A primary current focus in the study of depression is the means by which attachment disruption in childhood and other forms of early adversity increase vulnerability for developing major depressive disorder in later life. The mechanism for this effect remains obscure but is thought to involve sensitization of stress-related processes. A second recent emphasis in depression research has been the role of proinflammatory factors in mediating depressive symptoms. Research proposed here uses a guinea pig model to examine the possibility that proinflammatory activity induced by the stressor of maternal separation mediates a prolonged sensitization of depressive-like behavior. Guinea pigs exhibit a specific attachment process, display a depressive-like behavioral response to maternal separation that is mediated by proinflammatory activity, and show a sensitization of depressive-like behavior upon repeated separation that is accompanied by a sensitized core temperature response. Work proposed here will first determine if a prolonged (9 day) sensitization identified during the last funding period is mediated by a sensitization of proinflammatory activity (either enhanced proinflammatory response or increased sensitivity to a proinflammatory response (Aim 1). This will be done by attempting to block sensitization of depressive-like behavior and core temperature increase with anti-inflammatory agents (Interleukin-10 and indomethacin) and by determining whether prior separation increases the central cytokine and/or behavioral response to later immune challenge. Next, we will assess whether the sensitized behavioral response reflects sensitization of a broader underlying depressive-like state mediated by proinflammatory activity (Aim 2). This will be accomplished by determining if early separation enhances responsiveness in a validated behavioral test of depressive-like behavior (forced swim) that is independent of the initial inducing agent (separation), and whether the forced swim effect can be reversed by an anti-inflammatory compound.

Public Health Relevance

While it has become increasingly clear that childhood stressors such as abuse, neglect, and separation from attachment figures increase vulnerability for developing major depressive disorder in later life, the processes by which this occurs remain unknown. This proposal tests the hypothesis that a contributing factor is a sensitization of stress-induced increases in inflammatory processes in the brain. Further, the proposed research provides an initial test of a simple prophylactic procedure that might mitigate the effects of earl stress.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-BBBP-J (92))
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Desmond, Nancy L
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Wright State University
Schools of Arts and Sciences
United States
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Hennessy, Michael B; Kaiser, Sylvia; Tiedtke, Tobias et al. (2015) Stability and change: Stress responses and the shaping of behavioral phenotypes over the life span. Front Zool 12 Suppl 1:S18
Hennessy, Michael B; Stafford, Nathan P; Yusko-Osborne, Brittany et al. (2015) Naproxen attenuates sensitization of depressive-like behavior and fever during maternal separation. Physiol Behav 139:34-40
Hennessy, Michael B (2014) Filial attachment and its disruption: insights from the guinea pig. Dev Psychobiol 56:1747-54
Hennessy, Michael B; Deak, Terrence; Schiml, Patricia A (2014) Sociality and sickness: have cytokines evolved to serve social functions beyond times of pathogen exposure? Brain Behav Immun 37:15-20
Hennessy, Michael B; Jacobs, Sarah; Schiml, Patricia A et al. (2013) Maternal inhibition of infant behavioral response following isolation in novel surroundings and inflammatory challenge. Dev Psychobiol 55:395-403
Yusko, Brittany; Hawk, Kiel; Schiml, Patricia A et al. (2012) Sensitization of depressive-like behavior during repeated maternal separation is associated with more-rapid increase in core body temperature and reduced plasma cortisol levels. Physiol Behav 105:861-7
Schneider, Randi L; Schiml, Patricia A; Deak, Terrence et al. (2012) Persistent sensitization of depressive-like behavior and thermogenic response during maternal separation in pre- and post-weaning guinea pigs. Dev Psychobiol 54:514-22
Hennessy, Michael B; Fitch, Christopher; Jacobs, Sarah et al. (2011) Behavioral effects of peripheral corticotropin-releasing factor during maternal separation may be mediated by proinflammatory activity. Psychoneuroendocrinology 36:996-1004
Hennessy, Michael B; Paik, Kristopher D; Caraway, Jessica D et al. (2011) Proinflammatory activity and the sensitization of depressive-like behavior during maternal separation. Behav Neurosci 125:426-33
Hennessy, Michael B; Deak, Terrence; Schiml-Webb, Patricia A et al. (2010) Maternal separation produces, and a second separation enhances, core temperature and passive behavioral responses in guinea pig pups. Physiol Behav 100:305-10

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