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Translating Molecular and Neuroendocrine Findings in Posttraumatic Stress Disorder and Resilience to Novel Therapies.

ABSTRACT: Many biological systems are altered in association with posttraumatic stress disorder (PTSD) and resilience. However, there are only few approved pharmacological treatments for PTSD, and no approved medications to enhance resilience. This article provides a critical review of select neurobiological findings in PTSD and resilience, and also of pharmacologic approaches that have emerged from this work. The medications summarized involve engagement with targets in the adrenergic, hypothalamic-pituitary-adrenal axis, and neuropeptide Y systems. Other highlighted approaches involve the use of ketamine and 3,4-methylenedioxymethamphetamine-assisted psychotherapy, which recently surfaced as promising strategies for PTSD, though the neurobiological mechanisms underlying their actions, including for promoting resilience, are not yet fully understood. The former approaches fall within the broad concept of "rational pharmacotherapy," in that they attempt to directly target dysregulated systems known to be associated with posttraumatic symptoms. To the extent that use of ketamine and 3,4-methylenedioxymethamphetamine promotes symptom improvement and resilience in PTSD, this provides an opportunity for reverse translation and identification of relevant targets and mechanisms of action through careful study of biological changes resulting from these interventions. Promoting resilience in trauma-exposed individuals may involve more than pharmacologically manipulating dysregulated molecules and pathways associated with developing and sustaining PTSD symptom severity, but also producing a substantial change in mental state that increases the ability to engage with traumatic material in psychotherapy. Neurobiological examination in the context of treatment studies may yield novel targets and promote a greater understanding of mechanisms of recovery from trauma.

SUBMITTER: DePierro J

PROVIDER: S-EPMC6907400 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Translating Molecular and Neuroendocrine Findings in Posttraumatic Stress Disorder and Resilience to Novel Therapies.

DePierro Jonathan J Lepow Lauren L Feder Adriana A Yehuda Rachel R

Biological psychiatry 20190724 6

Many biological systems are altered in association with posttraumatic stress disorder (PTSD) and resilience. However, there are only few approved pharmacological treatments for PTSD, and no approved medications to enhance resilience. This article provides a critical review of select neurobiological findings in PTSD and resilience, and also of pharmacologic approaches that have emerged from this work. The medications summarized involve engagement with targets in the adrenergic, hypothalamic-pitui ...[more]

PMID: 31466562

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Project description:BackgroundThe limited neurobiological understanding of posttraumatic stress disorder (PTSD) has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible and stress-resilient subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies.MethodsWe employed a SEFL paradigm in inbred male and female C57BL/6 mice that combines acute stress with fear conditioning to precipitate traumatic-like memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence, and RNA sequencing of the basolateral amygdala.ResultsStressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced male subgroups with differential susceptibility that were identified without posttraining phenotyping. Additional phenotyping of male mice revealed PTSD-associated behaviors, including extinction-resistant fear memory, hyperarousal, generalization, and dysregulated corticosterone in stress-susceptible male mice. Altered Fos activation was also seen in the infralimbic cortex and basolateral amygdala of stress-susceptible male mice after remote memory retrieval. Key behavioral outcomes, including susceptibility, were replicated by two independent laboratories. RNA sequencing of the basolateral amygdala revealed transcriptional divergence between the male subgroups, including genes with reported polymorphic association to patients with PTSD.ConclusionsThis SEFL model provides a tool for development of PTSD therapeutics that is compatible with the growing number of mouse-specific resources. Furthermore, use of an inbred strain allows for investigation into epigenetic mechanisms that are expected to critically regulate susceptibility and resilience.

Project description:Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder that can result from experiencing traumatic events. Accurate diagnosis and optimal treatment strategies can be difficult to achieve, due to the heterogeneous etiology and symptomology of PTSD, and overlap with other psychiatric disorders. Advancing our understanding of PTSD pathophysiology is therefore critical. While functional connectivity alterations have shown promise for elucidating the neurobiological mechanisms of PTSD, previous findings have been inconsistent. Eleven patients with PTSD in our first cohort (PTSD-A) and 11 trauma-exposed controls (TEC) underwent functional magnetic resonance imaging. First, we investigated the intrinsic connectivity within known resting state networks (eg, default mode, salience, and central executive networks) previously implicated in functional abnormalities with PTSD symptoms. Second, the overall topology of network structure was compared between PTSD-A and TEC using graph theory. Finally, we used a novel combination of graph theory analysis and scaled subprofile modeling (SSM) to identify a disease-related, covarying pattern of brain network organization. No significant group differences were found in intrinsic connectivity of known resting state networks and graph theory metrics (clustering coefficients, characteristic path length, smallworldness, global and local efficiencies, and degree centrality). The graph theory/SSM analysis revealed a topographical pattern of altered degree centrality differentiating PTSD-A from TEC. This PTSD-related network pattern expression was additionally investigated in a separate cohort of 33 subjects who were scanned with a different MRI scanner (22 patients with PTSD or PTSD-B, and 11 healthy trauma-naïve controls or TNC). Across all participant groups, pattern expression scores were significantly lower in the TEC group, while PTSD-A, PTSD-B, and TNC subject profiles did not differ from each other. Expression level of the pattern was correlated with symptom severity in the PTSD-B group. This method offers potential in developing objective biomarkers associated with PTSD. Possible interpretations and clinical implications will be discussed.

Dataset Information

Translating Molecular and Neuroendocrine Findings in Posttraumatic Stress Disorder and Resilience to Novel Therapies.

Publications

Translating Molecular and Neuroendocrine Findings in Posttraumatic Stress Disorder and Resilience to Novel Therapies.

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