Educational Programs:

Few programs provide trainees with a well-structured training program in the neurobiology of aging, including opportunities to conduct research in basic molecular and cellular mechanisms of brain aging and their relationship to neural plasticity and behavior. We emphasize training in the application of molecular and quantitative mechanisms to the elucidation of cellular events, and of cellular and molecular mechanisms underlying neurodegeneration, brain plasticity, and learning and memory. Students from different backgrounds learn about research at other levels of analysis and interact with those in other disciplines. We focus particularly on understanding the mechanisms that underlie successful aging and early changes that result in loss of functions and the transition to Alzheimer's disease. Although most of the work involves animal studies, we train students to "bridge the gap" between animal and human studies. For example, Trainees regularly attend bimonthly clinical-pathological case presentations on autopsy cases seen in the UCI ADRC Clinic/Successful Aging Cohort. These objectives help to assure a steady source of new talent that will continue to stimulate the field, while providing a foundation for some of the issues associated with human research.

Proposed Training

This program is based on: (i) Preceptor mentored, hands-on research, (ii) seminars that focus basic and clinical research on the neurobiology of aging, including Trainee presentations, chalk-talks and specialized individual training on methods and, (iii) formal didactic course work including a special Brain Aging Track for upper level graduate students.

(i). Preceptor Mentored Research: The major focus of this proposal is on neurodegeneration, neural plasticity and the fundamental mechanisms that result in the preservation versus loss of learning and memory in the aged brain in animal models and humans. We emphasize training in conducting studies on molecular events in postmortem brain tissues including correlations also with clinical data.

(ii). Seminars, Trainee Presentations/Chalk Talks/Specialized Instruction: We sponsor seminars, Trainee data presentation forums, and supplemental instructional opportunities for predoctoral and postdoctoral students as discussed below:

• Brain Aging Lecture Series. Each week we hold a specialized lecture series focused on issues and new techniques relevant to understanding the mechanisms that compromise Brain Aging Lecture Series. Each week we hold a specialized lecture series focused on issues and new techniques relevant to understanding the mechanisms that compromise "successful aging".

On a bimonthly basis, recently autopsied clinical cases are presented by a team consisting of a neurologist, a neuropsychologist, and a neuropathologist. This forum facilitates the integration of basic and clinical neuroscience and has proven very popular among all and is often very engaging. One interesting recent case was a 94 year female followed longitudinally for the past 5 years and who passed away 3 days after the last assessment. The brain showed pathology consistent with AD but she was cognitively normal. An exciting and energized discussion followed between scientists and clinicians as to possible adaptive mechanisms underlying preserved function with extensive AD pathology. Most frequently. UCI faculty present, but we also feature pertinent outside lectures including topics such as the ethics of scientific writing, grant writing, criteria for diagnosing Mild Cognitive Impairment, etc. A list of topics from the last several months is presented in the Appendix (Summary of Neurobiology Aging Track).

• Joint Training Grant Meeting with USC. Each year, UCI and USC jointly host a day meeting in which Trainees present a poster on their research from the previous year. This is followed by a lecture on a contemporary topic in the neurobiology of aging. Participation by Trainees is required. This is an excellent means of exposing Trainees to additional input on research from other experts in the aging field. Because USC Trainees also include individuals with research on endocrinology, UCI Trainees are exposed to research on non-CNS work on aging. Most frequently Trainees comment that the issues share much in common and as a result there is cross-fertilization. The meeting site alternates between UCI and USC. A copy of the most current meeting agenda is contained in the Appendix (Summary, Neurobiology of Aging Track).

•Institute for Brain Aging and Dementia Colloquium Series. In the past grant period, we introduced this series to provide a forum for students and faculty to interact with leaders in the field. There are approximately 4 lectures per year. The format includes a lunch meeting between the Trainees and visiting scholar where the Trainees have an open forum to discuss topics ranging from research strategies to detailed data. The Training Committee has selected the speakers in the past but in the future we will ask the Trainees to select at least one speaker for the year. Recent visiting scholars include: Drs. Dennis Selkoe, Sangram Sisodia, Marilyn Albert, Mark Mattson, John Hardy, etc. (Summary, Neurobiology of Aging Track).

• Community awareness: Annual Alzheimer's Disease Research Conference. Each year, in collaboration with the Orange County Alzheimer's Association, we sponsor a daylong symposium that provides an update on current advances in Alzheimer's research with a particular emphasis on the potential significance of basic discoveries to community concerns. We aim to train scientists to consider not just their own research but also the responsible presentation of the relevance of their work and the field to the larger community. Likewise, research scientists and clinicians can benefit from learning directly from those concerned with care and management of dementia patients. Trainees are required to attend. A copy of the Program for this year's conference is presented in the Summary, Neurobiology of Aging Track. We also sponsor a Holiday Reception in which we feature a guest speaker. For example, Drs. John Hardy and Sangran Sisodia have presented over the past two years. This reception is for families, mildly impaired patients, investigators, staff, and students thus allowing students to interact with these patients and individuals in the community.

