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A Distributed Role for Nucleus Accumbens Cell Types and Inputs in Behavioural Inhibition and Compulsivity.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	A Distributed Role for Nucleus Accumbens Cell Types and Inputs in Behavioural Inhibition and Compulsivity./
作者:	Lafferty, Christopher K.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	204 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-11, Section: A.
Contained By:	Dissertations Abstracts International85-11A.
標題:	Hyperactivity. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31078881
ISBN:	9798382617909

A Distributed Role for Nucleus Accumbens Cell Types and Inputs in Behavioural Inhibition and Compulsivity.
Lafferty, Christopher K.

A Distributed Role for Nucleus Accumbens Cell Types and Inputs in Behavioural Inhibition and Compulsivity. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 204 p.

Source: Dissertations Abstracts International, Volume: 85-11, Section: A.

Thesis (Ph.D.)--McGill University (Canada), 2023.

Adaptive behaviour relies as much on suppressing context-inappropriate behaviour as selecting the best actions. Consequently, enduring deficits in behavioural inhibition are a common feature of numerous compulsive disorders, including OCD and Tourette syndrome. Although antagonistic interactions between nucleus accumbens (NAc) cell types and inputs are thought to play a key role in adjusting behavioural output, circuit mechanisms remain unclear. Here we examine the behavioural contributions of NAc direct and indirect pathway neurons and NAc afferents originating in the thalamus (PVT), amygdala (BLA), and hippocampus (vHPC). To test the causal role of NAc afferents in behavioural inhibition, we first validated an optical approach for projection-specific silencing. In brain slice recordings, we found that archaerhodopsin (ArchT)-mediated inhibition of axon terminals in the NAc elicited asynchronous vesicle release and increased local interneuron activity, undermining the pathway-specificity of this approach. We then identified soma-targeted ArchT inhibition as a valuable alternative, demonstrating that projection-specific silencing of PVT- or BLA-NAc afferents produced distinct behavioural outcomes. Much like direct and indirect pathway output neurons, evidence has also suggested that PVT and BLA inputs to the NAc exert antagonistic behavioural control. Accordingly, we hypothesized that effective behavioural control might arise from opposing activity between these cell types and pathways. To test this hypothesis directly, we then assessed the contributions of these circuit elements to mouse operant behavior during recurring periods of reward availability and unavailability. Although stimulation of direct and indirect pathway neurons was, respectively, reinforcing and aversive, inhibition of either cell type increased unproductive reward seeking. PVT and BLA inputs were also necessary for behavioral suppression even though they both supported self-stimulation behaviour and innervated different NAc subregions. These data suggest that effective reward seeking arises from the cooperative activity of NAc cell types and inputs, rather than opponent processes between them. We then considered the preclinical implications of our work and tested the role of PVT-NAc afferents in rodent models of compulsivity. Since striatal hyperactivity is a common feature of disorders like OCD and Tourette syndrome, we targeted repeated optical stimulation to PVT- and vHPC-NAc inputs over several days. While PVT-NAc activation elicited a progressive increase in repetitive selfgrooming and impairments on a reversal learning task, vHPC afferent stimulation only impinged upon reversal learning. These data suggest that NAc thalamic afferents complement fronto- striatal pathways as a convergent circuit vulnerability to compulsivity. Taken together, this body of work highlights NAc circuits as a key regulator of behavioural inhibition and lays the foundation for novel circuit-based therapies of compulsive disorders. Future models of basal ganglia function must recognize that behavioural inhibition is a distributed property of many neural circuits that arises from cross-regional population dynamics and not the aggregate activity of one cell type or neural pathway. From this perspective, dimensionality reduction and dynamical systems approaches represent a complement to existing circuit-interrogation techniques. These computational methods identify the low-dimensional structure of neural population dynamics and ground circuit perturbations in terms of their effects on physiological dynamics. By addressing significant hurdles in circuit neuroscience, these techniques pave a critical new path in the era of big data neuroscience.

ISBN: 9798382617909Subjects--Topical Terms:

