Helen E. Scharfman - US grants

One of the most technically challenging goals in neurophysiology is characterization of interneurons that typically exist in the mammalian brain with a sufficiently low density that there is only a very low probability of a successful intracellular recording. Even when successful, the duration of an intracellular recording from an interneuron can be very short; thus, the limited data from such recordings is particularly valuable. Dr. Helen Scharfman is one of only a few investigators in the world who has successfully developed techniques for recording intracellularly from principal (i.e., projection) neurons and interneurons of the hippocampus simultaneously. Because of the technical difficulties alluded to above, however, there are many instances in which simultaneous recordings are interrupted before electrical stimulation or intracellular filling (with dyes or other markers) can be completed which allow conclusive identification of the functional relation between the neuron pair being investigated. We are working with Dr. Scharfman to investigate the possibility that additional information can be extracted from the data successfully collected and that now is typically not used, e.g., spontaneous membrane potential fluctuations and action potential events that may contain information as to the synaptic connections between the two neurons. Both traditional cross-correlation approaches and analysis of coherence in activity of the neurons pairs is being explored. Dr. Scharfman's work on this project is supported by the NINIDS (to HES).

DESCRIPTION (Adapted from applicant's abstract): The New York Academy of Science is sponsoring a conference entitled: "The Parahippocampal Region: Basic Science and Clinical Implications" in Washington, D.C. in September, 1999. The principal investigator and chair is Helen Scharfman, Ph.D., Department Head, Neurology Research Center, Helen Hayes Hospital and Assistant Professor, Departments of Pharmacology and Neurology, Columbia University. The cochairs are Menno Witter PhD., Professor, Department of Anatomy, Vrije Universiteit, The Netherlands and Robert Schwarcz, Ph.D., Head, Neuroscience Program, Maryland Psychiatric Research Center, and Professor, Departments of Psychiatry and Pharmacology, University of Maryland. Several structures in the temporal lobe play a critical role in brain functions, such as learning and memory, emotions, and complex behavioral processes. These include the hippocampus, the most frequently studied structure in the temporal lobe, and the juxtaposed parahippocampal region, which is comprised of the entorhinal cortex, perirhinal, and parahippocampal cortex. During the last decade, it has become increasingly clear that pathological changes in the parahippocampal region occur during the early stages of several catastrophic neurological and psychiatric diseases, such as Alzheimer's disease, schizophrenia, and epilepsy. Thus, it is quite likely that parahippocampal neuropathology contributes to dysfunction in these, and perhaps other brain disorders. Notably, pathology in the parahippocampal region may be a critical element of several of these diseases, regardless of the state of the hippocampus proper. This meeting is intended to integrate past studies with the latest information about the structure and function of the parahippocampal region. A recurrent theme will be the use of this information to advance the diagnosis and treatment of debilitating brain disorders. Anatomical, biochemical, physiological, behavioral, and pathological studies in both laboratory animals and humans will be described by the leaders in the field, and will provide a comprehensive, up-to-date review of this important part of the brain. The presentations will be targeted to a wide range of basic and clinical researchers and to clinical practitioners. Special emphasis will be placed on attracting women and minorities, and on including individuals at a wide range of educational levels. Such a diverse audience will provide optimal opportunities for cross-fertilization of ideas, and thus ensure a dynamic and stimulating atmosphere, in which exciting new concepts and hypotheses can be generated.

? DESCRIPTION (provided by applicant): One of the outstanding problems in temporal lobe epilepsy is to understand the mechanisms contributing to treatment-resistant seizures that involve the hippocampus, and then to design mechanism-based novel therapeutic approaches. Such treatments are important both to control intractable seizures and to ameliorate the hippocampal-dependent memory deficits associated with epilepsy. This project will challenge current dogma that focuses on the role of neurons in the three major regions of the hippocampus: dentate gyrus, CA3 and CA1. Instead, this proposal focuses on area CA2, a relatively small region of hippocampus that has received little attention but is known to survive relatively intact in epileptic patients and may serve as a hyperexcitable seizure focus. Experimental tools developed in the laboratories of the two Principal Investigators now enable the direct investigation of the importance of CA2 in mouse models of epilepsy by employing a mouse line that selectively expresses the bacterial enzyme Cre recombinase only in CA2 neurons. Viral vectors that express tetanus toxin (or other proteins that can silence neural activity) in the presence of Cre will be injected into the hippocampus of these mice to turn off CA2 activity. In this manner it will be possible to test whether CA2 controls the pharmacological induction of seizures in the healthy brain and/or spontaneous seizures in the diseased, epileptic brain. The methods alone will advance the field because they are novel and provide more specificity and control than has been previously possible in epilepsy research. Moreover, by evaluating the role of CA2 in epilepsy, this project will result in the potential validation of sevral novel drug targets highly enriched in CA2 neurons.

