Abstract
Psychiatric and metabolic features appear several years before motor disturbances in the neurodegenerative Huntington’s disease (HD), caused by an expanded CAG repeat in the huntingtin (HTT) gene. Although the mechanisms leading to these aspects are unknown, dysfunction in the hypothalamus, a brain region controlling emotion and metabolism, has been suggested. A direct link between the expression of the disease causing protein, huntingtin (HTT), in the hypothalamus and the development of metabolic and psychiatric-like features have been shown in the BACHD mouse model of HD. However, precisely which circuitry in the hypothalamus is critical for these features is not known. We hypothesized that expression of mutant HTT in the ventromedial hypothalamus, an area involved in the regulation of metabolism and emotion would be important for the development of these non-motor aspects. Therefore, we inactivated mutant HTT in a specific neuronal population of the ventromedial hypothalamus expressing the transcription factor steroidogenic factor 1 (SF1) in the BACHD mouse using cross-breeding based on a Cre-loxP system. Effects on anxiety-like behavior were assessed using the elevated plus maze and novelty-induced suppressed feeding test. Depressive-like behavior was assessed using the Porsolt forced swim test. Effects on the metabolic phenotype were analyzed using measurements of body weight and body fat, as well as serum insulin and leptin levels. Interestingly, the inactivation of mutant HTT in SF1-expressing neurons exerted a partial positive effect on the depressive-like behavior in female BACHD mice at 4 months of age. In this cohort of mice, no anxiety-like behavior was detected. The deletion of mutant HTT in SF1 neurons did not have any effect on the development of metabolic features in BACHD mice. Taken together, our results indicate that mutant HTT regulates metabolic networks by affecting hypothalamic circuitries that do not involve the SF1 neurons of the ventromedial hypothalamus.
Highlights
Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene [1]
The region specificity of Cre recombination resulting in the excision of exon 1 of mutant HTT in BACHD-steroidogenic factor 1 (SF1) mice was validated with PCR analysis
Brain tissue from BACHD-SF1, BACHD, SF1 and WT mice showed the presence of the unrecombined mutant HTT allele (1050 bp) in the BACHD-SF1 and BACHD samples while the recombined mutant HTT allele (600 bp) was only detected in ventromedial hypothalamus (VMH) brain samples from the BACHD-SF1 mice (Figure 1B)
Summary
Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene [1]. It is clinically diagnosed when an individual presents with typical involuntary movements in combination with a positive gene test. It is well recognized that individuals with the mutant HTT gene often manifest psychiatric and cognitive disturbances many years before the motor onset of the disease [2,3]. The motor symptoms and the cognitive changes have been associated with the pathology in the basal ganglia as well in the cerebral cortex [5,6], but less is known about the neural substrate of other non-motor aspects of the disease
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