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1.  Exercise, Stress Resistance, and Central Serotonergic Systems 
Voluntary exercise reduces the incidence of stress-related psychiatric disorders in humans and prevents serotonin-dependent behavioral consequences of stress in rodents. Evidence reviewed herein is consistent with the hypothesis that exercise increases stress resistance by producing neuroplasticity at multiple sites of the central serotonergic system, which all help to limit the behavioral impact of acute increases in serotonin during stressor exposure.
doi:10.1097/JES.0b013e31821f7e45
PMCID: PMC4303035  PMID: 21508844
wheel running; learned helplessness; anxiety; depression; prefrontal cortex; dorsal raphe nucleus
2.  Six weeks of voluntary wheel running modulates inflammatory protein (MCP-1, IL-6, and IL-10) and DAMP (Hsp72) responses to acute stress in white adipose tissue of lean rats 
To prime local tissues for dealing with potential infection or injury, exposure to an acute, intense stressor evokes increases in circulating and local tissue inflammatory proteins. Regular physical activity facilitates stress-evoked innate reactivity and modulates the expression of inflammatory proteins in immuno-metabolic tissues such as white adipose tissue (WAT). The impact of regular physical activity on stress-evoked inflammatory protein expression in WAT, however, remains unclear. To investigate this question, lean male F344 rats (150–175 g) were allowed voluntary access to a running wheel for 6 weeks followed by exposure to an acute stressor (100, 1.5 mA-5 s inescapable tail shocks). Using ELISAs, corticosterone, heat shock protein 72 (Hsp72), macrophage chemoattractant protein (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-10 concentrations were measured in plasma and subcutaneous, intraperitoneal (epididymal and retroperitoneal WAT depots) and visceral (omental and mesenteric WAT depots) WAT compartments. Acute stress increased plasma concentrations of all proteins except TNF-α and, depending upon the compartment examined, WAT concentrations of MCP-1, IL-1β, IL-6, and IL-10. Exercise ubiquitously increased IL-1β within WAT, potentiated stress-evoked Hsp72 in plasma and WAT, and differentially increased stress-evoked MCP-1, IL-6, and IL-10 within WAT. These data suggest: (a) inflammatory proteins in non-obese WAT may serve compartment-specific immune and metabolic roles important to the acute stress response and; (b) voluntary habitual exercise may optimize stress-induced augmentation of innate immune function through increases in stress-evoked Hsp72, MCP-1, IL-6, and IL-10 and decreases in IL-1β/IL10 and TNF-α/IL10 ratios within white adipose tissue.
doi:10.1016/j.bbi.2013.10.028
PMCID: PMC4301739  PMID: 24246250
Innate immunity; Acute stress; Visceral adipose tissue; Sterile inflammation; Cytokine; Interleukin-1beta; Interleukin-6; Interleukin-10; Macrophage chemoattractant protein-1; Heat shock protein 72
3.  Exercise-induced stress resistance is independent of exercise controllability and the medial prefrontal cortex 
Exercise increases resistance against stress-related disorders such as anxiety and depression. Similarly, the perception of control is a powerful predictor of neurochemical and behavioral responses to stress, but whether the experience of choosing to exercise, and exerting control over that exercise, is a critical factor in producing exercise-induced stress resistance is unknown. The current studies investigated whether the protective effects of exercise against the anxiety- and depression-like consequences of stress are dependent on exercise controllability and a brain region implicated in the protective effects of controllable experiences, the medial prefrontal cortex. Adult male Fischer 344 rats remained sedentary, were forced to run on treadmills or motorised running wheels, or had voluntary access to wheels for 6 weeks. Three weeks after exercise onset, rats received sham surgery or excitotoxic lesions of the medial prefrontal cortex. Rats were exposed to home cage or uncontrollable tail shock treatment three weeks later. Shock-elicited fear conditioning and shuttle box escape testing occurred the next day. Both forced and voluntary wheel running, but not treadmill training, prevented the exaggerated fear conditioning and interference with escape learning produced by uncontrollable stress. Lesions of the medial prefrontal cortex failed to eliminate the protective effects of forced or voluntary wheel running. These data suggest that exercise controllability and the medial prefrontal cortex are not critical factors in conferring the protective effects of exercise against the affective consequences of stressor exposure, and imply that exercise perceived as forced may still benefit affect and mental health.
