The Harvard Brain Science Initiative (HBI) Bipolar Disorder Seed Grant Program supports research relevant to the basic understanding and eventual treatment of bipolar disorder. Supported by a generous gift from Kent and Liz Dauten and the Dauten Family Foundation, this program funds innovative, visionary projects with new ideas and approaches that otherwise may not attract seed funding from conventional sources. To date the program has awarded 30 grants totaling $3M, to laboratories with diverse areas of expertise, spread out across different campuses of Harvard University and its affiliated hospitals.
Mark Andermann, Beth Israel Deaconess Medical Center
Modeling Mental Imagery in Bipolar Disorder:
Effects of dopamine on ongoing patterns of cortical activity
Recent pharmacological and genetic animal models of bipolar disorder suggest that increased levels of the neuromodulator dopamine may contribute to the hyperexcitability associated with mania. Human studies suggest that manic states also involve elevated levels of imagery of positive emotional experiences, while depressive states involve elevated imagery of negative emotional experiences. These symptoms are sometimes treated using drugs that block the actions of dopamine. However, the underlying neural circuit mechanisms remain unknown, in part because no animal models exist to study the neural circuitry underlying mental imagery.
We have recently refined methods to image neural activity in the same set of hundreds of individual cortical neurons in awake mice during and following engagement in a visual task involving rewards and mild punishments. Preliminary data gathered in the first year of our HBI grant project suggest that patterns of brain cells that are activated by positive or negative emotional visual experiences become re-activated in the subsequent periods of quiet waking in the dark, at higher rates than for reactivation of neutral visual experiences. We now plan to test whether reactivations of positive and negative experiences during quiet waking can be attenuated by manipulations of dopamine, and to dissect the specific brain circuits through which dopamine affects emotional mental imagery. This work will set the stage for precise therapeutic strategies targeted to specific cell types and circuits, thereby increasing efficacy and reducing side effects of future treatments for positive symptoms of bipolar disorder and other psychiatric diseases
Todd Anthony, Boston Children’s Hospital
Connecting candidate bipolar disorder genetic risk factors to neural circuit-level phenotypes
Rare variations in the human genome are implicated in contributing to risk for developing Bipolar Disorder (BD). Ongoing sequencing efforts are identifying increasing numbers of such variations which track with affected status in families with multiple BD sufferers, but the rate at which such variants can be identified currently far exceeds that at which they can be tested to establish causality for particular symptoms, or to determine the neuronal cell types and circuits in which they act. As a step towards relieving this bottleneck, we will develop a novel rapid approach that enables candidate risk factor variants to be targeted to specific neuronal cell types in the mouse brain in order to define their function. Our focus will be on the lateral septum (LS), a region implicated in BD which rodent models have identified as a critical regulator of mood and motivation. We will test the hypothesis that a candidate BD mutation in a clinically relevant gene highly expressed in LS promotes persistent negative mood states and exerts opposite effects on the excitability of two distinct LS neuronal subsets that our previous Dauten-supported work revealed are differentially engaged by aversive stimuli.
Electroconvulsive Therapy (ECT) is the most effective treatment in psychiatry, with response rates of 70-90% and indications for bipolar depression and mania. Despite its great efficacy and rapid action, the mechanisms underlying ECT remain unknown. Our programs study the effects of ECT in rodents and human patients separately, with a shared focus on reward circuitry which is critically affected in mania and depression.
Unipolar and bipolar depression is associated with different sets of symptoms. In particular, anhedonia, defined as the lack of enjoyment, reward, and pleasure, is important and difficult to treat. In patients treated with ECT, Dr. Camprodon’s lab has described volume increases in specific parts of the brain that underlie anhedonia. Separately, Dr. Ressler’s group has used a novel translational mouse model of ECT to identify an increase in the expression of synaptic plasticity molecules that mediate brain structural changes in these same brain regions.
Understanding the molecular and cellular mechanisms by which ECT improves the anhedonia symptoms in bipolar disorder is an important and potentially tractable problem in neuropsychiatry. This proposal will support a collaborative translational effort across our laboratories to study the effects of ECT on reward circuitry. Using the resolution available in our mouse model, we will study the structural and functional alterations in the brain in response to ECT. This study will be the first mechanistic examination of ECT-mediated recovery at the molecular, cellular and circuit level, with implications for future advances in understanding Bipolar Disorder and novel treatment approaches.