Project Summary This training grant application proposes the centralization of training postdoctoral candidates interested in a career in brain aging and neurodegenerative disease at NYU Langone Medical Center (NYULMC). There is a critical need to train the next generation of MD and PhD researchers to investigate causes of disorders of brain aging, develop new therapeutics and interventions, and translate these findings from bench to bedside as well as from bedside to community. This application is designed to select four outstanding postdoctoral trainees from a well qualified pool of MD and PhD applicants, develop and implement a comprehensive curriculum and provide 2-years of high quality research training in basic, translational, clinical, and psychosocial research. This Training Program, centered in the Center for Cognitive Neurology (CCN), a school-wide, extradepartmental, multidisciplinary program designed to foster collaborative, translational research. The CCN will serve as the unifying umbrella under which this program will be implemented, sustained and financially supported while providing the infrastructure to guarantee success and supplying the trainees a ?sense of community? and a home-base within NYULMC. The future demand for highly skilled investigators with a proven track-record examining brain aging and neurodegenerative diseases will be substantial as aging-related neurodegenerative disorders continue to increase with an aging population. The training of the next generation of research scientists and research clinicians with expertise in these diseases is and will remain a public health priority in the United States for many years to come. The Institute on Medicine recognized the dearth of junior investigators and clinicians with expertise in geriatrics and gerontology. To date, these calls for increased entrance into aging investigation have been left unanswered. Thus, a strong and compelling rationale exists to consolidate and expand the research-training program for brain aging and neurodegenerative disorders through the support of a T32 training program. To do this we propose the following Specific Aims: 1. Develop research training opportunities for postdoctoral candidates in the area of brain aging and neurodegenerative disease; 2. Educate trainees to fundamentals of brain aging and neurodegenerative disease, rigorous research methodology, clinical approaches, statistical analyses, and the principles of responsible conduct of research.; 3. Provide an interactive, collaborative environment fostering personal and professional growth for clinical, psychosocial, translational and basic science trainees.; and 4. Enhance trainees' requisite skills to gain external funding in the form of K- and R- awards.

PROJECT ABSTRACT A key challenge in temporal lobe epilepsy (TLE) is to determine the neural mechanisms contributing to seizures because current drugs fail to treat all seizures and usually come with debilitating side effects. Moreover, current drugs do not treat alterations in social behavior often manifest by individuals with epilepsy, including increased social aggression. This project will challenge current dogma as to the pathophysiological bases of how the hippocampus contributes to seizures in TLE, which has focused on three major regions of the hippocampus: dentate gyrus, CA3 and CA1. Instead, we examine area CA2, a relatively small region of hippocampus that has received little attention but is known to survive relatively intact in TLE patients and rodent models, and may serve as a seizure focus or facilitate seizure propagation. Experimental tools developed in the laboratories of the two Principal Investigators now enable the direct investigation of the importance of CA2 in mouse TLE models by employing a mouse line that expresses Cre recombinase relatively selectively in CA2 principal neurons. Cre-dependent viral vectors will be used to express genetically encoded tools in CA2 principal neurons to examine both alterations in CA2 circuitry in TLE and the effects of CA2 acute or chronic silencing on seizures. Thus, we will determine whether CA2 controls the pharmacological induction of acute seizures in the healthy brain and/or chronic seizures in the epileptic brain. We will also determine the importance of CA2 in reported deficits in social cognition and social aggression in mouse models of acquired TLE, as we find that CA2 is required for social recognition memory and is implicated in social aggression. As the social hormone arginine vasopressin promotes social memory and social aggression by enhancing CA2 input and output, and has been shown to regulate seizures in animals, we will examine the role of CA2 regulation by this hormone on social behavioral alterations in epileptic mice. By evaluating the role of CA2 in epilepsy, this project offers the promise of providing both basic mechanistic insight into seizures and social behavioral comorbidity, and may validate novel drug targets highly enriched in CA2 neurons.