RESEARCH OVERVIEW 2005

Mailman Research Center

Behavioral Genetics Laboratory

William Carlezon, Ph.D., Director

Pre-clinical studies conducted by researchers in the Behavioral Genetics Laboratory in collaboration with scientists in the Laboratory of Developmental Neuropharmacology have shown that early exposure to Ritalin, which is prescribed for attention disorders, can reduce the psychological 'reward' effects of cocaine (a potentially beneficial effect), but can also lead to depression-like symptoms later on in adult life. Their research postulates that it is not Ritalin per se that causes the effect, but rather early exposure to stimulant drugs may affect the way that neuronal connections become hardwired during development.

ithe lab has also obtained additional evidence that drugs which block the actions of dynorphin, a opiate-like chemical normally made in the brain, produce antidepressant effects in animal models. Although the studies are still at an early stage, these findings raise the possibility that drugs that work through this mechanism may represent a fundamentally new approach to the treatment of depression and related disorders.

Bio-Organic and and Natural Products Research Laboratory

Dr. David Y-W Lee, Director

Key Personnel: Dr. Liu Yan-Ze, Dr. Ma Zhong-Ze, Dr. K. Leelakrishna, Dr. Ji Xiaoshen, Dr. Zhao Fengyu, Dr. He Minsheng

Researchers in the Bio-Organic and Natural Products Laboratory are working on the synthesis and evaluation of analogs of 3α, 5α-THP, a naturally occurring metabolite of progesterone that acts on the GABAA receptor in the brain. The GABAA receptor is one of the important neurological sites thought to be responsible for alcohol craving, drug abuse, and depression. Unfortunately, naturally occurring 3α, 5α-THP has therapeutic limitations because it is rapidly metabolized and thus rendered inactive. A great deal of effort is being directed toward development of a longer-acting, synthetic version of this neurosteroid as a potential pharmacotherapy to reduce the craving for alcohol, and early results appear quite promising.

Cellular Neurobiology Laboratory

Vadim Bolshakov, Ph.D., Director
Evgeny Tsvetkov, Ph.D., Research Fellow
Sodikjon Kodirov, Ph.D., Instructor
Ryong-Moon Shin, M.D., Ph.D., Research Fellow
Keith Tully, Ph.D., Research Fellow
Jason Neal, Graduate Student
Dawn Morrissey, Laboratory Assistant

Fear-conditioning is one of the most powerful paradigms in modern behavioral neuroscience and psychology. Alterations in fear-conditioning are thought to underlie such common psychiatric illnesses as post-traumatic stress disorder, generalized anxiety disorder and panic disorder. Investigators in the MRC’s Cellular Neurobiology Laboratory have shown that spike timing-dependent plasticity, which can be induced by precise temporal associations between presynaptic input and postsynaptic action potentials at the convergent thalamic and cortical pathways, is input-specific. The input specificity is determined by the differential inhibitory control of synaptic transmission in these two inputs. This finding explains how spatial specificity of the information flow contributing to the conditioned stimulus recognition is determined in fear conditioning pathways. This discovery could lead to a better understanding of a variety of the debilitating illnesses, from post traumatic stress disorder to anxiety.

Laboratory for Computational Neuroscience

Director: Peter Siekmeier MS, MD

The Laboratory for Computational Neuroscience at McLean is defined not by any particular disease or brain area, but by an approach to neuropsychiatric inquiry: the use of highly biologically realistic simulations to provide information about the emergent behaviors of a large number of neurons working together, with the goal of revealing how lesions or interventions at a cellular level can affect the system-level behavior of a brain region, or ultimately clinical behavior. Its orientation is multi-disciplinary, drawing on the skills of neuroanatomists, neurophysiologists, psychopharmacologists, psychologists, and psychiatrists as well as researchers expert in mathematics, statistics, and computer science. A guiding principle of the LCN is that a “systems biology” approach—one that emphasizes understanding a living thing via the interaction of the functioning of its components, rather than in-depth study according to any one scientific discipline—is particularly useful, if not necessary, in psychiatric research.

