Astrocytes are fundamental components of brain information processing and possess the ability to respond to synaptic signaling with increases in cytoplasmic calcium and modulate neuronal activity ...with the subsequent release of neuroactive transmitters. Dopamine signaling is essential for brain physiology and pathology, participating in learning and memory, motor control, neurological diseases, and psychiatric diseases, and astrocytes are emerging as a key cellular target of dopamine signaling. The present review will examine evidence revealing that astrocytes respond to dopamine and modulate information processing in the primary brain regions implicated in the mesolimbic dopamine system. Astrocytes exhibit circuit-specific modulation of neuronal networks and have the potential to serve as a therapeutic target for interventions designed for dopamine pathologies.
Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson’s disease and addiction. In contrast to the extensive ...studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.
•Astrocytes in the Nucleus Accumbens respond to synaptic dopamine in vivo•Astrocytes mediate the synaptic regulation induced by dopamine and amphetamine•Amphetamine-induced enhancement in locomotion activity is modulated by astrocytes
Corkrum et al. report that astrocyte activity is required for dopamine- and amphetamine-evoked synaptic regulation and amphetamine-induced locomotor effects. Their study reveals astrocytes as active components of dopaminergic signaling and the brain reward system.
Major hallmarks of astrocyte physiology are the elevation of intracellular calcium in response to neurotransmitters and the release of neuroactive substances (gliotransmitters) that modulate neuronal ...activity. While μ-opioid receptor expression has been identified in astrocytes of the nucleus accumbens, the functional consequences on astrocyte-neuron communication remains largely unknown. The present study has investigated the astrocyte responsiveness to μ-opioid signaling and the regulation of gliotransmission in the nucleus accumbens. Through the combination of calcium imaging and whole-cell patch clamp electrophysiology in brain slices, we have found that μ-opioid receptor activation in astrocytes elevates astrocyte cytoplasmic calcium and stimulates the release of the gliotransmitter glutamate, which evokes slow inward currents through the activation of neuronal N-methyl-D-aspartate (NMDA) receptors. These results indicate the existence of molecular mechanisms underlying opioid-mediated astrocyte-neuron signaling in the nucleus accumbens.
Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic ...structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD.
This pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD.
15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R).
14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response.
Main limitations include a small sample size and open-label design.
These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD.
•dTMS may be helpful for some adolescents with treatment resistant depression (TRD).•dTMS was tolerable for most adolescents with TRD in this sample.•Clinical improvements were observable within two weeks of treatment.•Additional research to test efficacy and to inform parameter selection is needed.
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.
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