Medical Sciences Commons^™

Distinct Adipose Progenitor Cells Emerging With Age Drive Active Adipogenesis, Guan Wang, Gaoyan Li, Anying Song, Yutian Zhao, Jiayu Yu, Yifan Wang, Wenting Dai, Martha Salas, Hanjun Qin, Leonard Medrano, Joan Dow, Aimin Li, Brian Armstrong, Patrick T Fueger, Hua Yu, Yi Zhu, Mengle Shao, Xiwei Wu, Lei Jiang, Judith Campisi, Xia Yang, Qiong A Wang

Children’s Nutrition Research Center Staff Publications

Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was …

A Deep Learning Strategy To Identify Cell Types Across Species From High-Density Extracellular Recordings, Maxime Beau, David J Herzfeld, Francisco Naveros, Marie E Hemelt, Federico D'Agostino, Marlies Oostland, Alvaro Sánchez-López, Young Yoon Chung, Michael Maibach, Stephen Kyranakis, Hannah N Stabb, M Gabriela Martínez Lopera, Agoston Lajko, Marie Zedler, Shogo Ohmae, Nathan J Hall, Beverley A Clark, Dana Cohen, Stephen G Lisberger, Dimitar Kostadinov, Court Hull, Michael Häusser, Javier F Medina

Faculty, Staff and Students Publications

High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but fail to reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals and reveal the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetics and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep learning classifier that predicts cell types with greater than 95% accuracy based on the waveform, discharge …

Nitrate Ameliorates Alcohol-Induced Cognitive Impairment Via Oral Microbiota, Xiangxue Li, Zhaojun Ni, Weixiong Shi, Kangqing Zhao, Yanjie Zhang, Lina Liu, Zhong Wang, Jie Chen, Zhoulong Yu, Xuejiao Gao, Ying Qin, Jingwen Zhao, Wenjuan Peng, Jie Shi, Thomas R Kosten, Lin Lu, Lei Su, Yanxue Xue, Hongqiang Sun

Faculty, Staff and Students Publications

Alcohol use is associated with cognitive impairment and dysregulated inflammation. Oral nitrate may benefit cognitive impairment in aging through altering the oral microbiota. Similarly, the beneficial effects of nitrate on alcohol-induced cognitive decline and the roles of the oral microbiota merit investigation. Here we found that nitrate supplementation effectively mitigated cognitive impairment induced by chronic alcohol exposure in mice, reducing both systemic and neuroinflammation. Furthermore, nitrate restored the dysbiosis of the oral microbiota caused by alcohol consumption. Notably, removing the oral microbiota led to a subsequent loss of the beneficial effects of nitrate. Oral microbiota from donor alcohol use disordered …

Somatodendritic Orientation Determines Tdcs-Induced Neuromodulation Of Purkinje Cell Activity In Awake Mice, Carlos A Sánchez-León, Guillermo Sánchez-Garrido Campos, Marta Fernández, Álvaro Sánchez-López, Javier F Medina, Javier Márquez-Ruiz

Faculty, Staff and Students Publications

Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits in vivo. We investigated how Cb-tDCS affects the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex to understand the underlying mechanisms behind the polarity-dependent modulation of neuronal activity induced by tDCS. Mice (n=9) were prepared for the chronic recording of local field potentials (LFPs) to assess the actual electric field gradient imposed by …

Region-Specific Roles Of Oviductal Motile Cilia In Oocyte/Embryo Transport And Fertility†, Deirdre M Scully, Tian Xia, Guzel R Musina, Michaela A Mccown, Kohei Umezu, Bonnie K Kircher, Richard R Behringer, Irina V Larina

Faculty, Staff and Students Publications

The physiological and clinical importance of motile cilia in reproduction is well recognized; however, the specific role they play in transport through the oviduct and how ciliopathies lead to subfertility and infertility are still unclear. The contribution of cilia beating, fluid flow, and smooth muscle contraction to overall progressive transport within the oviduct remains under debate. Therefore, we investigated the role of cilia in the oviduct transport of preimplantation eggs/embryos using a combination of genetic and advanced imaging approaches. We show that the region of the oviduct where cumulus-oocyte complex circling occurs, around the time of fertilization, is correlated with …

