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1.  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.
PMCID: PMC3637963  PMID: 23454291
Controllability; Stress; Diurnal Rhythm; Heart Rate; Body Temperature; Locomotor Activity
2.  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.
PMCID: PMC3548944  PMID: 23075500
3.  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.
PMCID: PMC3477269  PMID: 22769435
4.  Correction: 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  2013;8(8):10.1371/annotation/c7a5bcbd-3464-4e9e-bf74-e1aafe3f685b.
PMCID: PMC3752022  PMID: 23990859
5.  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.
PMCID: PMC3402647  PMID: 22610051
wheel running; depression; anxiety; learned helplessness; serotonin; social exploration
6.  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.
PMCID: PMC3650681  PMID: 23717271
Affymetrix gene microarray; Weighted Gene Correlational Network Analysis; bioinformatics; laser capture microdissection; stress resistance; dorsal raphe nucleus
7.  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.
PMCID: PMC3517493  PMID: 23236381
8.  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.
PMCID: PMC3235414  PMID: 21958863
Uncontrollable stress; serotonin; anxiety; amygdala; learned helplessness; instrumental learning
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.
PMCID: PMC3205218  PMID: 21907418
rats; proinflammatory cytokines; sickness response; sensitization; telemetry
10.  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.
PMCID: PMC3458100  PMID: 23049953
11.  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.
PMCID: PMC3444461  PMID: 23028992
12.  Interleukin-1 beta: a potential link between stress and the development of visceral obesity 
BMC Physiology  2012;12:8.
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.
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.
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.
PMCID: PMC3404929  PMID: 22738239
13.  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.
PMCID: PMC3062637  PMID: 21262267
exercise; stress; morphine; addiction; serotonin; learned helplessness
14.  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.
PMCID: PMC3021978  PMID: 21070820
Exercise; physical activity; conditioned place preference; ventral tegmental area; nucleus accumbens; FosB
15.  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.
PMCID: PMC3287388  PMID: 21790482
Stress resistance; stress resilience; exercise; controllability; neurogenesis; post-traumatic stress disorder
16.  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.
PMCID: PMC3287390  PMID: 19115374
Wheel running; amygdala; brain-derived neurotrophic factor; extinction; generalization
17.  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.
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.
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.
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.
These results suggest that the anxiety-like behavior observed after uncontrollable stress is mediated by exaggerated 5-HT acting at BLA 5-HT2C receptors.
PMCID: PMC3278236  PMID: 19914601
rat; learned helplessness; ptsd; serotonin; social exploration; 5-HT2c
18.  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.
PMCID: PMC2862138  PMID: 20226213
Learned helplessness; conditioned fear; stress; depression; freezing; inescapable shock; anxiety
19.  Stress Rapidly Increases Alpha-1d Adrenergic Receptor mRNA in the Rat Dentate Gyrus 
Brain research  2010;1323:109-118.
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 minutes 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.
PMCID: PMC2888891  PMID: 20138850
noradrenergic; dentate gyrus; hippocampus; alpha 1d adrenergic receptor; stress; exercise
20.  Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury 
Previous studies have shown that heat shock protein 72 (Hsp72) is found in the extracellular space (eHsp72) and that eHsp72 has potent immunomodulatory effects. However, whether eHsp72 is present in the distal air spaces and whether eHsp72 could modulate removal of alveolar edema is unknown. The first objective was to determine whether Hsp72 is released within air spaces and whether Hsp72 levels in pulmonary edema fluid would correlate with the capacity of the alveolar epithelium to remove alveolar edema fluid in patients with ALI/ARDS. Patients with hydrostatic edema served as controls. The second objective was to determine whether activation of the stress protein response (SPR) caused the release of Hsp72 into the extracellular space in vivo and in vitro and to determine whether SPR activation and/or eHsp72 itself would prevent the IL-1β-mediated inhibition of the vectorial fluid transport across alveolar type II cells. We found that eHsp72 was present in plasma and pulmonary edema fluid of ALI patients and that eHsp72 was significantly higher in pulmonary edema fluid from patients with preserved alveolar epithelial fluid clearance. Furthermore, SPR activation in vivo in mice and in vitro in lung endothelial, epithelial, and macrophage cells caused intracellular expression and extracellular release of Hsp72. Finally, SPR activation, but not eHsp72 itself, prevented the decrease in alveolar epithelial ion transport induced by exposure to IL-1β. Thus SPR may protect the alveolar epithelium against oxidative stress associated with experimental ALI, and eHsp72 may serve as a marker of SPR activation in the distal air spaces of patients with ALI.
