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Neuronal-Glial Mechanisms of Exercise-Evoked Stress Robustness
Abstract and Figures
Stress robustness by definition, incorporates both stress resistance stress resistance (organisms endure greater stressor intensity or duration before suffering negative consequences) and stress resilience (organisms recover faster after suffering negative consequences). Factors that influence stress robustness include the nature of the stressor, (i.e., controllability, intensity, chronicity) and features of the organism (i.e., age, genetics, sex, and physical activity status). Here we present a novel hypothesis for how physically active versus sedentary living promotes stress robustness in the face of intense uncontrollable stress. Advances in neurobiology have established microglia microglia as an active player in the regulation of synaptic activity, and recent work has revealed mechanisms for modulating glial function, including cross talk between neurons and glia. This chapter presents supporting evidence that the physical activity status of an organism may modulate stress-evoked neuronal-glial responses by changing the CX3CL1-CX3CR1 axis. Specifically, we propose that sedentary animals respond to an intense acute uncontrollable stressor with excessive serotonin (5-HT) and noradrenergic (NE) activity and/or prolonged down-regulation of the CX3CL1-CX3CR1 axis resulting in activation and proliferation of hippocampal microglia microglia in the absence of pathogenic signals and consequent hippocampal-dependent memory deficits and reduced neurogenesis. In contrast, physically active animals respond to the same stressor with constrained 5-HT and NE activity and rapidly recovering CX3CL1-CX3CR1 axis responses resulting in the quieting of microglia, and protection from negative cognitive and neurobiological effects of stress.
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... Physical exercise triggers communications between microglia and neurons through microglial activation, neural regeneration and cytokine secretion. For instance, CD200-CD200R, ATP, and CX3CL1-CX3CL1R interaction pathways are shown to be enhanced by exercise [70,71]. ...
... Interactions between microglia and neurons play an important role in many neurological disorders with altered neural network excitability [127]. Advanced understanding in the neurobiology field has revealed active roles of microglia in modulating neuron activities, glial function, the crosstalk between neurons and microglia [70]. Anti-inflammatory microglia are found to enhance neuronal growth, suggesting microglia's concomitant growth-promoting properties [63]. ...
... Physical exercise is believed to improve the cognitive function and neuroplasticity through the CX3CL1-CX3CR1 signal mediated by microglia [130]. Studies address that physical exercise could modulate stress-evoked neuronalmicroglial responses by altering the CX3CL1-CX3CR1 axis, which results in activation and proliferation of microglia and neuroplasticity [70]. These findings suggest that exercise-induced microglial-neuron communications somehow depend on the CX3CL1-CX3CR1 axis (Fig. 4). ...
Physical exercise is an effective therapy for neurorehabilitation. Exercise has been shown to induce remodeling and proliferation of astrocyte. Astrocytes potentially affect the recruitment and function of neurons; they could intensify responses of neurons and bring more neurons for the process of neuroplasticity. Interactions between astrocytes, microglia and neurons modulate neuroplasticity and, subsequently, neural circuit function. These cellular interactions promote the number and function of synapses, neurogenesis, and cerebrovascular remodeling. However, the roles and crosstalk of astrocytes with neurons and microglia and any subsequent neuroplastic effects have not been studied extensively in exercise-induced settings. This article discusses the impact of physical exercise on astrocyte proliferation and highlights the interplay between astrocytes, microglia and neurons. The crosstalk between these cells may enhance neuroplasticity, leading to the neuroplastic effects of exercise.
... Physical exercise also mediates the crosstalk between microglia and astrocytes/neurons to enhance neuroplasticity. For example, the CX3CL1-CX3CL1R axis and the CD200-CD200R axis were more responsive to the same stimulus in the exercised animals than in the sedentary animals (Sung et al., 2012;Fleshner et al., 2014). The molecular mechanisms involved in the crosstalk between astrocytes/neurons and microglia have been elaborated on in recent reviews . ...
... Physical exercise is reported to ameliorate cognitive function and neuroplasticity in depressed mice through microgliamediated CX3CL1-CX3CR1 signaling (Eyre et al., 2013). Similarly, it has been suggested that physical exercise could accelerate the response of the CX3CL1-CX3CR1 axis to stressors and rapidly quieten the activated microglia, thus avoiding the negative cognition-related effects of stress (Fleshner et al., 2014). However, whether exercise training may affect microglial phagocytosis by regulating CX3CL1-CX3CR1 needs further study. ...
