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Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors

Tyrosine hydroxylase (Th) expression has previously been reported in Purkinje cells (PCs) of rodents and humans, but its role in the regulation of behavior is not understood. Catecholamines are well known for facilitating cognitive behaviors and are expressed in many regions of the brain. Here, we i...

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Autores principales: Locke, Timothy M., Fujita, Hirofumi, Hunker, Avery, Johanson, Shelby S., Darvas, Martin, du Lac, Sascha, Zweifel, Larry S., Carlson, Erik S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403473/
https://www.ncbi.nlm.nih.gov/pubmed/32848620
http://dx.doi.org/10.3389/fncel.2020.00228
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author Locke, Timothy M.
Fujita, Hirofumi
Hunker, Avery
Johanson, Shelby S.
Darvas, Martin
du Lac, Sascha
Zweifel, Larry S.
Carlson, Erik S.
author_facet Locke, Timothy M.
Fujita, Hirofumi
Hunker, Avery
Johanson, Shelby S.
Darvas, Martin
du Lac, Sascha
Zweifel, Larry S.
Carlson, Erik S.
author_sort Locke, Timothy M.
collection PubMed
description Tyrosine hydroxylase (Th) expression has previously been reported in Purkinje cells (PCs) of rodents and humans, but its role in the regulation of behavior is not understood. Catecholamines are well known for facilitating cognitive behaviors and are expressed in many regions of the brain. Here, we investigated a possible role in cognitive behaviors of PC catecholamines, by mapping and testing functional roles of Th positive PCs in mice. Comprehensive mapping analyses revealed a distinct population of Th expressing PCs primarily in the posterior and lateral regions of the cerebellum (comprising about 18% of all PCs). To identify the role of PC catecholamines, we selectively knocked out Th in PCs using a conditional knockout approach, by crossing a Purkinje cell-selective Cre recombinase line, Pcp2-Cre, with a floxed tyrosine hydroxylase mouse line (Th(lox/lox)) to produce Pcp2-Cre;Th(lox/lox) mice. This manipulation resulted in approximately 50% reduction of Th protein expression in the cerebellar cortex and lateral cerebellar nucleus, but no reduction of Th in the locus coeruleus, which is known to innervate the cerebellum in mice. Pcp2-Cre;Th(lox/lox) mice showed impairments in behavioral flexibility, response inhibition, social recognition memory, and associative fear learning relative to littermate controls, but no deficits in gross motor, sensory, instrumental learning, or sensorimotor gating functions. Catecholamines derived from specific populations of PCs appear to support cognitive functions, and their spatial distribution in the cerebellum suggests that they may underlie patterns of activation seen in human studies on the cerebellar role in cognitive function.
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spelling pubmed-74034732020-08-25 Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors Locke, Timothy M. Fujita, Hirofumi Hunker, Avery Johanson, Shelby S. Darvas, Martin du Lac, Sascha Zweifel, Larry S. Carlson, Erik S. Front Cell Neurosci Cellular Neuroscience Tyrosine hydroxylase (Th) expression has previously been reported in Purkinje cells (PCs) of rodents and humans, but its role in the regulation of behavior is not understood. Catecholamines are well known for facilitating cognitive behaviors and are expressed in many regions of the brain. Here, we investigated a possible role in cognitive behaviors of PC catecholamines, by mapping and testing functional roles of Th positive PCs in mice. Comprehensive mapping analyses revealed a distinct population of Th expressing PCs primarily in the posterior and lateral regions of the cerebellum (comprising about 18% of all PCs). To identify the role of PC catecholamines, we selectively knocked out Th in PCs using a conditional knockout approach, by crossing a Purkinje cell-selective Cre recombinase line, Pcp2-Cre, with a floxed tyrosine hydroxylase mouse line (Th(lox/lox)) to produce Pcp2-Cre;Th(lox/lox) mice. This manipulation resulted in approximately 50% reduction of Th protein expression in the cerebellar cortex and lateral cerebellar nucleus, but no reduction of Th in the locus coeruleus, which is known to innervate the cerebellum in mice. Pcp2-Cre;Th(lox/lox) mice showed impairments in behavioral flexibility, response inhibition, social recognition memory, and associative fear learning relative to littermate controls, but no deficits in gross motor, sensory, instrumental learning, or sensorimotor gating functions. Catecholamines derived from specific populations of PCs appear to support cognitive functions, and their spatial distribution in the cerebellum suggests that they may underlie patterns of activation seen in human studies on the cerebellar role in cognitive function. Frontiers Media S.A. 2020-07-29 /pmc/articles/PMC7403473/ /pubmed/32848620 http://dx.doi.org/10.3389/fncel.2020.00228 Text en Copyright © 2020 Locke, Fujita, Hunker, Johanson, Darvas, du Lac, Zweifel and Carlson. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular Neuroscience
Locke, Timothy M.
Fujita, Hirofumi
Hunker, Avery
Johanson, Shelby S.
Darvas, Martin
du Lac, Sascha
Zweifel, Larry S.
Carlson, Erik S.
Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors
title Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors
title_full Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors
title_fullStr Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors
title_full_unstemmed Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors
title_short Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors
title_sort purkinje cell-specific knockout of tyrosine hydroxylase impairs cognitive behaviors
topic Cellular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403473/
https://www.ncbi.nlm.nih.gov/pubmed/32848620
http://dx.doi.org/10.3389/fncel.2020.00228
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