Glutamatergic Dysfunction of Astrocytes in Paraventricular Nucleus of Thalamus Contributes to Adult Anxiety Susceptibility in Adolescent Ethanol Exposed Mice.

Jun 6, 2025bioRxiv : the preprint server for biology

Problems with Glutamate Support Cells in a Brain Area Linked to Anxiety May Increase Adult Anxiety Risk After Teen Alcohol Exposure in Mice

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Abstract

Adolescent repeated intermittent ethanol exposure (AIE) triggers anxiety-like behaviors and induces glutamatergic adaptation in the paraventricular nucleus of thalamus (PVT) after four weeks of withdrawal.

Increased firing rates and spatiotemporal calcium transients in PVT neurons were observed in AIE mice compared to control mice.
Chemogenetic inhibition of PVT neurons alleviated anxiety-like behavior in AIE mice.
AIE was associated with a reduction of GLT1, an important glutamate transporter in astrocytes, contributing to increased neuronal activity.
Non-invasive magnetic resonance spectroscopy indicated an increased glutamate/GABA ratio in the PVT of GLT1 conditional knock-down mice exhibiting heightened anxiety-like behavior.
Selective knock-out of GLT1 in PVT astrocytes induced anxiety-like phenotypes in alcohol-naïve mice, while upregulation of GLT1 in AIE-treated mice alleviated anxiety-like behaviors.

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Repeated ethanol exposure during adolescence increases the risk for displaying anxiogenic phenotype in adulthood, but the underlying mechanisms are not fully understood. The paraventricular nucleus of thalamus (PVT) has been considered a hub brain area for controlling the anxiety network in the brain. Recent structural and functional investigations indicate that the PVT exhibits diverse neural signals aligned with early-life events, which are highly linked with anxiety-like behaviors. However, it remains unknown if repeated ethanol exposure during adolescence will affect the coordinated brain activities of the PVT in adulthood, and consequent behavioral adaptation. Here we show that adolescent repeated intermittent ethanol exposure (AIE) triggers anxiety-like behaviors and parallelly induces the glutamatergic adaptation in the PVT after four weeks withdrawal from the last ethanol exposure. The firing rates, along with the spatiotemporal calcium transients in the PVT neurons during behavior were increased in the AIE mice compared to those in the counterpart control mice. Importantly, with the chemogenetic inhibition of the PVT neurons, we found alleviated the anxiety-like behavior in the AIE mice. The increased neuronal activities in the PVT of AIE mice was, at least partly, via the reduction of GLT1 (an astrocyte dominant glutamate transporter, known as EAAT2, slc1a2). Our non-invasive magnetic resonance spectroscopy (MRS) measures also showed an increase in glutamate/GABA ratio in the thalamic area including the PVT of the GLT1 conditional knock-down mice, which exhibited the heightened anxiety-like behavior. In addition, while the selective knock-out of GLT1 in the astrocytes of PVT in the alcohol naïve mice induces anxiogenic phenotypes, the selective upregulation of GLT1 in the PVT astrocytes of the mice that were treated with AIE paradigm alleviated the anxiety-like behaviors as well. These findings highlight the significant role of PVT astrocytic GLT1 in the anxiogenic phenotype in adulthood induced by withdrawal from adolescent repeated ethanol exposure, suggesting that GLT1 in the PVT could serve as a therapeutic target for alcohol use disorder and comorbid emotional disorders.

Glutamatergic Dysfunction of Astrocytes in Paraventricular Nucleus of Thalamus Contributes to Adult Anxiety Susceptibility in Adolescent Ethanol Exposed Mice.

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