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Molecular substrates of action control in cortico-striatal circuits - PubMed

  • ️Sat Jan 01 2011

Review

Molecular substrates of action control in cortico-striatal circuits

Michael W Shiflett et al. Prog Neurobiol. 2011.

Abstract

The purpose of this review is to describe the molecular mechanisms in the striatum that mediate reward-based learning and action control during instrumental conditioning. Experiments assessing the neural bases of instrumental conditioning have uncovered functional circuits in the striatum, including dorsal and ventral striatal sub-regions, involved in action-outcome learning, stimulus-response learning, and the motivational control of action by reward-associated cues. Integration of dopamine (DA) and glutamate neurotransmission within these striatal sub-regions is hypothesized to enable learning and action control through its role in shaping synaptic plasticity and cellular excitability. The extracellular signal regulated kinase (ERK) appears to be particularly important for reward-based learning and action control due to its sensitivity to combined DA and glutamate receptor activation and its involvement in a range of cellular functions. ERK activation in striatal neurons is proposed to have a dual role in both the learning and performance factors that contribute to instrumental conditioning through its regulation of plasticity-related transcription factors and its modulation of intrinsic cellular excitability. Furthermore, perturbation of ERK activation by drugs of abuse may give rise to behavioral disorders such as addiction.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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Figures

Figure 1
Figure 1

A. Corticostriatal circuits involved in decision making. The learning processes controlling the acquisition of reward-related actions are mediated by converging projections from regions of dorsomedial prefrontal cortex (dMPC) to the rodent dorsomedial striatum (DM), whereas (2) the processes mediating the acquisition of stimulus-bound actions, or habits, are thought to be mediated by projections from sensorimotor cortex (SM) to the rodent dorsolateral striatum (DL). Reward and predictors of reward are the major motivational influences on the performance of goal-directed and habitual actions and are thought to be mediated by corticostriatal circuits involving, particularly, ventral MPC and amygdala inputs (not shown) to ventral striatum (VS). These corticostriatal connections are parts of distinct feedback loops that project back to their cortical origins via ventral tegementum/substantial nigra/globus pallidus (SNr/Gpi) (blue arrows) and the mediodorsal (MD)/posterior (PO) nuclei of the thalamus and project out to premotor and motor cortices through the globus pallidus and ventral pallidum (red arrows). Dopamine (green arrows) is an important modulator of plasticity in the dorsal striatum whereas its tonic release has long been associated with the motivational processes mediated by the ventral circuit. B. The major functional divisions of the striatum. The regions shown are anatomically continuous but, recent findings suggest, functionally heterogeneous. With regard to instrumental conditioning the dorsal and ventral striatum are broadly distinguished by their involvement in learning and performance respectively; the dorsal region in the acquisition of goal-directed actions (dorsomedial region), heterogeneous chains of actions (dorsocentral region) and habits (dorsolateral region); the ventral striatum in the motivation of these actions by experienced reward (the nucleus accumbens core) and predicted reward (the nucleus accumbens shell).

Figure 2
Figure 2

Intracellular signaling pathways integrate dopamine and glutamate signals. D1 receptor activation increases adenylyl cyclase (AC) activation, cAMP formation, and PKA activation. PKA phosphorylates DARPP-32 at Thr-34 residue, making it a potent inhibitor of protein phosphatase-1 (PP-1). Inhibition of PP-1 indirectly increases extracellular signal regulated kinase (ERK) activation, by preventing PP-1 from dephosphorylating striatal-enriched phosphatase (STEP), which, when dephosphorylated, inhibits ERK. NMDA and AMPA receptor activation increases ca++ influx, whereas mGluR1 activation causes release of intracellular calcium through the phospholipase C (PLC), inositol trisphosphate (IP3) pathway. Ca++ activates a number of signaling pathways, including calcium and calmodulin-dependent kinase II (CamKII), and protein phosphatase 2B (PP-2B). PP-2B activation results in Thr-75 DARPP-32 phosphorylation, through casein kinase (ck) and cyclin-dependent kinase 5 (cdk5). When phospohrylated at Thr-75, DARPP-32 becomes an inhibitor of PKA. PP-2B also dephosphoryltes DARPP-32 at Thr-34. These effects negatively regulate ERK activation. CamKII activates ERK via the ras-raf-mek cascade. Thus ERK activation depends on the phosphorylation state of DARPP-32, which itself is sensitive to the relative activation of glutamate and DA receptors. ERK regulates gene expression through its phosphorylation of transcription factors, such as cAMP response element binding protein (CREB), and regulates neural excitability through its phosphorylation of the Kv4.2 channel. Red arrows indicate negative regulation of ERK, green arrows indicate positive regulation of ERK.

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