Previous Fellows at McLean Hospital

Alison Foilb, PhD, is a research fellow in the Behavioral Genetics Lab at McLean Hospital where she studies the intersection of stress and learning. As a Rappaport Mental Health Research Scholar, Dr. Foilb will examine the relationship between fear-related experiences and sleep using mice as a preclinical model. Her research, which will focus on how sleep deprivation affects the impact of stress, promises to inform clinical approaches to mitigate the effects of stress, increase resilience, and develop new methods of relieving traumatic memories in people in people with debilitating psychiatric illnesses.

Maria Ironside, DPhil, investigates the neurobiological mechanisms underlying depression and anxiety disorders. Her doctoral work explored the mechanisms of action of a novel antidepressant treatment-transcranial direct current stimulation-using cognitive neuropsychological tasks, stress hormone measures and functional magnetic resonance imaging (fMRI). The ultimate aim of this work is to establish biomarkers of treatment response which could aid future treatment selection.

At McLean, Dr. Ironside is working on two, five-year projects examining the the effects of stress and sex steroid hormones on reward learning and anhedonia in depression. These projects take a multimodal approach with fMRI, magnetic resonance spectroscopy (MRS), position emission tomography (PET), as well as measures of various hormone, genetic, and inflammatory markers. The focus of this research is to build a detailed neurological profile of the (gender-dependent) effects of stress on reward learning, anhedonia, and depression to establish  multidimensional targets for treatment.

Gabriele Chelini, PhD, started his career in neuroscience joining a PhD program a the University of Florence, where he acquired expertise in working with in vitro and in vivo electrophysiology in mouse models of neurodevelopmental disorders. During this training, he spent 8 months with the Hensch-Fagiolini lab at Harvard Medical School, enhancing his understanding of experience dependent plasticity. During his experience at Harvard, he crossed paths with the Translational Neuroscience Laboratory at McLean Hospital, directed by Dr. Sabina Berretta, stimulating his interest in translational psychiatric research.

Dr. Chelini joined the Berretta lab in 2016 and divides his attention between animal model and postmortem research. His aim is to develop improved translational models in psychiatry. He is currently investigating the relationship between environment and synaptic plasticity in health and disease and will use this knowledge to unveil the complex mechanisms underlying psychiatric illnesses.

Galen Missig, PhD, joined the laboratory of Dr. Bill Carlezon as a post-doctoral research fellow in fall of 2015. His research is focused on inflammatory dysregulation in autism spectrum disorders and examines how perturbations of the early perinatal environment may subsequently alter neurodevelopment and manifest in abnormal behaviors.

To investigate these questions, Dr. Missig draws on his prior background in behavioral and molecular neuroscience techniques, collaborates with a number of researchers in different disciplines, and leads a team of three researchers.

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In addition to her research, Dr. Benham Vautour has mentored a number of students and research assistants in the Laboratory of Genetic Neuropharmacology. Furthermore, she has served as a reviewer for several peer-reviewed journals.

Darrick T. Balu, PhD, grew up in New York City where he earned his undergraduate and Master’s degrees. After receiving his PhD from the University of Pennsylvania, he was awarded the Division 28: Psychopharmacology and Substance Abuse Outstanding Dissertation Award from the American Psychological Association. Dr. Balu joined McLean Hospital as a post-doctoral fellow in 2008, was promoted to instructor in 2012, and to assistant professor in 2014. He is now director of his own laboratory.

Dr. Gonenç is the recipient of numerous awards, including the 2010 NARSAD Young Investigator Award, 2011 Rappaport Mental Health Research Scholar Award and 2013 ICGP International Junior Investigator Award. He has been the principal investigator of three foundation- and NIMH-funded studies and plans to extend his innovative MR data analytical strategies to understand the neurobiological substrates of mental illnesses and substance abuse using NIH, foundation and industry grants.

As a Rappaport Fellow, Dr. Gönenç undertook a project that uses neuroimaging technology to examine both structural and functional aspects of the brain in bipolar disorder. The study compared the white matter tracts that connect neurons with functional neuroimaging data that indicate level of neuron activity in different brain regions to determine the relationship, if any, between abnormal brain structure and abnormal brain function. Dr. Gönenç hopes that this research has the potential to advance our understanding of underlying causes of brain abnormalities in bipolar disorder.

