Amnesia for early life stress does not preclude the adult development of posttraumatic stress disorder symptoms in rats.

BackgroundTraumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms.MethodsNineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors.ResultsEarly trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks.ConclusionsThese results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma

D-Cycloserine Restores Experience-Dependent Neuroplasticity after Traumatic Brain Injury in the Developing Rat Brain

Traumatic brain injury (TBI) in children can cause persisting cognitive and behavioral dysfunction, and inevitably raises concerns about lost potential in these injured youth. Lateral fluid percussion injury (FPI) in weanling rats pathologically affects hippocampal N-methyl-d-aspartate receptor (NMDAR)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated glutamatergic neurotransmission subacutely within the first post-injury week. FPI to weanling rats has also been shown to impair enriched-environment (EE) induced enhancement of Morris water maze (MWM) learning and memory in adulthood. Recently, improved outcomes can be achieved using agents that enhance NMDAR function. We hypothesized that administering D-cycloserine (DCS), an NMDAR co-agonist, every 12 h (i.p.) would restore subacute glutamatergic neurotransmission and reinstate experience-dependent plasticity. Postnatal day 19 (P19) rats received either a sham or FPI. On post-injury day (PID) 1-3, animals were randomized to saline (Sal) or DCS. Firstly, immunoblotting of hippocampal NMDAR and AMPAR proteins were measured on PID4. Second, PID4 novel object recognition, an NMDAR- and hippocampal- mediated working memory task, was assessed. Third, P19 rats were placed in an EE (17 days), and MWM performance was measured, starting on PID30. On PID4, DCS restored reduced NR2A and increased GluR2 by 54%, and also restored diminished recognition memory in FPI pups. EE significantly improved MWM performance in shams, regardless of treatment. In contrast, FPI-EE-Sal animals only performed to the level of standard housed animals, whereas FPI-EE-DCS animals were comparable with sham-EE counterparts. This study shows that NMDAR agonist use during reduced glutamatergic transmission after developmental TBI can reinstate early molecular and behavioral responses that subsequently manifest in experience-dependent plasticity and rescued potential