Biology subjects

Reese, R.

Publications and source records attributed to Reese, R..

4 recordsLinked to original sources

bioRxiv2025

Inconsistent Subthalamic Beta Expression in the Local Field Potential amid In- and Anti-Phasic Neuronal Bursts.

BackgroundElevated beta (12-32 Hz) activity in the local field potential (LFP) of the subthalamic nucleus (STN) is a hallmark of Parkinsons disease and closely tied to synchronized spiking. Albeit the biomarkers prevalence has not been independently and reliably assessed, it is employed to guide deep brain stimulation (DBS) lead implantation. Likewise, beta is under investigation to inform DBS programming and adaptive DBS. This study assesses the applicability of these efforts by quantifying the biomarkers prevalence and investigating its relationship to synchronized beta-bursting neurons. MethodsSTN LFP and spiking activity of n = 156 patients with Parkinsons disease from six DBS centers recorded via microelectrodes was examined. Spectral peaks in the LFPs were classified and the absence of artifacts confirmed. The distribution of phase angles between beta LFP and spiking of individual beta-bursting neurons were explored. FindingsBilateral beta LFP expression was observed in 47{middle dot}25% of patients, and in 65{middle dot}59% of hemispheres. LFP-synchronized neuronal spiking clustered in two-thirds of neurons at a primary and in one-third at a secondary LFP phase (182{middle dot}84{degrees} phase shifted). This applied on the group level and for individual patients across different DBS centers. InterpretationBeta-informed approaches mandate reliable biomarker expression, a requirement not met by slightly more than half of herein investigated patients. This is particularly troublesome for intraoperative guidance wherein the cause of biomarker absence, including DBS lead misplacement or a balanced ratio of phasic and antiphasic spiking neurons, cannot be determined, decreasing insight and increasing doubt. Although beta LFPs remain a valuable biomarker, routine clinical practice should not rely on beta alone; instead, multiple biomarkers (i.e. beta-gamma coupling, finely tuned gamma and/or cortico-cortical beta-band coupling) should be evaluated simultaneously to increase robustness. FundingMaximilian Scherer received funding from the Alexander von Humboldt-Foundation. Thomas Koeglsperger has been supported by the Munich Clinician Scientist Program.

neuroscience↗

bioRxiv2025

Elevated plasma cholesterol causally improves sepsis outcome by promoting hepatic metabolic reprogramming

RationaleSepsis is a life-threatening condition with high mortality and limited therapeutic options. While hypocholesterolemia is associated with poor outcomes, the causal role of cholesterol and its underlying mechanisms remain unclear. ObjectivesTo determine whether elevated plasma cholesterol improves sepsis survival and to elucidate the mechanistic basis of this effect. MethodsWe analyzed septic patients from the MIMIC-IV database. Total cholesterol levels were compared between 28-day survivors and non-survivors using Wilcoxon rank-sum tests. Cox proportional hazards regression assessed the association between cholesterol levels and mortality, adjusting for age, sex, race, SOFA score, and Charlson comorbidity index. To establish causality, C57BL/6J mice were randomized to receive either a high-cholesterol diet (HCD) or regular diet (RD) for three days prior to cecal ligation and puncture (CLP) to induce sepsis. Measurements and Main ResultsSurvivors had significantly higher cholesterol levels than non-survivors (median, 135 vs. 126 mg/dL, p < 0.001). High cholesterol ([≥] 133 mg/dL) was independently associated with reduced 28-day mortality (adjusted HR = 0.80, 95% CI: 0.67-0.95, p = 0.012). In mice, HCD elevated plasma cholesterol and significantly improved survival (52.5% to 90%), independent of immune modulation.Hepatic transcriptomics revealed metabolic reprogramming, including upregulation of oxidative phosphorylation and glutathione-mediated antioxidant pathways, and suppression of endoplasmic reticulum proteostasis. Notably, inhibition of mitochondrial respiration abolished the survival benefit. ConclusionsElevated plasma cholesterol causally improves sepsis outcomes by promoting hepatic metabolic reprogramming. These findings offer mechanistic insight into clinical observations and suggest hepatic bioenergetics as a novel therapeutic target in sepsis.

