Publications (33)82.52 Total impact
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Dataset: Zhang et al., '11
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Article: Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear.
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ABSTRACT: Although the endocannabinoid system (ECS) has been implicated in brain development and various psychiatric disorders, precise mechanisms of the ECS on mood and anxiety disorders remain unclear. Here, we have investigated developmental and disease-related expression pattern of the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2) genes in the dorsolateral prefrontal cortex (PFC) of humans. Using mice selectively bred for high and low fear, we further investigated potential association between fear memory and the cannabinoid receptor expression in the brain. The CB1, not the CB2, mRNA levels in the PFC gradually decrease during postnatal development ranging in age from birth to 50 years (r2 > 0.6 & adj. p < 0.05). The CB1 levels in the PFC of major depression patients were higher when compared to the age-matched controls (adj. p < 0.05). In mice, the CB1, not the CB2, levels in the PFC were positively correlated with freezing behavior in classical fear conditioning (p < 0.05). These results suggest that the CB1 in the PFC may play a significant role in regulating mood and anxiety symptoms. Our study demonstrates the advantage of utilizing data from postmortem brain tissue and a mouse model of fear to enhance our understanding of the role of the cannabinoid receptors in mood and anxiety disorders.Journal of psychiatric research 04/2012; 46(7):882-9. · 3.72 Impact Factor -
Article: Biomarkers in an Animal Model for Revealing Neural, Hematologic, and Behavioral Correlates of PTSD.
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ABSTRACT: Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for objective diagnosis but also for the evaluation of therapeutic efficacy and resilience to trauma. Ongoing research is directed at identifying molecular biomarkers for PTSD, including traumatic stress induced proteins, transcriptomes, genomic variances and genetic modulators, using biologic samples from subjects' blood, saliva, urine, and postmortem brain tissues. However, the correlation of these biomarker molecules in peripheral or postmortem samples to altered brain functions associated with psychiatric symptoms in PTSD remains unresolved. Here, we present an animal model of PTSD in which both peripheral blood and central brain biomarkers, as well as behavioral phenotype, can be collected and measured, thus providing the needed correlation of the central biomarkers of PTSD, which are mechanistic and pathognomonic but cannot be collected from people, with the peripheral biomarkers and behavioral phenotypes, which can. Our animal model of PTSD employs restraint and tail shocks repeated for three continuous days - the inescapable tail-shock model (ITS) in rats. This ITS model mimics the pathophysiology of PTSD (17, 7, 4, 10). We and others have verified that the ITS model induces behavioral and neurobiological alterations similar to those found in PTSD subjects (17, 7, 10, 9). Specifically, these stressed rats exhibit (1) a delayed and exaggerated startle response appearing several days after stressor cessation, which given the compressed time scale of the rat's life compared to a humans, corresponds to the one to three months delay of symptoms in PTSD patients (DSM-IV-TR PTSD Criterian D/E (13)), (2) enhanced plasma corticosterone (CORT) for several days, indicating compromise of the hypothalamopituitary axis (HPA), and (3) retarded body weight gain after stressor cessation, indicating dysfunction of metabolic regulation. The experimental paradigms employed for this model are: (1) a learned helplessness paradigm in the rat assayed by measurement of acoustic startle response (ASR) and a charting of body mass; (2) microdissection of the rat brain into regions and nuclei; (3) enzyme-linked immunosorbent assay (ELISA) for blood levels of CORT; (4) a gene expression microarray plus related bioinformatics tools (18). This microarray, dubbed rMNChip, focuses on mitochondrial and mitochondria-related nuclear genes in the rat so as to specifically address the neuronal bioenergetics hypothesized to be involved in PTSD.Journal of Visualized Experiments 01/2012; -
Article: Startle response related genes.
