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 to be the hallmarks 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 at large are substantial. PTSD is characterized by impairments in fear and extinction learning whereby the perceived threat continues even when acute danger is no longer present and stimuli that are reminiscent of those that occurred during the trauma continue to provoke fear and alarm. Convincing evidence suggests that sleep is critical for fear learning and consolidation of extinction memories. However, it is yet unclear as to how or what sleep factor regulates fear and extinction learning. Recent studies implicate melanin concentrating hormone (MCH), a neuropeptide, in sleep regulation and in learning and memory consolidation. Thus, we asked: Does MCH have a role in pathogenesis of PTSD? Since PTSD is characterized by dysfunctional fear and extinction learning, we hypothesize that MCH may play a critical role in fear and extinction learning. We will use mice as our animal model and expose them to predator odor to induce contextual fear conditioning. We predict that a) mice exposed to predator odor will develop contextual fear conditioning and display fear, stress and protracted sleep disruptions; b) exposure to predator odor will activate brain regions associated with fear learning. We will use the cutting edge Designer Receptors Exclusively Activated by Designer Drug (DREADD) technology to selectively inhibit MCH neurons. We predict that inhibition of MCH neurons or blockade of MCH transmission, via selective MCH-1 receptor antagonist will attenuate fear learning. However, inhibition of MCH neurons coupled with local activation of MCH transmission in the hippocampus or amygdala will override the effects of MCH inhibition resulting in the development of contextual fear conditioning. We predict that extinction learning, after predator odor trauma, will activate infralimbic cortex, the brain region associated with extinction, and attenuate fear learning. However, inhibition of MCH neurons or selective blockade of MCH transmission in the infralimbic cortex during extinction training will attenuate extinction learnin. Overall, our project is innovative, translational and very 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:|