Biology subjects

Horvath, T.

Publications and source records attributed to Horvath, T..

13 recordsLinked to original sources

bioRxiv2025

AgRP Neuronal Suppression by Spontaneous Movement Encodes Exercise Reinforcement

Hypothalamic agouti-related peptide (AgRP) neurons that drive hunger-related behaviors are activated during energy deficit, encode negative valence but can be inhibited even by perception of food without digestion. Here, we show that in head-fixed mice, discrete motor actions such as spontaneous walking and conditioned licking rapidly suppress AgRP neuron activity. This suppression persisted throughout movement and terminated upon cessation, which was independent of food perception or conditioned cues. The degree of suppression was positively correlated with movement vigor. While optogenetic enhancement of AgRP neuron suppression did not initiate movement, it promoted reinforcement of concurrent walking behavior. These findings unmask that spontaneous, low intensity physical activity can reduce AgRP neuron activity reinforcing concurrent movement/exercise with implications for systemic health benefits.

neuroscience↗

bioRxiv2025

Diet context gates AgRP neuron involvement in Semaglutide-induced weight loss

Semaglutide, a GLP-1R agonist, is widely used for obesity and type 2 diabetes, but its neural mechanisms remain unclear. AgRP neurons regulate energy balance, yet their role in Semaglutides effects is unknown. We show that sustained treatment of female mice with Semaglutide leads to activation rather than inhibition of AgRP neurons. Ablation or hypofunction of AgRP neurons through cell-specific knockout of Sirt1 reduces Semaglutide-induced weight loss and impairs its hypoglycemic effects in female mice under Standard Diet. However, acute or chronic exposure to High-Fat Diet makes AgRP neurons dispensable for weight loss, suggesting that neural substrates for the actions of Semaglutide depends on dietary composition. Re-exposure to Standard Diet recovers the necessity for AgRP neurons, underscoring the influence of nutritional status on GLP-1R pathways. Our findings show the necessity for AgRP neurons in sustaining Semaglutide-induced weight loss in female mice on standard diet in vivo.

neuroscience↗

bioRxiv2024

Sympathetic neuron-derived NPY protects from obesity by sustaining the mural progenitors of thermogenic adipocytes.

Neuropeptide Y (NPY) is secreted by sympathetic nerves1,2, but its direct impact on thermogenic adipocytes is unknown. Here we uncover the mechanism by which peripheral NPY protects from obesity. Our imaging of cleared murine brown and white adipose tissue (BAT and WAT) established that NPY+ sympathetic axons are only a minority that mostly maps to the peri-vasculature; our analysis of single-cell RNA-sequencing datasets identifies mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains mural cells, which are known to be a source of beige cells in both BAT and WAT3-5 and that NPY facilitates the differentiation to thermogenic adipocytes. We found that diet-induced-obesity leads to neuropathy of NPY+ axons and concomitant depletion of the mural cell pool of beige fat progenitors. This defect is replicated in conditional knockout (cKO) mice with NPY specifically abrogated from sympathetic neurons. These cKO mice have whitened BAT with reduced thermogenic ability and lower energy expenditure even before the onset of obesity; they develop adult-onset obesity on a regular chow diet and are more susceptible to diet induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by the sympathetic nerves has the opposite effect on body weight homeostasis by sustaining the proliferation of the mural cell progenitors of thermogenic adipocytes.

physiology↗

bioRxiv2021

LINE-1 activation in the cerebellum drives ataxia

Previous studies have revealed that dysregulation of long interspersed nuclear element 1 (LINE-1), a dominant class of transposable elements in the human genome, correlates with neurodegeneration1-3. Yet whether LINE-1 dysregulation is causal to disease pathogenesis has not been proven directly. Here, we demonstrate that expression of evolutionarily younger LINE-1 families is elevated in the cerebella of ataxia telangiectasia (AT) patients, which was correlated with extensive downregulation of epigenetic silencers. To examine whether LINE-1 activation causes neurologic disease, we established an approach to directly target and activate the promoter of a young family of LINE-1 in mice. LINE-1 activation in the cerebellum was sufficient to lead to robust progressive ataxia. Purkinje cells in the diseased mice exhibited marked electrophysiological dysfunctions and degeneration with a significant accumulation of cytoplasmic ribonucleoprotein LINE-1Orf1p aggregates, endoplasmic reticulum (ER) stress, and DNA damage. Treatment with lamivudine, a nucleoside reverse transcriptase inhibitor, blunted the disease progression by reducing DNA damage, attenuating gliosis and interferon gene signature, and recovering the loss of key functional molecules for calcium homeostasis in Purkinje cells. This study provides direct evidence that young LINE-1 activation drives ataxia phenotype, and points to its pleiotropic effects leading to DNA damage, inflammation, and dysfunction and degeneration of neurons.