An Unsupervised Map Of Excitatory Neuron Dendritic Morphology In The Mouse Visual Cortex, Marissa A Weis, Stelios Papadopoulos, Laura Hansel, Timo Lüddecke, Brendan Celii, Paul G Fahey, Eric Y Wang, J Alexander Bae, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Manuel A Castro, Forrest Collman, Nuno Maçarico Da Costa, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, R Clay Reid, Casey M Schneider-Mizell, H Sebastian Seung, William Silversmith, Marc Takeno, Russel Torres, Nicholas L Turner, William Wong, Jingpeng Wu, Wenjing Yin, Szi-Chieh Yu, Jacob Reimer, Philipp Berens, Andreas S Tolias, Alexander S Ecker

Faculty, Staff and Students Publications

Neurons in the neocortex exhibit astonishing morphological diversity, which is critical for properly wiring neural circuits and giving neurons their functional properties. However, the organizational principles underlying this morphological diversity remain an open question. Here, we took a data-driven approach using graph-based machine learning methods to obtain a low-dimensional morphological "bar code" describing more than 30,000 excitatory neurons in mouse visual areas V1, AL, and RL that were reconstructed from the millimeter scale MICrONS serial-section electron microscopy volume. Contrary to previous classifications into discrete morphological types (m-types), our data-driven approach suggests that the morphological landscape of cortical excitatory neurons is …

The Medial Olivocochlear Efferent Pathway Potentiates Cochlear Amplification In Response To Hearing Loss, Patricia M Quiñones, Michelle Pei, Hemant Srivastava, Ariadna Cobo-Cuan, Marcela A Morán, Bong Jik Kim, Clayton B Walker, Michael J Serafino, Frank Macias-Escriva, Juemei Wang, James B Dewey, Brian E Applegate, Matthew J Mcginley, John S Oghalai

Faculty, Staff and Students Publications

The mammalian cochlea receives efferent feedback from the brain. Many functions for this feedback have been hypothesized, including on short timescales, such as mediating attentional states, and long timescales, such as buffering acoustic trauma. Testing these hypotheses has been impeded by an inability to make direct measurements of efferent effects in awake animals. Here, we assessed the role of the medial olivocochlear (MOC) efferent nerve fibers on cochlear amplification by measuring organ of Corti vibratory responses to sound in both sexes of awake and anesthetized mice. We studied long-term effects by genetically ablating the efferents and/or afferents. Cochlear amplification increased …

Gpat4 Sustains Endoplasmic Reticulum Homeostasis In Endocardial Cells And Safeguards Heart Development, Tianyang Zhao, Kuipei Jin, Xiaodong Wang, Xiong Su, Youjun Wang, Mingming Gao, Wen Luo, Hongyuan Yang, Zhongzhou Yang

Faculty, Staff and Student Publications

The endocardium plays a pivotal role in governing myocardial development, and understanding the intrinsic regulatory insights will help apprehend pathological cardiomyopathy. Glycerol-3-phosphate acyltransferase 4 (GPAT4) is an endoplasmic reticulum (ER) membrane anchored protein. While the role of GPAT4 in glycerophospholipid biosynthesis is well established, its function in the ER is less explored. Here, we generate Gpat4 global and tissue-specific knockout mice and identify the essential role of GPAT4 in endocardial development. Deficiency of GPAT4 provokes endocardial ER stress response and enhances ER-mitochondrial (ER-mito) communications, leading to mitochondrial DNA (mtDNA) escape. As a result, the cGAS-STING pathway is triggered to stimulate …

Vestibular Neurons Link Motion Sickness, Behavioural Thermoregulation And Metabolic Balance In Mice, Longlong Tu, Xing Fang, Yongjie Yang, Meng Yu, Hailan Liu, Hesong Liu, Na Yin, Jonathan C Bean, Kristine M Conde, Mengjie Wang, Yongxiang Li, Olivia Z Ginnard, Qingzhuo Liu, Yuhan Shi, Junying Han, Yi Zhu, Makoto Fukuda, Qingchun Tong, Benjamin Arenkiel, Mingshan Xue, Yang He, Chunmei Wang, Yong Xu

Children’s Nutrition Research Center Staff Publications

Motion sickness is associated with thermoregulation and metabolic control, but the underlying neural circuitry remains largely unknown. Here we show that neurons in the medial vestibular nuclei parvocellular part (MVePC) mediate the hypothermic responses induced by motion. Reactivation of motion-sensitive MVePC neurons recapitulates motion sickness in mice. We show that motion-activated neurons in the MVePC are glutamatergic (MVePCGlu), and that optogenetic stimulation of MVePCGlu neurons mimics motion-induced hypothermia by signalling to the lateral parabrachial nucleus (LPBN). Acute inhibition of MVePC-LPBN circuitry abrogates motion-induced hypothermia. Finally, we show that chronic inhibition of MVePCGlu neurons prevents diet-induced obesity and improves glucose homeostasis …