Michael Tri H. Do, Boston Children’s Hospital
A Circadian Control System for Counterbalancing Bipolar Disorder
Bipolar disorder and circadian rhythms are interlinked. Altered mood states can disrupt daily patterns of activity, but disruptions in these patterns also precede episodes of mania and depression. Moreover, artificial imposition of circadian structure can reduce symptoms of bipolar disorder—for example, regular periods of darkness can alleviate mania while light can mitigate depression. Indeed, light is the principal regulator of the circadian clock. The mechanisms by which light engages the clock are poorly understood. We are addressing this gap in knowledge by defining the pathway that connects the eye to the master clock in the brain. Our work will set the foundation for investigating whether this pathway is altered in bipolar disorder and how it may be leveraged to develop new treatments.
Susan Dymecki, Harvard Medical School
Understanding the role of serotonergic neurons in bipolar disorder circuitry
This project aims to delineate the specific serotonin (5HT)-producing subsystems in the brain that influence the opposing mania versus depression phases of bipolar disorder. Abnormalities in brain 5HT levels and the neurons that produce it are strongly linked to psychiatric illness, including bipolar disorder. We have recently found that the brain serotonergic system is comprised of functionally distinct subsystems, each specialized in the modulation of particular behavioral and physiological processes (e.g. anxiety-like behavior, aggression, sensorimotor gating, respiratory dynamics). In line with distinct functionalities, we also found distinguishing profiles of expressed genes. These findings reveal a subsystem responsive to neuropeptide Y (Npy) – a neurochemical also implicated in affective state. Through this seed grant, we will query the Npy2r-5HT subsystem in mouse models of depression-like traits versus mania-like traits elicited by chronic social defeat or positive winning experience, respectively. Genetic tools developed in the lab for cell-subtype-selective activity manipulation and cell marking will be used to probe the Npy2r-5HT subsystem at the organismal and circuit levels. Our preliminary findings—gathered in the first year of our HBI grant project—suggest that inhibition of Npy2r-5HT neurons safeguards against stress-associated dysfunctions, an outcome possibly akin to resilience. Paralleling anatomic studies, in which we visualize Npy2r-5HT neuron innervation targets, identify brain regions central to adult neurogenesis and arousal and stress responses, all of which are implicated in bipolar disorder. Here we test the functional link between Npy2r-5HT neuronal substrates and the behavioral outcomes mediated by this subsystem. Findings are expected to illuminate possible therapeutically relevant substrates for protecting against depression- and mania-like symptoms.
Bernardo Sabatini, Harvard Medical School
Elucidating the role of distinct cell types of the dorsal raphe nucleus in bipolar disorder
The serotonergic system has been widely implicated in the pathogenesis of mood disorders, yet little is known about the mechanisms by which dysfunction of serotonergic neurons causes behavioral deficits. Although reduced serotonin signaling has been associated with bipolar disorder, there is a paradoxical involvement of serotonin in both depressive and manic behaviors.
The dorsal raphe nucleus houses the majority of serotonergic neurons in the brain. It is a heterogeneous structure comprised of many neuronal and non-neuronal cell types that interact with serotonergic neurons. Additionally, distinct subtypes of dorsal raphe serotonergic neurons may serve contrasting functions, potentially accounting for the serotonergic system’s role in seemingly opposing behavioral deficits. This heterogeneity adds complexity to the problem of understanding the function of the dorsal raphe nucleus in the etiology of bipolar disorder.
In this study, we will use high-throughput single cell RNA sequencing to capture changes in gene expression across multiple cell types in the dorsal raphe nucleus. We will assess the transcriptional changes induced by stress and other perturbations that model both depressive and manic behaviors. We will also investigate the role of specific serotonergic neuron subtypes in the regulation of impulsivity and hyperactivity, two major features of manic behavior, by using intersectional viral and genetic tools to record the activity of these specific populations. This work will allow us to better understand the simultaneous involvement of multiple dorsal raphe cell types in the regulation of behaviors and the pathophysiology of bipolar disorder.
