Behavioral Neuroscience

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Closure realized on ongoing research initiatives in BNS include studies examining the influence of cytokine activation on brainstem catecholaminergic systems relevant to Parkinsons disease. In this study young and aged mice were challenged with a single peripheral injection of lipopolysaccharide (LPS). As expected, treatment induced a substantial proinflammatory cytokine response in brain. Alongside this robust response, however, the numbers of immunocytochemically labeled dopaminergic neurons, quantified stereologically, were similar in young and aged animals sacrificed 14 week after LPS injection. These findings count against the idea that early inflammatory events render the dopamine system vulnerable to late-life degeneration, comprising a risk for Parkinsons disease. Preliminary results from this project were presented at the 2009 Annual Society for Neuroscience convention, and a full-length report is currently 'in press'in Neurobiology of Aging. In other translational research efforts LEG investigators and IRP collaborators have pursued the development of an animal model for examining the cognitive effects of chemotherapy agents commonly used in the treatment of breast cancer. Although complaints of mild cognitive impairment are common among women who have received chemotherapy, a detailed account of the specific nature of dysfunction, and its potential cause, has remained elusive. Earlier studies in animal models have reported conflicting results, and in a recently completed investigation, we conducted an extensive analysis examining the effects of two doses of common chemotherapy agents using multiple tests of learning and memory. Specifically, rats were trained in contextual and cued fear conditioning and then received i.p. injections of either saline, a low dose of cyclophosphamide (CYP) and 5-fluorouracil (5FU;50 mg/kg CYP and 75 mg/kg 5FU) or a high dose (75 mg/kg CYP and 120 mg/kg 5FU) of the cocktail every 30 days for 2 months. After a 2-month recovery, the rats were assessed for the retention of the pretreatment conditioned fear response, and for acquisition in the water maze and 14-unit T- maze. Rats administered either a low or high dose cocktail of CYP/5FU were not impaired in long-term retrograde fear memory, despite marked toxicity evidenced by unrecoverable weight loss and 50% mortality at the higher dose. Furthermore, new task acquisition assessed in the water maze and Stone maze was unimpaired in rats treated with the CYP/5FU cocktail. Together these findings raise the possibility that cognitive impairment associated with chemotherapy may arise from the additive or interactive effects of cancer and treatment on brain function, rather than a neurotoxic effect of treatment alone. A full-length report of these results is currently in preparation.