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Andrew Holmes

Publications and source records attributed to Andrew Holmes.

At least 37 records · Page 2Linked to original sources
PubMed2006

The role of galanin in modulating stress-related neural pathways.

Galanin is a 29 or 30 amino acid peptide with a close anatomical and neurophysiological relationship with neural systems mediating stress. In rodent behavioral studies, the consequences of galanin activity on stress-related behaviors such as anxiety-like and depression-like behavior varies according to site of administration and behavioral assay used. However, galaninergic systems remain a promising novel target for new antianxiety and antidepressant drugs. Current work attempting to delineate which galanin receptor subtypes mediate which effects of galanin will undoubtedly inform the development of these drugs. Further, the well-established deleterious effects of galanin on cognitive function provide support for galanin as a novel link between stress, anxiety and memory. This link suggests that galaninergic drugs could provide a novel therapeutic option for psychopathologies, such as post-traumatic stress syndrome, in which abnormal memory and emotion are intertwined.

Animals↗
PubMed2005

Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter.

To evaluate the consequences of inactivation of the serotonin transporter (SERT) gene on 5-HT homeostasis and function, 5-HT synthesis and turnover rates were measured using the decarboxylase inhibition method in multiple brain regions (frontal cortex, striatum, brainstem, hippocampus and hypothalamus) from mice with a genetic disruption of SERT. 5-HT synthesis rates were increased 30-60% in the different brain regions of SERT -/- mice compared to littermate +/+ control mice despite 55-70% reductions in tissue 5-HT concentrations. Brain regions that possessed a greater capacity to increase synthesis and turnover (frontal cortex, striatum) demonstrated lesser reductions in tissue 5-HT. Female SERT -/- mice had greater increases (79%) in brain 5-HT synthesis than male -/- mice did (25%), a finding associated with higher brain tryptophan concentrations in females. Despite increased 5-HT synthesis, there was no change in either TPH2 or TPH1 mRNA levels or in maximal in vitro TPH activity in the brainstem of SERT -/- mice. Catecholamine homeostasis as reflected in brain tissue concentrations and in synthesis and turnover of dopamine and norepinephrine was unchanged in SERT -/- mice. Taken together, the results demonstrate a markedly altered homeostatic situation in SERT -/- mice that lack 5-HT reuptake, resulting in markedly depleted tissue stores that are inadequately compensated for by increased 5-HT synthesis, with brain region and gender specificity observed.

Animals↗
PubMed2005

Activation of the sphingosine kinase-signaling pathway by high glucose mediates the proinflammatory phenotype of endothelial cells.

Vascular endothelial cells are key targets for hyperglycemic damage that facilitates vascular inflammation and the vasculopathy associated with diabetes mellitus. However, the mechanisms underlying this damage remain undefined. We now demonstrate that hyperglycemia induces activation of sphingosine kinase (SphK), which represents a novel signaling pathway that mediates endothelial damage under ambient high glucose conditions. SphK activity was significantly increased in aorta and heart of streptozotocin-induced diabetic rats. Interestingly, this increase in SphK activity was prevented by insulin treatment, which achieved euglycemia in the diabetic animals. Hyperglycemia-induced increase in SphK activity was also evident in endothelial cells that received long-term exposure to high glucose (22 mmol/L). Studies using a small interfering RNA strategy demonstrated that endogenous SphK1, but not SphK2, is the major isoenzyme that was activated by high glucose. In addition, an increase in SphK1 phosphorylation was detected in a protein kinase C- and extracellular signal-regulated kinase 1/2-dependent manner, which accounts for the high glucose-induced increases in SphK activity. Importantly, inhibition of SphK1 by either a chemical inhibitor (N',N'-dimethylsphingosine) or expression of a dominant-negative mutant of SphK1 (SphK(G82D)), or SphK1-specific small interfering RNA, strongly protected endothelial cells against high glucose-induced damage, as characterized by an attenuation in the expression of proinflammatory adhesion molecules, adhesion of leukocytes to endothelial cells, and nuclear factor kappaB activation. Thus, interventions that target the SphK-signaling pathway may have the potential to prevent vascular lesions under hyperglycemic conditions.

Animals↗
PubMed2005

Early life genetic, epigenetic and environmental factors shaping emotionality in rodents.

