David H. Farb, Ph.D.
Professor and Chair of Pharmacology.
Research Interests: Dr. Farb’s research focuses on the identification of pharmacological treatments for mental disorders of learning and memory. His research integrates existing electrophysiological, behavioral, pharmacological, and molecular genetic technologies in a novel systems-level platform for assessing the impact of cognitive enhancers upon fundamental hippocampal systems for pattern separation (encoding), and pattern completion (retrieval) that are believed to be essential for cognition in all mammals, including man. Deficits in aspects of episodic memory dependent on hippocampal function are evident in a variety of mental disorders that have a huge social impact, including schizophrenia, autism, Alzheimer’s Disease, and normal aging. Existing pharmacotherapies for many such conditions are limited and carry substantial risk of adverse effects. High-density electrophysiological recordings in awake behaving rats are being used to identify deficits in hippocampal function that underlie cognitive deficits exhibited by aged animals and animals reared in social isolation, the latter being a model for environmental stress during development. A multidisciplinary approach that includes the techniques of neurophysiology, molecular biology, patch-clamp electrophysiology, cell biology, and molecular neuroanatomy are combined to elucidate the mechanisms and modalities of cognitive enhancers and the discovery of therapeutic treatments for disorders or diseases of the nervous system.
Carmela Abraham, Ph.D.
Professor of Biochemistry and Pharmacology.
Research Interests: Dr. Abraham’s laboratory studies the mechanisms of normal brain aging and the etiology of Alzheimer’s disease (AD). Dr. Abraham is studying the function of the amyloid precursor protein (APP) and a novel protease involved in the degradation of the amyloid beta peptide (A-ß) in order to understand the etiology of AD and design possible treatments. Dr. Abraham’s laboratory also investigates normal human brain aging and uses the rhesus monkey as a model. Specifically, they are interested in the expression of gene products that could contribute to the destruction of myelin. They have found, using microarray analyses, that the anti-aging gene, Klotho, is downregulated in the aging brain and are now characterizing the role of Klotho and ways to elevate its expression.
J. Krzysztof Blusztajn, Ph.D.
Professor of Pathology and Laboratory Medicine
Research Interests: We study the effects of perinatal availability of an essential nutrient, choline, on brain development and aging in experimental animals. This research endeavors to determine why it is that supplementation with choline during critical perinatal periods in rats and mice causes a long-term facilitation of visuospatial memory which persists until old age. To this end we are utilizing biochemical, neuroanatomical, and behavioral techniques in a highly unified experimental design. Our studies to date have focused on the development of the basal forebrain cholinergic system, hippocampal MAPK and CREB signaling, and on the developmental patterns of brain gene expression. Recent data prompted us to test the hypothesis that the actions of choline are mediated by an epigenetic mechanism involving DNA methylation. Because choline is a donor of metabolic methyl groups its levels modulate the concentrations of cellular S?adenosylmethionine, a compound that serves as a substrate for DNA methylating enzymes. In turn, DNA methylation patterns modulate transcription of multiple genes. These methylation patterns are inherited through cell divisions, providing a possible epigenetic mechanism for modifications in brain gene expression observed many months after the dietary manipulation. Indeed, we found that prenatal availability of choline alters global DNA methylation and patterns of DNA methylation of key genes (e.g. insulin-like growth factor II, Igf2) whose expression is known to be regulated by this process. Our data are the first to indicate that choline nutrition in pregnancy alters the epigenome of the brain.
Camron D. Bryant, Ph.D.
Assistant Professor of Pharmacology and Psychiatry.
Research Interests: Dr. Bryant is the Director of the Laboratory of Addiction Genetics. Dr. Bryant’s research program is focused on determining the genetic basis of behavioral and molecular traits relevant to substance dependence in mice. The ultimate goal is to improve our understanding of the neurobiological mechanisms of addiction and to translate these findings toward treatment and prevention strategies in humans. A current focus is to determine the genetic basis of the rewarding properties of opioids in mice by combining quantitative trait locus (QTL) analysis of behavior and gene expression in genetic reference populations that yield high resolution QTLs. This multi-pronged approach to gene mapping will accelerate the nomination of candidate genes for validation via direct gene targeting. A separate focus with regard to functional characterization of candidate genes is the dissection of the hypothesized opposing roles of casein kinase-1 (CK-1) isoforms in regulating dopaminergic signaling and the motivational properties of drugs of abuse. Last, Dr. Bryant has a longstanding interest in deciphering the neurobiological basis of the “placebo effect”, a phenomenon that has been hypothesized to be mediated by the reward expectation. He plans to develop and apply a forward genetic analysis toward Pavlovian conditioning mouse models across a variety of conditions that are notoriously sensitive to the placebo effect, including pain, anxiety, depression, and Parkinson’s Disease.
