Biomedical subjects

Victoria Arango

Publications and source records attributed to Victoria Arango.

32 records · Page 2Linked to original sources

PubMed2004

Immobilization stress elevates tryptophan hydroxylase mRNA and protein in the rat raphe nuclei.

BACKGROUND: Stress triggers adaptive and maladaptive changes in the central nervous system, including activation of the hypothalamic-pituitary-adrenal axis, and can trigger mood disorders and posttraumatic stress disorder. We examined the effect of immobilization stress (IMO) on gene expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, and the role of cortisol in that response. METHODS: Regular and adrenalectomized Sprague-Dawley rats were exposed to various repetitions of IMO. Tryptophan hydroxylase messenger ribonucleic acid (mRNA) was determined by competitive reverse transcriptase polymerase chain reaction, and TPH protein was examined by immunoblot and immunocytochemistry. RESULTS: Elevation of TPH mRNA by IMO was tissue-specific and dose-dependent. A single IMO elicited a threefold rise in TPH mRNA in median raphe nucleus (MRN), but repeated (3x) IMOs were needed for similar response in dorsal raphe nucleus (DRN). Repeated daily IMO, up to 7 days, triggered a robust induction (6-10-fold) in TPH mRNA, accompanied by corresponding rise in TPH protein levels in raphe nuclei but not in the pineal gland. The rise in TPH immunoreactivity was widespread throughout the DRN and MRN. Bilateral adrenalectomy did not prevent the IMO-triggered increase in TPH immunoreactive protein in the raphe nuclei. CONCLUSIONS: This study reveals adrenal glucocorticoid-independent induction of TPH gene expression in raphe nuclei in response to immobilization stress.

Animals↗

PubMed2004

Using the gene ontology for microarray data mining: a comparison of methods and application to age effects in human prefrontal cortex.

One of the challenges in the analysis of gene expression data is placing the results in the context of other data available about genes and their relationships to each other. Here, we approach this problem in the study of gene expression changes associated with age in two areas of the human prefrontal cortex, comparing two computational methods. The first method, "overrepresentation analysis" (ORA), is based on statistically evaluating the fraction of genes in a particular gene ontology class found among the set of genes showing age-related changes in expression. The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. We find that FCS yields more consistent results than ORA, and the results of ORA depended strongly on the gene selection threshold. Our findings highlight the utility of functional class scoring for the analysis of complex expression data sets and emphasize the advantage of considering all available genomic information rather than sets of genes that pass a predetermined "threshold of significance."

Adolescent↗

PubMed2004

Gene expression profiling of depression and suicide in human prefrontal cortex.

Mood disorders are a major cause of disability. Etiology includes genetic and environmental factors, but the responsible genes have yet to be identified. Using DNA microarrays, we have conducted a large-scale gene expression analysis, in two regions of the human prefrontal cortex from post-mortem matched groups of subjects with major depression who had died by suicide, and control subjects who died from other causes and were free from psychiatric disorders. Bioinformatic analysis was used to investigate molecular and cellular pathways potentially involved in depression and suicidal behavior. We tested several hypotheses of disease pathology and of their putative molecular impact, including changes in single genes, the existence of subgroups of patients or disease subtypes, or the possibility of common biological pathways being affected in the disease process. Within the analytical limits of this relatively large genomic study, we found no evidence for molecular differences that correlated with depression and suicide, suggesting a pathology that is below the detection level of current genomic approaches, or that is either localized to other brain areas, or more associated with post-transcriptional effects and/or changes in protein levels or functions, rather than altered transcriptome in the prefrontal cortex.

Adult↗

PubMed2004

Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression.

