Biology subjects

Fathi, P.

Publications and source records attributed to Fathi, P..

5 recordsLinked to original sources

bioRxiv2025

Hippocampal CA3 Nex/Neurod6+ neuron-specific TNFR2 alleviates chronic neuropathic pain by sex-dependently engaging opioid and endocannabinoid pathways

Chronic neuropathic pain (CNP) develops as a result of persistent neuroinflammation and maladaptive synaptic plasticity in the central nervous system following nerve injury. While tumor necrosis factor receptor 2 (TNFR2) signaling has been extensively studied in pain resolution, the expression of this receptor on specific neuronal populations and molecular pathways involved in spontaneous pain recovery still remains poorly defined. In this study, we investigated the role of TNFR2 signaling within hippocampal Nex/Neurod6 pyramidal neurons in promoting recovery from chronic constriction injury (CCI), a well-established rodent model of neuropathic pain. To achieve neuron-specific deletion of TNFR2, we generated tamoxifen-inducible conditional knockout mice (NexCreERT2:TNFR2F/F). We demonstrate that knocking out TNFR2 from Nex neurons prevents spontaneous pain recovery in both males and females. Thus, establishing that a supraspinal TNFR2 neuroimmune axis is necessary for pain recovery. Exogenous administration of a TNFR2 agonist at 7, 10, and 13 dpi (i.p.) significantly improved mechanical withdrawal thresholds in both sexes of wild-type mice but did not alleviate pain in Nex-specific TNFR2 knockouts, indicating that neuronal TNFR2 expression is required for TNFR2-mediated analgesia. Bulk RNA sequencing of hippocampal tissue collected at six weeks after CCI revealed that TNFR2 activation upregulates genes such as Pomc, involved in the opioid pathway, and oleoyl-ACP-hydrolase (OLAH), involved in the endocannabinoid pathway. Consistent with these findings, immunostaining and Western blot analyses showed that TNFR2 agonism restored cornu ammonis (CA3) region POMC and {beta}-endorphin protein levels that were otherwise suppressed after CCI. Behavioral experiment demonstrated that systemic blockade of the {micro}-opioid receptor with naltrexone (administered daily from 7-21 dpi (s.c.)) completely prevented TNFR2-mediated pain recovery in males but only partially in females. In contrast, inhibition of cannabinoid 1 receptor (CB1R) signaling with AM251 (administered at 7, 14, and 21 dpi (i.p.)) abolished TNFR2-driven analgesia in both sexes. Together, these results reveal that hippocampal TNFR2 signaling in Nex/Neurod6 neurons is critical in recovery from chronic neuropathic pain. TNFR2 activation promotes analgesia by engaging endogenous {beta}-endorphin/{micro}-opioid and endocannabinoid pathways in a sex-dependent manner, establishing TNFR2 agonism as a promising non-addictive therapeutic approach for chronic pain resolution. SignificanceChronic neuropathic pain (CNP) results from persistent neuroimmune signaling and is driven by maladaptive circuit plasticity. Due to the complexity of factors contributing to CNP, it often leaves patients with few treatment options, which, unfortunately, are either temporary or might be addictive. We have characterized a novel supraspinal mechanism through which tumor necrosis factor receptor 2 (TNFR2) signaling, specifically in hippocampal Neurod6/Nex+ expressing pyramidal neurons, is necessary for pain recovery following nerve injury. Pharmacological activation of TNFR2 in these neurons alleviates pain by engaging both endogenous opioid and endocannabinoid signaling pathways. We specifically demonstrate that TNFR2 agonism upregulates proopiomelanocortin (POMC) expression and {beta}-endorphin levels in the hippocampus. We further identify that pharmacological inhibition of either the -opioid receptor or cannabinoid 1 (CB1) receptor is sufficient to impair the effectiveness of TNFR2 agonist mediated pain resolution. Our findings thus uncover a novel neuroimmune mechanism where the TNFR2 agonist, exogenously activating the pro-resolving TNFR2, mitigates CNP by releasing endogenous pain neuromodulators. Here, we highlight that TNFR2 agonism could serve as a non-addictive therapeutic strategy for the resolution of chronic neuropathic pain.

pharmacology and toxicology↗

bioRxiv2024

AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation

During postnatal life, the adipocyte-derived hormone leptin is required for proper targeting of neural inputs to the paraventricular nucleus of the hypothalamus (PVH) and impacts the activity of neurons containing agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms are known to play a defining role during postnatal organization of neural circuits, but whether leptin-mediated postnatal neuronal activity specifies neural projections to the PVH or impacts downstream connectivity is largely unexplored. Here, we blocked neuronal activity of AgRP neurons during a discrete postnatal period and evaluated development of AgRP inputs to defined regions in the PVH, as well as descending projections from PVH oxytocin neurons to the dorsal vagal complex (DVC) and assessed their dependence on leptin or postnatal AgRP neuronal activity. In leptin-deficient mice, AgRP inputs to PVH neurons were significantly reduced, as well as oxytocin-specific neuronal targeting by AgRP. Moreover, downstream oxytocin projections from the PVH to the DVC were also impaired, despite the lack of leptin receptors found on PVH oxytocin neurons. Blocking AgRP neuron activity specifically during early postnatal life reduced the density of AgRP inputs to the PVH, as well as the density of projections from PVH oxytocin neurons to the DVC, and these innervation deficits were associated with dysregulated autonomic function. These findings suggest that postnatal targeting of descending PVH oxytocin projections to the DVC requires leptin-mediated AgRP neuronal activity, and represents a novel activity-dependent mechanism for hypothalamic specification of metabolic circuitry, with consequences for autonomic regulation. Significance statementHypothalamic neural circuits maintain homeostasis by coordinating endocrine signals with autonomic responses and behavioral outputs to ensure that physiological responses remain in tune with environmental demands. The paraventricular nucleus of the hypothalamus (PVH) plays a central role in metabolic regulation, and the architecture of its neural inputs and axonal projections is a defining feature of how it receives and conveys neuroendocrine information. In adults, leptin regulates multiple aspects of metabolic physiology, but it also functions during development to direct formation of circuits controlling homeostatic functions. Here we demonstrate that leptin acts to specify the input-output architecture of PVH circuits through an activity-dependent, transsynaptic mechanism, which represents a novel means of sculpting neuroendocrine circuitry, with lasting effects on how the brain controls energy balance.

