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 post-traumatic 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 prior to 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, elevated plus-maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid (G-R) 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 G-R, 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.
Mammals evolved a potent fear-motivated defensive system capable of single-trial fear learning that shows no forgetting over the lifespan of the animal. The basolateral amygdala complex (BLA) is considered an essential component of this conditional fear learning system. However, recent studies challenge this view and suggest that plasticity within other brain regions (i.e., central nucleus of the amygdala) may be crucial for fear conditioning. In the present study, we examine the mnemonic limits of contextual fear conditioning in the absence of the BLA using overtraining and by measuring remote fear memories. After excitotoxic lesions of the BLA were created, animals underwent overtraining and were tested at recent and remote memory intervals. Here we show that animals with BLA lesions can learn normal levels of fear. However, this fear memory loses its adaptive features: it is acquired slowly and shows substantial forgetting when remote memory is tested. Collectively, these findings suggest that fear-related plasticity acquired by brain regions outside of the BLA, unlike those acquired in the intact animals, do so for a relatively time-limited period.fear conditioning ͉ forgetting ͉ remote memory ͉ savings F ailure to defend against an environmental threat such as predation exacts an extreme cost on adaptive fitness (1). Unlike a single missed feeding or mating opportunity, a single failure to defend means you will have no future opportunities to pass on your genes. As a consequence, mammals have evolved a potent fear-motivated defensive system that is capable of singletrial learning (2) and shows no forgetting over the lifespan of the animal (3). Prior studies suggest that such memories are normally established and permanently maintained within the basolateral complex of the amygdala (BLA) (3-7). Typically, damage to the BLA eliminates the acquisition and expression of Pavlovian fear memories across a wide spectrum of mammals, including humans (8) and rodents (5, 6, 9-13). Both electrophysiological and molecular markers of neural activity within the BLA reveal a learning-and retrieval-specific pattern of activation (14-18). Moreover, blockade of NMDA receptors or de novo protein synthesis within the BLA disrupts the acquisition and consolidation of fear memories (19)(20)(21)(22)(23). In addition, regardless of whether fear memories are 1 day or 1.5 years old, posttraining BLA lesions completely abolish the expression of fear (3). Collectively, such findings are consistent with a mnemonic role of the BLA in fear learning.However, recent studies have challenged this view and suggest that plasticity in other brain regions are capable of supporting fear conditioning (24,25). Indeed, there is growing evidence that fear conditioning can be established in the absence of the BLA. In particular, deficits resulting from either lesions or inactivations of the BLA can be overcome with extensive overtraining (7,(25)(26)(27). Furthermore, both Zimmerman et al. (25) and Wilensky et al. (24) have recently shown that disrup...
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