He You

All Publications

• Ngfr+cholinergic projection from SI/nBM to mPFC selectively regulates temporal order recognition memory. Nature communications Mei, F., Zhao, C., Li, S., Xue, Z., Zhao, Y., Xu, Y., Ye, R., You, H., Yu, P., Han, X., Carr, G. V., Weinberger, D. R., Yang, F., Lu, B. 2024; 15 (1): 7342

  Abstract

  Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr-/- mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr-/- SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr-/- mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr-/- mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.

  View details for DOI 10.1038/s41467-024-51707-w

  View details for PubMedID 39187496

• Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo. Molecular psychiatry Yang, F., You, H., Mizui, T., Ishikawa, Y., Takao, K., Miyakawa, T., Li, X., Bai, T., Xia, K., Zhang, L., Pang, D., Xu, Y., Zhu, C., Kojima, M., Lu, B. 2024

  Abstract

  Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

  View details for DOI 10.1038/s41380-024-02595-5

  View details for PubMedID 38762692

• Regulation of Satiety by <i>Bdnf</i>-<i>e2</i>-Expressing Neurons through TrkB Activation in Ventromedial Hypothalamus BIOMOLECULES Chu, P., Guo, W., You, H., Lu, B. 2023; 13 (5)

  Abstract

  The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1-/-, Bdnf-e2-/-) results in obesity. Whereas Bdnf-e1-/- exhibited impaired thermogenesis, Bdnf-e2-/- showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2-/- mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2-/- mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.

  View details for DOI 10.3390/biom13050822

  View details for Web of Science ID 000995635100001

  View details for PubMedID 37238691

  View details for PubMedCentralID PMC10216274

• Diverse Functions of Multiple Bdnf Transcripts Driven by Distinct Bdnf Promoters. Biomolecules You, H., Lu, B. 2023; 13 (4)

  Abstract

  The gene encoding brain-derived neurotrophic factor (Bdnf) consists of nine non-coding exons driven by unique promoters, leading to the expression of nine Bdnf transcripts that play different roles in various brain regions and physiological stages. In this manuscript, we present a comprehensive overview of the molecular regulation and structural characteristics of the multiple Bdnf promoters, along with a summary of the current knowledge on the cellular and physiological functions of the distinct Bdnf transcripts produced by these promoters. Specifically, we summarized the role of Bdnf transcripts in psychiatric disorders, including schizophrenia and anxiety, as well as the cognitive functions associated with specific Bdnf promoters. Moreover, we examine the involvement of different Bdnf promoters in various aspects of metabolism. Finally, we propose future research directions that will enhance our understanding of the complex functions of Bdnf and its diverse promoters.

  View details for DOI 10.3390/biom13040655

  View details for PubMedID 37189402

  View details for PubMedCentralID PMC10135494

• A protocol for establishing a male GxE schizophrenia mouse model STAR PROTOCOLS Zhang, T., Li, S., Mei, F., You, H., Chen, Y., Yang, F., Li, B. 2022; 3 (4): 101856

  Abstract

  Schizophrenia pathogenesis involves both genetic and environmental factors (G×E). Here, we present a protocol to prepare a schizophrenia rodent model with a specific G×E pair. We describe the breeding of Bdnf-e6-/- mice with genetic deficiency in promoter-VI-driven BDNF expression. We then detail the procedure to expose the mice to postnatal environmental stress including hypoxia, social isolation, and corticosterone. This model better represents the etiology of schizophrenia and thus may facilitate basic research and drug development for schizophrenia. For complete details on the use and execution of this protocol, please refer to Chen et al. (2022).1.

  View details for DOI 10.1016/j.xpro.2022.101856

  View details for Web of Science ID 001060309600001

  View details for PubMedID 36595927

  View details for PubMedCentralID PMC9676628

• Engineering a Magnetic Protein Crystal Li, T., Wang, Z., You, H., Ong, Q., Varanasi, V., Dong, M., Lu, B., Pasca, S., Cui, B. CELL PRESS. 2020: 153A

  View details for Web of Science ID 000513023201017

• A subpopulation of Bdnf-e1-expressing glutamatergic neurons in the lateral hypothalamus critical for thermogenesis control. Molecular metabolism You, H., Chu, P., Guo, W., Lu, B. 2020; 31: 109-123

