A major obstacle to defining cellular and molecular mechanisms of memory is the enormous complexity of synaptic regions specialized for memory. Although synaptic plasticity is the major focus of memory research, a simpler modification, long-term hyperexcitability (LTH), also appears important for memory, even though it has received far less experimental attention. The properties and mechanisms of newly discovered forms of LTH in highly accessible peripheral axons of sensory and motor neurons of the invertebrate, Aplysia, will be investigated. This LTH is characterized by key features associated with current memory models, including 1) long-lasting modifications induced by localized depolarization, 2} restriction of the modifications to intensely depolarized regions, and 3) dependence of the modifications upon local protein synthesis. The proposed studies will use behavioral, electrophysiological, and biochemical methods to investigate physiological and behavioral functions of axonal LTH (as well as short-term hyperexcitability, STH), mechanisms of induction of STH and LTH, mechanisms of expression of STH and LTH, and relationships of STH/LTH in axons to STH/LTH at other neuronal sites including presynaptic terminals and dendrites, and its role in short- and long-term sensitization of withdrawal behavior. Specific questions concern the contributions of STH/LTH to long-term synaptic facilitation, the roles (if any) of potential Ca2+ signals in inducing STH/LTH, the roles of other second messengers and protein kinases, the roles of serotonin, TGFbeta1, NO, and sensorin, and the identification of ionic conductances altered during STH/LTH. Mechanisms and functions of axonal LTH in diverse types of neurons in Aplysia may point to neglected or unrecognized plasticity mechanisms in the mammalian nervous system, and provide insight into fundamental mechanisms important both for normal memory and disorders of memory (such as occur following stroke), as well as for neuropathic pain and other clinical problems related to peripheral nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS035979-09
Application #
6922654
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Porter, Linda L
Project Start
1997-08-01
Project End
2010-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
9
Fiscal Year
2005
Total Cost
$320,009
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Bedi, Supinder S; Lago, Michael T; Masha, Luke I et al. (2012) Spinal cord injury triggers an intrinsic growth-promoting state in nociceptors. J Neurotrauma 29:925-35
Crook, Robyn J; Lewis, Trevor; Hanlon, Roger T et al. (2011) Peripheral injury induces long-term sensitization of defensive responses to visual and tactile stimuli in the squid Loligo pealeii, Lesueur 1821. J Exp Biol 214:3173-85
Crook, Robyn J; Walters, Edgar T (2011) Nociceptive behavior and physiology of molluscs: animal welfare implications. ILAR J 52:185-95
Reyes, Fredy D; Walters, Edgar T (2010) Long-lasting synaptic potentiation induced by depolarization under conditions that eliminate detectable Ca2+ signals. J Neurophysiol 103:1283-94
Bedi, Supinder S; Yang, Qing; Crook, Robyn J et al. (2010) Chronic spontaneous activity generated in the somata of primary nociceptors is associated with pain-related behavior after spinal cord injury. J Neurosci 30:14870-82
Kunjilwar, Kumud K; Fishman, Harvey M; Englot, Dario J et al. (2009) Long-lasting hyperexcitability induced by depolarization in the absence of detectable Ca2+ signals. J Neurophysiol 101:1351-60
Walters, Edgar T; Moroz, Leonid L (2009) Molluscan memory of injury: evolutionary insights into chronic pain and neurological disorders. Brain Behav Evol 74:206-18
Weragoda, Ramal M S; Walters, Edgar T (2007) Serotonin induces memory-like, rapamycin-sensitive hyperexcitability in sensory axons of aplysia that contributes to injury responses. J Neurophysiol 98:1231-9
Gasull, Xavier; Liao, Xiaogang; Dulin, Michael F et al. (2005) Evidence that long-term hyperexcitability of the sensory neuron soma induced by nerve injury in Aplysia is adaptive. J Neurophysiol 94:2218-30
Sung, Ying-Ju; Ambron, Richard T (2004) Pathways that elicit long-term changes in gene expression in nociceptive neurons following nerve injury: contributions to neuropathic pain. Neurol Res 26:195-203

Showing the most recent 10 out of 20 publications