Abstract
SummaryCholinergic interneurons (ChIs) of the striatum pause their firing in response to salient stimuli and conditioned stimuli after learning. Several different mechanisms for pause generation have been proposed, but a unifying basis has not previously emerged. Here, using in vivo and ex vivo recordings in rat and mouse brain and a computational model, we show that ChI pauses are driven by withdrawal of excitatory inputs to striatum and result from a delayed rectifier potassium current (IKr) in concert with local neuromodulation. The IKr is sensitive to Kv7.2/7.3 blocker XE-991 and enables ChIs to report changes in input, to pause on excitatory input recession, and to scale pauses with input strength, in keeping with pause acquisition during learning. We also show that although dopamine can hyperpolarize ChIs directly, its augmentation of pauses is best explained by strengthening excitatory inputs. These findings provide a basis to understand pause generation in striatal ChIs.Video
Highlights
Interest in Cholinergic interneurons (ChIs) pauses has been reinforced by the finding that they coincide with phasic activity in midbrain dopamine (DA) neurons (Joshua et al, 2008; Morris et al, 2004)
When ChIs and DA neurons are recorded in the same tasks in vivo, the ChI pause response does not show proportionality to DA neuron firing rate in either latency or amplitude (Joshua et al, 2008; Morris et al, 2004), suggesting that acute activation of D2 receptors plays a limited role in pause generation in vivo
ChIs In Vivo Respond to Changing Excitatory Input We explored ChI pause generation in vivo by recording singleunit activity in putative ChIs in urethane-anaesthetized rats (Figures S1A and S1B)
Summary
Cholinergic interneurons (ChIs) constitute only 1%–2% of striatal neurons but are emerging as key players in action selection, reinforcement, associative learning, and behavioral flexibility (Aoki et al, 2015; Bertran-Gonzalez et al, 2013; Bradfield et al, 2013; Joshua et al, 2008; Matamales et al, 2016; Maurice et al, 2015; Morris et al, 2004; Okada et al, 2014). ChIs fire tonically at 3–10 Hz (Apicella et al, 2009; Kimura et al, 1984; Wilson et al, 1990) and demonstrate phasic responses consisting of short pauses flanked by preceding and/or ‘‘rebound’’ phases of increased ChI activity (Aosaki et al, 1994a, 1994b; Apicella, 2007; Apicella et al, 2011; Kimura et al, 1984; Ravel et al, 1999) These phasic changes occur in response to salient or reward prediction-related stimuli after conditioning, implicating them in learning and action selection. We show that pauses are driven during recession from excitatory input by a delayed rectifier current and with regulation of excitatory synapse strength by neuromodulators serving to modulate pause acquisition
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