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Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action.

ABSTRACT: BACKGROUND:The nucleus accumbens (NAc) controls multiple facets of impulsivity but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma-aminobutyric acid signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of gamma-aminobutyric acid-mediated synaptic inhibition in the NAc. METHODS:Male and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task to measure both impulsive action and sustained attention. During the 5-choice serial reaction time task, we monitored FSI activity with fiber photometry calcium imaging and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs. RESULTS:In mice performing the 5-choice serial reaction time task, NAc FSIs showed sustained activity on trials ending with correct responses, but FSI activity declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity. CONCLUSIONS:These experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through gamma-aminobutyric acid-mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity and may inform the development of circuit-based therapeutic interventions.

SUBMITTER: Pisansky MT

PROVIDER: S-EPMC6823148 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action.

Pisansky Marc T MT Lefevre Emilia M EM Retzlaff Cassandra L CL Trieu Brian H BH Leipold David W DW Rothwell Patrick E PE

Biological psychiatry 20190710 11

<h4>Background</h4>The nucleus accumbens (NAc) controls multiple facets of impulsivity but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma-aminobutyric acid signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of gamma-aminobutyric acid-mediated synaptic inhibition in the NAc.<h4>Methods</h4>Male and female transgenic mice expressing Cre recombina ...[more]

PMID: 31471038

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Project description:Fast-spiking (FS) interneurons are important elements of neocortical circuitry that constitute the primary source of synaptic inhibition in adult cortex and impart temporal organization on ongoing cortical activity. The highly specialized intrinsic membrane and firing properties that allow cortical FS interneurons to perform these functions are attributable to equally specialized gene expression, which is ultimately coordinated by cell-type-specific transcriptional regulation. Although embryonic transcriptional events govern the initial steps of cell-type specification in most cortical interneurons, including FS cells, the electrophysiological properties that distinguish adult cortical cell types emerge relatively late in postnatal development, and the transcriptional events that drive this maturational process are not known. To address this, we used mouse whole-genome microarrays and whole-cell patch clamp to characterize the transcriptional and electrophysiological maturation of cortical FS interneurons between postnatal day 7 (P7) and P40. We found that the intrinsic and synaptic physiology of FS cells undergoes profound regulation over the first 4 postnatal weeks and that these changes are correlated with primarily monotonic but bidirectional transcriptional regulation of thousands of genes belonging to multiple functional classes. Using our microarray screen as a guide, we discovered that upregulation of two-pore K leak channels between P10 and P25 contributes to one of the major differences between the intrinsic membrane properties of immature and adult FS cells and found a number of other candidate genes that likely confer cell-type specificity on mature FS cells. Experiment Overall Design: We characterized the transcriptional maturation of genetically labeled FS interneurons in mouse S1 cortex using whole-genome microarrays.mRNA was harvested from manually sorted GFPexpressing neurons dissociated from acutely prepared brain slices at a range of developmental time points (P7, P10, P15, P25, and P40) and subsequently reverse transcribed, amplified, labeled, and hybridized to Affymetrix 430 2.0 whole-genome microarrays (three microarrays from three different animals per condition). We used the G42 transgenic mice described by Chattopadhyaya et al. (2004) for all experiments.

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.

Project description:The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met5]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study demonstrates that spontaneous dopamine release is (1) dependent of the activation of nicotinic receptors, (2) independent on the spontaneous activity of cholinergic interneurons, and (3) that cocaine increased the detection of dopamine transients by prolonging the presence and increasing the diffusion of dopamine in the extracellular space. The release of acetylcholine is therefore responsible for spontaneous dopamine transients, and cocaine augments dopamine tone without altering activity of cholinergic interneurons.

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Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action.

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Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action.

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