Striatal circuits, habits, and implications for obsessive–compulsive disorder

doi:10.1016/j.conb.2014.08.008

Current Opinion in Neurobiology

Volume 30, February 2015, Pages 59-65

https://doi.org/10.1016/j.conb.2014.08.008 Get rights and content

Highlights

•
Involvement of corticostriatal circuits in OCD is receiving strong new experimental support.
•
This evidence is concordant with clinical evidence based on OCD patient studies.
•
Clinical and experimental work further converge on OFC-ACC corticostriatal circuits as critical.

Increasing evidence implicates abnormalities in corticostriatal circuits in the pathophysiology of obsessive–compulsive disorder (OCD) and OC-spectrum disorders. Parallels between the emergence of repetitive, compulsive behaviors and the acquisition of automated behaviors suggest that the expression of compulsions could in part involve loss of control of such habitual behaviors. The view that striatal circuit dysfunction is involved in OC-spectrum disorders is strengthened by imaging and other evidence in humans, by discovery of genes related to OCD syndromes, and by functional studies in animal models of these disorders. We highlight this growing concordance of work in genetics and neurobiology suggesting that frontostriatal circuits, and their links with basal ganglia, thalamus and brainstem, are promising candidates for therapeutic intervention in OCD.

Introduction

OCD is a neuropsychiatric disorder characterized by obsessions (intrusive thoughts) and compulsions (physical or mental rituals such as washing or checking), often associated with high levels of anxiety. OCD has an estimated lifetime prevalence of 2–3% worldwide. In recognition of the core clustering of symptoms in OCD, and in the light of neurological findings, OCD has newly been separated from the class of anxiety disorders in the revised Diagnostic and Statistical Manual of Mental Disorders [1]. Among the heterogeneous symptoms observed in OCD patients, four clusters have been identified in this new classification: symmetry/ordering, hoarding, contamination/cleaning, and obsessions/checking. These symptom-clusters all have features of repetitive thought and action, expressed in relation to external and internal stimuli, and often appear in ritualized form. Here we emphasize emerging evidence that the striatum is critical to the establishment of such ritualized sequences of actions [2, 3, 4, 5], and that the striatal connections of anterior cingulate and orbitofrontal cortical regions are linked to OCD and OC-spectrum disorders, based on physiological, genetic and neuroimaging evidence. We point to remaining challenges to characterize the endophenotypes of OCD in relation to a reconsideration of the central role of the striatum in the emergence of this complex neuropsychiatric pathophysiology.

Section snippets

Striatum-based circuitry and the pathophysiology of OCD: insights from studies in human

New neuroimaging studies are helping to characterize both the circuits implicated in OCD and the potential circuit functions that might contribute, when disturbed, to the symptoms of OCD and related disorders. These studies highlight a special relationship between the caudate nucleus, the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC). At a morphological level, differences in volumes between OCD patients and healthy controls have been reported for the putamen [6, 7] and,

Genetic evidence for the involvement of striatal circuitry in OCD

Genetically engineered mice that exhibit both corticostriatal dysfunction and OCD-like behaviors support a function for candidate OCD-related genes in the pathogenesis of OCD and point toward a common dysfunction in glutamatergic signaling, including dysfunction within the striatum, as a major contributor to the OCD-like behaviors. These mouse models include the transgenic D1CT-7 model (over-activation of glutamatergic input to the striatum produced by chronic potentiation of dopamine

Striatum-based circuitry and the pathophysiology of OCD: insights from studies in animals

Major advances are coming from the use of genetically engineered models of OCD and OCD-like disorders together with the use of new methods now available to neuroscientists, such as optogenetic. Animal models of OC-spectrum symptoms were originally generated by employing either behavioral conditioning, pharmacological treatment or physical manipulation, and these studies suggested that corticostriatal circuitry contributed to OCD-like symptoms, in keeping with the growing clinical literature

In search of relevant corticostriatal-dependent behavioral and neurophysiological endophenotypes of OCD

The evidence that we have reviewed points to new opportunities to refine our understanding of both the neural correlates of OCD and the endophenotypes of OCD and OC-spectrum disorders. Many lines of evidence point to the caudate nucleus-anterior putamen and their connected cortical regions, the OFC and the ACC, as important to the disorder (Figure 1). A major current challenge is to identify core functions supported by these corticostriatal loops, circuits likely affected in patients.