Beth Stevens, Boston Children’s Hospital
High-content, super-resolution synapse analysis in human prefrontal cortex
Synaptic pruning, a normal process by which extra synapses are eliminated, occurs throughout the mammalian brain during fetal and early postnatal development, but in the human prefrontal cortex is most pronounced during adolescence. A longstanding hypothesis is that aberrant synaptic pruning in the adolescent cortex may contribute to the onset of bipolar disorder and schizophrenia during this developmental period. Several studies have found small but significant reductions in synapse numbers in the brains of patients compared to healthy controls, consistent with over-pruning. However, these studies have been limited by the small number of available postmortem patient brain samples, especially for bipolar disorder, as well as by the low-throughput nature of age-old methods for counting synapses. To address these critical limitations, we are collaborating with colleagues at the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard to develop new techniques for synapse counting and analysis, which we will apply to a large cohort of patient and control brain tissue samples from the Stanley Medical Research Institute. Specifically, we are working with the MIT labs of Ed Boyden and Mark Bathe to modify tissue expansion and barcoded antibody methods for combined application in human tissue, which will enable high-content, super-resolution synapse analyses: by imaging a large number of synaptic proteins simultaneously, we will be able to take an unbiased “census” of many synapse types in patient and healthy control brains, while also investigating cellular mechanisms of aberrant pruning.
Naoshige Uchida, Faculty of Arts and Sciences, Harvard University
Competition between multiple dopamine systems as a model of bipolar disorders
Patients of bipolar disorder (BD) alternate between manic and depressive states. In manic states, patients tend to seek new and exciting stimulation, called novelty seeking and hyper-exploration. It has been thought that dopamine is released during these situations, and the drugs that affect dopamine transmissions in the brain are known to ameliorate symptoms of bipolar disorders. However, the actions of these drugs have been difficult to understand and largely anecdotal, preventing rational treatment methods.
Much of the work on dopamine has been guided by the dogma that dopamine neurons encode reward prediction errors (RPE = actual minus expected reward) and that they do so in a uniform manner. However, work from several groups, including ours, now indicates that dopamine neurons projecting to different targets exhibit distinct properties and serve distinct functions. These new data on the multiple dopamine system raises the possibility that this new knowledge can greatly improve our understanding of the neural mechanisms underlying BD. Here, we propose that exploratory behaviors including novelty-seeking are regulated by the balance between approach and avoidance behaviors promoted by the two distinct dopamine systems (dopamine in the ventral striatum [VS] versus the tail of the striatum [TS]). We hypothesize that VS dopamine promotes approach whereas TD dopamine promotes ‘timidity’ and avoidance in response to novel stimuli. Our results, if true, will raise the possibility that alternations between manic and depressive states in BD are caused by unbalance between the VS and TS dopamine, and provide a foundation toward mechanistic understanding of BD.
Charles J. Weitz, Harvard Medical School
Cytoplasmic circadian clock complexes in mammals:
Could they be autonomous post-translational oscillators?
Circadian clocks are internal oscillators that drive daily biological rhythms. Such clocks are found in animals, plants, fungi, and bacteria called cyanobacteria. In mammals, circadian clocks are found in the brain and in all peripheral tissues. These distributed clocks govern the daily timing of our physiology and behavior, and it has long been known that abnormal circadian rhythms are associated with mood disorders. Recent human genetic and anti-depressive drug studies have further suggested that abnormal circadian clocks might contribute causally to bipolar disorder. The nature of the abnormality is unknown.
Circadian clocks of animals, plants, and fungi are built on a transcriptional feedback loop, a process in cells in which the handful of circadian clock proteins periodically inhibit their own production, generating 24-hour molecular rhythms. Cyanobacteria have a circadian feedback loop, but it turns out to be of minor importance. Cyanobacterial clock proteins, in addition to participating in the feedback loop, also work together to generate a molecular rhythm purely at the protein level (“post-translational”), now known to be the predominant factor for cyanobacterial rhythms.
Tracy Young-Pearse, Brigham and Women’s Hospital
Targeting Bipolar Disorder Genes in Human Neurons in a Dish
Bipolar disorder is characterized by severe and unusual shifts in mood, energy and activity levels. Both genetic and environmental factors play a role in the onset of disease, but the cell and molecular mechanisms underlying the disease are poorly understood. Genetic studies provide the field with valuable clues to the causes of bipolar disorder. Under this award, we will use a new technology to genetically engineer human stem cells to introduce mutations in specific genes that cause bipolar disorder. We then will take these stem cells and use them to make human brain cells in a dish. We will compare brain cells with the mutations to those without the mutation, to examine how these mutations affect brain cell development. By understanding how bipolar brain cells are different, we hope to identify new therapeutic strategies for this disorder.