doi:10.1111/ejn.12044
PMCID: PMC4285393  PMID: 23121339
anxiety; depression; forced wheel running; learned helplessness; rat; voluntary wheel running
4.  Repeated Exposure to Conditioned Fear Stress Increases Anxiety and Delays Sleep Recovery Following Exposure to an Acute Traumatic Stressor 
Repeated stressor exposure can sensitize physiological responses to novel stressors and facilitate the development of stress-related psychiatric disorders including anxiety. Disruptions in diurnal rhythms of sleep–wake behavior accompany stress-related psychiatric disorders and could contribute to their development. Complex stressors that include fear-eliciting stimuli can be a component of repeated stress experienced by human beings, but whether exposure to repeated fear can prime the development of anxiety and sleep disturbances is unknown. In the current study, adult male F344 rats were exposed to either control conditions or repeated contextual fear conditioning for 22 days followed by exposure to no, mild (10), or severe (100) acute uncontrollable tail shock stress. Exposure to acute stress produced anxiety-like behavior as measured by a reduction in juvenile social exploration and exaggerated shock-elicited freezing in a novel context. Prior exposure to repeated fear enhanced anxiety-like behavior as measured by shock-elicited freezing, but did not alter social exploratory behavior. The potentiation of anxiety produced by prior repeated fear was temporary; exaggerated fear was present 1 day but not 4 days following acute stress. Interestingly, exposure to acute stress reduced rapid eye movement (REM) and non-REM (NREM) sleep during the hours immediately following acute stress. This initial reduction in sleep was followed by robust REM rebound and diurnal rhythm flattening of sleep/wake behavior. Prior repeated fear extended the acute stress-induced REM and NREM sleep loss, impaired REM rebound, and prolonged the flattening of the diurnal rhythm of NREM sleep following acute stressor exposure. These data suggest that impaired recovery of sleep/wake behavior following acute stress could contribute to the mechanisms by which a history of prior repeated stress increases vulnerability to subsequent novel stressors and stress-related disorders.
doi:10.3389/fpsyt.2014.00146
PMCID: PMC4202708  PMID: 25368585
REM; NREM; anxiety; diurnal rhythm; conditioning; classical; sleep; chronic stress
5.  Acute Stressor Exposure Modifies Plasma Exosome-Associated Heat Shock Protein 72 (Hsp72) and microRNA (miR-142-5p and miR-203) 
PLoS ONE  2014;9(9):e108748.
Exosomes, biologically active nanoparticles (40–100 nm) released by hematopoietic and non-hematopoietic cells, contain a variety of proteins and small, non-coding RNA known as microRNA (miRNA). Exposure to various pathogens and disease states modifies the composition and function of exosomes, but there are no studies examining in vivo exosomal changes evoked by the acute stress response. The present study reveals that exposing male Fisher 344 rats to an acute stressor modulates the protein and miRNA profile of circulating plasma exosomes, specifically increasing surface heat shock protein 72 (Hsp72) and decreasing miR-142-5p and -203. The selected miRNAs and Hsp72 are associated with immunomodulatory functions and are likely a critical component of stress-evoked modulation of immunity. Further, we demonstrate that some of these stress-induced modifications in plasma exosomes are mediated by sympathetic nervous system (SNS) activation of alpha-1 adrenergic receptors (ADRs), since drug-mediated blockade of the receptors significantly attenuates the stress-induced modifications of exosomal Hsp72 and miR-142-5p. Together, these findings demonstrate that activation of the acute stress response modifies the proteomic and miRNA profile of exosomes released into the circulation.
doi:10.1371/journal.pone.0108748
PMCID: PMC4178201  PMID: 25259839
6.  Multivalency Amplifies the Selection and Affinity of Bradykinin-Derived Peptide for Lipid Nanovesicles 
Molecular bioSystems  2013;9(8):2005-2009.
The trimer of a Bradykinin derivative displayed more than five-fold increase in binding affinity for phosphatidylserine-enriched nanovesicles as compared to its monomeric precursor. The nanovesicle selection is directly correlated to multivalency, which amplified the electrostatic attraction. This strategy may lead to novel molecular probes for detecting highly curved membrane bilayers.
doi:10.1039/c3mb70109c
PMCID: PMC3764994  PMID: 23715428
7.  Effects of Stressor Controllability on Diurnal Physiological Rhythms 
Physiology & behavior  2013;0:32-39.