  Abstract

  Brown adipose tissue (BAT)-mediated thermogenesis plays a key role in energy homeostasis and the maintenance of body temperature. Previous work suggests that brain-derived neurotrophic factor (BDNF) is involved in BAT thermogenesis, but the underlying neural circuits and molecular mechanism remain largely unknown. This is in part due to the difficulties in manipulating BDNF expression in different brain regions through different promoters and the lack of tools to identify neurons in the brain specifically involved in BAT thermogenesis.We have created several lines of mutant mice in which BDNF transcription from a specific promoter was selectively disrupted by replacing Bdnf with green fluorescent protein (GFP; Bdnf-e1, -e4, and -e6-/- mice). As such, cells expressing Bdnf-e1, -e4, or -e6 were labeled with GFP. To identify BAT-connected thermogenesis neurons in brain, we applied the retrograde pseudorabies virus labeling method from BAT. We also used chemogenetic tools to manipulate specific neurons coupled with BAT temperature recording. Moreover, we developed a new TrkB agonist antibody to rescue the BAT thermogenesis deficits.We show that selective disruption of Bdnf expression from promoter 1 (Bdnf-e1) resulted in severe obesity and deficits of BAT-mediated thermogenesis. Body temperature response to cold was impaired in Bdnf-e1-/- mice. BAT expression of Ucp1 and Pcg1a, genes known to regulate thermogenesis, was also reduced, accompanying a decrease in the sympathetic activity of BAT. Staining of cells expressing Bdnf-e1 transcript, combined with transsynaptic, retrograde-tracing labeling of BAT-connected neurons, identified a group of excitatory neurons in lateral hypothalamus (LH) critical for thermogenesis regulation. Moreover, an adaptive thermogenesis defect in Bdnf-e1-/- mice was rescued by injecting an agonistic antibody for TrkB, the BDNF receptor, into LH. Remarkably, activation of the excitatory neurons (VGLUT2+) in LH through chemogenetic tools resulted in a rise of BAT temperature.These results reveal a specific role of BDNF promoter I in thermogenesis regulation and define a small subset of neurons in LH that contribute to such regulation.

  View details for DOI 10.1016/j.molmet.2019.11.013

  View details for PubMedID 31918913

  View details for PubMedCentralID PMC6920260

• TrkB agonistic antibodies superior to BDNF: Utility in treating motoneuron degeneration. Neurobiology of disease Guo, W., Pang, K., Chen, Y., Wang, S., Li, H., Xu, Y., Han, F., Yao, H., Liu, H., Lopes-Rodrigues, V., Sun, D., Shao, J., Shen, J., Dou, Y., Zhang, W., You, H., Wu, W., Lu, B. 2019; 132: 104590

  Abstract

  While Brain-derived Neurotrophic Factor (BDNF) has long been implicated in treating neurological diseases, recombinant BDNF protein has failed in multiple clinical trials. In addition to its unstable and adhesive nature, BDNF can activate p75NTR, a receptor mediating cellular functions opposite to those of TrkB. We have now identified TrkB agonistic antibodies (TrkB-agoAbs) with several properties superior to BDNF: They exhibit blood half-life of days instead of hours, diffuse centimeters in neural tissues instead millimeters, and bind and activate TrkB, but not p75NTR. In addition, TrkB-agoAbs elicit much longer TrkB activation, reduced TrkB internalization and less intracellular degradation, compared with BDNF. More importantly, some of these TrkB-agoAbs bind TrkB epitopes distinct from that by BDNF, and work cooperatively with endogenous BDNF. Unlike BDNF, the TrkB-agoAbs exhibit a half-life of days/weeks and diffused readily in nerve tissues. We tested one of TrkB-agoAbs further and showed that it enhanced motoneuron survival in the spinal-root avulsion model for motoneuron degeneration in vivo. Thus, TrkB-agoAbs are promising drug candidates for the treatment of neural injury.

  View details for DOI 10.1016/j.nbd.2019.104590

  View details for PubMedID 31470106

• Engineering a Genetically Encoded Magnetic Protein Crystal. Nano letters Li, T. L., Wang, Z., You, H., Ong, Q., Varanasi, V. J., Dong, M., Lu, B., Pasca, S. P., Cui, B. 2019

  Abstract

  Magnetogenetics is a new field that leverages genetically encoded proteins and protein assemblies that are sensitive to magnetic fields to study and manipulate cell behavior. Theoretical studies show that many proposed magnetogenetic proteins do not contain enough iron to generate substantial magnetic forces. Here, we have engineered a genetically encoded ferritin-containing protein crystal that grows inside mammalian cells. Each of these crystals contains more than 10 million ferritin subunits and is capable of mineralizing substantial amounts of iron. When isolated from cells and loaded with iron in vitro, these crystals generate magnetic forces that are 9 orders of magnitude larger than the forces fromthe single ferritin cages used in previous studies. These protein crystals are attracted to an applied magnetic field and move toward magnets even when internalized into cells. While additional studies are needed to realize the full potential of magnetogenetics, these results demonstrate the feasibility of engineering protein assemblies for magnetic sensing.

  View details for DOI 10.1021/acs.nanolett.9b02266

  View details for PubMedID 31552740

• MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation. Frontiers in neural circuits Pang, K., You, H., Chen, Y., Chu, P., Hu, M., Shen, J., Guo, W., Xie, C., Lu, B. 2017; 11: 11

  Abstract

  Magnetic manipulation of cell activity offers advantages over optical manipulation but an ideal tool remains elusive. The MagR protein was found through its interaction with cryptochrome (Cry) and the protein in solution appeared to respond to magnetic stimulation (MS). After we initiated an investigation on the specific role of MagR in cellular response to MS, a subsequent study claimed that MagR expression alone could achieve cellular activation by MS. Here we report that despite systematically testing different ways of measuring intracellular calcium and different MS protocols, it was not possible to detect any cellular or neuronal responses to MS in MagR-expressing HEK cells or primary neurons from the dorsal root ganglion and the hippocampus. By contrast, in neurons co-expressing MagR and channelrhodopin, optical but not MS increased calcium influx in hippocampal neurons. Our results indicate that MagR alone is not sufficient to confer cellular magnetic responses.

  View details for DOI 10.3389/fncir.2017.00011

  View details for PubMedID 28360843

  View details for PubMedCentralID PMC5352684