Jiang-Fan Chen, M.D., Ph.D.
Associate Professor of Neurology and Pharmacology.
Research Interests: Dr. Chen’s research focuses on the neurobiology of adenosine and the A2A adenosine receptor and the role they may play in the development and treatment of neuropsychiatric disorders. Dr. Chen has developed an A2A receptor knockout mouse model and couples this genetic approach with pharmacological manipulation to explore the pathophysiological role of A2A receptors in animal and cellular models of neuropsychiatric disorders. The knowledge derived from these studies may provide the neurobiological basis for rational development of A2A receptor agents as treatment strategies for neuropsychological disorders, ranging from Parkinson’s disease to drug addiction.
Pietro Cottone, Ph.D.
Assistant Professor of Pharmacology and Psychiatry.
Research Interests: Dr. Cottone is co-director of the Laboratory of Addictive Disorders. Research interests: a focus on the neurobiological substrates of motivated behaviors including feeding and addiction. The major goal of Dr. Cottone’s research is identifying the biological bases of and potential treatments for obesity and eating disorders. Current studies concern the role of stress in compulsive eating and palatable food dependence. Areas of focused research include the investigation of the neurobiological bases of stress-related disorders such as anxiety and depression. Dr. Cottone’s studies are carried out on environmental and genetic animal models, using behavioral, biochemical, and molecular approaches.
Howard Eichenbaum, Ph.D.
Professor of Psychology and Pharmacology. Director, Center for Memory and Brain; Director, Cognitive Neurobiology Laboratory; Director, Center for Neuroscience.
Research Interests: Dr. Eichenbaum’s major research goals are elucidation of the function of the hippocampus and the functional organization of the medial temporal lobe memory system. Specific projects include: 1.) Hippocampal and cortical coding, a study to assess the functional correlates of single neuron and neuronal ensemble activity in the cortex and hippocampus of rats performing memory tasks, 2.) Hippocampal lesions or localized NMDA receptor KO and memory, projects that will characterize the roles of the hippocampus and parahippocampal region in rats and mice, 3.) The effect of aging on hippocampal behavioral physiology and memory performance in rats, 4.) A study to test the hypothesis that schizophrenia is associated with decreased function of corticolimbic NMDA receptors.
Lindsay A. Farrer, Ph.D.,
Chief, Genetics Program; Professor, Depts. of Medicine, Neurology, and Genetics and Genomics, Boston University School of Medicine and Depts. of Epidemiology and Biostatistics, Boston University School of Public Health. Dr. Farrer’s research investigates genetic risk factors in familial neurodegenerative and other chronic diseases. In collaboration with other laboratories worldwide, his group has localized genes causing rare and common disorders including Alzheimer disease (AD), age-related macular degeneration, dependence on illicit substances (cocaine, opiates, nicotine, and alcohol), complications of sickle cell disease, Wilson disease, Machado-Joseph disease, Waardenburg syndrome, asthma, and metabolic syndrome. Many of these projects are collaborative and multi disciplinary efforts aimed at linking human genetic variation to biological mechanisms and developing novel therapeutic targets.
Christopher V. Gabel, Ph.D.
Assistant Professor of Physiology & Biophysics and Pharmacology.
Research Interests: Dr. Gabel’s research program is focused on the development and application of femtosecond laser surgery and optical neurophysiology to the study of the nervous system of the nematode worm C. elegans. Using tightly focused pulses from an ultrafast laser, Dr. Gebel can ablate regions of biological tissue with submicron precision, making it possible to snip individual nerve fibers within an intact worm (Fig 1). This enables in vivo study of neural regeneration and dissection of neurocircuitry at a new level of resolution. A small transparent body, simple stereotyped nervous system and powerful genetic tools combined to make C. elegans an ideal model organism for this work. Femtosecond laser technology applied to this versatile and tractable system allows Dr. Gabel to tackle fundamental questions in neural regeneration and function.
Xue Han, Ph.D.Assistant Professor, Biomedical Engineering.
Research Interests: Brain disorders represent the biggest unmet medical need, with many disorders being untreatable, and most treatments presenting serious side effects. Accordingly, we are discovering design principles for novel neuromodulation therapies. We invent and apply a variety of genetic, molecular, pharmacological, optical, and electrical tools to correct neural circuits that go awry within the brain. As an example, we have pioneered several technologies for silencing specific cells in the brain using pulses of light. We have also recently participated the first pre-clinical testing of a novel neurotechnology, optical neural modulation. Using these novel neurotechnologies and classical ones such as deep brain stimulation (DBS), we modulate the function of neural circuits to establish causal links between neural dynamics and behavioral phenomena (e.g., movement, attention, memory, and decision making). One of our current interests is the investigation of how neural synchrony arises within and across brain regions, and how synchronous activity contributes to normal cognition and pathology.
Michael Hasselmo, Ph.D.
Professor of Psychology.
Research Interests: Dr. Hasselmo’s laboratory research concerns cortical dynamics of memory-guided behavior, including effects of neuromodulatory receptors and the role of theta rhythm oscillations in cortical memory. Neurophysiological techniques are used to analyze effects of modulators on synaptic and neuronal activity in cortical circuits in the rat, and computational modeling is used to link this physiological data to behavior. Experiments using multiple single-unit recording in behavioral tasks are designed to test predictions of the computational models. Areas of focused research include episodic memory function and theta rhythm dynamics in hippocampal formation. Research addresses physiological effects relevant to Alzheimer’s disease, schizophrenia and depression.
David A. Harris, M.D., Ph.D.
Professor and Chair of Biochemistry
Research Interests: The Harris laboratory investigates the molecular and cellular mechanisms underlying human and animal prion diseases. These fatal neurodegenerative disorders are of great public health concern because of the global emergence of bovine spongiform encephalopathy (“mad cow disease”), and its likely transmission to human beings. Prions also exemplify a novel mechanism of biological information transfer based on self-propagating changes in protein conformation, rather than on inheritance of nucleic acid sequence. Prion diseases share important similarities with a larger group of neurodegenerative disorders, including Alzheimer’s, Huntington’s and Parkinson’s diseases, that are due to protein misfolding and aggregation.
Tsuneya Ikezu, M.D., Ph.D.
Professor of Pharmacology & Therapeutics.
Research Interests: Dr. Ikezu’s laboratory is focusing on the neuroimmunological modulation of synaptic activities, neurogenesis, and cognitive function using genetically engineered mouse models of neurodegenerative disorders, such as Alzheimer’s disease. His work utilizes adeno-associated virus (AAV) gene transfer of genes of interest (such as cytokines, chemokines, and growth factors) to protect neuronal and cognitive function of disease brain in the animal models. We are also investigating the roles of tau-tubulin kinases (TTBK1 and 2) on neurocognitive disorders using novel animal models of frontotemporal dementia, and spinocerebellar ataxia type 11. Standard biochemistry, neuropathology, and behavioral tests are employed for the characterization of gene-delivered mouse models. HIV-associated neurological disorders (HAND) are an emerging epidemic in the elderly AIDS population, which involves insulin resistance, cognitive dysfunction, and beta-amyloidosis. His research focuses on development and characterization of a new mouse model for understanding the role of chronic HIV infection and anti-retroviral drugs on the progression of beta-amyloidosis and insulin resistance. Their long-range goals are therapeutic invention for the treatment of selected neurodegenerative disorders.
Kathleen Kantak, Ph.D.
Professor of Psychology
Research Interests: Dr. Kantak’s research uses animal models to conduct translational research related to drug addiction, attention deficit hyperactivity disorder and their co-morbidity. Using intravenous drug self-administration procedures in rats, she investigates how multiple memory systems regulate drug-seeking and drug-taking behavior as well as how drug exposure influences the neurocognitive functioning of multiple memory systems. In addition, she investigates how cognitive-enhancing therapeutics may be useful to facilitate extinction learning for drug-conditioned cues and attenuate drug relapse. Other studies focus on evaluating the frontostriatal and medial temporal lobe neurocognitive deficits in rats with an ADHD phenotype and their response to medications as well as comorbidity between ADHD and vulnerability to drug addiction. In the context of all this research, she collaborates with other investigators to conduct image analysis or to understand the neurochemical and molecular correlates of these disorders and their treatment.
Gary B. Kaplan, M.D.
Professor of Psychiatry and Pharmacology.
Research Interests: In addiction, cognitive and motivational brain regions are responsive to salient environmental and contextual drug cues that serve as triggers for continued vulnerability to relapse. Our research examines drug reward and craving responses to drug-associated cues and contexts in animal models. Extinction is a form of learning that can reduce the rewarding properties associated with drug cues and contexts but such learning occurs over long periods of time. Our translational research examines the neural mechanisms underlying extinction of conditioned drug reward and drug priming induced reacquisition of conditioned drug preferences. To study long term changes in synaptic plasticity in extinction of conditioned drug reward, we examine regulation of transcription factors is relevant limbic and cortical circuitry. To enhance extinction learning, we utilize translational pharmacological approaches using N-methyl-D-aspartate (NMDA) glutamate and aminobutyric acid (GABA) receptor agonists and examine behavioral and neurochemical effects of these agents. By understanding the behavioral and the neural mechanisms for enhancement of drug related reward extinction, we hope to block craving and relapse in clinical populations.
Vidhya Kumaresan, Ph.D.
Research Assistant Professor of Pharmacology.
Research Interests: Dr. Kumaresan’s overall research objective is to study neuronal activity-dependent plasticity and its relevance for brain disorders. The current focus of Dr. Kumaresan’s research is to understand the neurobiological bases of addiction to psychostimulants. Recidivism to drug abuse is a major hurdle in the successful treatment of addiction. Illicit drug use usurps neural circuits involved in survival enhancing behaviors. The goal is to elucidate the cellular and molecular underpinnings of drug-induced enduring neural plasticity in these circuits using a combination of behavioral, cellular and molecular approaches. In particular, Dr. Kumaresan employs a novel approach of using cell-permeable peptides that disrupt protein-protein interactions in vivo in order to study ongoing behavior. These approaches are expected to lead to successful treatment of relapse precipitated by drug re-exposure, drug-associated cues and stress. Knowledge gained from these studies will also be applicable to the treatment of other brain dysfunctions involving persistent memories such as PTSD.
Susan E. Leeman, Ph.D.
Professor of Pharmacology.
Research Interests: Dr. Leeman’s work focuses on the two peptides, substance P (SP) and neurotensin, which were isolated and chemically defined in her laboratory. Projects that are currently underway include: 1. the role of glycosylation of the NK1 receptor on its signal transduction pathways, 2. the roles of SP in several models of inflammation in the gastrointestinal tract, including post-surgical cell adhesion formation, and the effect of non-peptide SP antagonists. 3. the role of LITAF, a newly described transcription factor participating in TNF alpha synthesis in macrophages obtained from inflamed colonic tissue.
Jen-Wei Lin, Ph.D.
Associate Professor of Biology.
Research Interests: Dr. Lin’s research program focuses on the use of axons at the crayfish neuromuscular junction (NMJ) as a model system to study the excitability of axons. Typical axons in the mammalian brain are very thin, < 1 m in diameter, and difficult to study with microelectrodes. Since axons at the crayfish NMJ have large diameters and are mostly on the upper surface of the preparation, they provide excellent accessibility for microelectrode and imaging studies. In addition to the technical advantages, the axons exhibit a branching pattern similar to that observed in mammalian brain and could serve as a model for mammalian axons. A newly developed technique for this preparation, using a voltage indicator, enables reporting of physiological activities in fine axon branches and terminal varicosities and allows direct monitoring of action potential (AP) propagation along any point of a branching axon. The short-term goal of Dr. Lin’s research is to understand the function of the persistent sodium current (iNaP) in this branching and unmyelinated axon. The persistent sodium current has been implicated or associated with several neurological conditions. For example, in patients with multiple sclerosis, and in animal models of this disease, iNaP–like channels are increased in demyelinated internodal regions. The up regulation of iNaP channels has been speculated as the cause of neuronal death. In addition to multiple sclerosis, abnormalities of iNaP have been observed in neurological diseases, such as degenerative lower motor neuron diseases and epilepsy. Dr. Lin’s research program should be able to contribute to the understanding of the function of iNaP and to evaluate how this current might be related to the cause or consequence of these diseases. The long-term goal of Dr. Lin’s research program will be to quantitatively investigate the interaction of a constellation of ion channels in shaping axonal function.
Jennifer I. Luebke, Ph.D.
Associate Professor of Anatomy & Neurobiology
Research Interests: Dr. Luebke maintains a laboratory in which whole-cell patch-clamp and intracellular filling techniques are used to examine the electrophysiological and morphological properties of neurons in in vitro slices of monkey and transgenic mouse neocortex. Research is focused on action potential firing patterns (and underlying ionic currents), glutamatergic and GABAergic synaptic response properties and detailed dendritic architecture. Data from single neurons are incorporated into computational models in collaboration with mathematicians at Mt. Sinai School of Medicine. In addition, collaborations are ongoing with investigators at BUSM who use molecular biological (single cell PCR and microarray) and electron microscopic (ultrastructural analysis) techniques to examine cells from which recordings are obtained. Overall goals include: 1) to examine the individual and network properties of cells in the prefrontal cortex; 2) to determine the effects of normal aging on these properties in the rhesus monkey, and; 3) to determine the effects of tau and amyloid on these properties in transgenic mouse models of Alzheimer’s disease.
Hengye Man, Ph.D.
Assistant Professor of Biology
Research Interests: Dr. Man’s laboratory studies cellular/molecular mechanisms by which synaptic activity, and thus, neuronal communication is plastically regulated, specifically focusing on AMPA receptor (AMPAR) trafficking, localization and turnover. In the brain, most of the fast excitatory synaptic transmission is mediated mainly by the glutamatergic AMPARs, which are heteretetromeric glutamate-gated sodium channels composed of GluR1-4 subunits. The distribution of AMPARs is not static, but is instead very dynamic with AMPARs constantly trafficking between the plasma membrane and intracellular compartments. Surface AMPAR number is controlled via a balance between receptor insertion (exocytosis) and internalization (endocytosis). Regulation of AMPAR trafficking results in an alteration in receptor abundance at the synaptic sites, which is a major cellular means for the expression of many types of synaptic plasticity including long-term potentiation (LTP), long-term depression (LTD) and homeostatic plasticity. Currently there are four active research directions in the lab: (1) AMPAR trafficking and homeostatic plasticity at single synapses; (2) Cross-talk between glutamate receptors and the sodium pump (Na, K-ATPase); (3) Regulation of AMPAR localization and stability by glutamate transporters; (4) Regulation of neuronal morphogenesis and polarization. In our study, we use cultured rat cortical/hippocampal neurons and organotypic brain slices, and employ multiple techniques including immunocytochemistry, live imaging, biochemistry, molecular biology and electrophysiology.
Wendy W. Qiu, M.D., Ph.D.
Associate Professor of Psychiatry and Pharmacology.
Research Interests: Dr. Qiu is a board-certified psychiatrist who conducts research on the pathogenesis, risk factors, and behavioral manifestations of Alzheimer’s disease (AD). Multiple studies have shown that type 2 diabetes, another common disease in the elderly, and hyperinsulinemia increase the risk of AD. She identified the role of insulin-degrading enzyme (IDE) in the clearance of amyloid beta peptides (Aβ), components of deposits in brains of AD patients. Her team is using both human and animal studies to investigate whether insulin competes with Aβ for IDE activity and therefore accelerates AD pathology. Recently she and her research team have defined a possible depression subtype as a prodromal stage of AD. Dr. Qiu’s team proposes that late life depression can serve both as a risk factor and a prodromal stage of AD. They are using biomarkers, especially Aβ peptides in blood and cerebral spinal fluid, to identify this prodromal depression of AD. As aggression/agitation is one of the principal precipitants of institutionalization for Alzheimer’s patients, another of Dr. Qiu’s research interests is the development of novel strategies for intervention of this behavioral problem of the disease.