Disruptions in circadian and diurnal rhythms are associated with stress-related psychiatric disorders and stressor exposure can disrupt these rhythms. The controllability of the stressor can modulate various behavioral and neurochemical responses to stress. Uncontrollable, but not controllable, stress produces behaviors in rats that resemble symptoms of anxiety and depression. Whether acute stress-induced disruptions in physiological rhythms are sensitive to controllability of the stressor, however, remains unknown. To examine the role of controllability in diurnal rhythm disruption, adult male Sprague Dawley rats were implanted with Data Sciences International (DSI) biotelemetry devices. Real-time measurements were obtained before, during and after exposure to a controllable or yoked uncontrollable stressor. Controllable and uncontrollable stress equally disrupted diurnal rhythms of locomotor activity and body temperature but not heart rate. The diurnal heart rate the day following stressor exposure was flattened to a greater extent and was significantly higher in rats with control over stress suggesting a relationship between stressor controllability and the heart rate response. Our results are consistent with the conclusion that acute stress-induced disruptions in diurnal physiological rhythms likely contribute little to the behavioral and affective consequences of stress that are sensitive to stressor controllability.
doi:10.1016/j.physbeh.2013.02.009
PMCID: PMC3637963  PMID: 23454291
Controllability; Stress; Diurnal Rhythm; Heart Rate; Body Temperature; Locomotor Activity
8.  MARCKS-ED Peptide as a Curvature and Lipid Sensor 
ACS chemical biology  2012;8(1):218-225.
Membrane curvature and lipid composition regulate important biological processes within a cell. Currently, several proteins have been reported to sense and/or induce membrane curvatures, e.g. Synaptotagmin-1 and Amphiphysin. However, the large protein scaffold of these curvature sensors limits their applications in complex biological systems. Our interest focuses on identifying and designing peptides that can sense membrane curvature based on established elements observed in natural curvature-sensing proteins. Membrane curvature remodeling also depends on their lipid composition, suggesting strategies to specifically target membrane shape and lipid components simultaneously. We have successfully identified a 25-mer peptide, MARCKS-ED, based on the effector domain sequence of the intracellular membrane protein myristoylated alanine-rich C-kinase substrate that can recognize PS with preferences for highly curved vesicles in a sequence specific manner. These studies further contribute to the understanding of how proteins and peptides sense membrane curvature, as well as provide potential probes for membrane shape and lipid composition.
doi:10.1021/cb300429e
PMCID: PMC3548944  PMID: 23075500
9.  Detection of Highly Curved Membrane Surfaces Using a Cyclic Peptide Derived from Synaptotagmin-I 
ACS chemical biology  2012;7(10):1629-1635.
The generation of highly curved membranes is essential to cell growth, division and movement. Recent research in the field is focused to answer questions related to the consequences of changes in the topology of the membrane once it is created, broadly termed as membrane curvature sensing. Most probes that are used to study curvature sensing are intact membrane active proteins like DP1/Yop1p, ArfGAP1, BAR domains, and Synaptotagmin-I (Syt1). Taking a cue from nature, we created the cyclic peptide C2BL3C based on the membrane penetration C2B loop 3 of Syt1 via ‘Click’ chemistry. Using a combination of spectroscopic techniques, we investigated the peptide-lipid interactions of this peptide with synthetic phospholipid vesicles and exosomes from rat blood plasma. We found that the macrocycle peptide probe was selective for lipid vesicles with highly curved surfaces (d <100 nm). These results suggested that C2BL3C functions as a selective detector of highly curved phospholipid bilayers.
doi:10.1021/cb3002705
PMCID: PMC3477269  PMID: 22769435
11.  The protective effects of voluntary exercise against the behavioral consequences of uncontrollable stress persist despite an increase in anxiety following forced cessation of exercise 
Behavioural Brain Research  2012;233(2):314-321.
Humans who exercise are less likely to suffer from stress-related mood disorders. Similarly, rats allowed voluntary access to running wheels have constrained corticosterone responses to mild stressors and are protected against several behavioral consequences of uncontrollable stress which resemble symptoms of human anxiety and depression, including exaggerated fear and deficits in shuttle box escape learning. Although exercise conveys clear stress resistance, the duration of time the protective effects of exercise against the behavioral consequences of uncontrollable stress persist following exercise cessation is unknown. The current studies investigated 1) whether exercise-induced stress resistance extends to social avoidance, another anxiety-like behavior elicited by uncontrollable stressor exposure, and 2) the duration of time the protective effects of exercise persist following forced cessation of exercise. Six weeks of wheel running constrained the increase in corticosterone elicited by social exploration testing, and prevented the reduction in social exploration, exaggerated shock-elicited fear, and deficits in escape learning produced by uncontrollable stress. The protective effect of voluntary exercise against stress-induced interference with escape learning persisted for 15 days, but was lost by 25 days, following cessation of exercise. An anxiogenic effect, as revealed by a reduction in social exploration and an increase in fear behavior immerged as a function of time following cessation of exercise. Results demonstrate that the protective effect of voluntary exercise against the behavioral consequences of uncontrollable stress extends to include social avoidance, and can persist for several days following exercise cessation despite an increase in anxiety produced by forced cessation of exercise.