Mark Andermann, Beth Israel Deaconess Medical Center
Modeling mental imagery in bipolar disorder
Recent pharmacological and genetic animal models of bipolar disorder suggest that increased levels of the neuromodulator dopamine may contribute to the hyperexcitability associated with mania. Human studies suggest that manic states also involve elevated levels of imagery of positive emotional experiences, while depressive states elevated imagery of negative emotional experiences. These symptoms can be treated with drugs that block the actions of dopamine. The underlying neural circuit mechanisms remain unknown, in part because no animal models exist to study the neural circuitry underlying mental imagery. We have developed methods to track the activity of the same set of hundreds of individual brain cells in awake mice across weeks. In this proposal, we will test whether patterns of brain cells that are activated by positive or negative emotional experiences become re-activated in the quiet periods following these experiences. We will then test whether this surrogate of emotional imagery can be attenuated by blockade of dopamine. If so, we will then attempt to pinpoint the precise brain circuits through which dopamine affects emotional mental imagery. This work will set the stage for precise therapeutic strategies targeted to specific neurons and circuits, thereby increasing efficacy and reducing side effects.
Justin Baker and Dost Öngür, McLean Hospital
Circuit dynamics underlying longitudinal fluctuations in mood and cognition in bipolar patients
Even at “baseline” individuals with bipolar disorder often show fluctuations in mood and cognition that may be picked up by others (e.g., an astute caregiver or family member), and may represent the early warning signs of an impending episode of mania or depression. Until recently, technical and logistical challenges have prevented the careful study of these fluctuations and the factors that drive them. Over the past year, we have developed a robust “deep phenotyping” platform to track symptoms, behavior and neurobiology of individuals over extended periods by combining continuous data from smartphones and wearable devices with repeated neuroimaging and conventional study visits. We have already learned how to deploy this powerful approach in individuals with clinically significant bipolar illness, yielding important insights about the stability of our measurements and about the relationships between neurobiological change and behavioral change. In the present study, we will build and test individual-specific models that combine neurobiological, behavioral, and environmental factors to explain and even predict changes in mood and cognition. This project is intended as the precursor for real-time, individually tailored illness detection systems that could pick up on early warning signs and deliver warnings to the patient, a family member, and/or a preferred care giver to avoid costly clinical outcomes and engage the individual in their own recovery.
Michael Crickmore, Boston Children’s Hospital
Linking the mitochondrial dysfunction and dopamine hypotheses of bipolar disorder
Two prominent hypotheses about the root cause of bipolar disorder are the mitochondrial dysfunction hypothesis and the dopamine hypothesis. My lab is exploring a potential unification of these two hypotheses. Bipolar patients show many signs of mitochondrial dysfunction in the brain, one of which is an increase in lactate production. High lactate levels likely reflect an increase in glycolysis, which indicates that oxidative phosphorylation in mitochondria is not able to produce enough ATP to meet the energy demands of the neurons. Aside from its role in storing chemical energy, ATP is also used as a signaling molecule. For example, intracellular ATP closes KATP potassium channels. Several studies in nonneuronal tissues have shown that pyruvate kinase (Pyk, the terminal kinase in glycolysis that phosphorylates ADP to make ATP), is present in KATP complexes. In an unbiased screen for genes that regulated a dopamine-mediated motivated behavior, we unexpectedly hit Pyk. We then found that the two core subunits of KATP channels also regulate motivation in this system. Our working hypothesis is that localized glycolysis in the vicinity of KATP channels sculpts the output of dopaminergic activity so that it is appropriate for the internal state of the animal. The shift to glycolysis seen in bipolar disorder may result in altered activity of KATP channels, which I propose regulate dopaminergic circuitries that control our moods and behaviors.