Microglia are considered the main phagocytic cells in the central nervous system, remodeling neural circuits by pruning synapses during development. Microglial phagocytosis is also a crucial process in maintaining adult brain homeostasis and clearing potential toxic factors, which are recognized to be associated with neurodegenerative and neuroinflammatory disorders. For example, microglia can engulf amyloid-β plaques, myelin debris, apoptotic cells, and extracellular harmful substances by expressing a variety of specific receptors on the cell surface or by reprogramming intracellular glucose and lipid metabolism processes. Furthermore, physical exercise has been implicated to be one of the non-pharmaceutical treatments for various nervous system diseases, which is closely related to neuroplasticity and microglia functions including proliferation, activation, and phagocytosis. This review focuses on the central regulatory mechanisms related to microglia phagocytosis and the potential role of exercise training in this process.
... Conversely, microglia from aged animals or young sedentary animals were not effective in recruiting and stimulating neuronal precursors [54]. The same CSF-1 signalling cascade underlies emergence of stress resilience following physical exercise [55]. Positive regulation of neurogenesis may also be mediated by an increase in microglial production of BDNF, which is well known enhancer of neurogenesis [56]. ...
Lifestyle is one of the most powerful instruments shaping mankind; the lifestyle includes many aspects of interactions with the environment, from nourishment and education to physical activity and quality of sleep. All these factors taken in complex affect neuroplasticity and define brain performance and cognitive longevity. In particular, physical exercise, exposure to enriched environment and dieting act through complex modifications of microglial cells, which change their phenotype and modulate their functional activity thus translating lifestyle events into remodelling of brain homoeostasis and reshaping neural networks ultimately enhancing neuroprotection and cognitive longevity.
... It is this latter stressor, inescapable stress, with which exercise-induced stress resilience has been most well characterized (Greenwood & Fleshner, 2008, 2011. Male rats allowed voluntary access to running wheels for six weeks prior to exposure to inescapable tail shock are protected from the shuttle box escape deficit (Greenwood et al., 2003), exaggerated freezing (Greenwood et al., 2003), social avoidance (Greenwood, Loughridge, Sadaoui, Christianson, & Fleshner, 2012), circadian disruption (Thompson, Roller, Greenwood, & Fleshner, 2016), amnesia (Fleshner, Greenwood, & Yirmiya, 2014) and potentiation of the rewarding effects of morphine (Rozeske et al., 2011), typically produced by exposure to inescapable stress in sedentary rats. Although forced treadmill training generally fails to produce stress resilience, stress resilience can be produced by forced wheel running of a pattern similar to voluntary running . ...
Adverse life events can lead to stable changes in brain structure and function and are considered primary sources of risk for post-traumatic stress disorder, depression, and other neuropsychiatric disorders. However, most individuals do not develop these conditions following exposure to traumatic experiences, and research efforts have identified a number of experiential factors associated with an individual's ability to withstand, adapt to, and facilitate recovery from adversity. While multiple animal models of stress resilience exist, so that the detailed biological mechanisms can be explored, studies have been disproportionately conducted in male subjects even though the prevalence and presentation of stress-linked disorders differ between sexes. This review focuses on 1) the mechanisms by which experiential factors (behavioral control over a stressor, exercise) reduce the impact of adverse events as studied in males; 2) whether other manipulations (ketamine) that buffer against stress-induced sequelae engage the same circuit features; and 3) whether these processes operate similarly in females. We argue that investigation of experiential factors that produce resistance/resilience rather than vulnerability to adversity will generate a unique set of biological mechanisms that potentially underlie sex differences in mood disorders.
... stress resilient). We have described organisms that possess both stress resistance and stress resilience as stress robust [18]. Exercise is unique among stress-protective factors because it produces a stress robust phenotype. ...
Despite evidence that exercise reduces the negative impacts of stressor exposure and promotes stress robustness, health and well-being, most people fail to achieve recommended levels of physical activity. One reason for this failure could be our fundamental lack of understanding the brain motivational and motor circuits underlying voluntary exercise behavior. Wheel running is an animal model used to reveal mechanisms of exercise-induced stress robustness. Here, we detail the strengths and weakness of wheel running as a model; and propose that running begins as a purposeful, goal-directed behavior that becomes habitual with continued access. This fresh perspective could aid in the development of novel strategies to motivate and sustain exercise behavior and maximize the stress-robust phenotype.
