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Principal Investigator: Thomas J Carew
Organization: NEW YORK UNIVERSITY
Fiscal Year: 2024
Award: $476,413
Funding agency: National Institute of Mental Health
PROJECT SUMMARY/ABSTRACT
A growing body of evidence suggests that growth factors (GFs), once considered to function mainly in
development, also regulate synaptic plasticity and memory in the adult. This proposal reflects on an ongoing
research program in our laboratory that has focused on the role of GFs in memory formation. The primary
focus of this current project is to examine GF-mediated memory formation from a novel perspective, which
takes into account the temporal aspect of their activity as part of the cellular computation involved in forming
memories.
Repeated-trial learning, a fundamental form of memory acquisition exhibited by virtually all animals, including
man, requires a temporal interaction between an ongoing stimulus and the delayed effects of a previous
stimulus. We will use a powerful paradigm to study repeated-trial training in the marine mollusk Aplysia, which
develops long-term memory (LTM) for sensitization after only two training trials, but only if they are separated
by a permissive and surprisingly specific time interval of ~45 min. This minimal system clearly separates the
initiating stimulus (Trial 1) from the repeated stimulus (Trial 2), providing unparalleled access to the temporal
interactions underlying repeated-trial LTM. We will investigate two GF-dependent mechanisms that our
preliminary evidence suggests contribute significantly to temporal processing at the heart of repeated-trial
learning. The first (explored in AIM 1) is a distributed mechanism for GF-dependent phosphorylation of
extracellularly regulated kinase (ERK). The second mechanism (explored in AIM 2) is the multi-step signaling
of a specific GF, TGFβ, which we propose similarly integrates the timing of training trials. Finally, in AIM 3 we
will try to establish causal connections between the timing of single ERK phosphorylation, TGFβ availability,
and the persistent effects of two-trial training
The project holds promise for significant impact from both a basic scientific perspective and a clinical
perspective. From a basic scientific perspective, Aplysia provides an exceptional experimental system that has
the potential to demonstrate causal linkages between GF-mediated memory formation and its underlying
synaptic and molecular mechanisms, while simultaneously exploring the temporal features of those
mechanisms. And from a clinical perspective, the impact of this project addresses a major challenge in mental
health: to understand and treat the devastating cognitive disorders that accompany neurodegenerative
diseases. GF signaling has been directly implicated in many of these diseases and, since GFs are extracellular
proteins, understanding when and where they act in the brain during memory formation could provide novel
strategies for developing more specific and more effective therapeutic agents.
Terms: <21+ years old><5-HT><5-Hydroxytryptamine><5HT><Address><Adult><Adult Human><Afferent Neurons><Animals><Aplysia><Attention><Binding><Biologic Models><Biological><Biological Models><Bone-Derived Transforming Growth Factor><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Circulatory Collapse><Clinical><Cognition Disorders><Cytosol><Data><Degenerative Neurologic Disorders><Development><Disease><Disorder><ERK MAP Kinases><Encephalon><Enteramine><Event><Exhibits><Extracellular Protein><Extracellular Signal Regulated Kinases><Extracellular Signal-Regulated MAP Kinases><Extracellular Space><Gene Transcription><Genetic Transcription><Goals><Growth Agents><Growth Factor><Growth Substances><Heart><Hippophaine><Human><Intercellular Space><Intracellular Communication and Signaling><Kinases><Laboratories><Learning><Ligands><MAP kinase><MAPK ERK Kinases><MEKs><Mediating><Memory><Mental Health><Mental Hygiene><Milk Growth Factor><Mitogen-Activated Protein Kinases><Model System><Modern Man><Molecular><Molecular Interaction><Nature><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neurosciences><Nuclear><Nucleus><Pathway interactions><Pattern><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiologic pulse><Platelet Transforming Growth Factor><Predisposition><Process><Protein Phosphorylation><Proteins Growth Factors><Psychological Health><Publishing><Pulse><RNA Expression><Regulation><Research><Role><Sensory Neurons><Series><Serotonin><Shock><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specificity><Stimulus><Susceptibility><Synapses><Synaptic><Synaptic plasticity><System><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic Agents><Threonine/Tyrosine Protein Kinase><Time><Training><Transcription><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transphosphorylases><Up-Regulation><Upregulation><Work><adulthood><analog><biologic><biological signal transduction><causal diagram><causal model><circulatory shock><cognitive disease><cognitive disorder><cognitive syndrome><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><detector><developmental><experiment><experimental research><experimental study><experiments><extracellular><extracellular signal related kinase><inhibitor><insight><long term memory><longterm memory><man><marine><marine environment><memory acquisition><neurodegenerative illness><neurological disease><new approaches><novel><novel approaches><novel strategies><novel strategy><pathway><permissiveness><programs><response><shocks><social role><success><synapse><therapeutically effective><time interval><training project><virtual>