PMCID: PMC2765126  PMID: 16679378
pulmonary edema; alveolar fluid clearance; heat shock response; respiratory distress syndrome; heat shock protein 70
21.  Role of Central β-Adrenergic Receptors in Regulating Proinflammatory Cytokine Responses to a Peripheral Bacterial Challenge 
Brain, behavior, and immunity  2008;22(7):1078-1086.
Elevation of proinflammatory cytokines in the brain have potent effects on altering physiological, behavioral, and cognitive processes. The mechanism(s) by which brain cytokines are induced during a peripheral immune challenge remains unclear since microorganisms/cytokines do not cross the blood-brain barrier (BBB). Recent studies indicate that central β-adrenergic receptors (β-ADRs) may mediate brain interleukin-1beta (IL-1) production. This has direct implications for the production of brain cytokines during a peripheral immune response since peripheral pathogens and cytokines rapidly stimulate brainstem catecholamine neurons via peripheral nerves and circumventricular pathways. Studies here examine the role of central β-ADRs in regulating brain cytokine production following peripheral Escherichia coli (E.coli) challenge. Rats were centrally administered propranolol (β-ADR antagonist) or vehicle followed by peripheral E.coli or saline and sacrificed 6h later for measurement of cytokines. Pretreatment with propranolol completely blocked the induction of brain IL-1 following E.coli. Surprisingly, central propranolol also attenuated E.coli-induced peripheral cytokines. To examine whether the attenuated peripheral cytokine response following central propranolol administration was due leakage of propranolol into the general circulation and blockade of peripheral β-blockade, nadolol (β-ADR antagonist that does not cross the BBB) was administered peripherally prior to E.coli. Nadolol administration did not block central cytokine production following E.coli, but instead enhanced both peripheral and central proinflammatory cytokine production. Furthermore, central administration of isoproterenol (β-ADR agonist) results in a time-dependent increase in brain IL-1 production. These data demonstrate central β-ADRs may play a critical role to induce brain IL-1, while peripheral β-ADRs inhibit cytokine response to bacterial challenge.
PMCID: PMC2603469  PMID: 18468841
catecholamine; brain; E.coli; norepinephrine; propranolol; IL-1
22.  Tianeptine: An Antidepressant with Memory-Protective Properties 
Current Neuropharmacology  2008;6(4):311-321.
The development of effective pharmacotherapy for major depression is important because it is such a widespread and debilitating mental disorder. Here, we have reviewed preclinical and clinical studies on tianeptine, an atypical antidepressant which ameliorates the adverse effects of stress on brain and memory. In animal studies, tianeptine has been shown to prevent stress-induced morphological sequelae in the hippocampus and amygdala, as well as to prevent stress from impairing synaptic plasticity in the prefrontal cortex and hippocampus. Tianeptine also has memory-protective characteristics, as it blocks the adverse effects of stress on hippocampus-dependent learning and memory. We have further extended the findings on stress, memory and tianeptine here with two novel observations: 1) stress impairs spatial memory in adrenalectomized (ADX), thereby corticosterone-depleted, rats; and 2) the stress-induced impairment of memory in ADX rats is blocked by tianeptine. These findings are consistent with previous research which indicates that tianeptine produces anti-stress and memory-protective properties without altering the response of the hypothalamic-pituitary-adrenal axis to stress. We conclude with a discussion of findings which indicate that tianeptine accomplishes its anti-stress effects by normalizing stress-induced increases in glutamate in the hippocampus and amygdala. This finding is potentially relevant to recent research which indicates that abnormalities in glutamatergic neurotransmission are involved in the pathogenesis of depression. Ultimately, tianeptine’s prevention of depression-induced sequelae in the brain is likely to be a primary factor in its effectiveness as a pharmacological treatment for depression.
