Regional Striatal Cholinergic Involvement in Human Behavioral Flexibility (original) (raw)
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Functional neurochemical imaging of the human striatal cholinergic system during reversal learning
The European journal of neuroscience, 2017
Animal studies have shown that acetylcholine (ACh) levels in the dorsal striatum play a role in reversal learning. However, this has not been studied in humans due to a lack of appropriate non-invasive techniques. Proton magnetic resonance spectroscopy (H-MRS) can be used to measure metabolite levels in humans in vivo. Although it cannot be used to study ACh directly,H-MRS can be used to study choline, an ACh precursor, which is linked to activity-dependent ACh release. The aim of this study was to use functional-H-MRS (fMRS) to measure changes in choline levels in the human dorsal striatum during performance of a probabilistic reversal learning task. We demonstrate a task-dependent decrease in choline, specifically during reversal, but not initial, learning. We interpret this to reflect a sustained increase in ACh levels, which is in line with findings from the animal literature. This task-dependent change was specific to choline and was not observed in control metabolites. These f...
Acetylcholine actions in the dorsomedial striatum support the flexible shifting of response patterns
Neurobiology of learning and memory, 2003
There is accumulating evidence that the dorsomedial striatum plays a significant role in the learning of a new response pattern and the inhibiting of old response patterns when conditions demand a shift in strategies. This paper proposes that activity of cholinergic neurons in the dorsomedial striatum is critical for enabling behavioral flexibility when there is a change in task contingencies. Recent experimental findings are provided supporting this idea. Measuring acetylcholine efflux from the dorsomedial striatum during the acquisition and reversal learning of a spatial discrimination shows that acetylcholine efflux selectively increases during reversal learning as a rat begins to learn a newly reinforced spatial location, but returns to near basal levels when a rat reliably executes the new choice pattern. Experimental findings are also described indicating that the blockade of muscarinic cholinergic receptors in the dorsomedial striatum does not impair acquisition of an egocent...
Dynamic Changes in Acetylcholine Output in the Medial Striatum During Place Reversal Learning
Learning & Memory, 2004
The present studies explored the role of the medial striatum in learning when task contingencies change. Experiment 1 examined whether the medial striatum is involved in place reversal learning. Testing occurred in a modified cross-maze across two consecutive sessions. Injections of the local anesthetic, bupivacaine, into the medial striatum, did not impair place acquisition, but impaired place reversal learning. The reversal-learning deficit was due to an inability to maintain the new choice pattern following the initial shift. Experiment 2 determined whether changes in acetylcholine (ACh) output occur during the acquisition or reversal learning of a place discrimination. Extracellular ACh output from the medial striatum was assessed in samples collected at 6-min intervals using in vivo microdialysis during behavioral testing. ACh output did not change from basal levels during place acquisition. During reversal learning, ACh output significantly increased as rats began to learn the new choice pattern, and returned to near basal levels as a rat reliably executed the new place strategy. The present results suggest that the medial striatum may be critical for flexible adaptations involving spatial information, and that ACh actions in this area enable the shifting of choice patterns when environmental conditions change. 1 Corresponding author. E-MAIL mrago@uic.edu; FAX (312) 413-4122. Article and publication are at
Neuron, 2013
The capacity for goal-directed action depends on encoding specific action-outcome associations, a learning process mediated by the posterior dorsomedial striatum (pDMS). In a changing environment, plasticity has to remain flexible, requiring interference between new and existing learning to be minimized, yet it is not known how new and existing learning are interlaced in this way. Here we investigated the role of the thalamostriatal pathway linking the parafascicular thalamus (Pf) with cholinergic interneurons (CINs) in the pDMS in this process. Removing the excitatory input from Pf to the CINs was found to reduce the firing rate and intrinsic activity of these neurons and produced an enduring deficit in goal-directed learning after changes in the action-outcome contingency. Disconnection of the Pf-pDMS pathway produced similar behavioral effects. These data suggest that CINs reduce interference between new and existing learning, consistent with claims that the thalamostriatal pathway exerts state control over learning-related plasticity.
Cholinergic mechanisms in adaptive behaviour
European Journal of Neuroscience, 2018
April 14th to 15th, 2016, a group of researchers investigating the role of acetylcholine within brain circuits responsible for learning and behaviour gathered in Okinawa, Japan, for a mini-symposium hosted by the Okinawa Institute of Science and Technology Graduate University. The aim was to work towards an integrated concept of the contribution of acetylcholine to higher brain functions, and the underlying neural mechanisms, by integrating the most recent results into a coherent concept of the role of acetylcholine in overall brain function, focusing on the basal ganglia in interaction with the thalamus and cerebral cortex. This Special Section of the European Journal of Neuroscience brings together several papers based on invited talks presented at this mini-symposium. Acetylcholine has long been known to play a crucial role in adaptive behaviour, but the limited access to the cholinergic neurons which release acetylcholine has limited progress. The recent availability of genetic approaches to targeting cholinergic neurons for experimental study, combined with sophisticated electrophysiological, behavioural and imaging approaches, has led to an
Neurobiology of Learning and Memory, 2013
Two experiments examined whether muscarinic cholinergic systems play a role in rats' ability to perform well-learned highly-structured serial response patterns, particularly focusing on rats' performance on pattern elements learned by encoding rules versus by acquisition of stimulus-response (S-R) associations. Rats performed serial patterns of responses in a serial multiple choice task in an 8-lever circular array for hypothalamic brain-stimulation reward. Two experiments examined the effects of atropine, a centrally-acting muscarinic cholinergic receptor antagonist, on rats' ability to perform pattern elements where responses were controlled by rules versus elements, such as rule-inconsistent ''violation elements'' and elements following ''phrasing cues,'' where responses were controlled by associative cues. In Experiment 1, 3-element chunks of both patterns were signaled by pauses that served as phrasing cues before chunk-boundary elements, but one pattern also included a violation element that was inconsistent with pattern structure. Once rats reached a high criterion of performance, the drug challenge was intraperitoneal injection of a single dose of 50 mg/kg atropine sulfate. Atropine impaired performance on elements learned by S-R learning, namely, chunk-boundary elements and the violation element, but had no effect on performance of rule-based within-chunk elements. In Experiment 2, patterns were phrased and unphrased perfect patterns (i.e., without violation elements). To control for peripheral effects of atropine, rats were treated with a series of doses of either centrally-acting atropine or peripherally-acting atropine methyl nitrate (AMN), which does not cross the blood-brain barrier. Once rats reached a high criterion, the drug challenges were on alternate days in the order 50, 25, and 100 mg/kg of either atropine sulfate or AMN. Atropine, but not AMN, impaired performance in the phrased perfect pattern for pattern elements where S-R associations were important for performance, namely, chunk-boundary elements. However, in the structurally more ambiguous unphrased perfect pattern where rats had fewer cues and presumably relied more on S-R associations throughout, atropine impaired performance on all pattern elements. Thus, intact muscarinic cholinergic systems were shown to be necessary for discriminative control previously established by S-R learning, but were not necessary for rule-based serial pattern performance.
