Behavioral, metabolic, and lipidomic characterization of the 5xFADxTg30 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is associated with both extracellular amyloid-ß (Aß) plaques and intracellular tau-containing neurofibrillary tangles (NFT). We characterized the behavioral, metabolic and lipidomic phenotype of the 5xFADxTg30 mouse model which contains overexpression of both Aß and tau. Our results independently reproduce several phenotypic traits described previously for this model, while providing additional characterization. This model develops many aspects associated with AD including frailty, decreased survival, initiation of aspects of cognitive decline and alterations to specific lipid classes and molecular lipid species in the plasma and brain. Notably, some sex-specific differences exist in this model and motor impairment with aging in this model does compromise the utility of the model for some movement-based behavioral assessments of cognitive function. These findings provide a reference for individuals interested in using this model to understand the pathology associated with elevated Aß and tau or for testing potential therapeutics for the treatment of AD.

Persistent downregulation of hippocampal CREB mRNA parallels a Y-maze deficit in adolescent rats following semi-chronic amphetamine administration.

BACKGROUND AND PURPOSE: We investigated possible differences in the impact of chronic amphetamine administration during adolescence and adulthood on aspects of behaviour and brain chemistry. EXPERIMENTAL APPROACH: Adult (n=32) and adolescent (n=32) male Sprague-Dawley rats were given either D-amphetamine sulphate (10 mg kg(-1) daily, i.p.) or saline (1 mL kg(-1), i.p.) for 10 days. Rats were subsequently tested for anxiety-like behaviour, learning and memory, and sensorimotor gating. Nine weeks later, rats received saline (1 mL kg(-1)) or acute amphetamine challenge (1.5 mg kg(-1)) and the expression levels of mRNA for tyrosine kinase B (TrkB) or cAMP response element-binding protein (CREB) were measured in the hippocampus. KEY RESULTS: The adolescent amphetamine pretreated group revealed a deficit in exploration on the Y-maze during a 6 h retention test. The frequency of visits to the novel arm was 35% lower for the amphetamine group compared with controls. In parallel, a 43% decrease in hippocampal CREB mRNA, but not TrkB mRNA, was observed in periadolescent rats treated chronically with amphetamine 9 weeks earlier. None of the effects were detected in the adult treated cohort. CONCLUSIONS AND IMPLICATIONS: Chronic amphetamine treatment during periadolescence resulted in altered behaviour on the Y-maze and persistent downregulation of hippocampal CREB mRNA expression. Given that this group had intact spatial learning and reference memory, it would appear that the deficits observed on the Y-maze reflect a dysfunction in response to novelty. Because no effects of amphetamine treatment were observed in the adult cohort, these data suggest idiosyncratic sensitivity of periadolescence to the long-term effects of psychostimulants.

Chronic cold stress regulates ascending noradrenergic pathways.

Chronic exposure to cold in rats alters the activity of locus coeruleus (LC) neurons. In this study we aimed to examine the cellular effect of cold stress on catecholamine neurons, and determine whether this is specific to the LC compared with other catecholamine cell groups. Male Sprague-Dawley rats were subjected to 21 days of isolation under ambient conditions, chronic cold exposure at 5 degrees C, or after chronic cold followed by return to ambient temperature for 7 or 14 days. In the LC, chronic cold exposure significantly reduced tyrosine hydroxylase (TH) mRNA expression by approximately 45% compared with control rats, and remained significantly reduced (approximately 36%) after return to ambient conditions for 7 days; however, expression returned to normal after 14 days' recovery. There were no significant changes in TH mRNA in the substantia nigra or ventral tegmental area. Chronic cold increased expression of alpha2A adrenoceptor mRNA in the LC (approximately 27%). There were decreases in alpha2A expression in the nucleus tractus solitarius; however, this was seen only in rats returned to ambient conditions for 7 days. Additionally, alpha2A mRNA in the caudal ventrolateral medulla (A1 region) increased following cold exposure (approximately 84%) compared with controls. Binding of [125I]iodoclonidine to alpha2-like protein increased in the olfactory bulbs but decreased in the medial amygdala following cold exposure. Collectively, these data indicate robust effects of cold on central catecholamine neurons, not necessarily specific to the LC.