vasoactive-intestinal-peptide and Huntington-Disease

Topics: Alzheimer Disease; Basal Ganglia; Brain; Brain Chemistry; Cerebral Cortex; Choline O-Acetyltransferase; Enkephalin, Methionine; FMRFamide; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Humans; Huntington Disease; Nerve Tissue Proteins; Neurofibrils; Neuropeptide Y; Neurotensin; Oligopeptides; Peptides; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies indicate there may be sex differences in disease progression. One of the early symptoms of HD is disruptions in the circadian timing system, but it is currently unknown whether sex is a factor in these alterations. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s) and designing early intervention strategies, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Similar to BACHD males, BACHD females display circadian disruptions at both 3 and 6 months of age; however, deficits to BACHD female mouse activity levels, rhythm precision, and behavioral fragmentation are either delayed or less severe relative to males. These sex differences are associated with a smaller suprachiasmatic nucleus (SCN) in BACHD male mice at age of symptom onset (3 months), but are not associated with sex-specific differences in SCN daytime electrical activity deficits, or peptide expression (arginine vasopressin, vasoactive intestinal peptide) within the SCN. Notably, BACHD females exhibited delayed motor coordination deficits, as measured using rotarod and challenge beam. These findings suggest a sex specific factor plays a role both in non-motor and motor symptom progression for the BACHD mouse.

Topics: Animals; Arginine Vasopressin; Chromosomes, Artificial, Bacterial; Circadian Rhythm; Disease Models, Animal; Disease Progression; Female; Founder Effect; Gene Expression; Humans; Huntington Disease; Male; Mice; Mice, Transgenic; Motor Activity; Rotarod Performance Test; Sex Factors; Suprachiasmatic Nucleus; Time Factors; Vasoactive Intestinal Peptide

To study whether sleep and circadian rhythm disturbances in patients with Huntington's disease (HD) arise from dysfunction of the body's master clock, the hypothalamic suprachiasmatic nucleus.. Postmortem cohort study.. Eight patients with HD and eight control subjects matched for sex, age, clock time and month of death, postmortem delay, and fixation time of paraffin-embedded hypothalamic tissue.. Using postmortem paraffin-embedded tissue, we assessed the functional integrity of the suprachiasmatic nucleus in patients with HD and control subjects by determining the expression of two major regulatory neuropeptides, vasoactive intestinal polypeptide and arginine vasopressin. Additionally, we studied melatonin 1 and 2 receptor expression. Compared with control subjects, the suprachiasmatic nucleus contained 85% fewer neurons immunoreactive for vasoactive intestinal polypeptide and 33% fewer neurons for arginine vasopressin in patients with HD (P = 0.002 and P = 0.027). The total amount of vasoactive intestinal polypeptide and arginine vasopressin messenger RNA was unchanged. No change was observed in the number of melatonin 1 or 2 receptor immunoreactive neurons.. These findings indicate posttranscriptional neuropeptide changes in the suprachiasmatic nucleus of patients with HD, and suggest that sleep and circadian rhythm disorders in these patients may at least partly arise from suprachiasmatic nucleus dysfunction.

Topics: Arginine Vasopressin; Chronobiology Disorders; Circadian Rhythm; Cohort Studies; Female; Humans; Huntington Disease; Hypothalamus; In Situ Hybridization; Male; Neuropeptides; Sleep Wake Disorders; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide

