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Citation |
Hassell JE, Fox JH, Arnold MR, Siebler PH, Lieb MW, Schmidt D, Spratt EJ, Smith TM, Nguyen KT, Gates CA, Holmes KS, Schnabel KS, Loupy KM, Erber M, Lowry CA. Brain Behav. Immun. 2019; ePub(ePub): ePub. |
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Affiliation |
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309-0354, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA; Department of Physical Medicine & Rehabilitation and Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Rocky Mountain Mental Illness Research Education and Clinical Center, Aurora, CO 80220, USA; Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE), Aurora, CO 80220, USA;. Electronic address: christopher.lowry@colorado.edu. |
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Copyright |
(Copyright © 2019, Elsevier Publishing) |
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DOI |
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PMID |
31175996 |
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Abstract |
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 vaccaeis a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has demonstrated to enhance fear extinction in the fear potentiated startle paradigm when given prior to fear conditioning. To determine if immunization withM. vaccaeafter 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 ofM. vaccaeNCTC 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 ofTph2,Htr1a,Slc6a4,Slc22a3, andCrhr2mRNA expression throughout the brainstem dorsal and median raphe nuclei. Immunization withM. vaccaedid not affect fear expression on day 1. However,M. vaccae-immunized rats showed enhanced between-session and within-session extinction beginning on day 2, relative to vehicle-immunized controls. Immunization withM. vaccaeand 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 withM. vaccae, have potential for both prevention and treatment of trauma- and stressor-related psychiatric disorders. Language: en |
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Keywords |
Dorsal raphe; Extinction; Fear-potentiated startle; Posttraumatic stress disorder; Serotonin |