Discovery Research

Study Rationale

Previous work from the Sawa lab identified dysregulation of calcium signaling in neurons from bipolar patients, driven by abnormal interactions between the BK potassium channel and CaV1.2 calcium channel. This abnormal potassium-calcium channel interaction correlated with manic episodes, suggesting a role in mood switching through an unknown mechanism.

Hypothesis

Abnormal potassium-calcium channel interactions lead to calcium signaling dysregulation that underlies a key mechanism of mood state switching. Addressing this causal mechanism can lead to a novel therapeutic strategy.

Study Design

This project first identifies molecules that strengthen or weaken the interaction between the BK and CaV1.2 channels, using electrical recordings in patient-derived neurons. It then uses nasal swabs from individuals in the BD² Integrated Network cohort to test this channel interaction in neurons as a scalable biomarker. Finally, using calcium imaging, it studies neural activity in cells lacking BK, linking this cellular deficit to circuit and behavioral changes.

Impact on Diagnosis & Treatment

This project aims to build a simple, non-invasive biomarker test using a nasal swab, providing a new tool for clinical diagnosis. It could also uncover new drug targets centered on the BK channel, which could help inform new treatments for patients.

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. This study is providing 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 through 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 is first considering the molecular basis of VGCC genetic associations with bipolar disorder by examining postmortem tissue. Second, they are interrogating the protein structure and channel composition of VGCCs in the brain using the native mass spectrometry technique. Third, they are investigating the properties of identified VGCC proteoforms. These aims 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 is leading 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

This study is uncovering 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 is examining 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 is investigating the causal biological effects of the genetic variants. Biological readouts are examined to determine how these genetic variants may converge onto common biological pathways.

Impact on Diagnosis & Treatment

The team is identifying several molecular targets that have therapeutic potential and examining links between genetic variation and therapeutic response. Additionally, they are generating impactful cell-based tools that are substantially beneficial to 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 multiomic 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 are verified in in vivo models focusing on circadian intervention. When the team identifies promising treatments and treatment targets, they 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.

Study Rationale

The retrosplenial cortex has been implicated in attention switching and dissociation, and expresses genes tied to mood-related switching, including lithium’s mechanism of action, sleep-wake switching, and a psychedelic target. How it contributes to mood switching in bipolar disorder remains unknown.

Hypothesis

Retrosplenial switch cells are essential for psychiatric health, and their dysfunction mediates mood switching in bipolar disorder.

Study Design

This project first determines how retrosplenial cortex cell types differ in bipolar disorder versus matched controls, using molecular labeling in human brain tissue. Next, it analyzes the BD² Integrated Network dataset to predict treatment response and mood switching using genetic risk scores. Finally, it analyzes brain imaging samples within the BD² Integrated Network dataset to deepen understanding of retrosplenial cortex function in bipolar disorder.

Impact on Diagnosis & Treatment

This work significantly advances understanding of the brain regions and cell types that underlie mood state switches. It also identifies molecular changes between individuals with bipolar disorder and matched controls, which could reveal additional targets for future therapeutics.

Study Rationale

People with bipolar disorder are highly sensitive to changes in light, including seasonal daylength shifts, nighttime screen use, and time zone crossing, which commonly trigger mood-switch episodes. This project investigates the Rorβ-Fev circuit, which regulates sleep and circadian adaptation to light cycles, and how it relates to mood switching.

Hypothesis

Dysfunction in Rorβ-Fev circuits, via altered genes or neural activity, drives circadian and light-triggered mood instability in bipolar disorder.

Study Design

This project, using opto- and chemogenetics, tests how Rorβ-Fev neurons regulate sleep-wake adaptation to daylength shifts and bipolar-relevant behaviors in mice. Using developmentally timed gene knockouts, the project assesses Rorβ-Fev circuit formation and function, its dependence on Rorß (a bipolar risk gene), and capacity to regulate the circadian clock. Gene expression in these cells is mapped across circadian time and following genetic and daylength perturbations. Finally, human RORβ-FEV neurons modeled in brain organoids will assess how genetic factors shape neuron and gene activity.

Impact on Diagnosis & Treatment

This work advances understanding of how circadian disruption and light-related triggers, such as daylength shifts, and time zone crossing, drive mood switching in bipolar disorder. Findings could help reveal new circuit nodes and therapeutic targets thus informing clinical strategies for patient care.

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 involves engineering mice with bipolar disorder risk gene mutations and uses sleep as a biological readout.

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 is pioneering 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 is then focused 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 is delivering a more complete picture of the roles of each genetic risk factor. This study is providing a powerful tool to test any new gene targets identified within the BD² network, and the approach is also being used to test multiple gene disruption on mania-related behaviors.

Study Rationale

Bipolar disorder is characterized by significant disturbances in sleep/wake cycles. This project is providing a picture of dopamine 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 dopamine dynamics and related behaviors across the circadian cycle in humans and mice. First, the team is using multi region in vivo imaging in mice to determine specific neural loci underlying the circadian mediation of reward sensitivity. Second, they are using neuroimaging techniques in human subjects to characterize the neurobiological mechanisms driving sustained evening reward sensitivity in people with bipolar disorder. Third, a smartphone platform is characterizing disrupted diurnal modulation of real-world mood and reward processes.

