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Adaptation of sequential action benefits from timing variability related to lateral basal ganglia circuitry.

ABSTRACT: Streamlined action sequences must remain flexible should stable contingencies in the environment change. By combining analyses of behavioral structure with a circuit-specific manipulation in mice, we report on a relationship between action timing variability and successful adaptation that relates to post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). In a two-lever instrumental task, mice formed successful action sequences by, first, establishing action scaffolds and, second, smoothly extending action duration to adapt to increased task requirements. Interruption of DLS neurons in M1 projection territories altered this process, evoking higher-rate actions that were more stereotyped in their timing, reducing opportunities for success. Based on evidence from neuronal tracing experiments, we propose that DLS neurons in M1 projection territories supply action timing variability to facilitate adaptation, a function that may involve additional downstream subcortical processing relating to collateralization of descending motor pathways to multiple basal ganglia centers.

SUBMITTER: Ferguson LA

PROVIDER: S-EPMC10943431 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Adaptation of sequential action benefits from timing variability related to lateral basal ganglia circuitry.

Ferguson Lachlan A LA Matamales Miriam M Nolan Christopher C Balleine Bernard W BW Bertran-Gonzalez Jesus J

iScience 20240220 3

Streamlined action sequences must remain flexible should stable contingencies in the environment change. By combining analyses of behavioral structure with a circuit-specific manipulation in mice, we report on a relationship between action timing variability and successful adaptation that relates to post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). In a two-lever instrumental task, mice formed successful action sequences by, first, establishing acti ...[more]

PMID: 38496293

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Project description:Basal ganglia (BG) circuitry plays a crucial role in the control of movement. Degeneration of its pathways and imbalance of dopaminergic signalling goes along with movement disorders such as Parkinson's disease. In this study, we explore the interaction of degeneration in two BG pathways (the nigro-striatal and dentato-pallidal pathway) with D2 receptor signalling to elucidate an association to motor impairment and medication response. Included in the study were 24 parkinsonian patients [male, 62 years (± 9.3 SD)] compared to 24 healthy controls [male, 63 years (± 10.2 SD)]; each participant passed through three phases of the study (i) acquisition of metadata/clinical testing, (ii) genotyping and (iii) anatomical/diffusion MRI. We report a decline in nigro-striatal (p < .003) and dentato-pallidal (p < .0001) connectivity in the patients compared to controls, which is associated with increasing motor impairment (relating to nigro-striatal, r = -0.48; p < .001 and dentato-pallidal connectivity, r = -0.36; p = .035). Given, that variations of the ANKK1 Taq1 (rs 1,800,497) allele alters dopamine D2-dependent responses, all participants were genotyped respectively. By grouping patients (and controls) according to their ANKK1 genotype, we demonstrate a link between D2 receptor signalling and decline in connectivity in both investigated pathways for the A1- variant (nigro-striatal pathway: r = -0.53; p = .012, dentato-pallidal pathway: r = -0.62; p = .0012). In patients with the A1+ variant, we only found increased brain connectivity in the dentato-pallidal pathway (r = 0.71; p = .001) correlating with increasing motor impairment, suggesting a potentially compensatory function of the cerebellum. Related to medication response carriers of the A1+ variant had a better drug effect associated with stronger brain connectivity in the nigro-striatal pathway (r = 0.54; p < .02); the A1- group had a good medication response although nigro-striatal connectivity was diminished (r = -0.38; p < .05); these results underscore differences in receptor availability between both groups in the nigro-striatal pathway. No effect onto medication response was found in the dentato-pallidal pathway (p > .05). Interplay between basal ganglia connectivity and D2 receptor availability influence the clinical presentation and medication response of parkinsonian patients. Furthermore, while current models of basal-ganglia function emphasize that balanced activity in the direct and indirect pathways is required for normal movement, our data highlight a role of the cerebellum in compensating for physiological imbalances in this respect.

Project description:The timing of perceptual events depends on an anatomically and functionally connected network comprising basal ganglia, cerebellum, pre-frontal cortex and supplementary motor area. Recent studies demonstrate the cerebellum to be involved in absolute, duration-based timing, but not in relative timing based on a regular beat. Conversely, functional involvement of the striatum is observed in relative timing, but its role in absolute timing is unclear. This work tests the specific role of the basal ganglia in the perceptual timing of auditory events. It aims to distinguish the hypothesised unified model of time perception (Teki, Grube, & Griffiths, 2012), in which the striatum is a mandatory component for all timing tasks, from a modular system in which they subserve relative timing, with absolute timing processed by the cerebellum. Test groups comprised individuals with Multiple System Atrophy, a disorder in which similar pathology can produce clinical deficits associated with dysfunction of the cerebellum (MSA-C, n = 8) or striatum (MSA-P, n = 10), and early symptomatic Huntington's disease (HD, n = 14). Individuals with chronic autoimmune peripheral neuropathy (n = 11) acted as controls. Six adaptive tasks were carried out to assess perceptual thresholds for absolute timing through duration discrimination for sub- and supra-second time intervals, and relative timing through the detection of beat-based regularity and irregularity, detection of a delay within an isochronous sequence, and the discrimination of sequences with metrical structure. All three patient groups exhibited impairments in performance in comparison with the control group for all tasks, and severity of impairment was significantly correlated with disease progression. No differences were demonstrated between MSA-C and MSA-P, and the most severe impairments were observed in those with HD. The data support an obligatory role for the basal ganglia in all tested timing tasks, both absolute and relative, as predicted by the unified model. The results are not compatible with models of a brain timing network based upon independent modules.

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Adaptation of sequential action benefits from timing variability related to lateral basal ganglia circuitry.

Publications

Adaptation of sequential action benefits from timing variability related to lateral basal ganglia circuitry.

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