Kisspeptin signaling in astrocytes modulates the reproductive axis.

Reproduction is safeguarded by multiple, often cooperative regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein-interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular co-expression of Kiss1r with the astrocyte markers, GFAP and S100-ß, occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells, in the G-KiRKO mouse, altered gene expression of key factors in PGE2 synthesis in astrocytes, and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiRKO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity and LH-secretory profiles. Our data unveil a non-neuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress.

Hypothalamic hormone deficiency enables physiological anorexia.

Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5-7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24-48-hour periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center.

Searching for the Achilles' Heel of Urethane Linkage-An Energetic Perspective.

A sudden increase in polyurethane (PU) production necessitates viable recycling methods for the waste generated. PU is one of the most important plastic materials with a wide range of applications; however, the stability of the urethane linkage is a major issue in chemical recycling. In this work, termination reactions of a model urethane molecule, namely methyl N-phenyl carbamate (MPCate), are investigated using G3MP2B3 composite quantum chemical method. Our main goal was to gain insights into the energetic profile of urethane bond termination and find an applicable chemical recycling method. Hydrogenation, hydrolysis, methanolysis, peroxidation, glycolysis, ammonolysis, reduction with methylamine and termination by dimethyl phosphite were explored in both gas and condensed phases. Out of these chemicals, degradation by H2, H2O2 and CH3NH2 revealed promising results with lower activation barriers and exergonic pathways, especially in water solvation. Implementing these effective PU recycling methods can also have significant economic benefits since the obtained products from the reactions are industrially relevant substances. For example, aniline and dimethyl carbonate could be reusable in polymer technologies serving as potential methods for circular economy. As further potential transformations, several ionizations of MPCate were also examined including electron capture and detachment, protonation/deprotonation and reaction with OH-. Alkaline digestion against the model urethane MPCate was found to be promising due to the relatively low activation energy. In an ideal case, the transformation of the urethane bond could be an enzymatic process; therefore, potential enzymes, such as lipoxygenase, were also considered for the catalysis of peroxidation, and lipases for methanolysis.

A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.

Effect of Sex, Age, and Cardiovascular Risk Factors on Aortoiliac Segment Geometry.

Background: To investigate the geometry of the aortoiliac (AI) segment and its correlation with sex, age, and cardiovascular (CV) risk factors. Methods: Abdominal and pelvic CTA/MRA scans of 204 subjects (120 males; median age: 53 [IQR, 27-75] years) without AI steno-occlusive disease or scoliosis were retrospectively analyzed. The participants were enrolled consecutively, ensuring the representation of each age decade. An in-house written software was developed to assess AI elongation using the tortuosity index (TI) and absolute average curvature (AAC). Aortic bifurcation angle, common iliac artery (CIA) take-off and planarity angles, bifurcation asymmetry, and deviation from optimal bifurcation were calculated and evaluated. Demographic data, CV risk factors, and medical history were collected from electronic health records. Results: The elongation of the iliac arteries was more pronounced in males (TI: left CIA, p = 0.011; left EIA, p < 0.001; right CIA, p = 0.023; right EIA, p < 0.001; AAC: left EIA, p < 0.001; right EIA, p = 0.001). Age significantly influenced TI and AAC in all AI segments (all p < 0.001), but was also positively associated with the aortic bifurcation angle (p < 0.001), both CIA planarities (left, p < 0.001; right, p = 0.002), aortic bifurcation asymmetry (p = 0.001), and radius discrepancy (p < 0.001). Significant positive correlations were found between infrarenal aortic TI/AAC and chronic kidney disease (CKD) (p = 0.027 and p = 0.016), AAC of both CIAs and hypertension (left, p = 0.027; right, p = 0.012), right CIA take-off angle and CKD (p = 0.031), and left CIA planarity and hyperlipidemia (p = 0.006). Conclusion: Sex, age, and CV risk factors have a significant effect on the geometry of the AI segment.

microRNA-33 controls hunger signaling in hypothalamic AgRP neurons.