... Considerable data indicate that the physical fitness status of an organism modulates that organism's response to a stressor Fleshner et al., 2002;Fleshner, Greenwood, & Yirmiya, 2014;Lloyd et al., 2017). Therefore, we were surprised to observe in the current study that physical activity status did not influence the highest HR observed (Figure 2) nor the change in HR observed throughout the work shift (Figure 3(A,B)). ...
Cardiovascular disease (CVD) remains the leading cause of disease burden globally and chronic stress is associated with increased risk of CVD. Recognition of chronic occupational stressors as a potential contributor to CVD highlights the need to recognize and prevent stress during work. The ubiquity of wearable technology devices to monitor health provides a new opportunity to noninvasively examine the cardiovascular system throughout a work shift. In the current study, we examined changes in heart rate (HR) during a work shift in a retail store setting using 23 healthy female and male subjects that differed in their physical fitness status. Subjects had their HR tracked via an Apple Watch during three typical work shifts. The results demonstrated an increase in HR during a work shift to a level observed during a moderate stressor (resting HR = 83.2 BPM ± 7.8; highest HR mean = 109.1 BPM ± 11.7; p < .0001). Female subjects demonstrated a significantly elevated maximum HR, a larger change in HR, and a larger percent change in HR compared with males (all p < .05). Physical activity status did not influence the observed changes in HR for females or males. Neither the time of day the work shift occurred nor the length of the shift modulated the observed pattern of HR changes. Collectively, our findings demonstrate the potential for wearables in biomedical research and personalized health.
... In the present review paper, we have based our discussion in a model that highlights the effects of exercise on key depressive symptoms, and on key biomarkers of depression, rather than on depression as a global outcome. In this regard, stress, intense or chronic, and likely both, is a major agent [10] have proposed an hypothesis outlining a mechanism through which physical exercise, as opposed to sedentary living, promotes stress robustness in the face of intense uncontrollable stress. According to this notion, individuals with a sedentary existence respond to an intense acute uncontrollable stressor with excessive 5-HT and NA activity and/or prolonged down-regulation of the CX3CL1-CX3CR1 axis resulting in activation and proliferation of hippocampal microglia with consequent hippocampal-dependent memory deficits and reduced neurogenesis. ...
The exact mechanisms concerning how exercise affects the brain,
under conditions of health or disorder, are not fully understood and
the literature lacks a sufficiency of well-designed studies concerning
the effects of exercise training on depressive disorders. Nevertheless,
the observed antidepressant actions of exercise are strong enough to
warrant its application as a viable alternative to current medications
in the treatment of depressive disorders. The beneficial effects
of exercise upon cognitive, executive function and working
memory, emotional, self-esteem and depressed mood, motivational,
anhedonia and psychomotor retardation, and somatic/physical, sleep
disturbances and chronic aches and pains, categories of depression
are discussed. The ameliorative effects of physical exercise upon
several biomarkers associated with depressive states: hypothalamicpituitary-adrenal
(HPA) axis homeostasis, anti-neurodegenerative
effects, monoamine metabolism regulation and neuro-immune
functioning have been outlined
... Specifically, physical activity and exercise decreased the activation of microglia, thereby reducing a characteristic feature of neu- roinflammation [48,49]. Physical activity has also been found to initiate neuroprotective mechanisms, including re- ducing the levels of TNF-α in an IL-6-dependent manner, a phenomenon which ultimately shields the brain from the adverse effects of pro-inflammatory cytokines released dur- ing inflammatory responses [50,51]. ...
Background:
Alzheimer's Disease (AD) and Parkinson's Disease (PD) are among the most common causes of dementia, which increasingly contribute to morbidity and mortality worldwide. A common hallmark in the pathogenesis of these two diseases is neuroinflammation, which is initially triggered by the presence of pathological structures associated with these disorders. Chronic neuroinflammation is sustained by persistent and aberrant microglial activation in the brain, which results in damage and death of neighboring cells, including neurons and glial cells. Two types of risk factors contribute to the development of AD and PD: non-modifiable risk factors and modifiable risk factors. Non-modifiable risk factors include genetic susceptibility that increases an individual's risk of developing the disease, whereas modifiable risk factors include a wide variety of health- and lifestyle-related factors that may be altered by changing individual behaviors.
