This is an application for a MERIT extension to study neuroanatomical, cellular and molecular mechanisms involved in conditioned fear, anxiety, extinction and learned safety, using the acoustic startle reflex in rats. Acoustic startle is a short latency reflex mediated by a simple neural pathway. Startle amplitude can be increased by eliciting the reflex in the presence of a light or odor previously paired with a shock (fear- potentiated startle). During the previous grant period we delineated a new connection between the medial nucleus of the amygdala and the acoustic startle pathway critical for fear-potentiated startle, discovered a new method to try to understand the neural basis of conditioned fear vs. anxiety, analyzed the differential roles of NMDA-2A and 2B receptors in the acquisition vs. expression of fear-potentiated startle, uncovered a role for brain derived neurotropin in the development of both fear conditioning and extinction,as well as observing interactions between cholecystokinin and cannabinoid receptors in extinction. One of the most vexing problems in studying the cellular and molecular mechanisms of learning and memory in a complex organism is the problem of signal-to-noise ratio. Given billons of neurons and trillions of synapses, how will we ever be able to figure out at a cellular level the molecular events necessary for memory formation and storage? By using genetically engineered mice, namely mice in which the promoter for a particular olfactory sensory receptor (m71) is fused to the gene that codes for either green fluorescent protein or B- galactosidase, in combination with olfactory-mediated fear-potentiated startle using acetophenone as the conditioned stimulus, we hope to overcome some of these problems. We will use manganese(Mn) enhanced MRI,in conjunction with standard histological techniques, to trace brain circuits involved in conditioned fear, extinction, and conditioned inhibition, using a small animal, 9.4 T magnet. Other studies will evaluate changes in M71 axon number following fear conditioning and whether the amygdala modulates these changes. Other studies will evaluate the role of corticotropin releasing factor receptors in the amygdala or bed nucleus of the stria terminalis in fear vs. anxiety and other studies will use high speed voltammetry to assess changes in glutamate release in the acoustic startle pathway during fear-potentiated startle testing.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Vicentic, Aleksandra
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Emory University
Schools of Medicine
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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
Kazama, Andy M; Heuer, Eric; Davis, Michael et al. (2012) Effects of neonatal amygdala lesions on fear learning, conditioned inhibition, and extinction in adult macaques. Behav Neurosci 126:392-403
Parsons, Ryan G; Davis, Michael (2012) A metaplasticity-like mechanism supports the selection of fear memories: role of protein kinase a in the amygdala. J Neurosci 32:7843-51

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