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ABSTRACT: The startle reaction (also known as the startle response, the startle reflex, or the alarm reaction) is the psychological and physiological response to a sudden unexpected stimulus, such as a flash of light, a loud noise (acoustic startle reflex), or a quick movement near the face. Abnormalities of startle response have been observed in many stress-related mental disorders, such as schizophrenia and post-traumatic stress disorder (PTSD). However, the molecular mechanisms of startle in stress-associated conditions--for example, whether the startle reaction is associated with any gene variance--is still unknown. In this paper, we will carry out a systematic review by retrieving, assessing, and combining, when applicable, individual studies investigating association of the molecular variation of candidate gene with the startle response. The systematic review is based on the search for numerous publications using the keywords "startle gene" on September 15, 2010 using PubMed, which comprises more than 20 million citations for biomedical literature from MEDLINE and life science journals. A total of 486 publications regarding genes associated with startle have been obtained and reviewed here. There are fewer than 20 publications associating genes with the startle response between 1979, when the first valuable paper was published, and 1999. However, publications have dramatically increase from 2001 and reaches over 70 in 2009. We have characterized them into three categories: startle-associated gene studies in humans, in animals, as well as in both human and animals. This review of research strategy may provide the information for identifying a biomarker for startle response, with the objective of translating research into clinical utility: diagnosis and treatment of stress-induced mental disorders.Medical Hypotheses 08/2011; 77(4):685-91. · 1.39 Impact Factor -
Article: P11 expression and PET in bipolar disorders.
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ABSTRACT: Bipolar disorder (BD) is a common mental disorder, subdivided into BD-I and BD-II. Currently, few biomarkers differentiate BD-I from BD-II. However, it is suggested that peripheral blood mononuclear cell (PBMC) mRNA levels of p11 and positron emission tomography (PET) might be potential biomarkers for BD. Healthy controls (HCs), BD-I, and BD-II patients in remission (n = 20 in each group) underwent a resting PET study with the radiotracer [(18)F]-2-deoxy-2-fluoro-d-glucose ((18)F-FDG). PBMC p11 mRNA levels were determined by quantitative real-time PCR. Comparing BD patients to HCs, normalized glucose metabolism (NGM) was higher in the hippocampus, parahippocampus, and amygdala, but lower in the anterior cingulate cortex (aCC), medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (dlPFC), insula and thalamus. Compared to BD-II, BD-I had hypometabolism of glucose in the aCC, bilateral middle and inferior gyrus, insula and striatum, and hypermetabolism of glucose in the left parahippocampus. PBMC p11 mRNA was over-expressed in both BD-I and BD-II, although there was no significant difference in its expression levels between BD-I and B-II patients. Further, there were significant positive correlations between PBMC p11 mRNA and NGM in the mPFC, aCC, left insula, bilateral orbitofrontal cortex (OFC), and left middle, inferior and superior temporal gyri. Also, PBMC p11 mRNA was positively correlated to the number of depressive episodes in BD patients, especially in BD-I patients. This study demonstrates that PBMC p11 mRNA expression is associated with neural activation in the brain of BD patients and warrants a larger translational study to determine its clinical utility.Journal of psychiatric research 06/2011; 45(11):1426-31. · 3.72 Impact Factor -
Article: Cannabinoid receptor expression and phosphorylation are differentially regulated between male and female cerebellum and brain stem after repeated stress: implication for PTSD and drug abuse.
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ABSTRACT: Recent study demonstrated a close relationship between cerebellum atrophy and symptom severity of pediatric maltreatment-related posttraumatic stress disorder (PTSD). It has also been known that females are more vulnerable than males in developing anxiety disorders after exposure to traumatic stress. The mechanisms are unknown. Because cannabinoid receptors (CB₁ and CB₂) are neuroprotective and highly expressed in the cerebellum, we investigated cerebellar CB expression in stressed rats. Young male and female Sprague-Dawley rats were given 40 unpredictable electric tail-shocks for 2h daily on 3 consecutive days. CB₁ and CB₂ mRNA and protein levels in rat cerebellum and brain stem were determined using quantitative real-time PCR and Western blot, respectively. Two-way ANOVA revealed significant gender and stress effects on cerebellar CB₁ mRNA expression, with females and non-stressed rats exhibiting higher CB₁ mRNA levels than the males (3 fold, p<0.01) and stressed rats (30%, p<0.01), respectively. CB₁ and CB₂ mRNA levels in brain stem were also greater in female rats than males (p<0.01, p<0.05, respectively). Repeated stress increased the level of phosphorylated CB₁ receptors, the inactivated CB₁, in rat cerebellum (p<0.01), particularly in female rats as revealed by the significant gender × stress interaction. Thus, repeated severe stress caused greater CB₁ mRNA suppression and CB₁ receptor phosphorylation in female cerebellum that could lead to increased susceptibility to stress-related anxiety disorders including PTSD.Neuroscience Letters 05/2011; 502(1):5-9. · 2.11 Impact Factor -
Article: P11 (S100A10) as a potential biomarker of psychiatric patients at risk of suicide.
