SUMMARY
The ability to associate environmental stimuli with positive outcomes is a fundamental form of learning. While extensive research has focused on the response profiles of midbrain dopamine neurons during associative learning, less is known about learning-mediated changes in the afferents that shape their responses. We demonstrate that during critical phases of learning, anion homeostasis in midbrain GABA neurons – a primary source of input to dopamine neurons – is disrupted due to downregulation of the chloride transporter KCC2. This alteration in GABA neurons preferentially impacted lateral mesoaccumbal dopamine pathways and was not observed after learning was established. At the network level, learning-mediated KCC2 downregulation was associated with enhanced synchronization between individual GABA neurons and increased dopamine responses to reward-related stimuli. Conversely, enhancing KCC2 function during learning reduced GABA synchronization, diminished relevant dopamine signaling, and prevented cue-reward associations. Thus, circuit-specific adaptations in midbrain GABA neurons are crucial for forming new reward-related behaviors.
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