Destructive And Protective Effects And Therapeutic Targets Of Il-36 Family Cytokines In Dry Eye Disease, Xin Chen, Na Lin, Haixia Liu, Jing Lin, Ning Gao, Zhao Liu, Cintia S De Paiva, Stephen C Pflugfelder, De-Quan Li

Faculty, Staff and Students Publications

Purpose: To explore the destructive and protective effects and therapeutic targets of IL-36 cytokines in dry eye disease using a murine dry eye model.

Methods: A dry eye model was established in C57BL/6 mice exposed to desiccating stress (DS) with untreated mice as controls. A topical challenge model was performed in normal mice with exogenous rmIL-36α, rhIL-38 and 2 % ectoine, or PBS vehicle. IL-36 cytokine expression was assessed by RT-qPCR and immunofluorescent (IF) staining. Corneal epithelial damage was evaluated by corneal smoothness score, Oregon Green Dextran (OGD) fluorescent staining, and tight junction barrier.

Results: All members of the IL-36 …

Klf4 Enhances Transplantation-Induced Hematopoiesis By Inhibiting Tlrs And Noncanonical Nfκb Signaling At A Steady State, Chun Shik Park, Cory S Bridges, Andrew H Lewis, Taylor J Chen, Saptarsi Shai, Wa Du, Monica Puppi, Barry Zorman, Sumazin Pavel, H Daniel Lacorazza

Faculty, Staff and Students Publications

The transcription factor Krüppel-like factor 4 (KLF4) acts as a transcriptional activator and repressor. KLF4 plays a role in various cellular processes, including the dedifferentiation of somatic cells into induced pluripotent stem cells. Although it has been shown to enhance self-renewal in embryonic and leukemia stem cells, its role in adult hematopoietic stem cells (HSCs) remains underexplored. We demonstrate that conditional deletion of the Klf4 gene in hematopoietic cells led to an increased frequency of immunophenotypic HSCs in the bone marrow, along with a normal distribution of lymphoid and myeloid progenitor cells. Noncompetitive bone marrow transplants showed normal engraftment and …

Mapping The Transcriptional And Epigenetic Landscape Of Organotypic Endothelial Diversity In The Developing And Adult Mouse, Manuel E Cantu Gutierrez, Matthew C Hill, Gabrielle E Largoza, William B Gillespie, James F Martin, Joshua D Wythe

Faculty, Staff and Students Publications

The vascular endothelium features unique molecular and functional properties across different vessel types, such as between arteries, veins and capillaries, as well as between different organs, such as the leaky sinusoidal endothelium of the liver versus the impermeable vessels of the brain. However, the transcriptional networks governing endothelial organ specialization remain unclear. Here we profile the accessible chromatin and transcriptional landscapes of the endothelium from the mouse liver, lung, heart, kidney, brain and retina, across developmental time, to identify potential transcriptional regulators of endothelial heterogeneity. We then determine which of these putative regulators are conserved in human brain endothelial cells, …

Sialidase Fusion Protein Protects Against Influenza Infection In A Cigarette Smoke-Induced Model Of Copd, Cheng-Yen Chang, Dominique Armstrong, John M Knight, Trevor V Gale, Stephen Hawley, Max Wang, Nancy Chang, David B Corry, Farrah Kheradmand

Faculty, Staff and Students Publications

First- and secondhand smokers are at an increased risk for influenza virus (IFV)-related respiratory failure and death. Despite approved influenza antiviral treatments, there is an unmet need for treatments that can improve outcomes in populations at risk for respiratory failure, including tobacco users with Chronic Obstructive Pulmonary Disease (COPD). Here we show that the sialidase fusion protein, DAS181, reduced viral burden, mitigated inflammation, and attenuated lung function loss, consistent with broad-spectrum anti-influenza responses in a mouse model of COPD and IFV-A infection. Treatment with DAS181 reprogramed the sialic acid-binding immunoglobulin-like lectins (Siglecs) in alveolar macrophages, increased expression of phagocytic marker …

Foamy Monocytes And Atherogenesis In Mice With Combined Hyperlipidemia And Effects Of Antisense Knockdown Of Apociii, Xueying Peng, Zeqin Lian, Veronica O'Brien, Jing Xiao, Benjamin A Litchfield, Xiao-Yuan Dai Perrard, Lu Xu, Jing Ni, Aparna Mukherjee, Timothy Simmons, Henry Dong, Adam E Mullick, Rosanne Crooke, Henry J Pownall, Scott I Simon, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

