Dataset Information

Contributions of striatal dopamine signaling to the modulation of cognitive flexibility.

ABSTRACT: Although cognitive flexibility is mediated by different areas of the prefrontal cortex, evidence from patients with Parkinson's disease suggests an additional involvement of striatal dopamine (DA) signaling. Because both dorsal and ventral striatum receive prefrontal cortex projections, it is unclear whether DA signaling to either one or both of these regions is required for cognitive flexibility.Cognitive flexibility was examined with a water U-maze paradigm in which mice had to shift from an initially acquired escape strategy to a new strategy or to reverse the initially learned strategy. We tested mice with conditionally inactive tyrosine hydroxylase genes that can be activated by Cre recombinase. With region-specific viral gene therapy we selectively restricted DA signaling to either dorsal or ventral striatum.Restricting DA signaling to the ventral striatum did not impair learning of the initial strategy or reversal-learning but strongly disrupted strategy-shifting. In contrast, mice with DA signaling restricted to the dorsal striatum had intact learning of the initial strategy, reversal-learning, and strategy-shifting.Dopamine signaling in both dorsal and ventral striatum is sufficient for reversal-learning, whereas only DA signaling in the dorsal striatum is sufficient for the more demanding strategy-shifting task.

SUBMITTER: Darvas M

PROVIDER: S-EPMC3120097 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Contributions of striatal dopamine signaling to the modulation of cognitive flexibility.

Darvas Martin M Palmiter Richard D RD

Biological psychiatry 20101111 7

<h4>Background</h4>Although cognitive flexibility is mediated by different areas of the prefrontal cortex, evidence from patients with Parkinson's disease suggests an additional involvement of striatal dopamine (DA) signaling. Because both dorsal and ventral striatum receive prefrontal cortex projections, it is unclear whether DA signaling to either one or both of these regions is required for cognitive flexibility.<h4>Methods</h4>Cognitive flexibility was examined with a water U-maze paradigm i ...[more]

PMID: 21074144

Similar Datasets

Project description:BackgroundThe prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.Methodology/principal findingsWe show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Conclusions/significanceAcquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food lifestyle" creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.

Dataset Information

Contributions of striatal dopamine signaling to the modulation of cognitive flexibility.

Publications

Contributions of striatal dopamine signaling to the modulation of cognitive flexibility.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets