Senior Scientist & Director of Behavioral Neuroscience
Robert S. Dow Neurobiology Labs
Legacy Research Institute
1225 NE 2nd Avenue
Portland, OR 97232
Dr. Yee is a behavioral neuroscientist who joined the Dow Labs in 2011. He comes to Legacy from the Swiss Federal Institute of Technology in Zurich (Eidgenössische Technische Hochschule Zürich) where he was a senior scientist in the Laboratory of Behavioural Neurobiology and began collaborating with Dr. Detlev Boison, Director of Basic and Translational Research at the LRI, on his NIH grant related to schizophrenia. Dr. Yee received his bachelor degree (BSc Hons) in psychology from University College London and his doctoral degree (DPhil) from the University of Oxford. He subsequently held positions as a postdoctoral scientist at the Swiss Federal Institute of Technology Zurich and the University of Oxford, and as a lecturer and research fellow at the University of Hong Kong, before returning to the Swiss Federal Institute of Technology for eleven years as a senior scientist and group leader before moving to Oregon to accept his current position. Dr. Yee has published more than 120 articles in peer-reviewed journals with a total of 3,853 citations and an h-index of 34 (Source: Scopus.com) and mentored twenty postgraduate students. He has received funding from various national and internal grantmakers, including the Swiss National Science Foundation and the NIH. The addition of Dr. Yee to the Dow Neurobiology Laboratories complements the expansion of neurobiology research within the Institute, coinciding with increasing demands for transgenic mouse models of CNS disorders. He has established the Murine Neurobehavioral Research Core with an aim to provide a holistic attempt to incorporate reductionist approaches and biological methods into an integrated and unified understanding of the behavior of the total organism to support expansion into translational neuropsychiatric research. The Neurobehavioral Research Core is staffed with the assistance of Dr. Yee's former students Dr. Philipp Singer and Dr. Sylvain Dubroqua, who joined the RS Dow Labs in the same year.
Our research seeks to explain behavior and its underlying psychological and cognitive processes across multiple biological levels - from genes, development, and brain circuitry to neurotransmitter systems. By identifying and dissecting the neural bases underlying discrete brain functions, therapeutic remedies to ameliorate their specific dysfunction can be devised. I am heading the murine behavioural core facility to support effective translational research using animal models of neuropsychiatric disorders. My experimental approach emphasizes the use of in-depth and comprehensive behavioral analysis of rodent animal models to study the consequences of defined genetic, pharmacological, surgical and environmental (including prenatal and nutritional) interventions at the holistic in vivo level. As the repertoire of interventions expands, so does our ability to achieve a cohesive, multi-level understanding of normal and diseased brain functions.
Schizophrenia is a major psychiatric disorder affecting 1% of the world population. Its complex manifestation is characterized by the disintegration of multiple psychological functions leading to the emergence of psychotic symptoms as well as cognitive deficiency. We investigate the pathological processes of the disease in an attempt to understand how the disease develops and symptoms generated. Genetic and environmental risk factors are modelled to delineate their relative contributions to etiological processes, and to allow effective assessment of novel therapeutic avenues including possible preventative treatment. Currently available treatments remain unsatisfactory, particularly in the control of cognitive and negative symptoms. We have therefore focused on novel neuromodulatory targets to correct major neurotransmitter dysfunctions implicated in schizophrenia. One approach targets glycine - an endogenous modulator of NMDA receptor in response to glutamate neurotransmission. We have demonstrated that NMDA receptor function can be boosted by elevating glycine availability when the regulator of extracellular glycine - glycine transporter 1 (GlyT1) -- is blocked. Mice lacking GlyT1 exhibited multiple schizophrenia-resilient phenotypes, resembling the actions of antipsychotic drugs. Importantly, memory and attention processes deficient in schizophrenia are enhanced, and the mutant mice exhibited resistance to psycho-stimulant drug challenges. We are currently mapping the multiple effects of GlyT1 blockade onto specific brain regions to achieve a circuitry-based appreciation of this potentially novel therapy. This is achieved by focal brain manipulations through the innovative use of virus vectors as well as conventional intracerebral drug delivery. Another target under active investigation is adenosine, which is a regulatory molecule of dopamine as well as glutamate neurotransmissions via receptors with opposing actions. The neuromodulation by adenosine is widespread and represents an intricate system whereby its contribution to schizophrenia symptoms is far from understood. Our research shows that a subtle adenosine imbalance between cortical and striatal brain regions can either induce schizophrenia-like behavior or schizophrenia-resilience. Delineating the precise mechanisms involved would be essential in the design of adenosine-based therapeutic interventions against schizophrenia.
