Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disease caused by a high number of trinucleotide CAG repeats in the Huntingtin (Htt) gene. HD is classically associated with psychomotor symptoms including dyskinesia and dystonia, induced by degeneration of the basal ganglia. However, cognitive and emotional systems are also dysregulated in HD, and altered function in these systems frequently predates overt motor dysfunction in affected patients. Apathy, which is characterized by a loss of motivation to seek pleasure, is increasingly recognized as a feature of the disease. Given the strong genetic basis of HD, the disease can be effectively modeled pre-clinically in transgenic mouse models, such as the Q175 mouse model. In this transgenic mouse strain, a sequence of about 190 trinucleotide CAG repeats is knocked into the mouse Htt gene, resulting in age-dependent impairments in psychomotor, cognitive, and reward processes, including apathy-like behavior.
Q175 mice have reduced drive
for food reward compared to controls
Male and female Q175 heterozygotic mice were trained to perform in an operant task aimed at evaluating differences in hedonic processing. In the first 10 minutes of a given test session, mice were awarded a milk reinforcer for every five lever presses (i.e., an FR5 reinforcement schedule). After the initial 10-minute session, a progressive ratio (PR) task was implemented in which the number of lever responses required to earn a reinforcer increased after each successfully completed ratio requirement. In this task, we found that male and female Q175 heterozygote mice were less willing to work for reward in the PR task than control mice. Furthermore, we found that the dopamine reuptake inhibitor GBR-12909 (10 mg/kg, 30 min IP) increased the number of reinforcers earned in the PR portion of the task in both sexes. Interestingly, behavior directed at consuming the reinforcer was similar in both genotypes, which may suggest that the hedonic value of the reinforcer was not diminished once it was available. This model may be appropriate for testing compounds expected to improve symptoms of apathy in neurodegenerative and psychiatric disorders.
Male and female Q175 mice aged 31-43 weeks had lower breaking points in a progressive ratio task compared to controls (Panels A and B), suggesting that they were less willing to work for an appetitive reinforcer (access to condensed milk). The dopamine reuptake inhibitor GBR-12909 increased breakpoints in both sexes but did not interact with genotype. However, Q175 heterozygotes did not differ from controls in the number of licks emitted per reinforcement opportunity (Panels C and D), suggesting they liked the reinforcer equally when it was available. These data suggest that symptoms of apathy and anhedonia may be separable phenomena in Q175 heterozygotes.