Magnetic resonance imaging (MRI) studies in depressed subjects report smaller volumes of amygdala, hippocampus, inferior anterior cingulate, and the orbital prefrontal cortex (OPFC), components of the limbic-cortico-thalamic circuit. Major depression occurs more commonly in women, raising the possibility of an additional psychopathological process affecting women and not men. We sought to determine whether volumetric differences related to mood disorders are dependent on sex. Eight male and 10 female depressed subjects, meeting DSM III R criteria for a major depressive episode, and eight male and 10 female healthy volunteers had MRI scans on a 1.5 T GE Signa Advantage scanner. The regions of interest included amygdala, hippocampus, inferior anterior cingulate, and OPFC. In all analyses, regional volumes were normalized for total cerebral volume. Volumetric changes in the ROIs showed a significant sex by diagnosis interaction, indicating a different pattern of volumetric changes in depressed males compared with females relative to controls. Relative to sex-matched controls, the left inferior anterior cingulate was smaller in depressed males (23%) compared with depressed females (11%). Depressed females but not depressed males had smaller amygdala compared with controls (F-value = 4.946, p = 0.033). No significant volumetric differences were noted in the hippocampus or OPFC. No volumetric correlations were noted with clinical variables, depression subtypes, or a reported history of sexual or physical abuse. Sex may affect volumetric deficits in amygdala and anterior cingulate cortex in mood disorders, but no effects were found in the hippocampus or OPFC. The biology of mood disorders in females may differ in some aspects from males, and may contribute to the higher rate of depression in women.

Adult↗

PubMed2004

Serotonergic and noradrenergic neurobiology of alcoholic suicide.

BACKGROUND: Alcoholism is associated with alterations in the serotonergic and noradrenergic systems. Alcoholics are at a significantly higher risk for suicide than the general population. Altered serotonin (5-HT) function is associated with suicide and serious suicide attempts. We hypothesized patterns of abnormality associated independently with suicide and with alcoholism. METHODS: Quantitative autoradiographic experiments were performed in human postmortem brain tissue sections from alcoholics, alcoholic-suicide decedents, nonalcoholic suicide decedents, and normal controls diagnosed by psychological autopsy. RESULTS: Binding to 5-HT1A receptors is lower in both alcoholic suicides and alcoholic nonsuicides, suggesting that this effect is related to alcoholism and not suicide. In nonalcoholic suicides, there is a localized increase in 5-HT1A binding in ventral prefrontal cortex, hypothesized to be a response to less serotonin input. Therefore, alcoholic suicides may fail to up-regulate ventral prefrontal 5-HT1A receptors in response to decreased serotonergic transmission, failing to mitigate the impact of less serotonin upon signal transduction and thereby increasing the risk of suicidal behavior. Binding to the serotonin transporter is low in alcoholic suicides but not in alcoholic nonsuicides, suggesting an association with suicide, as nonalcoholic suicides also have decreased binding compared with controls. Evidence of impaired serotonergic innervation associated with alcoholism is also manifested by less 5-HT1D terminal autoreceptor binding in alcoholics. Nonalcoholic suicides do not have lower 5-HT1D binding. In the noradrenergic system, alcoholics (suicide and nonsuicide) and nonalcoholic suicide victims all have fewer pigmented locus ceruleus neurons compared with controls, yet beta1-adrenergic binding is low in both alcoholic groups, whereas alpha1-and alpha2-adrenergic binding decreases are more pronounced in the alcoholic suicide group. These noradrenergic findings differ from those in nonalcoholic suicides, which have a common feature with alcoholics in having less alpha2-and beta1-adrenergic binding but more alpha1-adrenergic binding in ventrolateral and orbital cortex. CONCLUSION: Extensive but different abnormalities in both the serotonergic and noradrenergic systems have been identified in alcoholics and suicides, suggesting two separate patterns: one related to alcoholism and the other related to suicide. The different patterns suggest different causes and homeostatic responses for alcoholism and suicide.

Adult↗

PubMed2004

Absence of histological lesions in primate models of ECT and magnetic seizure therapy.

OBJECTIVE: The authors present preliminary findings from the first nonhuman primate neuropathological study of ECT to use perfusion fixation and adequate controls and the first to compare ECT with magnetic seizure therapy, to their knowledge. METHOD: Twelve Macaca mullata received 6 weeks of daily ECT, magnetic seizure therapy, or anesthesia alone. After perfusion fixation, their brains were examined while masked to intervention. RESULTS: No identified lesions were attributable to the interventions. Cortical and hippocampal immunoreactivity for glial fibrillary acidic protein (an astrocytic marker) was most intense in the group that received ECT. CONCLUSIONS: This small but rigorous primate study supports the view that ECT does not produce histological lesions in the brain and provides the first comparable safety data on magnetic seizure therapy.

