oxytocin and Huntington-Disease

People with Huntington's disease (HD) exhibit altered processing of emotional information, especially disgust and other negative emotions. These impairments are likely due to the effects of the disease on underlying brain networks. We examined whether oxytocin, when given intranasally, would normalise aberrant brain reactivity to emotional faces in participants with the gene-expansion for HD. In a double-blind placebo-controlled cross-over design, we measured brain activity, using functional magnetic resonance imaging, whilst nine medication-free HD carriers, and ten control participants viewed emotional (disgust, fear, angry, sad, surprise, happy) and neutral faces, following acute intranasal oxytocin (24IU) and placebo. Subjective mood changes were assessed before and after the neuroimaging on each visit. Permutation-based non-parametric statistical testing for the whole brain, showed significant group×drug interactions (p's<0.05, TFCE corrected) in areas of the left frontal pole, superior frontal, and middle frontal gyri cortically, and left putamen and thalamus sub-cortically. Parameter estimates extracted from the middle frontal gyrus and putamen showed that, under placebo, the HD group had lower brain activity to disgust stimuli, compared with controls. After intranasal oxytocin, the pattern of activation to disgust stimuli was normalised in the HD group to similar levels as controls; eight of the nine HD carriers showed increased response in the middle frontal gyrus, and seven of the nine HD carriers showed increased response in the putamen. The observed effects of oxytocin occurred in the absence of changes in subjective mood or state anxiety. These findings provide early evidence for a physiological role of oxytocin in the neuropathology of HD. Our findings are the first reported oxytocin effects in a neurodegenerative disease. Further research should examine the therapeutic benefits of oxytocin in alleviating emotional and social cognition deficits in HD and related disorders.

Topics: Administration, Intranasal; Adult; Brain; Brain Mapping; Cross-Over Studies; Double-Blind Method; Emotions; Facial Recognition; Heterozygote; Humans; Huntingtin Protein; Huntington Disease; Magnetic Resonance Imaging; Male; Middle Aged; Nasal Sprays; Neuropsychological Tests; Oxytocin; Psychotropic Drugs; Trinucleotide Repeat Expansion; Young Adult

Early non-motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non-motor features and neuropathology.. To express mHTT only in OXT neurons, we used a novel flex-switch adeno-associated viral vector design to selectively express either mHTT or wild-type HTT in the paraventricular nucleus of the hypothalamus using OXT-Cre-recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3 months post-injection or at 2 months of age, respectively. Post-mortem analyses were performed to assess the effects on the OXT system.. Our results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT-immunopositive neurons as well as increased anxiety-like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point.. Our results indicate that mHTT expression can exert cell-autonomous toxic effects on OXT neurons without affecting the non-motor phenotype at early time points in mice.

Topics: Animals; Disease Models, Animal; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Neurons; Oxytocin; Phenotype

Huntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition.. We recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay.. We found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002).. This is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

Topics: Cognitive Dysfunction; Emotions; Humans; Huntington Disease; Oxytocin

The role of oxytocin (OT) in social cognition of patients with Huntington's disease (HD) has been studied, but its impact on executive functioning has not been explored yet. Healthy controls, premanifest HD, and manifest HD participants underwent executive functioning assessment and OT plasma measurement. There were no significant group differences in plasma OT levels. Higher OT levels were associated with better executive functioning in premanifest HD participants. Our findings revealed an association between OT levels and depressive symptoms in premanifest and manifest HD participants. The potential role of OT in HD deserves further investigation.

Topics: Executive Function; Humans; Huntington Disease; Neuropsychological Tests; Oxytocin; Pilot Projects

Learning and memory impairment manifests years before the onset of motor impairments in Huntington's disease (HD). Oxytocin (OXT), as a neurohypophyseal neuropeptide has a key role in both learning and memory. Hence, we investigated possible protective effect of OXT on instrumental fear conditioning memory impairment by 3-Nitropropionic acid (3-NP) induced HD, considering sex and prenatal stress effects. Pregnant Wistar rats were exposed to restraint stress for 45 min three times a day, from the gestational day 8 to parturition. 3-NP was injected intraperitoneally (20 mg/kg) for 5-7 days after OXT (10 μg/μl. icv) injection in the male and female offspring rats respectively. One day after the last 3-NP injection, the rotarod and passive avoidance task were conducted. As the key molecular determinants in metabolism and memory processes, we measured the activity of acetylcholinesterase (AChE) and the amount of receptor interacting protein3 (RIP3) in the hippocampus, prefrontal cortex, striatum and amygdala using spectrophotometry and western blotting respectively. Besides, the activity of glutamate dehydrogenase was measured (GDH) as a chain between metabolism and memory formation. The results indicated that OXT improved learning and memory impairment caused by 3-NP or prenatal stress in both sexes. It was along with a significant decrease in the level of RIP3, AChE and GDH activities. However, in the presence of prenatal stress, the OXT could improve 3-NP induced learning and memory impairments just in female rats. So it could be suggested as an effective neurotherapeutic agent in diseases such as HD, but its sex and context dependency should be considered carefully.

