One of the greatest challenges in modern neuroscience is to achieve an understanding of how the brain acquires, stores and retrieves information. A particularly exciting new development in exploring this general question is the recent identification of the possible role of growth factors, once considered to function mainly in brain development, in synaptic plasticity and memory in the adult. While this idea is truly seminal, a causal role of growth factors in memory formation has yet to be established. Thus the broad, long-term goal of this research project is to elucidate in mechanistic detail the ways in which growth factors participate in the formation and maintenance of long-term memories. To achieve this goal we will explore two interrelated Specific Aims.
In AIM 1 we will test the hypothesis that growth factor signaling plays an essential role in memory formation and its underlying synaptic plasticity, and in Aim 2 we will test the hypothesis that growth factors re-employ molecular signaling cascades originally engaged in development in the service of adult memory formation and synaptic plasticity. Of direct relevance to the health-related mission of the NIMH, these two Aims will address a major challenge in mental health: to achieve a basic understanding of the brain mechanisms that are engaged in normal memory formation, and how those mechanisms are impaired when memory is compromised by disease or injury. Thus, understanding the molecular mechanisms whereby growth factors contribute to normal memory formation can provide an important and novel means of identifying therapeutic targets for a variety of health related cognitive disorders. To directly explore how growth factors participate i memory formation requires multiple levels of analysis (behavioral, cellular, synaptic, and molecular levels). Aplysia californica is a powerful model system to address this question because it allows such a simultaneous multi-level analysis, as well as a time-dependent analysis of when critical changes occur, and a spatial analysis of where changes occur in different regions of individual neurons. Thus a unique feature of this proposal is our use of a system that has the potential to demonstrate causal linkages between growth factor-mediated memory formation and the temporal and spatial features of the underlying synaptic mechanisms.

Public Health Relevance

A major challenge in mental health is to achieve a basic understanding of the brain mechanisms that are engaged in normal memory formation, and how those mechanisms are impaired when memory is compromised by disease or injury, such as in Alzheimer's Disease, Post-Traumatic Stress Disorders, and in victims of accidents or strokes. Thus, the major focus of this project, understanding the molecular mechanisms whereby growth factors contribute to normal memory formation, can provide a means of developing effective therapies for a wide range of cognitive problems involving memory impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094792-03
Application #
8686080
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10012
Shobe, Justin; Philips, Gary T; Carew, Thomas J (2016) Transforming growth factor β recruits persistent MAPK signaling to regulate long-term memory consolidation in Aplysia californica. Learn Mem 23:182-8
Mirisis, Anastasios A; Alexandrescu, Anamaria; Carew, Thomas J et al. (2016) The Contribution of Spatial and Temporal Molecular Networks in the Induction of Long-term Memory and Its Underlying Synaptic Plasticity. AIMS Neurosci 3:356-384
Kopec, Ashley M; Philips, Gary T; Carew, Thomas J (2015) Distinct Growth Factor Families Are Recruited in Unique Spatiotemporal Domains during Long-Term Memory Formation in Aplysia californica. Neuron 86:1228-39
Stough, Shara; Kopec, Ashley M; Carew, Thomas J (2015) Synaptic generation of an intracellular retrograde signal requires activation of the tyrosine kinase and mitogen-activated protein kinase signaling cascades in Aplysia. Neurobiol Learn Mem 125:47-54
Menges, Steven A; Riepe, Joshua R; Philips, Gary T (2015) Latent memory facilitates relearning through molecular signaling mechanisms that are distinct from original learning. Neurobiol Learn Mem 123:35-42
Pu, Lu; Kopec, Ashley M; Boyle, Heather D et al. (2014) A novel cysteine-rich neurotrophic factor in Aplysia facilitates growth, MAPK activation, and long-term synaptic facilitation. Learn Mem 21:215-22
Fischbach, Soren; Kopec, Ashley M; Carew, Thomas J (2014) Activity-dependent inhibitory gating in molecular signaling cascades induces a novel form of intermediate-term synaptic facilitation in Aplysia californica. Learn Mem 21:199-204
Philips, Gary T; Kopec, Ashley M; Carew, Thomas J (2013) Pattern and predictability in memory formation: from molecular mechanisms to clinical relevance. Neurobiol Learn Mem 105:117-24
Philips, Gary T; Ye, Xiaojing; Kopec, Ashley M et al. (2013) MAPK establishes a molecular context that defines effective training patterns for long-term memory formation. J Neurosci 33:7565-73
Kopec, Ashley M; Carew, Thomas J (2013) Growth factor signaling and memory formation: temporal and spatial integration of a molecular network. Learn Mem 20:531-9

Showing the most recent 10 out of 11 publications