Biomedical subjects

Stanley J Watson

Publications and source records attributed to Stanley J Watson.

At least 19 recordsLinked to original sources

PubMed2006

Relationship of presympathetic-premotor neurons to the serotonergic transmitter system in the rat brainstem.

Numerous physiological conditions and emotionally motivated behaviors require concomitant activation of somatomotor and sympathetic efferents. Using a virally mediated retrograde transsynaptic tract-tracing approach, we have previously determined locations of presympathetic-premotor neurons (PSPMNs) in the rat brainstem. These putative dual-function neurons send projections to somatomotor and sympathetic targets and likely participate in sympatho-somatomotor integration. A significant portion of these neurons is found within brainstem areas known to contain serotonergic neurons. Thus, we hypothesized that some of the PSPMNs utilize serotonin as their neurotransmitter. To test this hypothesis we first produced an antibody against TPH2, a brain-specific isoform of tryptophan hydroxylase (serotonin synthetic enzyme). We identified PSPMNs by using recombinant strains of the pseudorabies virus (PRV) for transsynaptic tract-tracing. PRV-152, a strain that expresses enhanced green fluorescent protein, was injected into sympathectomized gastrocnemius muscle, while PRV-BaBlu, which expresses beta-galactosidase, was injected into the adrenal gland in the same animals. Using immunofluorescent methods we determined whether coinfected neurons expressed TPH2. Our findings demonstrate that TPH2-positive PSPMNs are present at different rostrocaudal levels of the brainstem. Just over half of them are found at the pontomedullary junction within raphe obscurus, raphe magnus, and gigantocellular nucleus pars alpha. These cells may play a role in mediating responses to acute pain stimuli and/or participate in the central control of exercise. Overactivity of these serotonergic sympatho-somatomotor circuits may also play a role in the pathophysiology of serotonin syndrome.

Animals↗

PubMed2006

Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats.

RATIONALE: The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders. OBJECTIVES: We studied individual differences in Pavlovian conditioned approach behavior and examined the expression of neurobiological markers associated with the dopaminergic system, the same neural system implicated in incentive motivational processes. METHODS: Pavlovian autoshaping procedures consisted of the brief presentation of an illuminated retractable lever (conditioned stimulus) followed by the response-independent delivery of a food pellet (unconditioned stimulus), which lead to a Pavlovian conditioned response. In situ hybridization was performed on brains obtained either following the first or last (fifth) day of training. RESULTS: Two phenotypes emerged. Sign-trackers (ST) exhibited behavior that seemed to be largely controlled by the cue that signaled impending reward delivery; whereas goal-trackers (GT) preferentially approached the location where the reward was delivered. Following a single training session, ST showed greater expression of dopamine D1 receptor mRNA relative to GT. After 5 days of training, GT exhibited greater expression levels of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor mRNA relative to ST. CONCLUSIONS: These findings suggest that the development of approach behavior towards signals vs goal leads to distinct adaptations in the dopamine system. The sign-tracker vs goal-tracker phenotype may prove to be a valuable animal model to investigate individual differences in the way incentive salience is attributed to environmental stimuli, which may contribute to the development of addiction and other compulsive behavioral disorders.

Adaptation, Physiological↗

PubMed2006

SNP Function Portal: a web database for exploring the function implication of SNP alleles.

MOTIVATION: Finding the potential functional significance of SNPs is a major bottleneck in understanding genome-wide SNP scanning results, as the related functional data are distributed across many different databases. The SNP Function Portal is designed to be a clearing house for all public domain SNP functional annotation data, as well as in-house functional annotations derived from different data sources. It currently contains SNP functional annotations in six major categories including genomic elements, transcription regulation, protein function, pathway, disease and population genetics. Besides extensive SNP functional annotations, the SNP Function Portal includes a powerful search engine that accepts different types of genetic markers as input and identifies all genetically related SNPs based on the HapMap Phase II data as well as the relationship of different markers to known genes. As a result, our system allows users to identify the potential biological impact of genetic markers and complex relationships among genetic markers and genes, and it greatly facilitates knowledge discovery in genome-wide SNP scanning experiments. AVAILABILITY: http://brainarray.mbni.med.umich.edu/Brainarray/Database/SearchSNP/snpfunc.aspx.

