The ability to learn, remember and recall information about the world is critical to every aspect of adaptive behavior. Despite striking recent advances in understanding neural mechanisms of memory, surprisingly little is known about how synaptic and nuclear events in neurons are coordinated in space and time in the induction of memory. This question forms the core of the present research program, which has the unique feature of combining the strengths of two independent laboratories, both of which utilize the marine mollusk Aplysia as a powerful preparation for studying the molecular basis of memory. The Carew group at UCI will contribute expertise in relating synaptic and molecular plasticity directly to bone fide learning and memory, and the Martin group at UCLA will contribute expertise in the analysis of signaling mechanisms between the synapse and the nucleus. The combined efforts of these two groups provide a unique opportunity to explore a fundamental question in cell biology, the mechanisms by which different compartments of a neuron communicate during memory formation. The project will be carried out at three interactive levels of analysis, captured in three Specific Aims:
AIM I is a BEHAVIORAL ANALYSIS which will utilize a novel behavioral preparation that permits examining a monosynaptic sensory-motor (SN-MN) component of a reflex during intermediate-term and long-term memory formation, while simultaneously manipulating the local molecular environment of somatic and synaptic components of the reflex.
AIM II is a SYNAPTIC ANALYSIS examining the SN-MN component of the reflex in the intact CNS in a preparation that allows specifying the contribution of somatic and synaptic events to synaptic facilitation. Here we will examine the mechanisms of (i) local induction of intermediateterm facilitation (ITF), (ii) synaptic induction of long-term facilitation (LTF), and (iii) conjoint synaptic and nuclear induction of LTF.
AIM III is a MOLECULAR ANALYSIS examining the requirement for memory formation of (i) local translation at the synapse, focusing on two specific molecules, sensorin, a SN-specific neuropeptide, and cytoplasmic polyadenylation element binding protein (CPEB), a localized mRNA, (ii) facilitated importin-mediated transport of signals from synaptic compartments to the nucleus, and (iii) MARK signaling to the nucleus, CREB and C/EBP-mediated transcription, and induction of the immediate early gene C/EBP. Relevance to public health: Understanding the mechanisms whereby synapticallv generated signals trigger changes in gene expression in the nucleus during memory formation provides a means of identifying therapeutic targets for a variety of disorders including mental retardation, age-related memory loss and neuropsvchiatric diseases such as anxiety and mood disorders.
|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|
|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|
|Ye, Xiaojing; Marina, Andreea; Carew, Thomas J (2012) Local synaptic integration of mitogen-activated protein kinase and protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia. Proc Natl Acad Sci U S A 109:18162-7|
|Ye, Xiaojing; Carew, Thomas J (2011) Transsynaptic coordination of presynaptic and postsynaptic modifications underlying enduring synaptic plasticity. Neuron 70:379-81|
|Philips, Gary T; Sherff, Carolyn M; Menges, Steven A et al. (2011) The tail-elicited tail withdrawal reflex of Aplysia is mediated centrally at tail sensory-motor synapses and exhibits sensitization across multiple temporal domains. Learn Mem 18:272-82|
|Carew, Thomas J; Magsamen, Susan H (2010) Neuroscience and education: an ideal partnership for producing evidence-based solutions to Guide 21(st) Century Learning. Neuron 67:685-8|
|Ye, Xiaojing; Carew, Thomas J (2010) Small G protein signaling in neuronal plasticity and memory formation: the specific role of ras family proteins. Neuron 68:340-61|
|Shobe, Justin L; Zhao, Yali; Stough, Shara et al. (2009) Temporal phases of activity-dependent plasticity and memory are mediated by compartmentalized routing of MAPK signaling in aplysia sensory neurons. Neuron 61:113-25|