Hypertriglyceridemia (HTG), particularly in combined hyperlipidemia, increases risk for atherosclerotic cardiovascular disease, but the underlying mechanisms remain incompletely understood. We sought to determine contributions of circulating monocytes to atherosclerosis associated with HTG in combined hyperlipidemia, created by transgenic expression of human apoCIII in Ldlr−/− mice (Ldlr−/−ApoCIIItg) fed Western high-fat diet (WD). Tissue culture with THP-1 and primary human monocytes was used to examine effects of triglyceride (TG)-rich lipoproteins on monocytes. Ldlr−/−ApoCIIItg mice were also treated with apoCIII antisense oligonucleotide (ASO) and examined for foamy monocytes and atherosclerosis. Compared to Ldlr−/− mice, Ldlr−/−ApoCIIItg mice fed …

Foraging Animals Use Dynamic Bayesian Updating To Model Meta-Uncertainty In Environment Representations, James Webb, Paul Steffan, Benjamin Y Hayden, Daeyeol Lee, Caleb Kemere, Matthew Mcginley

Faculty, Staff and Students Publications

Foraging theory predicts animal behavior in many contexts. In patch-based foraging behaviors, the marginal value theorem (MVT) gives the optimal strategy for deterministic environments whose parameters are fully known to the forager. In natural settings, environmental parameters exhibit variability and are only partially known to the animal based on its experience, creating uncertainty. Models of uncertainty in foraging are well established. However, natural environments also exhibit unpredicted changes in their statistics. As a result, animals must ascertain whether the currently observed quality of the environment is consistent with their internal models, or whether something has changed, creating meta-uncertainty. Behavioral strategies …

Sialidase Fusion Protein Protects Against Influenza Infection In A Cigarette Smoke-Induced Model Of Copd, Cheng-Yen Chang, Dominique Armstrong, John M Knight, Trevor V Gale, Stephen Hawley, Max Wang, Nancy Chang, David B Corry, Farrah Kheradmand

Faculty, Staff and Students Publications

First- and secondhand smokers are at an increased risk for influenza virus (IFV)-related respiratory failure and death. Despite approved influenza antiviral treatments, there is an unmet need for treatments that can improve outcomes in populations at risk for respiratory failure, including tobacco users with Chronic Obstructive Pulmonary Disease (COPD). Here we show that the sialidase fusion protein, DAS181, reduced viral burden, mitigated inflammation, and attenuated lung function loss, consistent with broad-spectrum anti-influenza responses in a mouse model of COPD and IFV-A infection. Treatment with DAS181 reprogramed the sialic acid-binding immunoglobulin-like lectins (Siglecs) in alveolar macrophages, increased expression of phagocytic marker …

Insulin-Like Growth Factor 2 As A Driving Force For Exponential Expansion And Differentiation Of The Neonatal Thymus, Seung Woo Kang, Bryan R Helm, Yu Wang, Shiyun Xiao, Wen Zhang, Anusha Vasudev, Ken S Lau, Qi Liu, Ellen R Richie, Laura P Hale, Nancy R Manley

Faculty, Staff and Student Publications

Like all organs, the thymus grows in size and function rapidly during development, but this growth comes to a halt after birth. However, the molecular mechanisms behind such a transition in the thymus remain obscure. Using single-cell RNA sequencing (scRNA-seq) of the murine thymic stroma, we identified that major transcriptomic changes occur in the endothelium and mesenchyme across the transition to homeostasis. Differentially expressed gene and intercellular network analyses of temporally resolved scRNA-seq data revealed fibroblast-derived insulin-like growth factor 2 (IGF2) as a candidate driving neonatal thymic expansion. We demonstrated that IGF2 activity promotes a cortical thymic epithelial cell-specific proliferation …

In Vivo Antibody Labeling Route And Fluorophore Dictate Labeling Efficiency, Sensitivity, And Longevity, Natalie B Hagan, Charles Inaku, Nikesh Kunder, Tayleur White, Thierry Iraguha, Anna Meyer, Kristen E Pauken, Jason M Schenkel