Learning and Memory
Learning enables us to adapt to the changing demands imposed by our environment, and epitomizes intelligent behavior in the animal kingdom. We are interested in all facets of learning and memory, whereby past experiences mould our current behavior, color our emotions, alter our perception of the world, and provide us a sense of personal identity. While memory impairments are prominent in conditions such as Alzheimer's disease and schizophrenia, persistent memories are implicated in specific anxiety disorders such as post-traumatic stress disorder (PTSD) and phobias. We study how memories are acquired, stored and expressed, and how conflicting memories may interfere and compete with each other. Following the traditions in learning theories, we examine and characterize the conditions that facilitate or impede learning. For example, attention can determine what are preferentially learned and how fast learning may proceed. In turn, the allocation of attention can be modified by our past experiences. We are particularly interested in the roles of the hippocampus and related brain structures (e.g., septum, entorhinal cortex, amygdala, prefrontal cortex and ventral striatum) in sustaining normal learning and memory. We perform specific surgical, pharmacological and molecular manipulations targeting the hippocampus and other prescribed structures, and deduce from the resulting effects on behavior the cellular and molecular mechanisms that underlie learning and memory. By studying mutant mice with deletion of glycine transporter 1, for instance, we are able to determine specific memory processes modifiable by forebrain NMDA receptors, and how this might be translated into potential cognitive enhancing therapies.
While elevation of glycine in the vicinity of NMDA receptor-containing synapses could confer anti-psychotic and pro-cognitive potential, facilitation of glycinergic inhibitory neurotransmission may assist cessation of alcohol dependence. Substance dependence, such as alcohol addiction, is maintained by the motivation and reward system centred on the mesolimbic dopamine connection from ventral tegmental area (VTA) to nucleus accumbens (NAC). Alcohol can activate this system via inhibition of the GABAergic NAC?VTA negative feedback. Local application of glycine transporter 1 inhibiting drugs into the NAC can partially substitute as well as blocking this effect of alcohol, thereby reducing the craving and the positive reinforcing property of alcohol consumption on the motivation system. We are attempting to cell-type identify of the critical GlyT1 population responsible for the hypothesized anti-alcohol effects. Viral vectors specific either to neurons or glial cells will allow us to dissociate the contributions of these two populations of GlyT1. We wish to determine if these two populations act in unison or in opposition in the regulation of alcohol dependence; and to explore if the other major regulator of reuptake at inhibitory glycinergic synapses - GlyT2 - might also assume a critical role.
The clinical relevance of co-existing mental and cognitive symptoms amongst many neurological conditions such as epilepsy and Parkinson's disease has been increasingly recognized. These psychiatric disturbance and cognitive deficiency are often persistent and represent significant clinical challenges even when the core symptoms of the disease are brought under control. Such symptoms seriously impede the patients' ability to regain quality of life. However, it is unclear whether these deficits are primary symptoms directly linked to the disease process of the relevant disease or secondary reactive symptoms. The precise causes and mechanisms responsible are therefore far from understood. Using animal models with construct validity of the prescribed diseases, we wish to characterize the precise nature of such comorbid symptoms, distinguish primary from secondary symptoms, and identify the mechanism responsible for their emergence.
Mental disorders often represent extremities of psychological traits that can be effectively evaluated in animals with appropriate tests. By measuring individual difference in normal mouse population, associations between extreme psychological traits can be identified statistically, and possible links with underlying physiological and genetic 'traits' might be revealed. Such analysis enhances our appreciation of the power of behavioural evaluation in animals and exposes hitherto unidentified biologically meaningful associations. One of our major focuses is the prepulse inhibition (PPI) test of sensorimotor gating which represents a key translational paradigm in schizophrenia research. We have demonstrated that PPI expression in normal animals might demarcate the propensity to develop amphetamine sensitization - a key marker for stress and psychoticism. We are expanding our research to explore in normal animals possible association between different forms of anxiety expression, and between impulsivity and vulnerability to alcohol addiction. We are also interested in examining whether pre-existing psychological traits might predict outcomes of mild traumatic brain injuries, especially with respect to the emergence of post-injury emotional and cognitive disabilities.