Summary Lattice-like structures known as perineuronal nets (PNNs) are key components of the extracellular matrix (ECM). Once fully crystallized by adulthood, they are largely stable throughout life. Contrary to previous reports that PNNs inhibit processes involving plasticity, here we report that the dynamic regulation of PNN expression in the adult auditory cortex is vital for fear learning and consolidation in response to pure tones. Specifically, after first confirming the necessity of auditory cortical activity for fear learning and consolidation, we observed that mRNA levels of key proteoglycan components of PNNs were enhanced 4 hours after fear conditioning but were no longer different from the control groups 24 hours later. A similar pattern of regulation was observed in numbers of cells surrounded by PNNs and area occupied by them in the auditory cortex. Finally, the removal of auditory cortex PNNs resulted in a deficit in fear learning and consolidation.

BACKGROUND:Stressors affect populations exposed to them as well as offspring. Strategies preventing the intergenerational propagation of effects of stress would benefit public health. Olfactory cue-based fear conditioning provides a framework to address this issue. METHODS:We 1) exposed adult male mice to an odor, acetophenone (Ace) or Lyral (parental generation [F0]-Exposed), 2) trained mice to associate these odors with mild foot shocks (F0-Trained), and 3) trained mice to associate these odors with mild foot shocks and then extinguished their fear toward these odors with odor-only presentations (F0-Extinguished). We then examined sensitivity of future generation (F1) offspring to these odors, expression of M71 odorant (Aceresponsive) and MOR23 odorant (Lyral-responsive) receptor-expressing cell populations in F1 offspring, and DNA methylation at genes encoding the Ace-(Olfr151, Olfr160) and Lyral-(Olfr16) responsive receptors in F0 sperm. RESULTS:Extinguishing fear toward Ace or Lyral of F0 male mice (F0-Extinguished) that had been fear conditioned with Ace or Lyral, respectively, results in F1-Extinguished offspring that do not demonstrate behavioral sensitivity to Ace or Lyral, respectively, and do not have enhanced representation for M71 or MOR23 odorant receptors in the olfactory system, as is observed in F1-Trained-Ace or F1-Trained-Lyral cohorts, respectively. The promoters of genes encoding Olfr151 and Olfr160 receptors are less methylated in F0-Trained-Ace sperm compared with F0-Exposed-Ace sperm. The Olfr16 promoter is less methylated in F0-Trained-Lyral sperm compared with F0-Exposed-Lyral sperm, and F0Extinguished-Lyral sperm have methylation levels comparable to F0-Exposed-Lyral sperm. CONCLUSIONS:Our study demonstrates the potential of using extinction-based behavioral strategies to reverse influences of parental stress in offspring and in the parental germline.

BACKGROUND Post-traumatic stress disorder is a severe psychobiological disorder associated with hyperactivity of the amygdala, particularly on the right side. Highly selective laser ablation of the amygdalohippocampal complex is an effective neurosurgical treatment for medically refractory medial temporal lobe epilepsy that minimizes neurocognitive deficits relative to traditional open surgery. OBJECTIVE To examine the impact of amygdalohippocampotomy upon symptoms and biomarkers of post-traumatic stress disorder. METHODS Two patients with well-documented chronic post-traumatic stress disorder who subsequently developed late-onset epilepsy underwent unilateral laser amygdalohippocampotomy. Prospective clinical and neuropsychological measurements were collected in patient 1. Additional prospective measurements of symptoms and biomarkers were collected pre- and post-surgery in patient 2. RESULTS After laser ablation targeting the nondominant (right) amygdala, both patients experienced not only reduced seizures, but also profoundly abated post-traumatic stress symptoms. Prospective evaluation of biomarkers in patient 2 showed robust improvements in hyperarousal symptoms, fear potentiation of the startle reflex, brain functional magnetic resonance imaging responses to fear-inducing stimuli, and emotional declarative memory. CONCLUSION These observations support the emerging hypothesis that the right amygdala particularly perpetuates the signs and symptoms of post-traumatic stress disorder and suggests that focal unilateral amydalohippocampotomy can provide therapeutic benefit.

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