AgRP neurons drive hunger, and excessive nutrient intake is the primary driver of obesity and associated metabolic disorders. While many factors impacting central regulation of feeding behavior have been established, the role of microRNAs in this process is poorly understood. Utilizing unique mouse models, we demonstrate that miR-33 plays a critical role in the regulation of AgRP neurons, and that loss of miR-33 leads to increased feeding, obesity, and metabolic dysfunction in mice. These effects include the regulation of multiple miR-33 target genes involved in mitochondrial biogenesis and fatty acid metabolism. Our findings elucidate a key regulatory pathway regulated by a non-coding RNA that impacts hunger by controlling multiple bioenergetic processes associated with the activation of AgRP neurons, providing alternative therapeutic approaches to modulate feeding behavior and associated metabolic diseases.

Molecularly stratified hypothalamic astrocytes are cellular foci for obesity.

Astrocytes safeguard the homeostasis of the central nervous system1,2. Despite their prominent morphological plasticity under conditions that challenge the brain's adaptive capacity3-5, the classification of astrocytes, and relating their molecular make-up to spatially devolved neuronal operations that specify behavior or metabolism, remained mostly futile6,7. Although it seems unexpected in the era of single-cell biology, the lack of a major advance in stratifying astrocytes under physiological conditions rests on the incompatibility of 'neurocentric' algorithms that rely on stable developmental endpoints, lifelong transcriptional, neurotransmitter, and neuropeptide signatures for classification6-8 with the dynamic functional states, anatomic allocation, and allostatic plasticity of astrocytes1. Simplistically, therefore, astrocytes are still grouped as 'resting' vs. 'reactive', the latter referring to pathological states marked by various inducible genes3,9,10. Here, we introduced a machine learning-based feature recognition algorithm that benefits from the cumulative power of published single-cell RNA-seq data on astrocytes as a reference map to stepwise eliminate pleiotropic and inducible cellular features. For the healthy hypothalamus, this walk-back approach revealed gene regulatory networks (GRNs) that specified subsets of astrocytes, and could be used as landmarking tools for their anatomical assignment. The core molecular censuses retained by astrocyte subsets were sufficient to stratify them by allostatic competence, chiefly their signaling and metabolic interplay with neurons. Particularly, we found differentially expressed mitochondrial genes in insulin-sensing astrocytes and demonstrated their reciprocal signaling with neurons that work antagonistically within the food intake circuitry. As a proof-of-concept, we showed that disrupting Mfn2 expression in astrocytes reduced their ability to support dynamic circuit reorganization, a time-locked feature of satiety in the hypothalamus, thus leading to obesity in mice. Overall, our results suggest that astrocytes in the healthy brain are fundamentally more heterogeneous than previously thought and topologically mirror the specificity of local neurocircuits.

Predicting residual cholesteatoma with the Potsic staging system still lacks evidence: a systematic review and meta-analysis.

PURPOSE: To investigate the rate of residual disease in the Potsic staging system for congenital cholesteatomas. METHODS: A protocol registration was published on PROSPERO (CRD42022383932), describing residual disease as a primary outcome and hearing improvement as secondary. A systematic search was performed in four databases (PubMed, Embase, Cochrane Library, Web of Science) on December 14, 2022. Articles were included if cholesteatomas were staged according to the Potsic system and follow-up duration was documented. Risk of bias was evaluated using the Quality In Prognosis Studies (QUIPS) tool. In the statistical synthesis a random effects model was used. Between-study heterogeneity was assessed using I2. RESULTS: Thirteen articles were found to be eligible for systematic review and seven were included in the meta-analysis section. All records were retrospective cohort studies with high risk of bias. Regarding the proportions of residual disease, analysis using the χ2 test showed no statistically significant difference between Potsic stages after a follow-up of minimum one year (stage I 0.06 (confidence interval (CI) 0.01-0.33); stage II 0.20 (CI 0.09-0.38); stage III 0.06 (CI 0.00-0.61); stage IV: 0.17 (CI 0.01-0.81)). Postoperative and preoperative hearing outcomes could not be analyzed due to varied reporting. Results on cholesteatoma location and mean age at staging were consistent with those previously published. CONCLUSION: No statistically significant difference was found in the proportions of residual disease between Potsic stages, thus the staging system's applicability for outcome prediction could not be proven based on the available data. Targeted studies are needed for a higher level of evidence.

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.

Assessment of cerebral autoregulatory function and inter-hemispheric blood flow in older adults with internal carotid artery stenosis using transcranial Doppler sonography-based measurement of transient hyperemic response after carotid artery compression.