neuroscience↗

bioRxiv2023

Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide in Male Mice fed High Carbohydrate Diets

Glucagon-like peptide-1 receptor (GLP-1R) agonists and fibroblast growth factor 21 (FGF21) confer similar metabolic benefits. Studies report that GLP-1RA induce FGF21. Here, we investigated the mechanisms engaged by the GLP-1R agonist liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. We show that liraglutide increases FGF21 levels via neuronal GLP-1R activation. We also demonstrate that lack of liver Fgf21 expression confers partial resistance to liraglutide-induced weight loss. Since FGF21 reduces carbohydrate intake, we tested whether the contribution of FGF21 to liraglutide-induced weight loss is dependent on dietary carbohydrate content. In control and liver Fgf21 knockout (LivFgf21-/-) mice fed calorically matched diets with low- (LC) or high-carbohydrate (HC) content, we found that only HC-fed LivFgf21-/- mice were resistant to liraglutide-induced weight loss. Similarly, liraglutide-induced weight loss was partially impaired in LivFgf21-/- mice fed a high-fat, high-sugar (HFHS) diet. Lastly, we show that loss of neuronal {beta}-klotho expression also diminishes liraglutide-induced weight loss in mice fed a HC or HFHS diet, indicating that FGF21 mediates liraglutide-induced weight loss via neuronal FGF21 action. Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in the presence of high dietary carbohydrate content.

physiology↗

bioRxiv2022

The CD103-XCR1 axis mediates the recruitment of immunoregulatory dendritic cells after traumatic injury

During wounding and material implantation there is a disturbance in tissue homeostasis and release of self-antigen, and regulation between tolerance and auto-inflammation in injury is not well understood. Here, we analyzed antigen-presenting cells in biomaterial-treated muscle injury and found that pro-regenerative materials enrich Batf3-dependent CD103+XCR1+CD301b+ dendritic cells associated with cross-presentation and self-tolerance. Muscle trauma was accompanied by CD8+ iTregs and expansion of CD103+XCR1+CD62L- adaptive immune cells. Up-regulation of E-Cadherin (the ligand for CD103) and XCL-1 in injured tissue suggests a mechanism for cell recruitment to trauma. Without cross-presenting cells T cell activation increases, pro-regenerative macrophage polarization decreases, and muscle healing is impaired. These data describe a regulatory communication network through CD103+XCR1+ immune cells resulting in downstream effects on tissue regeneration.

bioengineering↗

bioRxiv2021

In Situ Surface-Directed Assembly of 2D Metal Nanoplatelets for Drug-Free Treatment of Antibiotic-Resistant Bacteria

The development of antibiotic resistance among bacterial strains is a major global public health concern. To address this, drug-free antibacterial approaches are needed. High-touch surfaces in particular can serve as a means for the spread of bacteria and other pathogens from one infected person to another. Copper surfaces have long been known for their antibacterial properties. To further enhance the surfaces antibacterial properties, we used a one-step surface modification technique to assemble 2D copper chloride nanoplatelets directly onto copper surfaces such as copper tape, transmission electron microscopy (TEM) grids, electrodes, and granules. The nanoplatelets were formed using copper ions from the copper surfaces, enabling their direct assembly onto these surfaces in a one-step process that does not require separate nanoparticle synthesis. The synthesis of the nanoplatelets was confirmed with TEM, scanning electron microscopy, energy dispersive spectroscopy (EDS), x-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). Antibacterial properties of the surfaces with copper chloride nanoplatelets were demonstrated in multi-drug-resistant (MDR) E. coli. The presence of copper chloride nanoplatelets on the surface led to a marked improvement in antibacterial properties compared to the untreated copper surfaces. Surfaces with copper chloride nanoplatelets affected bacterial cell morphology, prevented bacterial cell division, reduced their viability, damaged bacterial deoxyribonucleic acid (DNA), and altered protein expression. In particular, proteins corresponding to cell division, DNA division, and mediation of copper toxicity were down-regulated. This work presents a robust method to directly assemble copper chloride nanoplatelets onto any copper surface to imbue it with improved antibacterial properties. To demonstrate that our method of particle generation can be used with other metal surfaces, we also demonstrate the synthesis of other metal-derived nanoarchitectures on a variety of metal surfaces.

bioengineering↗