Fei Deng

All Publications

• Serotonin release in the habenula during emotional contagion promotes resilience SCIENCE Mondoloni, S., Molina, P., Lecca, S., Wu, C., Michel, L., Osypenko, D., Cachin, F., Flanigan, M., Congiu, M., Lalive, A. L., Kash, T., Deng, F., Li, Y., Mameli, M. 2024; 385 (6713): 1081-1086

  Abstract

  Negative emotional contagion-witnessing others in distress-affects an individual's emotional responsivity. However, whether it shapes coping strategies when facing future threats remains unknown. We found that mice that briefly observe a conspecific being harmed become resilient, withstanding behavioral despair after an adverse experience. Photometric recordings during negative emotional contagion revealed increased serotonin (5-HT) release in the lateral habenula. Whereas 5-HT and emotional contagion reduced habenular burst firing, limiting 5-HT synthesis prevented burst plasticity. Enhancing raphe-to-habenula 5-HT was sufficient to recapitulate resilience. In contrast, reducing 5-HT release in the habenula made witnessing a conspecific in distress ineffective to promote the resilient phenotype after adversity. These findings reveal that 5-HT supports vicarious emotions and leads to resilience by tuning definite patterns of habenular neuronal activity.

  View details for DOI 10.1126/science.adp3897

  View details for Web of Science ID 001348962900003

  View details for PubMedID 39236168

• Monitoring norepinephrine release in vivo using next-generation GRABNE NE sensors NEURON Feng, J., Dong, H., Lischinsky, J. E., Zhou, J., Deng, F., Zhuang, C., Miao, X., Wang, H., Li, G., Cai, R., Xie, H., Cui, G., Lin, D., Li, Y. 2024; 112 (12): 1930-1942.e6

  Abstract

  Norepinephrine (NE) is an essential biogenic monoamine neurotransmitter. The first-generation NE sensor makes in vivo, real-time, cell-type-specific and region-specific NE detection possible, but its low NE sensitivity limits its utility. Here, we developed the second-generation GPCR-activation-based NE sensors (GRABNE2m and GRABNE2h) with a superior response and high sensitivity and selectivity to NE both in vitro and in vivo. Notably, these sensors can detect NE release triggered by either optogenetic or behavioral stimuli in freely moving mice, producing robust signals in the locus coeruleus and hypothalamus. With the development of a novel transgenic mouse line, we recorded both NE release and calcium dynamics with dual-color fiber photometry throughout the sleep-wake cycle; moreover, dual-color mesoscopic imaging revealed cell-type-specific spatiotemporal dynamics of NE and calcium during sensory processing and locomotion. Thus, these new GRABNE sensors are valuable tools for monitoring the precise spatiotemporal release of NE in vivo, providing new insights into the physiological and pathophysiological roles of NE.

  View details for DOI 10.1016/j.neuron.2024.03.001

  View details for Web of Science ID 001336365200001

  View details for PubMedID 38547869

  View details for PubMedCentralID PMC11364517

• Improved green and red GRAB sensors for monitoring spatiotemporal serotonin release in vivo. Nature methods Deng, F., Wan, J., Li, G., Dong, H., Xia, X., Wang, Y., Li, X., Zhuang, C., Zheng, Y., Liu, L., Yan, Y., Feng, J., Zhao, Y., Xie, H., Li, Y. 2024; 21 (4): 692-702

  Abstract

  The serotonergic system plays important roles in both physiological and pathological processes, and is a therapeutic target for many psychiatric disorders. Although several genetically encoded GFP-based serotonin (5-HT) sensors were recently developed, their sensitivities and spectral profiles are relatively limited. To overcome these limitations, we optimized green fluorescent G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensors and developed a red fluorescent GRAB5-HT sensor. These sensors exhibit excellent cell surface trafficking and high specificity, sensitivity and spatiotemporal resolution, making them suitable for monitoring 5-HT dynamics in vivo. Besides recording subcortical 5-HT release in freely moving mice, we observed both uniform and gradient 5-HT release in the mouse dorsal cortex with mesoscopic imaging. Finally, we performed dual-color imaging and observed seizure-induced waves of 5-HT release throughout the cortex following calcium and endocannabinoid waves. In summary, these 5-HT sensors can offer valuable insights regarding the serotonergic system in both health and disease.

