Extinction Learning Deficits Develop Prior to Acquisition Deficits in Mice Expressing Alzheimer's PathologiesShow full item record
|Extinction Learning Deficits Develop Prior to Acquisition Deficits in Mice Expressing Alzheimer's Pathologies
|Alzheimer's Disease (AD) is a progressive neurodegenerative disease that currently affects roughly 5.8 million Americans and has no cure and few treatments of limited efficacy. Although the etiology of AD has yet to be fully understood, the production of neurotoxic oligomers and plaques of Amyloid-beta (A-beta) is thought to play a critical role in the progression of the disease. AD presents in one of two distinct forms. Familial AD, which presents before the age of 65 and accounts for less than 6% of all clinical cases of AD, arises from mutations in the Presenilin-1 (PS1 or PSEN-1) or Amyloid precursor protein (APP) genes, leading to production of amyloid plaques beginning in early life. Sporadic AD, the more common form, arises from a multitude of genetic and environmental factors, including neuroinflammatory events. The progressive nature of the disease, coupled with the limitations of current treatments in preventing advancement of the illness, necessitates early identification of AD pathology in both laboratory and clinical settings. Extinction learning, or the acquisition and retention of information that supersedes previously-learned information, has not been assessed in the 5xFAD (FAD) mouse model, a transgenic model expressing multiple mutations in the PSEN-1 and APP genes leading to accumulation of plaques in early life. At the same time, changes in extinction learning have not been assessed in non-transgenic C57BL/6J (BL/6) mice following repeated inflammatory insults, which previous studies in Chumley-Boehm Lab have shown to induce amyloid plaque pathologies and associated AD-associated cognitive deficits. Thus, the current study seeks to determine whether extinction behavioral testing could be useful in identifying AD symptoms prior to symptom presentation via other behavioral assessments, which generally begin around six months of age in FAD mice. To assess this, FAD subjects were subjected to behavioral testing via the contextual fear conditioning (CFC) paradigm to assess changes in freezing behavior over several days following initial exposure to an adverse stimulus, with results compared to non-transgenic controls. Concurrently, BL/6 subjects were subjected to repeated injections of lipopolysaccharide (LPS, a bacterial mimetic and known inflammatory stimulus) as previously established by Weintraub et al. (2012) to induce A-beta production prior to testing. Changes in freezing behavior in these subjects were then compared to that observed in saline-injected controls. Repeated contextual fear testing revealed deficits in extinction learning behavior approaching significance as indicated by reductions in freezing time in FAD subjects compared with nontransgenic subjects beginning at three months of age, with significant deficits observed at four months of age. Additionally, significant deficits in extinction of contextual fear learning was observed in LPS-injected BL/6 subjects compared to controls. These results imply that assessing extinction of contextual learning can be a far more sensitive tool than assessing acquisition of contextual learning.
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- Undergraduate Honors Papers