Epigenetic Mechanisms Underlying Fear Memory Consolidation and the Effects of Chronic Stress on Fear Memory.

摘要

Acquired fears are involved in a variety of anxiety related disorders, post-traumatic stress disorder (PTSD) being perhaps one of the most debilitating among them. It is widely accepted that fear memories are established and stored a key brain structure: the lateral nucleus of the amygdala (LA; LeDoux et al., 1990; Nader et al., 2001; Rodrigues et al., 2004). Interestingly, the LA is also a region that contains an abundant supply of glucocorticoid receptors and is therefore capable of modulating responses to stress (Johnson et al., 2005). During periods of prolonged or chronic stress, however, this innate regulatory system becomes disrupted leading to negative functional and behavioral outcomes. Thus, it is not surprising that accumulating evidence suggests that chronic stress may be a major precipitating factor in the development of psychological disorders, such as PTSD (Miller et al., 2007; Sinha, 2008; Ota & Duman, 2013).;Conventional views of memory formation emphasize NMDA receptor (NMDAR)-driven modifications to downstream targets ultimately leading to changes in gene transcription and synaptic transmission, which result in phenotypic alterations in behavioral. However, it has recently become clear that additional programming occurs at the level of the epigenome, which is also capable of modulating behavioral outcomes. Epigenetics is the study of post-translational modifications that occur without altering the actual DNA sequence, but which still result in a change in cellular phenotype (Levenson & Sweatt 2005; Roth & Sweatt, 2009). While increasing evidence suggests the involvement of epigenetic processes in psychiatric disorders, little has been done to investigate the role of epigenetics in amygdala-dependent memory consolidation or the effects of chronic stress on fear memory consolidation processes. It is therefore the aim of the present dissertation to explore epigenetic mechanisms involved in these processes.;In Chapter 2, I first systematically demonstrate that epigenetic alterations are critical for auditory Pavlovian fear memory consolidation and associates synaptic plasticity in the LA. Using a series of behavioral and pharmacological experiments, I show that auditory fear conditioning regulates histone acetylation and the expression of DNA methyltransferases (DNMTs) in the LA, events that are both associative and dependent on upstream activity of the extracellular-regulated kinase (ERK). Next, I show that a histone deacetylase (HDAC) inhibitor can enhance the consolidation of a fear memory as well as LTP at thalamic and cortical inputs. Conversely, I show that a DNMT inhibitor is capable of impairing memory consolidation as well as LTP at thalamic and cortical inputs. Collectively, these findings suggest a vital role for histone acetylation and DNA methylation in auditory Pavlovian fear memory consolidation.;In Chapter 3, I use the naturally occurring histone acetyltransferase (HAT) inhibitor, curcumin, to explore a more clinically suitable means by which to alter fear memory consolidation. Here, I find that dietary curcumin impairs training-related increases in histone acetylation and the expression of memory-related proteins in the LA and impairs the consolidation of an auditory fear memory. I then further explore the therapeutic use of this compound by demonstrating that dietary curcumin can impair the reconsolidation of a fear memory in an enduring manner that is not subject to reinstatement or renewal.;In Chapter 4, I set focus on examining epigenetic mechanisms involved in stress-associated modulation of fear memory as modeled by a chronic oral corticosterone (CORT) exposure paradigm. Here, I show that chronic CORT exposure acutely enhances histone acetylation and persistently enhances the expression of memory-related genes in the LA, as well as the consolidation of an auditory fear memory. I next use curcumin as a potential therapeutic tool by which to prevent these effects of chronic stress in a proactive manner. I first show that dietary curcumin prevents chronic CORT exposure from increasing levels of histone acetylation, memory-related, and synaptically localized proteins in the LA. I next show that curcumin is capable of preventing the CORT-induced persistent elevation in memory-related gene expression in the LA as well as the CORT-induced enhancement in auditory fear memory consolidation.;In sum, the present dissertation systematically explores epigenetic mechanisms involved in amygdala-dependent fear memory consolidation and the effects of chronic stress on fear memory. Additionally, I explore the novel use of the naturally occurring compound, curcumin, in impairing fear memory consolidation and reconsolidation. Further, I have provided evidence that dietary curcumin during a period of chronic stress is capable of preventing long-lasting effects on memory-related gene expression in the LA and on fear memory consolidation. Collectively, the present set of studies provides support for potential clinical use of curcumin in the treatment of psychological disorders such as PTSD and other anxiety related disorders.