Alleles↗

PubMed2006

Beta1 adrenergic receptors in the bed nucleus of stria terminalis mediate differential responses to opiate withdrawal.

The negative physical and affective aspects of opioid abstinence contribute to the prolongation of substance abuse. Withdrawal treatment is successful only in a subset of subjects, yet little is known about the neurobiological causes of these individual differences. Here, we compare the somatic and motivational components of opioid withdrawal in animals with high reactivity (HR) vs low reactivity (LR) to novelty, a phenotype associated with differential vulnerability to drug abuse. During withdrawal, HR relative to LR showed increased teeth chattering and eye twitching episodes, somatic signs associated with adrenergic modulation. Given the role of noradrenergic circuitry of the extended amygdala in opioid withdrawal, we examined adrenergic receptor gene expression in the bed nucleus of stria terminalis (BST) and central nucleus of the amygdala. Relative to LR, HR rats exhibit a selective increase in beta(1) adrenergic receptor expression in lateral and medial BST. To uncover the functional relevance of this difference, we microinjected betaxolol, a selective beta(1) receptor antagonist, into dorsal BST and assessed somatic and affective responses during withdrawal. Betaxolol microinjection dose-dependently decreased teeth chattering episodes in HR to levels observed in LR animals. Moreover, the antagonist blocked conditioned place aversion, a measure of negative affect associated with withdrawal, in HR but not in LR animals. Our results reveal for the first time that reactivity to novelty predicts somatic and affective aspects of opiate dependence, and that beta(1) receptors in BST are implicated in opiate withdrawal but only in novelty-seeking individuals.

Adrenergic beta-Antagonists↗

PubMed2006

SNPs on chips: the hidden genetic code in expression arrays.

Gene expression microarray analysis in postmortem brains is one of the fastest growing fields of psychiatric research. Here we show that common polymorphisms (SNPs) present on probe sets can masquerade as significant "gene expression" differences. After first observing this artifact in the Catechol-O-methyl transferase (COMT) gene, we replicate the finding in two additional genes predicted to show this artifact. Many Affymetrix chips contain thousands of SNPs that are both common and in the central probe region affecting hybridization, and thus have the potential to confound expression analysis.

Analysis of Variance↗

PubMed2006

The fibroblast growth factor system and mood disorders.

Recent evidence now suggests the involvement of the fibroblast growth factor (FGF) system in mood disorders. Specifically, several members of the FGF family have been shown to be dysregulated in individuals with major depression. In this review, we will introduce the FGF system in terms of structure and function during development, in adulthood, and in various regions and cell types. We will also review the FGF system as a mediator of neural plasticity. Furthermore, this review will summarize animal as well as human studies. The majority of animal studies have focused on stress, environmental enrichment, pharmacological manipulations, and the hippocampus. By contrast, human studies have focused on volumetric measurements, antidepressant literature, and, most recently, post-mortem microarray experiments. In summary, a reduced tone in the FGF system might alter brain development or remodeling and result in a predisposition or vulnerability to mood disorders, including major depression.

Animals↗

PubMed2006

Rostral elements of sympatho-motor circuitry: a virally mediated transsynaptic tracing study.