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ABSTRACT: Although suicide represents 1.8% of the global burden of disease, there are few objective assays for suicide risk. Being associated with depressive disorders, which have a high risk of suicide, the proteins P11, P2RX7, and S100β may be biomarkers for a suicidal disposition. We measured levels of p11 and P2RX7 mRNA in peripheral blood mononuclear cells (PBMCs) of 26 psychiatric patients (11 suicide attempters, 15 suicide non-attempters) with post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), and 14 normal controls, using quantitative real-time PCR. We also conducted a meta-analysis of microarray data of p11, P2RX7 and S100β from post-mortem prefrontal cortex (PFC) of patients who committed suicide (n = 56) and non-suicide controls (n = 61). We found that PBMC p11 mRNA levels were significantly lower in suicide attempters and higher in suicide non-attempters, when compared to normal controls. The PFC p11 mRNA levels in suicide completers were also lower than non-suicide controls (adjusted p = 0.007). Unlike p11, PBMC P2RX7 mRNA levels were significantly lower than normal controls in all patients including suicide attempters, suicide non-attempters, and suicide completers. In addition, levels of S100β in PFC did not differ between suicide completers and non-suicide controls. These results suggest that PBMC p11 mRNA levels may be a potential adjunctive biomarker for the assessment of suicide risk in mental disorders and warrants a larger translational study to determine its clinical utility.Journal of psychiatric research 04/2011; 45(4):435-41. · 3.72 Impact Factor -
Article: Glucocorticoid-induced p11 over-expression and chromatin remodeling: a novel molecular mechanism of traumatic stress?
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ABSTRACT: While the actions of glucocorticoids on brain function have been comprehensively studied, understanding of the underlying genomic mechanisms is advancing slowly. Recently, it was found that p11 is associated with traumatic stress and depression, and glucocorticoids regulate expression of the p11 gene. The ligand-activated glucocorticoid receptor (GR) interacts with two glucocorticoid response elements (GREs) in the p11 promoter region to up-regulate the p11 gene. RU486, a glucocorticoid receptor antagonist, and mutation of GREs both block glucocorticoid-induced p11 over-expression, suggesting that glucocorticoid-induced p11 over-expression is mediated by GR and GREs. Thus, the p11 gene can be transcriptionally activated. There is evidence that this transcriptional activation is mediated by the remodeling of chromatin complexes in response to glucocorticoid receptor-regulated promotors. The regulation of eukaryotic gene expression by chromatin remodeling is complex and is essential for numerous cellular processes. The association of linker-histone, non-histone and heterochromatin-specific proteins plays a key role in the generation of higher-order chromatin structures. Understanding the chromatin remodeling involved in the glucocorticoid-mediated increase of p11 expression by stress may clarify stress-induced over-expression of p11 and also identify a new therapeutic target for post-traumatic disorder and depressive disorders, i.e., chromatin remodeling.Medical Hypotheses 02/2011; 76(6):774-7. · 1.39 Impact Factor -
Article: Posttraumatic stress disorder and traumatic stress: from bench to bedside, from war to disaster.
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ABSTRACT: War is a tragic event and its mental health consequences can be profound. Recent studies indicate substantial rates of posttraumatic stress disorder and other behavioral alterations because of war exposure. Understanding the psychological, behavioral, and neurobiological mechanism of mental health and behavioral changes related to war exposure is critical to helping those in need of care. Substantial work to encourage bench to bedside to community knowledge and communication is a core component of addressing this world health need.Annals of the New York Academy of Sciences 10/2010; 1208:72-81. · 3.15 Impact Factor -
Chapter: Heat Shock Proteins and Post-Traumatic Stress Disorder
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ABSTRACT: Heat shock proteins (HSPs), a highly conserved family of stress response proteins, play a very important role in traumatic stress associated with Post-traumatic Stress disorder (PTSD), a psychiatric disorder observed in a high number of combat veterans and in others exposed to natural disasters, traffic accidents, terrorist attacks, etc. In this chapter, we will briefly review the expression of HSPs in the central nervous system (CNS) and discuss the underlying molecular mechanisms of HSPs in PTSD. We will also present evidence regarding the possible role of HSPs in glucocorticoid receptor (GR) trafficking and in the regulation of p11, a PTSD-associated protein. Advances in the understanding of the functions of HSPs have reached a point where clinical trials are warranted to determine the role of HSPs in the treatment and diagnosis of PTSD Keywords:HSP-CNS-GR translocation-p11-mitochondrial function12/2009: pages 179-192; -
Article: 5-HT2A receptor antagonism by MDL 11,939 during inescapable stress prevents subsequent exaggeration of acoustic startle response and reduced body weight in rats.
