Impairment of reward-related learning by cholinergic cell ablation in the striatum

Abstract

The striatum in the basal ganglia-thalamocortical circuitry is a key neural substrate that is implicated in motor balance and procedural learning. The projection neurons in the striatum are dynamically modulated by nigrostriatal dopaminergic input and intrastriatal cholinergic input. The role of intrastriatal acetylcholine (ACh) in learning behaviors, however, remains to be fully clarified. In this investigation, we examine the involvement of intrastriatal ACh in different categories of learning by selectively ablating the striatal cholinergic neurons with use of immunotoxin-mediated cell targeting. We show that selective ablation of cholinergic neurons in the striatum impairs procedural learning in the tone-cued T-maze memory task. Spatial delayed alternation in the T-maze learning test is also impaired by cholinergic cell elimination. In contrast, the deficit in striatal ACh transmission has no effect on motor learning in the rota-rod test or spatial learning in the Morris water-maze test or on contextual-and tone-cued conditioning fear responses. We also report that cholinergic cell elimination adaptively upregulates nicotinic ACh receptors not only within the striatum but also in the cerebral cortex and substantia nigra. The present investigation indicates that cholinergic modulation in the local striatal circuit plays a pivotal role in regulation of neural circuitry involving reward-related procedural learning and working memory. Memory consists of several separate entities that depend on different brain systems (1). Clinical and behavioral evidence suggests that the basal ganglia is involved in the procedural learning that leads to habit formation and in the performance of routine behaviors that have been acquired (2, 3). The striatum in the basal ganglia-thalamocortical circuitry receives input from all areas of the cerebral cortex (4) and comprises a major cell population of medium-sized spiny neurons that mediate neurotransmission via ␥-aminobutyric acid (5). The neural activity of these projection neurons is dynamically regulated by nigrostriatal dopaminergic input (6), and impairment of dopaminergic transmission in patients with Parkinson's disease causes not only extrapyramidal motor imbalance but also habit-learning dysfunction (2, 3). Electrophysiological and morphological studies have indicated the existence of another minor but important neuronal subpopulation in the striatum (7). These neurons are tonically active, thus termed tonically active neurons. They respond to stimuli that serve to trigger a learned and rewarded motor task and are implicated in learning processes of the basal ganglia function (8-13). Accumulating evidence suggests that tonically active neurons are cholinergic interneurons (9-12) that involve dynamic modulation of the basal ganglia circuitry through rich synaptic connections with the medium-sized spiny neurons within the striatum (4). However, the behavioral role of the striatal cholinergic interneurons in different categories of learning remains poorly understood, due to...

Dietary supplementation with uridine-5′-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat

“…Microdialysis studies have shown that when rats used response strategies rather than spatial strategies for learning, striatal ACh release increased (Chang et al, 2003). Moreover, selective ablation of striatal cholinergic neurons impairs procedural learning in mice (Kitabatake et al, 2003). Thus, the enhancement in striatal cholinergic neurotransmission, after oral UMP administration, that we observe (e.g.…”

Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome

“…ChAT interneuron ablation in the striatum has been previously performed using proteinaceous toxins coupled to specific antibodies (29)(30)(31)(32). Unfortunately, whereas ChAT interneuron ablation was apparent after ChAT-saporin (SAP), we also found reductions in ChAT immunoreactivity, qualitative changes in ChAT cell morphology, and patchy cell loss after treatment with IgG-SAP, even at low doses (Fig.…”

“…We found an immunotoxin that has been used previously to target striatal ChAT interneurons (29)(30)(31)(32) to produce nonspecific effects (Fig. S1).…”

Differential Effects of Systemic Cholinergic Receptor Blockade on Pavlovian Incentive Motivation and Goal-Directed Action Selection

“…For instance, acetylcholinedepleting striatal lesions have been shown to disrupt appetitive, but spare aversive, learning (Kitabatake et al, 2003). Furthermore, both scopolamine (Sharf et al, 2006;Pratt and Kelley, 2004;Tikhonravov et al, 1997) and mecamylamine (Levin et al, 2000) tend to suppress foodreinforced lever pressing.…”