Numerous physiological and emotionally motivated behaviors, including locomotion, exercise, escape, and attack behaviors as well as passive coping responses, require concomitant activation of motor and sympathetic efferents. Such functional heterogeneity suggests the existence of dual function neurons that can simultaneously coordinate motor and sympathetic output. Because previous physiological investigations have implicated a number of mesencephalic and telencephalic regions in mediating these behaviors, we hypothesized the presence of dual function sympatho-motor neurons in these neural structures. To test this hypothesis, we used recombinant strains of the pseudorabies virus (PRV) for transsynaptic tract-tracing. PRV-152, a strain that expresses enhanced green fluorescent protein, was injected into sympathectomized gastrocnemius muscle, whereas PRV-BaBlu, which expresses beta-galactosidase, was injected into the adrenal gland in the same animals. Although coinfected neurons were detected in a number of mesencephalic and telencephalic regions, >50% of such neurons were located within specific subdivisions of two general areas: the hypothalamus and periaqueductal gray. These subdivisions included the ventrolateral periaqueductal gray, dorsomedial hypothalamus, dorsolateral lateral hypothalamus, and ventral portion of the medial parvocellular subdivision of the paraventricular nucleus of the hypothalamus (PVN). A subset of the sympatho-motor neurons within the PVN also contained either arginine vasopressin or oxytocin. This sympatho-motor circuitry likely plays an important role in mediating different aspects of stress responses and emotionally motivated behaviors.

Adrenal Glands↗

PubMed2006

Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects.

Nonpeptidic delta-opioid receptor agonists produce antidepressant-like effects in rodents, and compounds that inhibit the breakdown of endogenous opioid peptides have antidepressant-like effects in animal models. In this study, the behavioral effects of the enkephalinase inhibitor, RB101 (N-[(R, S)-2-benzyl-3-[(S)(2-amino-4-methyl-thio)-butyldithio]-1-oxopropyl]-l-phenylalanine benzyl ester), were examined. Specifically, the effects of RB101 on convulsive activity, locomotor activity, and antidepressant-like effects in the forced swim test were studied in Sprague-Dawley rats, and the opioid receptor types mediating these effects were examined by antagonist studies. In addition, the effects of RB101 on brain-derived neurotrophic factor (BDNF) mRNA expression were evaluated in relation to its antidepressant effects. RB101 produced delta-opioid receptor-mediated antidepressant effects (32 mg/kg i.v. and 100 mg/kg i.p.) and increased locomotor activity (32 mg/kg i.v.) in rats. RB101 did not produce convulsions or seizures and did not alter BDNF mRNA expression. In conclusion, RB101 has the potential to produce antidepressant effects without convulsions.

Adrenocorticotropic Hormone↗

PubMed2006

Transcriptional profiling of the developing rat brain reveals that the most dramatic regional differentiation in gene expression occurs postpartum.

Neural development involves the expression of ensembles of regulatory genes that control the coordinate and region-specific expression of a host of other genes, resulting in the unique structure, connectivity, and function of each brain region. Although the role of some specific genes in neural development has been studied in detail, we have no global view of the orchestration of spatial and temporal aspects of gene expression across multiple regions of the developing brain. To this end, we used transcriptional profiling to examine expression levels of 9955 genes in the hypothalamus, hippocampus, and frontal cortex across seven stages of postnatal development and up to four stages of prenatal development in individual male rats (six per group). The results reveal dramatic changes across development in >97% of the neurally expressed genes. They also uncover a surprising degree of regional differentiation occurring after birth and through the first 2 weeks of life. Cluster analysis identifies 20 clusters of transcripts enriched in genes related to particular functions, such as DNA metabolism, nuclear function, synaptic vesicle transport, myelination, and neuropeptide hormone activity. Thus, groups of genes with related functions change in the brain at specific times, possibly marking critical periods for each function. These findings can broadly serve as a backdrop for studying the role of individual genes in neural development. They also underscore the importance of early postnatal life in the rat, which corresponds to late gestation in the human, as a critical late phase of neural organization and differentiation, even in subcortical regions.

Animals↗

PubMed2006

Selective breeding for divergence in novelty-seeking traits: heritability and enrichment in spontaneous anxiety-related behaviors.