Amygdala↗

PubMed2003

Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice.

BACKGROUND: As a key regulator of serotonergic activity and target of many antidepressant treatments, the serotonin transporter (SERT) represents a potential mediator of anxiety- and depression-related behaviors. Using mice lacking the SERT (SERT KO), we examined the role of SERT function in anxiety- and depression-related behaviors and serotonergic neuron function. METHODS: Serotonin transporter knockout mice were evaluated in paradigms designed to assess anxiety-, depression-, and stress-related behaviors. Dorsal raphe nucleus (DRN) function was assessed by quantitative serotonergic cell counting and extracellular electrical recording of neuronal firing properties. RESULTS: Serotonin transporter knockout mice showed an increase in latency to feed in a novel situation, more immobility in a forced swim, increased escape latency in a shock escape paradigm, and decreased immobility in tail suspension. No differences in anxiety-related behaviors were seen in the open field and the elevated plus maze. Serotonin transporter knockout mice exhibit a 50% reduction in serotonergic cell number and a fourfold decrease in firing rate in the DRN. CONCLUSIONS: Developmental loss of SERT produces altered behaviors in models of depression that are generally opposite to those produced by antidepressant treatment. The reduced serotonergic cell number and firing rate in the DRN of adult SERT KO mice suggest a mechanism for these altered behaviors.

Action Potentials↗

PubMed2003

Sex genes for genomic analysis in human brain: internal controls for comparison of probe level data extraction.

BACKGROUND: Genomic studies of complex tissues pose unique analytical challenges for assessment of data quality, performance of statistical methods used for data extraction, and detection of differentially expressed genes. Ideally, to assess the accuracy of gene expression analysis methods, one needs a set of genes which are known to be differentially expressed in the samples and which can be used as a "gold standard". We introduce the idea of using sex-chromosome genes as an alternative to spiked-in control genes or simulations for assessment of microarray data and analysis methods. RESULTS: Expression of sex-chromosome genes were used as true internal biological controls to compare alternate probe-level data extraction algorithms (Microarray Suite 5.0 [MAS5.0], Model Based Expression Index [MBEI] and Robust Multi-array Average [RMA]), to assess microarray data quality and to establish some statistical guidelines for analyzing large-scale gene expression. These approaches were implemented on a large new dataset of human brain samples. RMA-generated gene expression values were markedly less variable and more reliable than MAS5.0 and MBEI-derived values. A statistical technique controlling the false discovery rate was applied to adjust for multiple testing, as an alternative to the Bonferroni method, and showed no evidence of false negative results. Fourteen probesets, representing nine Y- and two X-chromosome linked genes, displayed significant sex differences in brain prefrontal cortex gene expression. CONCLUSION: In this study, we have demonstrated the use of sex genes as true biological internal controls for genomic analysis of complex tissues, and suggested analytical guidelines for testing alternate oligonucleotide microarray data extraction protocols and for adjusting multiple statistical analysis of differentially expressed genes. Our results also provided evidence for sex differences in gene expression in the brain prefrontal cortex, supporting the notion of a putative direct role of sex-chromosome genes in differentiation and maintenance of sexual dimorphism of the central nervous system. Importantly, these analytical approaches are applicable to all microarray studies that include male and female human or animal subjects.

Algorithms↗

PubMed2003

Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase.

Positron emission tomography studies in major depression show reduced serotonin (5-HT)1A receptor antagonist-binding potentials in many brain regions including occipital cortex. The functional meaning of this observation in terms of signal transduction is unknown. We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of 5-HT1A receptor activation. The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders (DSM) III-R criteria. Measurements of [35S]GTPgammaS binding to Galphai/o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of 5-HT1A receptor to adenylyl cyclase. No significant group differences were detected in the expression levels of Galphai/o, Galphaq/11 or Galphas proteins, or in the activity of cAMP-dependent protein kinase A. Studies of a parallel transduction pathway downstream from 5-HT1A receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3-kinase and its downstream effector Akt, as well as an increase in PTEN (phosphatase and tensin homolog deleted on chromosome 10), the phosphatase that hydrolyzes phosphatidylinositol 3,4,5-triphosphate. Finally, the activation of extracellular signal-regulated kinases 1 and 2 was attenuated in suicide victims. These data suggest that the alterations in agonist-stimulated 5-HT1A receptor activation in depressed suicide victims are also manifest downstream from the associated G protein, affecting the activity of second messengers in two 5-HT1A receptor transduction pathways that may have implications for cell survival.

