Draft:Zhen Yan

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
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
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. In the Rockefeller University, Yan continued to work on dopamine signaling cascades in the striatum using electrophysiological and biochemical techniques.

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.

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. , whereas repeated stress induces synaptic depression by increasing the ubiquitin/proteasome-mediated degradation of NMDAR and AMPAR subunits, resulting in impaired working memory. 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. These findings have attracted widespread attention in scientific community and general public. See news reports in Los Angeles Times, Huffington Post, 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. 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. 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. 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. See news report in New York Post.

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 ). 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 for outstanding scientific achievement.