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ABSTRACT: Activation of central 5-HT(2A) receptor signaling and its subsequent alterations have been implicated in the pathophysiological response to stress and the pathogenesis of stress-associated psychiatric disorders. To further examine the association between alterations in central 5-HT(2A) receptor signaling and the occurrence of stress-induced psychiatric symptoms, the present study, utilizing a learned helplessness stress model in rats, determined whether 5-HT(2A) receptor signaling blockade during stress could prevent the occurrence of stress-induced physical and behavioral abnormalities. Rats subjected to restraint/tail shock for three days developed long-lasting elevated acoustic startle response (ASR) and reduced body weight, compared to non-stressed control animals. However, administration of the selective 5-HT(2A) receptor antagonist, MDL 11,939 (α-phenyl-1-(2-phenylethyl)-4-piperidinemethanol), 30 min prior to exposure of the animals to the stress protocol prevented the subsequent occurrence of elevated ASR and reduced body weight in a dose-dependent manner in stressed subjects. Administration of MDL 11,939 to the animals immediately after exposure to the stress protocol also prevented the occurrence of exaggerated ASR, but was not able to normalize body weight. These findings suggest a critical role of the central 5-HT(2A) receptor activation in developing the pathophysiology associated with elevated ASR and reduced body weight during stress. The differential effects of MDL 11,939 on startle response and body weight and its potential clinical significance are discussed.Journal of Psychopharmacology 11/2009; 25(2):289-97. · 3.04 Impact Factor -
Article: A strategy for the development of biomarker tests for PTSD.
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ABSTRACT: Posttraumatic stress disorder (PTSD) is a chronic and disabling anxiety disorder that occurs after a traumatic event. It is associated with an increased risk of suicide and marked deficits in social and occupational functioning. Currently, the diagnosis for PTSD is established on the basis of a patient's clinical history, mental status examination, duration of symptoms, and clinician administered symptom checklists or patient self-reports. However, there are no available laboratory biomarker tests for PTSD. To begin intervention at the earliest possible time, priority must be given to developing objective approaches to determine the presence of PTSD. Thus, a simple blood test or a biomarker that could detect PTSD in its earliest and potentially most treatable stages would be beneficial for physicians and patients. Currently, many potential biomarkers have been identified in the animal model or in patients with PTSD. But those biomarkers have not been well validated. Here, we hypothesize the development of a strategy for the identification of a biomarker for PTSD. This strategy involves pre-clinical screening, analytical validations and clinical validations. This strategy will enhance not only the study of the molecular mechanisms of PTSD, but also the translation of basic science to clinical implications.Medical Hypotheses 06/2009; 73(3):404-9. · 1.39 Impact Factor -
Article: Topiramate reduces excitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons.
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ABSTRACT: Topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] is a structurally novel antiepileptic drug that has broad efficacy in epilepsy, but the mechanisms underlying its therapeutic activity are not fully understood. We have found that topiramate selectively inhibits GluK1 (GluR5) kainate receptor-mediated excitatory postsynaptic responses in rat basolateral amygdala (BLA) principal neurons and protects against seizures induced by the GluK1 kainate receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA). Here, we demonstrate that topiramate also modulates inhibitory function in the BLA. Using whole-cell recordings in rat amygdala slices, we found that 0.3 to 10 microM topiramate 1) inhibited ATPA-evoked postsynaptic currents recorded from BLA interneurons; 2) suppressed ATPA-induced enhancement of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from BLA pyramidal cells; and 3) blocked ATPA-induced suppression of evoked IPSCs, which is mediated by presynaptic GluK1 kainate receptors present on BLA interneurons. Topiramate (10 microM) had no effect on the AMPA [(R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid]-induced enhancement of spontaneous activity of BLA neurons. Thus, although topiramate inhibits GluK1 kainate receptor-mediated enhancement of interneuron firing, it promotes evoked GABA release, leading to a net inhibition of circuit excitability. In addition, we found that topiramate (0.3-10 microM) increased the amplitude of evoked, spontaneous, and miniature IPSCs in BLA pyramidal neurons, indicating an enhancement of postsynaptic GABA(A) receptor responses. Taken together with our previous findings, we conclude that topiramate protects against hyperexcitability in the BLA by suppressing the GluK1 kainate receptor-mediated excitation of principal neurons by glutamatergic afferents, blocking the suppression of GABA release from interneurons mediated by presynaptic GluK1 kainate receptors and directly enhancing GABA(A) receptor-mediated inhibitory currents.Journal of Pharmacology and Experimental Therapeutics 06/2009; 330(2):558-66. · 3.83 Impact Factor -
Article: Levels of the potential biomarker p11 in peripheral blood cells distinguish patients with PTSD from those with other major psychiatric disorders.
