Erica R. Glasper

Social modulation of stress responses.

Social interactions can profoundly affect the hypothalamic-pituitary-adrenal (HPA) axis. Although most research on social modulation of glucocorticoid concentrations has focused on the consequences of exposure to stressful social stimuli, there is a growing body of literature which suggests that social support in humans and affiliative behaviors in some animals can provide a buffer against stress and have a positive impact on measures of health and well-being. This review will compare HPA axis activity among individuals for whom social relationships are maintained through aggressive displays, such as dominance hierarchies, vs. individuals engaging in high levels of prosocial behavior. We also will examine oxytocin, a neuropeptide that is well known for promoting social behavior, as the physiological link between positive social interactions and suppression of the HPA axis. Despite many examples of social interaction modulating the HPA axis and improving health outcomes, there is relatively little known regarding the underlying mechanisms through which social behavior can provide a buffer against stress-related disease.

Social facilitation of wound healing

It is well documented that psychological stress impairs wound healing in humans and rodents. However, most research effort into influences on wound healing has focused on factors that compromise, rather than promote, healing. In the present study, we determined if positive social interaction, which influences hypothalamic-pituitary-adrenal (HPA) axis activity in social rodents, promotes wound healing. Siberian hamsters received a cutaneous wound and then were exposed to immobilization stress. Stress increased cortisol concentrations and impaired wound healing in isolated, but not socially housed, hamsters. Removal of endogenous cortisol via adrenalectomy eliminated the effects of stress on wound healing in isolated hamsters. Treatment of isolated hamsters with oxytocin (OT), a hormone released during social contact and associated with social bonding, also blocked stress-induced increases in cortisol concentrations and facilitated wound healing. In contrast, treating socially housed hamsters with an OT antagonist delayed wound healing. Taken together, these data suggest that social interactions buffer against stress and promote wound healing through a mechanism that involves OT-induced suppression of the HPA axis. The data imply that social isolation impairs wound healing, whereas OT treatment may ameliorate some effects of social isolation on health.

Sexual Experience Promotes Adult Neurogenesis in the Hippocampus Despite an Initial Elevation in Stress Hormones

Aversive stressful experiences are typically associated with increased anxiety and a predisposition to develop mood disorders. Negative stress also suppresses adult neurogenesis and restricts dendritic architecture in the hippocampus, a brain region associated with anxiety regulation. The effects of aversive stress on hippocampal structure and function have been linked to stress-induced elevations in glucocorticoids. Normalizing corticosterone levels prevents some of the deleterious consequences of stress, including increased anxiety and suppressed structural plasticity in the hippocampus. Here we examined whether a rewarding stressor, namely sexual experience, also adversely affects hippocampal structure and function in adult rats. Adult male rats were exposed to a sexually-receptive female once (acute) or once daily for 14 consecutive days (chronic) and levels of circulating glucocorticoids were measured. Separate cohorts of sexually experienced rats were injected with the thymidine analog bromodeoxyuridine in order to measure cell proliferation and neurogenesis in the hippocampus. In addition, brains were processed using Golgi impregnation to assess the effects of sexual experience on dendritic spines and dendritic complexity in the hippocampus. Finally, to evaluate whether sexual experience alters hippocampal function, rats were tested on two tests of anxiety-like behavior: novelty suppressed feeding and the elevated plus maze. We found that acute sexual experience increased circulating corticosterone levels and the number of new neurons in the hippocampus. Chronic sexual experience no longer produced an increase in corticosterone levels but continued to promote adult neurogenesis and stimulate the growth of dendritic spines and dendritic architecture. Chronic sexual experience also reduced anxiety-like behavior. These findings suggest that a rewarding experience not only buffers against the deleterious actions of early elevated glucocorticoids but actually promotes neuronal growth and reduces anxiety.