neuroscience↗

bioRxiv2021

A novel approach in heart-rate-variability analysis

Heart-rate variability (HRV), measured by the fluctuation of beat-to-beat intervals, has been growingly considered the most important hallmark of heart rate (HR) time series. HRV can be characterized by various statistical measures both in the time and frequency domains, or by nonlinear methods. During the past decades, an overwhelming amount of HRV data has been piled up in the research community, but the individual results are difficult to reconcile due to the different measuring conditions and the usually HR-dependent statistical HRV-parameters applied. Moreover, the precise HR-dependence of HRV parameters is not known. Using data gathered by a wearable sensor of combined heart-rate and actigraphy modalities, here, we introduce a novel descriptor of HRV, based on a modified Poincare plot of 24-h RR-recordings. We show that there exists a - regressive biexponential - HRV versus HR "master" curve ("M-curve") that is highly conserved for a healthy individual on short and medium terms (on the hours to months scale, respectively). At the same time, we reveal how this curve is related to age in the case of healthy people, and establish alterations of the M-curves of heart-attack patients. A stochastic neuron model accounting for the observed phenomena is also elaborated, in order to facilitate physiological interpretation of HRV data. Our novel evaluation procedure applied on the time series of interbeat intervals allows the description of the HRV(HR) function with unprecedented precision. To utilize the full strength of the method, we suggest a 24-hour-long registration period under natural, daily-routine circumstances (i.e., no special measuring conditions are required). By establishing a patients M-curve, it is possible to monitor the development of his/her status over an extended period of time. On these grounds, the new method is suggested to be used as a competent tool in future HRV analyses for both clinical and training applications, as well as for everyday health promotion.

physiology↗

bioRxiv2020

Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior

Microglia have been implicated in synapse remodeling by phagocytosis of synaptic elements in the adult brain. However, the underlying mechanism of such process is ill-defined. By examining microglia-neuronal interaction in the ventral hippocampus, we found a significant reduction in spine synapse number during the light phase of the light/dark cycle accompanied by increased microglial phagocytosis. This was followed by a transient rise in microglial production of reactive oxygen species (ROS) and uncoupling protein 2 (Ucp2) expression, which is a regulator of mitochondrial ROS generation. Conditional ablation of microglial Ucp2 hindered phasic elimination of spine synapses, increased accumulations of ROS and lysosome-lipid droplet complexes leading to hippocampal circuitry disruption assessed by electrophysiology, and, altered anxiety-like behavior. These observations unmasked a novel and chronotypical interaction between microglia and neurons involved in control of brain functions.

neuroscience↗

bioRxiv2020

Defective Autophagy in Sf1 Neurons Perturbs the Metabolic Response to Fasting and Causes Mitochondrial Dysfunction

ObjectiveThe ventromedial nucleus of the hypothalamus (VMH) is a critical component of the forebrain pathways that regulate energy homeostasis. It also plays an important role in the metabolic response to fasting. However, the mechanisms contributing to these physiological processes remain elusive. Autophagy is an evolutionarily conserved mechanism that maintains cellular homeostasis by turning over cellular components and providing nutrients to the cells during starvation. Here we investigated the importance of the autophagy-related gene Atg7 in Sf1-expressing neurons of the VMH in control and fasted conditions. MethodsWe generated Sf1-Cre; Atg7loxP/loxP mice and examined their metabolic and cellular response to fasting. ResultsFasting induces autophagy in the VMH, and mice lacking Atg7 in Sf1-expressing neurons display altered regulation in glucose and leptin homeostasis and impaired energy expenditure regulation in response to fasting. Moreover, loss of Atg7 in Sf1 neurons causes alterations in the central response to fasting. Furthermore, alterations in mitochondria morphology and activity are observed in mutant mice. ConclusionTogether, these data show that autophagy is nutritionally regulated in VMH neurons and that VMH autophagy participates in the control of energy homeostasis during fasting.

