Changes in key hypothalamic neuropeptide populations in Huntington disease revealed by neuropathological analyses

Abstract

Huntington disease (HD) is a fatal neurodegenerative disorder caused by expansion of a CAG repeat in the HD gene. Degeneration concentrating in the basal ganglia has been thought to account for the characteristic psychiatric symptoms, cognitive decline and motor dysfunction. However, the homeostatic control of emotions and metabolism are disturbed early in HD, and focused studies have identified a loss of orexin (hypocretin) neurons in the lateral hypothalamus in HD patients. There has been limited assessment of other hypothalamic cell populations that may be involved. In this study, we quantified the neuropeptide-expressing hypothalamic neurons known to regulate metabolism and emotion in patients with HD compared to healthy controls using unbiased stereological methods. We confirmed the loss of orexin-expressing neurons in HD and revealed substantial differences in the peptide expression of other neuronal populations in the same patients. Both oxytocin- and vasopressin-expressing neurons were decreased by 45 and 24%, respectively, while the number of cocaine- and amphetamine-regulated transcript (CART)-expressing neurons was increased by 30%. The increased expression of CART in the hypothalamus is consistent with a previous study showing increased CART levels in cerebrospinal fluid from HD patients. There was no difference in the numbers of neuropeptide Y-expressing neurons. These results show significant and specific alterations in the peptide expression of hypothalamic neurons known to regulate metabolism and emotion. They may be important in the development of psychiatric symptoms and metabolic disturbances in HD, and may provide potential targets for therapeutic interventions.

Increased brain tissue sodium concentration in Huntington's Disease — A sodium imaging study at 4T

“…Although huntingtin is ubiquitously expressed, the expression of huntingtin with a polyglutamin repeat expansion leads to selective neuronal cell death in the striatum and cortex. Neuropathological changes have been found to be most pronounced in the striatum (Reiner et al, 1988;Vonsattel and DiFiglia, 1998) but there are also clear effects in the cerebral cortex, globus pallidus, thalamus, subthalamic nucleus, substantia nigra, hypothalamus, and cerebellum in later stages of the disease (Gabery et al, 2010;Heinsen et al, 1996;Petersen and Bjorkqvist, 2006;Thu et al, 2010;Vonsattel and DiFiglia, 1998). Overall, striatal atrophy correlates with that of other brain regions (Vonsattel, 2008) and the brunt of the degenerative process involves the striatum, a key component of the basal ganglia, an interconnected set of subcortical nuclei involved in the regulation of action (Balleine et al, 2009).…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…In HD, the most striking pathology is observed in the striatum and cortex [52]. Importantly, a number of other areas of the brain have been noted to be affected in this condition, including the globus pallidus, hypothalamus [53], thalamus, and cerebellum [54].…”

Brain networks in Huntington disease

“…Neuropathological changes have been found in the cerebral cortex, globus pallidus, thalamus, subthalamic nucleus (STN), substantia nigra, hypothalamus, and cerebellum in later stages of the disease (5,(20)(21)(22)(23)(24). Imaging studies also have shown widespread volumetric changes in HD patients, particularly in the cerebral cortex (25).…”