Susan Dymecki, Harvard Medical School
Understanding the role of serotonergic neurons in bipolar disorder circuitry
The goal of this project is to delineate the specific serotonin-producing subsystems in the brain that influence the opposing mania versus depression phases of bipolar disorder. Abnormalities in brain serotonin levels and the neurons that produce it have been strongly linked to psychiatric illness, including bipolar disorder. We have recently found in rodent models that the brain serotonergic neuronal system is comprised of functionally distinct subsystems, each specialized in the modulation of particular behavioral and physiological processes (e.g. anxiety-like behavior, aggression, sensorimotor gating, respiratory dynamics). In line with distinct functionalities, we also found distinguishing profiles of expressed genes. In certain cases, these findings have pointed to subsystem responsiveness to other neuromodulators such as dopamine or neuropeptide Y – neurochemicals also implicated in affective state. Through this seed grant, we will query two serotonergic subsystems – the Drd2/5-HT subsystem and the Npy2R/5-HT subsystem – in recently developed models of depression-like traits versus mania-like traits elicited by chronic social defeat experience or chronic positive winning, respectively. Innovative genetic tools developed in the lab for subsystem activity manipulation and cell marking will be used to probe subsystem function at the organismal and circuit levels. A deeper understanding of these neuronal subsystems and their interplay with other neuromodulators may lead to new substrates for protecting against depression- and mania-like symptoms.
Corey Harwell, Harvard Medical School
Understanding Hippocampal Neurogenesis for the Treatment of Psychiatric Disease
Hippocampal circuit function has been shown to be important for a variety of cognitive and behavioral functions including learning and memory. The hippocampus is also unique in that it contains a population of neuronal progenitor cells capable of producing new granule neurons throughout adulthood. These newly generated neurons integrate into the existing circuits of the hippocampus where they are required for hippocampal circuit function. Reduced adult hippocampal neurogenesis is implicated in the pathogenesis of variety of psychiatric diseases in humans including major depression and bipolar disorder. However the circuit mechanisms and signaling pathways that regulate adult neurogenesis is still not understood. It has long been known that secreted growth factor signaling can promote hippocampal neurogenesis, but their mechanism of action remains unknown. We have identified a subset of growth factor expressing neurons that project into the hippocampus where they may function to regulate hippocampal circuit activity and neurogenesis. We plan to test whether neuronal activity and growth factor release from this subset of neurons is necessary and sufficient to promote hippocampal neurogenesis and resistance to depression related behaviors. The results from these studies will provide a deeper understanding of the molecular pathways and brain circuits that regulate adult neurogenesis and provide new targets for therapeutic treatments of psychiatric disease.
Pascal Kaeser, Harvard Medical School
Structural roles of calcium channels in the brain and their disruption in bipolar disorder
Bipolar disorder is a severe brain disorder that affects about 3% of the American population, but its causes and pathophysiology are not well understood. In recent years, human genetic studies have found that mutations in brain calcium channels are strongly associated with bipolar disorder. A well understood function of calcium channels in the brain is their role in mediating activity induced calcium influx into nerve cells. However recent data suggest that calcium channels may have additional structural roles for nerve cells by building protein complexes that are important for brain wiring and signaling. A leading hypothesis is that these structural roles are mediated through interactions with scaffolding proteins, but these roles are not well understood. Compellingly, some of the scaffolding proteins that we have found to interact with brain calcium channels are also associated with bipolar disorder in human genetic studies. Thus, we hypothesize that calcium channels operate in a structural scaffolding network, and that disruption of this network contributes to the pathogenesis of bipolar disorder. We use a broad spectrum of methods including brain biochemistry, mouse gene targeting, electrophysiology and imaging to dissect the roles of calcium channels and interacting proteins in scaffolding. Our work will reveal new mechanisms of calcium channel function and will likely provide insight into how calcium channels and interacting proteins contribute to the pathophysiology of bipolar disorder.
Bence Olveczky, Harvard Faculty of Arts and Sciences
Analyzing the relationship between neural activity and behavior in rodent models of bipolar disorder
Bipolar disorder and other mental illnesses are caused by deficits in neural circuit function. Our ability to treat the underlying pathologies is contingent on better understanding how neural circuits fail in different disorders, and how these failure modes lead to altered behavior. Rodent models of psychiatric disease hold promise in this regard, but capitalizing on it will require measuring neural activity and behavior simultaneously and at high resolution over timescales relevant for mood disorders (i.e. days and weeks), something not feasible with current technology. To enable this, we will develop an innovative experimental platform for recording activity from many neurons in different parts of the brain continuously over weeks and months in freely behaving animals. High-resolution behavioral data from accelerometers and a video-based motion capture system will be collected simultaneously. Our system will be completely automated, including unsupervised extraction of behavioral and neural states, thus allowing for efficient and high-throughput experimental approaches and unbiased analysis of resulting data. We will use our system to relate changes in brain activity to changes in behavior, and observe the effects of various disease states and mood-stabilizing drugs, thus making important progress towards a neural circuit-level understanding of psychiatric disorders.