Adenylyl Cyclases↗

PubMed2002

Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635.

Serotonin (5-HT) 1A receptors have been implicated in a variety of conditions including, depression, suicidal behavior, and aggression. Post-mortem brain studies and in vivo imaging studies report a variety of age and sex effects on brain 5-HT(1A) binding. Behavioral data from 5-HT(1A) specific pharmacological challenges suggest a role for 5-HT(1A) receptors in aggression. The goal of the present study was to determine age, sex, and severity of life-time aggression effects on 5-HT(1A) binding potential (BP) in vivo using positron emission tomography (PET) and the high affinity 5-HT(1A) antagonist, [carbonyl-C-11]WAY-100635 in 12 healthy females (ages 41.0+/-15.7 years) and 13 healthy males (ages 39.6+/-15.5 years). Regions of interest included the dorsal raphe, anterior cingulate cortex, cingulate body, hippocampus, amygdala, medial prefrontal cortex (PFC), and orbital PFC. No significant correlation between age and BP was detected in any brain region. MANOVA of the first three principle components demonstrated a significantly higher BP in females compared with males (P=0.0127). Post-hoc tests confirmed sex differences (P<0.05) in the following regions: dorsal raphe, amygdala, anterior cingulate, cingulate body, medial PFC, and orbital PFC. The cerebellar volume of distribution was also significantly higher in females. There is a significant negative correlation between binding in several regions and lifetime aggression. We have replicated our post-mortem finding of higher 5-HT(1A) binding in females compared to males. We did not detect an age dependent decrease in binding in males or females. Lower 5-HT(1A) binding in more aggressive individuals is consistent with pharmacological challenge studies. Future studies should determine whether the binding is a state or trait effect.

Adult↗

PubMed2002

Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims.

Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites). In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD. In suicide victims with a history of major depression, C' site editing is significantly increased, D site editing is significantly decreased, and the C site shows a trend toward increased editing. Treatment of mice with the antidepressant drug fluoxetine (Prozac) causes changes in C', C, and D site editing that are exactly opposite to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims.

Adult↗

PubMed2002

Serotonin brain circuits involved in major depression and suicide.

Throughout his life and his work, Cajal realized the potential of the neurons he was so carefully studying and how, grouped in systems, they served the special senses and the maintenance and proper functioning of the organism. Over the past 25 years, major depression and suicide have come to be recognized as associated with alteration in serotonergic neurons and their target receptors. We examined whether prefrontal cortical (PFC) serotonin transporter sites (SERT) differ in major depression and suicide by quantitative receptor autoradiography. Clinical information was obtained by psychological autopsy. We found regionally distinct neurobiological correlates of major depression and suicide. A diffuse reduction of SERT binding throughout the dorsoventral extent of the PFC in major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathology in major depression. The localized reduction in SERT binding in ventral PFC found in suicide victims may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. It is conceivable that Cajal envisioned that psychiatric illness would be the result of "psychic neuron" pathophysiology. Today's informed psychiatrists will not be able to deny the role of the brain in the mental ailments that afflict their patients.

Animals↗

PubMed2002

Abnormalities of SNARE mechanism proteins in anterior frontal cortex in severe mental illness.

