Astrocytes are key elements of brain circuits that are involved in different aspects of the neuronal physiology relevant to brain functions. Although much effort is being made to understand how the biology of astrocytes affects brain circuits, astrocytic network heterogeneity and plasticity is still poorly defined. Here, we have combined structural and functional imaging of astrocyte activity recorded in mice using the Ca2+-modulated photoactivatable ratiometric integrator and specific optostimulation of glutamatergic pathways to map the functional neuron-astrocyte circuitries in the nucleus accumbens (NAc). We showed pathway-specific astrocytic responses induced by selective optostimulation of main inputs from the prefrontal cortex, basolateral amygdala, and ventral hippocampus. Furthermore, co-stimulation of glutamatergic pathways induced non-linear Ca2+-signaling integration, revealing integrative properties of NAc astrocytes. All these results demonstrate the existence of specific neuron-astrocyte circuits in the NAc, providing an insight to the understanding of how the NAc integrates information.

Drug use is a growing problem in actual society. Usually, the first experience with drugs takes place during adolescence, being cannabis the most used illicit drug. Although cannabis could be considered a harmless drug, we are beginning to appreciate its consequences. Chronic exposure to addictive drugs has shown to imbalance glutamate homeostasis in Nucleus Accumbens (NAc), altering plasticity mechanisms such as long-term depression. Therefore, it is crucial to elucidate the mechanisms underlying these alterations and how to reverse them. It is known the activation of cannabinoid receptors in astrocytes modulate synaptic plasticity and could be involved in glutamate homeostasis. However, the functional role of astrocytes in alterations derived from chronic drug exposure is not fully understood. In this study, we analyzed how astrocytes contribute to alterations produced by tetrahydrocannabinol (THC). Using fiber photometry in vivo we analyzed astrocytic activity (Ca2+ and glutamate dynamics) in NAc after 1mg/kg THC chronic administration in wildtype and p38αMAPK-/- (Astrop38α) mice4 and we performed electrophysiology experiments to analyze synaptic plasticity. Moreover, we performed behavioral tests to assess whether THC had reinforcing properties or affected learning and memory. Furthermore, using a chemogenetic approaches (DREADDs) we activated NAc astrocytes to analyze their behavioral implications. We observed: 1)THC increases astrocytic calcium activity; 2)THC induces glutamate release in NAc in wildtype, but not Astrop38α; 3)NAc astrocytes are involved in learning; 4)Removal of p38αMAPK in NAc astrocytes restores THC-related impairments. Altogether, our results reveal astrocytes as critical elements for the maintenance of glutamate signaling, with a significant role in drug-use-related alterations.