neuroscience↗

bioRxiv2020

Mitochondrial fission governed by Drp1 regulates exogenous fatty acid usage and storage

The bioenergetic function of mitochondrial fission is associated with uncoupled respiration or elimination of damaged mitochondria to maintain a healthy mitochondrial population. In the presence of a high abundance of exogenous fatty acids, cells can either store fatty acids in lipid droplets or oxidize them in mitochondria. Even though carnitine palmitoyltransferase-1 (CPT1) controls the respiratory capacity of mitochondria in fatty acid oxidation, we observed that it did not dictate the balance of storage and usage of lipids in HeLa cells. On the other hand, inhibition of mitochondrial fission by silencing dynamic-related protein 1 (DRP1) resulted in an increase in fatty acid content of lipid droplets and a decrease in fatty acid oxidation. Mitochondrial fission was not only reflective of the amount of exogenous fatty acid being processed by mitochondria, but also found to be actively involved in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning.

cell biology↗

bioRxiv2020

DRP1 IS REQUIRED FOR AGRP NEURONAL ACTIVITY AND FEEDING

The hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons are crucial for the regulation of whole-body energy homeostasis. Here, we show that fasting-induced AgRP neuronal activation is associated with dynamin-related peptide 1 (Drp1)-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking Drp1 in adult AgRP neurons (Drp1AgRPKO) show decrease in fasting-or ghrelin-induced AgRP neuronal activity and feeding and exhibited a significant decrease in body weight, fat mass, and feeding accompanied by a significant increase in energy expenditure. In support of the role for mitochondrial fission and fatty acids oxidation, Drp1AgRPKO mice showed attenuated palmitic acid-induced mitochondrial respiration. Altogether, our data revealed that mitochondrial dynamics and fatty acids oxidation in hypothalamic AgRP neurons is a critical mechanism for AgRP neuronal function and associated behavior.

physiology↗

bioRxiv2020

Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model

Increasing age is the strongest predictor of risk of COVID-19 severity. Unregulated cytokine storm together with impaired immunometabolic response leads to highest mortality in elderly infected with SARS-CoV-2. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain MHV-A59 (mCoV-A59) that recapitulated majority of clinical hallmarks of COVID-19. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of {gamma}{delta} T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective {gamma}{delta} T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against COVID-19 in the elderly. Highlights - Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly. - Aged infected mice have systemic inflammation and inflammasome activation - Murine beta coronavirus (mCoV) infection results in loss of pulmonary {gamma}{delta} T cells. - Ketones protect aged mice from infection by reducing inflammation. eTOC BlurbElderly have the greatest risk of death from COVID-19. Here, Ryu et al report an aging mouse model of coronavirus infection that recapitulates clinical hallmarks of COVID-19 seen in elderly. The increased severity of infection in aged animals involved increased inflammasome activation and loss of {gamma}{delta} T cells that was corrected by ketogenic diet.

immunology↗

bioRxiv2020

The mammalian CLU homolog FMT controls development and behavior in Arabidopsis

Mitochondria in animals are associated with development, as well as physiological and pathological behaviors. Several conserved mitochondrial genes exist between plants and higher eukaryotes. Yet, comparative mitochondrial function among plant and animal species is poorly understood. Here, we show that FMT (FRIENDLY MITOCHONDRIA) from Arabidopsis thaliana, a highly conserved homolog of the mammalian CLU (CLUSTERED MITOCHONDRIA) gene family encoding mitochondrial proteins associated with developmental alterations and adult physiological and pathological behaviors, affects whole plant morphology and development under salt stress and control conditions. FMT was found to regulate mitochondrial morphology and dynamics as well as germination, root length, and flowering time. Here, we show that it also affects leaf expansion growth, salt stress-responses and hyponasty. Strikingly, FMT impacted the speed of hyponasty with corresponding change in speed of locomotion of CLU heterozygous knockout mice. These observations indicate that homologous genes affect homologous functions in plants and animals offering the possibility to develop plant models for the study of mammalian behaviors.

plant biology↗

bioRxiv2020

Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

microbiology↗

bioRxiv2018

Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation

Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5Gy x 5 fractions (total of 62.5Gy, D2EQ=140.6Gy), which would likely ablate pancreatic cancer. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.

cancer biology↗