PMCID: PMC2701287  PMID: 19587852
Depression; tianeptine; stress; memory; synaptic plasticity; animal models.
23.  Chronic voluntary wheel running facilitates corticosterone response habituation to repeated audiogenic stress exposure in male rats 
Stress (Amsterdam, Netherlands)  2008;11(6):425-437.
Voluntary exercise is associated with the prevention and treatment of numerous physical and psychological illnesses, yet the mechanisms by which it confers this protection remain unclear. In contrast, stress, particularly under conditions of prolonged or repeated exposure when glucocorticoid levels are consistently elevated, can have a devastating impact on health. It has been suggested that the benefits of physical exercise may lie in an ability to reduce some of the more deleterious health effects of stress and stress hormones. The present series of experiments provides evidence that voluntary exercise facilitates habituation of corticosterone but not adrenocorticotropin hormone responses to repeated stress presentations. After 6 weeks of running wheel access or sedentary housing conditions, rats were exposed to 11 consecutive daily 30 min presentations of 98 dB noise stress. Similar corticosterone responses in exercised rats and sedentary controls were observed following the first, acute stress presentation. While both groups demonstrated habituation of corticosterone secretory responses with repeated noise stress exposures, the rate of habituation was significantly facilitated in exercised animals. These results suggest that voluntary exercise may reduce the negative impact of prolonged or repeated stress on health by enhancing habituation of hypothalamo-pituitary–adrenocortical axis responses at the level of the adrenal cortex, ultimately reducing the amount of glucocorticoids the body and brain are exposed to.
PMCID: PMC2600621  PMID: 19065456
Adaptation; corticosterone; HPA-axis; repeated stress; voluntary exercise
24.  Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats 
We have studied the effects of an acute predator stress experience on spatial learning and memory in adult male and female Sprague-Dawley rats. All rats were trained to learn the location of a hidden escape platform in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. In the control (non-stress) condition, female rats were superior to the males in the accuracy and consistency of their spatial memory performance tested over multiple days of training. In the stress condition, rats were exposed to the cat for 30 min immediately before or after learning, or before the 24-h memory test. Predator stress dramatically increased corticosterone levels in males and females, with females exhibiting greater baseline and stress-evoked responses than males. Despite these sex differences in the overall magnitudes of corticosterone levels, there were significant sex-independent correlations involving basal and stress-evoked corticosterone levels, and memory performance. Most importantly, predator stress impaired short-term memory, as well as processes involved in memory consolidation and retrieval, in male and female rats. Overall, we have found that an intense, ethologically relevant stressor produced a largely equivalent impairment of memory in male and female rats, and sex-independent corticosterone-memory correlations. These findings may provide insight into commonalities in how traumatic stress affects the brain and memory in men and women.
PMCID: PMC2327269  PMID: 18391188
25.  Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder 
Stress (Amsterdam, Netherlands)  2008;11(4):259-281.
People who are exposed to horrific, life-threatening experiences are at risk for developing post-traumatic stress disorder (PTSD). Some of the symptoms of PTSD include persistent anxiety, exaggerated startle, cognitive impairments and increased sensitivity to yohimbine, an α2-adrenergic receptor antagonist. We have taken into account the conditions known to induce PTSD, as well as factors responsible for long-term maintenance of the disorder, to develop an animal model of PTSD. Adult male Sprague–Dawley rats were administered a total of 31 days of psychosocial stress, composed of acute and chronic components. The acute component was a 1-h stress session (immobilization during cat exposure), which occurred on Days 1 and 11. The chronic component was that on all 31 days the rats were given unstable housing conditions. We found that psychosocially stressed rats had reduced growth rate, reduced thymus weight, increased adrenal gland weight, increased anxiety, an exaggerated startle response, cognitive impairments, greater cardiovascular and corticosterone reactivity to an acute stressor and heightened responsivity to yohimbine. This work demonstrates the effectiveness of acute inescapable episodes of predator exposure administered in conjunction with daily social instability as an animal model of PTSD.
PMCID: PMC2535807  PMID: 18574787
Animal model; anxiety; corticosterone; post-traumatic stress disorder (PTSD); trauma; startle

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