  View details for DOI 10.1038/s41592-024-02188-8

  View details for PubMedID 38443508

  View details for PubMedCentralID PMC11377854

• Mesoscopic Imaging of Neurotransmitters and Neuromodulators with Genetically Encoded Sensors Awake Behaving Mesoscopic Brain Imaging Deng, F., Feng, J., Xie, H., Li, Y. Springer Nature. 2024: 3-28

  View details for DOI 10.1007/978-1-0716-4120-0_1

• Dorsal raphe serotonergic neurons suppress feeding through redundant forebrain circuits. Molecular metabolism Aklan, I., Sayar-Atasoy, N., Deng, F., Kim, H., Yavuz, Y., Rysted, J., Laule, C., Davis, D., Li, Y., Atasoy, D. 2023; 69: 101676

  Abstract

  Serotonin (5HT) is a well-known anorexigenic molecule, and 5HT neurons of dorsal raphe nucleus (DRN) have been implicated in suppression of feeding; however, the downstream circuitry is poorly understood. Here we explored major projections of DRN5HT neurons for their capacity to modulate feeding.We used optogenetics to selectively activate DRN5HT axonal projections in hypothalamic and extrahypothalamic areas and monitored food intake. We next used fiber photometry to image the activity dynamics of DRN5HT axons and 5HT levels in projection areas in response feeding and metabolic hormones. Finally, we used electrophysiology to determine how DRN5HT axons affect downstream neuron activity.We found that selective activation of DRN5HT axons in (DRN5HT → LH) and (DRN5HT → BNST) suppresses feeding whereas activating medial hypothalamic projections has no effect. Using in vivo imaging, we found that food access and satiety hormones activate DRN5HT projections to LH where they also rapidly increase extracellular 5HT levels. Optogenetic mapping revealed that DRN5HT → LHvGAT and DRN5HT → LHvGlut2 connections are primarily inhibitory and excitatory respectively. Further, in addition to its direct action on LH neurons, we found that 5HT suppresses GABA release from presynaptic terminals arriving from AgRP neurons.These findings define functionally redundant forebrain circuits through which DRN5HT neurons suppress feeding and reveal that these projections can be modulated by metabolic hormones.

  View details for DOI 10.1016/j.molmet.2023.101676

  View details for PubMedID 36682413

  View details for PubMedCentralID PMC9923194

• Brainstem serotonin neurons selectively gate retinal information flow to thalamus. Neuron Reggiani, J. D., Jiang, Q., Barbini, M., Lutas, A., Liang, L., Fernando, J., Deng, F., Wan, J., Li, Y., Chen, C., Andermann, M. L. 2023; 111 (5): 711-726.e11

  Abstract

  Retinal ganglion cell (RGC) types relay parallel streams of visual feature information. We hypothesized that neuromodulators might efficiently control which visual information streams reach the cortex by selectively gating transmission from specific RGC axons in the thalamus. Using fiber photometry recordings, we found that optogenetic stimulation of serotonergic axons in primary visual thalamus of awake mice suppressed ongoing and visually evoked calcium activity and glutamate release from RGC boutons. Two-photon calcium imaging revealed that serotonin axon stimulation suppressed RGC boutons that responded strongly to global changes in luminance more than those responding only to local visual stimuli, while the converse was true for suppression induced by increases in arousal. Converging evidence suggests that differential expression of the 5-HT1B receptor on RGC presynaptic terminals, but not differential density of nearby serotonin axons, may contribute to the selective serotonergic gating of specific visual information streams before they can activate thalamocortical neurons.

  View details for DOI 10.1016/j.neuron.2022.12.006

  View details for PubMedID 36584680

  View details for PubMedCentralID PMC10131437

• Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle. iScience Natsubori, A., Hirai, S., Kwon, S., Ono, D., Deng, F., Wan, J., Miyazawa, M., Kojima, T., Okado, H., Karashima, A., Li, Y., Tanaka, K. F., Honda, M. 2023; 26 (1): 105830

  Abstract

  The central serotonergic system has multiple roles in animal physiology and behavior, including sleep-wake control. However, its function in controlling brain energy metabolism according to the state of animals remains undetermined. Through in vivo monitoring of energy metabolites and signaling, we demonstrated that optogenetic activation of raphe serotonergic neurons increased cortical neuronal intracellular concentration of ATP, an indispensable cellular energy molecule, which was suppressed by inhibiting neuronal uptake of lactate derived from astrocytes. Raphe serotonergic neuronal activation induced cortical astrocytic Ca2+ and cAMP surges and increased extracellular lactate concentrations, suggesting the facilitation of lactate release from astrocytes. Furthermore, chemogenetic inhibition of raphe serotonergic neurons partly attenuated the increase in cortical neuronal intracellular ATP levels as arousal increased in mice. Serotonergic neuronal activation promoted an increase in cortical neuronal intracellular ATP levels, partly mediated by the facilitation of the astrocyte-neuron lactate shuttle, contributing to state-dependent optimization of neuronal intracellular energy levels.