Childhood trauma is known to increase risk for emotional disorders and addiction. However, little is currently understood about the neurodevelopmental basis of these effects, or how genetic and epigenetic factors interact with the environment to shape the systems subserving emotionality. In this review, we discuss the use of rodent models of early life emotional experience to study these issues in the laboratory and present some of our pertinent findings. In rats, postnatal maternal separation can produce lasting increases in emotional behavior and stressor-reactivity, together with alterations in various brain neurotransmitter systems implicated in emotionality, including corticotropin-releasing factor, serotonin, norepinephrine, and glutamate. Genetic differences between inbred mouse strains have been exploited to further study how maternal behavior affects emotional development using techniques such as cross-fostering and generation of inter-strain hybrids. Together with our own recent data, the findings of these studies demonstrate the pervasive influence of maternal and social environments during sensitive developmental periods and reveal how genetic factors determine how these early life experiences can shape brain and behavior throughout life.

Animals↗
PubMed2005

Functional roles of NMDA receptor NR2A and NR2B subunits in the acute intoxicating effects of ethanol in mice.

The present study examined the roles of NR2A and NR2B subunit-containing NMDA receptors in the mediation of the sedative/hypnotic effects of ethanol in mice. The ability of the competitive NMDA antagonist, CGP-37849 (0, 1, or 3 mg/kg), and the NR2B-selective antagonist, Ro 25-6981 (0, 3, or 10 mg/kg), to alter (3 g/kg) ethanol-induced sleep time was measured in C57BL/6J mice and NR2A knockout (KO) mice. The results show that pretreatment with either antagonist significantly potentiated the sedative/hypnotic effects of ethanol in C57BL/6J mice. These effects were not significantly altered in NR2A KO mice. Basal sleep time responses to ethanol were also normal in NR2A KO mice. These findings confirm a major role for NMDA receptors in the acute intoxicating actions of ethanol and provide tentative support for a prepotent role of the NR2B subunit in these effects.

2-Amino-5-phosphonovalerate↗
PubMed2005

Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice.

There is growing evidence that serotonin (5-hydroxtryptamine, 5-HT) has major influences on brain development in mammals. Genetic and pharmacological disruption of 5-HT signaling during early postnatal development in rodents causes neuroanatomical cortical abnormalities, including malformations in the somatosensory cortex. Possible functional consequences of this developmental perturbation by 5-HT are not yet understood. We have examined the effects of deletion of the 5-HT transporter (5-HTT) gene on somatosensory responses to sensory stimulation in mice. Local cerebral glucose utilization (lCMR(glc)) was measured by the quantitative 2-deoxy[(14)C]glucose method during unilateral whisker stimulation in awake adult mice. lCMR(glc) was increased by stimulation but to a markedly lesser extent in 5-HTT(-/-) mice than in 5-HTT(+/+) controls in each of four major stations in the whisker-to-barrel cortex pathway (the spinal and principal sensory trigeminal nuclei, the ventral posteromedial thalamic nucleus, and the barrel region of the somatosensory cortex). Lowering brain 5-HT levels by administration of the selective tryptophan hydroxylase inhibitor p-chlorophenylalanine on postnatal days 0 and 1 restored the metabolic responses to functional activation in the whisker-to-barrel cortex pathway in adult 5-HTT(-/-) mice. These results indicate that functional deficits in this pathway in 5-HTT(-/-) mice may be due to excessive postnatal 5-HT activity. With or without postnatal p-chlorophenylalanine treatment, 5-HTT(-/-) mice exhibited lower resting (unstimulated) lCMR(glc) than did 5-HTT(+/+) controls in the whisker-to-barrel cortex pathway and throughout the brain. These findings have implications for understanding the potential long-term consequences of genetic and pharmacological disruption of 5-HT neurotransmission on cerebral functions during critical periods of postnatal development.

Animals↗
PubMed2005

Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice.