Topics: Animals; Behavior, Animal; Brain; Cognitive Dysfunction; Conditioning, Operant; Disease Models, Animal; Fear; Female; Huntington Disease; Male; Neurotoxins; Nitro Compounds; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Propionates; Rats; Rats, Wistar; Receptor-Interacting Protein Serine-Threonine Kinases; Sex Characteristics; Stress, Psychological

Neuropsychiatric disturbances with altered social cognition, depression and anxiety are among the most debilitating early features in the fatal neurodegenerative disorder Huntington disease (HD) which is caused by an expanded CAG repeat in the huntingtin gene. The underlying neurobiological mechanisms are not known. Neuropathological analyses of postmortem human HD hypothalamic tissue have demonstrated loss of the neuropeptides oxytocin and vasopressin. The dynamic interplay between these neuropeptides is crucial for modulating emotional and social behavior but its role in HD is unclear. In the present study, we have investigated the effect of expressing the mutant huntingtin gene on the development of behavioral changes using the transgenic BACHD mouse model at different ages. We show for the first time that BACHD mice exhibit deficits in social behavior with parallel aberrations in the balance of the oxytocin-vasopressin system. Importantly, our data also show that restoration of the interplay within the system with an acute dose of intranasal oxytocin immediately prior to behavioral testing can rescue the depressive-like phenotype but not anxiety-like behavior in this transgenic model. These findings demonstrate that imbalances in the oxytocin-vasopressin interplay contribute to the neuropsychiatric component of HD and suggest that interventions aimed at restoring the blunted levels of oxytocin may confer therapeutic benefits for this disease.

Topics: Administration, Intranasal; Animals; Animals, Newborn; Anxiety; Behavior, Animal; Disease Models, Animal; Female; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Oxytocin; Phenotype; Signal Transduction; Social Behavior; Vasopressins

Topics: Corpus Striatum; Humans; Huntington Disease; Hypothalamus; Male; Middle Aged; Neurons; Oxytocin; Vasopressins

Neuroendocrine, metabolic and autonomic nervous system dysfunctions are prevalent among patients with Huntington's disease (HD) and may underlie symptoms such as depression, weight loss and autonomic failure. Using post-mortem paraffin-embedded tissue, we assessed the integrity of the major neuropeptide populations in the paraventricular nucleus (PVN)-the hypothalamic neuroendocrine and autonomic integration center-in HD patients. The number corticotropin-releasing hormone, cocaine- and amphetamine-regulated transcript, arginine vasopressin and oxytocin immunoreactive (ir) neurons did not differ between HD patients and control subjects. However, the significant positive correlation between arginine vasopressin and oxytocin ir neurons in control subjects (P = 0.036) was absent in patients. Corticotropin-releasing hormone mRNA levels were 68% higher in HD patients (P = 0.046). Thyrotropin-releasing hormone mRNA levels did not differ between HD patients and control subjects, although a negative correlation with disease duration was present in the former (P = 0.036). These findings indicate that the PVN is largely unaffected in HD patients. However, our findings suggest that hypothalamic-pituitary-thyroid axis activity may alter during the course of the disease and that autonomic nervous system dysfunction might partly arise from an imbalance between arginine vasopressin and oxytocin neurons in the PVN.

Topics: Adult; Aged; Aged, 80 and over; Arginine Vasopressin; Corticotropin-Releasing Hormone; Female; Humans; Huntington Disease; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Neuropeptides; Oxytocin; Paraventricular Hypothalamic Nucleus; RNA, Messenger; Statistics, Nonparametric

Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.

Topics: Animals; Brain Chemistry; Down-Regulation; Green Fluorescent Proteins; Humans; Huntingtin Protein; Huntington Disease; Hypothalamus; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuropeptides; Nuclear Proteins; Oxytocin; Peptides; Promoter Regions, Genetic; RNA, Messenger; Vasopressins