Astrocyte-neuron signaling in the nucleus accumbens: implications for brain reward signaling

Abstract

Dopamine is one of the major reward signaling molecules in the brain. Dopaminergic transmission contributes to physiological states such as learning, memory encoding, movement and motivated behaviors; and, the disruption of dopamine signaling can contribute to neuropsychiatric diseases such as substance use disorders. The majority of research on reward signaling has focused on neurons; however, astrocytes are emerging as key components of brain information processing. Astrocytes are a subset of glial cell, one of the most abundant cell types in the brain. Although astrocytes are not electrically excitable, in response to brain activity, they demonstrate increases in intracellular calcium and the subsequent release of neuroactive substances, termed gliotransmitters. Therefore, my dissertation aimed to investigate the hypothesis that astrocytes respond to brain reward signaling with elevations in cytoplasmic calcium, and subsequently modulate neuronal activity in the nucleus accumbens, one of the major reward centers of the brain. Utilizing fiber photometry, I found that astrocytes in the nucleus accumbens respond to dopamine and amphetamine with cytoplasmic calcium elevations in vivo. To elucidate the cellular mechanisms of this phenomenon and the consequences of astrocyte calcium signals on neuronal activity, we conducted experiments applying multiphoton calcium imaging and whole-cell patch clamp electrophysiology in acute brain slices containing the nucleus accumbens core. We found that astrocytes respond to dopamine, amphetamine and opioids with intracellular calcium elevations and subsequently modulate neuronal activity, either through adenosine signaling in the case of dopamine and amphetamine or glutamatergic signaling in the case of opioid exposure. Furthermore, we demonstrate that astrocytes contribute to the acute psychomotor behavioral effects of amphetamine, illustrating astrocyte modulation of drug-related behaviors. Overall, the current body of work provides evidence that astrocytes actively contribute to brain reward processing via responding to dopamine and drugs of abuse with intracellular calcium increases and modulating neuronal and synaptic activity in the nucleus accumbens, one of the major nodes of the reward system.