Review article
Obsessive-compulsive disorder: Insights from animal models

https://doi.org/10.1016/j.neubiorev.2016.04.019Get rights and content

Highlights

  • Utility of animal models in research on OCD is considered and insights gained reviewed.

  • Optogenetic studies in mice demonstrate that hyperactivity in CBGTC circuits can result in compulsive behavior.

  • Parallel use of several animal models indicates DBS targets may depend on specific OCD endophenotypes.

  • Mechanisms of compulsive behavior are revealed by considering spontaneous behavior in deer mice, animal models of enhanced SIP, and compulsive checking induced by quinpirole.

  • Methods of analysis in animal models provide tools for translational research and clinical tests in OCD patients.

Abstract

Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.

Introduction

Animal models of psychiatric disorders simulate signs or symptoms of a psychiatric disorder to provide a preparation for testing specific etiological theories and underlying mechanisms of the disorder as well as for conducting preclinical drug evaluations (Eilam and Szechtman, 2005a, Jones et al., 2011, Lazar et al., 2011, McKinney, 1988, Szechtman and Eilam, 2005, Willner, 1984). The use of animal models in psychiatry has had a stormy history in part because of the need to work out their proper place in the context of psychiatry as a scientific discipline (Szechtman and Eilam, 2005). One challenge often levelled at animal models is scepticism that the model fully replicates the clinical condition or bears relevance for the mechanisms of the human condition. Attempts at dealing with this challenge led to influential formulations of criteria to evaluate animal models in psychiatry (Abramson and Seligman, 1977, Belzung and Lemoine, 2011, Geyer and Markou, 1995, Hoffman, 2016b, McKinney and Bunney, 1969, Willner, 1984, Willner, 2005, Willner et al., 1992). While the use of animal models in psychiatry is accepted as proper today, it is worthwhile to reiterate briefly what constitutes a “model.”

A scholarly exposition regarding what a “model” is and the “tortuous” history of models in psychology was provided by Chapanis (1961). Of relevance to the present review using animal models of OCD, Chapanis (1961) pointed out that a model is “…only an analogy, a statement that in some ways the thing modeled behaves ‘like this’ (p. 188). Indeed, “…the worst error committed in the name of models is to forget that at best a model represents only a part – and usually only a small part – of the thing being modeled” (Chapanis, 1961 p. 126). The same notion had been echoed by McKinney (1988), in Models of Mental Disorders: A New Comparative Psychiatry, who admonished against the quest for comprehensive animal models of psychiatric disorders because no model can be a miniature replica of the entire human condition. Unfortunately, even today this crucial point is not always remembered. Chapanis (1961) has argued that because of their inherently limited scope, models should be evaluated differently from theories: “Models, in a word, are judged by criteria of usefulness; theories, by criteria of truthfulness” (p. 119). In other words, good models generate novel insights and new research. Of course, models designed to test particular theory regarding an aspect of the human disorder are evaluated by criteria of both usefulness and truthfulness.

This paper reviews several animal models of OCD symptoms and highlights the insights derived from research using those models. OCD is a severe and highly prevalent disorder (Koran, 2000, Murray and Lopez, 1996), with a lifetime prevalence of 1–2% (Crino et al., 2005, Karno et al., 1988, Rasmussen and Eisen, 1991). Symptoms consist of recurrent and persistent thoughts (“obsessions”) and/or repetitive, relatively stereotyped behaviors (“compulsions”) that the person feels compelled to think or perform but recognizes as irrational or excessive (Goodman et al., 1990, Leckman et al., 2010, Stein, 2002). The most common subjective clinical features are doubt and indecision; and the two most common compulsive behaviors are checking (repeated redoing of actions related to security, orderliness, or accuracy) and washing (generally of hands but sometimes also of clothes, etc.) (Henderson and Pollard, 1988, Rasmussen and Eisen, 1992, Reed, 1985). In the following sections, some aspects of the disorder that benefited from research using an animal model are considered.

When modeling OCD in animals, it is difficult to assess obsessions because their detection depends heavily on verbal or written communications. Compulsions, on the other hand, are manifested behaviourally and therefore observable in animal models. As a result, all of the animal models discussed in this review are putative models of compulsive behavior involving repetitive actions and often focusing on the structure of those actions. Results provide convergent insights into brain circuits and neurotransmitters involved in the overt, behavioral component of OCD.

Importantly, the review does not provide an exhaustive summary of the growing area of research using animal models of OCD, as a number of such first-rate publications exists (Ahmari, 2015, Ahmari and Dougherty, 2015, Albelda and Joel, 2012a, Albelda and Joel, 2012b, Alonso et al., 2015, Boulougouris et al., 2009, Camilla d’Angelo et al., 2014, Diniz et al., 2012, Eilam and Szechtman, 2005b, Eilam et al., 2012, Grados et al., 2015, Gunaydin and Kreitzer, 2016, Hoffman, 2011, Hoffman, 2016a, Joel, 2006a, Korff and Harvey, 2006, Man et al., 2004, Ting and Feng, 2011b, Wang et al., 2009, Westenberg et al., 2007). Instead, the current synthesis is unique by bringing together several independent investigators who highlight a piece of their research where animal models served as the source and exemplars of fruitful questions and areas of investigation into OCD.

