Xiaoke Chen

All Publications

• A tissue-like neurotransmitter sensor for the brain and gut. Nature Li, J., Liu, Y., Yuan, L., Zhang, B., Bishop, E. S., Wang, K., Tang, J., Zheng, Y., Xu, W., Niu, S., Beker, L., Li, T. L., Chen, G., Diyaolu, M., Thomas, A., Mottini, V., Tok, J. B., Dunn, J. C., Cui, B., Pașca, S. P., Cui, Y., Habtezion, A., Chen, X., Bao, Z. 2022; 606 (7912): 94-101

  Abstract

  Neurotransmitters play essential roles in regulating neural circuit dynamics both in the central nervous system as well as at the peripheral, including the gastrointestinal tract1-3. Their real-time monitoring will offer critical information for understanding neural function and diagnosing disease1-3. However, bioelectronic tools to monitor the dynamics of neurotransmitters in vivo, especially in the enteric nervous systems, are underdeveloped. This is mainly owing to the limited availability of biosensing tools that are capable of examining soft, complex and actively moving organs. Here we introduce a tissue-mimicking, stretchable, neurochemical biological interface termed NeuroString, which is prepared by laser patterning of a metal-complexed polyimide into an interconnected graphene/nanoparticle network embedded in an elastomer. NeuroString sensors allow chronic in vivo real-time, multichannel and multiplexed monoamine sensing in the brain of behaving mouse, as well as measuring serotonin dynamics in the gut without undesired stimulations and perturbing peristaltic movements. The described elastic and conformable biosensing interface has broad potential for studying the impact of neurotransmitters on gut microbes, brain-gut communication and may ultimately be extended to biomolecular sensing in other soft organs across the body.

  View details for DOI 10.1038/s41586-022-04615-2

  View details for PubMedID 35650358

• Orchestrating Opiate-Associated Memories in Thalamic Circuits. Neuron Keyes, P. C., Adams, E. L., Chen, Z., Bi, L., Nachtrab, G., Wang, V. J., Tessier-Lavigne, M., Zhu, Y., Chen, X. 2020

  Abstract

  Disrupting memories that associate environmental cues with drug experiences holds promise for treating addiction, yet accessing the distributed neural network that stores such memories is challenging. Here, we show that the paraventricular nucleus of the thalamus (PVT) orchestrates the acquisition and maintenance of opiate-associated memories via projections to the central nucleus of the amygdala (CeA) and nucleus accumbens (NAc). PVTCeA activity associates morphine reward to the environment, whereas transient inhibition of the PVTNAc pathway during retrieval causes enduring protection against opiate-primed relapse. Using brain-wide activity mapping, we revealed distributed network activities that are altered in non-relapsing mice, which enabled us to find that activating the downstream NAclateral hypothalamus (LH) pathway also prevents relapse. These findings establish the PVT as a key node in the opiate-associated memory network and demonstrate the potential of targeting the PVTNAcLH pathway for treating opioid addiction.

  View details for DOI 10.1016/j.neuron.2020.06.028

  View details for PubMedID 32679036

• The coding of valence and identity in the mammalian taste system. Nature Wang, L., Gillis-Smith, S., Peng, Y., Zhang, J., Chen, X., Salzman, C. D., Ryba, N. J., Zuker, C. S. 2018; 558 (7708): 127-131

  Abstract

  The ability of the taste system to identify a tastant (what it tastes like) enables animals to recognize and discriminate between the different basic taste qualities1,2. The valence of a tastant (whether it is appetitive or aversive) specifies its hedonic value and elicits the execution of selective behaviours. Here we examine how sweet and bitter are afforded valence versus identity in mice. We show that neurons in the sweet-responsive and bitter-responsive cortex project to topographically distinct areas of the amygdala, with strong segregation of neural projections conveying appetitive versus aversive taste signals. By manipulating selective taste inputs to the amygdala, we show that it is possible to impose positive or negative valence on a neutral water stimulus, and even to reverse the hedonic value of a sweet or bitter tastant. Remarkably, mice with silenced neurons in the amygdala no longer exhibit behaviour that reflects the valence associated with direct stimulation of the taste cortex, or with delivery of sweet and bitter chemicals. Nonetheless, these mice can still identify and discriminate between tastants, just as wild-type controls do. These results help to explain how the taste system generates stereotypic and predetermined attractive and aversive taste behaviours, and support the existence of distinct neural substrates for the discrimination of taste identity and the assignment of valence.

