While diagnosis of PTSD is based on behavioral symptom clusters that are most directly associated with brain function, epigenetic studies of PTSD in humans to date have been limited to peripheral tissues. Animal models of PTSD have been key for understanding the epigenetic alterations in the brain most directly relevant to endophenotypes of PTSD, in particular those pertaining to fear memory and stress response. This chapter provides an overview of neuroepigenetic studies based on animal models of PTSD, with an emphasis on the effect of stress on fear memory. Where relevant, we also describe human-based studies with relevance to neuroepigenetic insights gleaned from animal work and suggest promising directions for future studies of PTSD neuroepigenetics in living humans that combine peripheral epigenetic measures with measures of central nervous system activity, structure and function.
Humans with mutations in either DCX or LIS1 display nearly identical neuronal migration defects, known as lissencephaly. To define subcellular mechanisms, we have combined in vitro neuronal migration assays with retroviral transduction. Overexpression of wild-type Dcx or Lis1, but not patient-related mutant versions, increased migration rates. Dcx overexpression rescued the migration defect in Lis1+/-neurons. Lis1 localized predominantly to the centrosome, and after disruption of microtubules, redistributed to the perinuclear region. Dcx outlined microtubules extending from the perinuclear "cage" to the centrosome. Lis1+/-neurons displayed increased and more variable separation between the nucleus and the preceding centrosome during migration. Dynein inhibition resulted in similar defects in both nucleus-centrosome (N-C) coupling and neuronal migration. These N-C coupling defects were rescued by Dcx overexpression, and Dcx was found to complex with dynein. These data indicate Lis1 and Dcx function with dynein to mediate N-C coupling during migration, and suggest defects in this coupling may contribute to migration defects in lissencephaly.