Biology subjects

De Angelis, M.

Publications and source records attributed to De Angelis, M..

6 recordsLinked to original sources

bioRxiv2026

Midbrain Tet1 dosage defines inter-individual binge-eating susceptibility

Binge-eating disorder (BED) is the most common eating disorder worldwide and carries life-altering comorbidities. While genetic and environmental risk factors have been identified, the mechanisms that determine inter-individual susceptibility to BED remain largely unknown. Here, we demonstrate that developmental dosage of the DNA hydroxymethylase Tet1 defines stable inter-individual differences in binge-eating susceptibility. In mice, midbrain dopaminergic neurons of the ventral tegmental area (VTADA) are essential for the induction of addictive binge-eating behavior, express high levels of Tet1, and undergo rapid and widespread DNA hydroxymethylation remodeling upon experimental binge eating. Strikingly, Tet1 haploinsufficiency creates pronounced inter-individual variation in binge-eating susceptibility even among genetically identical mice, which we trace to reduced connectivity between the prelimbic medial prefrontal cortex (mPFCPL) and the VTA. Chemogenetic inhibition of mPFCPL[->]VTA projections reduces binge-eating susceptibility, whereas EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restores susceptibility, supporting a causal role for this axis. Importantly, TET1 promoter methylation in patients associates with binge-eating behavior and reward-circuit function, suggesting conservation of this regulatory network in humans. Collectively, these findings identify Tet1 dosage as a novel regulator of binge-eating susceptibility and provide a mechanistic basis for how inter-individual differences in behavior are established.

neuroscience↗

bioRxiv2025

Central T3 deprivation disturbs cortical cilia formation, oligodendrocyte lineage and neuronal cell-cell-communication in a MCT8/OATP1C1 deficient Allan-Herndon-Dudley Syndrome mouse model

BackgroundThe Allan-Herndon-Dudley syndrome (AHDS) is a rare, X-linked human genetic disorder caused by mutations in the monocarboxylate transporter 8 (MCT8), essential for thyroid hormone (TH) transport across the blood-brain-barrier. The resulting central TH deprivation disrupts brain maturation and function, leading to intellectual disability and movement disorders. Cortical development, highly dependent on TH, is particularly affected and contributes significantly to AHDS pathologies. MethodsTo elucidate disrupted cortical processes, we conducted single nucleus RNA sequencing in a mouse model engineered to mimic the central TH deficiency characteristic of human AHDS. This murine AHDS model features the concomitant deletion of both MCT8 and OATP1C1, a T4 transporter largely absent in human brain capillaries that in mice plays a role in TH transport. The phenotype of dKO mice bears striking resemblance to the pathologies observed in human AHDS patients. ResultsSingle nuclei were isolated from the cortex and attached striatum of 21-day old WT and MCT8/OATP1C1 dKO mice and sequenced using the 10x Genomics workflow. Cell proportion analyses on the resulting 48 clusters suggested elevated numbers of GABAergic striatal D1 and D2 neurons in the dKO mice. Diminished levels of mature oligodendrocytes coincided with a bifurcation within the oligodendrocyte lineage trajectory, leading to distinct subpopulations of WT and dKO oligodendrocytes. Differentially expressed gene (DEG) patterns align poorly with Slc16a2 and Slco1c1 mRNA levels in the respective clusters, but closely with prior published cortical bulk RNAseq data of mice with systemic hypothyroidism or MCT8/OATP1C1 deficiency. These parallels confirm the reliability of our data and provide new insights by pinpointing TH-responsive DEGs to specific cellular clusters. Moreover, inferred cell-cell communication using NeuronChat suggested a disbalance in GABAergic versus glutamatergic signaling. We further uncovered perturbed primary cilia formation in several GABAergic and glutamatergic clusters of the dKO cortex. DiscussionMolecular signatures and perturbations uncovered by our snRNAseq study reveal new molecular characteristics of the AHDS. The imbalance in GABAergic versus glutamatergic cell-cell-communication, perturbed primary cilia formation, and bifurcation of the oligodendrocyte lineage align with pathologies observed in AHDS patients and highlight the role of TH signaling in maintaining neuronal network homeostasis in the cortex.

neuroscience↗

bioRxiv2025

Loss of noradrenergic Fkbp5 disrupts social behavior and norepinephrine dynamics in the basolateral amygdala

