Social interaction modulates autonomic, inflammatory, and depressive-like responses to cardiac arrest and cardiopulmonary resuscitation

Abstract

Psychological factors, including depression and social isolation, are important determinants of cardiovascular health. The current study uses a well-validated mouse model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR) to examine the effect of social environment on several pathophysiological and behavioral responses to cerebral ischemia. Male experimental mice were either housed in pairs with an ovariectomized female or socially isolated for the duration of the experiment. Cardiac arrest increased the mRNA expression of the proinflammatory cytokines TNF-α, IL-1β, and IL-6, as well as the microglia marker MAC-1; expression of each of these factors, except IL-6, was further increased among socially isolated mice. Furthermore, socially isolated animals exposed to the CA/CPR procedure displayed significantly higher levels of neuronal cell death and microglia staining within the hippocampus at 7 d following surgery. Social isolation also exacerbated CA/CPR-induced depressive-like behavior and cardiac autonomic dysregulation. In the absence of ischemic damage, social environment had no significant effect on the expression of neuronal cell death, autonomic cardiac control, or behavior. Together, these data suggest that social factors influence the pathophysiological trajectory following cardiac arrest.

Cardiopulmonary Arrest and Resuscitation Disrupts Cholinergic Anti-Inflammatory Processes: A Role for Cholinergic α7 Nicotinic Receptors

“…Slides were then treated with potassium permanganate (0.06%) for 10 min, rinsed with water, and then incubated in Fluoro-Jade C (0.0001% in a 1% acetic acid solution); sections were rinsed in dH 2 O, and dried on a slide warmer and coverslipped with DPX (Sigma). Consistent with previous studies (Weil et al, 2008(Weil et al, , 2009Norman et al, 2010), Fluoro-Jade C-positive cells were counted in the hippocampus (CA1, CA2, CA3, and dentate gyrus). Images of fluorescently stained sections were captured with a digital camera (Axiocam, Zeiss) connected to a fluorescent microscope (Axioskop, Zeiss) using Axiovision software (Zeiss).…”

“…For the purposes of histological analysis, another cohort of animals survived for 7 d following either normothermic CA/CPR (n ϭ 10) or control surgeries (n ϭ 15). The control groups consisted of hypothermic CA/CPR (n ϭ 7) and sham (n ϭ 8) animals (see below, CA/CPR procedure, for detailed surgery description); consistent with previous reports (Neigh et al, 2004;Norman et al, 2010), the sham and hypothermic groups did not differ from one another on any of the dependent measures and were subsequently collapsed into a single control group for statistical comparisons. An additional 20 mice (control, n ϭ 10; normothermic CA/CPR, n ϭ 10) survived for 7 d following surgery for analysis of choline acetyltransferase (ChAT) enzymatic activity.…”

Social interaction modulates the neuroinflammatory response to global cerebral ischemia in male mice

“…Specifically, rodent experiments have demonstrated that the negative effects of social isolation on cerebral ischemia include an increased neuroinflammatory response, greater neuronal death, and impaired functional recovery (Craft, et al 2005; Weil, et al 2008; Norman, et al 2010a; Venna, et al 2012; Karelina, et al 2011). These detrimental effects are likely linked to increased ischemia-induced activation of microglia among socially isolated mice relative to socially integrated mice (Weil, et al 2008; Karelina, et al 2011).…”

“…Activated microglia can secrete pro-inflammatory cytokines and produce reactive oxygen species (Hanish, 2002; Block, et al 2007; Iadecola and Anrather, 2011). Specifically, following cerebral ischemia, gene expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and nuclear factor kappa b (Nfκb) are significantly upregulated, indicating a pro-inflammatory response (Schneider, et al 1999; Stephenson, et al 2000; Norman, et al 2010a; Doll, et al 2014). Generally, increased post-ischemic neuroinflammation is associated with increased cell death and worse neurological outcome (Wang and Shuaib, 2002; Weil, et al 2008; Neigh, et al 2009; Norman, et al 2010a; Stuller, et al 2012; Doll, et al 2014; Wang, et al 2015).…”

“…To date, all studies identifying social interaction as neuro-protective against ischemic damage were completed using in vivo models (Craft, et al 2005; Weil, et al 2008; Norman, et al 2010a; Venna, et al 2012; Venna, et al 2014; Verma, et al 2014). With the ex vivo OGD model one can determine whether the social environment prior to an ischemic event is sufficient to influence the post-ischemic inflammatory response.…”