Two examples of substantive areas of research for the LCN are as follows:

Schizophrenia. While research on the biological basis of schizophrenia over the past 30-40 years has identified a large number of potential neuroanatomic and biochemical abnormalities, it is still not clear how these findings, alone or in combination, give rise to the clinical syndrome. Using a computational model of hippocampus that we have developed, we are conducting “virtual experiments” investigating the manner in which abnormalities in the GABA, glutamate, and dopamine systems, alone or in combination, may underlie the symptoms of the illness. This promises to shed light on the cellular etiology of the disease.
Drug development. Traditionally, researchers in the area of drug development have tended to emphasize the isolation of one or two receptor “targets” in the effort to identify effective agents. Given that this is based on a somewhat reductionistic view of the nervous system, it is not surprising that drugs discovered in this way proved to be at best partially effective and at worst ineffective. In as much as neuropsychiatric drugs likely exert their effects through a constellation of actions, a systems biology approach could be instrumental in identifying more effective agents. Using the power of neurocomputational modeling to reveal the non-obvious system-level implications of cellular and sub-cellular changes and to analyze a large number of such things simultaneously, we have described a methodology to use computational models to identify more efficacious medications for neuropsychiatric illness; patents on this process are pending.

Laboratory of Developmental Neuropharmacology

Susan L. Andersen, Ph.D., Department Head
Lee Napierata, Research Associate

Studies conducted in the Laboratory of Developmental Neuropharmacology demonstrated age-related changes in the brain during the transition between childhood and adolescence that are disrupted by early life insults in the form of stress or stimulants. This year we provide evidence that a delay occurs in the normal age-related loss of synaptic connections in the memory-related area of the hippocampus following exposure to early life stress. The loss in synaptic density continues to decline into adulthood. This delayed loss of synapses may explain why the effects of child abuse on neuroanatomy do not appear until adulthood and why stress may be a major precipitating factor in the onset of schizophrenia during young adulthood. In collaboration with the Developmental Biopsychiatry Research Program, we have also shown that child neglect significantly reduces the size of the corpus callosum, a brain region that connects the right and left hemisphere, in children with an abuse history relative to psychiatric and normal controls.

We have also demonstrated the presence of important regulatory processes that are present in the cortex of normal preadolescent animals and subsequently lost with maturation. This functional "pruning" allows increased dopaminergic activity in the cortex during a time when cognitive processes are coming on-line and reaching an adult state. In separate, but collaborative studies with researchers in the MGH-NMR Center at MGH, we have shown that these regulatory "autoreceptors" can be visualized with the non-invasive technique of pharmacologicMRI. This approach may permit functional assessment in such activity in humans in the near future.

Ongoing studies on the effects of childhood stimulant exposure on brain development suggest that pharmacokinetics play a minimal role in the age-related differences of methylphenidate (Ritalin TM) exposure, reaffirming hypotheses that a sensitive period in brain development is vital to altered behavioral responses. In addition, a reorganization in the responsiveness of the cortex to methylphenidate challenge is observable in cerebral blood volume measures (in collaboration with MGH-NMR Center at MGH) that increases with maturation. These data suggest that pre-adolescent exposure to methylphenidate may help children with ADHD increase hypofunctional cortical activity that is believed to underlie symptoms of inattention and impulsivity.

Finally, in collaboration with the Behavioral Genetics Laboratory, data in juvenile-exposed rats suggest a reduction in the rewarding properties of stimulant challenge later in life and an increase in anhedonia.

Laboratory for Functional Neuroanatomy

Dost Ongur, M.D., Ph.D., and his colleagues study anatomical and molecular abnormalities in the brains of patients with schizophrenia and bipolar disorder. The focus of the laboratory is on cellular and molecular changes of the hippocampus, a brain region implicated in the pathogenesis of psychotic symptoms as well as cognitive deficits.

Genetics Laboratory

Dennis K. Kinney, Ph..D., Director
Sherry L. Anders, Ph.D., Research Fellow
Ruth L. Richards, M.D., Ph.D., Consultant
Sharon J. Tramer, Supervising Clinical Research Technologist

A new study conducted by the Genetics Laboratory has found that risk for schizophrenia is significantly increased among persons who were in utero when their mothers were exposed to the stress of severe hurricanes - confirming our earlier research findings that risk for schizophrenia was increased by exposure during vulnerable weeks of gestation to either a severe tornado or extreme temperatures. In complementary research, we have found that risk for autism is also increased by prenatal exposure to severe storms during these same vulnerable weeks of gestation; a new grant will make it possible to investigate whether this finding on autism can be replicated when the effects of other natural disasters are examined. Research conducted in collaboration with investigators in the Psychology Laboratory indicates that these prenatal factors are independent of established genetic risk factors for schizophrenia. This research supports a “two-factor” model in which pre- or perinatal environmental stressors often interact with genetic risk factors to produce schizophrenia.

