Indiana University-Purdue University Indianapolis (IUPUI) / Fear is an evolutionarily conserved response that can facilitate avoidance learning
and promote survival, but excessive and persistent fear responses lead to development of
phobias, generalized fear, and post-traumatic stress disorder. The primary goal of
experiments in this dissertation is to determine the molecular mechanisms underlying
formation of fear memories. The acquisition and consolidation of fear is dependent upon
activation of N-methyl-D-aspartic acid receptors (NMDARs). Stimulation of NMDARs
recruits neuronal nitric oxide synthase (nNOS) to the synaptic scaffolding protein,
postsynaptic density protein 95 (PSD95), to produce nitric oxide (NO). Our laboratory
has previously shown that disruption of the PSD95-nNOS interaction attenuates fear
consolidation and impairs long-term potentiation of basolateral amygdala (BLA) neurons
in a rodent model of auditory fear conditioning. However, the molecular mechanisms by
which disrupting the PSD95-nNOS interaction attenuates fear consolidation are not well
understood.
Here, we used pharmacological and genetic approaches to study the effects
underlying nNOS activity in the BLA during fear consolidation. During the early stage of
fear memory consolidation (4-6 hours after fear acquisition), we observed increased α-
Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated
current and synaptosomal AMPAR GluR1 subunit trafficking in the BLA; while during
the late stage (24h after fear acquisition), we detected a combination of enhanced
AMPAR- and NMDAR-mediated currents, increased synaptosomal NMDAR NR2B
subunit expression, and phosphorylation of synaptosomal AMPAR GluR1 and NMDAR
NR2B subunits in the BLA. Importantly, we showed that pharmacological and genetic
blockade of nNOS activity inhibits all of these glutamatergic synaptic plasticity changes
in the BLA. Additionally, we discovered whole transcriptome changes in the BLA
following fear consolidation. In the group with pharmacological inhibition of nNOS
activity, however, gene expression levels resembled control-like levels. We also observed
altered expression of multiple genes and identified the insulin-like growth factor system,
D3/D4 dopamine receptor binding, and cGMP effects as key pathways underlying nNOSmediated
consolidation of fear.
Our results reveal nNOS-mediated, sequentially orchestrated synaptic plasticity
changes facilitated by AMPA and NMDA receptors in the BLA during early and late
stages of fear memory consolidation. We also report novel genetic targets and pathways
in the BLA underlying NMDAR-PSD95-nNOS axis-mediated formation of fear
memories.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/26001 |
| Date | 05 1900 |
| Creators | Patel, Jheel |
| Contributors | Sheets, Patrick, Shekhar, Anantha, McKinzie, David, Yamamoto, Bryan, Liu, Yunlong |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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