Endophenotypes (or intermediate phenotypes) are heritable, disease-associated neurophysiologic, cognitive, or neurobiological traits. The study of endophenotypes is an important strategy for understanding the brain functional abnormalities associated with psychiatric disorders and the neurobiological mechanisms underlying these impairments. In addition, the use of endophenotypes in genetic studies may facilitate the identification of susceptibility genes and provide important neurobiological understanding of the functional effects of risk genes.

My research has been studying the brain dysfunction in schizophrenia and bipolar disorder and understanding the overlapping (shared) genetic influences and mechanisms between these diseases as well as the heterogeneous mechanisms within each disease category. Further, I use neurophysiological and neuropsychological methods to characterize functional deficits as endophenotypes of schizophrenia and bipolar disorder. The results of my work indicate that patients with schizophrenia and psychotic bipolar disorder share some neurophysiologic deficits, as reflected in brain functions relevant to the attention and inhibitory mechanisms. However, the two disorders also differ in terms of the brain’s functional echoic memory processes. My work has also indicated that a number of neurocognitive processes and brain functions are heritable traits and are strong candidates for endophenotypes for both schizophrenia and bipolar disorder. In light of this evidence, I am now translating my research into molecular genetic studies, with the aim of characterizing the functional effects of risk genetic variants for psychotic illnesses.

My overall career goal is to contribute to the understanding of how genetic variations impact the neural functions in the brain that contribute to the development of psychotic illnesses. My research focus in the next few years will therefore be to carry out translational psychiatric genetics research, combining molecular genetics and genomics, cognitive neuroscience, and bioinformatics approaches. I will genotype variants that have been most strongly associated with bipolar disorder, schizophrenia, or psychosis by GWAS and examine their associations with neurophysiologic endophenotypes to characterize their effects on specific domains of brain function. Elucidating the functional effects of disease risk variants will provide essential insights into the mechanisms by which these genes may be risk factors for disease. Her project, “Do Patterns of Deficits in Brain Function in Bipolar Disorder and Schizophrenia Support the DSM Classification?”, was an exploration of the commonalities as well as distinctions between bipolar disorder and schizophrenia.

More recently it has been established that patients with major depression exhibit over-activation of specific cortical brain areas and a lack of cortical glial cells, which serve to support neurons and modulate the communication between neural cells. The major goal my work is to recapitulate these abnormalities by preventing glial cells from processing the excitatory neurotransmitter glutamate. The hypothesis guiding this work is that decreased glial trafficking of glutamate can precipitate deleterious effects that underlie the pathophysiology of depression. Through the support of the Rappaport Foundation I have been able to demonstrate that a lack of glial cell function is sufficient to induce a depressive-like state, suggesting that a lack of glial cells in the depressed brain may indeed have a causal role in depression. In the future I hope to target the function of glial cells to develop new treatment ideas that, unlike the currently available treatments, are based in what we know is different about the depressed brain.

My major interest in this work is from a perspective of compassion. I find it tragic that so many people suffer from this painful disorder that is not well treated or understood. The support of the Rappaport Foundation has allowed me to work on improving this situation by making important contributions to the depression field that will certainly improve treatment over time. These discoveries also have important role in the advancement of my scientific career. Since beginning my Rappaport Foundation Fellowship I have been able to collect exciting data will be the basis for additional grant applications and publications, but have also been promoted and invited to influential scientific meetings. Taken together, the Rappaport Foundation is allowing me to reach my aspirations of becoming independent investigator, which will help me achieve my ultimate goal of reducing human suffering.

Researching noradrenergic modulation of synaptic plasticity in fear conditioning pathways.
Anxiety disorders, which include panic, phobias, post-traumatic stress disorder, obsessive-compulsive disorder, and generalized anxiety, are the most common mental illnesses in the U.S., with 40 million of the adult U.S. population affected. According to a study published in the Journal of Clinical Psychiatry, anxiety disorders cost the U.S. more than $42 billion a year, almost one third of the $148 billion total mental health bill for the U.S.

Fear, when expressed in atypical ways, can lead to a number of anxiety disorders and depression. It has been my goal — with the support of the Rappaport Foundation — to enhance our understanding of human mental pathology by defining the cellular and molecular mechanisms underlying learned fear. One of the fundamental questions in the study of learning in the mammalian brain is to what degree changes in synaptic strength in the neural circuit of a learned behavior is a critical mechanism for memory storage. In both humans and experimental animals, emotional memory – such as that following learned fear – critically depends on a part of the brain called the amygdala complex.

