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. Using rat and mouse models, we have identified the growth factor insulin like growth factor 2 (IGF-2) as a potent memory and cognitive enhancer in healthy conditions. Using models of memory impairment in both developmental disorders and aging we found that IGF-2 significantly reverses memory losses. Our studies of the last 5 years also started elucidating some of the action mechanisms by which IGF-2 promotes memory enhancement and reverse memory deficits. One of these mechanisms emerged as the autophagy/lysosomal degradation system, a key regulator of cell functions. Furthermore, investigations of mechanisms of memory formation and enhancement in cortical regions provided evidence for slow-developing learning-induced changes distinct from the known synaptic plasticity. This proposal aims at continuing these mechanistic investigations in order to: 1- Determine the role of autophagy/lysosomal degradation in memory consolidation and IGF-2-mediated memory enhancement, as well as their critical target mechanisms; 2- Determine identity and regulation of novel biological mechanisms occurring in cortical areas following training that are critical for memory consolidation and enhancement; and 3- Determine the role of myelination in long-term memory formation. Results from these studies should significantly advance our knowledge of brain plasticity mechanisms, which may be targeted to achieve memory enhancement and to treat cognitive disorders.

Public Health Relevance

Capitalizing on recent findings from our ongoing studies using rats and mice as animal models this project continuation aims at identifying the role of autophagy/lysosomal degradation in memory formation and enhancement and of novel biological mechanisms occurring in cortical areas following training that are critical for memory consolidation and persistence. This understanding may significantly help preventing or reversing memory loss which is a most important goal in mental health research.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Kim, Douglas S
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New York University
Schools of Arts and Sciences
New York
United States
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Jia, Margaret; Travaglia, Alessio; Pollonini, Gabriella et al. (2018) Developmental changes in plasticity, synaptic, glia, and connectivity protein levels in rat medial prefrontal cortex. Learn Mem 25:533-543
Steinmetz, Adam B; Stern, Sarah A; Kohtz, Amy S et al. (2018) Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice. J Neurosci 38:1015-1029
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Alberini, Cristina M; Travaglia, Alessio (2017) Infantile Amnesia: A Critical Period of Learning to Learn and Remember. J Neurosci 37:5783-5795
Travaglia, Alessio; Bisaz, Reto; Sweet, Eric S et al. (2017) Erratum: Infantile amnesia reflects a developmental critical period for hippocampal learning. Nat Neurosci 20:1033
Zhang, Yili; Smolen, Paul; Alberini, Cristina M et al. (2016) Computational model of a positive BDNF feedback loop in hippocampal neurons following inhibitory avoidance training. Learn Mem 23:714-722
Knight, Elysse M; Kim, Soong Ho; Kottwitz, Jessica C et al. (2016) Effective anti-Alzheimer A? therapy involves depletion of specific A? oligomer subtypes. Neurol Neuroimmunol Neuroinflamm 3:e237
Finsterwald, Charles; Steinmetz, Adam B; Travaglia, Alessio et al. (2015) From Memory Impairment to Posttraumatic Stress Disorder-Like Phenotypes: The Critical Role of an Unpredictable Second Traumatic Experience. J Neurosci 35:15903-15

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