Growth factors (GF) are secreted molecules important for many aspects of plasticity during development including axon outgrowth, actin cytoskeleton rearrangement, and synapse formation. There are multiple families of GFs, such as the neurotrophins and the transforming-growth factor ? (TGF?) superfamily, which mediate distinct outcomes during development by tightly regulated signaling in both space (e.g. at the cell body vs. at the synapse) and time (e.g. during synapse formation vs. during synapse stabilization). Importantly, GFs are highly evolutionarily conserved, making information derived from animal models informative for human neuroscience. A major challenge in neuroscience is to understand how the brain acquires and stores information for long periods of time, and how these long-term memories (LTMs) become susceptible to neurological disorders and neurodegenerative diseases. GFs are required for LTM, but it is not known how GF each family uniquely contributes to LTM formation. My work will directly explore the hypothesis that different GF families not only engage spatiotemporally coordinated signaling pathways that induce distinct gene expression profiles, but also synergistically interact to mediate LTM formation. This project aims to test several hypotheses by using the model organism Aplysia californica, which is a powerful system for elucidating the spatiotemporal coordination of molecular mechanisms relevant for adaptive behavioral change. I will focus on two GF families: neurotrophins signaling via the tropomysin-related kinase B receptor (TrkB) and TGF superfamily signaling via the TGF receptor II (TGF?r-II). First, I will test the hypothesis that different GF families engage spatiotemporally regulated signaling cascades which induce different gene expression profiles. To test this notion, I will block TrkB or TGF?r-II signaling using receptor body chimeras at either the soma or the synapse, during or after an analog form of LTM training, and then determine if mitogen-activated protein kinase (MAPK) activation, a protein required for LTM, is inhibited. Using the same methods, I will determine if the expression of evolutionarily conserved genes required for LTM formation, C/EBP, Uch, kinesin, and neurexin, are blocked by blocking GF signaling. Second, I will explore the behavioral relevance of observations derived at the molecular level by (i) blocking GF signaling at the soma and/or the synapse, during or after LTM training to determine if behavioral expression of LTM requires spatiotemporally regulated GF signaling, and (ii) testing whether or not GF signaling cascades synergistically interact to subserve LTM formation. This overall project will provide a better understanding of GF signaling during LTM formation. Elucidating the mechanism of GF signaling will both inform the field from a basic scientific perspective, as well as potentially provide clinically relevant hypotheses for therapeutic targets relevant to neurological disorders and related diseases.
Deficits in neuronal plasticity and memory formation contribute to the pathology of many neurological disorders, neurodegenerative diseases, and brain injuries. Understanding how growth factor (GF) signaling mediates normal plasticity and memory formation is extremely beneficial for two reasons: (1) GFs are highly evolutionarily conserved molecules which have well characterized roles during developmental plasticity, thus providing clear experimental paths for studying adult plasticity, and (2) GFs are secreted molecules, making them attractive therapeutic targets. Hence, investigating (i) how GF signaling is regulated spatially and temporally, (ii) how downstream effectors of GFs may broker their contributions to LTM formation, and (iii) whether and how GF signaling cascades synergistically interact will help to elucidate how a healthy brain acquires and stores information, while also revealing possible novel targets for therapeutic intervention.
|Stough, Shara; Kopec, Ashley M; Carew, Thomas J (2015) Synaptic generation of an intracellular retrograde signal requires activation of the tyrosine kinase and mitogen-activated protein kinase signaling cascades in Aplysia. Neurobiol Learn Mem 125:47-54|
|Kopec, Ashley M; Philips, Gary T; Carew, Thomas J (2015) Distinct Growth Factor Families Are Recruited in Unique Spatiotemporal Domains during Long-Term Memory Formation in Aplysia californica. Neuron 86:1228-39|
|Pu, Lu; Kopec, Ashley M; Boyle, Heather D et al. (2014) A novel cysteine-rich neurotrophic factor in Aplysia facilitates growth, MAPK activation, and long-term synaptic facilitation. Learn Mem 21:215-22|
|Fischbach, Soren; Kopec, Ashley M; Carew, Thomas J (2014) Activity-dependent inhibitory gating in molecular signaling cascades induces a novel form of intermediate-term synaptic facilitation in Aplysia californica. Learn Mem 21:199-204|