Differential Activation of Infiltrating Monocyte-Derived Cells After Mild and Severe Traumatic Brain Injury.

Microglia are the resident innate immune cells of the brain. Although embryologically and functionally distinct, they are morphologically similar to peripheral monocyte-derived cells, resulting in a poor ability to discriminate between the two cell types. The purpose of this study was to develop a rapid and reliable method to simultaneously characterize, quantify, and discriminate between whole populations of myeloid cells from the brain in a murine model of traumatic brain injury. Male C57BL/6 mice underwent traumatic brain injury (n = 16) or sham injury (n = 14). Brains were harvested at 24 h after injury. Multiparameter flow cytometry and sequential gating analysis were performed, allowing for discrimination between microglia and infiltrating leukocytes as well as for the characterization and quantification of individual subtypes within the infiltrating population. The proportion of infiltrating leukocytes within the brain increased with the severity of injury, and the predominant cell types within the infiltrating population were monocyte derived (P = 0.01). In addition, the severity of injury altered the overall makeup of the infiltrating monocyte-derived cells. In conclusion, we describe a flow cytometry-based technique for gross discrimination between infiltrating leukocytes and microglia as well as the ability to simultaneously characterize and quantify individual myeloid subtypes and their maturation states within these populations.

Disruption of social bonds induces behavioral and physiological dysregulation in male and female prairie voles.

The social disruption of losing a partner may have particularly strong adverse effects on psychological and physiological functioning. More specifically, social stressors may play a mediating role in the association between mood disorders and cardiovascular dysfunction. This study investigated the hypothesis that the disruption of established social bonds between male and female prairie voles would produce depressive behaviors and cardiac dysregulation, coupled with endocrine and autonomic nervous system dysfunction. In Experiment 1, behaviors related to depression, cardiac function, and autonomic nervous system regulation were monitored in male prairie voles during social bonding with a female partner, social isolation from the bonded partner, and a behavioral stressor. Social isolation produced depressive behaviors, increased heart rate, heart rhythm dysregulation, and autonomic imbalance characterized by increased sympathetic and decreased parasympathetic drive to the heart. In Experiment 2, behaviors related to depression and endocrine function were measured following social bonding and social isolation in both male and female prairie voles. Social isolation produced similar levels of depressive behaviors in both sexes, as well as significant elevations of adrenocorticotropic hormone and corticosterone. These alterations in behavioral and physiological functioning provide insight into the mechanisms by which social stressors negatively influence emotional and cardiovascular health in humans.

Traumatic brain injury-induced alterations in peripheral immunity.

BACKGROUND: The complex alterations that occur in peripheral immunity after traumatic brain injury (TBI) have been poorly characterized to date. The purpose of this study was to determine the temporal changes in the peripheral immune response after TBI in a murine model of closed head injury. METHODS: C57Bl/6 mice underwent closed head injury via a weight drop technique (n = 5) versus sham injury (n = 3) per time point. Blood, spleen, and thymus were collected, and immune phenotype, cytokine expression, and antibody production were determined via flow cytometry and multiplex immunoassays at 1, 3, 7, 14, 30, and 60 days after injury. RESULTS: TBI results in acute and chronic changes in both the innate and adaptive immune response. TBI resulted in a striking loss of thymocytes as early as 3 days after injury (2.1 × 10 TBI vs. 5.6 × 10 sham, p = 0.001). Similarly, blood monocyte counts were markedly diminished as early as 24 hours after TBI (372 per deciliter TBI vs. 1359 per deciliter sham, p = 0.002) and remained suppressed throughout the first month after injury. At 60 days after injury, monocytes were polarized toward an anti-inflammatory (M2) phenotype. TBI also resulted in diminished interleukin 12 expression from Day 14 after injury throughout the remainder of the observation period. CONCLUSION: TBI results in temporal changes in both the peripheral and the central immune systems culminating in an overall immune suppressed phenotype and anti-inflammatory milieu.

