Biology subjects

An, J. J.

Publications and source records attributed to An, J. J..

6 recordsLinked to original sources

bioRxiv2026

A PVH-to-parabrachial BDNF circuit mediates non-aversive feeding suppression

Parabrachial nucleus (PBN) CGRP neurons mediate aversive feeding suppression, but PBN circuitry governing homeostatic, non-aversive feeding suppression remains poorly understood. Here, we identify a circuit in which paraventricular hypothalamus (PVH) neurons innervate BDNF-expressing ventrolateral/dorsolateral PBN (vl/dlPBNBDNF) neurons, which project to multiple hypothalamic nuclei. Refeeding strengthens excitatory and weakens inhibitory synaptic transmission in LPBN-projecting PVH neurons and preferentially induced Bdnf and Fos in vl/dlPBNBDNF neurons compared with elPBNCGRP neurons, whereas noxious LPS preferentially activated elPBNCGRP neurons. Gain- and loss-of-function experiments demonstrated that vl/dlPBNBDNF neurons are sufficient and necessary for feeding suppression without inducing conditioned taste aversion and that this effect require BDNF-TrkB signaling. In addition to hypothalamic inputs, vl/dlPBNBDNF neurons receive dense inputs from major downstream targets of elPBNCGRP neurons. Thus, vl/dlPBNBDNF neurons define a non-aversive feeding-suppression circuit positioned to integrate hypothalamic homeostatic signals with aversive signals, thereby coordinating food intake with internal energy needs and potentially harmful physiological conditions.

neuroscience↗

bioRxiv2026

Sexual dimorphism of autism-like phenotypes in microglial eIF4E overexpression mice

Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficits in social communication and interaction, and restricted interests or repetitive behaviors. ASD is approximately four times more prevalent in males than in females. In this study, we investigated whether sex hormones or sex chromosomes underlie the male bias in ASD susceptibility. Methods: We used the MG4E mouse model, in which microglial eIF4E overexpression produces robust male-biased ASD-like phenotypes. To distinguish the contributions of sex hormones and sex chromosomes, MG4E mice were crossed with four-core-genotype (FCG) mice carrying Sry gene manipulations, generating eight genotypes of experimental mice. Social interaction and repetitive behaviors were assessed using standard behavioral assays. Dendritic spine density was quantified in Thy1-GFP mice. Expression of estrogen receptors (ERs) and androgen receptor (AR) was examined in microglia isolated from control and MG4E mice. Results: Sex hormones, rather than non-Sry genes on sex chromosomes, are responsible for the male-biased deficits in social interaction and the increase in dendritic spine density. At postnatal day 14, ERs were undetectable in microglia, whereas ER expression was readily detected in neurons. Conclusions: These findings demonstrate that sex hormones are a major determinant of the increased susceptibility of males to ASD-like phenotypes in MG4E mice. The absence of ER expression in microglia suggests that sex hormones may act indirectly through hormone-responsive neurons to regulate microglia-neuron interactions during neurodevelopment.

genetics↗

bioRxiv2023

Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and contextual memory

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the 1st two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice had normal hippocampal cytoarchitecture but displayed elevated anxiety level and impairments in contextual memory, spatial reference memory and nest building. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice showed impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

neuroscience↗

bioRxiv2023

Genetic dissection of BDNF and TrkB expression in glial cells

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL), and a lower level of truncated TrkB (TrkB.T). With conflicting results, glial cells also have been reported to express BDNF and TrkB. In the current study, we employed a more sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent EGFP reporter mice to label BDNF- or TrkB-expressing cells. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB-expressing microglia in the brain and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the adult brain. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the adult brain. These results not only clarify the expression of BDNF and TrkB in glial cells, but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in glial cells.

neuroscience↗

bioRxiv2019

TrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits

The TrkB receptor is critical for the control of energy balance, as mutations in its gene (NTRK2) lead to hyperphagia and severe obesity in humans and mice. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within the paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVHTrkB) neurons suppresses or increases food intake, respectively. PVHTrkB neurons project to multiple brain regions, including the ventromedial hypothalamus (VMH) and the lateral parabrachial nucleus (LPBN). We found that PVHTrkB neurons projecting to LPBN are distinct from those projecting to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Therefore, TrkB signaling is a key regulator of a previously uncharacterized and heterogenous neuronal population within the PVH that impinges upon multiple circuits to govern appetite.

neuroscience↗

bioRxiv2018

Anxiety induced by extra-hypothalamic BDNF deficiency instigates resistance to diet-induced obesity

Anxiety disorders are associated with body weight changes in humans. However, mechanisms underlying anxiety-related weight changes remain poorly understood. Using Emx1Cre/+ mice, we deleted the gene for brain-derived neurotrophic factor (BDNF) in the cortex, hippocampus, and some parts of the amygdala. The resulting mutant mice displayed elevated anxiety levels and were markedly lean when fed either chow diet or high-fat diet (HFD). The mice showed higher levels of sympathetic activity, thermogenesis and lipolysis in both brown and white adipose tissues, and higher oxygen consumption and body temperature, compared with control mice. They were still lean at thermoneurality when fed HFD, indicating elevated basal metabolism in addition to activated thermogenesis. Anxiety induced by site-specific Bdnf deletion similarly increased energy expenditure and minimized HFD-induced weight gain. These results reveal that anxiety can stimulate adaptive thermogenesis and basal metabolism by activating sympathetic nervous system, which enhances lipolysis and limits weight gain.

physiology↗