doi:10.1016/j.bbr.2012.05.017
PMCID: PMC3402647  PMID: 22610051
wheel running; depression; anxiety; learned helplessness; serotonin; social exploration
12.  Microarray analyses reveal novel targets of exercise-induced stress resistance in the dorsal raphe nucleus 
Serotonin (5-HT) is implicated in the development of stress-related mood disorders in humans. Physical activity reduces the risk of developing stress-related mood disorders, such as depression and anxiety. In rats, 6 weeks of wheel running protects against stress-induced behaviors thought to resemble symptoms of human anxiety and depression. The mechanisms by which exercise confers protection against stress-induced behaviors, however, remain unknown. One way by which exercise could generate stress resistance is by producing plastic changes in gene expression in the dorsal raphe nucleus (DRN). The DRN has a high concentration of 5-HT neurons and is implicated in stress-related mood disorders. The goal of the current experiment was to identify changes in the expression of genes that could be novel targets of exercise-induced stress resistance in the DRN. Adult, male F344 rats were allowed voluntary access to running wheels for 6 weeks; exposed to inescapable stress or no stress; and sacrificed immediately and 2 h after stressor termination. Laser capture micro dissection selectively sampled the DRN. mRNA expression was measured using the whole genome Affymetrix microarray. Comprehensive data analyses of gene expression included differential gene expression, log fold change (LFC) contrast analyses with False Discovery Rate correction, KEGG and Wiki Web Gestalt pathway enrichment analyses, and Weighted Gene Correlational Network Analysis (WGCNA). Our results suggest that physically active rats exposed to stress modulate expression of twice the number of genes, and display a more rapid and strongly coordinated response, than sedentary rats. Bioinformatics analyses revealed several potential targets of stress resistance including genes that are related to immune processes, tryptophan metabolism, and circadian/diurnal rhythms.
doi:10.3389/fnbeh.2013.00037
PMCID: PMC3650681  PMID: 23717271
Affymetrix gene microarray; Weighted Gene Correlational Network Analysis; bioinformatics; laser capture microdissection; stress resistance; dorsal raphe nucleus
13.  Commensal Bacteria and MAMPs Are Necessary for Stress-Induced Increases in IL-1β and IL-18 but Not IL-6, IL-10 or MCP-1 
PLoS ONE  2012;7(12):e50636.
Regular interactions between commensal bacteria and the enteric mucosal immune environment are necessary for normal immunity. Alterations of the commensal bacterial communities or mucosal barrier can disrupt immune function. Chronic stress interferes with bacterial community structure (specifically, α-diversity) and the integrity of the intestinal barrier. These interferences can contribute to chronic stress-induced increases in systemic IL-6 and TNF-α. Chronic stress, however, produces many physiological changes that could indirectly influence immune activity. In addition to IL-6 and TNF-α, exposure to acute stressors upregulates a plethora of inflammatory proteins, each having unique synthesis and release mechanisms. We therefore tested the hypothesis that acute stress-induced inflammatory protein responses are dependent on the commensal bacteria, and more specifically, lipopolysaccharide (LPS) shed from Gram-negative intestinal commensal bacteria. We present evidence that both reducing commensal bacteria using antibiotics and neutralizing LPS using endotoxin inhibitor (EI) attenuates increases in some (inflammasome dependent, IL-1 and IL-18), but not all (inflammasome independent, IL-6, IL-10, and MCP-1) inflammatory proteins in the blood of male F344 rats exposed to an acute tail shock stressor. Acute stress did not impact α- or β- diversity measured using 16S rRNA diversity analyses, but selectively reduced the relative abundance of Prevotella. These findings indicate that commensal bacteria contribute to acute stress-induced inflammatory protein responses, and support the presence of LPS-mediated signaling in stress-evoked cytokine and chemokine production. The selectivity of the commensal bacteria in stress-evoked IL-1β and IL-18 responses may implicate the inflammasome in this response.
doi:10.1371/journal.pone.0050636
PMCID: PMC3517493  PMID: 23236381
14.  5-hydroxytrptamine 2C receptors in the dorsal striatum mediate stress-induced interference with negatively-reinforced instrumental escape behavior 
Neuroscience  2011;197:132-144.
