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.

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

BACKGROUND: Traumatic 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. METHODS: Nineteen-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. RESULTS: Early 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. CONCLUSIONS: These 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.

Concussive brain injury enhances fear learning and excitatory processes in the amygdala.

BACKGROUND: Mild traumatic brain injury (cerebral concussion) results in cognitive and emotional dysfunction. These injuries are a significant risk factor for the development of anxiety disorders, including posttraumatic stress disorder. However, because physically traumatic events typically occur in a highly emotional context, it is unknown whether traumatic brain injury itself is a cause of augmented fear and anxiety. METHODS: Rats were trained with one of five fear-conditioning procedures (n = 105) 2 days after concussive brain trauma. Fear learning was assessed over subsequent days and chronic changes in fear learning and memory circuitry were assessed by measuring N-methyl-D-aspartate receptor subunits and glutamic acid decarboxylase, 67 kDa isoform protein levels in the hippocampus and basolateral amygdala complex (BLA). RESULTS: Injured rats exhibited an overall increase in fear conditioning, regardless of whether fear was retrieved via discrete or contextual-spatial stimuli. Moreover, injured rats appeared to overgeneralize learned fear to both conditioned and novel stimuli. Although no gross histopathology was evident, injury resulted in a significant upregulation of excitatory N-methyl-D-aspartate receptors in the BLA. There was a trend toward decreased γ-aminobutyric acid-related inhibition (glutamic acid decarboxylase, 67 kDa isoform) in the BLA and hippocampus. CONCLUSIONS: These results suggest that mild traumatic brain injury predisposes the brain toward heightened fear learning during stressful postinjury events and provides a potential molecular mechanism by which this occurs. Furthermore, these data represent a novel rodent model that can help advance the neurobiological and therapeutic understanding of the comorbidity of posttraumatic stress disorder and traumatic brain injury.

Ontogeny of Rat Recognition Memory measured by the novel object recognition task.

Detection of novelty is an essential component of recognition memory, which develops throughout cerebral maturation. To better understand the developmental aspects of this memory system, the novel object recognition task (NOR) was used with the immature rat and ontogenically profiled. It was hypothesized that object recognition would vary across development and be inferior to adult performance. The NOR design was made age-appropriate by downsizing the testing objects and arena. Weanling (P20-23), juvenile (P29-40), and adult (P50+) rats were tested after 0.25, 1, 24, and 48 hr delays. Weanlings exhibited novel object recognition at 0.25 and 1 hr, while older animals showed a preference for the novel object out to 24 hr. These findings are consistent with previous research performed in humans and monkeys, as well as to studies using the NOR after medial temporal lobe damage in adult rats.