Redundant Neuromodulatory Mechanisms That Control Fear Memory Consolidation

The ability to reliably and powerfully store memories for frightening experiences is crucial to survival in an ever-changing and potentially dangerous environment. Consolidation is the process by which long-term memories are stored in the brain, and much is understood about the processes that occur within a neuron in the hours after a learning event that stabilize learning-induced changes. However, the specific mechanisms through which fear exacerbates those processes remains unclear. Neuromodulators are a prime object of research to understand the consolidation of fear memory given that their release is a hallmark of the fear response. While several neuromodulatory systems are known to facilitate consolidation, no individual system yet appears to be essential. This dissertation explores the hypothesis that several neuromodulators work together to ensure proper consolidation of fear memory. The research contained in this dissertation employs pharmacologic and genetic manipulation of individual neuromodulatory receptor systems and associated intracellular signaling pathways to determine the essential neurobiology for consolidating of Pavlovian fear conditioning in mice. The results of this investigation reveal that β2-adrenergic, D5-dopaminergic and M1-muscarinic receptors in the basolateral amygdala (BLA) are essential to fear conditioning in a redundant manner, wherein two or more receptor types must be blocked in order to prevent consolidation. Furthermore, these three receptors are observed to redundantly activate phospholipase C (PLC), which this dissertation shows is necessary for consolidation in the BLA. Finally, evidence is provided to suggest that PLC promotes fear memory consolidation by inhibiting a voltage-dependent potassium channel (KCNQ/M) that regulates neuronal excitability and also appears to control consolidation. Together, this dissertation proposes that fear-induced neuromodulatory release promotes consolidation through redundant neuromodulatory activation of PLC, which puts the BLA in an excitable state that does not persist into the consolidation window after emotionally neutral experiences