Method:
Ovid Medline and PubMed databases were used to perform an ordered search of the peerreviewed research literature described in this review.
Results:
This review focuses on four modifiable risk factors including physical inactivity, vascular disease-related conditions, obesity and type two diabetes mellitus, all of which have been identified as risk factors for the development of AD and PD.
Conclusion:
We highlight that control of the modifiable risk factors is a valid approach for managing the increased incidence of AD and PD. We describe neuroinflammatory mechanisms, which are common to AD and PD that may link both these neurodegenerative diseases with the four common modifiable risk factors. Understanding neuroinflammatory mechanisms could help identify novel therapeutic targets for combating these neurodegenerative diseases.
... ness" (5,13,17). Thus, it is possible that motivation to locate the escape box was increased in the OB group vs. the CON group as well as in both sedentary groups vs. the RUN group. From this perspective, cerebrovascular insulin resistance may be associated with increased anxiety-like behavior/stress vulnerability (reflected by an increased motivation to locate the escape box), which can be reversed and improved by chronic spontaneous physical activity treatment (reflected by decreased motivation to locate the escape box and increased exploratory behavior, which increased over time). ...
This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism, and treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups; 20-wk old food-controlled (CON-20); 20-wk old free-food access (model of obesity, OB-20); 40-wk old food-controlled (CON-40); 40-wk old free-food access (OB-40); and 40-wk old free-food access+RUN (RUN-40; wheel-running access from 20-40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere-infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P≤0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P≥0.56) and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P<0.01). At 40-wk of age, cerebellum BF decreased during the EHC in the OB-40 group (P=0.02), but not CON or RUN groups (P≥0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P<0.01). These findings indicate OB-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased NO signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.
Inflammation is an essential tissue response to injury, stress, or infection resulting in debris and/or pathogen clearance intended to promote healing and recovery. Due to the status as an immune ‘privileged’ tissue, microglia serve as endogenous regulators of inflammation in the central nervous system, but maintain communication with peripheral immune system to enable recruitment of peripheral immune cells in case of injury or infection. While microglia retain the functional capacity for a full range of inflammatory functions – microglia express a range of pattern-recognition receptors and function as innate immune cells, carry out phagocytosis of pathogens, and act as antigen presenting cells – in the healthy central nervous system (CNS) these functions are rarely engaged. Subsequently microglia are being recognized to occupy an increasing number of homeostatic niches, and in many cases have adopted immune or inflammatory mechanisms to carry out these niche functions absent immune activation. These sterile inflammatory functions are challenging long-held views of the role of inflammation in the central nervous system while simultaneously expanding the potential for the development of truly novel therapeutic interventions for a range of neuroinflammatory, neurodegenerative, and neuropsychiatric disorders. In the present review we discuss recent preclinical evidence for conserved niche functions for microglia whose disruption may causally contribute to various psychiatric disorders, and prospective targets for restoring disrupted niches.
The seven-transmembrane receptor CX3CR1 is a specific receptor for the novel CX3C chemokine fractalkine (FKN) (neurotactin). In vitro data suggest that membrane anchoring of FKN, and the existence of a
shed, soluble FKN isoform allow for both adhesive and chemoattractive properties. Expression on activated endothelium and
neurons defines FKN as a potential target for therapeutic intervention in inflammatory conditions, particularly central nervous
system diseases. To investigate the physiological function of CX3CR1-FKN interactions, we generated a mouse strain in which the CX3CR1 gene was replaced by a green fluorescent protein (GFP) reporter gene. In addition to the creation of a mutant CX3CR1 locus, this approach enabled us to assign murine CX3CR1 expression to monocytes, subsets of NK and dendritic cells, and the brain microglia. Analysis of CX3CR1-deficient mice indicates that CX3CR1 is the only murine FKN receptor. Yet, defying anticipated FKN functions, absence of CX3CR1 interferes neither with monocyte extravasation in a peritonitis model nor with DC migration and differentiation in response
to microbial antigens or contact sensitizers. Furthermore, a prominent response of CX3CR1-deficient microglia to peripheral nerve injury indicates unimpaired neuronal-glial cross talk in the absence of CX3CR1.