Tracey Petryshen, Massachusetts General Hospital
Human iPSC Models to Bridge Gene Discovery and Neurobiological Mechanisms in Bipolar Disorder
Recent human genetic studies have been remarkably successful in identifying sequence changes in the genome that increase the risk of developing bipolar disorder. However, it is unknown how these genetic variants contribute to the disease. This project will leverage recent landmark studies and technological innovations to develop a biological platform to investigate the effects of these genetic variants in human neurons. The ankyrin 3 gene (ANK3), one of the strongest bipolar disorder risk genes, will serve as a prototype to develop this platform. The latest information regarding functional elements in the genome will be used to identify genetic variants in ANK3 that are likely to be deleterious. Using advanced genome editing technology, human induced pluripotent stem cells (iPSCs) will be engineered to carry the selected ANK3 genetic variants. Following differentiation of the iPSCs into functioning neurons, molecular and cellular functions will be studied to delineate how the ANK3 genetic variants on may contribute to disease. This project is expected to bridge a gap between the genetics and neurobiology of bipolar disorder by delivering a biological platform for studying genetic risk variants in human neurons.
Uwe Rudolph and Vadim Y. Bolshakov, McLean Hospital
From genetic variant to disease biology: elucidating a genomic rearrangement associated with bipolar disorder
In a large study looking for variations in the copy number of genes in patients with bipolar disorder, others have identified additional copies of 15 genes in a defined chromosomal region, 9p24.1, including 4 (instead of the normal 2) copies of the GLDC gene encoding glycine decarboxylase, an enzyme which degrades glycine. Glycine is a co-agonist at excitatory NMDA receptors in the brain. Our hypothesis is that the extra copies of GLDC increase degradation of glycine, and thus result in hypofunction of NMDA receptors and of NMDA receptor-dependent synaptic plasticity. We have generated mice which mimic the genetic copy number changes seen in patients. These mice display behavioral changes consistent with neurodevelopmental dysfunctions. In the brain, GLDC is only expressed in astrocytes. We therefore want to test the hypothesis that there is a local glycine deficit in astrocytes and that glycine release from activated astrocytes is reduced, which then results in hypofunction of NMDA receptors on nerve cells. In addition, we are analyzing changes in global gene expression patterns. Using bioinformatics analysis, we will evaluate whether biochemical risk pathways for neurodevelopmental disorders or other biological parameters are affected by the mutation. Finally, we plan to generate a mouse line in which the increase in copy number is restricted to the GLDC gene. This novel mouse line will enable us to unequivocally determine whether all or only part of the phenotypic changes observed are due to the extra copies of GLDC and not the extra copies of other genes in this chromosomal region. In summary, we plan to provide a direct link from a genetic variant to biochemical pathways, to synaptic functions, and to disease biology.
Hisashi Umemori, Boston Children’s Hospital
Protocadherin-17 Dysregulation and Bipolar Disorder
Protocadherin-17 (Pcdh17) is a cell-cell adhesion molecule that is highly expressed in the developing brain. Single nucleotide polymorphisms (SNPs), a type of genetic variation among people, in the Pcdh17 gene are significantly correlated with human bipolar disorder. These SNPs may cause dysregulation of Pcdh17 expression. However, whether dysregulation of Pcdh17 expression affects brain development and contributes to bipolar disorder remains to be elucidated. We hypothesize that dysregulated Pcdh17 expression impairs neuron-neuron connections that underlie the regulation of mood, leading to bipolar disorder. We will test our hypothesis by creating novel animal models in which Pcdh17 expression is dysregulated and performing in vitro and in vivo experiments.
