A reverse-translational study of dysfunctional exploration in psychiatric disorders: from mice to men

Abstract

Context: Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, which raises the question of whether they are 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 2 disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans.

Objectives: To quantify the exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses.

Design: Static group comparison by the use of a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM).

Setting: Psychiatric hospital.

Participants: Fifteen patients with bipolar mania and 16 patients with schizophrenia were compared with 26 healthy volunteers in the human BPM. The effects of amphetamine sulfate, the selective dopamine transporter inhibitor GBR12909, and the genetic knockdown of the dopamine transporter were compared with controls in the mouse BPM.

Main outcome 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: Patients with bipolar mania demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Patients with schizophrenia did not show the expected habituation of motor activity. Selective genetic or pharmacologic inhibition of the dopamine transporter matched the mania phenotype better than the effects of amphetamine, which has been the criterion standard for animal models of mania.

Conclusions: These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from those of 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 the identification of the neurobiological underpinnings of neuropsychiatric disorders.

Figure 1

The human Behavioral Pattern Monitor and mouse Behavioral Pattern Monitor and sample x-y tracings.

Figure 2

Bipolar mania (BD) and schizophrenia (SCZ) subjects compared to healthy volunteers (HV) in the hBPM. Acceleration (A), entropy h (B), counts (C), spatial d (D), and object interactions (E) are presented. Values represent mean ± standard error. * denotes p<0.05 when compared to HV, † denotes p<0.05 when compared to SCZ. ^# denotes an overall significant difference when compared to HV.

Figure 3

Mouse models in the mBPM: amphetamine (AMP); DAT KD (DAT); and GBR12909 (GBR) Activity levels (A), locomotor patterns (B), hole interactions (C) and rearing (D) behaviors are presented. Data are presented as mean + standard error for control (vehicle, DAT WT mice, vehicle respectively) and treatment (AMP at 2.4 mg/kg, DAT KD mice, GBR at 16 mg/kg respectively) groups. * denotes p<0.05 compared to respective control group.

Figure 4

X-Y plots of mice and men – tracking movements in the hBPM and mBPM. Case examples of a healthy volunteer, a patient with Bipolar Disorder, a DAT wildtype mouse, and a DAT knockdown mouse.