Exercise has been shown to positively augment adult hippocampal neurogenesis; however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippocampal microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippocampal cultures. Conversely, microglia from the hippocampi of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX(3)CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blocking antibody against the CX(3)CL1 receptor, CX(3)CR1, but not control IgG, dramatically reduced the neurosphere formation frequency in mice that had exercised. While an increase in soluble CX(3)CL1 was observed following running, reduced levels of this chemokine were found in the aged brain. Lower levels of CX(3)CL1 with advancing age correlated with the natural decline in neural precursor cell activity, a state that could be partially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippocampus, and that signaling through the CX(3)CL1-CX(3)CR1 axis critically contributes toward this process.
Introduction:
The chemokine fractalkine/CX3CL1 and its highly selective receptor CX3CR1 mediate critical physiological events during inflammatory responses. The fractalkine/CX3CR1 axis has been shown to play a key role in the pathogenesis and the progression of a large number of diseases in which imbalance of the immune response is frequently seen. Since our last review published in early 2010, the fractalkine/CX3CR1 axis has gained vast attention as a potential therapeutic target in the scientific community, which can be clearly seen in the large number of studies that have been published on this issue since then.
Areas covered:
A Medline/PubMed search was performed to detect all recently published studies on the role of the fractalkine/CX3CR1 axis as a therapeutic target in a wide range of clinical diseases.
Expert opinion:
Recently published studies further underline the high potential of the fractalkine/CX3CR1 axis as a major target for future treatment of pain, inflammation and cancer. However, no clinical trials on novel therapeutics targeting fractalkine or CX3CR1 have been initiated so far, so that the fractalkine/CX3CR1 axis does still not find application in daily clinical practice.
New neurons are continuously generated in two adult brain regions: the subgranular zone of the hippocampus and the subependyma by the lateral ventricles, referred to as the neurogenic niches. During their development from neural stem cells to mature functionally integrated neurons numerous choices are made, such as proliferation or quiescence, cell survival or death, migration or establishment, growth or retraction of processes, synaptic assembly or pruning, or tuning of synaptic transmission. The process is altered by physiological stimuli as well as several brain diseases. Microglia are located within the neurogenic niches and have become interesting candidates for modulating neurogenesis in both the healthy and injured brain. They become activated by foreign antigens or changes in the brain homeostasis and transform this innate immunity into an adaptive immune response by recruiting systemic immune cells. Most studies report an acute decrease in the survival of new neurons following this classically activated microglia reaction. The long-term effects are more complex. In neurodegenerative diseases, microglial activation is more heterogeneous and the transformation from a pro- to an anti-inflammatory cytokine profile and the deactivation of microglia is not well defined. The diversity is reflected by numerous reports describing both beneficial and detrimental effects on neurogenesis, primarily on the proliferation, survival, and cell fate. However, relatively few studies have investigated alterations at later stages of neurogenesis including the functional integration. Though likely, it is not established how a fine-tuned cross-talk between microglia and adult-born neurons would work and how it changes upon microglia activation. This review will therefore launch three hypotheses for how microglia might direct synaptic integration of newborn neurons, currently a fast expanding research field.
A physically active lifestyle incurs many health benefits. One recently recognized benefit of regular moderate exercise is stress reduction. The current review develops the hypothesis that physical activity may prevent stress-induced suppression of the immune system and suggests an immunophysiological mechanism (sympathetic nervous system constraint) for this effect.
Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.
Previous research has indicated that chronic stress induces inflammatory responses, cognitive impairments, and changes in microglia and astrocytes. However, whether stress-induced changes following recovery are reversible is unclear. The present study examined the effects of chronic unpredictable stress (CUS) following recovery on spatial learning and memory impairments, changes in microglia and astrocytes, and interleukine-1β (IL-1β) and glial-derived neurotrophic factor (GDNF) levels. Mice were randomly divided into control, stress, and recovery groups, and CUS was applied to mice in the stress and recovery groups for 40 days. Following the application of CUS, the recovery group was allowed 40 days without stress. The results of the Morris water maze illustrated that CUS-induced spatial learning and memory impairments could be reversed or even improved by a period of recovery. Immunohistochemical tests revealed that CUS-induced alterations in microglia could dissipate with time in the CA3 region of the hippocampus and prelimbic areas. However, CUS-induced activation of astrocytes was sustained in the CA3 area following recovery. Western blot analyses revealed that CUS induced a significant increase of GDNF and a significant decrease in IL-1β. Additionally, increased GDNF levels were sustained in the hippocampus during recovery. In conclusion, this study provides evidence that CUS-induced learning and memory impairments could be reversible following recovery. However, activated astrocytes and increased GDNF levels in the hippocampus remained elevated after recovery, suggesting that activated astrocytes and increased GDNF play important roles in the adaptation of the brain to CUS and in repairing CUS-induced impairments during recovery.