Huntington's disease (HD) is a fatal genetic neurodegenerative disorder caused by a CAG triplet repeat expansion in the gene encoding the protein huntingtin. The most studied model of HD, the R6/2 transgenic mouse, replicates many features of the disease. In addition to motor, cognitive, and endocrine dysfunctions, these mice exhibit a progressive disruption of circadian rhythms. This is accompanied by an altered expression of the circadian clock genes in the suprachiasmatic nucleus/nuclei (SCN), the principal circadian pacemaker in the brain. The neuropeptide vasoactive intestinal polypeptide (VIP) and its receptor VPAC2 are highly expressed in the SCN, and VIPergic signaling plays an essential role in maintenance of ongoing circadian rhythmicity. We found a marked reduction in both VIP mRNA and VPAC2 receptor mRNA, quantified by RT-PCR, as well as a decrease in VIP immunostaining in the SCN of R6/2 mice. These changes were coupled to a disruption of circadian rhythm. We observed no loss of neurons in the SCN and therefore suggest that the changes in VIP and VPAC2 receptor are due to their decreased expression. In conclusion, we propose that impaired VIPergic signaling is an additional candidate mechanism for disruption of circadian rhythms in R6/2 mice.

Topics: Animals; Behavior, Animal; Biological Clocks; Circadian Rhythm; Disease Models, Animal; Humans; Huntington Disease; Male; Mice; Mice, Transgenic; Neurons; Receptors, Vasoactive Intestinal Peptide, Type II; RNA, Messenger; Signal Transduction; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide

Patients with Huntington's disease (HD) develop pathological changes in cerebral cortex as well as in striatum. We studied levels of neuropeptide immunoreactivity in 13 areas of postmortem cerebral cortex dissected from 24 cases of HD and 12 controls. Concentrations of immunoreactive cholecystokinin (CCK-LI) were consistently elevated 57 to 153% in HD cortex. Levels of vasoactive intestinal polypeptide (VIP-LI) and neuropeptide Y (NPY-LI) were significantly increased in 10 and 8 of the 13 cortical regions, respectively. Concentrations of somatostatin (SRIF-LI) were increased in only 3 areas, while substance P (SP-LI) was, for the most part, unchanged. Detailed analyses of the CCK-LI and VIP-LI data showed there to be no relationship between the increased cortical peptide levels and the degree of striatal atrophy. We studied the same cortical peptides in rats with long-standing striatal lesions and found no significant changes of CCK-LI, NPY-LI, VIP-LI, or SRIF-LI in any of the 8 cortical regions that were examined. These results indicate that there are widespread and differential changes in cortical neuropeptide systems in HD and that these changes occur independently of the striatal pathology that characterizes the illness.

Topics: Animals; Cerebral Cortex; Corpus Striatum; Humans; Huntington Disease; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

The location of the neuropeptides methionine-enkephalin (ME), neurotensin (NT), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) within the amygdaloid complex of healthy human individuals, schizophrenics and patients suffering from Huntington's chorea was studied qualitatively by means of immunohistochemistry. VIP-like immunoreactivity (IR) was present predominantly in a dense cluster of fibers and terminals in the central amygdaloid nucleus. ME-IR was observed in fibers, terminals and cell bodies in the same subnucleus, exhibiting a characteristical distribution pattern. NT-positive cell bodies were situated within the center of the central amygdaloid nucleus, fibers and terminals being encountered mainly at the periphery. NPY-IR was found to be evenly distributed throughout the amygdala. Distribution and staining intensity of ME, NPY and NT in the amygdala showed no qualitatively recognizable difference between the normal and schizophrenic specimens, whereas VIP-IR appeared to be slightly increased in the central amygdaloid nucleus of schizophrenics. In the choreic cases, the considerably shrunken amygdala exhibited only very low staining intensity of the four investigated neuropeptides.

Topics: Adult; Aged; Amygdala; Enkephalin, Methionine; Female; Humans; Huntington Disease; Immunoenzyme Techniques; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Neurotensin; Schizophrenia; Vasoactive Intestinal Peptide

Topics: Amygdala; Animals; Basal Ganglia; Brain; Brain Mapping; Brain Stem; Cerebellum; Cerebral Cortex; Gastrointestinal Hormones; Hippocampus; Humans; Huntington Disease; Hypothalamus; Limbic System; Mice; Thalamus; Vasoactive Intestinal Peptide