It is a longstanding goal in neuroscience to reveal how specific cell types contribute to different neural circuits that underlie cognition, behavior, and disease pathology. Although cell types can be grouped into descriptive categories (excitatory, inhibitory, peptidergic etc.), we know there is a great combinatorial diversity of cels that differ in ion channel and receptor expression levels and fulfill discrete roles within neural circuits. Thus, to improve the resolution of neural circuit maps, to understand how the brain works on a mechanistic level, and to better understand disease pathologies there is a great need for manipulating ever more specific sets of cell in neural circuits. Genetically targeting these different subsets is difficult when delivering transgenes to many neurons (with potentially adverse effects) and relying on cell-type specific promoters for selective expression - the current state of the art. Our agenda is to fundamentally change how cell type specific genetic manipulation is achieved: Since the functional definition of a neuron - its electrophysiological response to a stimulus - is intrinsically a proteomic problem, we propose a novel viral delivery method able to deliver transgenes selectively to neurons that express, on the cell surface, a targeted set of ion channels and receptors. When using this novel method transgene expression can be driven from generic and reliable promoters or other engineered promoter systems (e.g. sensitive to light or drugs). To achieve this transformative goal of a broadly useful tool for in vvo viral gene delivery, we build on Dr. Schmidt's expertise in protein engineering using genetically encoded peptide toxins, and Dr. Thomas' expertise with in vivo models of addiction disorders. In this application we describe the development of a generalizable method for creating engineered viruses with user-selectable tropism that can target specific subsets of neuronal cell types. We furthermore propose to demonstrate utility of these engineered viruses in intact brain tissue, including optogenetically targeting - without relying on transgenic animals or specific promoters - two sets of neurons involved in reward-related synaptic plasticity. The outcome of this work will be a broadly useful and first-in-class viral delivery technology that enables the genetic manipulation of defined sets neuron types in the brain based on what surface receptors they express. This method will enable completely new ways of exploring molecular and cellular mechanism of neural activity.

Public Health Relevance

It is a longstanding goal of the neuroscience community to reveal how specific cell types contribute to different neural circuits that underlie cognition, behavior, and disease pathology. To improve the resolution of neural circuit maps, to understand how the brain works on a mechanistic level, and to better understand disease pathologies there is a great need for genetically manipulating ever more specific sets of cells in neural circuits. The outcome of this work will be a broadly useful and first-in-class viral deliver technology that overcomes current limitations of cell-type specific targeting in the brain, and tha enables completely new ways of exploring molecular and cellular mechanism of neural activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH109038-02
Application #
9149316
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Freund, Michelle
Project Start
2015-09-24
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455