Harvard Brain Tissue Resource Center

Francine Benes, M.D., Ph.D., Director

The Harvard Brain Tissue Resource Center is supported by federal funding, and a special supplemental grant recently awarded is being used to launch the National Databank, an international repository for postmortem findings from studies of psychotic disorders, such as schizophrenia and bipolar disorder, and neurodegenerative disorders such as Huntington's chorea, Parkinson's disease and Alzheimer's dementia.

All of the data will be in the public domain and available to all investigators, allowing them unprecedented access to data from many different laboratories and technologies. The National Databank is a novel entity that will make it possible to perform the extraordinarily complex analyses necessary to identify genes of interest in neuropsychiatric disorders.

Laboratory of Molecular and Developmental Neurobiology

Dona Lee Wong, Ph.D., Director

Key Personnel:
Sally Seraphin, Ph.D. Postdoctoral Fellow
Robert Claycomb, B.S., Research Assistant
Linda Don, Administrative Secretary

Investigators in the Mailman Research Center's Molecular and Developmental Neurobiology Laboratory are using animal and cell culture models to study how stress leads to over-expression of adrenaline. These models help to identify changes that different types of stress cause in nerve cells, leading to increases in PNMT (the protein producing adrenaline) and adrenaline itself. Adrenaline, by activating specific brain receptors, appears to regulate other neurotransmitter systems that have been associated with mental illness and also controls cardiovascular systems, whose dysfunction may occur concurrent with illness. Stress is also linked to nicotine addiction and increased incidence of smoking in patients. Research, such as this, may permit the design of new therapies to treat neuropsychiatric disorders by altering the adverse effects of over-expression of the body’s chemical signals.

Molecular Neurobiology Laboratory

Kwang-Soo Kim, Ph.D., Director

Researchers in the Molecular Neurobiology Laboratory are working on the development of novel therapies for disorders associated with dysfunction of dopamine neurons in the brain, such as Parkinson's disease. They have genetically engineered mouse embryonic stem cells and found that these cells differentiate into dopamine cells very efficiently. These genetically modified mouse stem cells are being tested in transplantation experiments using animal models of Parkinson's disease.

Molecular Neurogenetics Laboratory

Rachael L. Neve, Ph.D., Director

Key Personnel: Donna L. McPhie, Ph.D., Daphna Laifenfeld, Ph.D.

The Molecular Neurogenetics Laboratory have developed a model for Alzheimer's disease (AD) that we term "Alzheimer's disease in a dish" We have used this model to show that familial AD (FAD) mutants of the amyloid precursor protein (APP), which invariably cause AD in individuals possessing this mutation, causes nerve cells to try and divide, after which they die This leads to a new way of viewing AD, in which the illness looks like cancer: the difference is that rather than cells proliferating as in cancer, nerve cells die because they cannot divide.

Molecular Neuropathology Laboratory

Anne Cataldo, Ph.D., Director

Alzheimer's disease (AD) ends in damage to much of the brain, but the disease process starts decades earlier in individual nerve cells. Researchers in the Molecular Neuropathology Laboratory have found that in brain cells, the presence of unusually large compartments which process proteins (including a protein fragment called Aβ that accumulates in the brains of AD patients) are one of the first signs of AD. This cellular pathology is aggravated by dietary cholesterol which may accelerate disease progression. Continuing studies will focus on the development of these abnormal nerve cell compartments and their relationship with Aβ and AD risk factors such as cholesterol. Research such as this could lead to novel methods for the detection of these early changes in the brain and, ultimately, strategies for therapeutic intervention.

Molecular Pharmacology Laboratory

Bruce M. Cohen, M.D., Ph.D., Director
Cecile Beguin, Ph.D.
Jianyi Ma, Ph.D.
Michele Richards, M.S.
Nancy Ye, M.S.

Scientists in the Molecular Pharmacology Laboratory have discovered that all known antipsychotic drugs change the activity of cells which release the neurotransmitters GABA and dynorphin to signal other nerve cells. The results suggest that agents which work directly at receptors for GABA and dynorphin such as the so-called kappa receptor may be better, more effective, treatments for disorders such as schizophrenia. Agents to target this receptor are under development in collaboration with the Behavioral Genetics Laboratory.

