Neuroanatomical and neurochemical mechanisms involved in conditioned fear and anxiety will be investigated in rats and in humans using the acoustic startle reflex. In both rats and humans, startle amplitude can be increased by eliciting the reflex in the presence of a cue previously paired with a shock (fear-potentiated startle equal explicit cue conditioning) as well as exposure to the experimental situation where fear conditioning occurred (context conditioning). In rats, lesions of the amygdala block both explicit cue conditioning and context conditioning, whereas lesions of the bed nucleus of the stria terminalis (BNST), which also projects to the startle pathway, block context conditioning but not explicit cue conditioning. Hence, the Bnst may be especially important for context conditioning because it receives a heavy inputs from the hippocampus. The test this, effects of chemical lesions of either the lateral and basolateral amygdala, the dorsal vs. Ventral hippocampus of the bed nucleus of the stria terminalis will be given either before or after training to asses the possible differential effects of these lesions on both the acquisition and expression of explicit cue and contextual fear conditioning. Patients with post-traumatic stress syndrome (PTSD) seem to display abnormal context conditioning buy normal explicit cue conditioning. Because PTSD has been associated with a dysregulation of brain norepinephrine (NE), and central beta- adrenergic receptors are important for modulation of aversive memories, we hypothesize that context conditioning will be more sensitive than explicit cue conditioning to manipulations of central NE. In rats and healthy humans the effects of the drugs propranolol, yohimbine, or buspirone given systemically will be tested on both context and explicit cue conditioning. We hypothesize that propranolol will be more effective in blocking the acquisition of context conditioning than explicit cue conditioning, that yohimbine will be more effective in facilitating the acquisition of context conditioning than explicit cue conditioning, and that buspirone will block the expression of explicit cue conditioning but not the expression of contextual fear conditioning. In PTSD patients and age-matched healthy controls the effects of propranolol will be evaluated on context conditioning vs. Explicit cue conditioning. Similar predictions are made for these patients excepts that the magnitude of context conditioning is expected to be greater in PTSD vs age-matched controls and this difference in startle magnitude may be normalized by propranolol.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH025642-27
Application #
6471802
Study Section
Project Start
2001-07-01
Project End
2002-06-30
Budget Start
Budget End
Support Year
27
Fiscal Year
2001
Total Cost
$110,670
Indirect Cost
Name
Yale University
Department
Type
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian et al. (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742-9
Duric, Vanja; Banasr, Mounira; Stockmeier, Craig A et al. (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16:69-82
Duric, Vanja; Duman, Ronald S (2013) Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes. Cell Mol Life Sci 70:39-53
Newton, Samuel S; Fournier, Neil M; Duman, Ronald S (2013) Vascular growth factors in neuropsychiatry. Cell Mol Life Sci 70:1739-52
Fournier, Neil M; Lee, Boyoung; Banasr, Mounira et al. (2012) Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology 63:642-52
Fournier, Neil M; Duman, Ronald S (2012) Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav Brain Res 227:440-9
Son, Hyeon; Banasr, Mounira; Choi, Miyeon et al. (2012) Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress. Proc Natl Acad Sci U S A 109:11378-83
Voleti, Bhavya; Tanis, Keith Q; Newton, Samuel S et al. (2012) Analysis of target genes regulated by chronic electroconvulsive therapy reveals role for Fzd6 in depression. Biol Psychiatry 71:51-8
Kang, Hyo Jung; Voleti, Bhavya; Hajszan, Tibor et al. (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18:1413-7
Li, Nanxin; Liu, Rong-Jian; Dwyer, Jason M et al. (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69:754-61

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