Maintaining and promoting healthy cognitive functions, of which memory is a most important one, is one of the major goals of mental health research. Diseases, stress, injury and aging can lead to cognitive and memory impairments. It is estimated that up to one third of adults will experience a gradual decline in cognitive function known as mild cognitive impairment as they age. Furthermore, a number of diseases such as Alzheimer's disease, autism, mental retardation are associated with memory impairments. Thus, minimizing or preventing cognitive and memory impairments is a very important goal in mental health. A principal approach toward this goal is to understand the physiological mechanisms of memory formation, persistence and storage and identify molecular mechanisms and targets that can be used to enhance memory, not only for potentiating normal functions but also for developing strategies that may prevent or reverse memory loss. Newly learned information that will become a long-term memory remains in a labile state for some time and becomes a long- term memory through a process of stabilization, known as memory consolidation. Using contextual fear conditioning types of memories in rats, we have recently found that hippocampal administration of the growth factor insulin like growth factor 2 (IGF-2) leads to potent memory enhancement and also increases memory persistence. Using inhibitory avoidance (IA) and other tasks like fear extinction and social transmission of food preference in rats and mice, this proposal aims at identifying the molecular mechanisms and brain circuitry of the IGF-2-mediated memory consolidation and enhancement. It will also test whether other members of the IGF system (IGF-1 and insulin) have memory-enhancing effects. Finally, with preclinical and translational goals in mind, given that IGF-2 readily passes the blood brain barrier, it will determine whether systemic treatments with IGF-2 are effective in enhancing memories retention and persistence and whether the IGF-2-dependent effect alters memory flexibility. Results from these studies should advance our knowledge of neural mechanisms that may be employed to achieve memory enhancement and to treat cognitive impairments.

Public Health Relevance

Capitalizing on recent findings from our ongoing project using rats and mice as animal models, this project continuation aims at identifying the mechanisms by which insulin like growth factor 2 (IGF-2), IGF-1 and insulin promote memory consolidation, enhancement and persistence in adult animals. The results of these studies should lead to the understanding of mechanisms of memory consolidation and enhancement and the discovery of novel tools and targets important for strengthening normal memories and reducing the progression of memory decay and/or reversing memory loss in diseases. Preventing or rescuing cognitive and memory loss, is a most important goal in mental health research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37MH065635-12A1
Application #
8460313
Study Section
Special Emphasis Panel (ZRG1-IFCN-N (02))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2002-07-01
Project End
2017-11-30
Budget Start
2012-12-04
Budget End
2013-11-30
Support Year
12
Fiscal Year
2013
Total Cost
$535,234
Indirect Cost
$182,967
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Stern, Sarah A; Kohtz, Amy S; Pollonini, Gabriella et al. (2014) Enhancement of memories by systemic administration of insulin-like growth factor II. Neuropsychopharmacology 39:2179-90
Finsterwald, Charles; Alberini, Cristina M (2014) Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies. Neurobiol Learn Mem 112:17-29
Bisaz, Reto; Travaglia, Alessio; Alberini, Cristina M (2014) The neurobiological bases of memory formation: from physiological conditions to psychopathology. Psychopathology 47:347-56
Pascual-Lucas, Maria; Viana da Silva, Silvia; Di Scala, Marianna et al. (2014) Insulin-like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice. EMBO Mol Med 6:1246-62
Stern, Sarah A; Chen, Dillon Y; Alberini, Cristina M (2014) The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation. Learn Mem 21:556-63
Bambah-Mukku, Dhananjay; Travaglia, Alessio; Chen, Dillon Y et al. (2014) A positive autoregulatory BDNF feedback loop via C/EBP? mediates hippocampal memory consolidation. J Neurosci 34:12547-59