Outbred Sprague-Dawley rats can be classified as high responders (HR) or low responders (LR) based on their levels of exploratory locomotion in a novel environment. While this novelty-seeking dimension was originally related to differential vulnerability to substance abuse, behavioral, neuroendocrine and gene expression studies suggest a fundamental difference in emotional reactivity between these animals. Here, we report the first study to selectively breed rats based on this novelty-seeking dimension. Response to novelty was clearly heritable, with a > 2-fold difference in behavior seen after eight generations of selection. Three tests of anxiety-like behavior consistently showed significantly greater anxiety in LR-bred rats compared to HR-bred animals, and this difference was diminished in the open field test by administration of the anxiolytic benzodiazepine drug, chlordiazepoxide. Cross-fostering revealed that responses to novelty were largely unaffected by maternal interactions, though there was an effect on anxiety-like behavior. These selected lines will enable future research on the interplay of genetic, environmental and developmental variables in controlling drug seeking behavior, stress and emotional reactivity.

Animals↗

PubMed2006

Application of microarray technology in primate behavioral neuroscience research.

Gene expression profiling of brain tissue samples applied to DNA microarrays promises to provide novel insights into the neurobiological bases of primate behavior. The strength of the microarray technology lies in the ability to simultaneously measure the expression levels of all genes in defined brain regions that are known to mediate behavior. The application of microarrays presents, however, various limitations and challenges for primate neuroscience research. Low RNA abundance, modest changes in gene expression, heterogeneous distribution of mRNA among cell subpopulations, and individual differences in behavior all mandate great care in the collection, processing, and analysis of brain tissue. A unique problem for nonhuman primate research is the limited availability of species-specific arrays. Arrays designed for humans are often used, but expression level differences are inevitably confounded by gene sequence differences in all cross-species array applications. Tools to deal with this problem are currently being developed. Here we review these methodological issues, and provide examples from our experiences using human arrays to examine brain tissue samples from squirrel monkeys. Until species-specific microarrays become more widely available, great caution must be taken in the assessment and interpretation of microarray data from nonhuman primates. Nevertheless, the application of human microarrays in nonhuman primate neuroscience research recovers useful information from thousands of genes, and represents an important new strategy for understanding the molecular complexity of behavior and mental health.

Animals↗

PubMed2006

Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects.

Systemic administration of delta-opioid receptor (DOR) agonists decreases immobility in the forced swim test (FST) and increases brain-derived neurotrophic factor (BDNF) mRNA expression in rats, indicating that DOR agonists may have antidepressant-like effects. The aim of this study was to investigate the effects of central administration of endogenous opioid peptides on behavior in the FST and on brain BDNF mRNA expression in rats. Effects of endogenous opioids were compared with those produced by intracerebroventricular administration of a selective non-peptidic DOR agonist (+)BW373U86. Antidepressant-like effects were measured by decreased immobility in the FST. BDNF mRNA expression was determined by in situ hybridization. Centrally administered (+)BW373U86 decreased immobility and increased BDNF mRNA expression in the frontal cortex through a DOR-mediated mechanism, because these effects were blocked by the DOR antagonist naltrindole, but not by the micro-opioid receptor (MOR) antagonist naltrexone (NTX) or the kappa-opioid receptor antagonist nor-binaltorphimine. Of all the endogenous opioids tested, only leu- and met-enkephalin produced behavioral effects like those of (+)BW373U86 in the FST. Unlike (+)BW373U86, the enkephalins upregulated BDNF mRNA expression in the hippocampus through DOR- and MOR-mediated mechanisms. beta-Endorphin, endomorphin-1 and endomorphin-2 significantly increased BDNF mRNA levels in the frontal cortex, hippocampus and amygdala without reducing immobility; and most of these effects were reversed by NTX. This study is the first to provide evidence that endogenous opioids can upregulate BDNF mRNA expression through the DOR and MOR, and that leu- and met-enkephalin have similar pharmacological profiles to synthetic DOR agonists in producing antidepressant-like effects.

Analgesics, Opioid↗

PubMed2005

Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats.