Neuropharmacology Laboratory

Ross J. Baldessarini, MD, DSc (hon), Director
Kehong Zhang, MD, PhD., Associate Laboratory Director:

The Neuropharmacology Laboratory/Psychopharmacology Program continued its long-standing program of experimental studies on the neuropharmacology of dopamine (DA) and other neurotransmitter receptors and transporters in mammalian brain, as well as collaborative clinical investigations with McLean clinical investigators and external collaborators, concerning the biology and pharmacological treatment of psychotic, bipolar and major depressive disorders, as well as maintaining responsibility for the main McLean Hospital teaching and consultation programs in clinical psychopharmacology. This year also marked the establishment of a new and independent Psychiatric Neuroscience Laboratory, directed by Frank Tarazi, PhD, who continues as a principal collaborator with the Neuropharmacology Laboratory.

Laboratory of Neuroplasticity

Christine Konradi, Ph.D., Director

Key personnel: Yolanda Black, Ph.D., John Levine, M.D., Matthew MacDonald, BS, Melissa Chu, BA, Fair MacLaren, BA

The Laboratory of Neuroplasticity is working to elucidate how neuropsychiatric disorders and psychotropic agents affect the molecular composition of the brain. We study gene expression in the cells of the central nervous system. The amount and types of genes expressed is important for the structure and function of the brain, and has a direct bearing on normal and abnormal behavior. Recently, we found that genes involved in energy regulation in the brain are expressed at a lower level in bipolar disorder. These genes contribute to two major sources of energy generation in the brain: mitochondrial respiration and phosphocreatine metabolism. We have examined these genes in two brain areas, the hippocampus and the prefrontal cortex, and found their expression to be reduced in both areas. In collaboration with the Schizophrenia and Bipolar Disorder Program we are currently testing these genes for their ability to serve as markers for Bipolar Disorder. Such markers could be measured in blood samples.

Center for Neuroregeneration Research / Neuroregeneration Laboratories

Ole Isacson, Dr. Med. Sc., Director

Other laboratory staff: Rosario Sanchez-Pernaute, M.D., Ph.D., Anna-Liisa Brownell, Ph.D., Craig van Horne, M.D., Ph.D., Kai Sonntag, M.D., Ph.D., Rosario Hyemyung Seo, Ph.D., Travis Tierney, M.D., Ph.D., Chee Yeun Chung, Ph.D., Eva Hedlund, Ph.D., Ling Lin, M.D., Ph.D., Haruhisa Inoue, M.D., Ph.D., Angel Vinuela, M.D., Ph.D., Jan Pruszak, M.D., Takahito Yoshizaki, M.D., Ph.D., Jack McDowell, Therese Andersson, Gabriella Brunlid, Joris van Arensbergen, Dorothy Kester, Jennifer Pagel, Sandra Pohlman, Apolo Ndyabahika

Scientists in the Neuroregeneration Laboratories have shown that primate and even human embryonic stem cells can become dopamine nerve cells capable of restoring lost function in animal models of Parkinson’s disease. Molecules that regulate cell differentiation, function and growth of neuronal connections in the brain have also been discovered by this group.

Researchers in the program also use disease models and neuroprotective approaches to reduce the speed of progression of neurodegenerative disorders, such as Alzheimer’s, Huntington’s, Amyotrophic Lateral Sclerosis and Parkinson’s diseases. Recently, these scientists have shown that neurotrophic factors and anti-inflammatory drugs can halt the progression of Parkinson’s disease. Moreover, in a highly publicized paper (Seo et al. 2004) these scientists revealed a new concept by demonstrating that the mutated protein in Huntington’s disease has effects throughout the body’s cellular system -- but causes pathology in only a few select groups of neurons. These insights may lead to new methods and substances to bolster resistance to brain disease.

Psychiatric Neuroscience Laboratory

Frank I. Tarazi, PhD, MSc, Director

Co-Investigators, Staff, & Trainees: Rita Burke, AB; Christopher Grady , AB; Nora S. Kula, MS; Carla Massari, AB; Taylor Moran-Gates, AB; Young-Shik Park, PhD

The newly established Psychiatric Neuroscience Laboratory conducted several experimental studies aimed at better understanding of the neurobiology and pathophysiology of neurpsychiatric disorders and their improved treatment. This has been accomplished through close collaborations with colleagues in Neuropharmacology Laboratory and others in Mailman Research Center, as well as with external collaborators from other academic institutions and pharmaceutical companies in the USA and worldwide.

Studies led by Dr. Tarazi, Taylor Moran-Gates and Chris Grady examined acute effects of multiple doses of amphetamine (0.3, 1 and 3 mg/kg) on locomotor activity in juvenile vs. adult animals. A dose of 1 mg/kg of amphetamine was sufficient to induce significant and sustained levels of motor stimulation in adult animals throughout the period of behavioral testing. In contrast, a higher dose of amphetamine (3 mg/kg) was required to achieve similar sustained increases in motor activity in juvenile animals. These findings suggest that there are metabolic and pharmacodynamic differences between juvenile and adult animals that may contribute to the observed functional dose differences in amphetamine-induced locomotor activity in juvenile vs. adult animals.