  View details for DOI 10.1016/j.isci.2022.105830

  View details for PubMedID 36713262

  View details for PubMedCentralID PMC9881222

• Distinct serotonergic pathways to the amygdala underlie separate behavioral features of anxiety. Nature neuroscience Yu, X. D., Zhu, Y., Sun, Q. X., Deng, F., Wan, J., Zheng, D., Gong, W., Xie, S. Z., Shen, C. J., Fu, J. Y., Huang, H., Lai, H. Y., Jin, J., Li, Y., Li, X. M. 2022; 25 (12): 1651-1663

  Abstract

  Anxiety-like behaviors in mice include social avoidance and avoidance of bright spaces. Whether these features are distinctly regulated is unclear. We demonstrate that in mice, social and anxiogenic stimuli, respectively, increase and decrease serotonin (5-HT) levels in basal amygdala (BA). In dorsal raphe nucleus (DRN), 5-HT∩vGluT3 neurons projecting to BA parvalbumin (DRN5-HT∩vGluT3-BAPV) and pyramidal (DRN5-HT∩vGluT3-BAPyr) neurons have distinct intrinsic properties and gene expression and respond to anxiogenic and social stimuli, respectively. Activation of DRN5-HT∩vGluT3→BAPV inhibits 5-HT release via GABAB receptors on serotonergic terminals in BA, inducing social avoidance and avoidance of bright spaces. Activation of DRN5-HT∩vGluT3→BA neurons inhibits two subsets of BAPyr neurons via 5-HT1A receptors (HTR1A) and 5-HT1B receptors (HTR1B). Pharmacological inhibition of HTR1A and HTR1B in BA induces avoidance of bright spaces and social avoidance, respectively. These findings highlight the functional significance of heterogenic inputs from DRN to BA subpopulations in the regulation of separate anxiety-related behaviors.

  View details for DOI 10.1038/s41593-022-01200-8

  View details for PubMedID 36446933

  View details for PubMedCentralID 4176700

• Serotonin-releasing agents with reduced off-target effects. Molecular psychiatry Mayer, F. P., Niello, M., Cintulova, D., Sideromenos, S., Maier, J., Li, Y., Bulling, S., Kudlacek, O., Schicker, K., Iwamoto, H., Deng, F., Wan, J., Holy, M., Katamish, R., Sandtner, W., Li, Y., Pollak, D. D., Blakely, R. D., Mihovilovic, M. D., Baumann, M. H., Sitte, H. H. 2022

  Abstract

  Increasing extracellular levels of serotonin (5-HT) in the brain ameliorates symptoms of depression and anxiety-related disorders, e.g., social phobias and post-traumatic stress disorder. Recent evidence from preclinical and clinical studies established the therapeuticpotential of drugs inducing the release of 5-HT via the 5-HT-transporter. Nevertheless, current 5-HT releasing compounds under clinical investigation carry the risk for abuse and deleterious side effects. Here, we demonstrate that S-enantiomers of certain ring-substituted cathinones show preference for the release of 5-HT ex vivo and in vivo, and exert 5-HT-associated effects in preclinical behavioral models. Importantly, the lead cathinone compounds (1) do not induce substantial dopamine release and (2) display reduced off-target activity at vesicular monoamine transporters and 5-HT2B-receptors, indicative of low abuse-liability and low potential for adverse events. Taken together, our findings identify these agents as leadcompounds that may prove useful for the treatment of disorders where elevation of 5-HT has proven beneficial.

  View details for DOI 10.1038/s41380-022-01843-w

  View details for PubMedID 36352123

• Real-time denoising enables high-sensitivity fluorescence time-lapse imaging beyond the shot-noise limit. Nature biotechnology Li, X., Li, Y., Zhou, Y., Wu, J., Zhao, Z., Fan, J., Deng, F., Wu, Z., Xiao, G., He, J., Zhang, Y., Zhang, G., Hu, X., Chen, X., Zhang, Y., Qiao, H., Xie, H., Li, Y., Wang, H., Fang, L., Dai, Q. 2022

  Abstract

  A fundamental challenge in fluorescence microscopy is the photon shot noise arising from the inevitable stochasticity of photon detection. Noise increases measurement uncertainty and limits imaging resolution, speed and sensitivity. To achieve high-sensitivity fluorescence imaging beyond the shot-noise limit, we present DeepCAD-RT, a self-supervised deep learning method for real-time noise suppression. Based on our previous framework DeepCAD, we reduced the number of network parameters by 94%, memory consumption by 27-fold and processing time by a factor of 20, allowing real-time processing on a two-photon microscope. A high imaging signal-to-noise ratio can be acquired with tenfold fewer photons than in standard imaging approaches. We demonstrate the utility of DeepCAD-RT in a series of photon-limited experiments, including in vivo calcium imaging of mice, zebrafish larva and fruit flies, recording of three-dimensional (3D) migration of neutrophils after acute brain injury and imaging of 3D dynamics of cortical ATP release. DeepCAD-RT will facilitate the morphological and functional interrogation of biological dynamics with a minimal photon budget.

