A Reverse-Translational Study of Dysfunctional Exploration in Psychiatric Disorders

Abstract

Context Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, raising the question of whether they are in fact the same disorder on different ends of a continuum. The lack of distinct endophenotypes of bipolar mania and schizophrenia has complicated the development of animal models that are specific to these disorders. Exploration is fundamental to survival and is dysregulated in these two disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans. Objective We used a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM), to quantify exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses. Design Static group comparison. Setting Psychiatric hospital. Participants 15 bipolar mania and 16 schizophrenia subjects were compared to 26 healthy volunteers in the human BPM. The effects of amphetamine, the selective dopamine transporter (DAT) inhibitor GBR12909, and genetic knockdown of the DAT were compared to controls in the mouse BPM. Measures The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs. Results Bipolar manic subjects demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Schizophrenia subjects did not show the expected habituation of motor activity. Selective genetic or pharmacological inhibition of the DAT matched the mania phenotype better than the “gold standard” model of mania (amphetamine). Conclusion These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to identify neurobiological underpinnings of neuropsychiatric disorders.

Reduced Dopamine Transporter Functioning Induces High-Reward Risk-Preference Consistent with Bipolar Disorder

“…Although impaired decision making of the reduced DAT model animals here could therefore resemble other clinical populations, the consistencies of BD patient IGT performance including the sensitivity for rewards, to our reduced DAT functioning in mice are striking. These findings are reinforced by previous observations of parallels between behavior of these DAT models and that of BD patients in other paradigms (Henry et al, 2013;Perry et al, 2009;van Enkhuizen et al, 2012). Moreover, supporting the increased reward-seeking trait of DAT KD mice, chronic DAT reduction also resulted in faster reaction times, fewer omissions, and increased premature responses in both the present and previous studies (Young et al, 2011).…”

“…Previously, we reported that mice with reduced DAT functioning mimicked abnormal behaviors of BD mania patients (Perry et al, 2009). Mice that are hyperdopaminergic via genetic DAT knockdown (KD; Zhuang et al, 2001) or pharmacological DAT inhibition (GBR12909 treatment) exhibited this profile.…”

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

“…Mice with constitutive genetic knockdown of DAT (DAT-KD) express 10% of wild-type (WT) DAT levels and also show high DA levels. They display mania-like behaviors such as hyperactivity in a novel environment (Zhuang et al, 2001), replicating hyper-exploration and increased risk-taking behavior of manic BD patients (Perry et al, 2009;van Enkhuizen et al, 2014;Young et al, 2011b) without concomitant developmental defect. For these reasons, DAT-KD mice have been used as a model for mania.…”

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers

“…understand its pathophysiology and to develop new treatments for the condition (22)(23)(24)(25). In two previous studies, Shank2 mice bearing deletions of exon 6 or exons 6-7 displayed autism-like behaviors and cognitive impairment (26,27).…”