Rodent models of obsessive compulsive disorder: Evaluating validity to interpret emerging neurobiology

Abstract

Obsessive Compulsive Disorder (OCD) is a common neuropsychiatric disorder with unknown molecular underpinnings. Identification of genetic and non-genetic risk factors has largely been elusive, primarily because of a lack of power. In contrast, neuroimaging has consistently implicated the cortico-striatal-thalamo-cortical (CSTC) circuits in OCD. Pharmacological treatment studies also show specificity, with consistent response of OCD symptoms to chronic treatment with serotonin reuptake inhibitors; although most patients are left with residual impairment. In theory, animal models could provide a bridge from the neuroimaging and pharmacology data to an understanding of pathophysiology at the cellular and molecular level. Several mouse models have been proposed using genetic, immunological, pharmacological, and optogenetic tools. These experimental model systems allow testing of hypotheses about the origins of compulsive behavior. Several models have generated behavior that appears compulsive-like, particularly excessive grooming, and some have demonstrated response to chronic serotonin reuptake inhibitors, establishing both face validity and predictive validity. Construct validity is more difficult to establish in the context of a limited understanding of OCD risk factors. Our current models may help us to dissect the circuits and molecular pathways that can elicit OCD-relevant behavior in rodents. We can hope that this growing understanding, coupled with developing technology, will prepare us when robust OCD risk factors are better understood.

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

“…The glutamatergic hypothesis of OCD has accumulated support over the last decades [4,5]. Neuroimaging studies indicate alterations in the cortical-striatal-thalamic-cortical (CSTC) circuitry, which includes glutamatergic corticostriatal projections synapsing onto striatal spiny projection neurons and/or interneurons [4,[6][7][8][9][10]. Altered glutamate levels from cerebrospinal fluid studies have been reported in OCD [11,12].…”

“…Beneficial effects of anti-glutamatergic agents including memantine, N-acetylcysteine, riluzole, ketamine, and rapastinel have been reported in treatment-resistant OCD individuals [5,[13][14][15][16][17]. In addition, some genetic animal models with altered glutamatergic neurotransmission at the CSTC circuitry exhibit OCD relevant behaviors [10,[18][19][20].…”

Neurotransmitter mechanisms of paraphilic disorders

“…Наличие при парафилиях навязчивых аномальных сексуальных фантазий и компульсивных их реализаций приближает расстройства сексуального предпочтения по своей психопатологической структуре к обсессивно-компульсивным расстройствам (ОКР). Необходимо также отметить, что связь между дисфункцией серотонинергической системы и обсессивными расстройствами достаточно давно обсуждается в литературе, и в 2017 г. был опубликован обзор литературы, в котором на этом основании предлагались различные патогенетические модели ОКР [14]. В более ранних исследованиях [15] также предполагалось наличие дисфункции серотониновых 5-НТ-рецепторов с патогенезом ОКР.…”

“…Кроме того, дисфункция ПФК у лиц с ОКР была выявлена и при применении позитронной эмиссионной томографии [19]. По имеющимся в литературе данным, в патогенез ОКР могут быть вовлечены и другие, в частности эмоциогенные и мотивационные, структуры -островок, миндалина [14].…”

Repetitive Skin Focused Disorders May Express a Functional Connectome

“…Onychophagia (nail biting), trichotillomania (hair pulling), cutting and picking, repetitive piercing and tattooing, excessive use of cosmetic procedures, are common observations in clinical practice (Figures 1 and 2). [13][14][15][16][17] Repeated behaviors that involve the skin, especially those that leave marks or are accompanied by specimens, can be seen, graded and noted in the chart. In laboratory settings, neuroscientists have created maps of brain function and circuitry in task and non-task related situations.…”