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ABSTRACT: Posttraumatic stress disorder (PTSD) is a severely debilitating anxiety disorder. Over 80% of patients with PTSD also exhibit other psychiatric condition, such as bipolar disorder (BP) or major depression (MDD). Previously, it has been found that p11 mRNA expression was significantly changed in post mortem cortex of patients with PTSD and depression. We hypothesize that p11 mRNA levels in the peripheral blood cells will be a potential biomarker for PTSD with heterogeneity in terms of type of trauma, time since trauma and duration of illness. We examined the peripheral blood mononuclear cell (PBMC) P11 mRNA of patients with PTSD (n=13), major depressive disorder (MDD, n=16), bipolar disorder (BP, n=24), and schizophrenia (SCZ, n=12) or controls (n=14) using quantitative real-time PCR and the circulating levels of cortisol in blood plasma and saliva of PTSD using radioimmunoassay kit CORT-CT2. The Hamilton Rating Scale for Depression (HAMD) and Anxiety (HARS), the Chinese version of the Davidson Trauma Scale-Frequency (CDTS-F) and the Chinese version of the Davidson Trauma Scale-Severity (CDTS-S), and Impact of Event Scale-Revised (IES-R) were administered. We found that patients with PTSD had lower levels of p11 mRNA than control subjects, while those with MDD, BP and SCZ had significantly higher p11 levels than the controls. P11 mRNA levels were positively correlated with the scores of HAMD (r=0.62, p<0.05), CDTS-F (r=0.71, p<0.05) and CDTS-S (r=0.62, p<0.05), while they did not correlate with scores of HARS and IES-R. Basal levels of plasma and salivary cortisol of PTSD patients were not statistically different from those of controls. Our findings suggest that PBMC p11 mRNA expression levels may serve as a potential biomarker to distinguish PTSD from BP, MDD and SCZ.Journal of psychiatric research 05/2009; 43(13):1078-85. · 3.72 Impact Factor -
Article: PTSD and traumatic stress from gene to community and bench to bedside.
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ABSTRACT: Individuals and communities are exposed to traumatic events, those that are accidents or naturally occurring and those that are intentional or human made. Although resilience is the expected response, for some, posttraumatic stress disorder may be the outcome. Brain models of PTSD require understanding the phenomenology of the disorder and the brain "break down" that occurs. Among several models, importantly, is the perspective that PTSD is a "forgetting" disorder. Other elements in the onset and triggers of PTSD can identify further models to examine at the bench. New studies of the 5-HT(2A) receptor, the glucocorticoid receptor, p11, mitochondrial genes and cannabinoids are bringing new perspectives to understanding brain function in PTSD. Effective treatments indicate areas for bench research on the mechanisms of the disorder.Brain research 04/2009; 1293:2-12. · 2.46 Impact Factor -
Article: The injury profile after the 2008 earthquakes in China.