  View details for DOI 10.1038/s41586-018-0165-4

  View details for PubMedID 29849148

  View details for PubMedCentralID PMC6201270

• Dynamic salience processing in paraventricular thalamus gates associative learning. Science (New York, N.Y.) Zhu, Y., Nachtrab, G., Keyes, P. C., Allen, W. E., Luo, L., Chen, X. 2018; 362 (6413): 423–29

  Abstract

  The salience of behaviorally relevant stimuli is dynamic and influenced by internal state and external environment. Monitoring such changes is critical for effective learning and flexible behavior, but the neuronal substrate for tracking the dynamics of stimulus salience is obscure. We found that neurons in the paraventricular thalamus (PVT) are robustly activated by a variety of behaviorally relevant events, including novel ("unfamiliar") stimuli, reinforcing stimuli and their predicting cues, as well as omission of the expected reward. PVT responses are scaled with stimulus intensity and modulated by changes in homeostatic state or behavioral context. Inhibition of the PVT responses suppresses appetitive or aversive associative learning and reward extinction. Our findings demonstrate that the PVT gates associative learning by providing a dynamic representation of stimulus salience.

  View details for PubMedID 30361366

• The coding of cutaneous temperature in the spinal cord. Nature neuroscience Ran, C., Hoon, M. A., Chen, X. 2016; 19 (9): 1201-1209

  Abstract

  The spinal cord is the initial stage that integrates temperature information from peripheral inputs. Here we used molecular genetics and in vivo calcium imaging to investigate the coding of cutaneous temperature in the spinal cord in mice. We found that heating or cooling the skin evoked robust calcium responses in spinal neurons, and their activation threshold temperatures distributed smoothly over the entire range of stimulation temperatures. Once activated, heat-responding neurons encoded the absolute skin temperature without adaptation and received major inputs from transient receptor potential (TRP) channel V1 (TRPV1)-positive dorsal root ganglion (DRG) neurons. By contrast, cold-responding neurons rapidly adapted to ambient temperature and selectively encoded temperature changes. These neurons received TRP channel M8 (TRPM8)-positive DRG inputs as well as novel TRPV1(+) DRG inputs that were selectively activated by intense cooling. Our results provide a comprehensive examination of the temperature representation in the spinal cord and reveal fundamental differences in the coding of heat and cold.

  View details for DOI 10.1038/nn.4350

  View details for PubMedID 27455110

• A thalamic input to the nucleus accumbens mediates opiate dependence NATURE Zhu, Y., Wienecke, C. F., Nachtrab, G., Chen, X. 2016; 530 (7589): 219-?

  Abstract

  Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

  View details for DOI 10.1038/nature16954

  View details for Web of Science ID 000369916700039

  View details for PubMedID 26840481

  View details for PubMedCentralID PMC4814115

• Valence processing in pons. Neuron Chen, X. 2023; 111 (9): 1353-1354

  Abstract

  In this issue of Neuron, Xiao et al.1 reported that inhibitory and excitatory neurons in the pontine central gray encode and transmit opposite valences of sensory stimuli through parallel circuits to a distributed brain network.

  View details for DOI 10.1016/j.neuron.2023.04.009

  View details for PubMedID 37141860

• Plastic and stimulus-specific coding of salient events in the central amygdala. Nature Yang, T., Yu, K., Zhang, X., Xiao, X., Chen, X., Fu, Y., Li, B. 2023

  Abstract

  The central amygdala (CeA) is implicated in a range of mental processes including attention, motivation, memory formation and extinction and in behaviours driven by either aversive or appetitive stimuli1-7. How it participates in these divergent functions remains elusive. Here we show that somatostatin-expressing (Sst+) CeA neurons, which mediate much of CeA functions3,6,8-10, generate experience-dependent and stimulus-specific evaluative signals essential for learning. The population responses of these neurons in mice encode the identities of a wide range of salient stimuli, with the responses of separate subpopulations selectively representing the stimuli that have contrasting valences, sensory modalities or physical properties (for example, shock and water reward). These signals scale with stimulus intensity, undergo pronounced amplification and transformation during learning, and are required for both reward and aversive learning. Notably, these signals contribute to the responses of dopamine neurons to reward and reward prediction error, but not to their responses to aversive stimuli. In line with this, Sst+ CeA neuron outputs to dopamine areas are required for reward learning, but are dispensable for aversive learning. Our results suggest that Sst+ CeA neurons selectively process information about differing salient events for evaluation during learning, supporting the diverse roles of the CeA. In particular, the information for dopamine neurons facilitates reward evaluation.

  View details for DOI 10.1038/s41586-023-05910-2

  View details for PubMedID 37020025

• Treatment of a genetic brain disease by CNS-wide microglia replacement. Science translational medicine Shibuya, Y., Kumar, K. K., Mader, M. M., Yoo, Y., Ayala, L. A., Zhou, M., Mohr, M. A., Neumayer, G., Kumar, I., Yamamoto, R., Marcoux, P., Liou, B., Bennett, F. C., Nakauchi, H., Sun, Y., Chen, X., Heppner, F. L., Wyss-Coray, T., Südhof, T. C., Wernig, M. 2022; 14 (636): eabl9945

  Abstract

  Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.

  View details for DOI 10.1126/scitranslmed.abl9945

  View details for PubMedID 35294256

• An adaptive optics module for deep tissue multiphoton imaging in vivo. Nature methods Rodriguez, C., Chen, A., Rivera, J. A., Mohr, M. A., Liang, Y., Natan, R. G., Sun, W., Milkie, D. E., Bifano, T. G., Chen, X., Ji, N. 2021; 18 (10): 1259-1264

  Abstract

  Understanding complex biological systems requires visualizing structures and processes deep within living organisms. We developed a compact adaptive optics module and incorporated it into two- and three-photon fluorescence microscopes, to measure and correct tissue-induced aberrations. We resolved synaptic structures in deep cortical and subcortical areas of the mouse brain, and demonstrated high-resolution imaging of neuronal structures and somatosensory-evoked calcium responses in the mouse spinal cord at great depths in vivo.

  View details for DOI 10.1038/s41592-021-01279-0

  View details for PubMedID 34608309

• Modality specific modulation of temperature representations in the spinal cord after injury. The Journal of neuroscience : the official journal of the Society for Neuroscience Ran, C., Kamalani, G. N., Chen, X. 2021

  Abstract

  Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the central nervous system encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated upon ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push/pull mechanism in processing cold and heat inputs and reveal a synergic mechanism to shift thermosensation after injury.SIGNIFICANCE STATEMENTIn this paper, we combine our novel in vivo spinal cord two-photon calcium imaging, mouse genetics and persistent pain models to study how tissue injury alter the sensation of temperature. We discover modality specific changes of spinal temperature responses in different models of injury. Chemotherapy medication oxaliplatin leads to cold hypersensitivity and heat hyposensitivity. By contrast, inflammation increases heat sensitivity and decreases cold sensitivity. This decrease in cold sensitivity results from the stronger crossover inhibition from the hyperactive heat inputs. Our work reveals the bi-directional change of thermosensitivity by injury and suggests the crossover inhibitory circuit underlies the shifted thermosensation, providing a mechanism to the biased perception towards a unique thermal modality that observed clinically in chronic pain patients.

  View details for DOI 10.1523/JNEUROSCI.1104-21.2021

  View details for PubMedID 34408066

• Differential Co-release of Two Neurotransmitters from a Vesicle Fusion Pore in Mammalian Adrenal Chromaffin Cells. Neuron Zhang, Q., Liu, B., Wu, Q., Liu, B., Li, Y., Sun, S., Wang, Y., Wu, X., Chai, Z., Jiang, X., Liu, X., Hu, M., Wang, Y., Yang, Y., Wang, L., Kang, X., Xiong, Y., Zhou, Y., Chen, X., Zheng, L., Zhang, B., Wang, C., Zhu, F., Zhou, Z. 2019; 102 (1): 173-183.e4

  Abstract

  Co-release of multiple neurotransmitters from secretory vesicles is common in neurons and neuroendocrine cells. However, whether and how the transmitters co-released from a single vesicle are differentially regulated remains unknown. In matrix-containing dense-core vesicles (DCVs) in chromaffin cells, there are two modes of catecholamine (CA) release from a single DCV: quantal and sub-quantal. By combining two microelectrodes to simultaneously record co-release of the native CA and ATP from a DCV, we report that (1) CA and ATP were co-released during a DCV fusion; (2) during kiss-and-run (KAR) fusion, the co-released CA was sub-quantal, whereas the co-released ATP was quantal; and (3) knockdown and knockout of the DCV matrix led to quantal co-release of both CA and ATP even in KAR mode. These findings strongly imply that, in contrast to sub-quantal CA release in chromaffin cells, fast synaptic transmission without transmitter-matrix binding is mediated exclusively via quantal release in neurons.

  View details for DOI 10.1016/j.neuron.2019.01.031

  View details for PubMedID 30773347

• Probing the coding logic of thermosensation using spinal cord calcium imaging. Experimental neurology Ran, C. n., Chen, X. n. 2019

  Abstract

  The spinal cord dorsal horn is the first relay station of the neural network for processing somatosensory information. High-throughput recording methods facilitate the study of sensory coding in the cortex but have not been successfully applied to study spinal cord circuitry until recently. Here, we review the development of the in vivo two-photon spinal calcium imaging preparation and biological findings from the first systematic characterization of the spinal response to cutaneous thermal stimuli, focusing on the difference between the coding of heat and cold, and the contribution of different peripheral inputs to thermosensory response in the spinal cord. Here we also report that knockout of TRPV1 channel impairs sensation of warmth, and somatostatin- and calbindin2-expressing neurons in the spinal dorsal horn preferentially respond to heat. Future work combining this technology with genetic tools and animal models of chronic pain will further elucidate the role of each neuronal type in the spinal thermosensory coding and their plasticity under pathological condition.

  View details for PubMedID 31014574

• Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration. Proceedings of the National Academy of Sciences of the United States of America Lu, W. J., Mann, R. K., Nguyen, A. n., Bi, T. n., Silverstein, M. n., Tang, J. Y., Chen, X. n., Beachy, P. A. 2018; 115 (2): E200–E209

  Abstract

  How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.

  View details for PubMedID 29279401

  View details for PubMedCentralID PMC5777079