Kevin Beier, PhD

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.

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