Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors.

Timothy M Locke,Sascha du Lac,Larry S Zweifel,Shelby S Johanson,Avery Hunker,Martin Darvas,Erik S Carlson,Hirofumi Fujita

doi:10.3389/fncel.2020.00228

Abstract

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 (Thlox/lox) to produce Pcp2-Cre;Thlox/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;Thlox/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.

Highlights

A role for the cerebellum in cognition has been primarily understood from an anatomical perspective, with several studies focusing on how specific regions of the cerebellum have connectivity with other brain regions that are more traditionally associated with cognitive function, such as the ventral tegmental area (VTA) or prefrontal cortex (PFC; Catecholaminergic Purkinje Cells Modulate CognitionKelly and Strick, 2003; Rogers et al, 2011; Watson et al, 2014; Parker et al, 2017; Locke et al, 2018; Carta et al, 2019)
We have confirmed and quantified the location and begun to characterize the role of Tyrosine hydroxylase (Th)+ Purkinje cells (PCs)-derived catecholamine signaling in the cerebellum in the mouse, with a focus on cognitive behaviors
Previous studies have shown that catecholaminergic signaling in the PFC, thalamus, amygdala, and striatum are important for top-down and bottom-up control of cognitive functions, in explorative and exploitative cognitive strategies in approach and avoidance behaviors in novel contingencies or environments (Aston-Jones and Cohen, 2005; Yu and Dayan, 2005)

Summary

Introduction

A role for the cerebellum in cognition has been primarily understood from an anatomical perspective, with several studies focusing on how specific regions of the cerebellum have connectivity with other brain regions that are more traditionally associated with cognitive function, such as the ventral tegmental area (VTA) or prefrontal cortex (PFC; Catecholaminergic Purkinje Cells Modulate CognitionKelly and Strick, 2003; Rogers et al, 2011; Watson et al, 2014; Parker et al, 2017; Locke et al, 2018; Carta et al, 2019). Neurotransmitter systems classically known for their involvement in cognitive functions are abundant within the cerebellum. Cerebellar nuclei have higher concentrations of norepinephrine and DA than the cerebellar cortex in the rat, as well as similar levels of these catecholamines relative to the frontal cortex (Versteeg et al, 1976). NE is necessary for cerebellardependent motor learning (Watson and McElligott, 1983, 1984), modulates plasticity of the vestibulo-ocular reflex (McElligott and Freedman, 1988), and is important for multiple phases of cerebellar-dependent classical conditioning of eyeblink responses, including acquisition, consolidation and extinction (McCormick and Thompson, 1982; Winsky and Harvey, 1992; Paredes et al, 2009)

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