A considerable amount of progress has been made in defining the neurobiological mechanisms of Pavlovian fear conditioning, both at the systems level, and also more recently at the biochemical and/or molecular levels. These findings suggest that fear conditioning involves integration of sensory information about the CS and US in lateral nucleus of the amygdala (LA), where N-Methyl-D-aspartate receptor (NMDAR)-mediated alterations in synaptic transmission are thought to encode key aspects of the learning. Most recent studies have focused their efforts on examining the role of downstream effectors of NMDAR-mediated signaling in LA cells, defining some of the key protein kinase signaling pathways that are thought to promote long-term plasticity and memory formation, in part, by engaging activators of transcription and translation in the nucleus. It has become increasingly clear, however, that the cellular mechanisms that underlie the consolidation of fear memories are not confined to alterations in LA neurons, but instead comprise a rich interaction between the LA and its afferent sensory regions that may act to promote 1) structural changes at presynaptic sites to LA neurons and 2) alterations in cell excitability throughout the wider fear network. As such, a complete understanding of the cellular and biochemical basis of fear memory consolidation will require attention to intracellular signaling cascades not only in the LA, but also in its afferent regions. The experiments outlined in each of the three Specific Aims of the present proposal are aimed at thoroughly testing this hypothesis using a combination of behavioral, biochemical, and neurophysiological recording techniques.
In Specific Aim I, we will begin by further exploring the downstream nuclear substrates and transcriptional mechanisms of key protein kinase cascades in both LA and MGm/PIN, and assessing their role in the process of fear memory consolidation.
In Specific Aims II and III, we will turn to the question of whether intracellular signaling cascades in the MGm/PIN that are critical for fear memory consolidation are driven by synaptic plasticity and retrograde signaling in the LA, and, in turn, whether those same thalamic signaling cascades function to promote presynaptic aspects of plasticity back in the LA. Investigation into the molecular mechanisms of conditioned fear in animals has both the potential to shed light on normal processes governing learning and memory in general, as well as implications for the etiology and treatment of various psychological disorders in humans, including anxiety, phobic and panic disorders, in which acquired fears are a prominent underlying symptom. ? ? This proposal aims to study the neural and molecular mechanisms underlying the consolidation of emotional memories in the lateral nucleus of the amygdala. Investigation into the molecular mechanisms of learned fear in animals has both the potential to shed light on normal processes governing learning and memory in general, as well as implications for the etiology and treatment of various psychological disorders in humans, including anxiety, phobic and panic disorders, in which acquired fears are a prominent underlying symptom. ? ? ?
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