Laboratory Of Psychiatric and Molecular Neuroscience

Joseph Coyle, M.D., Director

Investigators in the Laboratory of Psychiatric and Molecular Neuroscience have discovered that an enzyme which regulates an important neurotransmitter, glutamate, is less active in critical brain regions of patients with schizophrenia. They are using recombinant DNA methods to create mice with altered expression of processes that regulate glutamate receptors in the brain. The studies will aid in developing more effective treatments for schizophrenia and related psychotic disorders.

Psychology Research Laboratory

Deborah L. Levy, Ph.D., Director

During this past year the Psychology Research Laboratory has continued to work on the pathophysiology and genetics of schizophrenia. The specific topics under study include thought disorder, eye tracking dysfunction, working memory, relational memory and hippocampal function, lexical access and craniofacial dysmorphology. The lab is pleased to have received NIMH funding for their study, Pleiotropic Effects of Genes Linked to Schizophrenia, which will allow them to undertake linkage studies of endophenotypes that have been characterized in this laboratory.

Statistical Neuroimaging Laboratory

Nick Lange, D.Sci, Director

Researchers in the Statistical Neuroimaging Laboratory are acting as the analytic center for a worldwide collaborative project documenting developmental changes in the healthy human brain, from newborn through 18 years of age. Neuroimaging techniques will be employed to measure changes in brain structure and chemistry, and to map changes in nerve cell connections as the brain grows. Psychological tests administered concurrently with the imaging will uncover possible behavioral and neuroanatomical correlates of brain development. The goal of the study is to produce an atlas of pediatric brain development more complex than, but in some ways similar to, growth curves for childhood height and weight.

Program for Structural and Molecular Neuroscience

Francine M. Benes, M.D., Ph.D., Director

Researchers in the Program for Structural and Molecular Neuroscience, using a 'partial' rodent model of schizophrenia, have discovered that neural connections running from the amygdala are capable of inducing complex changes in gene expression in the hippocampus. The changes in gene expression seen in the hippocampus in response to amygdalar stimulation are remarkably similar to those seen in schizophrenia and bipolar disorder. These findings provide support for the idea that an important limbic circuit is probably playing a central role in psychotic disorders. Additionally, these experiments are also pointing to the importance of certain genes that heretofore were not thought to play a role in schizophrenia and bipolar disorder.

Laboratory for Translational Neuroscience

Sabina Berretta, M.D., Director

Key personnel:
Harry Pantazopoulos, Research Assistant
Ying Liu, Research Assistant
Linda Hassinger, Research Specialist

Researchers in the Translational Neuroscience Laboratory use postmortem investigations and animal models to study the pathophysiology of schizophrenia and bipolar disorder. The hypothesis being tested is that the clinical manifestations of these diseases arise from an array of pathological changes affecting, in a related manner, several interconnected brain regions involved in the processing of emotions. Recent findings from this laboratory point at intriguing patterns of abnormalities affecting the amygdala and entorhinal cortex. As an example, a distinct distribution of changes relative to specific subpopulations of intrinsic neurons within these limbic regions was found in each of these diseases. Animal modeling studies currently in progress in this laboratory indicate that such changes may be the result of a disruption of inhibitory transmission in the cingulate gyrus, such as it has been shown in major psychotic illnesses. By increasing our knowledge on the specific pathophysiological mechanisms at the basis of schizophrenia and bipolar disorder, researchers in this laboratory hope to contribute to a deeper understanding of these diseases and to the improvement of medical treatment.

Visual Psychophysiology Laboratory

Yue Chen, Ph.D., Director

Key Personnel:
Daniel Norton, B.A, Research Assistant

Researchers in the Visual Psychophysiology Laboratory are conducting a series of studies on the functional organization of visual processing in schizophrenia. Studies on face detection found that schizophrenia patients are deficient in detecting primitive face images that include only basic facial components, but not other cues such as gender, age or race. The results suggest that impaired social functions (such as recognition of emotions) in schizophrenia may stem from inefficient sensory processing of facial information. Other ongoing studies explored spatial and temporal interactions of visual motion processing in schizophrenia. The goal of these studies is to use the visual system as a model to increase our understanding of the pathophysiological mechanisms underlying major psychiatric disorders and to accelerate the development of neurobiologically based intervention strategies.