Faculty, Staff and Student Publications

Leukocytes migrate through the blood and extravasate into organs to surveil the host for infection or cancer. Recently, we demonstrated that intravenous (IV) anti-CD45.2 antibody labeling allowed for precise tracking of leukocyte migration. However, the narrow labeling window can make this approach challenging for tracking rare migration events. Here, we show that altering antibody administration route and fluorophore can significantly extend the antibody active labeling time. We found that while both IV and intraperitoneal (IP) anti-CD45.2 antibody labeled circulating leukocytes after injection, they had different kinetic properties that impacted labeling time and intensity. Quantification of circulating antibody revealed that while …

Suppression Of Hypothalamic Oestrogenic Signal Sustains Hyperprolactinemia And Metabolic Adaptation In Lactating Mice, Meng Yu, Bing Feng, Jonathan C Bean, Qianru Zhao, Yongjie Yang, Hailan Liu, Yongxiang Li, Benjamin P Eappen, Hesong Liu, Longlong Tu, Kristine M Conde, Mengjie Wang, Xi Chen, Na Yin, Darah Ave Threat, Nathan Xu, Junying Han, Peiyu Gao, Yi Zhu, Darryl L Hadsell, Yang He, Pingwen Xu, Yanlin He, Chunmei Wang

Faculty, Staff and Students Publications

17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia …

Alpha-Synuclein Phosphomimetic Y39e And S129d Knock-In Mice Show Cytosolic Alpha-Synuclein Localization Without Developing Neurodegeneration Or Motor Deficits, Youngdoo Kim, Bhupesh Vaidya, Joseph Mcinnes, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor symptoms. Its pathological hallmarks include the accumulation of misfolded alpha-synuclein (α-Syn) in Lewy bodies and Lewy neurites. Phosphorylation of α-Syn is a prominent feature of these inclusions, but its role in disease pathogenesis remains unclear. To identify the role of α-Syn phosphorylation in synucleinopathy, we generated two Snca knock-in (KI) mouse models carrying phosphomimetic mutations at SncaY39 or SncaS129 (Snca^Y39E or Snca^S129D) which manipulated epitopes phosphorylated in the PD brain. Both Snca^Y39E and Snca^S129D KI mice displayed increased α-Syn phosphorylation, enhanced …

Characterization Of Hepatic Pathology During Azoxymethane-Induced Acute Liver Failure, Shadikchhya Maya Bhattarai, Ashwin Jhawer, Gabriel Frampton, Eleonora Troyanovskaya, Sharon Demorrow, Matthew Mcmillin

Faculty, Staff and Students Publications

Background: Acute liver failure (ALF) is a loss of liver function due to a severe hepatic insult. Studies utilizing the azoxymethane (AOM) mouse model of ALF, which also generates hepatic encephalopathy, have primarily focused on development of neurological deficits. However, the molecular processes that generate liver damage have not been fully characterized. Therefore, a more comprehensive characterization of the hepatic consequences of AOM toxicity is needed to better understand this disease model.

Aim: To identify molecular pathology contributing to hepatic injury during the progression of AOM-induced ALF.

Methods: C57BL/6 mice were injected with AOM to produce ALF and hepatic encephalopathy. …

Effects Of Prebiotic Phytocompound Administration In Gestational Diabetic Dams And Its Influence On Offspring Cognitive Outcomes, Gayathri Jagadeesan, Tushar K Das, Jennifer M Mendoza, Ghalya Alrousan, Maria P Blasco-Conesa, Parimelazhagan Thangaraj, Bhanu Priya Ganesh

Faculty, Staff and Student Publications

Gestational diabetes mellitus (GD)-induced gut dysbiosis in pregnant mothers may increase the risk of cognitive impairment and neurological disorders in both the mother and offspring as they age. Restoring gut balance could improve cognitive outcomes for both. Despite advancements in GD treatment, side effects have increased, and long-term neurocognitive impacts on offspring born to GD mothers remain underexplored. This study uses a GD mouse model, inducing pancreatic dysfunction in 3-month-old pregnant C57BL/6J mice with Streptozotocin. The efficacy and mechanism of the prebiotic phytocompound green leaf extract (

Distinct Patterns Of Pv And Sst Gabaergic Neuronal Activity In The Basal Forebrain During Olfactory-Guided Behavior In Mice, Elizabeth H Moss, Evelyne K Tantry, Elaine Le, Pey-Shyuan Chin, Priscilla Ambrosi, Katie L Brandel-Ankrapp, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Sensory perception relies on the flexible detection and interpretation of stimuli across variable contexts, conditions, and behavioral states. The basal forebrain (BF) is a hub for behavioral state regulation, supplying dense cholinergic and GABAergic projections to various brain regions involved in sensory processing. Of GABAergic neurons in the BF, parvalbumin (PV) and somatostatin (SST) subtypes serve opposing roles toward regulating behavioral states. To elucidate the role of BF circuits in sensory-guided behavior, we investigated GABAergic signaling dynamics during odor-guided decision-making in male and female mice. We used fiber photometry to record cell type-specific BF activity during an odor discrimination task …

