Abstract
Two subpopulations of midbrain dopamine (DA) neurons are known to have different dynamic firing ranges in vitro that correspond to distinct projection targets: the originally identified conventional DA neurons project to the dorsal striatum and the lateral shell of the nucleus accumbens, whereas an atypical DA population with higher maximum firing frequencies projects to prefrontal regions and other limbic regions including the medial shell of nucleus accumbens. Using a computational model, we show that previously identified differences in biophysical properties do not fully account for the larger dynamic range of the atypical population and predict that the major difference is that originally identified conventional cells have larger occupancy of voltage-gated sodium channels in a long-term inactivated state that recovers slowly; stronger sodium and potassium conductances during action potential firing are also predicted for the conventional compared to the atypical DA population. These differences in sodium channel gating imply that longer intervals between spikes are required in the conventional population for full recovery from long-term inactivation induced by the preceding spike, hence the lower maximum frequency. These same differences can also change the bifurcation structure to account for distinct modes of entry into depolarization block: abrupt versus gradual. The model predicted that in cells that have entered depolarization block, it is much more likely that an additional depolarization can evoke an action potential in conventional DA population. New experiments comparing lateral to medial shell projecting neurons confirmed this model prediction, with implications for differential synaptic integration in the two populations.
Highlights
Midbrain dopaminergic signaling is strongly implicated in reward-based learning, motivation, action, and cognition [1,2,3,4]
We developed a theoretical and mathematical framework that could explain the major electrophysiological differences between the conventional midbrain dopamine (DA)
More recent work indicates that these processes are not independent, we utilized a simple Markov model of this channel instead, modified from [27], in order to better capture the sodium channel dynamics crucial to the entry into depolarization block that limits the maximal firing rate
Summary
Midbrain dopaminergic signaling is strongly implicated in reward-based learning, motivation, action, and cognition [1,2,3,4]. The intrinsic pacemaking activity exhibited by these neurons in a slice preparation is observed in vivo [8,9], where it is sculpted by synaptic inputs into less regular discharge patterns, including transient high frequency bursts and long pauses of electrical silence [8]. Twenty percent of the neurons recorded in that study exhibited regular pacemaking activity at 2–4 Hz in awake behaving animals, the intrinsic activity of these neurons is important for their firing patterns in vivo. The relative participation of these subpopulations in dopaminergic signaling is an unresolved, ongoing topic of investigation, an understanding of the biophysical basis for their intrinsic differences in firing range can lay the groundwork for understanding how the differences in dynamic range in vivo emerge
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