To study the neurochemical and behavioral effects of altered brain-derived neurotrophic factor (BDNF) expression on a brain serotonin system with diminished serotonin transport capability, a double-mutant mouse model was developed by interbreeding serotonin transporter (SERT) knockout mice with BDNF heterozygous knockout mice (BDNF +/-), producing SERT -/- x BDNF +/- (sb) mice. Prior evidence implicates serotonin and SERT in anxiety and stress responses. Some studies have shown that BDNF supports serotonergic neuronal development, leading to our hypothesis that reduced BDNF availability during development might exaggerate the consequences of absent SERT function. In the present study, brain serotonin and 5-hydroxyindol acetic acid concentrations in male sb mice were significantly reduced in the hippocampus and hypothalamus compared with wild-type control SB mice, BDNF-deficient Sb mice, and serotonin transporter knockout sB mice. The sb mice had significantly increased anxiety-like behaviors compared with SB, Sb, and sB mice as measured on the elevated plus maze test. These sb mice also had significantly greater increases in plasma adrenocorticotrophic hormone than mice with other genotypes after a stressful stimulus. Analysis of neuronal morphology showed that hypothalamic and hippocampal neurons exhibited 25-30% reductions in dendrites in sb mice compared with SB control mice. These findings support the hypothesis that genetic changes in BDNF expression interact with serotonin and other circuits that modulate anxiety and stress-related behaviors. Thus, this double-mutant mouse model should prove valuable in studying other gene x gene consequences for brain plasticity as well as in evaluating epistatic interactions of BDNF and serotonin transporter gene polymorphisms in neuropsychiatric disorders.

Adrenocorticotropic Hormone↗
PubMed2005

Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL/6J mice.

Neuropeptide Y (NPY) and galanin (GAL) are densely localized in brain regions subserving stress, fear and anxiety. While previous research supports a role for both neuropeptides in the mediation of rodent emotional behaviors, there is currently a lack of information on the effects of central administration of NPY and GAL on fear- and anxiety-related behaviors in mice. In the present study, the effects of intracerebroventricularly administered NPY and GAL were assessed in C57BL/6J mice on a battery of tests for fear- and anxiety-related behavior. NPY (0.5, 1.0 nmol) produced clear anxiolytic-like effects in the elevated plus-maze and light<-->dark exploration test, whereas GAL (0.5, 1.0 nmol) was without effect. NPY (0.5 nmol) also increased locomotor activity in the open field test. In the fear conditioning paradigm, NPY administered prior to training reduced freezing to context (0.5, 1.0 nmol) and auditory cue (1.0 nmol). Pre-training GAL (0.5 nmol) treatment reduced freezing to context. Taken together, results demonstrate robust effects of centrally-administered NPY, but not GAL, on anxiety-like behaviors and fear conditioning in mice. These findings provide a basis for future studies of mice with targeted gene mutations, directed at delineating the anatomical regions and receptor subtypes mediating the effects of NPY and GAL on emotion.

Animals↗
PubMed2005

Galanin impairs performance on learning and memory tasks: findings from galanin transgenic and GAL-R1 knockout mice.

Galanin (GAL) impairs performance on cognitive tasks when administered centrally to rats. GAL transgenic (GAL-tg) mice overexpressing endogenous GAL show deficits on the probe trial of the Morris water maze spatial learning task, on the social transmission of food preference olfactory memory task, and on the trace cued fear conditioning emotional learning and memory task. Knockout mice deficient in the GAL-R1 receptor subtype were normal on most memory tasks, while showing a small deficit in trace cued fear conditioning, suggesting a selective role for the GAL-R1 in aversive memories, and implicating other GAL receptor subtypes in spatial learning and olfactory social memory. The growing body of rodent literature implicating excess GAL in cognitive impairment is relevant to the overexpression of GAL in the basal forebrain during the progression of Alzheimer's disease.

Animals↗
PubMed2005

The ascent of mouse: advances in modelling human depression and anxiety.

Psychiatry has proven to be among the least penetrable clinical disciplines for the development of satisfactory in vivo model systems for evaluating novel treatment approaches. However, mood and anxiety disorders remain poorly understood and inadequately treated. With the explosion in the use of genetically modified mice, enormous research efforts have been focused on developing mouse models of psychiatric disorders. The success of this approach is largely contingent on the usefulness of available behavioural models of depression- and anxiety-related behaviours in mice. Here, we assess the current status of research into developing appropriate tests for assessing such behaviours.

Animals↗
PubMed2004

Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.

Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT1A receptors in the hypothalamus. The expression of the 5-HT1A genes is controlled by the 5-HT1A promoter, so that they are only expressed in 5-HT1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT1A receptors in the medial hypothalamus; this effect was accompanied by elimination of the exaggerated adrenocorticotropin responses to a saline injection (minor stress) and reduced locomotor activity but not by a change in increased exploratory anxiety-like behavior. (2) To further confirm the observation in SERT-/- mice, Ad-1AP-antisense was injected into the hypothalamus of normal mice. The density and the function of 5-HT1A receptors in the medial hypothalamus were significantly reduced in Ad-1AP-antisense-treated mice. Compared with the control group (injected with Ad-track), Ad-1A-antisense-treated mice showed a significant reduction in locomotor activity, but again no changes in exploratory anxiety-like behaviors, tested by elevated plus-maze and open-field tests. Thus, the present results demonstrate that medial hypothalamic 5-HT1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors.

