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1.  Influence of Post-Traumatic Stress Disorder on Neuroinflammation and Cell Proliferation in a Rat Model of Traumatic Brain Injury 
PLoS ONE  2013;8(12):e81585.
Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed cell proliferation may evolve into more severe neurodegenerative diseases and psychiatric disorders currently being recognized in traumatized TBI patients.
doi:10.1371/journal.pone.0081585
PMCID: PMC3857205  PMID: 24349091
2.  Brief Treatment of Co-Occurring Post-Traumatic Stress and Depressive Symptoms by Use of Accelerated Resolution Therapy® 
This uncontrolled prospective cohort study evaluated the use of accelerated resolution therapy (ART) for treatment of comorbid symptoms of post-traumatic stress disorder (PTSD) and major depressive disorder. Twenty-eight adult subjects, mean age of 41 years (79% female, 36% Hispanic), received a mean of 3.7 ± 1.1 ART treatment sessions (range 1–5). ART is a new exposure-based psychotherapy that makes use of eye movements. Subjects completed a range of self-report psychological measures before and after treatment with ART including the 17-item PCL-C checklist (symptoms of PTSD) and 20-item Center for Epidemiologic Studies Depression Scale (CES-D). For the PCL-C, the pre-ART mean (±standard deviation) was 62.5 (8.8) with mean reductions of −29.6 (12.5), −30.1 (13.1), and −31.4 (14.04) at post-ART, 2-month, and 4-month follow-up, respectively (p < 0.0001 for comparisons to pre-ART score). Compared to pre-ART status, this corresponded to standardized effect sizes of 2.37, 2.30, and 3.01, respectively. For the CES-D, the pre-ART mean was 35.1 (8.8) with mean reductions of −20.6 (11.0), −18.1 (11.5), and −15.6 (14.4) at post-ART, 2-month, and 4-month follow-up, respectively (p ≤ 0.0001 compared to Pre-ART score). This corresponded to standardized effect sizes of 1.88, 1.58, and 1.09, respectively. Strong correlations were observed at 2-month and 4-month follow-up for post-treatment changes in PTSD and depression symptom scores (r = 0.79, r = 0.76, respectively, p ≤ 0.0002). No serious treatment-related adverse effects were reported. In summary, ART appears to be a promising brief, safe, and effective treatment for adults with clinically significant comorbid symptoms of PTSD and depression. Future controlled and mechanistic studies with this emerging therapy are warranted, particularly given its short treatment duration, and in light of current heightened emphasis on health care cost constraints.
doi:10.3389/fpsyt.2013.00011
PMCID: PMC3591743  PMID: 23482431
psychological trauma; PTSD; depression; exposure therapy; eye movements; brief treatment
3.  Epigenetic Modification of Hippocampal Bdnf DNA in Adult Rats in an Animal Model of Post-Traumatic Stress Disorder 
Journal of Psychiatric Research  2011;45(7):919-926.
Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been linked with memory, stress, and neuropsychiatric disorders. Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and BdnfDNA methylation. Adult male Sprague-Dawley rats were given psychosocial stress composed of two acute cat exposures in conjunction with 31 days of daily social instability. These manipulations have been shown previously to produce physiological and behavioral sequelae in rats that are comparable to symptoms observed in traumatized people with PTSD. We then assessed BdnfDNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased BdnfDNA methylation in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion. Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3). No changes in BdnfDNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of BdnfmRNA in both the dorsal and ventral CA1. These results provide evidence that traumatic stress occurring in adulthood can induce CNS gene methylation, and specifically, support the hypothesis that epigenetic marking of the Bdnfgene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal BdnfDNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD.
doi:10.1016/j.jpsychires.2011.01.013
PMCID: PMC3335738  PMID: 21306736
Animal model; post-traumatic stress disorder (PTSD); epigenetic; DNA methylation; brain-derived neurotrophic factor (Bdnf) gene; hippocampus
4.  Linear and Non-Linear Dose-Response Functions Reveal a Hormetic Relationship Between Stress and Learning 
Dose-Response  2008;7(2):132-148.
Over a century of behavioral research has shown that stress can enhance or impair learning and memory. In the present review, we have explored the complex effects of stress on cognition and propose that they are characterized by linear and non-linear dose-response functions, which together reveal a hormetic relationship between stress and learning. We suggest that stress initially enhances hippocampal function, resulting from amygdala-induced excitation of hippocampal synaptic plasticity, as well as the excitatory effects of several neuromodulators, including corticosteroids, norepinephrine, corticotropin-releasing hormone, acetylcholine and dopamine. We propose that this rapid activation of the amygdala-hippocampus brain memory system results in a linear dose-response relation between emotional strength and memory formation. More prolonged stress, however, leads to an inhibition of hippocampal function, which can be attributed to compensatory cellular responses that protect hippocampal neurons from excitotoxicity. This inhibition of hippocampal functioning in response to prolonged stress is potentially relevant to the well-described curvilinear dose-response relationship between arousal and memory. Our emphasis on the temporal features of stress-brain interactions addresses how stress can activate, as well as impair, hippocampal functioning to produce a hormetic relationship between stress and learning.
doi:10.2203/dose-response.08-015.Zoladz
PMCID: PMC2695571  PMID: 19543480
hippocampus; amygdala; corticosterone; dose-response; stress; memory
5.  The Temporal Dynamics Model of Emotional Memory Processing: A Synthesis on the Neurobiological Basis of Stress-Induced Amnesia, Flashbulb and Traumatic Memories, and the Yerkes-Dodson Law 
Neural Plasticity  2007;2007:60803.
