I have a diverse educational and research background that drives me to take a non-traditional approach to neuroscience. My undergraduate education and early research was in biophysics and biochemistry, where I worked laboratory of M. Thomas Record in the Department of Chemistry at UW-Madison, investigating the thermodynamics of protein structural transitions upon protein-DNA binding. In my PhD work, I used my molecular and biochemistry training to engineer viruses that can label connected neurons in defined ways. In Dr. Connie Cepko’s laboratory at Harvard University, I engineered the first monosynaptic anterograde virus, which can be used to map outputs of targeted neuronal populations (Beier et al., PNAS 2011), as well as other variants which we used to uncover novel visual circuits in the retina (Beier et al., Journal of Neuroscience 2013). In my postdoctoral training with Drs. Liqun Luo and Dr. Robert Malenka at Stanford University, I devised a viral-genetic intersectional strategy, termed TRIO, to build a high-resolution input-output map of heterogeneous ventral tegmental area dopamine (VTA-DA) neurons. I used the three-node maps to uncover unique global connectivity relationships of these subpopulations whose function I validated using classical behavioral pharmacology and optogenetics (Beier et al., Cell 2015). Precise synaptic maps have significant value as static pictures in time, but I sought to augment TRIO to map how motivational ensembles are modified by experience. As drugs of abuse with distinct molecular mechanisms trigger common neuroplastic changes onto VTA-DA neurons required for the development and maintenance of drug addiction, I screened for changes induced by drugs of abuse.
I found that exposure to a single dose of any of a variety of abused substances causes a long-term enhancement of activity in the globus pallidus (GPe), and that inhibiting the GPe during drug exposure prevents cocaine-induced behavioral adaptations. I then showed using a combination of behavior, optogenetics, chemogenetics, synaptic physiology, and calcium imaging that the GPe drives these behavioral adaptations through disinhibition of VTA-DA neurons (Beier et al., Nature 2017). This method is not limited to drug addiction, but can be applied to any question where activity is modulated by time or experience. As the approach is unbiased, it enables identification of novel circuit substrates underlying behavioral adaptation. This includes pathology caused by neurodegeneration, including Parkinson’s disease and Alzheimer’s Disease (AD). Very little is known about the circuit-level changes that occur during AD, particularly those that occur prior to the onset of protein aggregation and cognitive deficits. My rabies activity screening method is ideally suited to address these questions. I will first start with the hippocampus and layer 5 entorhinal cortex neurons, and screen for how activity in these circuits is modulated over the development of pathology in mouse models of AD. Once brain sites have been identified that show activity differences prior to the onset of pathology, I will optogenetically manipulate these substrates to either slow or prevent the development of cognitive deficits in these mouse models.