Draft:Zhen Yan

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Dr. Zhen Yan, Neuroscientist, is a SUNY Distinguished Professor in the Department of Physiology & Biophysics, State University of New York (SUNY) at Buffalo, School of Medicine and Biomedical Sciences. Her research is focused on the pathophysiological mechanisms of brain disorders, particularly the role of synaptic and epigenetic aberrations in autism, stress-linked neuropsychiatric disorders and Alzheimer's disease.  

Biography[edit]

Yan was born in Nanjing, China in 1968. She earned the Bachelor's degree in Biomedical Engineering from Xi'an Jiaotong University (Xi'an, China) in 1990. She then received a Master's degree in Computer Engineering from Southeast University (Nanjing, China) in 1993 and worked briefly in a China-US joint-venture company as a software engineer.

In Nov. 1993, Yan went to the United States. She earned her Ph.D. in Neurobiology from the University of Tennessee Health Science Center in 1997 under the mentorship of Dr. James Surmeier. In Dec. 1997, she went to the Rockefeller University, working as a postdoctoral associate with Dr. Paul Greengard, a prominent neuroscientist who won the Nobel Prize in Physiology or Medicine in the year of 2000.

In May 2000, Yan was recruited to State University of New York at Buffalo, School of Medicine and Biomedical Sciences as an assistant professor. She was promoted to associate professor with tenure in 2004, full professor in 2008, and SUNY Distinguished Professor in 2018.

Research[edit]

While working as a graduate student, Yan became interested in basal ganglia physiology, which is important for understanding the pathophysiological mechanism of Parkinson's disease. By using the innovative single-cell mRNA profiling and patch-clamp recording approaches, she has revealed the role of dopamine and muscarinic acetylcholine receptors in the regulation of voltage-gated and ligand-gated ion channels in striatal projection neurons and cholinergic interneurons.[1] In the Rockefeller University, Yan continued to work on dopamine signaling cascades in the striatum using electrophysiological and biochemical techniques.[2]    

Since Yan established her own lab in SUNY-Buffalo, she has been focusing on prefrontal cortex (PFC), a key brain region controlling "high-level" executive functions. Yan's research has discovered how the glutamatergic and GABAergic neurotransmission in prefrontal cortex is regulated by various neuromodulators, including disease susceptibility genes, stress hormones and monoamines (e.g. serotonin and dopamine), which is important for cognitive and emotional control under normal conditions. Her research has also uncovered how the aberrant action of neuromodulators under pathological conditions leads to dysregulation of synaptic transmission in PFC.[3]

One example of Yan's series of important discoveries is in the stress field. Stress has a profound impact on the brain and body, however the neuronal basis underlying the complex actions of stress hormones remains elusive. Yan's research has found that acute stress causes a long-lasting potentiation of the membrane trafficking and synaptic function of NMDARs and AMPARs in PFC, leading to the facilitated working memory.[4][5], whereas repeated stress induces synaptic depression by increasing the ubiquitin/proteasome-mediated degradation of NMDAR and AMPAR subunits, resulting in impaired working memory.[6] Moreover, they have found that females and males show different cognitive and emotional responses to repeated stress and estrogen prevents the detrimental effects of repeated stress on glutamatergic transmission and cognition.[7] These findings have attracted widespread attention in scientific community and general public. See news reports in Los Angeles Times,[8] Huffington Post,[9] and England's Daily Mail. In 2018, Yan's group started to study physiological basis underlying the effects of chronic adolescent social isolation stress. They have revealed the neural circuitry and molecular mechanism causally linked to heightened aggression in isolated male mice and social withdrawal in isolated female mice.[10][11] These studies shed light on the role of isolation stress in influencing psychological health and provide therapeutic targets to modify neuronal stress response in a sex-specific manner.

Over the past decade, Yan's research team is focused on epigenetic mechanisms and treatment strategies for brain disorders. One line of research is on autism. They have found that small molecule compounds targeting histone modifiers can persistently rescue autism-like social deficits in Shank3-deficient mice (an autism model) by restoring gene expression and NMDAR function in prefrontal cortex.[12][13][14] See news report in England's Daily Mail. Yan's group has also revealed how the top-ranking autism risk genes, many of which are epigenetic regulators, cause synaptic dysfunction and behavioral abnormality.[15][16] An additional line of research is to discover epigenetic mechanisms linked to cognitive dysfunction in Alzheimer's disease (AD). Using AD human postmortem tissues and AD mouse models, Yan's research group has found aberrant histone methylation in PFC of AD, leading to the downregulation of synaptic genes that are essential for cognition and the upregulation of cell stress-related genes that are detrimental to cognition. Targeting epigenetic enzymes to normalize histone methylation results in the restoration of gene expression, synaptic function and cognitive behaviors in AD models.[17][18][19] See news report in New York Post.[20]