The usual emphasis in translational research of psychiatric disorders is to consider clinical studies as primary, directing animal model research in the laboratory. However, there is another equally important and invaluable property of animal models in psychiatry—using animal models to generate novel findings and hypotheses about the disorder that should be examined in the clinic. The 5 sections which follow each highlights how studies using different animal models of obsessive-compulsive disorder (OCD) generated some novel insights into this disorder. In so doing, the review acknowledges the value of animal work in directing research on OCD and encourages pursuit of theory-driven behavioral neuroscience research on this disorder.

Section snippets

Insights into OCD from optogenetics in mice: using new technologies to build bridges between mice and humans

Treatment options for OCD are still limited. To develop new, more effective treatments, a better understanding of the underlying pathophysiology is required. Many current models center on the idea that disruption of CBGTC circuit activity may directly lead to obsessions and/or compulsions in OCD patients (Maia et al., 2008, Rauch et al., 1997, Rotge et al., 2010, Saxena et al., 2001). However, this inference is based on very strong correlative evidence from functional imaging studies in

The SIP paradigm

Schedule-induced polydipsia (SIP) is a ritualized act that neither serves an obvious physiological need nor the overall goal of obtaining food, and can lead to functional impairments associated with excessive fluid intake. SIP therefore has several features of the compulsions observed in OCD and related illnesses. As suggested by Moreno and Flores (2012), consideration of the variables affecting SIP and the neurocircuitry underlying this maladaptive behavior may provide novel insights into OCD.

Spontaneous stereotypy in the deer mouse

As a naturalistic animal model of OCD, deer mice exhibit two topographies of stereotypy, viz. pattern running and vertical stereotypies (backward somersaulting, repetitive jumping) (Hadley et al., 2006, Korff et al., 2008). The perseverative and seemingly goalless quality of such stereotypy, and that it develops spontaneously, provides face validity for OCD (American Psychiatric Association, 2013). Heterogeneous distribution within a population of animals (see Fig. 5) (Korff et al., 2008)

Description of the quinpirole sensitization rat model of OCD

The notion that the transformation in behavior induced by chronic treatment with the DA agonist QNP could serve as an animal model of OCD arose by serendipity, during the course of research with animal models of psychosis. Specifically, experimental attempts to obtain from the behavior of QNP rats evidence of a psychotic state—expected from the DA hypothesis of schizophrenia (Carlsson, 1988, Willner, 1997)—did not yield the predicted result of disorganized activity (Szechtman et al., 1994b).

Endophenotypes in OCD

In concordance with the existence of a heterogeneous group of patients, OCD patients do not show consistent responsiveness to treatment, as some patients respond well whereas others show partial or no response. In other words, the capacity of a treatment strategy to modulate specific pathophysiological disease substrates may not suffice as an efficient treatment for all OCD patients due to the existence of endophenotypes entailing a specific neurobiological substrate of behavior. It needs to be

Translational research

The field of translational research was introduced to promote the application of basic research in clinical practice (Zerhouni, 2003). In other words, this field of research offers an interface between basic science and clinical medicine, coined by Woolf (2008) as ‘bench to bedside’. Relying on Darwin’s notion that the difference between humans and non-humans is one of degree, not of kind (Dalgleish, 2004, Darwin, 1871), the concept of translational research in animals may seem obvious. Indeed,

Conclusions

Good models generate novel insights, and this should be the case for animal models of psychiatric disorders as well. The present review considered the use and utility of animal models in research on mechanisms underlying the psychiatric disorder, OCD. This review was not intended to summarize the growing area of research using animal models of OCD, as a number of such first-rate publications already exists (Ahmari, 2015, Ahmari and Dougherty, 2015, Albelda and Joel, 2012a, Albelda and Joel,

Conflict of interests

Brian H. Harvey has participated in advisory boards and received honoraria from Servier®, and has received research funding from Servier® and Lundbeck®. BHH acknowledges that opinions, findings and conclusions or recommendations expressed in any publication generated by National Research Foundation (NRF) supported research are those of the authors, and that the NRF accepts no liability whatsoever in this regard. Remaining authors declare no competing interests.

Acknowledgements

Supported by operating grants from the Canadian Institutes of Health Research (CIHR MOP-64424), the Natural Sciences and Engineering Research Council of Canada (NSERC RGPIN A0544) and the Ontario Mental Health Foundation (OMHF) to HS; NSERC (RGPIN-2015-05465) and OMHF to RJB; South African Medical Research Council and National Research Foundation (grant number 77323) to BHH who also acknowledges Lundbeck A/S® for sponsoring the escitalopram used in the presented work; Else Kröner-Fresenius

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    Based on a symposium with the same title (co-chairs: HS, RJB) at the International Behavioral Neuroscience Society (IBNS) meeting held in Victoria, BC, Canada. Each major section describes the work in the laboratories of the investigators; the sequence of sections in the paper is conceptual. All authors contributed equally to the writing of this paper.

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