Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease

Abstract

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD.

Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease

“…The number of successful trials and premature responses as well as the inter-response time were recorded per test session and animal. Performance efficiency was defined as ratio of reinforced to total responses (El Massioui et al, 2016 ). The relative number of burst responses (latency to second lever press <1 s) was calculated as the ratio of burst responses to total premature responses.…”

“…Emotional alterations were found to precede motor symptoms in tgHD rats, measured as reduced anxiety-like behavior in the elevated plus maze and social interaction test of anxiety from 2 months of age (von Hörsten et al, 2003 ; Nguyen et al, 2006 ; Kirch et al, 2013 ). Moreover, tgHD rats displayed increased impulsivity traits when performing specific operant tasks (Cao et al, 2006 ; Temel et al, 2006 ; Urbach et al, 2014 ; El Massioui et al, 2016 ). First signs of progressive cognitive decline were detected between 6 and 9 months of age in different maze tests (Nguyen et al, 2006 ; Kirch et al, 2013 ) and at older ages in object recognition (Zeef et al, 2012a ) and choice reaction time tasks (Cao et al, 2006 ; Kantor et al, 2006 ; Temel et al, 2006 ).…”

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

“…The reduced level of freezing in the younger (4 and 12 months) BACHD rats was mainly due to a more rapid extinction of freezing responses compared to WT, a difference which was not observed in 18‐month‐old rats, with both groups exhibiting a high level of freezing. Shorter durations of each bout of immobility suggest that the younger animals were less able to stand still during the CS, maybe due to the high level of impulsivity already described in 4‐month‐old BACHD rats or in TgHD rats, another rat model of HD . This effect disappeared in older groups of age.…”

“…Atrophies and/or changes in gray matter volume in emotion‐relevant and memory related structures (insula, orbito‐frontal cortex, amygdala and hippocampus) were observed as correlating with emotion recognition deficits in symptomatic patients . In rat models of HD, a volume reduction of the amygdala (central nucleus) associated with an increased level of cellular activity was observed in tgHD transgenic rats, associated with emotional blunting of hedonic perception and high level of impulsive behaviors . In BACHD rats, a basal pathological hyper‐reactivity of amygdala to threat compared to WT rats were observed .…”

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

“…The cognitive decline starts at early stages and typically precedes motor signs (Lawrence et al., ). The most prominent early cognitive signs are inflexibility during executive tasks and decision making (Dominguez et al., ; El Massioui et al., ). Organization, multitasking, and planning also deteriorate over the course of HD (Morkl et al., ).…”