It has been suggested that fear learning is influenced by norepinephrine, a hormone released in the amygdala, such that emotionally charged events, which are associated with a norepinephrine surge, often lead to the creation of vivid memories. Using recordings from neurons in the amygdala of experimental animals, we explored some of the mechanisms that could underlie modulation of fearful memories. We found that norepinephrine suppressed inhibitory currents recorded in the amygdala. This suppression of inhibitory signals allows greater strengthening of synaptic connections, a cellular reflection of learning.

These findings suggest that norepinephrine may contribute to the formation of fear memories by altering cellular mechanisms. Understanding these mechanisms aids our ability to develop treatments for individuals afflicted with anxiety disorders.

When I made the decision to pursue a career in science it was my hope that through my research I could impact the lives of individuals afflicted with neurobiological diseases. It is with the support of the Rappaport Foundation that I am now closing in on the realization of that hope. My scientific focus has sharpened as I have become aware of the terrible impact that intense anxiety can have on individuals. With the support of the Rappaport Foundation, I am rapidly getting new and exciting results and demonstrating the feasibility of my long-term research program, which I hope will contribute to our understanding of the neurobiological basis of mental illness. This will enable me to obtain long-term independent funding from other sources, such as N.I.H., and to work toward my ultimate career goal of becoming an independent investigator by producing the data, publications, and securing the funding needed to establish my own laboratory.

The role of over-activation of the endocytic pathways in the neurodegeneration observed in Alzheimer’s Disease.
Alzheimer’s Disease (AD) is a neurodegenerative disease leading to a progressive destruction of brain cells and decline in mental function. AD affects the individual’s ability to remember, judge, learn, and carry out daily activities. It is estimated that up to 4 million people suffer from the disease, and the annual national cost of care is estimated at $50 billion. Given the debilitating effect of the disease on a personal as well as on a national level, research leading to new and effective treatments for the disease is much needed. It is my belief that each new line of research brings us closer to finding that treatment.

Two key discoveries initiated the research I’ve conducted with the help of the Rappaport Foundation. The first is that one of the earliest abnormalities in brains of individuals with AD is found in their endosomes, which are the structures that enable substances to enter cells and circulate from one structure to the other. The second discovery is that AD involves pathways that can lead to a specific form of cell death called apoptosis, the genetically programmed cell death that limits cell life span, which may be regulated through the amyloid precursor protein (APP), the source of the brain plaques that are the hallmark of AD.

I hypothesized, based on these and other findings, that the interaction between APP and APP-BP1, which is an APP binding protein, may normally play a role in endocytosis, and when APP signaling goes awry, as we hypothesize happens when genetic Alzheimer mutations of APP occur, the interaction between the two proteins leads to over-activation and sustained stimulation of the endocytic process. This over-activation could play a role in the brain changes observed in AD.

During the course of the study I was able to show ways to rescue neurons from death by changing the activity of endosomal proteins along this pathway that is activated by interaction between APP and APP-BP1. The significance of these findings is two-fold. On the one hand, it validates previous findings of endosomal abnormalities in AD as being part of the causal chain of events leading to neurodegeneration, and on the other hand, it suggests that intervening in those steps in the pathway resulting in abnormal endocytosis may positively affect the fate of neurons in the disease. I was able to show further the specificity of the pathway, by demonstrating that blocking other proteins involved in endocytosis does not inhibit the cell death.

Through further data collection and research into the causes and potential prevention of cell death, my work as a Rappaport fellow has had significant implications in terms of our understanding of the processes of neurodegeneration occurring in the disease. My work shed light on one of the missing pieces of the puzzle in AD – the connection between abnormal processes of endocytosis and signaling through the APP pathway.

Not only did my experiments yield promising results, but this fellowship enabled me, within one year, to successfully develop this new field of research in AD. In addition, as a result of the data obtained and the further hypotheses stemming from it, I am seeking further collaborations with scientists in the Boston area focusing on different aspects of AD in order to assume a more integrated approach toward research in AD. This research has given me the opportunity to broaden my scientific knowledge as well as my methodological expertise, and has motivated me to proceed and further elaborate on this particular research project.

Modulation of Emotional Circuitry with Neural Cell Engraftment
My original research project supported by the Rappaport fellowship program proposed to discretely transplant GABAergic neurons into the amygdala to study fear and anxiety. The amygdala is perhaps the most important brain region in processing these strong emotions.  When we are emotionally tense, anxious, frightened, or in a state of terror, the activity of the amygdala is increased. And when we are calm and content, the activity of the amygdala is decreased. Most psychiatric diseases have one thing in common, and that is a state of anxiety, fear, or frank horror, which may be ever-present in the patient. It is imperative then that we attempt to understand the role of the amygdala and its connections with other brain regions in the generation of fear.

