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Chronic nicotine impairs sparse motor learning via striatal fast-spiking parvalbumin interneurons.

ABSTRACT: Nicotine can diversely affect neural activity and motor learning in animals. However, the impact of chronic nicotine on striatal activity in vivo and motor learning at long-term sparse timescale remains unknown. Here, we demonstrate that chronic nicotine persistently suppresses the activity of striatal fast-spiking parvalbumin interneurons, which mediate nicotine-induced deficit in sparse motor learning. Six weeks of longitudinal in vivo single-unit recording revealed that mice show reduced activity of fast-spiking interneurons in the dorsal striatum during chronic nicotine exposure and withdrawal. The reduced firing of fast-spiking interneurons was accompanied by spike broadening, diminished striatal delta oscillation power, and reduced sample entropy in local field potential. In addition, chronic nicotine withdrawal impaired motor learning with a weekly sparse training regimen but did not affect general locomotion and anxiety-like behavior. Lastly, the excitatory DREADD hM3Dq-mediated activation of striatal fast-spiking parvalbumin interneurons reversed the chronic nicotine withdrawal-induced deficit in sparse motor learning. Taken together, we identified that chronic nicotine withdrawal impairs sparse motor learning via disruption of activity in striatal fast-spiking parvalbumin interneurons. These findings suggest that sparse motor learning paradigm can reveal the subtle effect of nicotine withdrawal on motor function and that striatal fast-spiking parvalbumin interneurons are a neural substrate of nicotine's effect on motor learning.

SUBMITTER: Kim B

PROVIDER: S-EPMC8243919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Striatal fast-spiking interneurons (FSIs) fire in variable-length runs of action potentials at 20-200 spikes/s separated by pauses. In vivo, or with fluctuating applied current, both runs and pauses become briefer and more variable. During runs, spikes are entrained specifically to gamma-frequency components of the input fluctuations. We stimulated parvalbumin-expressing striatal FSIs in mouse brain slices with broadband noise currents added to direct current steps and measured spike entrainment across all frequencies. As the constant current level was increased, FSIs produced longer runs and showed sharper frequency tuning, with best entrainment at the stimulus frequency matching their intrarun firing rate. We separated the contributions of previous spikes from that of the fluctuating stimulus, revealing a strong contribution of previous action potentials to gamma-frequency entrainment. In contrast, after subtraction of the effect inherited from the previous spike, the remaining stimulus contribution to spike generation was less sharply tuned, showing a larger contribution of lower frequencies. The frequency specificity of entrainment within a run was reproduced with a phase resetting model based on experimentally measured phase resetting curves of the same FSIs. In the model, broadly tuned phase entrainment for the first spike in a run evolved into sharply tuned gamma entrainment over the next few spikes. The data and modeling results indicate that for FSIs firing in brief runs and pauses firing within runs is entrained by gamma-frequency components of the input, whereas the onset timing of runs may be sensitive to a wider range of stimulus frequency components.NEW & NOTEWORTHY Specific types of neurons entrain their spikes to particular oscillation frequencies in their synaptic input. This entrainment is commonly understood in terms of the subthreshold voltage response, but how this translates to spiking is not clear. We show that in striatal fast-spiking interneurons, entrainment to gamma-frequency input depends on rhythmic spike runs and is explained by the phase resetting curve, whereas run initiation can be triggered by a broad range of input frequencies.

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Chronic nicotine impairs sparse motor learning via striatal fast-spiking parvalbumin interneurons.

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