The ‘habit

Conclusions and perspectives

Converging findings from clinical and experimental work, across anatomical, physiological, genetic and behavioral levels, point to the importance of the striatum and corticostriatal pathways in the pathophysiology of OCD and related OC-spectrum disorders. The strength of these studies comes both from their diversity of approaches and from the increasing specificity with which underlying genetic and neural circuit level mechanisms can be identified. The challenge presented by these studies is to

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was supported by the Simons Initiative on Autism and the Brain at MIT (to AMG and EB), NIH/NICHD (R37 HD028341 to AMG), Defense Advanced Research Projects Agency and the U.S. Army Research Office (W911NF-10-1-0059 to AMG), EMBO Long-term Fellowship (to EB), NIH/NIMH (R01 MH081201 to GF) and the Simons Foundation Autism Research Initiative (to GF).

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Autism spectrum disorder (ASD) is a series of highly inherited neurodevelopmental disorders. Loss-of-function (LOF) mutations in the CACNA2D3 gene are associated with ASD. However, the underlying mechanism is unknown. Dysfunction of cortical interneurons (INs) is strongly implicated in ASD. Parvalbumin-expressing (PV) INs and somatostatin-expressing (SOM) INs are the two most subtypes. Here, we characterized a mouse knockout of the Cacna2d3 gene in PV-expressing neurons (PV^Cre;Cacna2d3^f/f mice) or in SOM-expressing neurons (SOM^Cre;Cacna2d3^f/f mice), respectively. PV^Cre;Cacna2d3^f/f mice showed deficits in the core ASD behavioral domains (including impaired sociability and increased repetitive behavior), as well as anxiety-like behavior and improved spatial memory. Furthermore, loss of Cacna2d3 from a subset of PV neurons results in a reduction of GAD67 and PV expression in the medial prefrontal cortex (mPFC). These may underlie the increased neuronal excitability in the mPFC, which contribute to the abnormal social behavior in PV^Cre;Cacna2d3^f/f mice. Whereas, SOM^Cre;Cacna2d3^f/f mice showed no obvious deficits in social, cognitive, or emotional phenotypes. Our findings provide the first evidence suggesting the causal role of Cacna2d3 insufficiency in PV neurons in autism.
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View full text

Striatal circuits, habits, and implications for obsessive–compulsive disorder

Highlights

Introduction

Section snippets

Striatum-based circuitry and the pathophysiology of OCD: insights from studies in human

Genetic evidence for the involvement of striatal circuitry in OCD

Striatum-based circuitry and the pathophysiology of OCD: insights from studies in animals

In search of relevant corticostriatal-dependent behavioral and neurophysiological endophenotypes of OCD

Conclusions and perspectives

Conflict of interest statement

References and recommended reading

Acknowledgements

Prog Neuropsychopharmacol Biol Psychiatry

Biol Psychiatry

Psychiatry Res

Biol Psychiatry

Biol Psychiatry

Eur Psychiatry J Assoc Eur Psychiatr

Prog Neuropsychopharmacol Biol Psychiatry

Lancet

Biol Psychiatry

Lancet

Biol Psychiatry

J Chem Neuroanat

Clin Neurol Neurosurg

Biol Psychiatry

Nature

Mol Psychiatry

Mol Psychiatry

Am J Med Genet B: Neuropsychiatr Genet

Mol Psychiatry

Science

PLoS ONE

Nat Rev Neurosci

Diagnostic and statistical manual of mental disorders (DSM-V)

Habits, rituals, and the evaluative brain

Annu Rev Neurosci

Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories

Nature

Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill

Nat Neurosci

A specific role for posterior dorsolateral striatum in human habit learning

Eur J Neurosci

Mapping structural brain alterations in obsessive–compulsive disorder

Arch Gen Psychiatry

The major symptom dimensions of obsessive–compulsive disorder are mediated by partially distinct neural systems

Brain J Neurol

Resting-state functional connectivity abnormalities in patients with obsessive–compulsive disorder and their healthy first-degree relatives

J Psychiatry Neurosci JPN

Abnormally high degree connectivity of the orbitofrontal cortex in obsessive–compulsive disorder

JAMA Psychiatry

Abnormalities of white matter microstructure in unmedicated obsessive–compulsive disorder and changes after medication

PLoS ONE

Obsessive–compulsive symptoms in Parkinson's disease

J Neurol Neurosurg Psychiatry

Treatment of late-onset OCD following basal ganglia infarct

Depress Anxiety

High-frequency stimulation of deep brain structures in obsessive–compulsive disorder: the search for a valid circuit

Eur J Neurosci

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive–compulsive disorder: worldwide experience

Mol Psychiatry