Physical versus psychological social stress in male rats reveals distinct cardiovascular, inflammatory and behavioral consequences

<div><p>Repeated exposure to social stress can precipitate the development of psychosocial disorders including depression and comorbid cardiovascular disease. While a major component of social stress often encompasses physical interactions, purely psychological stressors (i.e. witnessing a traumatic event) also fall under the scope of social stress. The current study determined whether the acute stress response and susceptibility to stress-related consequences differed based on whether the stressor consisted of physical versus purely psychological social stress. Using a modified resident-intruder paradigm, male rats were either directly exposed to repeated social defeat stress (intruder) or witnessed a male rat being defeated. Cardiovascular parameters, behavioral anhedonia, and inflammatory cytokines in plasma and the stress-sensitive locus coeruleus were compared between intruder, witness, and control rats. Surprisingly intruders and witnesses exhibited nearly identical increases in mean arterial pressure and heart rate during acute and repeated stress exposures, yet only intruders exhibited stress-induced arrhythmias. Furthermore, re-exposure to the stress environment in the absence of the resident produced robust pressor and tachycardic responses in both stress conditions indicating the robust and enduring nature of social stress. In contrast, the long-term consequences of these stressors were distinct. Intruders were characterized by enhanced inflammatory sensitivity in plasma, while witnesses were characterized by the emergence of depressive-like anhedonia, transient increases in systolic blood pressure and plasma levels of tissue inhibitor of metalloproteinase. The current study highlights that while the acute cardiovascular responses to stress were identical between intruders and witnesses, these stressors produced distinct differences in the enduring consequences to stress, suggesting that witness stress may be more likely to produce long-term cardiovascular dysfunction and comorbid behavioral anhedonia while exposure to physical stressors may bias the system towards sensitivity to inflammatory disorders.</p></div

Inflammatory-related protein concentrations in the LC and plasma in response to contextual re-exposure.

<p>Inflammatory-related protein concentrations in the LC and plasma in response to contextual re-exposure.</p

Study design and timeline.

<p>Rats were implanted with cardiovascular (CV) radio-telemetric transmitters 10 days prior (D -10) to the start of stress manipulation. Baseline CV measurements were collected for 2 days (D -2—D 0) prior to the start of the daily control, defeat, or witness stress exposure and continued for 3 days post stress/control. Sucrose preference tests were administered 2 days prior to (D -1) and 5 after (D 10) stress manipulations to determine changes in hedonic behavior. On the day of sacrifice (D 11) all rats were exposed to a 15-minute contextual re-exposure.</p

The long-term changes in resting blood pressure and heart rate induced by social stress exposure.

<p>Dark cycle systolic pressure increased across the duration of the study (A). This effect was moderately enhanced in witness rats on days 4 and 6 compared to control and intruder rats, respectively. Conversely, heart rate (HR) measured during the dark cycle was significantly reduced in intruder rats across the duration of the study, compared to both witness and control animals (B). *p<0.05 witness vs. intruder; ^#p<0.05 witness vs. control; ^αp<0.05 control vs. intruder.</p

The effect of contextual re-exposure on plasma cytokine levels of control, intruder, and witness stressed rats.

<p>Intruder rats exhibit greater proinflammatory IL-1β (A), IL-13 (B), TNF-α (C), and anti-inflammatory IL-10 (D) in response to contextual re-exposure 6 days after the final stress exposure compared to both witnesses and control rats. *p<0.05, **p<0.01, ***p<0.001 intruders vs. controls and witnesses.</p

Stress-related behavioral and physiological effects of control, witness, and social defeat exposure.

<p>Stress-related behavioral and physiological effects of control, witness, and social defeat exposure.</p

Cardiovascular and epinephrine responses to contextual re-exposure.

<p>Contextual re-exposure 6 days after the fifth and final social stress or control exposure produces robust increases in mean arterial pressure (MAP; A) and heart rate (HR; B) in both intruder and witness rats (^αp<0.0001 control vs. intruders and witnesses across exposure). Interestingly, intruder rats had a more robust hemodynamic response to being placed in a resident’s empty cage compared with witnesses (^βp<0.0001 witnesses vs. intruders across exposure) and the tachycardic response was more prolonged than in witness stressed rats (^#p<0.05 witness vs. intruders). However, HPLC analysis of plasma indicates that both intruders and witnesses exhibit enhanced circulating epinephrine during this re-exposure (C). Surprisingly, this robust increase in MAP and HR was not associated with an increase in the number of premature ventricular contractions (D) that occurred during the first 5 minutes. *p<0.05, **p<0.01 vs. controls.</p

The effect of social defeat and witness stress on Premature Ventricular Contractions (PVCs).

<p>Social defeat stress exposure on days 1 and 5 produced an increased incidence of PVCs in intruder rats compared with both control and witness exposure (A). PVCs were determined by analyzing electrical activity within the ECG trace and the corresponding blood pressure traces (B). *p<0.05 vs. control+witness rats; ^ƒp = 0.053 vs. control.</p

Hemodynamic and tachycardic response to social defeat and witness stress on the first and fifth exposure to stress.

<p>Physical interaction with the resident in the form of social defeat (intruder) and witnessing such an interaction produced nearly identical increases in mean arterial pressure (MAP) on days 1 (A) and 5 (B) of stress exposure above that of controls. Similarly, the heart rate (HR) response was also equally elevated in intruder and witness groups on days 1 (C) and 5 (D) of stress, significantly above that of controls. Upon being returned to their home cage, MAP and HR exhibited a time dependent decreases during the 30-minute home cage recovery period. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 intruders/witnesses vs. controls; There were two instances during the home cage recovery where the cardiovascular response in witnesses recovered more quickly than intruders (^#p<0.05 witnesses vs. intruders).</p