Systemically active, nonpeptidic delta opioid receptor agonists have been shown to produce antidepressant and anxiolytic effects in animal models in rodents. In addition, delta agonists have been shown to increase expression of brain-derived neurotrophic factor (BDNF) mRNA, an effect of some antidepressants, which may be important for the clinical efficacy of antidepressant drugs. The present study examined whether a variety of peptidic delta agonists, DPDPE, JOM-13, a systemically active derivative of DPDPE, deltorphin II, and H-Dmt-Tic-NH-CH2-Bid could produce convulsions and antidepressant-like effects in the forced swim test. In addition, some of these compounds were examined for their influence on BDNF mRNA expression. All four agonists dose-dependently decreased immobility in the forced swim test, indicating an antidepressant-like effect. Only JOM-13 produced convulsions at doses required for antidepressant-like effects. In addition, DPDPE increased BDNF mRNA expression, as measured by in situ hybridization, in the frontal cortex. The antidepressant-like effect of the agonists in the forced swim test and the increase in BDNF mRNA expression produced by DPDPE were blocked by the delta antagonist naltrindole. Therefore, activation of the delta receptor by centrally administered peptidic agonists and intravenously administered JOM-13 produces behavioral antidepressant-like effects without producing convulsions, and some peptidic agonists can increase BDNF mRNA expression, however, not as consistently as the systemically active nonpeptidic agonists.

Adamantane↗

PubMed2005

Combining laser capture microdissection with quantitative real-time PCR: effects of tissue manipulation on RNA quality and gene expression.

Laser capture microdissection (LCM) is increasingly being used in quantitative gene expression studies of the nervous system. The current study aimed at determining the impact of various tissue manipulations on the integrity of extracted RNA in LCM studies. Our data indicate that various tissue preparation strategies prior to microdissection may decrease RNA quality by as much as 25%, thus affecting expression profiles of some genes. To circumvent this problem, we developed a strategy for reverse transcriptase real-time PCR that has considerable sensitivity and can be used to calculate relative changes in gene expression. This approach was validated in subregions of the rat cerebellum. Accordingly, expression of glial gene markers - myelin-associated glycoprotein and proteolipid protein 1 - was found 70-160-fold higher in the white matter layer of the cerebellar cortex as compared to the neuron-enriched granular layer. In contrast, expression of a specific neuronal maker, neuron-specific enolase, was found seven-fold higher in the granular layer, as compared to the white matter layer. Furthermore, this approach had high sensitivity and specificity as we were able to detect a 38% decrease in the expression of neuron-specific enolase without a change in the expression of glial markers following administration of the neurotoxin, ibotenic acid. These results demonstrate feasibility of performing accurate semi-quantitative gene expression analyses in LCM samples.

Animals↗

PubMed2005

Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data.

Genome-wide expression profiling is a powerful tool for implicating novel gene ensembles in cellular mechanisms of health and disease. The most popular platform for genome-wide expression profiling is the Affymetrix GeneChip. However, its selection of probes relied on earlier genome and transcriptome annotation which is significantly different from current knowledge. The resultant informatics problems have a profound impact on analysis and interpretation the data. Here, we address these critical issues and offer a solution. We identified several classes of problems at the individual probe level in the existing annotation, under the assumption that current genome and transcriptome databases are more accurate than those used for GeneChip design. We then reorganized probes on more than a dozen popular GeneChips into gene-, transcript- and exon-specific probe sets in light of up-to-date genome, cDNA/EST clustering and single nucleotide polymorphism information. Comparing analysis results between the original and the redefined probe sets reveals approximately 30-50% discrepancy in the genes previously identified as differentially expressed, regardless of analysis method. Our results demonstrate that the original Affymetrix probe set definitions are inaccurate, and many conclusions derived from past GeneChip analyses may be significantly flawed. It will be beneficial to re-analyze existing GeneChip data with updated probe set definitions.

Alleles↗

PubMed2005

Chronic administration of the delta opioid receptor agonist (+)BW373U86 and antidepressants on behavior in the forced swim test and BDNF mRNA expression in rats.

