The BACHD Rat Model of Huntington Disease Shows Signs of Fronto-Striatal Dysfunction in Two Operant Conditioning Tests of Short-Term Memory

Abstract

The BACHD rat is a recently developed transgenic animal model of Huntington disease, a progressive neurodegenerative disorder characterized by extensive loss of striatal neurons. Cognitive impairments are common among patients, and characterization of similar deficits in animal models of the disease is therefore of interest. The present study assessed the BACHD rats' performance in the delayed alternation and the delayed non-matching to position test, two Skinner box-based tests of short-term memory function. The transgenic rats showed impaired performance in both tests, indicating general problems with handling basic aspects of the tests, while short-term memory appeared to be intact. Similar phenotypes have been found in rats with fronto-striatal lesions, suggesting that Huntington disease-related neuropathology might be present in the BACHD rats. Further analyses indicated that the performance deficit in the delayed alternation test might be due to impaired inhibitory control, which has also been implicated in Huntington disease patients. The study ultimately suggests that the BACHD rats might suffer from neuropathology and cognitive impairments reminiscent of those of Huntington disease patients.

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

“…The BACHD model carries ∼97 CAG repeats and exhibits late‐onset motor deficits similar to YAC mice (Gray et al., ). Although this model shows corticostriatal dysfunction (Gray et al., ; Clemensson, Clemensson, Ries, & Nguyen, ), the mutant HTT aggregates are almost entirely detected in the cortex rather than in the striatum (Gray et al., ). In fact, it was recently reported that the motor phenotype occurs in the absence of striatal degeneration (Mantovani et al., ).…”

“…Similar to YAC128s, BAHD mice show deficits in reversal learning and set‐shifting strategy in the cross maze at 9 to 10 months of age (Abada, Nguyen, Ellenbroek, & Schreiber, ). Recently, deficits in short‐term memory were reported for this model using operant conditioning models (Clemensson et al., ).…”

“…Organization, multitasking, and planning also deteriorate over the course of HD (Morkl et al., ). The cognitive decline progressively worsens until dementia emerges (Clemensson, Clemensson, Riess, & Nguyen, ; Righi et al., ).…”

“…In fact, it was recently reported that the motor phenotype occurs in the absence of striatal degeneration (Mantovani et al., ). Because of the slow progression of the behavioral phenotype, both YAC and BAC models have been mainly used to study neuropathology and neurophysiological HD features at both pre‐ and post‐symptomatic stages (Andre et al., ; Estrada‐Sanchez et al., ; Hodgson et al., ; Clemensson, Clemensson, Ries, & Nguyen, ).…”

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

“…This model represents the late‐onset HD similar to the human disease . Another recent rat model, BACHD, is characterized by progressive neurodegenerative impairments and extensive loss of striatal neurons …”