Colin J. Saldanha, Ph.D. - US grants

DESCRIPTION (provided by applicant): The estrogen (E) synthetic enzyme aromatase is localized in presynaptic boutons of many vertebrates including humans. In songbirds and rodents, E-receptors at postsynaptic loci support the idea that synaptocrine hormone provision is a bona fide method of steroid delivery. Thus, with prior support we have established the incidence, prevalence, and potential mechanism of action of synaptically produced E. The songbird affords unparalleled advantages towards the further understanding of synaptocrinology. In the zebra finch, synaptic aromatase comprises about half of all aromatase activity in the brain. In contrast to all other species studied, synaptic aromatase is abundant in areas with no somal aromatase. Thus, the specific contribution of synaptic E to local steroid levels in the brain can be easily studied. Presynaptic aromatase is higher in males relative to females, suggesting a sex- associated, behavioral role for synaptic hormone provision. However, we know very little about the how synaptic E contributes to local E levels, how synaptic E may be regulated, and what role synaptic E plays in brain physiology. Using recently developed sensitive measurements of steroid levels, I will specifically test how local brain levels of E are affected by synaptic aromatization. Then, using electron-microscopy, I will test which parts of the brain contribute to local E levels by identifying the projection neurons that contain synaptic aromatase. Lastly, with established behavioral paradigms, I will test the role of synaptic aromatization on the mechanisms of learning and memory. These studies will greatly increase our understanding of how synaptocrine E contributes to the hormonal, electrical, and behavioral functioning of the vertebrate brain. This work, supported by NS 047267, suggests a coupling of chemical and electrical signaling. The abundance and exclusivity of synaptic aromatase in brain areas known to modulate behavior, make the songbird an excellent model to understand this novel mechanism in neuroendocrinology. PUBLIC HEALTH RELEVANCE In humans and other animals, estrogen affects many structural and functional endpoints by its action on the nervous system. These endpoints include aggression, mood, balance, neuroprotection, and learning. How estrogens are provided to discrete brain areas is a field of intense investigation. Estrogen is synthesized in presynaptic boutons of humans, rodents, and songbirds. In previously supported work we have learned that synaptic estrogen synthesis is abundant and localized within brain areas important for learning and plasticity in the songbird brain. The proposed experiments seek to understand the contribution of synaptically produced estrogen to local brain areas, their source, and their physiological function. These studies are critical in order to evaluate the role of synaptic estrogen in learning, memory, and neuroprotection. This will greatly inform therapeutic advances in the treatment of diseases that involve the loss of memory and brain degeneration such as Alzheimer's, Parkinson's, and stroke.

A direct and tangible contribution of any scientific discovery or science-education lies in the creation of a springboard to success for the future generation of scientists. A resilient principle of the Society for Behavioral Neuroendocrinology (SBN) is our commitment to trainees. We see our trainees as the future of the field and thus; recruiting and welcoming them into, encouraging their participation in, rewarding their input to, and nurturing their continued inclusion among the SBN are all inherently critical aspects of the SBN mission. The SBN Education Committee will use NSF funds to stimulate, maintain, nurture, and reward the participation of post-doctoral fellows, graduate and undergraduate students at the 15th and 16th annual SBN meetings. In keeping with our commitment to recruit, retain, and reward trainees, funds will be used for: (1) Travel Awards. This allows trainees to present their work in a supportive environment and gain exposure to the breadth and depth of the field. (2) Career Development Workshops. Workshops are offered at each meeting to educate trainees on important career development topics and retain trainees in the sciences. (3) Mentor-Mentee Lunches. One-on-one discussions with senior mentors help trainees gain insight into the research enterprise, create new relationships, and find strong mentors. (4) Trainee Poster Competition. The competition an educational experience for all and it also provides an opportunity to encourage and reward success at each level, and, (5) the Young Investigator?s Symposium. Outstanding senior graduate students or post-docs are chosen to present talks in a dedicated symposium at the meeting. This format recognizes the accomplishments of such trainees, facilitates their movement into more advanced positions, and motivates younger scientists. The trainee events at the SBN meeting will play a key role in the attraction, retention, and reward of the brightest and best-trained transdisciplinary scientists.

DESCRIPTION (provided by applicant): Chronic neuroinflammation contributes to neuropathy and is implicated in a number of serious health conditions such as Stroke, Parkinson's and Alzheimer's disease. Emerging evidence strongly supports an anti-inflammatory role for circulating estrogens (E) since removal and replacement of this steroid dramatically exacerbates and mitigates several indices of inflammation respectively. Indeed, E-administration decreases the expression and secretion of several pro-inflammatory cytokines including IL1, IL6 and TNF?. The vertebrate brain responds to mechanical perturbation or endotoxin with a rapid increase in cytokine expression in microglia and aromatase (E- synthase) expression in reactive astrocytes. Importantly, microglial cytokine induction occurs prior to astrocytic aromatase expression suggesting that cytokines may induce the expression of aromatase in reactive glia. Given the well-studied anti-inflammatory role of peripheral E, we propose that neural E, via glial aromatization, may serve as a rapidly induced and potent anti-inflammatory signal in the vertebrate brain. More specifically, we hypothesize that cytokines rapidly induce sustained glial aromatase expression and consequent E synthesis, which in turn, causes a decrease in cytokines. This down-regulation prevents chronic exposure of neural tissue to the deleterious effects of prolonged cytokine secretion. To elucidate and hone this model we will use a molecular approach and behavioral assays to test the role of specific pro-inflammatory cytokines in the induction of aromatase transcription following central or peripheral endotoxin administration. Next, using a pharmacological inhibitor of aromatase, we will test the role of aromatization in the mitigation of cytokine expression and sickness behavior following central endotoxin administration. Taken together these experiments will explore an exciting new role for pro-inflammatory cytokines in the induction of encephalic, glial aromatization and further, a mechanism whereby cytokine activity is curtailed by neural E-provision. These data are necessary for the development of therapies that target and prevent inflammatory processes, thereby reducing the severity of neurodegenerative disease.

With this award from the Major Research Instrumentation (MRI) and Chemistry Research Instrumentation and Facilities (CRIF) programs Professor Shouzhong Zou from American University and colleagues Colin Saldanha, Matthew Hartings and Douglas Fox have acquired an analytical transmission electron microscope (TEM). A TEM propels a beam of electrons at a thin sample. The electrons interact with the material to produce an image of the substance much as an optical microscope. However, the magnification is typically better than with optical microscopes. The microscope is used in a broad area of fields from materials research, to chemistry and biology to medicine. The microscopic knowledge gleamed from the TEM images can help understand the properties of the material and perhaps improve them. At American University the TEM is used to advance a number of research projects and it also impacts undergraduate research training and it is used in lecture and laboratory courses. It is also used in outreach activities to local institutions such as the University of the District of Columbia and Montgomery College to further enhance research and student training.

The proposal is aimed at enhancing research and education at all levels, especially in areas such as (a) revealing structure-catalytic activity relationships of catalysts for fuel cell reactions, carbon dioxide to organic fuel conversion and gas sensing, (b) understanding formation mechanisms and exploring structure-function properties of polymer-nanocomand organic ligand-stabilized noble metal nanoparticles, (c) developing advanced functional materials for water purification and disease detection, (d) understanding the expression and regulation of synaptic aromatase that synthesizes estrogens, (e) exploring structural modifications of retina associated with ambient light conditions and (f) revealing the reproductive system structure of decapod crustaceans.