We have reviewed research on the effects of stress on LTP in the hippocampus, amygdala and prefrontal cortex (PFC) and present new findings which provide insight into how the attention and memory-related functions of these structures are influenced by strong emotionality. We have incorporated the stress-LTP findings into our “temporal dynamics” model, which provides a framework for understanding the neurobiological basis of flashbulb and traumatic memories, as well as stress-induced amnesia. An important feature of the model is the idea that endogenous mechanisms of plasticity in the hippocampus and amygdala are rapidly activated for a relatively short period of time by a strong emotional learning experience. Following this activational period, both structures undergo a state in which the induction of new plasticity is suppressed, which facilitates the memory consolidation process. We further propose that with the onset of strong emotionality, the hippocampus rapidly shifts from a “configural/cognitive map” mode to a “flashbulb memory” mode, which underlies the long-lasting, but fragmented, nature of traumatic memories. Finally, we have speculated on the significance of stress-LTP interactions in the context of the Yerkes-Dodson Law, a well-cited, but misunderstood, century-old principle which states that the relationship between arousal and behavioral performance can be linear or curvilinear, depending on the difficulty of the task.
doi:10.1155/2007/60803
PMCID: PMC1906714  PMID: 17641736
6.  Apparent Behavioral Benefits of Tau Overexpression in P301L Tau Transgenic Mice 
Transgenic mice expressing human tau containing the P301L tau mutation (JNPL3; tau mice) develop motor neuron loss, paralysis and death between 7 and 12 months. Surprisingly, at 5 and 7 months of age, tau transgenic mice were superior to other genotypes in the rotarod task, and had near perfect scores on the balance beam and coat hanger tests. One tau transgenic mouse was performing at a superior level in the rotarod one day prior to developing paralysis. Cognitive function was also normal in the tau mice evaluated in the radial arm water maze and the Y-maze tasks. We also crossed the tau transgenic mice with Tg2576 amyloid-β protein precursor (AβPP) transgenic mice. Although AβPP mice were deficient in the radial arm maze task, AβPP+tau mice were not impaired, implying a benefit of the tau transgene. Some mice were homozygous for the retinal degeneration mutation (rd/rd) and excluded from the genotype analysis. Only the water maze task discriminated the rd/rd mice from nontransgenic mice. In conclusion, it seems that the modest tau overexpression or the presence of mutant tau in the JNPL3 tau mice may provide some benefit with respect to motor and cognitive performance before the onset of paralysis.
PMCID: PMC3018352  PMID: 19096159
tau; amyloid; water maze; rotarod; Y-maze; transgenic mice
7.  Influence of Pre-Training Predator Stress on the Expression of c-fos mRNA in the Hippocampus, Amygdala, and Striatum Following Long-Term Spatial Memory Retrieval 
We have studied the influence of pre-training psychological stress on the expression of c-fos mRNA following long-term spatial memory retrieval. Rats were trained to learn the location of a hidden escape platform in the radial-arm water maze, and then their memory for the platform location was assessed 24 h later. Rat brains were extracted 30 min after the 24-h memory test trial for analysis of c-fos mRNA. Four groups were tested: (1) Rats given standard training (Standard); (2) Rats given cat exposure (Predator Stress) 30 min prior to training (Pre-Training Stress); (3) Rats given water exposure only (Water Yoked); and (4) Rats given no water exposure (Home Cage). The Standard trained group exhibited excellent 24 h memory which was accompanied by increased c-fos mRNA in the dorsal hippocampus and basolateral amygdala (BLA). The Water Yoked group exhibited no increase in c-fos mRNA in any brain region. Rats in the Pre-Training Stress group were classified into two subgroups: good and bad memory performers. Neither of the two Pre-Training Stress subgroups exhibited a significant change in c-fos mRNA expression in the dorsal hippocampus or BLA. Instead, stressed rats with good memory exhibited significantly greater c-fos mRNA expression in the dorsolateral striatum (DLS) compared to stressed rats with bad memory. This finding suggests that stressed rats with good memory used their DLS to generate a non-spatial (cue-based) strategy to learn and subsequently retrieve the memory of the platform location. Collectively, these findings provide evidence at a molecular level for the involvement of the hippocampus and BLA in the retrieval of spatial memory and contribute novel observations on the influence of pre-training stress in activating the DLS in response to long-term memory retrieval.
doi:10.3389/fnbeh.2011.00030
PMCID: PMC3125520  PMID: 21738501
rat; c-fos; hippocampus; striatum; amygdala; spatial memory
8.  The neurobiological properties of Tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation 
Molecular psychiatry  2009;15(3):237-249.
Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key role of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine’s mechanism of action with a focus on the glutamatergic system which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.
doi:10.1038/mp.2009.80
PMCID: PMC2902200  PMID: 19704408
Tianeptine; hippocampus; amygdala; stress; antidepressant
9.  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.
doi:10.2174/157015908787386096
PMCID: PMC2701287  PMID: 19587852
Depression; tianeptine; stress; memory; synaptic plasticity; animal models.
10.  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.
doi:10.1101/lm.721108
PMCID: PMC2327269  PMID: 18391188
11.  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.
doi:10.1080/10253890701768613
PMCID: PMC2535807  PMID: 18574787
Animal model; anxiety; corticosterone; post-traumatic stress disorder (PTSD); trauma; startle
12.  Combination of high fat diet and chronic stress retracts hippocampal dendrites 
Neuroreport  2005;16(1):39-43.
Adult male rats were fed a low or high fat diet and given psychosocial stress (crowded and unstable housing with daily predator exposure) for 3 weeks. Neither stress nor high fat diet, alone, produced dendritic atrophy; only the group given the combination of stress and high fat diet developed a reduction of the length and number of branch points of apical dendrites of CA3 neurons. These findings indicate that a synergy between high fat diet and stress caused a retraction of CA3 dendrites. The findings are consistent with work on peripheral (e.g., cardiovascular) systems demonstrating a synergy between stress and high fat diet, and are relevant toward understanding how diet and stress interact to adversely a¡ectbrain and memory processing.
PMCID: PMC1363787  PMID: 15618887
Atrophy; Brain; CA3; High fat diet; Hippocampus; Psychological stress; Synergy
13.  Microinfusion of Pituitary Adenylate Cyclase-Activating Polypeptide into the Central Nucleus of Amygdala of the Rat Produces a Shift from an Active to Passive Mode of Coping in the Shock-Probe Fear/Defensive Burying Test 
Neural Plasticity  2007;2007:79102.
High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) nerve fibers are present in the central nucleus of amygdala (CeA), a brain region implicated in the control of fear-related behavior. This study evaluated PACAPergic modulation of fear responses at the CeA in male Sprague-Dawley rats. PACAP (50–100 pmol) microinfusion via intra-CeA cannulae produced increases in immobility and time the rats spent withdrawn into a corner opposite to the electrified probe compared to controls in the shock-probe fear/defensive burying test. Shock-probe burying and exploration, numbers of shocks received, locomotion distance, and velocity were all reduced by intra-CeA PACAP injection. Further, intra-CeA PACAP effects were manifested only when the animals were challenged by shock, as intra-CeA PACAP injections did not cause significant changes in the behaviors of unshocked rats. Thus, intra-CeA administration of PACAP produces a distinct reorganization of stress-coping behaviors from active (burying) to passive modes, such as withdrawal and immobility. These findings are potentially significant toward enhancing our understanding of the involvement of PACAP and the CeA in the neural basis of fear and anxiety.
doi:10.1155/2007/79102
PMCID: PMC1906870  PMID: 17641738
14.  Introduction 
Dose-Response  2006;4(1):1.
doi:10.2203/dose-response.004.01.001.Diamond
PMCID: PMC2477655
15.  Permissive Influence of Stress in the Expression of a U-Shaped Relationship Between Serum Corticosterone Levels and Spatial Memory Errors in Rats 
Dose-Response  2006;4(1):55-74.
The relationship between glucocorticoids (GCs) and memory is complex, in that memory impairments can occur in response to manipulations that either increase or decrease GC levels. We investigated this issue by assessing the relationship between serum corticosterone (the primary rodent GC) and memory in rats trained in the radial arm water maze, a hippocampus-dependent spatial memory task. Each day, rats learned a new location of the hidden escape platform and then 30 min later their memory of the location of the platform was tested. Under control conditions, well-trained rats had excellent spatial memory and moderately elevated corticosterone levels (~26 μg/dl versus a baseline of ~2 μg/dl). Their memory was impaired when corticosterone levels were either reduced by metyrapone (a corticosterone synthesis inhibitor) or increased by acute stress (predator exposure), forming an overall U-shaped relationship between corticosterone levels and memory. We then addressed whether there was a causal relationship between elevated corticosterone levels and impaired memory. If elevated corticosterone levels were a sufficient condition to impair memory, then exogenously administered corticosterone, alone, should have impaired performance. However, we found that spatial memory was not impaired in corticosterone-injected rats that were not exposed to the cat. This work demonstrates that an intermediate level of corticosterone correlated with optimal memory, and either a decrease or an increase in corticosterone levels, in conjunction with strong emotionality, impaired spatial memory. These findings indicate that fear-provoking conditions, which are known to engage the amygdala, interact with stress levels of corticosterone to influence hippocampal functioning.
doi:10.2203/dose-response.004.01.005.Park
PMCID: PMC2477653  PMID: 18648634
Glucocorticoids; Predator Stress; Hippocampus; Metyrapone; Water Maze; Amygdala, Rat
17.  Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS) 
Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people.
doi:10.1080/15401420490900290
PMCID: PMC2657507  PMID: 19330152
neurosteroid; dehydroepiandrosterone; DHEA; hippocampus; long-term potentiation; memory

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