Todd Anthony, Boston Children’s Hospital
Imaging activity in a neural circuit that controls behavioral indices of anxiety and bipolar disorder
Bipolar disorder is characterized by alternating bouts of depression and mania, and commonly co-occurs together with anxiety disorders. Although the neural circuit-level mechanisms that underlie these illnesses are unknown, abnormal activity in related, possibly overlapping neuronal subpopulations may be responsible. We have identified a neural circuit in the lateral septum (LS), a brain region implicated in human bipolar disorder whose activity can promote both anxiety and depression in mouse behavioral tests. To determine how neurons in this circuit are capable of mediating these distinct behaviors, we will optically record their activity with cellular resolution while mice are undergoing behavioral tests that measure indices of anxiety and depression. We anticipate that these imaging experiments will yield valuable information that will lay the foundation for future studies of LS control of mood states, and the ways in which abnormal activity in this circuit may influence susceptibility to psychiatric disorders.
Paola Arlotta, Harvard Faculty of Arts and Sciences
Understanding the neuronal substrate of bipolar disorder
Many sites in the human genome associated with an increased risk of bipolar disorder have been identified, and additional sequencing efforts are ongoing. There is a strong need for strategies to mine this wealth of genetic information to understand disease etiology and progression, as well as to inform treatment strategies. One major obstacle is that the particular neurons and circuits affected in bipolar disorder are not known—nor is it known whether the disease has a developmental origin. Our goal is to determine whether regions of the genome mutated in people with bipolar disorder are enriched for genes specifically expressed in distinct neuronal populations. We propose to build a database cataloging which genes are turned on and off in different neuronal classes at different developmental stages. Neurons will be isolated from both the mouse cortex and from human cerebral organoids derived from pluripotent stem cells. These cerebral organoids, although cultured in a dish, recapitulate some aspects of normal brain development. We expect that as the number of profiled neuronal classes grows, this type of resource will provide a platform to help identify which types of neurons are affected and when in development bipolar disorder is initiated.
Chinfei Chen, Boston Children’s Hospital
Circuit-based approach to understanding bipolar disorder
One characteristic symptom of bipolar disorder is dramatic and abnormal mood swings. This feature often becomes evident during adolescence. We aim to test the hypothesis that aberrant wiring between neurons in the cortex and subcortical regions of the brain can contribute to such difficulty in modulating mood. Connections between the cortex and the amygdala, a deep brain region important for emotions, are relayed through a subcortical hub called the thalamus. The thalamus serves as a gatekeeper or switchboard operator for information flow and therefore can modulate emotion. Neuronal connections between cortex and thalamus are known to develop during the adolescent years in humans and in mice. Here we will characterize the basic formation and maturation of this connection in mice using electrophysiological recordings in brain slices. We will also test whether transient disturbance of the cortex in adolescent mice can alter the wiring between cortex, thalamus, and amygdala. The results from these studies will help establish how brain circuits gating emotions develop normally and abnormally.
Michael Crickmore, Boston Children’s Hospital
Gaining control of dopamine levels to combat bipolar disorder
Aberrantly high and low dopamine levels are implicated in the manic and depressive phases of bipolar disorder, respectively. Many of the treatments for psychological disorders—including bipolar disorder—target dopaminergic signaling, demonstrating the efficacy of intervening in this system. We have developed a novel system with a sensitive behavioral readout of dopamine levels in the fruit fly, where powerful genetic tools are available. We are undertaking a molecular and circuit-level interrogation of this system as a means of discovering new principles of dopaminergic control that will be relevant to understanding and treating the motivational swings associated with bipolar disorder.
Pascal Kaeser, Harvard Medical School
Structural roles of calcium channels in assembling synapses and their disruption in bipolar disorder
In recent years, human genetic studies have found that mutations in calcium channels in the brain are strongly associated with bipolar disorder. Our recent data, together with studies from other laboratories, suggest that calcium channels may play structural roles in nerve cells by building protein complexes that are important for brain wiring and signaling. Compellingly, some of the proteins that we have found to interact with brain calcium channels are also associated with bipolar disorder. We hypothesize that calcium channels operate in a structural scaffolding network, and that disruption of this network contributes to the pathogenesis of bipolar disorder. We use a broad spectrum of methods including brain biochemistry, mouse gene targeting, electrophysiology, and imaging to dissect the roles of calcium channels and interacting proteins in scaffolding. Our work will reveal new mechanisms of calcium channel function and will likely provide insight into how calcium channels contribute to the pathophysiology of bipolar disorder.