3559054
Hyperactivity.

A Distributed Role for Nucleus Accumbens Cell Types and Inputs in Behavioural Inhibition and Compulsivity.
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245 1 2 $a A Distributed Role for Nucleus Accumbens Cell Types and Inputs in Behavioural Inhibition and Compulsivity.
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500 $a Source: Dissertations Abstracts International, Volume: 85-11, Section: A.
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502 $a Thesis (Ph.D.)--McGill University (Canada), 2023.
520 $a Adaptive behaviour relies as much on suppressing context-inappropriate behaviour as selecting the best actions. Consequently, enduring deficits in behavioural inhibition are a common feature of numerous compulsive disorders, including OCD and Tourette syndrome. Although antagonistic interactions between nucleus accumbens (NAc) cell types and inputs are thought to play a key role in adjusting behavioural output, circuit mechanisms remain unclear. Here we examine the behavioural contributions of NAc direct and indirect pathway neurons and NAc afferents originating in the thalamus (PVT), amygdala (BLA), and hippocampus (vHPC). To test the causal role of NAc afferents in behavioural inhibition, we first validated an optical approach for projection-specific silencing. In brain slice recordings, we found that archaerhodopsin (ArchT)-mediated inhibition of axon terminals in the NAc elicited asynchronous vesicle release and increased local interneuron activity, undermining the pathway-specificity of this approach. We then identified soma-targeted ArchT inhibition as a valuable alternative, demonstrating that projection-specific silencing of PVT- or BLA-NAc afferents produced distinct behavioural outcomes. Much like direct and indirect pathway output neurons, evidence has also suggested that PVT and BLA inputs to the NAc exert antagonistic behavioural control. Accordingly, we hypothesized that effective behavioural control might arise from opposing activity between these cell types and pathways. To test this hypothesis directly, we then assessed the contributions of these circuit elements to mouse operant behavior during recurring periods of reward availability and unavailability. Although stimulation of direct and indirect pathway neurons was, respectively, reinforcing and aversive, inhibition of either cell type increased unproductive reward seeking. PVT and BLA inputs were also necessary for behavioral suppression even though they both supported self-stimulation behaviour and innervated different NAc subregions. These data suggest that effective reward seeking arises from the cooperative activity of NAc cell types and inputs, rather than opponent processes between them. We then considered the preclinical implications of our work and tested the role of PVT-NAc afferents in rodent models of compulsivity. Since striatal hyperactivity is a common feature of disorders like OCD and Tourette syndrome, we targeted repeated optical stimulation to PVT- and vHPC-NAc inputs over several days. While PVT-NAc activation elicited a progressive increase in repetitive selfgrooming and impairments on a reversal learning task, vHPC afferent stimulation only impinged upon reversal learning. These data suggest that NAc thalamic afferents complement fronto- striatal pathways as a convergent circuit vulnerability to compulsivity. Taken together, this body of work highlights NAc circuits as a key regulator of behavioural inhibition and lays the foundation for novel circuit-based therapies of compulsive disorders. Future models of basal ganglia function must recognize that behavioural inhibition is a distributed property of many neural circuits that arises from cross-regional population dynamics and not the aggregate activity of one cell type or neural pathway. From this perspective, dimensionality reduction and dynamical systems approaches represent a complement to existing circuit-interrogation techniques. These computational methods identify the low-dimensional structure of neural population dynamics and ground circuit perturbations in terms of their effects on physiological dynamics. By addressing significant hurdles in circuit neuroscience, these techniques pave a critical new path in the era of big data neuroscience.
520 $a Le comportement adaptatif relie autant sur la selection des meilleures actions que sur la suppression des comportements inappropries au contexte. Par consequent, des deficits durables dans l'inhibition comportementale sont une caracteristique commune de nombreux troubles compulsifs, y compris les TOC et le syndrome de Gilles de la Tourette. Bien que l'on pense que les interactions antagonistes entre les types de cellules du noyau accumbens (NAc) et les afferences au NAc jouent un role cle dans l'ajustement de la production comportementale, les mecanismes du circuit restent peu clairs. Nous examinons ici les contributions comportementales des neurones des voies directes et indirectes du NAc et des afferences au NAc provenant du thalamus (TPV), de l'amygdale (ABL) et de l'hippocampe (HPCv). Pour evaluer le role causal des afferences au NAc dans l'inhibition comportementale, nous avons valide une approche optique pour l'inhibition specifique des projections. Dans les enregistrements de coupes de cerveau, nous avons constate que l'inhibition des terminaisons axonales dans le NAc par l'archaerhodopsine (ArchT) provoquait la liberation asynchrone de vesicules et augmentait l'activite locale des interneurones, ce qui mettait en doute la specificite de cette approche. Nous avons ensuite identifie l'inhibition de l'ArchT ciblee sur le soma comme une alternative, en demontrant que l'inhibition des afferences TPV- ou ABL-NAc produisait des resultats comportementaux distincts. Ce resultat est coherent avec la preuve que les afferences TPV et ABL au NAc exercent un controle comportemental antagoniste, tout comme les neurones des voies directes et indirectes. En consequence, nous avons propose l'hypothese qu'un controle comportemental efficace pourrait resulter d'une activite opposee entre ces types de cellules et ces afferences. Pour tester directement cette hypothese, nous avons ensuite evalue les contributions de ces elements du circuit au comportement operant de la souris pendant des periodes recurrentes de disponibilite et d'indisponibilite de la recompense. Bien que la stimulation des neurones directes et indirectes soit, respectivement, renforcante et aversive, l'inhibition de l'un ou l'autre type de cellule augmente la recherche improductive de recompense. Les afferences TPV et ABL etaient egalement necessaires pour la suppression du comportement, meme si elles soutenaient toutes deux le comportement d'autostimulation et innervaient differentes sous-regions du NAc. Ces donnees suggerent que la recherche efficace de recompense resulte de l'activite cooperative des types de cellules et des afferences au NAc, plutot que de processus opposes entre eux. Nous avons ensuite examine les implications precliniques de nos travaux et teste le role des afferences TPV-NAc dans des modeles murins de compulsivite. L'hyperactivite striatale etant une caracteristique commune de troubles tels que les TOC et le syndrome de Gilles de la Tourette, nous avons cible une stimulation optique repetee sur les entrees TPV- et HPCv-NAc pendant plusieurs jours. Alors que l'activation du TPV-NAc a provoque une augmentation progressive de l'autopalpation repetitive et des deficiences dans une tache d'apprentissage a renforcements inverses, la stimulation afferente du vHPC n'a eu d'impact que sur l'apprentissage inverse. Ces donnees suggerent que les afferences thalamiques du NAc jouent un role complementaire avec les voies fronto-striatales produisant un circuit convergent vulnerable a la compulsivite. Somme toute, ces travaux demontrent que les circuits du NAc sont un regulateur cle de l'inhibition comportementale et etablissent les fondements de nouvelles therapies basees sur les circuits pour les troubles compulsifs.
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