Unhealthy vascular aging promotes atherogenesis, which may lead to significant internal carotid artery stenosis (CAS) in 5 to 7.5% of older adults. The pathogenic factors that promote accelerated vascular aging and CAS also affect the downstream portion of the cerebral microcirculation in these patients. Primary treatments of significant CAS are eversion endarterectomy or endarterectomy with patch plasty. Factors that determine adequate hemodynamic compensation and thereby the clinical consequences of CAS as well as medical and surgical complications of carotid reconstruction surgery likely involve the anatomy of the circle of Willis (CoW), the magnitude of compensatory inter-hemispheric blood flow, and the effectiveness of cerebral microcirculatory blood flow autoregulation. This study aimed to test two hypotheses based on this theory. First, we hypothesized that patients with symptomatic and asymptomatic CAS would exhibit differences in autoregulatory function and inter-hemispheric blood flow. Second, we predicted that anatomically compromised CoW would associate with impaired inter-hemispheric blood flow compensation. We enrolled older adults with symptomatic or asymptomatic internal CAS (>70% NASCET criteria; n = 46) and assessed CoW integrity by CT angiography. We evaluated transient hyperemic responses in the middle cerebral arteries (MCA) after common carotid artery compression (CCC; 10 s) by transcranial Doppler sonography (TCD). We compared parameters reflecting autoregulatory function (e.g., transient hyperemic response ratio [THRR], return to baseline time [RTB], changes of vascular resistance) and inter-hemispheric blood flow (residual blood flow velocity). Our findings revealed that CAS was associated with impaired cerebral vascular reactivity. However, we did not observe significant differences in autoregulatory function or inter-hemispheric blood flow between patients with symptomatic and asymptomatic CAS. Moreover, anatomically compromised CoW did not significantly affect these parameters. Notably, we observed an inverse correlation between RTB and THRR, and 49% of CAS patients exhibited a delayed THRR, which associated with decreased inter-hemispheric blood flow. Future studies should investigate how TCD-based evaluation of autoregulatory function and inter-hemispheric blood flow can be used to optimize surgical techniques and patient selection for internal carotid artery revascularization.

Construction of Activity-based Anorexia Mouse Models.

Anorexia nervosa (AN) is a psychiatric disorder mainly characterized by extreme hypophagia, severe body weight loss, hyperactivity, and hypothermia. Currently, AN has the highest mortality rate among psychiatric illnesses. Despite decades of research, there is no effective cure for AN nor is there a clear understanding of its etiology. Since a complex interaction between genetic, environmental, social, and cultural factors underlines this disorder, the development of a suitable animal model has been difficult so far. Here, we present our protocol that couples a loss-of-function mouse model to the activity-based anorexia model (ABA), which involves self-imposed starvation in response to exposure to food restriction and exercise. We provide insights into a neural circuit that drives survival in AN and, in contrast to previous protocols, propose a model that mimics the conditions that mainly promote AN in humans, such as increased incidence during adolescence, onset preceded by negative energy balance, and increased compulsive exercise. This protocol will be useful for future studies that aim to identify neuronal populations or brain circuits that promote the onset or long-term maintenance of this devastating eating disorder.

A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of Tet3, which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.

Neonatal loss of FGFR2 in astroglial cells affects locomotion, sociability, working memory, and glia-neuron interactions in mice.

Fibroblast growth factor receptor 2 (FGFR2) is almost exclusively expressed in glial cells in postnatal mouse brain, but its impact in glia for brain behavioral functioning is poorly understood. We compared behavioral effects from FGFR2 loss in both neurons and astroglial cells and from FGFR2 loss in astroglial cells by using either the pluripotent progenitor-driven hGFAP-cre or the tamoxifen-inducible astrocyte-driven GFAP-creERT2 in Fgfr2 floxed mice. When FGFR2 was eliminated in embryonic pluripotent precursors or in early postnatal astroglia, mice were hyperactive, and had small changes in working memory, sociability, and anxiety-like behavior. In contrast, FGFR2 loss in astrocytes starting at 8 weeks of age resulted only in reduced anxiety-like behavior. Therefore, early postnatal loss of FGFR2 in astroglia is critical for broad behavioral dysregulation. Neurobiological assessments demonstrated that astrocyte-neuron membrane contact was reduced and glial glutamine synthetase expression increased only by early postnatal FGFR2 loss. We conclude that altered astroglial cell function dependent on FGFR2 in the early postnatal period may result in impaired synaptic development and behavioral regulation, modeling childhood behavioral deficits like attention deficit hyperactivity disorder (ADHD).