Intrastriatal injection of choline accelerates the acquisition of positively rewarded behaviors
Brain Research Bulletin, 1993
The prediction was made that by increasing the synthesis of striatal acetylcholine, through local injection of its precursor choline, the acquisition of a lever-pressing response in two different autoshaping situations would be accelerated. In the first experiment, choline was injected into the striatum or parietal cortex of rats immediately after dipper training; 24 h later and during 5 consecutive days the animals were submitted to an autoshaping procedure of the operant kind. In the second experiment, choline was administered to the same regions shortly after each of three classical-operant autoshaping sessions; during the next two sessions, autoshaping contingencies of the operant kind were in effect. In both experiments choline injection into the striatum induced a marked facilitation of acquisition of the conditioned responses, although cortical injection of choline produced a milder improvement only in the first experiment. These results indicate that striatal cholinergic activity is, indeed, involved in the early phases of positively reinforced learning.
Central vs peripheral anticholinergic effects on repeated acquisition of behavioral chains
1984
Monkeys that were required to repeatedly learn new sequences of responses to obtain food were injected with 0.2 mg/kg of atropine sulfate or methylatropine nitrate. Effects lasted 8 to 12 hr following injection. Both drugs decreased the rate at which the animals worked, but only atropine sulfate increased the number of attempts required to solve the problem and decreased overall accuracy, suggesting a peripheral mode of action for rate-decreasing effects, and a central mode of action for effects of atropine on qualitative asnects of performance. Over the last decade many studies have established the involvement of the central cholinergic system in memory processes (see Drachman, 1977). Cholinergic blockers such as scopolamine and atropine, were found to disrupt behaviors which depend on learning and memory tasks (e.g., Bartus, Dean, Beer, & Lippa, 1982). However the exact mechanism of this performance impairment is still unknown. Recently, the cholinergic system has also been associated with pathological human conditions affecting various cognitive functions, especially Alzheimer's disease, a fact which has raised the level of interest in cholinergic memory mechanisms. Animal behavior models have been useful in the study of cholinergic drugs. In a recent study we found that atropine sulfate impaired the performance of mice in a radial arm maze, by increasing both the running I Visiting scientist from the
Journal of Neuroscience, 2009
Individual variability in reward-based learning has been ascribed to quantitative variation in baseline levels of striatal dopamine. However, direct evidence for this pervasive hypothesis has hitherto been unavailable. We demonstrate that individual differences in reward-based reversal learning reflect variation in baseline striatal dopamine synthesis capacity, as measured with neurochemical positron emission tomography. Subjects with high baseline dopamine synthesis in the striatum showed relatively better reversal learning from unexpected rewards than from unexpected punishments, whereas subjects with low baseline dopamine synthesis in the striatum showed the reverse pattern. In addition, baseline dopamine synthesis predicted the direction of dopaminergic drug effects. The D2 receptor agonist bromocriptine improved reward-relative to punishment-based reversal learning in subjects with low baseline dopamine synthesis capacity, while impairing it in subjects with high baseline dopamine synthesis capacity in the striatum. Finally, this pattern of drug effects was outcome-specific, and driven primarily by drug effects on punishment-, but not reward-based reversal learning. These data demonstrate that the effects of D2 receptor stimulation on reversal learning in humans depend on task demands and baseline striatal dopamine synthesis capacity.
Pharmacology Biochemistry and Behavior, 1986
Is cholmergw activity of the ,trmtum revolved m the a~qulsmon of posmvelv-mottvated behavmrs ~ PHARMACOL BIOCHEM BEHAV 24(3) 715-719, 1986-Chohnerg~c activity of the caudate-putamen (CPU) ~s crucml for the acqmsttton of averslvely-relnforced behaviors (active and passive avoidance) To determine whether th~s activity ~s also revolved in the acqmsttlon of a posmvelyrewarded behavmr, m the present experimental senes the effects of scopolamine applications to the antero-dorsal or postero-dorsal aspects of the stnatum on auto-shaping were assessed The auto-shaping procedure that was used allowed rats to learn to bar press at their own rate It was found that scopolamine m.lecuon into e~ther regmn of the CPU produced a marked retardatmn m the acquisition of the conditioned behavior These results indicate that chohnerglc actwtty of the stnatum is critically mvolved m the early phases of posmvely-remforced learning Chohnerglc acuvtty Auto-shaping Stnatum Positively-reinforced learning