A Dynamic Circuit: Interactions between the Amygdala, Hippocampus and Prefrontal Cortex Control Context-Sensitive Fear and Extinction

Environments or contexts comprise the emotional fabric within which memories are weaved. Contextual factors can powerfully influence fear learning and memory and contribute to the successful survival of a species by directly signaling potential threat. Additionally, contexts can serve to modulate the meaning of a discrete, ambiguous cue, as is the case following extinction of a fear stimulus. The dorsal hippocampus, amygdala and medial prefrontal cortex have been implicated in contextual processing, fear, and extinction, respectively. However, the exact nature and dynamics governing their contribution to context-sensitive fear remains an open question. In this thesis, a series of studies were performed to determine the unique contributions made by the dorsal hippocampus and the medial prefrontal cortex to context-sensitive fear learning in the rat, while simultaneously placing these regions within a unified, dynamic fear circuit. Chapter 1 serves to introduce the nature of context-sensitive fear and the known role of the dorsal hippocampus and the infralimbic and prelimbic divisions of the medial prefrontal cortex in such fear. Chapter 2 demonstrates compensatory fear renewal for tone fear memories formed and extinguished in the absence of the dorsal hippocampus. Chapter 3 attempts to remove the context-sensitivity of extinction and finds that fear renewal is attenuated by disruption of hippocampal functioning during extinction using a clinically translatable pharmacological agent. Chapter 4 follows up on the compensation established by Chapter 2. Using immediate early gene expression analyses and retrograde tracing, Chapter 4 demonstrates that compensation requires the infralimbic and prelimbic cortices as well as communication within this prefrontal microcircuit, and correlates with a re-balancing between prelimbic and infralimbic activity in amygdala-projecting cells. Chapter 5 continues to unravel the nature of context fear memories formed in the absence of the dorsal hippocampus by testing their longevity, revealing that fear memories formed following hippocampal lesions lack the characteristic permanence of normal fear memories. Chapter 6 probes deeper into Chapter 4's finding that the infralimbic and prelimbic cortices comprise a microcircuit within the prefrontal cortex that underlies compensatory context-sensitive fear. This chapter employs the Arc mRNA imaging technique catFISH [cellular compartment analysis of temporal activity using fluorescent in situ hybridization) to demonstrate that under normal circumstances, the prelimbic and infralimbic are involved in contextual encoding and fear processing, and that damage to the infralimbic cortex disrupts context discrimination and Arc expression profiles in spatially-sensitive neuronal ensembles in the dorsal hippocampus. In Chapter 7, the data are discussed in terms of a unified amygdala-hippocampal-prefrontal circuit that underlies both direct context fear and context-modulated fear renewal after extinction, wherein structures are functionally distinct but nevertheless engage in continual crosstalk such that damage to one structure affects behavior of the remaining circuit.