2006 Curt P. Richter award winner: Social influences on stress responses and health.

Both positive and negative social interactions can modulate the hypothalamic-pituitary-adrenal (HPA) axis and influence recovery from injuries and illnesses, such as wounds, stroke, and cardiac arrest. Stress exacerbates neuronal death following stroke and cardiac arrest, and delays cutaneous wound healing, via a common mechanism involving stress-induced increases in corticosterone, acting on glucocorticoid receptors. In contrast, hamsters and mice that form social bonds are buffered against stress and heal cutaneous wounds more quickly than socially isolated animals, presumably because the physical contact experienced by the pairs releases oxytocin, which in turn suppresses the HPA axis and facilitates wound healing. Social housing also decreases stroke-induced neuronal death and improves functional recovery, but the mechanism appears to involve suppressing the inflammatory response that accompanies stroke, rather than alterations in HPA axis activity. An interaction between the HPA axis and immune system determines stroke outcome in neonatally manipulated mice that exhibit life-long dampening of the HPA axis. Taken together, these studies provide support for the detrimental effects of stress and identify potential mechanisms underlying the well-documented clinical observation that social support positively influences human health.

Maternal experience produces long-lasting behavioral modifications in the rat

From 5 to 22 months of age, cognitive and emotional responses of nulliparous, primiparous, and multiparous rats were assessed using a dry land maze (DLM) and an elevated plus-maze (EPM) at 4-month intervals. Parous rats exhibited improved spatial memory in the probe and competitive versions of the DLM, and more exploration in the EPM and a novel stimulus test relative to nulliparous females. The nulliparous females, however, outperformed parous rats during the DLM visual cue test at 17 months of age. At 23 months, no differences in stressed corticosterone levels or Golgi-stained hippocampal neurons were observed. Thus, cognitive and emotional modifications were observed in parous rats; the neurobiological mechanisms for these enduring effects, however, remain to be identified.

Social structure influences effects of pair-housing on wound healing

Chronic stress or noxious stimuli delay wound healing in humans and rodents. The effects of stress on wound healing appear to be mediated by the hypothalamic-pituitary-adrenal (HPA) axis and, in particular, increases in corticosteroids. As previously shown, positive social interaction faciltiates wound healing through suppression of corticosteroids. In the present study, we investigated the effects of pair-housing on wound healing and corticosteroid concentrations in three mouse species, the monogamous Peromyscus californicus, the facultative-monogamous Peromyscus eremicus, and the polygynous Peromyscus leucopus. Pair-housed P. californicus and P. eremicus had significantly smaller wounds than socially isolated cohorts. However, wound healing in P. leucopus was not affected by housing condition. P. californicus and P. eremicus mice that were pair-housed for 2 weeks, then separated from their partners 48h prior to wounding also had wounds comparable to socially isolated mice. The benefits of social housing diminished when P. californicus and P. eremicus pairs were prevented from interacting physically via a double screen barrier. Two hours of daily restraint did not affect basal corticosterone concentrations or wound healing in either P. californicus or P. eremicus. In contrast, restraint facilitated wound healing in P. leucopus. Taken together, these data suggest that social contact facilitates wound healing in two monogamous, but not a polygynous, mouse species.

Parenting and plasticity

As any new parent knows, having a baby provides opportunities for enrichment, learning and stress - experiences known to change the adult brain. Yet surprisingly little is known about the effects of maternal experience, and even less about the effects of paternal experience, on neural circuitry not directly involved in parenting. Here we discuss how caregiving and the accompanying experiential and hormonal changes influence the hippocampus and prefrontal cortex, brain regions involved in cognition and mood regulation. A better understanding of how parenting impacts the brain is likely to help in devising strategies for treating parental depression, a condition that can have serious cognitive and mental health consequences for children.

Thymidine analog methods for studies of adult neurogenesis are not equally sensitive.

