Discovery Research

Study Rationale

Genetic factors contribute to the risk for bipolar disorder. Of the many genes involved, those encoding voltage-gated calcium channels (VGCCs) are among the most robust findings. This study will provide a clear understanding of the roles of VGCCs in bipolar disorder, as well as a basis for future studies on their potential value in treatment.

Hypothesis

VGCCs are involved in bipolar due to convergent effects on VGCC structure, function and interactions, driven at least in part by VGCC variants enriched in the brain.

Study Design

The study has three primary aims to test the potential role of VGCCs in bipolar disorder. The team will first consider the molecular basis of VGCC genetic associations with bipolar disorder. Second, they will interrogate the protein structure and channel composition of VGCCs in the brain using the native mass spectrometry technique. Third, they will investigate the properties of identified VGCC proteoforms. These aims will allow the team to determine how changes in VGCC composition may affect protein trafficking of the channels and influence intrinsic properties of neurons.

Impact on Diagnosis & Treatment

By evaluating the role of VGCCs in bipolar disorder, this work will lead to an improved understanding of a genetic risk factor and how it contributes to bipolar disorder development. It also has the potential to personalize treatment strategy for individuals with VGCC-related risk variants. The work may identify drug targets within the VGCC pathways or of VGCCs directly.

Study Rationale

Bipolar disorder is characterized by significant disturbances in sleep/wake cycles. This project will provide a picture of dopamine (DA) dynamics and reward processing across the circadian cycle for both human subjects and a circadian-disrupted mouse model.

Hypothesis

In people with bipolar disorder, disruptions to circadian processes lead to a failure to dampen motivated behavior in the evening, furthering circadian disruption and exacerbating manic symptoms.

Study Design

This study uses a cross-species design to study DA dynamics and related behaviors across the circadian cycle in humans and mice. First, the team will use multi region in vivo imaging in mice to determine specific neural loci underlying the circadian mediation of reward sensitivity. Second, they will use fMRI and iron mapping MRI in human subjects in the evening to characterize the neurobiological mechanisms underlying sustained reward sensitivity at this time in people with bipolar disorder. Third, a smartphone platform will characterize disrupted diurnal modulation of real-world mood and reward processes.

Impact on Diagnosis & Treatment

This work will significantly advance understanding of the neural circuits/systems that mechanistically link circadian disruption and bipolar disorder.

Study Rationale

Large cohort studies have identified genetic risk factors for bipolar disorder. Although the exact mechanistic links to bipolar disorder are not understood, robust genetic findings serve as critical first steps to understand bipolar disorder etiology and reveal deficient neurocircuitry and potential targets.

Hypothesis

Cerebellar cortical and thalamocortical circuit impairment may drive dysregulation of sleep and affect in bipolar disorder.

Study Design

The team will characterize the basal properties of cerebellar cortical and thalamocortical circuits in relevant genetic models of bipolar risk using a variety of technologies such as single-cell transcriptomics, structural and functional neuroimaging, and electrophysiological recordings. They will further probe the relevant biology using genetic and pharmacological perturbations.

Impact on Diagnosis & Treatment

This study serves as a model for following up on genetic risk factors and develops a pipeline and tools that will be applicable for interrogating the cerebellar cortical and thalamocortical circuits.

Study Rationale

Both adaptive and innate immune dysfunction have been implicated in the pathogenesis of bipolar disorder. However, little is known about how these immune mechanisms drive increased risk for disease and contribute to disease progression.

Hypothesis

Immune mechanisms substantially contribute to bipolar disorder risk and progression. Targeting immune mechanisms therapeutically would meaningfully improve clinical outcomes.

Study Design

The study will use a cohort of bipolar patients and controls that have previously been established and have associated longitudinal clinical data. First, the team will identify novel therapeutic strategies that target mechanisms of innate and adaptive immune regulation, integrating data from blood samples and phenotyping to prioritize potential targets. Then, they will test novel therapeutic strategies targeting mechanisms of immune regulation in human experimental systems, establishing an in vitro system of modeling the blood-brain barrier using the organ-chip technology.

Impact on Diagnosis & Treatment

This project has the potential to identify immune biomarkers and/or therapeutic targets and establish a system to test candidate immune factors.

Study Rationale

Mitochondrial mechanisms are highly implicated in bipolar disorder. Growing evidence show involvement of mitochondrial-related genes and metabolic changes, and increased recognition of the central importance of energy- and activity-related symptoms at the onset of bipolar-related episodes.

Hypothesis

Mitochondrial mechanisms, such as the ATP synthase c subunit leak channel (ACLC), are causative in the development of bipolar disorder.

