Posttraumatic stress disorder (PTSD) is a multifaceted disorder precipitated by exposure to a psychologically distressing event. Although, diagnostic symptoms for PTSD include hyperarousal, re- experiencing (flashbacks/nightmares), and avoidance, sleep disruptions are considered the hallmark of PTSD. PTSD affects a large proportion of military personnel and veterans and is associated with numerous deleterious outcomes for veterans and active duty service personnel. The costs of PTSD to the individual and society are substantial. Strong evidence, from clinical and preclinical studies, suggest a dysregulation of brain regions and behavioral systems related to fear memory processes in the etiology and symptomatology of PTSD. Thus, to understand the pathophysiology of PTSD and to develop efficacious treatment strategies, it is important to understand the neurobiology of fear memory system. It is well established that sleep is critical for fear and extinction memory consolidation. Our recent studies suggests that the sleep-promoting melanin-concentrating hormone (MCH) mediates the effects of sleep on fear memory consolidation. Mice exposed to predator odor trauma show protracted sleep disruption along with contextual fear conditioning. However, pharmacogenetic silencing of MCH neurons or blockade of MCH receptors in the hippocampus or amygdala, immediately after fear memory acquisition, normalizes sleep and attenuates fear. In this proposal, we propose to extend our research and examine molecular mechanisms mediating the effects of MCH on fear memory. Since changes in the epigenome are the basis of memory consolidation, we hypothesized that MCH acts via MCH receptor and mitogen activated protein kinase (MAPK) signaling cascade to perturb the epigenome and consolidate, reconsolidate and promote extinction of fear memories. We will use wild type and transgenic (expressing Cre-recombinase under MCH promoter control) C57BL/6J mice as our animal model and contextual fear conditioning, with predator odor as unconditional stimulus, to examine consolidation, reconsolidation and extinction of fear memories.
Our first aim proposes that pharmacogenetic silencing of MCH neurons or blockade of MCH receptors will attenuate MAPK signaling, reduce histone acetylation and BDNF expression, which will result in the attenuation of memory consolidation and normalization of sleep. Pharmacogenetic silencing of MCH neurons coupled with infusion of MCH peptide, in the hippocampus or amygdala, will block the effects of MCH neuronal silencing and promote fear.
Our second aim proposes that MCH reconsolidates contextual fear memories by enhancing the expression of Zif268, in the hippocampus and amygdala, via MAPK signaling cascade. Pharmacogenetic silencing of MCH neurons or blockade of MCH receptor in the hippocampus or amygdala, immediately after fear reactivation, will attenuate MAPK signaling and Zif268 expression, which will attenuate fear reconsolidation. In contrast, infusion of MCH peptide, in the hippocampus or amygdala, along with MCH neuronal silencing will promote fear reconsolidation. Our last aim proposes that silencing of MCH neurons or blockade of MCH receptor, in the hippocampus or amygdala, immediately after extinction learning, will block MAPK signaling, reduce calcineurin and block fear extinction. However, infusion of MCH peptide, in the hippocampus or amygdala, along with silencing of MCH neurons will block the effects of MCH neuronal silencing and promote fear extinction. Overall, our hypotheses are logical and testable. Our project is innovative, translational and relevant to VA care and mission
The broad objective of our research program is to examine and understand the underlying neuronal mechanisms responsible for stress and anxiety disorders such as PTSD. This will help us better understand the disease, find ways to prevent it and/or develop efficacious treatment strategies.
|Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M (2018) Severe and protracted sleep disruptions in mouse model of post-traumatic stress disorder. Sleep 41:|