Image credit: Created by Khyati Trehan as part of the Visualising AI project launched by Google DeepMind @googledeepmind (CC0)
Dopamine is a neurotransmitter best known for its involvement in the brain’s reward and motivation system, but it also has major roles in learning, habit formation, and movement. It acts as a chemical messenger that enables neurons to communicate and reinforces beneficial behaviors, often promoting reward-seeking actions.
Many drugs stimulate the brain’s dopamine system by increasing dopamine release, blocking dopamine reuptake, or stimulating dopamine-producing neurons. A large proportion of dopaminergic neurons in mammals are located in the midbrain in a region known as the ventral tegmental area. However, so far, it has been unclear how drug exposure affects the inputs to these neurons across the brain.
One way to study brain circuits is to use engineered viruses as cell trackers. For example, scientists have used modified, fluorescent rabies viruses as ‘neural GPS trackers’ to map connections between neurons. Bartas et al. tested whether a modified rabies virus could measure how different drugs – including cocaine, amphetamine, morphine, and nicotine – affect brain-wide inputs to dopamine neurons in the ventral tegmental area.
They found that a single exposure to all addictive drugs tested induced a shared set of long-lasting changes in input neurons, many of which arise from brain regions typically associated with stress responses, such as the amygdala and related circuits. Moreover, repeated administration of a ketamine and xylazine mixture to induce anesthesia caused comparable input changes, suggesting that ketamine/xylazine anesthesia may have a similar long-term impact on the connectivity of these neurons.
These changes occurred only in select subtypes of input neurons, indicating that the effects are cell-type specific rather than global. Furthermore, the findings suggest that the rabies-based tracing reflects not only structural connectivity (i.e., the number of synapses) but also the functional state of input neurons, such as their baseline activity levels.
Bartas et al. then examined whether these effects were related to gene expression patterns in the input cells. By analyzing transcriptional data sets, they found that the expression of ion channels – in particular, calcium channels – was closely linked to drug-induced changes in the input neurons connecting with the dopamine neurons.
In summary, Bartas et al. demonstrate that addictive drugs all cause changes in similar sets of inputs to dopamine neurons that likely reflect long-term changes in input cell activity. In the future, this approach could be used to screen for experience-dependent changes in specific synapses and cell populations, further unravelling the dynamic properties of brain circuits.
