The overall goals of this project are to understand neural systems involved in conditioned fear using the fear potentiated startle test as a measure. Progress over the last 10 years has focused on the amygdala and its direct projection to a critical part of the acoustic startle pathway. In this application we will evaluate the role of the mesencephalic reticular formation, near the border of the deep white layers of the superior colliculus (deep SC/Me), in fear-potentiated startle. We will also test whether fear-potentiated startle results from activation of GABA containing neurons in the lateral division of the CeA (lateral CeA), which then inhibit GABA containing projection neurons in the medial CeA, thereby disinhibiting the deep SC/Me, leading to an increase in startle. During the prior grant period we found that over-expression of CREB (cAMP response element binding protein) dramatically increased fear conditioning. Here we propose to localize more exactly within the basolateral amygdala (Bla) where over-expression of CREB will facilitate fear conditioning using viral vector gene transfer. We also found that experimental extinction (presentation of lights in the absence of shock following fear conditioning) led to an up regulation of gephyrin mRNA, critical for the inhibitory neurotransmitters glycine and GABA. Here we will determine whether treatments that block (local AP5 or Map kinase inhibitors in Bla) or facilitate (D-cycloserine given systemically or directly into Bla) will alter gephyrin mRNA upregulation. We also found fear conditioning induced several genes within and afferent to the amygdala. Here we will determine whether treatments that block (local AP5 or Map kinase inhibitors in Bla) or facilitate acquisition (HSV-CREB) of fear potentiated startle will block or facilitate gene expression in amygdala and other areas. Finally, we will employ a discrimination procedure we developed to determine or GABA antagonists or inactivation of the hippocampus, septal nucleus, bed nucleus stria terminalis or frontal cortex will affect discrimination, inhibition and generalization. The work is relevant to human anxiety disorders and promises to elucidate critical events in the formation and elimination of fear and anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH047840-16
Application #
7086435
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Glanzman, Dennis L
Project Start
1991-04-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
16
Fiscal Year
2006
Total Cost
$333,964
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wheeler, Marina G; Duncan, Erica; Davis, Michael (2017) Low startle magnitude may be a behavioral marker of vulnerability to cocaine addiction. Synapse 71:46-50
Davis, Michael; Walker, David L (2014) Role of bed nucleus of the stria terminalis and amygdala AMPA receptors in the development and expression of context conditioning and sensitization of startle by prior shock. Brain Struct Funct 219:1969-82
Sink, K S; Chung, A; Ressler, K J et al. (2013) Anxiogenic effects of CGRP within the BNST may be mediated by CRF acting at BNST CRFR1 receptors. Behav Brain Res 243:286-93
Kazama, Andy M; Schauder, Kimberly B; McKinnon, Michael et al. (2013) A novel AX+/BX- paradigm to assess fear learning and safety-signal processing with repeated-measure designs. J Neurosci Methods 214:177-83
Glover, Ebony M; Mercer, Kristina B; Norrholm, Seth D et al. (2013) Inhibition of fear is differentially associated with cycling estrogen levels in women. J Psychiatry Neurosci 38:341-8
Jovanovic, Tanja; Sakoman, Andrea Jambrosic; Kozaric-Kovacic, Dragica et al. (2013) Acute stress disorder versus chronic posttraumatic stress disorder: inhibition of fear as a function of time since trauma. Depress Anxiety 30:217-24
Sink, K S; Walker, D L; Freeman, S M et al. (2013) Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Mol Psychiatry 18:308-19
Sink, Kelly S; Davis, Michael; Walker, David L (2013) CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear. Learn Mem 20:730-9
Christianson, John P; Fernando, Anushka B P; Kazama, Andy M et al. (2012) Inhibition of fear by learned safety signals: a mini-symposium review. J Neurosci 32:14118-24
Jovanovic, Tanja; Kazama, Andrew; Bachevalier, Jocelyne et al. (2012) Impaired safety signal learning may be a biomarker of PTSD. Neuropharmacology 62:695-704

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