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, 76 (4), 306-14

Amnesia for Early Life Stress Does Not Preclude the Adult Development of Posttraumatic Stress Disorder Symptoms in Rats

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Amnesia for Early Life Stress Does Not Preclude the Adult Development of Posttraumatic Stress Disorder Symptoms in Rats

Andrew M Poulos et al. Biol Psychiatry.

Abstract

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.

Keywords: Amnesia; development; early life stress; fear conditioning; hippocampus; rat.

Conflict of interest statement

All authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1
Experimental Design: Post-natal (P) 19 rats, were placed in a conditioning context and received No shock (Un-Shk) or 15 Shks and tested 2 months later. Experiment 1 – At P78-81 subjects were tested for Context fear memory (CXT), sensitization (SEN) and generalization (GEN). Experiment 2 – At P78-81 in separate group of animals, subjects were tested in Elevated plus maze or Odor Aversion and CXT and SEN. Experiment 3 – At P78-79 in separate group of animals, subjects were sacrificed and trunk blood was collected to analyze plasma CORT. Experiment 4 – At P78-79 in a portion of animals sacrificed in experiment 3, brains were removed for western blot analysis for glucocorticoid (GR) and neuropeptide Y1 (NPY1-R) receptor proteins.
Figure 2
Figure 2
Percent freezing was used to assess trauma related context fear memory (CXT), sensitization (SEN) and generalization (GEN) of fear. a) Group 1 – Initially tested for CXT, followed by SEN and then GEN. b) Group – Initially tested for SEN, followed by CXT. (* denotes p < .05)
Figure 3
Figure 3
Total time (sec) spent in the open arms of an elevated plus maze was used to assess anxiety. Also, depicted is total time closed arm and central portion of maze. (* denotes p < .05)
Figure 4
Figure 4
Percent time was used to assess odor aversion across 4 trials. Plotted are the mean percent time each group explored 1 of 3 compartments baited with: a) Early Trauma Odor (simple green), b) Familiar Odor (new cage bedding) and c) Neutral (no odor). (* denotes p < .05). d) Percent freezing was used to assess fear during CXT and SEN.
Figure 5
Figure 5
Total plasma concentration of CORT across 24 hours: Light Phase (7AM – 7PM) and Dark Phase (7PM – 7AM). Each data point represents mean CORT collected from trunk blood at 1 of 4 time points.
Figure 6
Figure 6
Percent change in protein levels in Shocked from Un-Shocked within the Amygdala, Hippocampus and Medial Prefrontal cortex. a) The Glucocorticoid receptor (GR) b) The Neuropeptide Y1 receptor (NPY1-R). (* denotes p < .05)
Figure 7
Figure 7
Scatter plot of Normalized (to Un-shocked controls) level of total GR as compared to NPY1 R for individual subjects. a) Amygdala: Shocked, b) UnShocked, Hippocampus: Shocked, c) Un-Shocked, d) Medial Prefrontal Cortex: e) Shocked f) Un-Shocked. (* denotes p < .05)

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