Chronic variable stress as a rodent model of PTSD; A potential role for neuropeptide Y (NPY)

Posttraumatic stress disorder (PTSD) occurs in 20-25% of people who experience trauma. Eight million people in the United States are treated for PTSD annually and the number is increasing. Sustained trauma exposure, such as combat, can develop into particularly severe and difficult to treat forms of PTSD. PTSD is thought to be a disorder of learning and memory in which hyperactivity of the amygdala leads to "overconsolidation", increased accessibility, and enhanced reconsolidation of emotional and fearful memories. Increased amygdalar activity is a consistent finding in PTSD imaging studies. Concurrent suppression of medial prefrontal cortical and hippocampal functioning could further exacerbate amygdalar excitability. There is currently an emphasis in PTSD research to identify the molecular mechanisms behind these changes and to identify "resilience factors" that may help prevent the development of PTSD following trauma. Neuropeptide Y (NPY) is a putative resilience factor based on multiple lines of evidence. NPY is abundantly expressed in PTSD-relevant brain regions, inhibits excitatory neurotransmission, and antagonizes the effects of the pro-stress hormones corticotropin-releasing hormone and norepinephrine. Directly relevant to PTSD, NPY levels are reduced in the cerebrospinal fluid of combat veterans diagnosed with PTSD. The hypothesis tested in these studies is that chronic traumatization, results in depletion of NPY in PTSD-relevant brain regions and the development of PTSD-relevant behaviors.;The emergence of PTSD-like behaviors following trauma was tested in a rodent model of chronic variable stress, a paradigm pertinent to chronic traumatization. The overwhelming majority of current animal models of PTSD focus on the effect of acute trauma. The 7-day CVS paradigm is intended to model multiple single-unit traumas within a traumatization period such as may be experienced during combat. Behavioral outcomes related to fear memory, anxiety and arousal as well as neuroendocrine stress response were measured at early (16hr) and delayed (1 week) post CVS recovery. In the contextual fear conditioning and extinction test, CVS rats allowed to recover for 1 week had a substantially increased freezing response to a trauma reminder than non-stressed rats. This is highly suggestive of enhanced fear recall and consistent with a PTSD-like phenotype. CVS rats allowed a 1-week recovery also had a reduced threshold for fearful arousal when tested on the EPM under aversive bright light. This behavior was not seen under dim light or 1 day after CVS under bright light indicating selective expression in fear-arousing contexts and a progression of physiological changes during recovery. At this same 7-day recovery timepoint, NPY peptide in CVS animals was significantly depleted in amygdala and increased in prefrontal cortex. Both of these changes are consistent with increased amygdalar excitability. Amygdalar NPY depletion persisted at least 15 days after CVS.;In summary, chronic trauma modeled by CVS potentiated fear memory recall and fearful arousal. Consistent with the hypothesis, chronic trauma induces a persistent depletion of NPY in the amygdala, which may contribute to these PTSD-like behaviors. Future studies supplementing NPY before, during and after stress are warranted to further investigate the relevance of NPY in trauma resilience.