Project Title

Behavioral Effects and Neurobiological Mechanisms of 3-Aminobenzimide in a Rodent Model of Chronic Psychological Stress

Authors' Affiliations

Liza J Wills, Ph.D., Department of Biomedical Sciences, College of Medicine, East Tennessee State University, Johnson City, TN Hui Wang-Heaton, Ph.D., Department of Biomedical Sciences, College of Medicine, East Tennessee State University, Johnson City, TN Michelle Chandley, Ph.D., , Department of Biomedical Sciences, College of Medicine, East Tennessee State University, Johnson City, TN Loren D. Peeters, B.A. , Department of Biomedical Sciences, College of Medicine, East Tennessee State University, Johnson City, TN Gregory A. Ordway, Ph.D., Department of Biomedical Sciences, College of Medicine, East Tennessee State University, Johnson City, TN Russell W. Brown, Ph.D., Department of Biomedical Sciences, College of Medicine, East Tennessee State University, Johnson City, TN

Location

Culp Ballroom

Start Date

4-7-2022 9:00 AM

End Date

4-7-2022 12:00 PM

Poster Number

16

Faculty Sponsor’s Department

Biomedical Sciences

Name of Project's Faculty Sponsor

Russell Brown

Classification of First Author

Post-doctoral Fellow

Competition Type

Competitive

Type

Poster Presentation

Project's Category

Stress, Inflammation

Abstract or Artist's Statement

Major depressive disorder (MDD) is a leading cause of disability worldwide, with a lifetime prevalence rate of approximately 20%. Inadequate pharmacological treatment methods for MDD are a significant debilitating factor. Patient estimates suggest that the treatment resistance rate for pharmacological interventions is over 30%. Postmortem analyses of human tissue of individuals diagnosed with MDD have shown an increase in Poly (ADP-ribose) polymerase 1 (PARP-1) mRNA gene expression in prefrontal cortical white matter when compared to psychiatrically normal brain tissue. In order to further investigate this issue, the present study used the social defeat stress/chronic unpredictable stress (SDS + CUS) rodent model of depression to induce a state of chronic psychological distress. Rats were treated with either the PARP-inhibitor, 3- aminobenzamide (3-AB); a common selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), or saline. During the stress manipulation we conducted the sucrose preference test, results revealed that saline-treated rats which had undergone SDS + CUS showed significant reductions in sucrose preference compared to all other groups. In addition, a social interaction test was conducted one day after the stress manipulation, and saline-treated stressed animals demonstrated less social interaction compared to all other groups, indicating the stress manipulation was effective. Neurobiological assays were conducted to examine PARP expression, microglial morphology, and proinflammatory cytokine expression. Though we expected to find a decrease, results from immunofluorescence studies of tissue sections revealed an elevation of PARP-1 protein expression in prefrontal cortical gray matter in the FLX/Stress group compared with SAL/Stress group. Microglial morphological changes indicated that the SAL/Stress group had significantly more prolate microglia when compared to all other treatment groups, suggesting early activation of microglia, an indicator of neuroinflammation. Increases in IL-1β and TNF-⍺ expression was observed in the hippocampus of the SAL/Stress group when compared to all other treatment groups. Interestingly, IL-6 expression was significantly elevated in the SAL/Stress group when compared to the FLX/Stress group and theCTRL/No stress group but did not significantly differ from the 3-AB/Stress group. This study revealed therapeutic potential of 3-AB for the treatment of stress-related disorders, as well as the neuroinflammatory mechanisms associated with chronic stress.

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Apr 7th, 9:00 AM Apr 7th, 12:00 PM

Behavioral Effects and Neurobiological Mechanisms of 3-Aminobenzimide in a Rodent Model of Chronic Psychological Stress

Culp Ballroom

Major depressive disorder (MDD) is a leading cause of disability worldwide, with a lifetime prevalence rate of approximately 20%. Inadequate pharmacological treatment methods for MDD are a significant debilitating factor. Patient estimates suggest that the treatment resistance rate for pharmacological interventions is over 30%. Postmortem analyses of human tissue of individuals diagnosed with MDD have shown an increase in Poly (ADP-ribose) polymerase 1 (PARP-1) mRNA gene expression in prefrontal cortical white matter when compared to psychiatrically normal brain tissue. In order to further investigate this issue, the present study used the social defeat stress/chronic unpredictable stress (SDS + CUS) rodent model of depression to induce a state of chronic psychological distress. Rats were treated with either the PARP-inhibitor, 3- aminobenzamide (3-AB); a common selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), or saline. During the stress manipulation we conducted the sucrose preference test, results revealed that saline-treated rats which had undergone SDS + CUS showed significant reductions in sucrose preference compared to all other groups. In addition, a social interaction test was conducted one day after the stress manipulation, and saline-treated stressed animals demonstrated less social interaction compared to all other groups, indicating the stress manipulation was effective. Neurobiological assays were conducted to examine PARP expression, microglial morphology, and proinflammatory cytokine expression. Though we expected to find a decrease, results from immunofluorescence studies of tissue sections revealed an elevation of PARP-1 protein expression in prefrontal cortical gray matter in the FLX/Stress group compared with SAL/Stress group. Microglial morphological changes indicated that the SAL/Stress group had significantly more prolate microglia when compared to all other treatment groups, suggesting early activation of microglia, an indicator of neuroinflammation. Increases in IL-1β and TNF-⍺ expression was observed in the hippocampus of the SAL/Stress group when compared to all other treatment groups. Interestingly, IL-6 expression was significantly elevated in the SAL/Stress group when compared to the FLX/Stress group and theCTRL/No stress group but did not significantly differ from the 3-AB/Stress group. This study revealed therapeutic potential of 3-AB for the treatment of stress-related disorders, as well as the neuroinflammatory mechanisms associated with chronic stress.