Retrograde signalling within fear neurocircuitry: Nitric oxide signalling from the lateral nucleus of the amygdala regulates thalamic EGR-1 mediated alterations of presynaptic protein levels during auditory fear conditioning
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Previous research has shown that nitric oxide signalling in the lateral nucleus of the amygdala is required for the consolidation of Pavlovian conditioned fear. Given the evidence that nitric oxide can act as a retrograde signalling molecule in in vitro models of memory consolidation the question arises whether this is also occurring within behavioural memory models? Using auditory fear conditioning this research shows that nitric oxide does indeed act as retrograde signalling molecule in the fear system. Its synthesis in the lateral nucleus of the amygdala regulates conditioning induced expression of the immediate early gene early growth response gene 1 (EGR-1) in cells of the auditory thalamus that project to the lateral nucleus of the amygdala. The regulation of EGR-1 expression by the lateral nucleus of the amygdala was proven to be dependent on amygdala-based cellular excitation, nitric oxide synthesis and NR2B-NMDA receptor activation but not ERK/MAPK activity. Using an EGR-1 antisense oligonucleotide to prevent training induced EGR-1 expressions in the auditory thalamus it was shown that this gene upregulation is necessary for the consolidation of conditioned fear. Finally, inhibition of EGR-1 upregulation in the auditory thalamus was proven to impair conditioning induced increases in the presynaptic proteins synaptophysin, and synapsin II and II back in the lateral nucleus of the amygdala. Overall, the results of this dissertation have shown that nitric oxide acts as a retrograde messenger in a mammalian memory system by modulating gene expression in presynaptic cells. This modulation of gene expression serves to increase levels of presynaptic proteins back at the origin of nitric oxide synthesis. This supports the long standing doctrine that nitric oxide acts as a retrograde signalling molecule to coordinate presynaptic changes associated with memory formation.