Novel Cage Stress Alters Remote Contextual Fear Extinction and Regional T₂ Magnetic Resonance Relaxation Times in TASTPM Mice Overexpressing Amyloid

Article type: Research Article

Authors: Rattray, Ivan^a | Pitiot, Alain^b | Lowe, James^c | Auer, Dorothee P.^d | Lima, Sarah-Jane^a | Schubert, Mirjam I.^d | Prior, Malcolm J.W.^b | Marsden, Charles A.^a | Diaz, Fernando Pérez^e | Kendall, David A.^a | Pardon, Marie-Christine^{a; *}

Affiliations: [a] School of Biomedical Sciences, Academic Radiology, Queen's Medical Centre, Nottingham, UK | [b] School of Psychology, University Park, Nottingham, UK | [c] School of Molecular Medical Sciences, Academic Radiology, Queen's Medical Centre, Nottingham, UK | [d] School of Clinical Sciences, Academic Radiology, Queen's Medical Centre, Nottingham, UK | [e] Centre Émotion, CNRS USR 3246, Pavillon Clérambault, Hôpital de La Salpêtrière, Paris, France

Correspondence: [*] Correspondence to: Marie-Christine Pardon, PhD, University of Nottingham Medical School, School of Biomedical Sciences, Queen's Medical Centre, Nottingham NG9 2UH, UK. Tel.: +44 115 82 3015; Fax: +44 11582 30142; E-mail: [email protected].

Note: [] Handling Associate Editor: Gemma Casadesus

Abstract: We have previously shown that repeated exposure to mild novel cage stress prevents the onset of recent contextual fear memory deficits and attenuated amyloid deposition in the TASTPM mouse model of Alzheimer's disease. Here, we extended this investigation to remote contextual fear memory and extinction. TASTPM and wild-type mice acquired contextual fear at 4 months of age. Retention and extinction of contextual fear were assessed at 5.5 months prior to in vivo MRI assessment of regional T2 relaxation times and brain volumes followed by immunostaining to determine amyloid plaque load. Remote contextual fear memory was preserved in TASTPM mice regardless of the stress condition. Stress impaired extinction in wild-type mice but facilitated this process in TASTPM mice. Genotype-dependent effects of stress were observed on regional T2 times which were prolonged in the subiculum and thalamus of stressed TASTPM, possibly reflecting reduced amyloid pathology. Amyloid plaque load was particularly decreased in the retrosplenial cortex of stressed TASTPM mice, which also showed an overall reduction in the number of diffuse plaques. These findings support the hypothesis that repeated mild levels of stress induced by novel activities can delay the progression of pathological changes relevant to Alzheimer's disease.

Keywords: Alzheimer's disease, amyloid-β, extinction, memory, MRI, stress, transgenic

DOI: 10.3233/JAD-2010-091354

Journal: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1049-1068, 2010