A considerable amount of progress has been made in defining the neurobiological mechanisms of Pavlovian fear conditioning, both at the systems level, and also more recently at the biochemical and/or molecular levels. These findings suggest that fear conditioning involves integration of sensory information about the CS and US in lateral nucleus of the amygdala (LA), where N-Methyl-D-aspartate receptor (NMDAR)-mediated alterations in synaptic transmission are thought to encode key aspects of the learning. Most recent studies have focused their efforts on examining the role of downstream effectors of NMDAR-mediated signaling in LA cells, defining some of the key protein kinase signaling pathways that are thought to promote long-term plasticity and memory formation, in part, by engaging activators of transcription and translation in the nucleus. It has become increasingly clear, however, that the cellular mechanisms that underlie the consolidation of fear memories are not confined to alterations in LA neurons, but instead comprise a rich interaction between the LA and its afferent sensory regions that may act to promote 1) structural changes at presynaptic sites to LA neurons and 2) alterations in cell excitability throughout the wider fear network. As such, a complete understanding of the cellular and biochemical basis of fear memory consolidation will require attention to intracellular signaling cascades not only in the LA, but also in its afferent regions. The experiments outlined in each of the three Specific Aims of the present proposal are aimed at thoroughly testing this hypothesis using a combination of behavioral, biochemical, and neurophysiological recording techniques.
In Specific Aim I, we will begin by further exploring the downstream nuclear substrates and transcriptional mechanisms of key protein kinase cascades in both LA and MGm/PIN, and assessing their role in the process of fear memory consolidation.
In Specific Aims II and III, we will turn to the question of whether intracellular signaling cascades in the MGm/PIN that are critical for fear memory consolidation are driven by synaptic plasticity and retrograde signaling in the LA, and, in turn, whether those same thalamic signaling cascades function to promote presynaptic aspects of plasticity back in the LA. Investigation into the molecular mechanisms of conditioned fear in animals has both the potential to shed light on normal processes governing learning and memory in general, as well as implications for the etiology and treatment of various psychological disorders in humans, including anxiety, phobic and panic disorders, in which acquired fears are a prominent underlying symptom. This proposal aims to study the neural and molecular mechanisms underlying the consolidation of emotional memories in the lateral nucleus of the amygdala. Investigation into the molecular mechanisms of learned fear in animals has both the potential to shed light on normal processes governing learning and memory in general, as well as implications for the etiology and treatment of various psychological disorders in humans, including anxiety, phobic and panic disorders, in which acquired fears are a prominent underlying symptom.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073949-05
Application #
8197398
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
2007-12-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$368,651
Indirect Cost
$145,901
Name
Yale University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Monsey, Melissa S; Gerhard, Danielle M; Boyle, Lara M et al. (2015) A diet enriched with curcumin impairs newly acquired and reactivated fear memories. Neuropsychopharmacology 40:1278-88
Monsey, Melissa S; Boyle, Lara M; Zhang, Melinda L et al. (2014) Chronic corticosterone exposure persistently elevates the expression of memory-related genes in the lateral amygdala and enhances the consolidation of a Pavlovian fear memory. PLoS One 9:e91530
Gould, Thomas J; Leach, Prescott T (2014) Cellular, molecular, and genetic substrates underlying the impact of nicotine on learning. Neurobiol Learn Mem 107:108-32
Maddox, Stephanie A; Watts, Casey S; Schafe, Glenn E (2014) DNA methyltransferase activity is required for memory-related neural plasticity in the lateral amygdala. Neurobiol Learn Mem 107:93-100
Maddox, Stephanie A; Watts, Casey S; Schafe, Glenn E (2013) p300/CBP histone acetyltransferase activity is required for newly acquired and reactivated fear memories in the lateral amygdala. Learn Mem 20:109-19
Maddox, Stephanie A; Watts, Casey S; Doyere, Valerie et al. (2013) A naturally-occurring histone acetyltransferase inhibitor derived from Garcinia indica impairs newly acquired and reactivated fear memories. PLoS One 8:e54463
Maddox, Stephanie A; Schafe, Glenn E (2011) Epigenetic alterations in the lateral amygdala are required for reconsolidation of a Pavlovian fear memory. Learn Mem 18:579-93
Monsey, Melissa S; Ota, Kristie T; Akingbade, Irene F et al. (2011) Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala. PLoS One 6:e19958
Ploski, Jonathan E; Monsey, Melissa S; Nguyen, Tam et al. (2011) The neuronal PAS domain protein 4 (Npas4) is required for new and reactivated fear memories. PLoS One 6:e23760
Maddox, Stephanie A; Schafe, Glenn E (2011) The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is required for reconsolidation of a Pavlovian fear memory. J Neurosci 31:7073-82

Showing the most recent 10 out of 17 publications