Cocaine experience induces functional adaptations in astrocytes: Implications for synaptic plasticity in the nucleus accumbens shell

Abstract

Astrocytes have become established as an important regulator of neuronal activity in the brain. Accumulating literature demonstrates that cocaine self‐administration in rodent models induces structural changes within astrocytes that may influence their interaction with the surrounding neurons. Here, we provide evidence that cocaine impacts astrocytes at the functional level and alters neuronal sensitivity to astrocyte‐derived glutamate. We report that a 14‐day period of short access to cocaine (2 h/day) decreases spontaneous astrocytic Ca2+ transients and precipitates changes in astrocyte network activity in the nucleus accumbens shell. This is accompanied by increased prevalence of slow inward currents, a physiological marker of neuronal activation by astrocytic glutamate, in a subset of medium spiny neurons. Within, but not outside, of this subset, we observe an increase in duration and frequency of N‐methyl‐D‐aspartate (NMDA) receptor‐mediated synaptic events. Additionally, we find that the link between synaptic NMDA receptor plasticity and neuron sensitivity to astrocytic glutamate is maintained independent of drug exposure and is observed in both cocaine and saline control animals. Imaging analyses of neuronal Ca2+ activity show no effect of cocaine self‐administration on individual cells or on neuronal network activity in brain slices. Therefore, our data indicate that cocaine self‐administration promotes astrocyte‐specific functional changes that can be linked to increased glutamate‐mediated coupling with principal neurons in the nucleus accumbens. Such coupling may be spatially restricted as it does not result in a broad impact on network structure of local neuronal circuits.

ER-GCaMP6f: An Endoplasmic Reticulum-Targeted Genetic Probe to Measure Calcium Activity in Astrocytic Processes

“…Animals with extended access exhibited lower duration and amplitude in ER Ca 2+ activity compared to the short-term access animals (Figure S9). Short-term access cocaine self-administration has been recently reported to decrease the amplitude and duration of astrocytic Ca 2+ transients recorded either at 1 or 14 days of withdrawal from self-administration in the NAc shell . The data in that publication were acquired using a cytosolic variant of GCaMP6f.…”

“…Animals were euthanized, and brain slices were acquired after 4 weeks to allow for GCaMP6f expression. 28,29 4. RESULTS AND DISCUSSION 4.1.…”

“…Then, 2.0 μL ER-GCaMP6f (full titer 2.86 × 10 13 ) virus solution was infused at a rate of 0.2 μL/min using a syringe pump, and the injector was left in place for 5 min following each infusion to allow for diffusion. Animals were euthanized, and brain slices were acquired after 4 weeks to allow for GCaMP6f expression. , …”

“…Shortterm access cocaine self-administration has been recently reported to decrease the amplitude and duration of astrocytic Ca 2+ transients recorded either at 1 or 14 days of withdrawal from self-administration in the NAc shell. 28 The data in that publication were acquired using a cytosolic variant of GCaMP6f. Our current data, using plasma membrane and ER variants of GCaMP6f and collected in the same brain area, indicate that the amplitude and duration of astrocytic Ca 2+ signals are also sensitive to the length of cocaine selfadministration sessions (Figures 6 and S9).…”

“…This demonstrates that the ER indicator detects physiological differences between conditions and has an additional impact for studies of cocaine-mediated plasticity of astrocyte and neuronal Ca 2+ signals. 28 Additionally, the dynamics measured in both groups were different for the ER indicator versus the plasma membrane indicator, where calcium activity in the ER was less frequent and shorter in duration than that at the plasma membrane, suggesting that near-ER activity is distinct from that occurring at the plasma membrane (Figures 6C,D and S9).…”