Peripheral oxytocin administration buffers autonomic but not behavioral responses to environmental stressors in isolated prairie voles.

Negative social experiences such as social stressors and isolation influence mental and physical illnesses, including affective disorders and heart disease. Studies focused on socially monogamous prairie voles can provide insight into neurobiological systems that underlie the consequences of negative social interactions. Female prairie voles were exposed to 28 days of social isolation or pairing with a female sibling (control). Voles were administered daily oxytocin [20 µg/50 µl, subcutaneous (sc)] or saline vehicle (50 µl, sc) for 14 days and exposed to two behavioral stressors [elevated plus maze (EPM) and resident-intruder test]. Brain tissue was collected for analysis of central peptide levels in the hypothalamic paraventricular nucleus (PVN). Isolation produced autonomic changes [increased heart rate (HR) and decreased HR variability) during both acute stressors and increased anxiety behaviors in the EPM. Oxytocin injection prevented the autonomic consequences of the acute stressors in isolated prairie voles, but did not affect the behaviors tested under the present conditions. Oxytocin had no effect on the behavioral or autonomic responsiveness in paired prairie voles. Oxytocin injection may exert a beneficial effect on autonomic responses to stressors in isolated animals through increasing the number of oxytocin-containing neurons and decreasing the number of corticotropin-releasing hormone-containing neurons in the PVN. Oxytocinergic mechanisms may serve to compensate for autonomic responses associated with chronic isolation and exposure to both social and non-social acute stressors.

Cardiac dysfunction and hypothalamic activation during a social crowding stressor in prairie voles.

Negative social interactions produce several detrimental consequences in humans and non-human animals; and conversely, positive social interactions may have stress-buffering effects on both behavior and physiology. However, the mechanisms underlying specific stressor-responsiveness in the context of the social environment are not well understood. The present study investigated the integration of behavior, cardiac function, and Fos-immunoreactivity in the hypothalamic paraventricular nucleus during an acute social stressor in female, socially monogamous prairie voles exposed to previous long-term pairing (control conditions) or isolation. Animals previously exposed to social isolation displayed increased heart rate, attenuated heart rate variability, and increased incidence of cardiac arrhythmias during an acute crowding stressor versus animals previously exposed to social pairing; these cardiac alterations were not secondary to behavioral changes during the crowding stressor. Furthermore, social isolation was associated with increased c-Fos-immunoreactivity in the hypothalamic paraventricular nucleus following the crowding stressor, versus social pairing. The prairie vole provides a useful model for understanding how the social environment contributes to changes in behavior, cardiac function, and central stress-regulatory processes in humans.

Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation.

Positive social interactions and social support may protect against various forms of mental and physical illness, although the mechanisms for these effects are not well identified. The socially monogamous prairie vole, which--like humans--forms social bonds and displays high levels of parasympathetic activity, has provided a useful model for investigating neurobiological systems that mediate the consequences of sociality. In the present study, adult female prairie voles were exposed to social isolation or continued pairing with a female sibling (control conditions) for 4 weeks. During weeks 3 and 4 of this period, animals were administered oxytocin (20 microg/50 microl, s.c.) or saline vehicle (50 microl, s.c.) daily for a total of 14 days. In Experiment 1, autonomic parameters were recorded during and following isolation or pairing. Isolation (vs. pairing) significantly increased basal heart rate (HR) and reduced HR variability and vagal regulation of the heart; these changes in isolated animals were prevented with oxytocin administration. In Experiment 2, behaviors relevant to depression [sucrose intake and swimming in the forced swim test (FST)] were measured as a function of isolation. Isolation reduced sucrose intake and increased immobility in the FST; these behaviors also were prevented by oxytocin. Administration of oxytocin did not significantly alter cardiac, autonomic or behavioral responses of paired animals. These findings support the hypothesis that oxytocinergic mechanisms can protect against behavioral and cardiac dysfunction in response to chronic social stressors, and can provide insight into social influences on behavior and autonomic function in humans.