Using a combination of cutting-edge electrophysiological, molecular biological, biochemical, chemogenetic, optogenetic and behavioral approaches, Yan leads a highly productive research team and has published more than 160 original articles, many of which are on high-impact journals (Google Scholar[21]). Yan's research has been continuously funded by National Institutes of Health. She has also mentored numerous graduate students and postdoctoral fellows. Yan has won several awards, including Stockton Kimball Award[22] for outstanding scientific achievement.

References[edit]

  1. ^ Yan, Zhen; Surmeier, James D. (1997-11-01). "D5 dopamine receptors enhance Zn2+-sensitive GABA(A) currents in striatal cholinergic interneurons through a PKA/PP1 cascade". Neuron. 19 (5). doi:10.1016/s0896-6273(00)80402-x. ISSN 0896-6273. PMID 9390524.
  2. ^ Yan, Zhen; Hsieh-Wilson, Linda; Feng, Jian; Tomizawa, Kazuhito.; Allen, Patrick. B.; Fienberg, Allen. A.; Nairn, Angus. C.; Greengard, Paul. (1999-01-20). "Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin". Nature Neuroscience. 2 (1): 13–17. doi:10.1038/4516. ISSN 1097-6256. PMID 10195174.
  3. ^ Yan, Zhen; Rein, Benjamin (2022-01-10). "Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications". Molecular Psychiatry. 27 (1): 445–465. doi:10.1038/s41380-021-01092-3. ISSN 1476-5578. PMC 8523584. PMID 33875802.
  4. ^ Yuen, Eunice Y.; Liu, Wenhua; Karatsoreos, Ilia N.; Feng, Jian; McEwen, Bruce S.; Yan, Zhen (2009-08-18). "Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory". Proceedings of the National Academy of Sciences of the United States of America. 106 (33): 14075–14079. Bibcode:2009PNAS..10614075Y. doi:10.1073/pnas.0906791106. ISSN 1091-6490. PMC 2729022. PMID 19666502.
  5. ^ Yuen, Eunice. Y.; Liu, Wenhua.; Karatsoreos, Ilia. N.; Ren, Yong.; Feng, Jian.; McEwen, Bruce. S.; Yan, Zhen. (2011-02-10). "Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory". Molecular Psychiatry. 16 (2): 156–170. doi:10.1038/mp.2010.50. ISSN 1476-5578. PMC 3108461. PMID 20458323.
  6. ^ Yuen, Eunice Y.; Wei, Jing; Liu, Wenhua; Zhong, Ping; Li, Xiangning; Yan, Zhen (2012-03-08). "Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex". Neuron. 73 (5): 962–977. doi:10.1016/j.neuron.2011.12.033. ISSN 1097-4199. PMC 3302010. PMID 22405206.
  7. ^ Wei, Jing.; Yuen, Eunice. Y.; Liu, Wenhua.; Li, Xiangning.; Zhong, Ping.; Karatsoreos, Ilia. N.; McEwen, Bruce. S.; Yan, Zhen. (2014-05-10). "Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition". Molecular Psychiatry. 19 (5): 588–598. doi:10.1038/mp.2013.83. ISSN 1476-5578. PMID 23835908.
  8. ^ Pandika, Melissa (2013-07-10). "Females respond better to stress, thanks to estrogen, study says". Los Angeles Times. Retrieved 2024-01-28.
  9. ^ "New Research Explains Why Women May Respond Better To Stress". HuffPost. 2013-07-11. Retrieved 2024-01-28.
  10. ^ Tan, Tao; Wang, Wei; Liu, Tiaotiao; Zhong, Ping; Conrow-Graham, Megan; Tian, Xin; Yan, Zhen (2021-03-23). "Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress". Cell Reports. 34 (12): 108874. doi:10.1016/j.celrep.2021.108874. ISSN 2211-1247. PMID 33761364.
