This project outlines a circuit-based approach to fear conditioning and interactive effects of stress that is designed to link the circuits that mediate and/or are affected by these behavioral events to the demonstrated roles of glutamate receptors in these processes. We hypothesize that long-term modifications of the functional attributes of amygdala that are induced by fear conditioning are associated with morphologic and neurochemical changes in the excitatory circuits that mediate this learned response. More precisely, we hypothesize that the glutamate receptor (GluR) profile of the circuits that are coupled through fear conditioning will be modified in a manner that will augment NMDA-mediated transmission and LTP-like events in these circuits. With respect to stress, extensive data are available from hippocampus demonstrating changes in morphology and NMDA receptor-mediated processes that lead to impairment of hippocampal function. Interestingly, while stress has a deleterious effect on hippocampal structure and function, it augments certain functional attributes of the amygdala. We further hypothesize that stress will lead to modifications in the interconnections between medial prefrontal cortex (mPFC) and amygdala that are interactive and in some cases augmentative of the modifications induced by fear conditioning. GluRs will be analyzed in the context of three key sets of circuits that will be targeted in this project: 1) the convergent sensory inputs from the medial geniculate nucleus (MG) and the auditory cortex to pyramidal neurons within lateral amygdala (LA), a set of circuits known to be crucial for fear conditioning; 2) the intra-amygdala projections from LA to the central nucleus (CE), both directly from LA as well as indirectly from LA to Basal (B) and Accessory Basal (AB) nuclei, and then to CE. These are the intra-amygdala circuits that are primarily responsible for linking the key sensory input to the autonomic output from the CE that is linked to the fear response; and 3) The reciprocal connections between mPFC and the amygdala nuclei LA, B, and CE, a set of circuits that may be directly impacted by stress. Our investigations of amygdala circuits will be carried out in close collaboration with Dr. LeDoux's project (Project 1) and the Quantitative Morphology Core. We will assist Dr. McEwen's team (Project 4) in their GluR analyses of hippocampus and carry out Specific Aim 3 of this project in collaboration with McEwen's group.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH058911-02
Application #
6336697
Study Section
Special Emphasis Panel (ZMH1)
Project Start
2000-09-01
Project End
2001-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$296,356
Indirect Cost
Name
New York University
Department
Type
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
McEwen, Bruce S (2017) Neurobiological and Systemic Effects of Chronic Stress. Chronic Stress (Thousand Oaks) 1:
McEwen, Bruce S; Gray, Jason; Nasca, Carla (2015) Recognizing Resilience: Learning from the Effects of Stress on the Brain. Neurobiol Stress 1:1-11
Ostroff, Linnaea E; Manzur, Mustfa K; Cain, Christopher K et al. (2014) Synapses lacking astrocyte appear in the amygdala during consolidation of Pavlovian threat conditioning. J Comp Neurol 522:2152-63
Kamphausen, Susanne; Schröder, Patricia; Maier, Simon et al. (2013) Medial prefrontal dysfunction and prolonged amygdala response during instructed fear processing in borderline personality disorder. World J Biol Psychiatry 14:307-18, S1-4
Bloss, Erik B; Puri, Rishi; Yuk, Frank et al. (2013) Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses. Neurobiol Aging 34:200-10
Debiec, Jacek; Diaz-Mataix, Lorenzo; Bush, David E A et al. (2013) The selectivity of aversive memory reconsolidation and extinction processes depends on the initial encoding of the Pavlovian association. Learn Mem 20:695-9
Burghardt, Nesha S; Sigurdsson, Torfi; Gorman, Jack M et al. (2013) Chronic antidepressant treatment impairs the acquisition of fear extinction. Biol Psychiatry 73:1078-86
Diaz-Mataix, Lorenzo; Ruiz Martinez, Raquel Chacon; Schafe, Glenn E et al. (2013) Detection of a temporal error triggers reconsolidation of amygdala-dependent memories. Curr Biol 23:467-72
Isogawa, Koichi; Bush, David E A; LeDoux, Joseph E (2013) Contrasting effects of pretraining, posttraining, and pretesting infusions of corticotropin-releasing factor into the lateral amygdala: attenuation of fear memory formation but facilitation of its expression. Biol Psychiatry 73:353-9
Hunter, Richard G; Murakami, Gen; Dewell, Scott et al. (2012) Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. Proc Natl Acad Sci U S A 109:17657-62

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