One approach to learning about how the amygdala functions is to introduce specific cell types into its circuitry that alter or modulate its activity.  GABAergic neurons are responsible for providing “inhibitory tone” in the brain.  That is, the neurotransmitter, GABA, decreases the firing rate of neurons.  Medicines that reduce anxiety, like the benzodiazepines (e.g., Valium, Serax, and Ativan), do so by enhancing the effects of GABA.  Therefore, the original proposal was to attempt to decrease the activity of the amygdala in fearful states by engrafting neurons that produce the neurotransmitter, GABA.

The first challenge was to produce a suspension of cells that was rich in GABAergic neurons and then to surgically inject small volumes of this suspension into specific areas of the amygdala.  With the assistance of my students and co-workers, we were indeed able to produce viable cell suspensions rich in GABAergic neurons by dissecting and dissociating tissue from embryonic animals from an area called the lateral ganglionic eminence (LGE). The LGE is where the GABAergic neurons of the brain are originally derived. After labeling a portion of the transplanted cells with red fluorescent microspheres (FLMs) to help identify them after transplantation, we were able to engraft these cells precisely into the lateral and basolateral subregions of the amygdala using the “micrografting” technique previously developed at the Massachusetts Institute of Technology.

It was then important to determine if transplanted cells could actually survive and interact within their new environment. Twelve weeks after transplantation, an immunoreaction against GABA was used to help identify GABA-producing cells. A large numbers of transplanted GABAergic neurons survived and integrated within the host amygdala.

Further proof of survival and integration was then achieved using electron microscopy (EM).  Because the FLMs can be “photoreacted” to form an electron-dense product, transplanted cells containing FLMs can undergo elegant ultrastructural analysis with EM.

The ultimate test however, was to determine if these grafts had any effect on how the animals experienced fear and anxiety. Three models of fear and anxiety were used: the elevated plus maze, light-enhanced startle, and fear potentiated startle. These tests exploit the rat’s innate fear and avoidance of heights, open space, and light. The elevated plus maze is a model of anxiety based on animals’ uneasiness for walking onto the narrow open arms, as opposed to the enclosed arms, of a plus-shaped platform elevated 50 cm above the floor.  Animals that have received anxiolytic drugs venture onto and spend more time on the open arms of the maze. Light-enhanced startle is another model of anxiety in which an animal’s startle response is augmented if the animal receives a startle-eliciting noise in an environment that is brightly lit as opposed to darkened. Fear-potentiated startle is a model in which an animal learns to fear a neutral, “conditioned” stimulus (such as a light or tone) after it is paired with an aversive stimulus (such as mild electrical shock). The level of fear in this model is quantified by the amount of the startle response after training. Anxiolytic drugs attenuate both fear-potentiated and light-enhanced startle.

Time spent on the open arms of the elevated plus maze was greater for the grafted animals than for control animals.  Fear-potentiated startle, however, demonstrated that the grafted animals responded similarly to the control animals, suggesting that the amygdala circuitry remained intact after grafting, and animals retained the capacity to learn.  Interestingly, grafted animals demonstrated a significantly less exaggerated startle response in the presence of light.  These dramatic results strongly suggests that grafts may have the ability to attenuate anxiety, but they do not appear to interfere with the learning of threatening stimuli and responding appropriately, which might be expected if the grafts were in effect interfering with or destroying part of the amygdalar circuitry.

In conclusion, these exciting and compelling results have opened a new area of neuroscience investigation: the use of neural transplantation for the study and treatment of psychiatric disease.  This approach has been studied for decades in the context of neurologic disorders, such as Parkinson’s disease, Huntington’s disease, stroke and epilepsy.  The present studies demonstrate that such techniques and principles may indeed be applicable to debilitating diseases of perception and mood.

In 1999, Dr. Berretta became the director of the Translational Neuroscience Laboratory at McLean Hospital. Her investigations are focused on the pathophysiology of major psychoses, testing the hypothesis that extracellular matrix abnormalities may represent a core feature of the pathology of these disorders. In 2014, Dr. Berretta became the scientific director of the Harvard Brain Tissue Resource Center.