Adenoviridae↗
PubMed2004

Phenotypic assessment of galanin overexpressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior.

RATIONALE: Galanin and its receptors exert inhibitory neuromodulatory control over brain monoamines. Rat studies revealed that galanin expression is upregulated by exposure to stressors and that galanin manipulations modify neuroendocrine and behavioral responses to stress, leading to the hypothesis that galanin mediates depression-related behaviors. METHODS: In the present study, we examined the role of galanin in modulating antidepressant-related behavior in galanin overexpressing transgenic (GAL-tg) mice and galanin receptor R1 knockout (GAL-R1 KO) mice, using the tail suspension test (TST). Quantitative autoradiography for 5-HT(1A)-R and serotonin transporter binding density tested for changes in these two major regulatory components of the 5-HT system in galanin mutant mice. RESULTS: Baseline TST behavior was normal in GAL-tg and GAL-R1 KO mice, and intracerebroventricular administration of galanin failed to alter TST behavior in normal C57BL/6J mice. The TST anti-immobility effects of acute treatment with the serotonin reuptake inhibitor, fluoxetine (0-30 mg/kg), and the norepinephrine reuptake inhibitor, desipramine (0-30 mg/kg), were unaltered in galanin mutant mice. Hippocampal 5-HT(1A)-R density was significantly elevated in GAL-tg and GAL-R1 KO mice, while hippocampal 5-HTT density was reduced in GAL-R1 KO mice, relative to controls. CONCLUSION: Neither pharmacological nor molecular genetic manipulations of galanin altered depression-related profiles in the TST. Possible functional alterations in hippocampal 5-HT neurotransmission may have contributed to these negative results. These preliminary findings provide evidence against the hypothesis that galanin plays a central role in mouse depression-related behaviors. It remains possible that galanin modulates depression-related responses in other experimental paradigms and species.

Animals↗
PubMed2004

Thalamic stimulation for parkinsonian tremor: correlation between regional cerebral blood flow and physiological tremor characteristics.

We used (15)O-labeled water (H(2)(15)O) positron emission tomography (PET) to study eight Parkinson's disease (PD) patients with unilateral ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS) for severe tremor. Triaxial accelerometry (TRIAX) was used during imaging to obtain on-line measures of tremor characteristics. Regional cerebral blood flow (rCBF) scans together with TRIAX recordings were collected in three stimulation conditions (OFF, MID, and ON, corresponding, respectively, to 0%, 50%, and 100% reductions in mean accelerometry signal). Statistical Parametric Mapping (SPM99) revealed significant rCBF reductions during stimulation in the ipsilateral sensorimotor cortex (SMC) and the contralateral cerebellum, as well as concurrent increases in the ipsilateral ventral thalamus (P < 0.05, corrected). Covariate analysis of rCBF with physiological tremor characteristics revealed that tremor acceleration correlated positively with changes in the SMC and supplementary motor cortex ipsilaterally (P < 0.05, uncorrected), and negatively with changes in the ipsilateral cuneus (P < 0.05, corrected). After removing tremor acceleration effects, changes in tremor frequency correlated negatively with changes in the contralateral dentate nucleus and pons (P < 0.05, uncorrected). Our results suggest that Vim DBS for PD tremor modulates the activity of cerebello-thalamo-cortical pathways. Specific tremor characteristics relate to activity in different nodes of this system.

Aged↗
PubMed2004

Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes.

The functional specificity of dopamine receptor subtypes remains incompletely understood, in part due to the absence of highly selective agonists and antagonists. Phenotypic analysis of dopamine receptor knockout mice has been instrumental in identifying the role of dopamine receptor subtypes in mediating dopamine's effects on motor function, cognition, reward, and emotional behaviors. In this article, we provide an update of recent studies in dopamine receptor knockout mice and discuss the limitations and future promise of this approach.

Animals↗
PubMed2004

Learning and memory performance in mice lacking the GAL-R1 subtype of galanin receptor.

