Age‐related alteration of emotional regulation in the BACHD rat model of Huntington disease

Abstract

Huntington's disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG repeat in the gene encoding the huntingtin protein. At the premanifest phase, before motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence in HD patients. Agitation, anxiety and irritability are often described but also depression and/or apathy, associated with a lack of emotional control. The aim of the present study was to better circumscribe and understand the emotional symptoms and assess their evolution according to the progression of the disease using a transgenic HD model, BACHD rats, at the age of 4, 12 and 18 months. To achieve this goal, we confronted animals to two types of tests: first, tests assessing anxiety like the light/dark box and the conflict test, which are situations that did not involve an obvious threat and tests assessing the reactivity to a present threat using confrontation with an unknown conspecific (social behavior test) or with an aversive stimulus (fear conditioning test). In all animals, results show an age-dependent anxiety-like behavior, particularly marked in situation requiring passive responses (light/dark box and fear conditioning tests). BACHD rats exhibited a more profound alteration than WT animals in these tests from an early stage of the disease whereas, in tasks requiring some kind of motivation (for food or for social contacts), only old BACHD rats showed high anxiety-like behavior compared to WT, may be partly due to the other symptoms' occurrence at this stage: locomotor difficulties and/or apathy. K E Y W O R D Sage-related deficits, anxiety, behavioral assessement, behavioral inhibition, fear conditioning, emotional regulation, Huntington disease, rat, reactivity to threat, social behavior

Rat models of major neurodegenerative disorders

“…Depression-like behavior reported in multiple studies in HD fragment and full-length mouse models [231][232][233][234] has not been studied in much detail in HD rat genetic models. An impaired hedonic reaction in response to sucrose in tgHD rats has been associated with anhedonia-like behavior [217] which was though not confirmed by later analyses [228] . BACHD rats show decreased sucrose preference at 3 months and this effect is maintained at later time points [235] .…”

“…While the available tests in rodents can only partially assess the multidimensional nature of the neuropsychiatric disturbances in HD patients, emotional changes have been shown with different behavioral paradigms in HD rat genetic models. Both tgHD and BACHD rats show a low anxiety phenotype in different behavioral setups [107,108,210,211,214,228] . In tgHD rats, the emotional phenotype is already detectable at the age of 1 month, before motor deficits [210] , whilst motor and emotional alterations in BACHD rats follow the opposite temporal pattern [107] .…”