The process by which organisms alter their behavior in response to experiences is known as learning. While the parameters and rules for acquisition and storage of learned information have been well established and are quite similar across species ranging from C. elegans to mammals, the molecular mechanisms that drive learning, in comparison, are not well understood. Habituation is a simple form of non-associative learning that enables animals to reduce their reaction to repeated harmless stimuli. For example, the startle reflex is stereotyped but highly modifiable, such that repeated presentation of startling stimuli suppresses the startle reflex. In humans, startle habituation deficits are an important feature of several cognitive disorders. We previously demonstrated that zebrafish larvae exhibit habituation learning with landmark behavioral and pharmacological characteristics. To identify genes and pathways underlying habituation learning, we conducted the first genetic screen for learning mutants in vertebrates. This screen identified a set of 18 mutants with defects in short-term habituation to acoustic stimuli. From this screen we identified the vertebrate specific pregnancy associated plasma protein-a (papp-a) gene as a previously unknown gene required for habituation. PAPP-A encodes a protease known to cleave insulin-like growth factor binding proteins, thereby increasing local IGF availability and hence IGF receptor signaling. While IGF receptor signaling has well documented roles in synaptic plasticity, learning and cognitive performance, the roles of papp-a gene in the nervous system and for habituation are unknown. The objective of this proposal is to determine the role of papp-a for habituation learning. The experiments in this proposal will: (1) determine the temporal and spatial requirements of papp-a critical for startle habituation;and (2) determine if papp-a regulates habituation through IGF receptor signaling. These studies are relevant to the study of human heath, as deficits in habituation and startle modulation have been described in mental disorders, including schizophrenia, attention deficit disorder, and autism, and are also common in individuals with a history drug abuse.

Public Health Relevance

Learning and memory are fundamental processes, yet the molecular mechanisms underlying learning and memory are poorly understood. Using a genetic approach, we recently identified a previously unknown, vertebrate specific gene, pregnancy associated plasma protein-a (papp-a) critical for habituation learning. This proposal aims to determine the molecular genetic mechanisms by which papp-a regulates learning behaviors. This is directly relevant to the study of mental health and drug abuse, because deficits in habituation are a central feature of several cognitive disorders, including schizophrenia and addiction.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Neurobiology of Learning and Memory Study Section (LAM)
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Asanuma, Chiiko
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Marsden, Kurt C; Granato, Michael (2015) In Vivo Ca(2+) Imaging Reveals that Decreased Dendritic Excitability Drives Startle Habituation. Cell Rep 13:1733-40
Wolman, Marc A; Jain, Roshan A; Marsden, Kurt C et al. (2015) A genome-wide screen identifies PAPP-AA-mediated IGFR signaling as a novel regulator of habituation learning. Neuron 85:1200-11