Contributions of ERK signaling in the striatum to instrumental learning and performance

doi:10.1016/j.bbr.2010.12.010

Behavioural Brain Research

Volume 218, Issue 1, 17 March 2011, Pages 240-247

https://doi.org/10.1016/j.bbr.2010.12.010 Get rights and content

Abstract

The striatum is critical for learning and decision making; however, the molecular mechanisms that govern striatum function are not fully understood. The extracellular signal regulated kinase (ERK) cascade is an important signaling pathway that underlies synaptic plasticity, cellular excitability, learning and arousal. This review focuses on the role of ERK signaling in striatum function. ERK is activated in the striatum by coordinated dopamine and glutamate receptor signaling, where it underlies corticostriatal synaptic plasticity and influences striatal cell excitability. ERK activation in the dorsal striatum is necessary for action-outcome learning and performance of goal-directed actions. In the ventral striatum, ERK is necessary for the motivating effects of reward-associated stimuli on instrumental performance. Dysregulation of ERK signaling in the striatum by repeated drug exposure contributes to the development of addictive behavior. These results highlight the importance of ERK signaling in the striatum as a critical substrate for learning and as a regulator of ongoing behavior. Furthermore, they suggest that ERK may be a suitable target for therapeutics to treat disorders of learning and decision making that arise from compromised striatum function.

Research highlights

▶ ERK signaling regulates learning, memory, synaptic plasticity and arousal. ▶ Dorsal striatum ERK mediates goal-directed learning and performance. ▶ Ventral striatum ERK mediates Pavlovian-instrumental transfer. ▶ ERK dysregulation may underlie addiction.

Introduction

The striatum, the largest of the basal ganglia nuclei, is a critical substrate for learning and decision making. Impairments in learning and decision making accompany a range of disorders that affect the striatum, including substance abuse disorder, obsessive-compulsive disorder, and Parkinson's disease [1], [2], [3]. Furthermore, the application of sophisticated procedures derived from instrumental conditioning in animals has identified parallel corticostriatal circuits that mediate distinct learning and action control processes [4], [5], [6], [7], [8]. Nevertheless, the molecular mechanisms that underlie learning and decision making in the striatum are not fully understood. One important regulator of neuronal function is the extracellular signal regulated kinase (ERK) pathway. ERK is a member of mitogen activated protein kinase (MAPK) family, and is critical for nervous system development and plasticity in the adult nervous system [9], [10]. ERK signaling in the nervous system has a critical role in memory formation, affect and arousal. Furthermore, the efficacy of a number of psychoactive substances, such as mood stabilizers and addictive drugs, depend, in part, on their ability to activate ERK in the nervous system.

In the following review, we highlight the role of ERK signaling in the striatum in learning and decision making. We begin with a brief overview of ERK signaling in the nervous system and its role in learning and behavior regulation. This is followed by a discussion of the role of ERK signaling in striatal-based learning and decision-making tasks. We conclude with a description of the role of ERK signaling in substance abuse, in which we discuss how alterations in ERK signaling by repeated drug exposure may compromise striatum function and produce features of addictive behavior.

Section snippets

The ERK signaling pathway

Like other MAPK signaling pathways, the ERK cascade consists of three kinases: ERK, of which there are two isoforms, ERK1 and ERK2, and their upstream kinases MEK and raf (see [11], [12] for review). ERK activation occurs in response to a variety of extracellular stimuli and forms an essential pathway for cells to generate adaptive responses to changing environments. These cellular responses include regulation of gene expression and synthesis of new proteins, alteration in cellular structure or

ERK signaling influences striatal synaptic plasticity and excitability

The striatum is the largest of the basal ganglia nuclei and serves as the primary input structure for basal ganglia-thalamo-cortical circuitry. The striatum receives excitatory glutamatergic inputs from cortical, limbic and thalamic regions, as well as dopaminergic input from the midbrain [58], [59]. Dopaminergic input to the striatum accounts for the majority of dopaminergic signaling in the brain. Glutamatergic and dopaminergic synapses form in close proximity on striatal medium spiny neurons

ERK and addiction

Exposure to a variety of substances with abuse potential, including psychostimulants, opioids and nicotine, acutely activate ERK in the striatum and other brain areas [104], [105]. Many enduring behavioral effects of acute drug exposure depend on ERK signaling. For example, pairing a context with drug exposure produces a conditioned place preference (CPP), and ERK inhibition prior to drug-context pairing prevents the formation of this preference [105], [106]. Since ERK does not prevent the

Conclusions

The role of ERK in addictive behavior in the striatum is consistent with its role in action-outcome learning and control of behavior by reward-associated stimuli more generally. This is not surprising given that drug-taking is a form of appetitive behavior. What is different about abused substances is they activate ERK more strongly than natural rewards and that with repeated exposure they increase basal levels of ERK activation. These properties may be responsible for some features of

Acknowledgements

This research was supported by NIH grants HD059527 to BWB and DA026559 to MWS.

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ReviewContributions of ERK signaling in the striatum to instrumental learning and performance

Abstract

Research highlights

Introduction

Section snippets

The ERK signaling pathway

ERK signaling influences striatal synaptic plasticity and excitability

ERK and addiction

Conclusions

Acknowledgements

Behav Brain Res

Behav Brain Res

Curr Opin Neurobiol

Neuron

Cell

J Biol Chem

J Biol Chem

Cell

Neuron

Neurobiol Learn Mem

Neurobiol Learn Mem

Neuroscience

Trends Neurosci

Trends Neurosci

Brain Res

Biol Psychiatry

Neuropharmacology

Biol Psychiatry

Biol Psychiatry

Neuropharmacology

Behav Brain Res

Trends Neurosci

Neuron

Neuron

Biol Psychiatry

Neuron

Neuron

Behav Brain Res

Behav Brain Res

Curr Opin Pharmacol

Neuropharmacology

Behav Brain Res

Neurobiol Learn Mem

Neurobiol Learn Mem

By carrot or by stick: cognitive reinforcement learning in parkinsonism

Science

The neural basis of addiction: a pathology of motivation and choice

Am J Psychiatry

Patterns of gene expression and behavior induced by chronic dopamine treatments

Ann Neurol

Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks

Eur J Neurosci

The role of the dorsal striatum in reward and decision-making

J Neurosci

Striatal contributions to reward and decision making—making sense of regional variations in a reiterated processing matrix

Reward and Decision Making in Corticobasal Ganglia Networks

Differential regulation and properties of MAPKs

Oncogene

ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions

Microbiol Mol Biol Rev

Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway

Science

MAPK cascade signaling and synaptic plasticity

Nat Rev Neurosci

The extracellular signal-regulated kinase cascade is required for NMDA receptor-independent LTP in area CA1 but not area CA3 of the hippocampus

J Neurosci

Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation

J Neurosci

Long-term depression in the adult hippocampus in vivo involves activation of extracellular signal-regulated kinase and phosphorylation of Elk-1

J Neurosci

Protein kinase C and ERK involvement in dendritic spine plasticity in cultured rodent hippocampal neurons

Eur J Neurosci

Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology

Nat Neurosci

The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo

J Neurosci

Review
Contributions of ERK signaling in the striatum to instrumental learning and performance