Adipose Progenitor Cell-Derived Extracellular Vesicles Suppress Macrophage M1 Program To Alleviate Midlife Obesity, Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu, Yanjun Liu, Cong-Yi Wang

Children’s Nutrition Research Center Staff Publications

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs …

Assessment Of Skin Fibrosis In A Murine Model Of Systemic Sclerosis With Multifunctional Optical Coherence Tomography, Harshdeep Singh Chawla, Yanping Chen, Minghua Wu, Pavel Nikitin, Jessica Gutierrez, Chandra Mohan, Manmohan Singh, Salavat R Aglyamov, Shervin Assassi, Kirill V Larin

Faculty, Staff and Student Publications

Significance: Systemic sclerosis (SSc) is a chronic idiopathic disease that causes immune dysregulation, vasculopathy, and organ fibrosis that affects more than 3 million people in the US alone. The modified Rodnan skin score (mRSS) is the current gold standard for diagnosing and staging skin fibrosis in SSc. However, mRSS is subjective, requires extensive training, and has high observer variability.

Aim: We aim to provide a quantitative method for the assessment of fibrosis.

Approach: We utilized optical coherence tomography (OCT), its extensions, optical coherence elastography (OCE), and OCT angiography (OCTA) to evaluate SSc-like fibrosis and therapy response in a mouse model. …

Altered Thermal Preference By Preoptic Estrogen Receptor Alpha Neurons In Postpartum Females, Nan Zhang, Meng Yu, Qianru Zhao, Bing Feng, Yue Deng, Jonathan C Bean, Qingzhuo Liu, Benjamin P Eappen, Yang He, Kristine M Conde, Hailan Liu, Yongjie Yang, Longlong Tu, Mengjie Wang, Yongxiang Li, Na Yin, Hesong Liu, Junying Han, Darah Ave Threat, Nathan Xu, Taylor Smiley, Pingwen Xu, Lulu Chen, Tianshu Zeng, Yanlin He, Chunmei Wang

Faculty, Staff and Students Publications

OBJECTIVE: This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA).

METHODS: Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERα

RESULTS: We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (>4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference …

Diet-Enhanced Lrg1 Expression Promotes Insulin Hypersecretion And Er Stress In Pancreatic Beta Cells, Desirae D Morales, Jiyoon Ryu, Cong Wei, Jason T Hadley, Maia R Smith, Juli Bai, Juan C Lopez-Alvarenga, Srinivas Mummidi, Ravindranath Duggirala, Jane L Lynch, Feng Liu, Lily Q Dong

Faculty, Staff and Student Publications

Aims/hypothesis: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells.

Methods: Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects …

Reducing Igg Accumulation Via Neonatal Fc Receptor (Fcrn) Blockade Relieves Neuropathic Pain, Nathan T Fiore, Kendal F Willcox, Dorsa Dayani, Younus A Zuberi, Cobi J Heijnen, Peter M Grace

Faculty, Staff and Student Publications

Preclinical and clinical studies have established that autoreactive immunoglobulin G (IgG) can drive neuropathic pain. We recently demonstrated that sciatic nerve chronic constriction injury (CCI) in male and female mice results in the production of pronociceptive IgG, which accumulates around the lumbar region, including within the dorsal root ganglia (DRG) and spinal cord, facilitating the development of neuropathic pain. These data raise the intriguing possibility that neuropathic pain may be alleviated by reducing the accumulation of IgG. To this end, we tested whether biologic inhibition or genetic deletion of the neonatal Fc receptor (FcRn) would attenuate mechanical hypersensitivity (allodynia) and …

Proteasome Augmentation Mitigates Age-Related Cognitive Decline In Mice, Danitra Parker, Kanisa Davidson, Pawel A Osmulski, Maria Gaczynska, Andrew M Pickering

Faculty, Staff and Student Publications

The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related …

Caloric Restriction And Telomere Preservation In Tert Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction Due To A Tert Function In Adipocyte Mitochondria, Zhanguo Gao, Yongmei Yu, Kristin Eckel-Mahan, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate …