Our laboratory has two major research interests: hippocampal memory formation and primary cilia. “Memory is the glue that holds our mental life together” (Kandel et al., 2014). Aberrant “glue” affects our cognitive capacities and causes numerous cognitive dysfunction-related disorders, including dementia, amnesia, post-traumatic stress disorder (PTSD), intellectual disability, schizophrenia, and autism spectrum disorder (ASD). Unraveling the mechanisms underlying learning and memory formation is needed not only to understand how we acquire and retain experiences and knowledge, but also to develop mechanism-based therapies to combat these disorders. Primary cilia are centriole-derived “cellular antennae” that detect many extracellular signals including hormones and morphogens and regulate a variety of physiological functions including sensation, cognition, and development. Human diseases caused by malfunctions in primary cilia encompass developmental disorders, obesity, neurodegeneration, psychiatric disorders, and cognitive impairments. To date, little is known about how neuronal primary cilia affect postnatal development, neuronal function in the adult brain, and hippocampal memory.
The first goal of our research is to understand how a fraction of neurons in the forebrain are recruited and synchronized to encode and store episodic memory. The second goal is to determine how ciliary signaling affects postnatal neurodevelopment and neuronal function in the adult brain, and thereby modulates hippocampal memory formation. Our long-term vision is to build bridges connecting fundamental neuroscience research with translational medicine, facilitating the development of novel therapies to treat cognitive dysfunction-related disorders. Our vision also includes increasing efforts to train the next-generation of leading scientific thinkers and support the growth of individuals pursuing biotech and health profession careers.
Our passion and dedication to science have recently led us to make many fundamental discoveries. We discovered that burst synchronization of primed hippocampal neurons is crucial (probably essential) for learning and forming trace fear memory (highlights: https://neurosciencenews.com/memory-learning-cell-synchronization-15649/; https://directorsblog.nih.gov/2021/03/25/the-synchronicity-of-memory/). We developed the first method to quantitatively measure in vivo hippocampal neuronal activity hierarchy, and we initially reported that the non-linear weighted synaptic conductance, likely mediated by the NMDARs, regulates the development and maintenance of neuronal activity hierarchy (Zhou et al., 2023 bioRxiv, 523038). We coined the concept that neuronal and astrocytic primary cilia exhibit a dichotomy, as distinguished by their morphological dynamics, signaling pathways, key molecular components, and functionality, as well as disease associations (Sterpka et al., 2020). We presented the first evidence showing that neuronal primary cilia direct the postnatal positioning of pyramidal cells, and late-born principal neurons in the neocortex and hippocampus undergo a previously unnoticed "reverse migration" for neuron positioning and cortical lamination (Yang et al., 2021 bioRxiv, 473383).
Research Approaches: molecular biology, cellular imaging, behavioral analysis, patch-clamp electrophysiology, EEG/EMG recording, in vivo deep-brain calcium imaging in freely behaving mice, pharmacological tools, viral vector delivery, and transgenic animal models
Lab Members: Yuxin Zhou, Juan Yang, Liyan Qiu, Soheila Mirhosseiniardakani, Sahar Jamialahmadi, Jordan Tropey, Jung-Kai Lin, Jenn Wang, and Sierra Walsh.
Funding: Our research is supported by NIH Grants K01AG054729, P20GM113131, R15MH126317, and R15MH125305, COLE Research Awards, CoRE PRP awards, UNH Teaching Assistantships, Summer TA Fellowships and Dissertation Year Fellowships, and awards from the Hamel Center for Undergraduate Research.
- BCHM 860: Pharmacology
- BCHM/BMCB 860/760: Pharmacology
- BIOL 411: Honor/Intro Biol: Mol/Cellular
- BIOL 411H: Hon/Principles of Biol I Lab
- BMCB 760: Pharmacology
- BMCB 795W: Invest in Molecular & Cell Bio
- BMCB 799H: Honors Senior Thesis
- BMS 799H: Senior Honors Thesis
- INCO 590: Rsrch Exp/MCBS
- INCO 790: Advanced Research Experience
- MCBS 901: Intro to Research in Life Sci
- MCBS 999: Doctoral Thesis
- NSB 799H: Honors Senior Thesis
Yang, J., Qiu, L., Strobel, M., Kabel, A., Zha, X. -M., & Chen, X. (2020). Acid-Sensing Ion Channels Contribute to Type III Adenylyl Cyclase-Independent Acid Sensing of Mouse Olfactory Sensory Neurons. MOLECULAR NEUROBIOLOGY, 57(7), 3042-3056. doi:10.1007/s12035-020-01943-0
Sterpka, A., Yang, J., Strobel, M., Zhou, Y., Pauplis, C., & Chen, X. (2020). Diverged morphology changes of astrocytic and neuronal primary cilia under reactive insults. MOLECULAR BRAIN, 13(1). doi:10.1186/s13041-020-00571-y
Zhou, Y., Qiu, L., Wang, H., & Chen, X. (2020). Induction of activity synchronization among primed hippocampal neurons out of random dynamics is key for trace memory formation and retrieval. FASEB JOURNAL, 34(3), 3658-3676. doi:10.1096/fj.201902274R
Zhou, Y., Qiu, L., Sterpka, A., Wang, H., Chu, F., & Chen, X. (2019). Comparative Phosphoproteomic Profiling of Type III Adenylyl Cyclase Knockout and Control, Male, and Female Mice. FRONTIERS IN CELLULAR NEUROSCIENCE, 13. doi:10.3389/fncel.2019.00034
Chen, X., Luo, J., Leng, Y., Yang, Y., Zweifel, L. S., Palmiter, R. D., & Storm, D. R. (2016). Ablation of Type III Adenylyl Cyclase in Mice Causes Reduced Neuronal Activity, Altered Sleep Pattern, and Depression-like Phenotypes. BIOLOGICAL PSYCHIATRY, 80(11), 836-848. doi:10.1016/j.biopsych.2015.12.012
Challis, R. C., Tian, H., Wang, J., He, J., Jiang, J., Chen, X., . . . Ma, M. (2015). An Olfactory Cilia Pattern in the Mammalian Nose Ensures High Sensitivity to Odors. CURRENT BIOLOGY, 25(19), 2503-2512. doi:10.1016/j.cub.2015.07.065
Chen, X., Cao, H., Saraf, A., Zweifel, L. S., & Storm, D. R. (2015). Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral Inhibition. JOURNAL OF NEUROSCIENCE, 35(1), 339-351. doi:10.1523/JNEUROSCI.2478-14.2015
Wardlaw, S. M., Phan, T. X., Saraf, A., Chen, X., & Storm, D. R. (2014). Genetic disruption of the core circadian clock impairs hippocampus-dependent memory. LEARNING & MEMORY, 21(8), 417-423. doi:10.1101/lm.035451.114
Xiang, Y. -Y., Chen, X., Li, J., Wang, S., Faclier, G., MacDonald, J. F., . . . Lu, W. -Y. (2013). Isoflurane Regulates Atypical Type-A gamma-Aminobutyric Acid Receptors in Alveolar Type II Epithelial Cells. ANESTHESIOLOGY, 118(5), 1065-1075. doi:10.1097/ALN.0b013e31828e180e
Chen, X., Xia, Z., & Storm, D. R. (2012). Stimulation of Electro-Olfactogram Responses in the Main Olfactory Epithelia by Airflow Depends on the Type 3 Adenylyl Cyclase. JOURNAL OF NEUROSCIENCE, 32(45), 15769-15778. doi:10.1523/JNEUROSCI.2180-12.2012
Chen, X., Whissell, P., Orser, B. A., & MacDonald, J. F. (2011). Functional Modifications of Acid-Sensing Ion Channels by Ligand-Gated Chloride Channels. PLOS ONE, 6(7). doi:10.1371/journal.pone.0021970
Chen, X., Qiu, L., Li, M., Duerrnagel, S., Orser, B. A., Xiong, Z. -G., & MacDonald, J. F. (2010). Diarylamidines: High potency inhibitors of acid-sensing ion channels. NEUROPHARMACOLOGY, 58(7), 1045-1053. doi:10.1016/j.neuropharm.2010.01.011
Chen, X., Numata, T., Li, M., Mori, Y., Orser, B. A., Jackson, M. F., . . . MacDonald, J. F. (2010). The modulation of TRPM7 currents by nafamostat mesilate depends directly upon extracellular concentrations of divalent cations. MOLECULAR BRAIN, 3. doi:10.1186/1756-6606-3-38
Beazely, M. A., Lim, A., Li, H., Trepanier, C., Chen, X., Sidhu, B., & MacDonald, J. F. (2009). Platelet-derived Growth Factor Selectively Inhibits NR2B-containing N-Methyl-D-aspartate Receptors in CA1 Hippocampal Neurons. JOURNAL OF BIOLOGICAL CHEMISTRY, 284(12), 8054-8063. doi:10.1074/jbc.M805384200
Paukert, M., Chen, X., Polleichtner, G., Schindelin, H., & Gruender, S. (2008). Candidate amino acids involved in H+ gating of acid-sensing ion channel 1a. JOURNAL OF BIOLOGICAL CHEMISTRY, 283(1), 572-581. doi:10.1074/jbc.M706811200
Chen, X., Polleichtner, G., Kadurin, I., & Gruender, S. (2007). Zebrafish acid-sensing ion channel (ASIC) 4, characterization of homo- and heteromeric channels, and identification of regions important for activation by H+. JOURNAL OF BIOLOGICAL CHEMISTRY, 282(42), 30406-30413. doi:10.1074/jbc.M702229200
Chen, X., & Gruender, S. (2007). Permeating protons contribute to tachyphylaxis of the acid-sensing ion channel (ASIC) 1a. JOURNAL OF PHYSIOLOGY-LONDON, 579(3), 657-670. doi:10.1113/jphysiol.2006.120733
Chen, X., Paukert, M., Kadurin, I., Pusch, M., & Gruender, S. (2006). Strong modulation by RFamide neuropeptides of the ASIClb/3 heteromer in competition with extracellular calcium. NEUROPHARMACOLOGY, 50(8), 964-974. doi:10.1016/j.neuropharm.2006.01.007
Chen, X. M., Kalbacher, H., & Grunder, S. (2006). Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent. JOURNAL OF GENERAL PHYSIOLOGY, 127(3), 267-276. doi:10.1085/jgp.200509409
Chen, X. M., Kalbacher, H., & Grunder, S. (2005). The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity. JOURNAL OF GENERAL PHYSIOLOGY, 126(1), 71-79. doi:10.1085/jgp.200509303