CTNA COMPONENTS

CTNA Design

The CTNA is designed to promote the translation of basic neuroscience advances into clinical neuroscience insights. Several features of the design of this Center promote this aim:

1) The CTNA encompasses critical research technologies necessary for the translational neuroscience mission. A translational research effort involves the interfacing of basic and clinical neuroscience investigators in a common aim. Thus, this Center brings basic and clinical researchers together in the evaluation of a set of hypotheses outlined above. In the current era, we believe that necessary technologies include the capacity to create and study transgenic animals, chip array technology for clinical molecular genetics, neuroreceptor imaging, magnetic resonance spectroscopy, functional magnetic resonance imaging, clinical electrophysiology, and experimental psychopharmacology. Additional research approaches are associated with the CTNA including in vivo microdialysis, and psychopharmacologic studies in rodents and primates.

2) The CTNA promotes interdisciplinary research within projects. Studies are designed to combine neurochemical, physiological, and addiction-related meaurements within studies. For example, Dr. Nestler's project bridges molecular biology, electrophysiology and behavior. The clinical studies link the biochemical measurements of PFC and NAc to functional measures (cognitive function, P300), and addiction measurements (ethanol cue reactivity and/or self-administration). Each clinical project also views the neurobiological assessments as “endophenotypes” and each one collects DNA from all subjects and, when possible, their family members, for exploratory studies.

3) The proposed basic and clinical projects provide convergent information related to the scientific theme. We believe that translational research includes, but is not limited to, conducting similar studies in animals and humans. The translational research mission requires each study to balance three objectives: a) to conduct the best possible science in each project, b) to articulate the relationship of the experimental hypotheses of a particular study to the experimental hypotheses articulated for the Center as a whole, and c) to frame the aims, design, and data interpretation of particular studies within a perspective that promotes the interplay of basic and clinical neuroscience. Thus, the CTNA has basic and clinical studies of the vulnerability to alcoholism, basic and clinical studies related to the neurobiology of ethanol reward and self-administration, and basic and clinical studies characterizing the nature of cortical dysregulation associated with ethanol dependence. Together, the whole is greater than the sum of its parts: the CTNA will aim to contribute to a synthetic new view of the role of cortico-limbic circuitry and its involvement in alcoholism.

Cores

The Administrative Core is responsible for the organizational, quality management, human subjects monitoring, ethical, educational, and data management functions. These tasks are managed by the Executive Committee (headed by Dr. Krystal), the Scientific Advisory Board (headed by Dr. C. O’Brien (UPenn), the Data Safety and Monitoring Board (headed by Dr. R. Swift (Brown), the Data Management and Biostatistics Component (headed by Peter Peduzzi Ph.D.), and the Local and Regional Education Committees (headed by Dr. Krystal).

The Molecular Core, Co-Directed by Drs. Laruelle and Nestler, supports CTNA projects that use molecular genetic tools. It has two major functions: 1) transgenic mice and viral vectors will be generated by the Core to support studies of the molecular and cellular mechanisms of alcohol action. These tools are needed to build causal bridges between the molecular, cellular, and behavioral levels of analysis; 2) DNA arraying using chip-based technologies will be made available to identify genes whose expression is regulated by alcohol in specific brain regions. It will also vastly increase the numbers of genes that can be assessed for their association with alcoholism.

The Clinical Core, directed Dr. O’Malley, provides for the centralized development of critical assessment tools, to maintain the quality and reliability of clinical assessments(both behavioral and electrophysiological), and to support and facilitate the recruitment of subjects (including family members) into clinical studies. This Core has four major components:

1) The Assessment Committee provides a mechanism for maintaining inter-rater reliability on a menu of measures from which the assessments for each study will be selected;

2) The Recruitment Committee provides a centralized mechanism to review the progress of recruitment for each study, to review recruitment techniques, to best match subjects to studies for which they are eligible, and to insure that every effort is made to recruit all subjects and their family members into the genetics studies;

3) Ligand Development: the CTNA two new ligands for neuroreceptor imaging: one targetting the 5-HT-1Bhuman receptor and one targetting the glycine-B site of the NMDA receptor; and

4) Clinical Electrophysiology: Projects involve assessment of P300 in subjects as an independent measure of the integrity of cortical networks including the PFC. These assessments will be completed within this component of this Core.

The Pilot Core, directed by Dr. Krystal, provides a mechanism to initiate small scale investigations that implement new technologies or to test important hypotheses associated with the CTNA mission. Projects proposed in the first two years will: 1) evaluate the modulatory effects of ethanol on the regulation of PFC circuitry associated with working memory in non-human primates (P. Goldman-Rakic, G. Williams); 2) evaluate the neural circuitry of P300 deficits and their association with craving utilizing standard and modified oddball paradigms including functional magnetic resonance imaging (fMRI) and event-related potentials (D. Mathalon).

In later years, projects may include: 1) evaluation of alcoholism-related disturbances in the coupling between glutamatergic neurotransmission and high energy phosphate metabolism (see (64)) by combining [13C]MRS and [31P]MRS (G. Mason, J. Krystal); 2) study of 5-HT-1Bhuman and glycine-B (site of NMDA receptor) binding in alcoholics and controls using PET (A. Abi-Dargham); 3) evaluation the role of nicotinic receptor subunit expression on the interaction of ethanol and nicotine in transgenic animals (M. Picciotto); 4) evaluation of candidate receptor targets for PET studies in post-mortem brain tissue from alcoholics and controls (V. Arrango, J. Mann).