Adult neurogenesis is often studied by labeling new cells with the thymidine analog bromodeoxyuridine (BrdU) and using immunohistochemical methods for their visualization. Using this approach, considerable variability has been reported in the number of new cells produced in the dentate gyrus of adult rodents. We examined whether immunohistochemical methods, including BrdU antibodies from different vendors (Vector, BD, Roche, Dako, Novocastra, and Accurate) and DNA denaturation pretreatments alter the quantitative and qualitative patterns of BrdU labeling. We also compared the sensitivity and specificity of BrdU with two other thymidine analogs, iododeoxyuridine (IdU) and chlorodeoxyuridine (CldU). We found that the number of BrdU‐labeled cells in the dentate gyrus of adult rats was dependent on the BrdU antibody used but was unrelated to differences in antibody penetration. Even at a higher concentration, some antibodies (Vector and Novocastra) stained fewer cells. A sensitive BrdU antibody (BD) was specific for dividing cells; all BrdU‐labeled cells stained for Ki67, an endogenous marker of cell proliferation. We also observed that DNA denaturation pretreatments affected the number of BrdU‐labeled cells and staining intensity for a marker of neuronal differentiation, NeuN. Finally, we found that IdU and CldU, when used at molarities comparable to those that label the maximal number of cells with BrdU, are less sensitive. These data suggest that antibody and thymidine analog selection, as well as the staining procedure employed, can affect the number of newly generated neurons detected in the adult brain, thus providing a potential explanation for some of the variability in the adult neurogenesis literature. J. Comp. Neurol. 517:123–133, 2009.

Social Interaction Improves Experimental Stroke Outcome

Background and Purpose— Social interaction can have a profound effect on health. The purpose of the present study was to determine whether affiliative social interactions before and after stroke improve ischemic outcomes as assessed through histological analysis and behavioral assays. Methods— Male and female C57BL/6 mice were housed individually or with an ovariectomized female. Behavioral assessments were made 24 hours before 60 or 90 minutes of transient intraluminal middle cerebral artery occlusion (MCAO) or SHAM surgery and after 7 days of reperfusion. Two hours after behavioral testing on day 7, infarct size was determined by 2,3,5-triphenyltetrazolium histology, and blood samples were collected for assessment of corticosterone and C-reactive protein (CRP) concentrations. Results— Pair housing significantly decreased infarct size and improved contralateral paw use in 60-minute MCAO males and 90-minute MCAO females compared with socially isolated cohorts. Housing condition had no significant effect on infarct size in females that underwent 60 minutes of MCAO, but pair housing was associated with improved contralateral paw use relative to socially isolated mice. In a separate cohort of males, intraischemic CRP concentration was significantly reduced in pair-housed males relative to isolated males. Conclusions— Affiliative interaction during the peri-ischemic period reduces intraischemic CRP concentration, decreases ischemic damage in male and female mice, and improves behavioral outcome.

CRMP3 is required for hippocampal CA1 dendritic organization and plasticity

In vitro studies have pointed to the collapsin response mediator proteins (CRMPs) as key regulators of neurite outgrowth and axonal differentiation. CRMP3 is expressed mostly in the nervous system during development but remains at high levels in the hippocampus of adults. To explore CRMP3 function in vivo, we generated mice with targeted disruption of the CRMP3 gene. Immunohistochemistry and Golgi staining of CA1 showed abnormal dendrite and spine morphogenesis in the hippocampus of CRMP3‐deficient mice. Apical dendrites displayed an increase in undulation and a reduction in length and branching points. Basal dendrites also exhibited a reduction in length with an alteration in soma stem distribution and an increased number of thick dendrites localized in stratum oriens (SO). Long‐term potentiation (LTP) was impaired in this area. These data indicate an important role for CRMP3 in dendrite arborization, guide‐posts navigation, and neuronal plasticity.—Quach, T. T., Massicotte, G., Belin, M. F., Honnorat, J., Glasper, E. R., Devries, A. C., Jakeman, L. B., Baudry, M., Duchemin, A. M., Kolattukudy, P. E. CRMP3 is required for hippocampal CA1 dendritic organization and plasticity. FASEB J. 22, 401–409 (2008)