Chronic psychological stress during adolescence induces sex-dependent adulthood inflammation, increased adiposity, and abnormal behaviors that are ameliorated by selective inhibition of soluble tumor necrosis factor with XPro1595

Brain Behav Immun. 2019 Oct;81:305-316. doi: 10.1016/j.bbi.2019.06.027. Epub 2019 Jun 25.

Abstract

Physical and psychosocial maltreatment experienced before the age of 18, termed early life adversity (ELA), affects an estimated 39% of the world's population, and has long-term detrimental health and psychological outcomes. While adult phenotypes vary following ELA, inflammation and altered stress responsivity are pervasive. Cytokines, most notably tumor necrosis factor (TNF), are elevated in adults with a history of ELA. While soluble TNF (solTNF) drives chronic inflammatory disease, transmembrane TNF facilitates innate immunity. Here, we test whether solTNF mediates the behavioral and molecular outcomes of adolescent psychological stress by administering a brain permeable, selective inhibitor of solTNF, XPro1595. Male and female C57BL/6 mice were exposed to an aggressive rat through a perforated translucent ball ('predatory stress') or transported to an empty room for 30 min for 30 days starting on postnatal day 34. Mice were given XPro1595 or vehicle treatment across the last 15 days. Social interaction, sucrose preference, and plasma inflammation were measured at 2 and 4 weeks, and open field behavior, adiposity, and neuroinflammation were measured at 4 weeks. Chronic adolescent stress resulted in increased peripheral inflammation and dysregulated neuroinflammation in adulthood in a sex-specific manner. Abnormal social and open field behavior, fat pad weight, and fecal boli deposition were noted after 30 days; solTNF antagonism ameliorated the effects of stress. Together, these data support our hypothesis, and suggest that targeting solTNF with XPro1595 may improve quality of life for individuals with a history of adolescent stress.

Keywords: Adolescent; Sex differences; Sociability; Stress; TNF.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adiposity / drug effects
  • Adiposity / physiology
  • Adverse Childhood Experiences
  • Age Factors
  • Animals
  • Female
  • Inflammation / etiology
  • Inflammation / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Obesity / etiology
  • Obesity / physiopathology
  • Sex Factors
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / pathology
  • Stress, Psychological / psychology*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Tumor Necrosis Factor-alpha
  • XENP 1595