The formation of normal long-term memory (LTM) requires alterations in gene expression and protein synthesis in neurons. These changes are critical for modifications in synaptic function and proceed through a time dependent consolidation process after training. Recent evidence strongly suggests that when a stable LTM is later recalled and moves into an active state, the neural substrate for this memory requires a period of "reconsolidation" that depends on some of the same cellular processes involved in initial memory formation. This project addresses the importance of two cellular processes in the formation and stability of memory: protein translation controlled by the mammalian target of rapamycin (mTOR) pathway, and protein degradation through the ubiquitin-proteosome system. We use Pavlovian fear conditioning in rodents as an established model system in which several brain structures critical for memory formation and storage have been identified. Using quantitative protein assays we will measure the activity of mTOR and related molecular targets at multiple behaviorally relevant brain sites during the formation and retrieval of LTM and test a series of specific hypotheses about the role of this translational control pathway in learning. We will also assess the importance of protein degradation in the formation and stability of memory and begin to analyze the interactions between activity dependent synthesis of new synaptic protein and its targeted degradation. The results should provide important new insights regarding the neurobiology of memory and the molecular events that underlie learning. These finding may help to identify important new therapeutic targets in the treatment of memory and anxiety disorders.

Public Health Relevance

This project addresses basic neurobiological questions about the formation and storage of long-term memory. The cellular mechanisms to be addressed here are and have little attention in whole animal studies and may form the basis for important new treatments for memory disorders, age related memory impairment, and diseases that affect synaptic plasticity and cognitive function. A better understanding of how fear memory is stored will also improve therapeutic approaches to anxiety disorders such as PTSD and phobias.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH069558-08
Application #
8247050
Study Section
Special Emphasis Panel (ZRG1-IFCN-M (02))
Program Officer
Asanuma, Chiiko
Project Start
2003-12-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$360,652
Indirect Cost
$113,152
Name
University of Wisconsin Milwaukee
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
627906399
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Kwapis, Janine L; Helmstetter, Fred J (2014) Does PKM(zeta) maintain memory? Brain Res Bull 105:36-45
Jarome, Timothy J; Kwapis, Janine L; Hallengren, Jada J et al. (2014) The ubiquitin-specific protease 14 (USP14) is a critical regulator of long-term memory formation. Learn Mem 21:9-13
Kwapis, Janine L; Jarome, Timothy J; Lee, Jonathan L et al. (2014) Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala. Neurobiol Learn Mem 113:41-54
Balderston, Nicholas L; Schultz, Douglas H; Baillet, Sylvain et al. (2014) Rapid amygdala responses during trace fear conditioning without awareness. PLoS One 9:e96803
Gilmartin, Marieke R; Balderston, Nicholas L; Helmstetter, Fred J (2014) Prefrontal cortical regulation of fear learning. Trends Neurosci 37:455-64
Balderston, Nicholas L; Schultz, Douglas H; Baillet, Sylvain et al. (2013) How to detect amygdala activity with magnetoencephalography using source imaging. J Vis Exp :
Gilmartin, Marieke R; Miyawaki, Hiroyuki; Helmstetter, Fred J et al. (2013) Prefrontal activity links nonoverlapping events in memory. J Neurosci 33:10910-4
Gafford, Georgette M; Parsons, Ryan G; Helmstetter, Fred J (2013) Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory. Hippocampus 23:842-7
Jarome, Timothy J; Helmstetter, Fred J (2013) The ubiquitin-proteasome system as a critical regulator of synaptic plasticity and long-term memory formation. Neurobiol Learn Mem 105:107-16
Gilmartin, Marieke R; Kwapis, Janine L; Helmstetter, Fred J (2013) NR2A- and NR2B-containing NMDA receptors in the prelimbic medial prefrontal cortex differentially mediate trace, delay, and contextual fear conditioning. Learn Mem 20:290-4

Showing the most recent 10 out of 25 publications