Factors influencing successful reconstruction of tympanic membrane perforations: a systematic review and meta-analysis.

PURPOSE: Based on a systematic review and meta-analysis, our study aimed to provide information about the factors that influence the success of tympanic membrane reconstruction. METHODS: Our systematic search was conducted on November 24, 2021, using the CENTRAL, Embase, and MEDLINE databases. Observational studies with a minimum of 12 months of follow-up on type I tympanoplasty or myringoplasty were included, while non-English articles, patients with cholesteatoma or specific inflammatory diseases, and ossiculoplasty cases were excluded. The protocol was registered on PROSPERO (registration number: CRD42021289240) and PRISMA reporting guideline was used. Risk of bias was evaluated with the QUIPS tool. A random effect model was used in the analyses. Primary outcome was the rate of closed tympanic cavities. RESULTS: After duplicate removal, 9454 articles were found, of which 39 cohort studies were included. Results of four analyses showed significant effects: age (OR: 0.62, CI 0.50; 0.78, p value: 0.0002), size of the perforation (OR: 0.52, CI 0.29; 0.94, p value: 0.033), opposite ear condition (OR: 0.32, CI 0.12; 0.85, p value: 0.028), and the surgeon's experience (OR: 0.42, CI 0.26; 0.67, p value: 0.005), while prior adenoid surgery, smoking, the site of the perforation, and discharge of the ear did not. Four factors: etiology, Eustachian tube function, concomitant allergic rhinitis, and duration of the ear discharge were analyzed qualitatively. CONCLUSIONS: The age of the patient, the size of the perforation, the opposite ear status, and the surgeon's experience have a significant effect on the success of tympanic membrane reconstruction. Further comprehensive studies are needed to analyze the interactions between the factors. LEVEL OF EVIDENCE: Not applicable.

[The efficacy of STOP-BANG questionnaire in screening of benign snoring and mild obstructive sleep apnea]. / A STOP-BANG kérdoív hatékonysága a benignus horkolás és az enyhe obstruktív alvási apnoe kiszurésében.

INTRODUCTION: Polysomnography is the gold standard for diagnosing sleep-related breathing disorders. Respiratory pulse oximetry can be used for screening, and several pre-screening questionnaires are available to assess the risk of obstructive sleep apnea. STOP-BANG questionnaire is simple and effective according to the literature. OBJECTIVE: Investigating the effectiveness of the STOP-BANG questionnaire for screening benign snoring and mild obstructive sleep apnea. METHOD: We analyzed the data of patients examined in our department for suspected sleep-related breathing disorder between 20. 06. 2021 and 19. 03. 2022. We compared the subsequently calculated STOP-BANG scores to the respiratory pulsoximetry results. Due to the lack of information regarding the intensity of snoring, the analysis was performed both with positive and negative results for this criterion. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: We analyzed the data of 36 patients, one of them was examined twice due to weight loss. Benign snoring was confirmed by 19 patients, mild obstructive sleep apnea in 9, moderate in 4, and severe in 5 cases. Assuming loud snoring, the sensitivity was 100%, the specificity 21%, the positive predictive value 29%, and the negative predictive value 100%. Assuming no loud snoring, the sensitivity was 100%, the specificity 54%, the positive predictive value 41%, and the negative predictive value 100%. CONCLUSION: STOP-BANG questionnaire is effective, and can also be used in primary care to screen benign snoring and mild obstructive sleep apnea. Unnecessary device tests can be reduced by using it, resulting in significantly shorter waiting times for the sleep tests for high-risk patients. Orv Hetil. 2023; 164(7): 265-272.

Primary ossiculoplasties provide better hearing results than revisions: a retrospective cohort study.