The neuropeptide galanin induces performance deficits in a wide range of cognitive tasks in rodents. Three G-protein-coupled galanin receptor subtypes, designated GAL-R1, GAL-R2 and GAL-R3, have been cloned. The present study examined the role of GAL-R1 in cognition by testing mice with a null mutation in Galr1 on several different types of learning and memory tasks. Assessments of general health, neurological reflexes, sensory abilities and motor functions were conducted as control measures. Mutant mice were unimpaired in social transmission of food preference and the Morris water maze. In tests of fear conditioning, mutant mice were unimpaired in a delay version of cued fear conditioning. However, mice homozygous for the null mutation were impaired in a trace version of cued fear conditioning. Mutant mice were unimpaired in contextual fear conditioning, whether training was by the delay or trace protocol. General health, neurological reflexes, sensory abilities and motor functions did not differ across genotypes, indicating that the trace fear conditioning deficit was not an artifact of procedural disabilities. The findings of normal performance on several cognitive tasks and a selective deficit in trace cued fear conditioning in homozygous GAL-R1 mutant mice are discussed in terms of hypothesized roles of the GAL-R1 subtype. The generally normal phenotype of GAL-R1 null mutants supports the use of this line for identification of the receptor subtypes that mediate the cognitive deficits produced by exogenous galanin.

Animals↗
PubMed2003

Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression.

Evidence of a link between genetic variation of the serotonin transporter and depression and anxiety prompted the generation of serotonin transporter knockout mice. Loss of serotonin reuptake function in knock-outs causes reduced clearance of extracellular serotonin and associated alterations in serotonin neuronal firing and receptor function. Behavioral phenotyping function in knock-outs revealed genetic background-related abnormalities, including increased anxiety-like behaviors, reduced aggression, and exaggerated stress responses. Ongoing studies focus on identifying environmental, genetic, and developmental factors interacting with the htt mutation to produce these abnormalities. Serotonin transporter null mutant mice provide a model system to study how genetic variation in serotonin transporter function affects risk for neuropsychiatric disease.

Animals↗
PubMed2003

Vertical instability in spondylolisthesis: a traction radiographic assessment technique and the principle of management.

STUDY DESIGN: Lateral radiographs of the lumbar spine were taken of 40 patients with lumbar spondylolisthesis. These radiographs were taken in the neutral, flexion, and extension positions for both erect and recumbent postures, and also in the prone and supine positions with traction applied via a traction table. OBJECTIVES: To define and demonstrate the presence of "vertical instability" in spondylolisthesis, and to determine the most useful radiographic views for clinical purposes and analysis of the surgical principle. SUMMARY OF BACKGROUND DATA: Lateral radiographs of patients in flexion and extension are widely used to obtain quantitative and qualitative data on lumbar spondylolisthesis. Changes in lumbar disc height and segmental translation in a group of patients with spondylolisthesis have been demonstrated with the addition of traction and compression. METHODS: Lateral and flexion extension radiographs of the lumbosacral spine in 37 patients with spondylolisthesis taken in standing and recumbent positions and under pelvic traction in the prone or supine positions were suitable for analysis. The changes in disc area, intervertebral kyphotic slip angle, and amount of anteroposterior shift (olisthesis) were measured from the radiographs using a computer digitizer. The disc area was normalized against the area of the superior vertebra, and the amount of anteroposterior shift was normalized against the anteroposterior width of the superior vertebra. Inter- and intraobserver error was found to be negligible, and results were analyzed by paired t test. RESULTS: Maximum slip angle, maximum olisthesis, and minimum normalized disc area were found with the subject under erect flexion. Conversely, prone traction and recumbent extension produced minimum slip angle, whereas the lowest anteroposterior shifts were seen with the subject under prone and supine traction. Prone traction also resulted in a significantly larger normalized disc area than any other posture. The change in kyphotic slip angle between erect flexion and prone traction is correlated with the change in normalized olisthesis and disc area. CONCLUSIONS: Erect flexion and prone traction radiographs represent the extremes of subluxation and reduction of the olisthesis, respectively, and the change in olisthesis seen between these extremes is correlated with the change in disc area and the intervertebral slip angle. Vertical laxity of the affected functional spinal unit resulting from disc degeneration produces laxity in the ligaments and disc anulus, allowing olisthetic motion. Restoration of disc height in turn restores tension to the soft tissues around the disc and results in a spontaneous reduction of the subluxation. Restoration and maintenance of disc height with a spacer or interbody fusion therefore is recommended as a goal in the treatment of spondylolisthesis. When spondylolytic spondylolisthesis involves a posterior column deficiency, additional reconstruction of this column with posterior instrumentation is recommended. Application of the traction radiographic technique in planning for spondylolisthesis reduction is discussed along with the technique of stabilization.

Adolescent↗