Uncontrollable stress can interfere with instrumental learning and induce anxiety in humans and rodents. While evidence supports a role for serotonin (5-HT) and serotonin 2C receptors (5-HT2CR) in the behavioral consequences of uncontrollable stress, the specific sites of action are unknown. These experiments sought to delineate the role of 5-HT and 5-HT2CR in the dorsal striatum (DS) and the lateral/basolateral amygdala (BLA) in the expression of stress-induced instrumental escape deficits and exaggerated fear, as these structures are critical to instrumental learning and fear behaviors. Using in vivo microdialysis, we first demonstrate that prior uncontrollable, but not controllable, stress sensitizes extracellular 5-HT in the dorsal striatum, a result that parallels prior work in the BLA. Additionally, rats were implanted with bilateral cannula in either the DS or the BLA and exposed to uncontrollable tail shock stress. One day later, rats were with injected 5-HT2CR antagonist (SB242084) and fear and instrumental learning behaviors were assessed in a shuttle box. Separately, groups of non-stressed rats received an intra-DS or an intra-BLA injection of the 5-HT2CR agonist (CP809101) and behavior was observed. Intra-DS injections of the 5-HT2CR antagonist prior to fear/escape tests completely blocked the stress-induced interference with instrumental escape learning; a partial block was observed when injections were in the BLA. Antagonist administration in either region did not influence stress-induced fear behavior. In the absence of prior stress, intra-DS administration of the 5-HT2CR agonist was sufficient to interfere with escape behavior without enhancing fear, while intra-BLA administration of the 5-HT2CR agonist increased fear behavior but had no effect on escape learning. Results reveal a novel role of the 5-HT2CR in the DS in the expression of instrumental escape deficits produced by uncontrollable stress and demonstrate that the involvement of 5-HT2CR activation in stress-induced behaviors is regionally specific.
doi:10.1016/j.neuroscience.2011.09.041
PMCID: PMC3235414  PMID: 21958863
Uncontrollable stress; serotonin; anxiety; amygdala; learned helplessness; instrumental learning
15.  PRIOR LAPAROTOMY OR CORTICOSTERONE POTENTIATES LIPOPOLYSACCHARIDE-INDUCED FEVER AND SICKNESS BEHAVIORS 
Journal of neuroimmunology  2011;239(1-2):53-60.
Stimulating sensitized immune cells with a subsequent immune challenge results in potentiated pro-inflammatory responses translating into exacerbated sickness responses (i.e. fever, pain and lethargy). Both corticosterone (CORT) and laparotomy cause sensitization, leading to enhanced sickness-induced neuroinflammation or pain (respectively). However, it is unknown whether this sensitization affects all sickness behaviors and immune cell responses equally. We show that prior CORT and prior laparotomy potentiated LPS-induced fever but not lethargy. Prior CORT, like prior laparotomy, was able to potentiate sickness-induced pain. Release of nitric oxide (NO) from peritoneal macrophages stimulated ex vivo demonstrates that laparotomy, but not CORT sensitizes these cells.
doi:10.1016/j.jneuroim.2011.08.011
PMCID: PMC3205218  PMID: 21907418
rats; proinflammatory cytokines; sickness response; sensitization; telemetry
16.  5-HT2C Receptors in the Basolateral Amygdala and Dorsal Striatum Are a Novel Target for the Anxiolytic and Antidepressant Effects of Exercise 
PLoS ONE  2012;7(9):e46118.
Physical activity reduces the incidence and severity of psychiatric disorders such as anxiety and depression. Similarly, voluntary wheel running produces anxiolytic- and antidepressant-like effects in rodent models. The specific neurobiological mechanisms underlying the beneficial properties of exercise, however, remain unclear. One relevant pharmacological target in the treatment of psychiatric disorders is the 5-HT2C receptor (5-HT2CR). Consistent with data demonstrating the anxiogenic consequences of 5-HT2CR activation in humans and rodents, we have previously reported that site-specific administration of the selective 5-HT2CR agonist CP-809101 in the lateral/basolateral amygdala (BLA) increases shock-elicited fear while administration of CP-809101 in the dorsal striatum (DS) interferes with shuttle box escape learning. These findings suggest that activation of 5-HT2CR in discrete brain regions contributes to specific anxiety- and depression-like behaviors and may indicate potential brain sites involved in the anxiolytic and antidepressant effects of exercise. The current studies tested the hypothesis that voluntary wheel running reduces the behavioral consequences of 5-HT2CR activation in the BLA and DS, specifically enhanced shock-elicited fear and interference with shuttle box escape learning. After 6 weeks of voluntary wheel running or sedentary conditions, the selective 5-HT2CR agonist CP-809101 was microinjected into either the BLA or the DS of adult Fischer 344 rats, and shock-elicited fear and shuttle box escape learning was assessed. Additionally, in-situ hybridization was used to determine if 6 weeks of voluntary exercise changed levels of 5-HT2CR mRNA. We found that voluntary wheel running reduced the behavioral effects of CP-809101 and reduced levels of 5-HT2CR mRNA in both the BLA and the DS. The current data indicate that expression of 5-HT2CR mRNA in discrete brain sites is sensitive to physical activity status of the organism, and implicates the 5-HT2CR as a target for the beneficial effects of physical activity on mental health.
doi:10.1371/journal.pone.0046118
PMCID: PMC3458100  PMID: 23049953
17.  Brain Activation Patterns at Exhaustion in Rats That Differ in Inherent Exercise Capacity 
PLoS ONE  2012;7(9):e45415.