• Responsible conduct of Research Lecture Series. We require all Trainees to participate in this lecture series (see Table 10). In addition in the past year, we featured a lecture and discussion on "Ethics on Scientific Writing" by Dr. Pamela Talay. We also sponsor a lecture on IRB issues in relationship to clinical-basic science research on brain aging and dementia informed consent, human tissue use guidelines, etc.

(iii). Formal Didactic Instruction: Specialized research and seminars are supplemented by a didactic component, especially designed for graduate students. The curriculum for training graduate students will consist of: 1) first year course-work within their own academic department, followed by 2) participation in a special advanced training track. This is supplemented by advanced courses, research presentations and special seminars, as discussed above, for both predoctoral and postdoctoral students. As a general rule, we seek to provide training grant slots to advanced graduate students who have fulfilled their departmental core requirements and have decided to purse research directed at topics in an area related to brain aging. Generally beginning in the second or third year, depending on the students' progress, the best and most promising graduate students who show an interest and commitment to the study of the neurobiology of aging topics are selected for appointment to the training grant and enter the track. It should be noted, however, that students other than Trainees commonly participate thus broadening the student training.

The central track consists of two specialty core courses supplemented by select advanced courses. The first course (Advanced Topics in the Neurobiology of Aging, Neurobiology and Behavior 245) is an advanced graduate course focused on molecular and cellular mechanisms relevant to brain aging. The second course focuses on age-related diseases of the nervous system and is more clinical in nature. The first course meets once a week for two hours and features a series of lectures, assigned readings and discussions. The first hour is lecture and the second discussion. At the end of the course, the students submit a small pilot NIH-like grant proposal, which is reviewed, discussed and revised, if necessary, in consultation with the student. An outline of lectures is presented below from the up and coming Fall course (the previous years course was similar):

Caleb Finch, USC Molecular Mechanisms of Aging in the Nervous System
Ron Kim, UCI Neuropathology of Alzheimer's Disease, Tauopothies, Cerebrovascular Disease, and Prions
Charles Glabe, UCI Protein Processing and Protein Misfolding in Neurodegenerative Diseases
Carl Cotman, UCI Death Receptors and Apoptosis-like Mechanisms in Brain Aging and Neurodegeneration
Frank LaFerla, UCI Genetics of Neurologic Diseases
Bill Van Nostrand, SUSB Molecular Mechanisms of Cerebrovascular Disease and Transgenic Models
Frank LaFerla, UCI The Role of Transgenic Animal Models in Investigating Neurological Diseases
Stephen Bondy, UCI Mechanisms of Oxidative Damage in Aging and Neurodegeneration
Greg Wittman, UCI The Glial Response in Neurodegeneration: Astrocytes, Microglia and Oligodendrocytes
Carl Cotman, UCI Protective Strategies for Intervention in Brain Aging and Neurodegenerative Diseases
Andrea Tenner, UCI The Innate Immune System and Neuroinflammation in Neurodegenerative Diseases
David Cribbs, UCI Prospects for Immunotherapy in the Treatment of Neurodegenerative Diseases
Douglas Wallace, UCI Mitochondrial Genetics and Oxidative Damage in Aging and Neurodegeneration
Gary Lynch, UCI Mechanisms of Neuronal Degeneration: Aberrant Processing of Proteins and Lysosomal Dysfunction

The second course focuses on age-related diseases of the nervous system and is more clinical in nature (Neurobiology and Behavior 251: Clinical Neurology for Neuroscientists). The course features presentation of problems of clinical neurology through patient presentation, examination, and discussion and is jointly taught by Drs. Starr and Kawas. Patients with lesions or defects at various levels of the nervous system are examined. There is a special emphasis on dementia and related illnesses. Each student, for example, in the last year's course attended for one morning the Alzheimer's Clinic where they observed evaluation and testing of patients with dementia. They discussed on the following evening the significance of the signs and symptoms of the disorder and the scientific mechanisms underlying the deficits. At the end of the course, the students write a paper on topics related to dementia or other age-related diseases, e.g., Mild Cognitive Impairment and AD, memory systems of the brain, factors that protect from dementia, Parkinson's disease, etc.

The central track can, of course, be supplemented by a selection of advanced courses relevant to career development, e.g., Genetics of Neurodegenerative Diseases taught by LaFerla. UCI, with its strong emphasis on neurosciences, has over 30 graduate course offerings. A complete list is provided in the Appendix.