Study Design

Investigate brain mitochondrial metabolism and function in vivo using a variety of neuroimaging approaches. Further explore molecular mechanisms, including mitochondrial mechanisms, of bipolar disorder using stem-cell approaches. Finally, the study will discover new neuronal mitochondrial metabolic mechanisms via a genomics and metabolomics platform that explores relevant mitochondrial-related genes.

Impact on Diagnosis & Treatment

The ACLC mitochondrial mechanism is inhibited by lithium, and there are specific ACLC inhibitors available, one with safety shown in humans. Thus, findings of this project could be translated rapidly to new therapeutics for bipolar disorder. In addition, as lifestyle changes, such as diet, can influence mitochondrial differences, their identification could provide support for behavioral interventions.

Study Rationale

Studies of people with bipolar disorder have indicated multiple genes associated with the disorder, notably those involved in sleep. Bipolar disorder is characterized by significant disturbances in sleep/wake cycles, and bipolar disorder drugs such as lithium correct sleep/wake disruption. This project will engineer mice with bipolar disorder risk gene mutations and use the biological readout of sleep. This approach is highly relevant to bipolar disorder, as mice share these human risk genes.

Hypothesis

Mutations in bipolar disorder-linked genes in neurons in the ventral tegmental area and lateral hypothalamus contribute to mania-related behaviors.

Study Design

This team has chosen a short list of genes to disrupt in mice based on their strong associations with bipolar disorder, mania-like behaviors in rodents, and the ability of mood stabilizers such as lithium to normalize these behaviors. The study will pioneer the use of cutting-edge CRISPR technology to disrupt bipolar disorder-linked genes from cells in two specific brain regions already linked to mania-like phenotypes, sleep regulation, and impulsive behavior. The team will then focus on sleep/wake disruption and mania-related behaviors in mice that are a hallmark of bipolar disorder in people.

Impact on Diagnosis & Treatment

By identifying the effects of bipolar disorder-linked gene disruptions on sleep, specific brain pathways, and behavior, this work will deliver a more complete picture of the roles of each genetic risk factor. This study will provide a powerful tool to test any new gene targets identified within the BD2 network, and the approach will also be used to test multiple gene disruption on mania-related behaviors. The team will also test stress and lithium (that stabilizes mood in many with bipolar disorder) when each gene is disrupted, helping us to understand who may be more susceptible to acute stress or more likely to be helped by lithium.

Study Rationale

This study aims to uncover the genetic underpinnings of bipolar disorder, using multiple stem cell approaches to unravel the shared biology of common and rare variants in people with African ancestry.

Hypothesis

Different genetic risk factors affect changes that converge onto shared genes, biological processes, and pathways.

Study Design

This study will examine the biology of common and rare genetic variants in a cohort of 70 people with African ancestry living with bipolar disorder and 70 matched control participants. The team will investigate the causal biological effects of the genetic variants. Biological readouts will be examined to determine how these genetic variants may converge onto common biological pathways.

Impact on Diagnosis & Treatment

The team’s ability to manipulate the biology of induced pluripotent stem cells will substantially benefit the field, further reducing the standard timeline of basic scientific discovery to clinical relevance.

Study Rationale

A holistic understanding of the molecular mechanisms leading to the onset of bipolar disorder as well as the successful outcomes after treatment is key to improving treatment regimens and robust alternatives. Current medications for bipolar disorder, including lithium and antipsychotics, have a narrow therapeutic impact and can have undesirable acute and long-term side effects.

Hypothesis

CircaVent probes the mechanisms of current interventions to identify alternative interventions and understand how they function in bipolar disorder.

Study Design

The CircaVent platform combines in silico drug prediction with data from state-of-the-art in vitro and -omics technologies. Hypothesis generation takes place in patient-derived brain organoids, a proxy of a patient’s brain generated from their own cells. Potential drug candidates are validated in organoids by evaluating their global effects on neuronal activity and other multi-dimensional datasets. Most promising drugs will be verified in in vivo models focusing on circadian intervention. Once the team identifies promising treatments and treatment targets, they will work with clinicians to bring them directly to patients and monitor outcomes.

Impact on Diagnosis & Treatment

Standard treatment orthodoxies, including lithium, rely heavily on addressing the symptoms without a complete understanding of their global effects on brain chemistry. The goal of the project is to understand the mechanism of current therapies to identify alternative therapeutics for bipolar disorder with a focus on measuring and mitigating its effects on circadian rhythms, neurochemistry, and a host of other factors that can adversely affect a patient’s quality of life.