In order to further understand the genetic basis for variation in inherent (untrained) exercise capacity, we examined the brains of 32 male rats selectively bred for high or low running capacity (HCR and LCR, respectively). The aim was to characterize the activation patterns of brain regions potentially involved in differences in inherent running capacity between HCR and LCR. Using quantitative in situ hybridization techniques, we measured messenger ribonuclease (mRNA) levels of c-Fos, a marker of neuronal activation, in the brains of HCR and LCR rats after a single bout of acute treadmill running (7.5–15 minutes, 15° slope, 10 m/min) or after treadmill running to exhaustion (15–51 minutes, 15° slope, initial velocity 10 m/min). During verification of trait differences, HCR rats ran six times farther and three times longer prior to exhaustion than LCR rats. Running to exhaustion significantly increased c-Fos mRNA activation of several brain areas in HCR, but LCR failed to show significant elevations of c-Fos mRNA at exhaustion in the majority of areas examined compared to acutely run controls. Results from these studies suggest that there are differences in central c-Fos mRNA expression, and potential brain activation patterns, between HCR and LCR rats during treadmill running to exhaustion and these differences could be involved in the variation in inherent running capacity between lines.
doi:10.1371/journal.pone.0045415
PMCID: PMC3444461  PMID: 23028992
18.  Interleukin-1 beta: a potential link between stress and the development of visceral obesity 
BMC Physiology  2012;12:8.
Background
A disproportionate amount of body fat within the abdominal cavity, otherwise known as visceral obesity, best predicts the negative health outcomes associated with high levels body fat. Growing evidence suggests that repeated activation of the stress response can favor visceral fat deposition and that visceral obesity may induce low-grade, systemic inflammation which is etiologically linked to the pathogenesis of obesity related diseases such as cardiovascular disease and type 2 diabetes. While the obesity epidemic has fueled considerable interest in these obesity-related inflammatory diseases, surprisingly little research is currently focused on understanding the functions of inflammatory proteins in healthy, non-obese white adipose tissue (WAT) and their possible role in modulating stress-induced shifts in body fat distribution.
Hypothesis
The current review presents evidence in support the novel hypothesis that stress-evoked interleukin-1 beta (IL-1β) signaling within subcutaneous adipose tissue, when repeatedly induced, contributes toward the development of visceral obesity. It is suggested that because acute stressor exposure differentially increases IL-1β levels within subcutaneous adipose relative to visceral adipose tissue in otherwise healthy, non-obese rats, repeated induction of this response may impair the ability of subcutaneous adipose tissue to uptake energy substrates, synthesize and retain triglycerides, and/or adapt to positive energy balance via hyperplasia. Consequently, circulating energy substrates may be disproportionately shunted to visceral adipose tissue for storage, thus driving the development of visceral obesity.
Conclusions
This review establishes the following key points: 1) body fat distribution outweighs the importance of total body fat when predicting obesity-related disease risk; 2) repeated exposure to stress can drive the development of visceral obesity independent of changes in body weight; 3) because of the heterogeneity of WAT composition and function, an accurate understanding of WAT responses requires sampling multiple WAT depots; 4) acute, non-pathogenic stressor exposure increases WAT IL-1β concentrations in a depot specific manner suggesting an adaptive, metabolic role for this cytokine; however, when repeated, stress-induced IL-1β in non-visceral WAT may result in functional impairments that drive the development of stress-induced visceral obesity.
doi:10.1186/1472-6793-12-8
PMCID: PMC3404929  PMID: 22738239
19.  Voluntary wheel running produces resistance to inescapable stress-induced potentiation of morphine conditioned place preference 
Behavioural brain research  2011;219(2):378-381.
In rodents, exposure to acute inescapable, but not escapable, stress potentiates morphine conditioned place preference (CPP), an effect that is dependent upon hyperactivation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Six weeks of voluntary wheel running constrains activation of DRN 5-HT neurons during exposure to inescapable stress. Six weeks of voluntary wheel running before inescapable stress blocked stress-induced potentiation of morphine CPP.
doi:10.1016/j.bbr.2011.01.030
PMCID: PMC3062637  PMID: 21262267
exercise; stress; morphine; addiction; serotonin; learned helplessness
20.  Physiological Consequences of Repeated Exposures to Conditioned Fear 
Behavioral Sciences  2012;2(2):57-78.