  View details for DOI 10.1038/s41587-022-01450-8

  View details for PubMedID 36163547

  View details for PubMedCentralID 5536967

• A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility. Cell Sheu, S. H., Upadhyayula, S., Dupuy, V., Pang, S., Deng, F., Wan, J., Walpita, D., Pasolli, H. A., Houser, J., Sanchez-Martinez, S., Brauchi, S. E., Banala, S., Freeman, M., Xu, C. S., Kirchhausen, T., Hess, H. F., Lavis, L., Li, Y., Chaumont-Dubel, S., Clapham, D. E. 2022; 185 (18): 3390-3407.e18

  Abstract

  Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto- and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical Gαq/11-RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron's epigenetic state.

  View details for DOI 10.1016/j.cell.2022.07.026

  View details for PubMedID 36055200

  View details for PubMedCentralID PMC9789380

• A sensitive GRAB sensor for detecting extracellular ATP in vitro and in vivo. Neuron Wu, Z., He, K., Chen, Y., Li, H., Pan, S., Li, B., Liu, T., Xi, F., Deng, F., Wang, H., Du, J., Jing, M., Li, Y. 2022; 110 (5): 770-782.e5

  Abstract

  The purinergic transmitter ATP (adenosine 5'-triphosphate) plays an essential role in both the central and peripheral nervous systems, and the ability to directly measure extracellular ATP in real time will increase our understanding of its physiological functions. Here, we developed a sensitive GPCR activation-based ATP sensor called GRABATP1.0, with a robust fluorescence response to extracellular ATP when expressed in several cell types. This sensor has sub-second kinetics, has ATP affinity in the range of tens of nanomolar, and can be used to localize ATP release with subcellular resolution. Using this sensor, we monitored ATP release under a variety of in vitro and in vivo conditions, including stimuli-induced and spontaneous ATP release in primary hippocampal cultures, injury-induced ATP release in a zebrafish model, and lipopolysaccharides-induced ATP-release events in individual astrocytes in the mouse cortex. Thus, the GRABATP1.0 sensor is a sensitive, versatile tool for monitoring ATP release and dynamics under both physiological and pathophysiological conditions.

  View details for DOI 10.1016/j.neuron.2021.11.027

  View details for PubMedID 34942116

• Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction. Science (New York, N.Y.) Li, Y., Simmler, L. D., Van Zessen, R., Flakowski, J., Wan, J. X., Deng, F., Li, Y. L., Nautiyal, K. M., Pascoli, V., Lüscher, C. 2021; 373 (6560): 1252-1256

  Abstract

  Compulsive drug use despite adverse consequences defines addiction. While mesolimbic dopamine signaling is sufficient to drive compulsion, psychostimulants such as cocaine also boost extracellular serotonin (5-HT) by inhibiting reuptake. We used SERT Met172 knockin (SertKI) mice carrying a transporter that no longer binds cocaine to abolish 5-HT transients during drug self-administration. SertKI mice showed an enhanced transition to compulsion. Conversely, pharmacologically elevating 5-HT reversed the inherently high rate of compulsion transition with optogenetic dopamine self-stimulation. The bidirectional effect on behavior is explained by presynaptic depression of orbitofrontal cortex–to–dorsal striatum synapses induced by 5-HT via 5-HT1B receptors. Consequently, in projection-specific 5-HT1B receptor knockout mice, the fraction of individuals compulsively self-administering cocaine was elevated.

  View details for DOI 10.1126/science.abi9086

  View details for PubMedID 34516792

  View details for PubMedCentralID PMC8817894

• A genetically encoded sensor for measuring serotonin dynamics. Nature neuroscience Wan, J., Peng, W., Li, X., Qian, T., Song, K., Zeng, J., Deng, F., Hao, S., Feng, J., Zhang, P., Zhang, Y., Zou, J., Pan, S., Shin, M., Venton, B. J., Zhu, J. J., Jing, M., Xu, M., Li, Y. 2021; 24 (5): 746-752

  Abstract

  Serotonin (5-HT) is a phylogenetically conserved monoamine neurotransmitter modulating important processes in the brain. To directly visualize the release of 5-HT, we developed a genetically encoded G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensor with high sensitivity, high selectivity, subsecond kinetics and subcellular resolution. GRAB5-HT detects 5-HT release in multiple physiological and pathological conditions in both flies and mice and provides new insights into the dynamics and mechanisms of 5-HT signaling.

  View details for DOI 10.1038/s41593-021-00823-7

  View details for PubMedID 33821000

  View details for PubMedCentralID PMC8544647