  11. ^ Wang, Zi-Jun; Shwani, Treefa; Liu, Junting; Zhong, Ping; Yang, Fengwei; Schatz, Kelcie; Zhang, Freddy; Pralle, Arnd; Yan, Zhen (2022-07-10). "Molecular and cellular mechanisms for differential effects of chronic social isolation stress in males and females". Molecular Psychiatry. 27 (7): 3056–3068. doi:10.1038/s41380-022-01574-y. ISSN 1476-5578. PMC 9615910. PMID 35449296.
  12. ^ Qin, Luye; Ma, Kaijie; Wang, Zi-Jun; Hu, Zihua; Matas, Emmanuel; Wei, Jing; Yan, Zhen (2018-04-10). "Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition". Nature Neuroscience. 21 (4): 564–575. doi:10.1038/s41593-018-0110-8. ISSN 1546-1726. PMC 5876144. PMID 29531362.
  13. ^ Wang, Zi-Jun; Zhong, Ping; Ma, Kaijie; Seo, Ji-Seon; Yang, Fengwei; Hu, Zihua; Zhang, Freddy; Lin, Lin; Wang, Jie; Liu, Tao; Matas, Emmanuel; Greengard, Paul; Yan, Zhen (2020-10-10). "Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice". Molecular Psychiatry. 25 (10): 2517–2533. doi:10.1038/s41380-019-0351-2. ISSN 1476-5578. PMC 6639159. PMID 30659288.
  14. ^ Rapanelli, Maximiliano; Williams, Jamal B.; Ma, Kaijie; Yang, Fengwei; Zhong, Ping; Patel, Rajvi; Kumar, Manasa; Qin, Luye; Rein, Benjamin; Wang, Zi-Jun; Kassim, Bibi; Javidfar, Behnam; Couto, Lizette; Akbarian, Schahram; Yan, Zhen (2022-08-10). "Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models". Molecular Psychiatry. 27 (8): 3355–3366. doi:10.1038/s41380-022-01508-8. ISSN 1476-5578. PMC 9477974. PMID 35296809.
  15. ^ Qin, Luye; Williams, Jamal B.; Tan, Tao; Liu, Tiaotiao; Cao, Qing; Ma, Kaijie; Yan, Zhen (2021-11-15). "Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures". Nature Communications. 12 (1): 6589. Bibcode:2021NatCo..12.6589Q. doi:10.1038/s41467-021-26972-8. ISSN 2041-1723. PMC 8593046. PMID 34782621.
  16. ^ Conrow-Graham, Megan; Williams, Jamal B.; Martin, Jennifer; Zhong, Ping; Cao, Qing; Rein, Benjamin; Yan, Zhen (2022-09-14). "A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders". Brain: A Journal of Neurology. 145 (9): 3250–3263. doi:10.1093/brain/awac152. ISSN 1460-2156. PMC 10233273. PMID 35775424.
  17. ^ Zheng, Yan; Liu, Aiyi; Wang, Zi-Jun; Cao, Qing; Wang, Wei; Lin, Lin; Ma, Kaijie; Zhang, Freddy; Wei, Jing; Matas, Emmanuel; Cheng, Jia; Chen, Guo-Jun; Wang, Xiaomin; Yan, Zhen (2019-03-01). "Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease". Brain: A Journal of Neurology. 142 (3): 787–807. doi:10.1093/brain/awy354. ISSN 1460-2156. PMC 6391616. PMID 30668640.
  18. ^ Cao, Qing; Wang, Wei; Williams, Jamal B.; Yang, Fengwei; Wang, Zi-Jun; Yan, Zhen (2020-12-10). "Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease". Science Advances. 6 (50): eabc8096. Bibcode:2020SciA....6.8096C. doi:10.1126/sciadv.abc8096. ISSN 2375-2548. PMC 7725456. PMID 33298440.
  19. ^ Williams, Jamal B.; Cao, Qing; Wang, Wei; Lee, Young-Ho; Qin, Luye; Zhong, Ping; Ren, Yong; Ma, Kaijie; Yan, Zhen (2023-01-06). "Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model". Nature Communications. 14 (1): 91. Bibcode:2023NatCo..14...91W. doi:10.1038/s41467-022-35749-6. ISSN 2041-1723. PMC 9822922. PMID 36609445.
  20. ^ Sparks, Hannah (2019-01-24). "Memory loss due to Alzheimer's could possibly be restored, study says". Retrieved 2024-01-28.
  21. ^ "Zhen Yan". scholar.google.com. Retrieved 2024-01-28.
  22. ^ "Leading Neuroscientist Yan Wins Stockton Kimball Award". medicine.buffalo.edu. Retrieved 2024-01-28.
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