Abstract
The striatum, the main input structure of the basal ganglia, is critical for action selection and adaptive motor control. To understand the neuronal mechanisms underlying these functions, an analysis of microcircuits that compose the striatum is necessary. Among these, cholinergic interneurons (ChIs) provide intrinsic striatal innervation whose dysfunction is implicated in neuropsychiatric diseases, such as Parkinson’s disease and Tourette syndrome. The ability to experimentally manipulate the activity of ChIs is critical to gain insights into their contribution to the normal function of the striatum and the emergence of behavioral abnormalities in pathological states. In this study, we generated and tested CAV-pChAT-GFP, a replication-defective canine adenovirus type 2 (CAV-2) vector carrying the green fluorescent protein (GFP) sequence under the control of the human choline acetyltransferase (ChAT) promoter. We first tested the potential specificity of CAV-pChAT-GFP to label striatal ChIs in a rat before performing experiments on two macaque monkeys. In the vector-injected rat and monkey striatum, we found that GFP expression preferentially colocalized with ChAT-immunoreactivity throughout the striatum, including those from local circuit interneurons. CAV-2 vectors containing transgene driven by the ChAT promoter provide a powerful tool for investigating ChI contributions to circuit function and behavior in nonhuman primates.
Highlights
Numerous studies have suggested that the striatum, the main recipient of afferents to the basal ganglia, has a critical function in motor control and motivation
Coronal sections of the rat brain injected with CAVpChAT-green fluorescent protein (GFP) and CAV-mCherry into the striatum of the right and left hemispheres, respectively (Figure 2A), were processed for simultaneous detection of GFP, mCherry, and choline acetyltransferase (ChAT) to determine the specificity of CAV-pChAT-GFP to label cholinergic neurons of the striatum, as compared to CAV-mCherry that potentially targets all neurons
We developed a cell-typespecific gene expression approach using a canine adenovirus type 2 (CAV-2) vector carrying a ChAT promoter to investigate the role of cholinergic interneurons (ChIs) in nonhuman primates
Summary
Numerous studies have suggested that the striatum, the main recipient of afferents to the basal ganglia, has a critical function in motor control and motivation This structure mostly consists of GABAergic spiny projection neurons (SPNs) that target the output nuclei of the basal ganglia. A reduction in the density of ChIs has been reported in brains from patients with Tourette syndrome (Kataoka et al, 2010), a neuropsychiatric disorder characterized by abnormal repetitive movements and altered behavioral flexibility. It remains unclear how these interneurons regulate the functioning of the striatal network underlying adaptive behavior. A major goal of research in this area is to develop animal models in which the activity of ChIs can be selectively modified to mimic behavioral impairments observed in human brain pathology
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