The hippocampal formation is a highly plastic brain region that is sensitive to stress. It receives extensive noradrenergic projections, and noradrenaline is released in the hippocampus in response to stressor exposure. The hippocampus expresses particularly high levels of the α1D adrenergic receptor (ADR) and we have previously demonstrated that α1d ADR mRNA expression in the rat hippocampus is modulated by corticosterone. One of the defining features of a stress response is activation of the hypothalamic pituitary adrenal (HPA) axis, resulting in the release of corticosterone from the adrenal glands. However, the effect of stress on hippocampal expression of α1d ADR mRNA has not been determined. In this study, male rats were exposed to inescapable tail shock, loud noise or restraint, and the effect on α1d ADR mRNA expression in the hippocampus was determined by semi-quantitative in situ hybridization. All three stressors resulted in a rapid upregulation of α1d ADR mRNA in the dentate gyrus, with expression peaking at approximately 90 min after the start of the stressor. Physical activity has previously been reported to counteract some of the effects of stress that occur within the dentate gyrus. However, 6 weeks of voluntary wheel running in rats did not prevent the restraint stress-induced increase in α1d ADR mRNA expression in the dentate gyrus. Although the function of the α1D ADR in the dentate gyrus is not known, these data provide further evidence for a close interaction between stress and the noradrenergic system in the hippocampus.
Immobilization stress decreases the expression of BDNF mRNA in the rat hippocampus, and this effect could contribute to the atrophy of hippocampal neurons. This study examines the influence of selective 5-HT, as well as norepinephrine, receptor antagonists on the stress-induced down-regulation of BDNF mRNA. Pretreatment with a selective 5-HT2A receptor antagonist, MDL100,907, significantly blocked the influence of stress on expression of BDNF mRNA. In contrast, pretreatment with either a selective 5-HT2C or 5-HT1A receptor antagonist did not influence the stress-induced decrease in levels of BDNF mRNA. The stress-induced decrease was also not influenced by pretreatment with antagonists of β1/2- or α1-adrenergic, or CRF-R1 receptors. The results demonstrate that 5-HT2A receptors mediate, at least in part, the stress-induced down-regulation of BDNF expression in the rat hippocampus.
Activation of the in vivo stress response can facilitate antibacterial host defenses. One possible mechanism for this effect is stress-induced release of heat shock protein 72 (Hsp72) into the extracellular environment. Hsp72 is a ubiquitous cellular protein that is up-regulated in response to cellular stress, and modulates various aspects of immune function including macrophage inflammatory/bactericidal responses and T-cell function when found in the extracellular environment. The current study tested the hypothesis that in vivo extracellular Hsp72 (eHsp72) at the site of inflammation contributes to stress-induced restricted development of bacteria, and facilitated recovery from bacteria-induced inflammation, and that this effect is independent of alpha beta (αβ) T cells. Male F344 rats were exposed to either inescapable electrical tail-shocks or no stress, and subcutaneously injected with Escherichia coli (ATCC 15746). The role of eHsp72 was investigated by Hsp72-immunoneutralization at the inflammatory site. The potential contribution of T cells was examined by testing male athymic (rnu/rnu) nude rats lacking mature αβ T cells and heterozygous thymic intact control (rnu/+) rats. The results were that stressor exposure increased plasma concentrations of eHsp72 and facilitated recovery from bacterial inflammation. Immunoneutralization of eHsp72 at the inflammatory site attenuated this effect. Stressor exposure impacted bacterial inflammation and eHsp72 equally in both athymic and intact control rats. These results support the hypothesis that eHsp72 at the site of inflammation, and not αβ T cells, contributes to the effect of stressor exposure on subcutaneous bacterial inflammation.