RATIONALE: Selective delta opioid receptor agonists have been shown to produce antidepressant-like behavioral effects and increase brain-derived neurotrophic factor (BDNF) mRNA expression when given acutely, but the chronic effects of delta agonists have been less well characterized. OBJECTIVE: The present study examined the effects of chronic exposure to the delta agonist (+)BW373U86 (BW) on antidepressant-like behavior in the forced swim test and on BDNF mRNA expression in comparison to chronic treatment with the antidepressants fluoxetine, desipramine, bupropion, and tranylcypromine. METHODS: Sprague-Dawley rats were treated chronic ally with one of the above treatments and were tested for antidepressant effects in the forced swim test, and assayed for BDNF mRNA expression by in situ hybridization. RESULTS: Acute administration of 10 mg/kg BW produced a significant antidepressant-like effect in the forced swim test, while chronic (8- or 21-day) BW administration did not produce a significant antidepressant-like effect. When 10 mg/kg BW was administered for 8 days, it produced a significant increase in BDNF mRNA expression in the frontal cortex, while having no effect on BDNF expression when given for 21 days. Chronic bupropion and desipramine significantly decreased BDNF expression in the dentate gyrus of the hippocampus, while fluoxetine had no effect in any brain region. Chronic tranylcypromine produced a significant increase in BDNF expression in the CA1 region of the hippocampus. CONCLUSIONS: Chronic exposure to BW produces tolerance to most effects, although at differential rates. In addition, increased BDNF mRNA expression does not appear to be a common effect of chronic administration of various antidepressants.

Animals↗

PubMed2005

Cognitive performance is highly sensitive to prior experience in mice with a learning and memory deficit: failure leads to more failure.

The impact of a previously successful or unsuccessful experience on the subsequent acquisition of a related task is not well understood. The nature of past experience may have even greater impact in individuals with learning deficits, as their cognitive processes can be easily disrupted. Mice with a targeted disruption of the alpha and delta isoforms of the cAMP-response element-binding protein (CREB) gene (CREB(alphadelta-)-deficient mice) have a genetic vulnerability to impaired learning and memory that is highly influenced by experimental conditions. Thus, we studied the impact of prior successful and unsuccessful experiences on the degree to which CREB(alphadelta-)-deficient mice exhibit impaired spatial learning and memory in the Morris water maze (MWM). In Experiment 1, we replicated the cognitive deficit of CREB(alphadelta-)-deficient mice when given two trials per day with a 1-min intertrial interval (MWM2), and labeled this experience as a "failure." We rescued the deficit using four trials per day with a 3- to 5-min intertrial interval (MWM4) and labeled this experience a "success." In Experiment 2, a new, naive set of wild-type (WT) and CREB(alphadelta-)-deficient mice were randomly assigned to one of two sequence protocols to assess the influence of a success or a failure on subsequent performance. In Group 1, mice were first exposed to the MWM4 condition, followed by the more difficult MWM2 task. As expected, CREB(alphadelta-)-deficient mice performed well in the MWM4; they also performed well during reversal testing (MWM4R) where the goal location is changed. With this initial successful learning experience, the CREB(alphadelta-)-deficient mice then performed as well as WT mice in the MWM2, the condition in which they are known to be impaired. In contrast, CREB(alphadelta-)-deficient mice in Group 2 had an unsuccessful experience when first exposed to the MWM2 condition, and then also showed impairment in the MWM4, the condition in which they would normally perform well. This deficit was amplified when CREB(alphadelta-)-deficient mice were then tested in the reversal test. Sex differences in learning among CREB(alphadelta-)-deficient mice were amplified upon exposure to an unsuccessful learning experience. These data indicate that, under conditions of cognitive impairment, past experience can-depending on its nature-significantly facilitate or hinder future performance.

Animals↗

PubMed2005

GeneInfoMiner--a web server for exploring biomedical literature using batch sequence ID.

GeneInfoMiner is a web-based system for searching Medline abstracts using sequence ID lists such as GenBank accession numbers derived from high-throughput experiments. It will map query results to MeSH topics to facilitate the exploration of the biological significance of the sequence ID lists. GeneInfoMiner is based on a custom gene and protein name identification engine that can map gene and protein names to important molecular biology databases.

Abstracting and Indexing↗