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ABSTRACT: The 8.0 magnitude earthquake that struck China on May 12, 2008, was the deadliest earthquake in 30 years. Most hospitals were destroyed and limited facilities were available for medical service in the earthquake regions. Over the first 5 days, three general hospitals and one children's hospital admitted 1770 injured individuals. We retrospectively collected data on 1770 injured subjects in three general hospitals (n=1723) and one children's hospital (n=47) in the quake-area during the first 5 days after the event. The diagnosis for the injuries was based on the final hospital diagnosis made by the physicians and classified by two-independent researchers using the International Statistical Classification of Diseases and Related Health Problems ICD-10 (WHO ICD-10 Code.1993). To ensure the accuracy of the information, any questionable data was reviewed by phone with hospital staff. In three general hospitals, 848 patients (48%) were male and 922 (52%) were female. Nine percent (n=84) of females and 8.8% (n=75) of males were over the age of 75. Four (0.4%) females and 5 (0.5%) males were less than 1-year old. The most common injuries were the injuries of the knee, lower leg, ankle and foot (36%), followed by head injuries (18%). In the children's hospital, 31 (65%) of the patients were males and 16 (35%) were females. 40% of the subjects were 10-14, while 21% were less than 1-year old. The most frequently seen injuries were also of the knee, lower leg, ankle or foot (19%), and of the abdomen, lower back, lumbar spine and pelvis, and hip and thigh (15%). We gathered information from resources in Chinese, which at the time contained more records on this event than any documents in English. The age of the patients ranged from 7 days to 84 years old. Subjects over age 75 and children between 10 and 14 were the largest population in their respective hospitals, indicating that these groups required the greatest medical resources. The injury profile presented here serves as a reference not only for present injury intervention but also for future earthquake disaster response.Injury 01/2009; 40(1):84-6. · 1.98 Impact Factor -
Article: Stress impairs 5-HT2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala.
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ABSTRACT: The occurrence of stress and anxiety disorders has been closely associated with alterations of the amygdala GABAergic system. In these disorders, dysregulation of the serotonergic system, a very important modulator of the amygdala GABAergic system, is also well recognized. The present study, utilizing a learned helplessness stress rat model, was designed to determine whether stress is capable of altering serotonergic modulation of the amygdala GABAergic system. In control rats, administration of 5-HT or alpha-methyl-5-HT, a 5-HT(2) receptor agonist, to basolateral amygdala (BLA) slices dramatically enhanced frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). This effect was blocked by selective 5-HT(2A) receptor antagonists while a selective 5-HT(2B) receptor agonist and a selective 5-HT(2C) receptor agonist were without effect on sIPSCs. Double immunofluorescence labeling demonstrated that the 5-HT(2A) receptor is primarily localized to parvalbumin-containing BLA interneurons. Thus, serotonin primarily acts via 5-HT(2A) receptors to facilitate BLA GABAergic inhibition. In stressed rats, the 5-HT(2A) receptor-mediated facilitative actions were severely impaired. Quantitative RT-PCR and western blot analysis showed that the impairment of 5-HT(2A) receptor signaling primarily resulted from receptor downregulation. The stress-induced effect appeared to be specific to 5-HT(2A) receptors because stress had no significant impact on other serotonin receptors, as well as histamine H(3) receptor and alpha(2) adrenoceptor signaling in the BLA. This severe impairment of 5-HT(2A) receptor-mediated facilitation of BLA GABAergic inhibition might result in an amygdala circuitry with hyperexcitability, and a lower threshold of activation, and thus be an important mechanism underlying the emergence of stress-associated psychiatric symptoms.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2008; 34(2):410-23. · 6.99 Impact Factor -
Article: beta1- and beta2-adrenoceptor induced synaptic facilitation in rat basolateral amygdala.
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ABSTRACT: The expression and characteristics of beta-adrenoceptor subtypes (beta1 and beta2) and their agonist actions on synaptic transmission in the basolateral amygdala (BLA) of the rat were examined using in situ hybridization, quantitative real-time PCR, Western blot analysis and field potential recording. In situ hybridization data revealed an intense distribution of beta1-and beta2-adrenoceptor mRNA in the BLA. Real-time PCR analysis of rat amygdala revealed significant transcriptional expression levels of both beta-adrenoceptors, with beta2-adrenoceptors outnumbering beta1-adrenoceptors in a ratio of 2.9 to 1. Bath application of the selective beta1-adrenoceptor agonist xamoterol hemifumarate (10 microM) facilitated the excitatory field synaptic potential evoked in the BLA by stimulation of the external capsule by 186.5+/-10.7% of control amplitude. In the presence of the selective beta1-adrenoceptor antagonist betaxolol hydrochloride (30 microM), the facilitating effects of field excitatory synaptic potential induced by the agonist were reduced to 126.1+/-2.3 % of control amplitude in the BLA. Bath application of the selective beta2-adrenoceptor agonist salmeterol (15 microM) facilitated the excitatory field synaptic potential evoked in the BLA by stimulation of the external capsule by 167.3+/-9.7 % of control amplitude. In the presence of the selective beta2-adrenoceptor antagonist ICI 118,551 HCl (30 microM), the facilitating effects of field excitatory synaptic potential induced by the agonist were reduced to 121.1+/-4.1 % of control amplitude in the BLA. These data suggest that beta-adrenoceptor mediated synaptic facilitation in the amygdala is mediated by both beta1 and beta2-adrenoceptor activation.Brain Research 06/2008; 1209:65-73. · 2.73 Impact Factor -
Article: Models of PTSD and traumatic stress: the importance of research "from bedside to bench to bedside".