PURPOSE: To evaluate the efficacy of ossicular chain reconstruction (OCR) in primary and revision surgeries, and to investigate the impact of the number of previous surgeries on hearing outcomes. METHODS: Retrospective analysis of cases with OCR due to chronic otitis in a tertiary center between January 2018 and September 2021. RESULTS: Altogether, 147 cases of ossicle involvement were assessed. In 91.83% (n = 135) OCR was performed, 96.26% of them with titanium TORP/PORP (n = 130), two cases with autologous prosthesis and three with piston. Mean follow-up was 8.8 months. The ABG significantly improved in the total group (TORP/PORP) from a mean (SD) of 30.94 (15.55) to 19.76 (13.36) dB (p < 0.0001) with 60.86% success. The best results were achieved in primary OCR with PORP implantation without cholesteatoma (89.47%). Primary cases have a significantly higher success rate in contrary to revision surgeries (72.27%, vs. 52.00%, p = 0.032). The only relevant predictive factor proved to be the fact of revision (p = 0.029). A statistically significant correlation between the number of previous surgeries and hearing results could not be proved. There was no difference in hearing outcomes between patients with only one or more than one previous surgeries in the revision groups. Neither the presence of cholesteatoma, nor the type of OCR (TOPR/PORP) and the indication of revision had an impact on postoperative ABG. CONCLUSIONS: Titanium prostheses are effective in OCR both in primary and revision cases. It is not the number of previous surgeries, but the fact of revision that influences postoperative hearing results.

Two-Year observational study of autonomic skin function in patients with Parkinson's disease compared to healthy individuals.

BACKGROUND AND PURPOSE: We characterized autonomic pilomotor and sudomotor skin function in early Parkinson's disease (PD) longitudinally. METHODS: We enrolled PD patients (Hoehn and Yahr 1-2) and healthy controls from movement disorder centers in Germany, Hungary, and the United States. We evaluated axon-reflex responses in adrenergic sympathetic pilomotor nerves and in cholinergic sudomotor nerves and assessed sympathetic skin response (SSR), predominantly parasympathetic neurocardiac function via heart rate variability, and disease-related symptoms at baseline, after 2 weeks, and after 1 and 2 years. CLINICALTRIALS: gov: NCT03043768. RESULTS: We included 38 participants: 26 PD (60% females, aged 62.4 ± 7.4 years, mean ± SD) and 12 controls (75% females, aged 59.5 ± 5.8 years). Pilomotor function was reduced in PD compared to controls at baseline when quantified via spatial axon-reflex spread (78 [43-143], median [interquartile range] mm2 vs. 175 [68-200] mm2 , p = 0.01) or erect hair follicle count in the axon-reflex region (8 [6-10] vs. 11 [6-16], p = 0.008) and showed reliability absent any changes from baseline to Week 2 (p = not significant [ns]). Between-group differences increased over the course of 2 years (p < 0.05), although no decline was observed within groups (p = ns). Pilomotor impairment in PD correlated with motor symptoms (rho = -0.59, p = 0.017) and was not lateralized (p = ns). Sudomotor axon-reflex and neurocardiac function did not differ between groups (p = ns), but SSR was reduced in PD (p = 0.0001). CONCLUSIONS: Impairment of adrenergic sympathetic pilomotor function and SSR in evolving PD is not paralleled by changes to cholinergic sudomotor function and parasympathetic neurocardiac function, suggesting a sympathetic pathophysiology. A pilomotor axon-reflex test might be useful to monitor PD-related pathology.

Impaired Ghrelin Signaling Does Not Lead to Alterations of Anxiety-like Behaviors in Adult Mice Chronically Exposed to THC during Adolescence.

As marijuana use during adolescence has been increasing, the need to understand the effects of its long-term use becomes crucial. Previous research suggested that marijuana consumption during adolescence increases the risk of developing mental illnesses, such as schizophrenia, depression, and anxiety. Ghrelin is a peptide produced primarily in the gut and is important for feeding behavior. Recent studies have shown that ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR), play important roles in mediating stress, as well as anxiety and depression-like behaviors in animal models. Here, we investigated the effects of chronic tetrahydrocannabinol (THC) administration during late adolescence (P42-55) in GHSR (GHSR -/-) knockout mice and their wild-type littermates in relation to anxiety-like behaviors. We determined that continuous THC exposure during late adolescence did not lead to any significant alterations in the anxiety-like behaviors of adult mice, regardless of genotype, following a prolonged period of no exposure (1 month). These data indicate that in the presence of intact or impaired ghrelin/GHSR signaling, THC exposure during late adolescence has limited if any long-term impact on anxiety-like behaviors in mice.