Graduate Thesis Or Dissertation

 

Activation of the Infralimbic Cortex Potentiates the Inhibitory Control of Conditioned Fear Public Deposited

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https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/p8418n381
Abstract
  • The formation of fear memories is important for learning what cues predict danger. However, the inability to inhibit fear is detrimental to physical and mental health and contributes to the development of anxiety-related disorders such as post-traumatic stress disorder. Thus an understanding of the neural mechanisms and pathways that inhibit fear is invaluable and potentiating structures that regulate fear could potentially treat and prevent the development of anxiety-related disorders. The infralimbic cortex (IL) of the ventromedial prefrontal cortex is a critical structure in fear inhibition and extinction learning. The IL suppresses the central amygdala and behavioral fear expression via activation of GABAergic intercalated cells of the amygdala. Mechanisms that enhance activity in the IL and IL-related pathways may blunt the later expression of fear. The studies presented in this dissertation stemmed from the idea that activation of the IL during an aversive experience could potentiate the ability of the IL to regulate conditioned fear expression in response to future conditioned fear stimuli. Our general findings are that IL activation (with the GABAA antagonist picrotoxin, IL-Ptx) during an aversive experience (mild tail shock or fear testing) both primes extinction learning and blunts the expression of future conditioned fear. Our data indicates that the activation of the IL induces long-lasting plastic changes in the IL that increase the recruitment of IL activity in response to fearful stimuli and result in the inhibition of conditioned fear responses. The effects of IL activation are highly dependent on NMDAR mechanisms at the time of activation and require IL activity during extinction learning. Furthermore, experiments presented in Chapters II, III, and IV demonstrate that the priming effect on future extinction learning is initially non-associative such that IL-Ptx administered in one fear context (or during conditioning) has transferrable effects on extinction in an entirely different context. The first two-thirds of this dissertation focus on the effects of IL activation on extinction whereas the last third focuses on the effects of IL activation on new fear learning. Chapter 4 investigates how IL activation decreases the future expression of conditioned fear that has not yet been learned. We demonstrate that IL activation is necessary during fear testing but not during fear conditioning. Thus, the reduction in fear is not caused by impairments in the formation of the fear memory, but, rather, it is due to increased IL inhibitory control of the CeA and fear expression during testing. Furthermore, we compared the pattern of plasticity-related proteins expressed following fear testing between animals that had received previous IL-Ptx or Sal. We found increased plasticity related proteins in regions that are involved in fear inhibition in animals that had received IL-Ptx with elevated phospho-ERK expression in the IL and elevated phospho-CREB expression in the ventromedial intercalated cells (ITC) and diminished phospho-CREB in the central amygdala (CeA) The elevated pattern of plasticity-related proteins in the IL and vmITC cells suggests that IL activation potentiates plasticity in the IL and ITC cells, which in turn results in diminished CeA activity. The research presented here extends the understanding of the role of the IL in fear inhibition and has exciting potential implications for prevention and treatment of anxiety disorders.
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  • 2013-01-01
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  • 2019-11-13
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