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ABSTRACT: The epidemiology and psychology of PTSD noted above is not often considered in neurobiological models of PTSD. Neurobiological models tend to focus on symptoms. This is an important perspective but it does not capture the brains total response to traumatic events. Similarly, neurobiologists have rarely used the extensive knowledge of animal behavioral responses to stress as a means to define the human stress phenomenology, looking for the human equivalent (rather than the other way around). The development of animal models for PTSD and other traumatic stress-related brain changes is an important part of advancing our neurobiological understanding of the disease process as well as recovery, resilience, and possible therapeutic targets. Animal models should address symptoms but also other aspects of PTSD that are seen in clinical care including the waxing and waning of symptoms, Understanding "forgetting", toxic exposure, failure to recover and how the neural systems fail rather than function are important perspectives on developing animal models. The cognitive process of identification is another important animal model to develop. Using these perspectives recent work has shown new avenues for understanding the trauma response in animal models and human brain tissue of individuals with PTSD. The 5-HT2A receptor and p11 protein and associated regulators are avenues of new investigation that warrant study and consideration in models of PTSD.Progress in brain research 02/2008; 167:203-15. · 3.04 Impact Factor -
Article: Dysregulated mitochondrial genes and networks with drug targets in postmortem brain of patients with posttraumatic stress disorder (PTSD) revealed by human mitochondria-focused cDNA microarrays.
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ABSTRACT: Posttraumatic stress disorder (PTSD) is associated with decreased activity in the dorsolateral prefrontal cortex (DLPFC), the brain region that regulates working memory and preparation and selection of fear responses. We investigated gene expression profiles in DLPFC Brodmann area (BA) 46 of postmortem patients with (n=6) and without PTSD (n=6) using human mitochondria-focused cDNA microarrays. Our study revealed PTSD-specific expression fingerprints of 800 informative mitochondria-focused genes across all of these 12 BA46 samples, and 119 (+/->1.25, p<0.05) and 42 (+/->1.60, p<0.05) dysregulated genes between the PTSD and control samples. Quantitative RT-PCR validated the microarray results. These fingerprints can essentially distinguish the PTSD DLPFC BA46 brains from controls. Of the 119 dysregulated genes (+/-> or =125%, p<0.05), the highest percentages were associated with mitochondrial dysfunction (4.8%, p=6.61 x 10(-6)), oxidative phosphorylation (3.8%, p=9.04 x 10(-4)), cell survival-apoptosis (25.2%, p<0.05) and neurological diseases (23.5%, p<0.05). Fifty (50) dysregulated genes were present in the molecular networks that are known to be involved in neuronal function-survival and contain 7 targets for neuropsychiatric drugs. Thirty (30) of the dysregulated genes are associated with a number of neuropsychiatric disorders. Our results indicate mitochondrial dysfunction in the PTSD DLPFC BA46 and provide the expression fingerprints that may ultimately serve as biomarkers for PTSD diagnosis and the drugs and molecular targets that may prove useful for development of remedies for prevention and treatment of PTSD.International journal of biological sciences 01/2008; 4(4):223-35. · 2.70 Impact Factor
Top co-authors
Top Journals
Institutions
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2003–2012
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Uniformed Services University of the Health Sciences
- Department of Psychiatry
Bethesda, MD, USA
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2011
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Texas Tech University Health Sciences Center
- Department of Psychiatry
Lubbock, TX, USA
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2009
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National Yang Ming University
- Department of Psychiatry
Taipei, Taipei, Taiwan
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2008
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University of Washington Seattle
- Department of Biochemistry
Seattle, WA, USA
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