Activation of the stress response evokes a cascade of physiological reactions that may be detrimental when repeated or chronic, and when triggered after exposure to psychological/emotional stressors. Investigation of the physiological mechanisms responsible for the health damaging effects requires animal paradigms that repeatedly evoke a response to psychological/emotional stressors. To this end, adult male Sprague Dawley rats were repeatedly exposed (2X per day for 20 days) to a context that they were conditioned to fear (conditioned fear test, CFT). Repeated exposure to CFT produced body weight loss, adrenal hypertrophy, thymic involution, and basal corticosterone elevation. In vivo biotelemetry measures revealed that CFT evokes sympathetic nervous system driven increases in heart rate (HR), mean arterial pressure (MAP), and core body temperature. Extinction of behavioral (freezing) and physiological responses to CFT was prevented using minimal reinstatement footshock. MAP responses to the CFT did not diminish across 20 days of exposure. In contrast, HR and cardiac contractility responses declined by day 15, suggesting a shift toward vascular-dominated MAP (a pre-clinical marker of CV dysfunction). Flattened diurnal rhythms, common to stress-related mood/anxiety disorders, were found for most physiological measures. Thus, repeated CFT produces adaptations indicative of the health damaging effects of psychological/emotional stress.
doi:10.3390/bs2020057
PMCID: PMC4217585  PMID: 25379216
stress; diurnal rhythms; blood pressure; stress-induced hyperthermia
21.  Long term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway 
Behavioural brain research  2010;217(2):354-362.
The mesolimbic reward pathway is implicated in stress-related psychiatric disorders and is a potential target of plasticity underlying the stress resistance produced by repeated voluntary exercise. It is unknown, however, whether rats find long-term access to running wheels rewarding, or if repeated voluntary exercise reward produces plastic changes in mesolimbic reward neurocircuitry. In the current studies, young adult, male Fischer 344 rats allowed voluntary access to running wheels for 6 weeks, but not 2 weeks, found wheel running rewarding, as measured by conditioned place preference (CPP). Consistent with prior reports and the behavioral data, 6 weeks of wheel running increased ΔFosB/FosB immunoreactivity in the nucleus accumbens (Acb). In addition, semi quantitative in situ hybridization revealed that 6 weeks of wheel running, compared to sedentary housing, increased tyrosine hydroxylase (TH) mRNA levels in the ventral tegmental area (VTA), increased delta opioid receptor (DOR) mRNA levels in the Acb shell, and reduced levels of dopamine receptor (DR)-D2 mRNA in the Acb core. Results indicate that repeated voluntary exercise is rewarding and alters gene transcription in mesolimbic reward neurocircuitry. The duration-dependent effects of wheel running on CPP suggest that as the weeks of wheel running progress, the rewarding effects of a night of voluntary wheel running might linger longer into the inactive cycle thus providing stronger support for CPP. The observed plasticity could contribute to the mechanisms by which exercise reduces the incidence and severity of substance abuse disorders, changes the rewarding properties of drugs of abuse, and facilitates successful coping with stress.
doi:10.1016/j.bbr.2010.11.005
PMCID: PMC3021978  PMID: 21070820
Exercise; physical activity; conditioned place preference; ventral tegmental area; nucleus accumbens; FosB
22.  The neurobiology of the stress-resistant brain 
Stress (Amsterdam, Netherlands)  2011;14(5):498-502.
The 2010 Neurobiology of Stress Workshop brought together scientists from all over the world to share and discuss their results from studies examining the consequences of acute, repeated, and chronic stressor exposure on health and disease. Session IV entitled “The neurobiology of the stress-resistant brain” explored how we can intervene to promote stress resistance and stress resilience. Four scientists, who explore this topic from unique and convergent perspectives, presented their experimental results derived from studies in rat (Fleshner and Maier), non-human primates (Lyons), and human (Raskind). Summaries of each presentation, supporting publications, and overall take-home messages from the session are presented.
doi:10.3109/10253890.2011.596865
PMCID: PMC3287388  PMID: 21790482
Stress resistance; stress resilience; exercise; controllability; neurogenesis; post-traumatic stress disorder
23.  A behavioral analysis of the impact of voluntary physical activity on hippocampus-dependent contextual conditioning 
Hippocampus  2009;19(10):988-1001.