Social dysfunction is common in depression and varies with stress exposure and genetic risk. The current study identifies a cell-type specific role for Fkbp5, a glucocorticoid receptor co-chaperone, in noradrenergic neurons engaged during social stress. Acute social stress upregulated Fkbp5 in the locus coeruleus (LC), whereas repeated exposure attenuated this effect. Noradrenergic Fkbp5 deletion (Fkbp5Nat) increased pro-social behavior exclusively in male mice. In the basolateral amygdala (BLA), social interaction reduced norepinephrine (NE) turnover in wild-type but not Fkbp5Nat mice. Consistently, proteomics revealed mitochondrial/energy and synapse-related remodeling in BLA neurons. Miniscope imaging showed that behavior-locked NE transients in BLA were selectively blunted in Fkbp5Nat mice during interaction with outbred CD1 conspecifics, while same-strain C57BL/6N encounters preserved NE dynamics. Together, this study indicates that Fkbp5 tunes LC-BLA output to social salience in a sex- and context-dependent manner, suggesting a circuit-specific route to normalize social salience without broadly suppressing noradrenergic function.

neuroscience↗

bioRxiv2025

Maternal Thyroid Supplementation Prevents Autistic-relevant Social Behavior and Hypothalamic Oxytocin Depletion Produced by Developmental Exposure to Environmental Toxicants

Environmental toxicants that target the developing brain are suspected of contributing to autism spectrum disorder risk but causative evidence is lacking. We and others have shown that the indoor flame retardants, polybrominated diphenyl ethers (PBDEs), reduce prosocial behavior, however, few studies have assessed the central targets and underlying mechanisms. PBDEs are well established endocrine disruptors of the expanded thyroid system, which also regulates the prosocial neuropeptides oxytocin (OXT) and vasopressin (AVP) and their hypothalamic signaling. The potential role of PBDE-induced thyroid hormone (TH) deregulation in mediating disruption of central OXT and ASD-like social behavior deficits remains unmapped. To address this gap, we conducted a study in C57BL6/N mice that examined behavioral and neuromolecular reprogramming after developmental exposure to the commercial PBDE mixture, DE-71, and evaluated the therapeutic potential of TH supplementation. Dams were exposed daily during gestation and lactation to corn oil vehicle, low dose (0.1 mg/kg) and high dose (0.4 mg/kg) of DE-71 with or without concurrent L-thyroxine (+mT4). In offspring, dose-dependent ASD-relevant behavioral responses and central neuroendocrine OXT neuron depletion after developmental PBDE exposure was prevented with mT4. mRNA transcripts for the TH transporter Mct8, deiodinase (Dio3) and estrogen receptor beta (Esr2) expressed on OXT neurons in PVH were upregulated in low dose females. In contrast, Mct8 and Dio3 were downregulated in low dose males. These findings uncover sex-specific mechanisms of PBDE-induced reprogramming of TH-regulated pathways in hypothalamic neuroendocrine cells leading to depleted central OXT signaling and ultimately ASD-relevant phenotypes. Importantly, we provide novel evidence of the therapeutic potential of maternal thyroid supplementation against toxicant-induced neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

Arabidopsis lateral shoots display two distinct phases of growth angle control

Shoot growth angle is a fundamental determinant of plant form. In their later development, lateral branches maintain gravitropic setpoint angles (GSAs) in which growth is set and maintained relative to gravity. The typically non-vertical GSAs are the product of an auxin-dependent antigravitropic offset that counteracts underlying gravitropic response in the branch (Roychoudhry et al., 2013). Here we describe an earlier phase of branch development in which the young lateral shoot grows rootward, independently of gravity, promoting a spreading growth habit. In normal development, this phase of growth is terminated with the onset of the GSA programme, with branches then growing upwards to assume their mature form. The biophysical basis of the early rootward phase of branch growth can be traced back to greater cell proliferation on the upper, adaxial side that upon expansion, drives asymmetric growth. Our data indicate that cytokinin is involved in this process and that the transcription factor TCP1 is an important regulator of lateral shoot adaxial identity and differential ad-abaxial cell proliferation.

plant biology↗

bioRxiv2021

Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism

The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD) induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.

neuroscience↗