A fundamental molecular component of neural connectivity is the SNARE (SNAP receptor) protein complex, which consists of three proteins, syntaxin, SNAP-25 and VAMP. Under appropriate conditions, the SNARE complex can be formed in vitro. To investigate the hypothesis that dysregulation of SNARE proteins or their interactions could be abnormal in severe mental disorders, the three SNARE proteins and the complex were studied in post-mortem anterior frontal cortex homogenates. An ELISA was used to quantify SNARE protein immunoreactivities in cortical homogenates from four groups: patients with schizophrenia who died of causes other than suicide (n = 6), patients with schizophrenia and suicide (n = 7), patients with depression and suicide (n = 11), and controls (n = 11). Differences between groups in patterns of SNARE protein immuno-reactivities were demonstrated [Wilks' Lambda F(9,68) = 3.57, P = 0.001]. Protein-by-protein analyses indicated a significant reduction in SNAP-25 immunoreactivity in the schizophrenia non-suicide group [28% decrease relative to controls, F(3,31) = 6.45, P = 0.002, Student-Newman-Keuls test, P < 0.01]. The intercorrelations between SNARE protein and synaptophysin immunoreactivities were high in controls, but lower in the other groups, further indicating disturbances in relationships between these proteins. The extent of SNARE complex formation in vitro was studied using immuno-blotting. Significant differences related to group membership were observed for the SNARE complexes identified by SNAP-25 [Wilks' Lambda F(3,31) = 4.76, P = 0.008] and by syntaxin immunostaining [Wilks' Lambda F(3,31) = 9.16, P = 0.0002]. In both groups with suicide as a cause of death, relatively more SNAP-25 and syntaxin was present in the heterotrimeric SNARE complex than in other molecular forms. These abnormalities in the SNARE complex could represent a molecular substrate for abnormalities of neural connectivity in severe mental disorders.

Adult↗

PubMedDate not supplied

Genetics of the serotonergic system in suicidal behavior.

Genetic factors contribute to the risk of psychopathology in many psychiatric conditions, but the specific genes are yet to be identified. Neurotransmitter alterations are implicated in the etiology of psychopathology based, in part, on studies of neurotransmitter receptors and their biosynthetic or degradative enzymes in postmortem tissue. Identification of the altered receptors and enzymes serves to identify candidate genes of potential etiological significance. Polymorphisms in these genes can contribute to alterations in protein function in vivo that are part of the neurochemical underpinnings of psychopathologies such as major depressive disorder, psychoses, alcoholism, personality disorders, aggressive-impulsive traits, or suicidal behavior. Altered serotonergic function is implicated in the etiology and pathogenesis of several major psychiatric conditions. In particular, there is much evidence for an association of lower serotonergic function and suicidal behavior. Thus genes related to the serotonergic system are candidate genes worthy of study as part of the genetic diathesis for suicidal behavior. This review examines the following polymorphisms in the serotonin biosynthetic enzyme tryptophan hydroxylase (TPH; A779C substitution), the serotonin transporter (5-HTT, 5-HTTLPR allele), the 5-HT(1B) receptor (G861C, C129T substitution) and the 5-HT(2A) receptor (T102C) for their relationship to suicidal behavior. For the TPH gene, we found the less common U or A allele variant of the A779C polymorphism was associated with suicide attempt. Other studies have found the U allele to be associated with aggression and lower serotonergic function in vivo. A 44 base pair insertion/deletion in the 5' flanking promoter region of the 5-HTT gene may result in less 5-HTT expression and 5-HTT binding. We examined 220 cases postmortem and found no association between the promoter genotype and 5-HTT binding. We also found no association with major depressive disorder (MDD), suicide or pathological aggression, despite finding significantly fewer 5-HTT sites in the prefrontal cortex of depressed and/or suicide cases. In genomic DNA samples from 178 unrelated subjects, we detected two polymorphisms for the 5-HT(1B) receptor at nucleotides 861 and 129. However, no association between either polymorphism and depression, suicide, aggression, or alcoholism was observed. There are two common polymorphisms for the 5-HT(2A) receptor gene in humans. The results of studies of 5-HT(2A) receptor gene polymorphisms do not indicate significant major associations with suicidal behavior. In contrast, the 5-HT(2A) receptor itself is reported to be increased in suicide. Functional polymorphisms involving the promoter region that affect gene expression may explain this finding. Studies of candidate genes related to serotonergic function in brain are increasingly used to establish genetic alterations contributing to psychiatric illness. The most meaningful studies combine the study of candidate genes with direct measures of related proteins as well as psychopathology.

Brain↗