Impact on Diagnosis & Treatment

This work is significantly advancing the 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 is characterizing 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 are further probing 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

A barrier to developing bipolar disorder treatments is the lack of mechanistic insight into the human brain regions causing symptoms. Brain imaging studies of bipolar patients can identify regions that correlate with symptoms but cannot determine which abnormalities are causing symptoms.

Hypothesis

Brain circuits that modulate affective valence and emotion regulation will be different, but both will align with neuroimaging changes in bipolar patients.

Study Design

This study is mapping brain circuits that drive bipolar disorder symptoms by integrating multimodal data. Researchers are analyzing symptom changes in stroke patients with focal brain damage, in epilepsy patients before and after deep brain stimulation (DBS), and in patients with psychiatric disease before and after TMS treatment. Results are being compared to imaging and deep phenotyping data from participants with bipolar disorder.

Impact on Diagnosis & Treatment

By building an understanding of brain circuitry in relation to symptoms for bipolar disorder patients, this research can guide analyses of brain imaging data from psychiatric patients and identify effective therapeutic targets for patients with primary psychiatric disease.

Study Rationale

Understanding mood state shifts at a circuit level is vital to developing more precise neuromodulation tools as a potential therapeutic intervention for people with bipolar disorder.

Hypothesis

Mood state shifts in bipolar disorder stem from dynamic shifts in fronto-striatal-limbic circuits.

Study Design

This study is validating a fronto-striatal-limbic circuit model of mood state shifts across three human cohorts. A group of individuals with bipolar disorder will undergo near-weekly fMRI and clinical phenotyping, and provide continuous wearable data. Fronto-striatal mechanisms will be assessed in a second group of patients with bipolar depression using transcranial magnetic stimulation; and mood-related circuits will be causally mapped via intracranial stimulation and stereo electroencephalography in epilepsy patients with comorbid bipolar disorder.

Impact on Diagnosis & Treatment

This project is establishing the causal role of brain circuitry in mood regulation for individuals with bipolar disorder, which can lead to the development of targeted treatments.

Study Rationale

Research has previously shown that using Personalized and Adaptive Cortico Electrostimulation (PACE), a type of brain stimulation, in people with unipolar depression can improve mood and thinking and provide long-term treatment benefits. A similar phenomenon may exist in bipolar disorder.

Hypothesis

Mood switching arises from instability in the balance between key large brain networks, with the salience network playing a key role in shifting between internally focused and externally driven states.

Study Design

The study is enrolling and scanning 25 individuals with bipolar disorder, five of whom will undergo PACE and intracranial electroencephalography (iEEG). The investigators aim to demonstrate that PACE in bipolar disorder induces positive changes in mood and attention, characterizes transitions in iEEG oscillatory dynamics underlying mood switching, and demonstrates the regional specificity of PACE.

Impact on Diagnosis & Treatment

The results will inform whether PACE is effective in improving mood and thinking for individuals with bipolar disorder.

Study Rationale

Unpredictable state transitions are a major source of disability and morbidity, but little is known about their neural underpinnings, partially due to the difficulty of monitoring human brain activity with sufficient neurobiological detail and adequate temporal sampling.

Hypothesis

Dynamical subcallosal cingulate/amygdala network activity can predict and be modulated to cause bidirectional transitions to and away from distinct mood states (mania/depression) in bipolar disorder.

Study Design

Investigators are collecting daily self-assessments, continuous brain field potentials, twice-daily video diaries, actigraphy data, bi-weekly behavioral tasks, and periodic fMRIs from patients with bipolar depression implanted with deep brain stimulation (DBS) electrodes in the subcallosal cingulate (SCC) and amygdala. Similar assessments and multi-areal stereo electroencephalography recordings are being collected from epilepsy patients who also have bipolar disorder, major depressive disorder, or no mood disorder, to identify network-level markers specific to bipolar.

Impact on Diagnosis & Treatment

The results of this project will lay the basis for new treatments based on the targeted neuromodulation of key brain areas underlying mania and depression states.

Study Rationale

Mitochondrial mechanisms are highly implicated in bipolar disorder. Growing evidence shows 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

Assess brain mitochondrial metabolism and function in humans using a non-invasive neuroimaging approach. Further explore molecular mechanisms, including mitochondrial mechanisms, of bipolar disorder using stem-cell approaches and animal models. And discover new neuronal mitochondrial metabolic mechanisms via a genomics and metabolomics platform that explores relevant mitochondrial-related genes.

Impact on Diagnosis & Treatment

Uncovering the specific molecular pathways that express abnormalities in bipolar disorder can inform therapeutic development and identify predictive biomarkers. In addition, as lifestyle changes, such as diet, can influence mitochondrial differences, better understanding of mitochondrial dysfunction could help refine recommendations for behavioral interventions.

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 is using a cohort of bipolar patients and controls that have previously been established and have associated longitudinal clinical data. First, the team is identifying 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 are testing 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.