MIDBRAIN DREADDS-GQ ASTROCYTE ACTIVATION ALTERS GLIOTRANSMITTER LEVELS AND COMPULSIVE BEHAVIORS

Astrocytes are increasingly recognized as regulators of neuronal activity, synaptic function, and behavior. Here, we investigate their role in the midbrain - a key region involved in motor control and reward processing. Using GFAPCre transgenic mice, we used an AAV-strategy to selectively express Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (hM3Dq-DREADDs) in midbrain astrocytes. hM3Dq activation of astrocytes was followed by behavioral and biochemical analyses. 45 minutes after CNO-injection i.p. for astrocyte activation, repetitive behaviors, such as digging and grooming were significantly reduced. Astrocyte activation did not affect motor coordination and homecage locomotion, nor did it influence affective behaviors. DREADDs-Gq activation of astrocytes significantly increased GFAP expression in astrocytes and c-Fos expression in nearby cells. Local c-Fos⁺ cell density negatively correlated with marble burying, indicating that astrocyte regulation of neural activity may be the cause of decreased compulsive behavior after hM3Dq astrocyte activation. In line with this, HPLC-analysis revealed altered levels of gliotransmitters following astrocyte activation - including decreased levels of serine and taurine in the midbrain, while glutamate, glutamine, and GABA remained unchanged.
To explore temporal dynamics of Astrocyte activation, we are currently investigating the consequences of initiating behavioral tests 10 min after CNO injections for hM3Dq Astrocyte activation, as well as hM4Di Gi-DREADDs manipulations.
Our preliminary findings suggest a new role for midbrain astrocytes in regulating compulsive-like behaviors, possibly via modulation of amino acid metabolism and neural excitability.