Rebound bursting selectively enables fast dynamics in dopamine midbrain neurons projecting to the dorso-lateral striatum

Dopamine midbrain (DA) neurons are involved in a wide array of key brain functions including movement control and reward-based learning. They are also critical for major brain disorders such as Parkinson Disease or schizophrenia. DA neurons projecting to distinct striatal territories are diverse with regards to their molecular makeup and cellular physiology, which are likely to contribute to the observed differences in temporal dopamine dynamics. Among these regions, the dorsolateral striatum (DLS) displays the fastest dopamine dynamics, which might control the moment-to-moment vigor and variability of voluntary movements. However, the underlying mechanisms for these DLS-specific fast DA fluctuations are unresolved. Here, we show that DLS-projecting DA neurons in the substantia nigra (SN) possess a unique biophysical profile allowing immediate 10-fold accelerations in discharge frequency via rebound bursting. By using a combination of in vitro patch-clamp recordings in projection-defined DA SN subpopulations from adult male mice and developing matching projection-specific computational models, we demonstrate that a strong interaction of Ca v 3 and SK channels specific for DLS-projecting Aldh1a1-positive DA SN (DLS-DA) neurons controls the gain of fast rebound bursting, while K v 4 and HCN channels mediate timing of rebound excitability. In addition, GIRK channels activated by D2- and GABA B -receptors prevent rebound bursting in these DLS-DA neurons. Furthermore, our in vivo patch-clamp recordings and matching in vivo computational models provide evidence that these unique rebound properties might be preserved in the intact brain, where they might endow specific computational properties well suited for the generation of fast dopamine dynamics present in the dorsolateral striatum. Significance Statement DLS-projecting DA neurons in the SN exhibit unique rebound bursting that enables rapid, 10-fold increases in firing frequency. This firing fingerprint is driven by Ca v 3 and SK channel interactions, modulating burst gain, and fine-tuned by K v 4 and HCN channels controlling rebound timing. GIRK channels, activated by D2- and GABA B -receptors, inhibit this bursting. In vivo patch-clamp recordings provide evidence that these rebound dynamics might be preserved in the intact brain, potentially supporting the fast dopamine fluctuations crucial for controlling movement vigor and variability in the DLS. These findings provide insights into the mechanisms underlying fast DA dynamics and their role in motor function, with implications for brain disorders like Parkinson disease and schizophrenia.