Consolidation of long-term synaptic plasticity - an important cellular mechanism underlying long-term memory - requires new macromolecular synthesis (genes and proteins). In many cases additional training or stimuli enhance the duration and amplitude of the long-term memory/synaptic plasticity by activating many of the same neurons and synapses activated during the initial training. However, exposure to the additional stimuli typically introduces a labile feature in the pre-existing memory/plasticity such that timely disruptions in critical cellular processes often produce amnesia-like responses for both the memory and the underlying cellular plasticity. This important neurobiological phenomenon is the basis for developing therapies to alleviate post- traumatic stress disorders. It remains unclear however: 1) how additional training or stimuli might prevent the natural reversal of macromolecular synthesis-dependent long-term memory/cellular plasticity evoked by the initial training or stimuli, 2) how additional training or stimuli evoke the labile property of the pre-existing long- term memory/cellular plasticity, and 3) whether additional stimuli that produce more persistent forms of long- term memory/cellular plasticity activate the same molecules and pathways required to initiate the long-term memory/plasticity. This proposal will address these questions using a tractable model system consisting of a behaviorally relevant synapse reconstituted in cell culture. The sensory-motor neuron synapse of Aplysia expresses different forms of macromolecular synthesis-dependent long-term facilitation (non-associative or associative LTF - cellular correlates of sensitization and classical conditioning of defensive reflexes) of variable duration that depends on the number of stimuli. Disrupting specific cellular processes during the additional stimuli produces an amnesia-like response, and the additional stimuli activate new signaling pathways to regulate the persistent synthesis, secretion and downstream signaling of a neurotrophin-like neuropeptide sensorin required for persistent long-term plasticity. Natural reduction in sensorin synthesis or downstream signaling following the initial stimuli or precipitous reduction in sensorin synthesis or downstream signaling by various manipulations during the additional stimuli leads to a reversal of the plasticity. With this tractable system consisting of large identified neurons and their synaptic connection that is amenable to cell-specific manipulations of specific molecules by intracellular injections, and allowing direct assays of gene or protein expression and synapse structure and strength, the following hypotheses will be explored: 1) The reversal of long-term plasticity (natural or when specific inhibitors are added during the additional stimuli) is mediated by specific homeostatic mechanisms affecting either the number of presynaptic varicosities (new or pre-existing) and/or postsynaptic receptor sensitivity/distribution at presynaptic varicosities. 2) The labile nature of the pre-existing long-term plasticity during the additional stimulation is produced by a disruption at various stages in a positive auto-regulatory feedback of downstream signaling of the secreted neurotrophin-like peptide sensorin and the transcription/translation of sensorin mRNA. 3) Different forms of persistent LTF converge by regulating this auto-regulatory feedback loop, but are mediated by different cell-specific mechanisms and signaling pathways.

Public Health Relevance

Consolidation of long-term memory - long-term retention of experience- or stimulus-dependent learning - is typically enhanced by additional experience or stimuli presented soon after the initial learning. It is generally believed that the synaptic connections within the neural circuits activated during the initial learning are re- activated with additional stimuli and leads first to a labile form of the memory followed by an enhancement of the memory. However little is known about the cellular mechanisms in the activated neural circuits that mediate natural or rapid reversal of long-term memory or how existing memory might be enhanced both in strength and duration by persistent changes in the strength of synaptic connections within the re-activated neural circuits. Knowledge of how synaptic connections in activated neural circuits acquire and consolidate changes induced with additional stimulation will facilitate our understanding of how memories might be regulated during natural ageing, with neurodegenerative diseases such as Alzheimer's or for developing therapies to reverse traumatic memories that cause inappropriate behavior with post-traumatic stress disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH060387-12A1
Application #
8238009
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
2001-02-15
Project End
2016-11-30
Budget Start
2011-12-05
Budget End
2012-11-30
Support Year
12
Fiscal Year
2012
Total Cost
$400,000
Indirect Cost
$150,000
Name
Columbia University (N.Y.)
Department
Neurosciences
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Schacher, Samuel; Hu, Jiang-Yuan (2014) The less things change, the more they are different: contributions of long-term synaptic plasticity and homeostasis to memory. Learn Mem 21:128-34
Hu, Jiang-Yuan; Schacher, Samuel (2014) Persistent long-term facilitation at an identified synapse becomes labile with activation of short-term heterosynaptic plasticity. J Neurosci 34:4776-85
Hu, Jiang-Yuan; Baussi, Orit; Levine, Amir et al. (2011) Persistent long-term synaptic plasticity requires activation of a new signaling pathway by additional stimuli. J Neurosci 31:8841-50
Hu, Jiang-Yuan; Chen, Yang; Bougie, Joanna K et al. (2010) Aplysia cell adhesion molecule and a novel protein kinase C activity in the postsynaptic neuron are required for presynaptic growth and initial formation of specific synapses. J Neurosci 30:8353-66
Hernandez, A Ivan; Wolk, Jason; Hu, Jiang-Yuan et al. (2009) Poly-(ADP-ribose) polymerase-1 is necessary for long-term facilitation in Aplysia. J Neurosci 29:9553-62
Hu, Jiang-Yuan; Chen, Yang; Schacher, Samuel (2007) Multifunctional role of protein kinase C in regulating the formation and maturation of specific synapses. J Neurosci 27:11712-24
Hu, Jiang-Yuan; Chen, Yang; Schacher, Samuel (2007) Protein kinase C regulates local synthesis and secretion of a neuropeptide required for activity-dependent long-term synaptic plasticity. J Neurosci 27:8927-39
Hu, Jiang-Yuan; Wu, Fang; Schacher, Samuel (2006) Two signaling pathways regulate the expression and secretion of a neuropeptide required for long-term facilitation in Aplysia. J Neurosci 26:1026-35
Liu, Jinming; Hu, Jiang-Yuan; Wu, Fang et al. (2006) Two mRNA-binding proteins regulate the distribution of syntaxin mRNA in Aplysia sensory neurons. J Neurosci 26:5204-14
Levine, Amir A; Guan, Zhonghui; Barco, Angel et al. (2005) CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc Natl Acad Sci U S A 102:19186-91

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