Animal models of obsessive-compulsive spectrum disorders

  • Type:#article
  • Year read:
  • Subject: animal models OCD
  • Bibtex: @dangelo2014
  • Bibliography: Camilla d’Angelo, L.-S., Eagle, D. M., Grant, J. E., Fineberg, N. A., Robbins, T. W., & Chamberlain, S. R. (2014). Animal models of obsessive-compulsive spectrum disorders. CNS Spectrums, 19(1), 28–49.

Key takeaways

  • Animal models can help us understand the neuroscience behind OCD
  • They can highlight the mechanisms of action of current treatments
  • Animal models can signal where to look for new treatments

“Multiple tiers of evidence link these conditions with underlying dysregulation of particular cortico-subcortical circuitry and monoamine systems, which represent targets for treatment. Animal models designed to capture aspects of these conditions are critical for several reasons. First, they help in furthering our understanding of neuroanatomical and neurochemical underpinnings of the obsessive-compulsive (OC) spectrum. Second, they help to account for the brain mechanisms by which existing treatments (pharmacotherapy, psychotherapy, deep brain stimulation) exert their beneficial effects on patients. Third, they inform the search for novel treatments”

“Animal models represent a useful means of studying behavioral phenomena of relevance to human OC spectrum conditions, including genetic, neurochemical, and neuroanatomical substrates. They are also of potential utility in identifying novel treatments, before they are put forward into human clinical trials, and in characterizing the mechanisms by which treatments exert their beneficial influences on overt symptomatology.”

Modern animal models of OCD

  • Sapap3 knockout mice (protein that is highly expressed in glutamatergic synapses in the striatum). Sapap3 knockout mice show excessive grooming that is alleviated by SSRI.
  • Slitrk5 knockout mice: Slitrk5 protein is important during development, and knockout-mice show excessive gromming that is alleviated by chronic SSRI. They show upregulated activity in the orbitofrontal cortex and deficits in the striatum (e.g. lower volume).
  • Aromatase knockout mice: Estrogen deficient mice that develop excessive grooming. Decrease in COMT protein expression, which is associated with increased risk of OCD in human males.

Behavioral models

Behavioral models of OC spectrum conditions comprise the following: (i) models that focus on overt behaviors that represent more extreme forms of what would otherwise constitute normal behaviors, including those brought about by stress (‘‘ethological models’’); and (ii) models that attempt to capture specific cognitive features of the OC spectrum and their neurochemical and neuroanatomical correlates (‘‘cognitive models’’).

  • Naturally occuring repetitive behavior was the first type of behavioral models. Examples are tail chasing, fur chewing, and circling in dogs, cribbing/weaving in horses.
  • Stressful environments sometimes induce repetitive behaviors, for example hair pulling in cats, feather picking in birds, licking in dogs, and barbering in mice.
  • Spontaneous stereotypy in deer mice: Chronic treatment with fluoxetine reduced this behavior. Researchers have also found alterations in striatum and frontal cortex.
  • Nest building in house mice: Artificial selection in house mice have resulted in big and small house mice, where the bigger ones show increased compulsivity in nest building.
  • Nest building in female rabbits: Some researchers have argued that this might resemble the “just right” feelings in OCD patients and tic-related OCD.
  • Natural responses under conditions of stress: These models capture “displacement behaviors”, marble burying for example. They may be induced by basic fear-avoidance mechanisms. Some have suggested that OCD symptoms in humans are analogous to displacement behaviors in animals.
  • Impaired fear extinction: It’s the basis for the cognitive behavioral model of OCD, and has good cross-species validity.

Thus, although impaired fear extinction does not attempt to explain the entire complex phenomenology of OCD, it may be beneficial for understanding the pathogenesis, pathophysiology, and treatment of OCD. Indeed, translational fear extinction research has already led to the development of novel therapeutic approaches in OCD, including reconsolidation blockade, and adjuncts to cognitive behavioral therapy such as D-cycloserine. Recent research using a rodent model of fear conditioning found that HFS (high frequency stimulation) of the ventral striatum strengthened fear extinction and retention.

Cognitive models

  • Signal attenuation: “The signal attenuation model is based on the theory that compulsive behaviors may result from a deficit in the feedback associated with performance of normal goal-directed responses.” Sounds like outcome devaluation
    • Rats are trained to press a lever for food, which is accompanied by a CS light and tone. The feedback stimulus is separately extinguished before the animal is allowed on the lever again, when the food is extinguished (light and tone but no food).
  • Perseveration in 5-choice-serial-reaction-time-task (5CSRTT): Could be caused by a failure to detect response feedback cues and therefore model incompleteness in OCD.
  • Impaired set-shifting: Shifting between different stimuli as they become relevant or irrelevant.
  • Impaired response inhibition: Response inhibition means being able to suppress pre-potent motor responses. Usually measured using stop-signal paradigms.
  • Aberrant habit learning. “The habit hypothesis of OCD suggests that heightened stimulus-response associations coupled with a generally weakened influence of the ultimate goal may underlie compulsive behavior.” Habits