Voluntary physical activity induces molecular changes in the hippocampus consistent with improved hippocampal function, but few studies have explored the effects of wheel running on specific hippocampal-dependent learning and memory processes. The current studies investigated the impact of voluntary wheel running on learning and memory for context and extinction using contextual fear conditioning which is known to be dependent on the hippocampus. When conditioning occurred prior to the start of 6 weeks of wheel running, wheel running had no effect on memory for context or extinction (assessed with freezing). In contrast, when wheel running occurred for 6 weeks prior to conditioning, physical activity improved contextual memory during a retention test 24 hours later, but did not affect extinction learning or memory. Wheel running had no effect on freezing immediately after foot shock presentation during conditioning, suggesting that physical activity does not affect the acquisition of the context – shock association or alter the expression of freezing, per se. Instead, it is argued that physical activity improves the consolidation of contextual memories in the hippocampus. Consistent with improved hippocampus-dependent context learning and memory, 6 weeks of wheel running also improved context discrimination and reduced the context pre-exposure time required to form a strong contextual memory. The effect of wheel running on brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in hippocampal and amygdala subregions was also investigated. Wheel running increased BDNF mRNA in the dentate gyrus, CA1, and the basolateral amygdala. Results are consistent with improved hippocampal function following physical activity.
doi:10.1002/hipo.20534
PMCID: PMC3287390  PMID: 19115374
Wheel running; amygdala; brain-derived neurotrophic factor; extinction; generalization
24.  5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress 
Biological Psychiatry  2009;67(4):339-345.
Background
Exposure to uncontrollable stressors often increases anxiety-like behavior in both humans and rodents. In rat, this effect depends upon stress-induced activity within the dorsal raphé nucleus (DRN). However, the role of serotonin in DRN projection regions is largely unknown. The goals of the current study were to 1) determine if DRN activity during a post-stress anxiety test is involved in anxiety-like behavior, 2) assess the effect of uncontrollable stress on extracellular serotonin in the basolateral amygdala during the anxiety test, and 3) determine the role of the serotonin 2C receptor (5-HT2C) in uncontrollable stress-induced anxiety.
Method
Rats were exposed to tailshocks that were uncontrollable. On the following day anxiety-like behavior was assessed in a JSE test. BLA extracellular serotonin concentrations were assessed during JSE by in vivo microdialysis 24 h after uncontrollable stress, controllable stress or no stress. In separate experiments drugs were administered before the JSE test to inhibit the DRN or to block 5-HT2C receptors.
Results
Exposure to uncontrollable shock reduced later social exploration. Prior uncontrollable stress potentiated serotonin efflux in the BLA during social exploration, but controllable stress did not. Intra-DRN 8-OH-DPAT and systemic and intra-BLA 5-HT2C receptor antagonist SB 242084 prevented the expression of potentiated anxiety in uncontrollably stressed rats. Intra-BLA injection of the 5-HT2C agonist CP 809101 mimicked the effect of stress.
Conclusion
These results suggest that the anxiety-like behavior observed after uncontrollable stress is mediated by exaggerated 5-HT acting at BLA 5-HT2C receptors.
doi:10.1016/j.biopsych.2009.09.011
PMCID: PMC3278236  PMID: 19914601
rat; learned helplessness; ptsd; serotonin; social exploration; 5-HT2c
25.  Lesions of the basolateral amygdala reverse the long-lasting interference with shuttle box escape produced by uncontrollable stress 
Behavioural brain research  2010;211(1):71-76.
Exposure to an uncontrollable, but not a controllable, stressor produces a constellation of behaviors called learned helplessness. In rodents, uncontrollable stress interferes with the ability to learn to escape from escapable shocks delivered in a shuttle box. The stress-induced shuttle box escape deficit is a common screening tool for potential antidepressant strategies. Inconsistencies in the literature exist regarding the time-course of, and mechanisms underlying, stress-induced escape deficits. When no common cues are shared between the stressor and testing environment, the escape deficit is short lived and independent of conditioned freezing. In contrast, when stress and testing occur in the same or similar environments, the escape deficit is very long-lasting. The current studies address the hypothesis that the long-lived escape deficit produced by uncontrollable stress is dependent upon conditioned fear and the basolateral amygdala (BLA). Rats received bilateral excitotoxic lesions of the BLA 2 wk following uncontrollable foot shocks. One wk after surgery, rats were tested for conditioned freezing and escape behavior in the same shuttle boxes in which prior foot shocks were delivered. Stressed rats with sham lesions displayed robust conditioned freezing and failed to escape during shuttle box testing. Lesions of the BLA eliminated conditioned freezing and completely restored stressed rats' ability to perform the escape contingency. These data indicate that the long-lived stress-induced escape deficit produced under conditions in which the stressor and testing environments share common cues is dependent upon conditioned freezing elicited by the BLA. Results have important implications for the mechanisms underlying learned helplessness phenomena.
doi:10.1016/j.bbr.2010.03.012
PMCID: PMC2862138  PMID: 20226213
Learned helplessness; conditioned fear; stress; depression; freezing; inescapable shock; anxiety

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