Douglas L. Rosene, Ph.D.
Professor of Anatomy and Neurobiology.
Research Interests: Dr. Rosene’s research interests center on identifying the neurobiological basis of normal learning and memory and related cognitive functions in the normal brain and the disruption of these processes in neurodegenerative diseases, localized neurological damage such as stroke and by stressors such as malnutrition. To accomplish this, multidisciplinary studies of animal models use combinations of behavioral, neurohistochemical, neurophysiological and neuroanatomical techniques to study these cognitive functions. Studies use the rhesus monkey as a model of normal aging, of cerebrovascular disease and neurological damage as well as a rat model of prenatal malnutrition.
Shelley J. Russek, Ph.D.
Professor of Pharmacology, Director, Graduate Program for Neuroscience.
Research Interests: Dr. Russek is interested in the genetic switches that regulate the development of the brain and its response to injury or disease. Current research in her laboratory focuses on the role of the GABA-A receptor system in epilepsy, autism and depression where a change in the number or kind of receptors at synaptic and extrasynaptic sites can disturb processes critical for healthy neurotransmission. Research in the laboratory tests the relationship between gene regulatory events such as those stimulated by brain derived neurotrophic factor (BDNF) and brain inhibition, combining genomics and proteomics with animal models of disease via pharmacological and biological techniques such as chromatin immunoprecipitation (ChIP), single cell promoter/reporter analysis, laser-capture microdissection for microgenomics, electroporation of mouse embryos and viral gene delivery in vivo to develop the foundations for future genetic therapies and as a basis for understanding disease etiology.
Valentina Sabino, Ph.D.,
Assistant Professor of Pharmacology and Psychiatry.
Dr. Sabino is co-director of the Laboratory of Addictive Disorders. Dr. Sabino is currently researching the neurobiology of addiction and stress-related disorders. Studies on addiction aim to understand the neurobiological substrates of alcohol abuse and dependence, by exploring the role of central neurochemical systems in excessive alcohol drinking. She is working toward the development of new therapeutic agents to alleviate alcohol addiction. Animal models for excessive drinking are studied in order to identify compounds for potential clinical development. Research is also conducted on the neurobiology of stress-related disorders such as anxiety and depression. The laboratory uses environmental and genetic animal models of disease, with a multidisciplinary approach to understand the neurobiology of psychiatric disorders and to develop novel therapies.
Jean-Jacques Soghomonian, Ph.D.
Associate Professor of Anatomy and Neurobiology.
Research Interests: The laboratory focuses on the functional neuroanatomy of the basal ganglia and the neurobiological basis of motor control, sensori-motor integration, and learning. His particular interest is the mechanisms of regulation of GABAergic neurons in the basal ganglia in the normal brain and in experimental models of Parkinson’s disease and the neuronal basis of l-DOPA-induced dyskinesias. Techniques include microdialysis, quantitative in situ hybridization histochemistry, immunohistochemistry, quantitative computerized image analysis and assessment of behavioral activity.
Benjamin Wolozin, M.D., Ph.D.
Professor of Pharmacology and Neurology.
Research Interests: Dr. Wolozin’s research investigates the pathophysiology of neurodegenerative diseases. Research on Parkinson’s Disease focuses on the interaction between genetic factors implicated in this disease and environmental factors. His studies utilize cell culture, mammalian brain slice culture and transgenic lines of C. elegans, and results are then investigated further in transgenic/knockout mice and in human brain samples or cell lines from patients. His projects are also focused on identifying pharmacological strategies for Parkinson’s disease. The research on Alzheimer’s disease focuses on the interaction between the proteins that produce beta-amyloid and the genes that regulate cholesterol metabolism. Finally, Dr. Wolozin has an active epidemiological research program that examines the effects of FDA-approved medications on the incidence and progression of both Alzheimer’s and Parkinson’s disease.