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Fear-potentiated startle response as an endophenotype: Evaluating metrics and methods for genetic applications.

ABSTRACT: The modulation of the startle response (SR) by threatening stimuli (fear-potentiated startle; FPS) is a proposed endophenotype for disorders of the fearful-fearlessness spectrum. FPS has failed to show evidence of heritability, raising concerns. However, metrics used to index FPS-and, importantly, other conditional phenotypes that are dependent on a baseline-may not be suitable for the approaches used in genetic epidemiology studies. Here, we evaluated multiple metrics of FPS in a population-based sample of preadolescent twins (N = 569 from 320 twin pairs, Mage = 11.4) who completed a fear-conditioning paradigm with airpuff-elicited SR on two occasions (~1 month apart). We applied univariate and multivariate biometric modeling to estimate the heritability of FPS using several proposed standardization procedures. This was extended with data simulations to evaluate biases in heritability estimates of FPS (and similar metrics) under various scenarios. Consistent with previous studies, results indicated moderate test-retest reliability (r = 0.59) and heritability of the overall SR (h2 = 34%) but poor reliability and virtually no unique genetic influences on FPS when considering a raw or standardized differential score that removes baseline SR. Simulations demonstrated that the use of differential scores introduces bias in heritability estimates relative to jointly analyzing baseline SR and FPS in a multivariate model. However, strong dependency of FPS on baseline levels makes unique genetic influences virtually impossible to detect regardless of methodology. These findings indicate that FPS and other conditional phenotypes may not be well suited to serve as endophenotypes unless such codependency can be disentangled.

SUBMITTER: Savage JE

PROVIDER: S-EPMC6454577 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Fear-potentiated startle response as an endophenotype: Evaluating metrics and methods for genetic applications.

Savage Jeanne E JE Moore Ashlee A AA Sawyers Chelsea K CK Bourdon Jessica L JL Verhulst Brad B Carney Dever M DM Moroney Elizabeth E Machlin Laura L Kaabi Oumaima O Vrana Scott S Grillon Christian C Brotman Melissa A MA Leibenluft Ellen E Pine Daniel S DS Roberson-Nay Roxann R Hettema John M JM

Psychophysiology 20190104 5

The modulation of the startle response (SR) by threatening stimuli (fear-potentiated startle; FPS) is a proposed endophenotype for disorders of the fearful-fearlessness spectrum. FPS has failed to show evidence of heritability, raising concerns. However, metrics used to index FPS-and, importantly, other conditional phenotypes that are dependent on a baseline-may not be suitable for the approaches used in genetic epidemiology studies. Here, we evaluated multiple metrics of FPS in a population-bas ...[more]

PMID: 30613993

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Project description:The hygiene hypothesis or "Old Friends" hypothesis proposes that inflammatory diseases are increasing in modern urban societies, due in part to reduced exposure to microorganisms that drive immunoregulatory circuits and a failure to terminate inappropriate inflammatory responses. Inappropriate inflammation is also emerging as a risk factor for anxiety disorders, affective disorders, and trauma-and stressor-related disorders, including posttraumatic stress disorder (PTSD), which is characterized as persistent re-experiencing of the trauma after a traumatic experience. Traumatic experiences can lead to long-lasting fear memories and fear potentiation of the acoustic startle reflex. The acoustic startle reflex is an ethologically relevant reflex and can be potentiated in both humans and rats through Pavlovian conditioning. Mycobacterium vaccae is a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has been demonstrated to enhance fear extinction in the fear-potentiated startle paradigm when given prior to fear conditioning. To determine if immunization with M. vaccae after fear conditioning also has protective effects, adult male Sprague Dawley rats underwent fear conditioning on days -37 and -36 followed by immunizations (3x), once per week beginning 24 h following fear conditioning, with a heat-killed preparation of M. vaccae NCTC 11659 (0.1 mg, s.c., in 100 µl borate-buffered saline) or vehicle, and, then, 3 weeks following the final immunization, were tested in the fear-potentiated startle paradigm (n = 12 per group). Rats underwent fear extinction training on days 1 through 6 followed by spontaneous recovery 14 days later (day 20). Rats were euthanized on day 21 and brain tissue was sectioned for analysis of Tph2, Htr1a, Slc6a4, Slc22a3, and Crhr2 mRNA expression throughout the brainstem dorsal and median raphe nuclei. Immunization with M. vaccae did not affect fear expression on day 1. However, M. vaccae-immunized rats showed enhanced enhanced within-session fear extinction on day 1 and enhanced between-session fear extinction beginning on day 2, relative to vehicle-immunized controls. Immunization with M. vaccae and fear-potentiated startle had minimal effects on serotonergic gene expression when assessed 42 days after the final immunization. Together with previous studies, these data are consistent with the hypothesis that immunoregulatory strategies, such as immunization with M. vaccae, have potential for both prevention and treatment of trauma- and stressor-related psychiatric disorders.

Dataset Information

Fear-potentiated startle response as an endophenotype: Evaluating metrics and methods for genetic applications.

Publications

Fear-potentiated startle response as an endophenotype: Evaluating metrics and methods for genetic applications.

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