-induced suppression of DLS astrocyte activity contributes to stimulation. Astrocyte calcium signaling is a well-known target of neuromodulation. Fiber photometry recordings of extracellular acetylcholine (ACh) levels via GRAB-ACh imaging showed inhibition of ACh release by acute EtOH. We virally expressed the excitatory chemogenetic actuator hM3Dq in striatal cholinergic interneurons to assess whether artificially increasing ACh release blocks EtOH-induced inhibition of astrocytic calcium activity. Despite facilitating ACh release, this manipulation did not impact astrocyte calcium activity under control (saline) or EtOH conditions. Together, this work identifies DLS astrocytes as key contributors to EtOH-induced stimulation and highlights the importance of considering astrocyte-neuron interactions in evaluating alcohol effects.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Ardinger, C., Kalelkar, A., Madden, M., Gunda, A., Patel, A., Xanthos, G., Mahboob, M., Khawaja, A., Collie-Beard, N., Bocarsly, M., Huda, R.. 2026-06-04. Dorsal striatal circuit mechanisms contributing to astrocyte modulation of alcohol-related behaviors. https://doi.org/10.64898/2026.06.01.729412

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A systems-level model of sleep-dependent memory-consolidation failure in neurodegeneration: the spindle-slow-oscillation decoupling cascade dissociates amyloid and tau

During non-rapid-eye-movement (NREM) sleep, the temporal coupling of cortical slow oscillations (SOs), thalamic spindles, and hippocampal sharp wave ripples drives the consolidation of declarative memories. This coupling degrades in ageing and Alzheimers disease (AD), and although A{beta} and tau leave dissociable signatures in human sleep, the mechanisms by which progressive pathology dismantles the consolidation machinery are difficult to isolate experimentally, and have not to our knowledge been reproduced in a model that can be perturbed directly. We built a systems-level model in which cortical SOs and thalamic spindles are generated by reduced oscillators, hippocampal ripples replay encoded spike sequences, and the measured per-event SO-spindle timing alignment causally gates spike-timing dependent plasticity on cortical sequence synapses. A post-sleep cued-recall test reads out consolidation. Five neurodegeneration parameters (amyloid, tau, synaptic density, GABAergic inhibition, cholinergic tone) map to dis tinct mechanisms grounded in the human and animal literature. The model reproduces graded healthy consolidation and a progressive collapse in which coupling, slow-wave power, spindle power and recall fall monotonically and the overnight memory effect flips from consolidation to net forgetting, with weak memories failing first. Scrambling SO-spindle timing while holding oscillation power fixed abolishes consolidation, establishing that coupling timing, rather than oscillation power, is what the plasticity gate depends on within the model. A{beta} and tau impair memory through orthogonal signatures (A{beta} collapses slow-wave power while sparing replay order, tau the reverse) and this orthogonality holds across the entire A{beta} x tau plane and survives simultaneous {+/-}50% resampling of every mapping coefficient (40/40 samples), so it is not an artefact of a single calibration point. The model yields a falsifiable clinical prediction: closed-loop slow-oscillation enhancement rescues memory only when the deficit is amplitude/coupling-dominated, not when it is replay(tau)-dominated, despite normalising slow-wave power in both cases. Because the therapy arms dissociate coupling from memory benefit, the model also cautions against adopting SO-spindle coupling as a standalone surrogate endpoint.

neuroscience↗

bioRxiv2026

Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS

MAPT (Tau) dysregulation is implicated in several neurodegenerative diseases, but its contribution to amyotrophic lateral sclerosis (ALS) is poorly understood. Here we show that mRNA isoforms encoding 4-repeat (4R) Tau are upregulated and cytoplasmically enriched in iPSC-derived motor neurons (MNs) from VCP-mutant and sporadic ALS, without a corresponding change in Tau protein. Using splice-switching antisense oligonucleotides and isoform-specific siRNAs, we find that enhanced 4R expression reduces MN viability, whereas its selective knockdown improves survival, with kinetics more consistent with an RNA-intrinsic effect than altered protein synthesis. Exon 10-containing MAPT RNA shows increased predicted secondary structure, self-association and altered Tau biocondensation in vitro. In post-mortem ALS cervical spinal cord, increased relative exon 10 usage is associated with a higher-risk clinical phenotype and shorter disease duration These findings identify an isoform-specific contribution of MAPT to MN vulnerability in ALS and nominate 4R MAPT RNA as a therapeutic target.

neuroscience↗

bioRxiv2026

30 Hz High-Definition Transcranial Alternating Current Stimulation at the Left Frontal Cortex Reduces the Spectral Slope of the EEG in the Contralateral Hemisphere

Background: High-definition transcranial alternating current stimulation (HD-tACS) is favored by the neurostimulation community for its precision and ability to influence neuronal dynamics. Yet, the exact mechanism by which the underlying brain structures are being affected remains unclear. We believe that the investigation of the aperiodic nature of the electroencephalograph (EEG) could shed light on the modulatory effects of HD-tACS. Methods: We analyzed the EEG of 9 participants during a compensatory tracking task (CTT) in two sessions, each with different HD-tACS protocols. Every session consisted of an initial period of no stimulation, followed by 30 Hz HD-tACS in the left motor (M30) or frontal (F30) cortex. We then isolated the aperiodic component of the EEG and calculated its spectral slope {beta}. Results and Discussion: {beta} decreased during F30 mainly in the right frontal cortex, indicating a shift towards higher frequencies and an increase of the excitatory/inhibitory balance. Additionally, we found that despite the long monotonus task the accuracy of the participants did not decrease, which might be attributed to the ability of both M30 and F30 to sustain attention for prolonged time. Finally, the change of CTT accuracy during the stimulation correlated with the {beta} of specific channels before the stimulation. This indicates the potential of {beta} to be used as a screening biomarker in future studies. In conclusion, we showed the ability of HD-tACS to alter EEG aperiodic dynamics and paved the way for future exploration of such dynamics in the field.

neuroscience↗