physiology↗

bioRxiv2025

Identifying and treating CLN3 disease outside the central nervous system

Background and aimsSevere gastrointestinal (GI) symptoms occur in people with CLN3 disease, a neurodegenerative disorder. If left untreated these GI symptoms compromise life quality and may contribute to death. We hypothesized GI symptoms in CLN3 disease are at least partially due to neurodegeneration in the enteric nervous system (ENS), the master regulator of bowel function. MethodsWe examined the integrity of the ENS in human CLN3 autopsy small bowel and colon, and in CLN3 deficient (Cln3{Delta}ex7/8) mice. We performed detailed immunohistological analyses of enteric neurons and glia and assessed bowel transit times at multiple disease stages. We then tested the therapeutic potential of neonatal intravenous gene therapy (AAV9-hCLN3) to prevent bowel phenotypes in Cln3{Delta}ex7/8 mice. ResultsHuman CLN3 bowel displayed a profound loss of enteric neurons and their neurites, with pathological effects upon enteric glia. Cln3{Delta}ex7/8 mice had normal appearing ENS at 1 month of age, but then experienced progressive loss of both enteric neurons and glia accompanied by marked bowel distention, resembling the human CLN3 phenotype. Degenerative changes in Cln3{Delta}ex7/8 mouse enteric neurons and glia were largely prevented by systemic neonatal delivery of AAV9-hCLN3 gene therapy, preventing bowel distention at disease endstage. ConclusionsOur findings demonstrate that CLN3 deficiency profoundly damages enteric neurons and glia in both murine and human CLN3 disease, contributing to GI dysfunction. This study provides preclinical evidence that systemic gene therapy may effectively treat multiple aspects of bowel pathology, expanding the therapeutic landscape beyond the CNS. What you need to know: Background and ContextSignificant gastrointestinal (GI) symptoms are evident in many pediatric neurological conditions. We hypothesized that, in addition to central nervous system (CNS) effects, defects in the enteric nervous system (ENS) may underlie these GI symptoms in some neurodegenerative diseases. Revealing such defects would open up new opportunities for treating these life-limiting and debilitating symptoms. New FindingsThe enteric nervous system is significantly impacted in human CLN3 disease, a feature that is recapitulated in CLN3 mice. Progressive enteric neurodegeneration in these mice follows a similar time course to neuron loss in the brain, resulting in severe bowel distention. Nevertheless, bowel distention and the majority of the pathology within the enteric nervous system can be mitigated via neonatal gene therapy. LimitationsOur human data will need to be replicated in larger numbers of CLN3 cases, and methods will need to be developed to treat the human bowel, avoiding the risk of liver tumors. ImpactThese results reveal that a neurodegenerative disease previously thought to primarily affect the CNS, damages the bowels enteric nervous system and that ENS degeneration can be prevented in mice by gene therapy. These data provide a new perspective on this pediatric disorder and may have relevance to other pediatric neurologic diseases. Lay SummaryThe progressive loss of neurons in CLN3 disease is not confined to the brain but also occurs in the bowel enteric nervous system, contributing directly to GI dysfunction. Neurodegeneration in the enteric nervous system can be prevented by treating the bowel with gene therapy.

neuroscience↗

bioRxiv2020

Altered patterning of interneuron progenitors in Down syndrome

Individuals with Down syndrome (DS, Ts21), the most common genetic cause of intellectual disability, have smaller brains that reflect fewer neurons at pre- and post-natal stages, implicating impaired neurogenesis during development. Our stereological analysis of adult DS cortex indicates a reduction of calretinin expressing interneurons. Using Ts21 human induced pluripotent stem cells (iPSCs) and isogenic controls, we find Ts21 progenitors generate fewer COUP-TFII+ progenitors with reduced proliferation. Single cell RNA-sequencing of Ts21 progenitors confirms the altered specification of progenitor subpopulations and identifies reduced WNT signaling. Activation of WNT signaling partially restores the COUP-TFII+ progenitor population in Ts21, suggesting that altered WNT signaling contributes to the defective development of cortical interneurons in DS.

developmental biology↗