Margaret Livingstone, Harvard Medical School
Focused ultrasound for treatment of psychiatric diseases
Psychiatrists lack non-invasive, safe, highly-specific, and reversible techniques to modulate brain activity in mood disorders and other diseases. We have developed a novel technique that accomplishes this in rats. The goal of this proposal is to extend this neuromodulation technique to a primate. The technique is to use focused ultrasound to permeabilize the blood- brain barrier (BBB) at a target site in the brain, and then to systemically administer a neuromodulatory substance that is active in the brain, ineffective in the periphery, and does not normally cross the BBB. Neuromodulation will therefore occur only at the sonicated site and nowhere else. Whereas neurosurgeons are currently exploring the potential for treating many neuropsychiatric disorders with deep brain stimulation, our approach can be safely tested for efficacy in psychiatric diseases without brain surgery.
Alexander Schier, Harvard Faculty of Arts and Science
Functional analysis of genes associated with bipolar disorder
The functions of the genes that have been implicated in causing bipolar disorder are largely unknown. Zebrafish are a powerful model system to determine the function of genes because gene activity can be easily manipulated and resulting changes in behavior, anatomy, and brain activity can be analyzed very efficiently. This project will mutate in zebrafish twenty genes associated with bipolar disorder and determine their functions, as well as assess how eight common drugs used to treat bipolar disorder affect the brain and behavior.
Hisashi Umemori, Boston Children’s Hospital
Excitatory and inhibitory synaptic organizers and bipolar disorder
In order for the brain to function properly, neurons must establish a balanced network of excitatory and inhibitory synapses. We have recently identified two related molecules (called Fibroblast Growth Factors, FGF22 and FGF7) that promote excitatory versus inhibitory synapse formation in the mammalian brain. We further found that mice lacking one of these molecules (FGF22) exhibit depression-like behavior, while mice deficient in the other (FGF7) show manic-like behavior. Other lines of evidence also link the signaling of FGF molecules to bipolar disorder. Here our goal is to determine how these FGFs contribute to neural circuit formation and mood disorders. Our work will reveal the molecular mechanisms underlying balanced synaptic network formation in the mammalian brain and suggest novel strategies for treating bipolar disorder.
Charles Weitz, Harvard Medical School
Is an autonomous protein oscillator embedded in the mammalian circadian clock?
The goal of the project is to provide new insights into the circadian clock, the body’s daily timekeeping system. The circadian clock is responsible for our myriad daily rhythms, the most obvious of which is the sleep-wake cycle. Abnormalities of the circadian clock have been strongly linked to bipolar disorder and other mood disorders, but the nature of the relationship between the clock and mood regulation is obscure. Deeper understanding of the circadian clock could ultimately reveal the nature of this link, leading to completely new approaches to the diagnosis and treatment of bipolar disorder.
Alik Widge, Massachusetts General Hospital
Engineering brain rhythms to improve emotion regulation
A core feature of bipolar disorders is a disruption of emotion regulation. Both the depressed and the (hypo)manic phase involve difficulties regulating one’s emotional responses to everyday situations. Brain imaging work has linked this to a failure of prefrontal cortex to control neuronal firing in the amygdala, as measured by poor connectivity between these structures. The disrupted connectivity is still present even when patients are “well” on medications, suggesting that it may be one of the neurologic causes of bipolar disorder. It might also explain why patients who are at the “right” mood level still show problems with impulsivity and mild mood swings. Our laboratory is developing electrical brain stimulation technologies that we think may be able to reduce or reverse this prefrontal cortex-amygdala circuit deficit. In stroke and spinal cord rehabilitation, other investigators have found that brain regions can be “re-wired” together by recording in one and stimulating in the other with very precise timing. Our group, which blends engineers and neuroscientists, will develop software and hardware tools to do combined recording and stimulating (“closed loop”) re-wiring between prefrontal cortex and amygdala. This first year of experiments will use a rat model, with a fear-conditioning test that is known to be sensitive to this specific connection. If this succeeds, the PI is a psychiatrist who works with a variety of deep brain stimulation technologies, and we will be able to work quickly towards human translation.