Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models: Rodent and human studies

Abstract

Psychiatric patients with bipolar disorder suffer from states of depression and mania, during which a variety of symptoms are present. Current treatments are limited and neurocognitive deficits in particular often remain untreated. Targeted therapies based on the biological mechanisms of bipolar disorder could fill this gap and benefit patients and their families. Developing targeted therapies would benefit from appropriate animal models which are challenging to establish, but remain a vital tool. In this review, we summarize approaches to create a valid model relevant to bipolar disorder. We focus on studies that use translational tests of multivariate exploratory behavior, sensorimotor gating, decision-making under risk, and attentional functioning to discover profiles that are consistent between patients and rodent models. Using this battery of translational tests, similar behavior profiles in bipolar mania patients and mice with reduced dopamine transporter activity have been identified. Future investigations should combine other animal models that are biologically relevant to the neuropsychiatric disorder with translational behavioral assessment as outlined here. This methodology can be utilized to develop novel targeted therapies that relieve symptoms for more patients without common side effects caused by current treatments.

Keywords: Animal model; Bipolar disorder; Dopamine transporter; Translational.

Figure 1

Illustration of the translational behavioral paradigms outlined in this review used to assess similar behaviors in patients with bipolar disorder and animal models. The behavioral pattern monitor (BPM) can be used to quantify ambulatory behavior of both humans and rodents, utilizing similar computational measures of activity, exploration, and behavioral organization (A) [see (Henry et al., 2010)]. Deficits of prepulse inhibition (PPI) are used in the sensorimotor gating assessment of humans as well as rodents (B). In humans, reactivity to the startling stimulus is often assessed using the eye-blink response, while in rodents a whole-body flinch is measured [see (Geyer et al., 2002)]. Poor decision-making of bipolar patients can be assessed with the human Iowa gambling task (IGT), while impaired risk-taking behavior of mice can be observed with the mouse IGT (C). The subject is required to learn to pick the “safe” cards / nosepoke the “safe” cue lights in order to gain the most reward over time [see (de Visser et al., 2011)]. Impaired vigilance and loss of inhibitory control are present in patients with bipolar disorder and can be successfully measured with both human and rodent 5-choice continuous performance tests (5C-CPT; D). Subjects are required direct a joystick / nosepoke at a target whenever one cue lights up or inhibit from responding whenever all cues light up [see (Young et al., 2013b)].

Figure 2

Translational behavioral assessment of the dopamine transporter (DAT) model animal for bipolar disorder (BD) mania based on altered DAT functioning observed in patients with BD. Polymorphisms in the gene encoding for the DAT and reduced cell surface expression of DAT, the primary reuptake mechanism of free dopamine (DA) from the synaptic cleft, have been associated with BD. Lower striatal DAT levels have also been observed in patients by using positron emission tomography (PET). Mice with reduced functioning of the DAT, through either genetic knockdown (KD) or pharmacological inhibition, displayed a range of behaviors consistent with that of BD mania patients in human analogues. These behaviors include hyper-exploration in the behavioral pattern monitor (BPM), reduced prepulse inhibition in the acoustic startle test, high-reward risk-preference in the Iowa gambling task (IGT), and inattention in the 5-choice continuous performance test. Risk-preference of both wild-type (WT) and KD mice in the IGT correlated with specific exploration (holepokes) in the BPM.

Figure 3. Schematic of process for developing targeted therapeutic for psychiatric disorders

In order to develop novel treatments for patients with psychiatric disorders such as bipolar disorder, a greater understanding of the neural mechanisms underlying the disorder is required. Initially, clinical behavioral observations can be quantified using behavioral tools. If tools with translational relevance are used, animal studies assessing mechanisms underlying these behaviors can be conducted. Moreover, in combination with the etiology/mechanisms of the disorder, model organisms targeted at these mechanisms will have increased relevance to these abnormal behaviors. These model organisms could then be tested in similar translational tests to confirm the mechanistic relevance of manipulating these organisms. If confirmed, such findings would then support more invasive and costly techniques such as positron emission tomography (PET) to confirm in vivo relevance of altered mechanisms linked to that behavior. Meanwhile, compounds targeting that mechanism can be developed. These compounds could then be combined with behavioral testing in conjunction with biomarkers to confirm target efficacy. These studies can be first conducted in healthy subjects, particularly if behavioral effects in normal animals are observed, then moved into the patient population. Finally, once target engagement is demonstrated, the compound can be tested in large clinical trials required for evidence for treatment efficacy. $ denotes the time and funding required for each aspect of this schematic. Because studies on biomarker confirmation/compound testing in humans are so expensive, generating evidence for target relevance using model organisms would greatly reduce the cost, effort, and burden on patients.