Understanding the molecular mechanism of memory from single-cell gene expression to protein folding

Project Summary / Abstract
Deficits in cognitive function and memory are a debilitating aspect of neurodegenerative disease resulting in
long-term disability, enormous suffering to individuals and their families, and significant socioeconomic cost.
Currently, more than 16 million Americans live with cognitive impairment, and this number is expected to continue
rising as the number of individuals affected by Alzheimer's disease and related dementias is predicted to double
by 2060. Long-term memory consolidation requires the induction of gene expression in a specific temporal
pattern. Newly synthesized transcripts are translated and folded into functional proteins and then trafficked to
the correct cellular location. Dysfunction in any of these steps can lead to memory impairment and may be
dysregulated in disease conditions, although the precise mechanisms by which this occurs are unclear. My long-
term goal is to determine the specific molecular mechanisms through which the Nr4A sub-family regulates gene
expression to control long-term memory in order to develop therapeutic tools to treat AD, which I will pursue as
an independent investigator at a research-focused institution. The overall objective of this proposal is to
determine the mechanisms that link transcriptional regulation and protein folding during memory formation and
how the disruption of these processes contributes to cognitive impairment in Alzheimer's disease. My central
hypothesis is that Nr4A regulates genes in specific cell types to facilitate protein folding and memory formation.
I will test this through the following three aims: Specific Aim 1 (K99): identify cell-type specific transcriptional
signatures of memory and identify direct gene targets of Nr4A during memory consolidation using a single-cell
RNA sequencing approach; Specific Aim 2 (K99): determine the role of an Nr4A target, the protein folding
chaperone Hspa5, in memory consolidation and identify its downstream protein targets; Specific Aim 3 (R00):
determine the effect of activating Nr4A transcription factors on memory deficits and gene expression in a mouse
model of Alzheimer's disease. This project provides training in cutting-edge research skills, including
computational analysis of single cell data and chromatin enrichment in memory research. The University of Iowa
is home to experts on memory, computational psychiatry, neurodegeneration, and molecular biology, and the
collaborative environment provides an ideal setting in which to obtain the necessary skills that will allow me to
transition into a successful independent research career. As such, during the mentored (K99) phase, I will
engage in activities designed to prepare me to successfully achieve independence, including training in scientific
presentations, laboratory management skills, grant writing tools, scientific peer-review, and interview/application
preparation. Collectively, this award will provide me with the cutting-edge skills and expertise in molecular
biology, neurodegeneration and behavioral pharmacology necessary to ensure a strong technical and
conceptual foundation to start my independent laboratory investigating mechanisms for the treatment of
Alzheimer's disease.

Grant Number: 5R00AG068306-05
NIH Institute/Center: NIH
Principal Investigator: Snehajyoti Chatterjee