Thomas J Carew

Molecular, cellular, and behavioral architecture of memory formation.

My laboratory is interested in understanding how the brain acquires, stores and retrieves information. We explore these questions using a simple model system, the marine mollusk Aplysia californica, because its nervous system affords significant advantages for identifying synaptic, biophysical, and molecular changes underlying memory formation.

We have two broad research programs. The first examines the temporal domains of memory. In this work we have identified three mechanistically distinct phases of synaptic facilitation in the CNS (short-term, intermediate-term and long-term), each of which predicted the existence and molecular features of distinct temporal phases of behavioral memory for sensitization. We are currently exploring the role of specific elements in the molecular cascades that underlie memory formation for sensitization, with a specific focus on (i) MAPK and G-protein signaling pathways, (ii) molecular "routing" of these elements to different cellular compartments, and (iii) synaptic and nuclear signaling underlying long-term memory formation.

The second program examines the role of growth factors in memory formation, with a specific focus on neurotrophins, because they are critically involved in developmental processes such as neuronal cell survival, growth, and differentiation, as well as in adult synaptic plasticity contributing to learning and memory. We have recently cloned and characterized a novel neurotrophin, Aplysia cysteine-rich neurotrophic factor (apCRNF), which is highly enriched in the CNS, and can facilitate MAPK activation and the induction of long-term synaptic facilitation, both of which are critically engaged in memory formation. We are currently exploring two guiding hypotheses: (i) Different families of GFs initiate signaling in distinct cellular compartments to contribute to different phases of memory formation and its underlying synaptic plasticity, and (ii) GFs re-employ dynamic molecular signaling cascades known to be engaged in development in the service of memory formation and synaptic plasticity.

Our laboratory works at several parallel levels of analysis, including (i) the intact animal, (ii) a "reduced preparation" that permits altering the molecular environment of the CNS while studying behavior, (iii) the isolated CNS, which, by virtue of its anatomy, permits studying somatic processing (top chamber) and/or synaptic processing (bottom chamber) while recording intracellularly from identified sensory neuron-motor neuron (SN-MN) synapses, and (iv) isolated SN-MN synapses in culture.

Intracellular recording from serotonergic (5HT) neurons that respond to sensitizing stimuli (tail nerve shock) that induce memory formation. Cells are stained to identiy them as 5HT neurons (red), then the recorded cells are injected with neurobiotin (green).

We have cloned and sequenced two G-Proteins (Ras and Rap) in Aplysia. Shown is the protein sequence for Aplysia Ras (ApRas). These G-proteins interact to mediate sensitivity to training patterns during memory formation.

Sherff, Carolyn M. and Carew, T. J. (1999) Coincident induction of long-term facilitation in Aplysia: Cooperativity between cell bodies and remote synapses. Science, 285: 1911-1914.

Sutton, M.A. and Carew, T.J. (2000) Parallel molecular pathways mediate the expression of distinct forms of intermediate-term facilitation at tail sensory-motor synapses in Aplysia. Neuron, 26: 219-232

Shobe, J., Zhao, Y., Ye, X., Stough,, S., Martin, K. and Carew, T.J. (2009) Temporal phases of activity-dependent plasticity and memory are mediated by compartmentalized routing of MAPK signaling in Aplysia sensory neurons. Neuron 61:113-125

Philips, G.T., Ye, X, Kopec, A., and Carew, T.J. (2013). MAPK establishes a molecular context that defines effective training patterns for long-term memory formation. J. Neuroscience, 33(17):7565-7573.

Kopec AM, Philips, GT and Carew, TJ (2015). Distinct growth factor families are recruited in unique spatiotemporal domains during long-term memory formation in Aplysia californica. Neuron, 86:1228-1239.

Kukushkin, N.V. and Carew, T.J. (2017) Memory takes time. Neuron, 95:259-279