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Biomedical subjects

Andrew Holmes

Publications and source records attributed to Andrew Holmes.

At least 19 recordsLinked to original sources
PubMed2007

An investigation of the behavioral actions of ethanol across adolescence in mice.

RATIONALE: The transition from adolescence into adulthood is characterized by rapid maturation of brain systems mediating reward and by increasing experimentation with drugs of abuse including ethanol (EtOH). Previous studies have found marked differences in sensitivity to the behavioral effects of EtOH in adolescent rats as compared to adults, but relatively few studies have been conducted in mice. OBJECTIVES: The present study examined sensitivity to various behavioral effects of EtOH in C57BL/6J mice at various stages of adolescence/adulthood (4, 6, 8 weeks old). Ages were compared for locomotor stimulant (open field), anxiolytic-like (elevated plus-maze), memory-impairing (Pavlovian fear conditioning) and ataxic (accelerating rotarod) effects of EtOH, and the sedative/hypnotic (sleep time) effects of EtOH and pentobarbital. EtOH self-administration was compared using a two-bottle choice paradigm. Measures of EtOH metabolism were also obtained. RESULTS: Early adolescent mice exhibited increased sensitivity to locomotor stimulant (1.5 g/kg), anxiolytic-like (1.5 g/kg) and ataxic (1.5-2.5 g/kg), but not memory impairing (2.0 g/kg), effects of EtOH relative to adults. Early adolescent, and to some extent peri-adolescent, mice were less sensitive than adults to the sedative/hypnotic effects of EtOH (3.5-4.5 g/kg), but not pentobarbital (40-50 mg/kg). Early adolescent mice showed lower EtOH preference, but not EtOH consumption, than adults. Blood EtOH concentrations were higher at early time points and lower at later time points after (3.0 g/kg) EtOH injection in early and peri-adolescents relative to adults. CONCLUSIONS: Present data demonstrate that sensitivity to the acute intoxicating effects of EtOH changes across mouse adolescent development in a behavior-dependent manner.

Age Factors↗
PubMed2007

Effects of mild early life stress on abnormal emotion-related behaviors in 5-HTT knockout mice.

A low-expressing polymorphic variant of the serotonin transporter (5-HTT) gene has been associated with emotional disorders in humans and non-human primates following exposure to early life trauma. 5-HTT gene knockout (KO) mice exhibit increased anxiety- and depression-related behaviors, and provide a model to study interactions between 5-HTT gene variation and early life stress. The present study assessed the effects of postnatal footshock stress on the development of emotion-related behaviors in 5-HTT KO mice. Results showed that 5-HTT KO mice displayed a profile of suppressed exploratory behavior and increased anxiety-like behavior in the light/dark, elevated plus-maze and open field tests, as well as increased depression-related behavior in the forced swim test following repeated exposure to the test. Postnatal exposure to footshock stress did not affect emotion-related behaviors in non-mutant C57BL/6J mice or modify phenotypic abnormalities in 5-HTT KO. Data provide further evidence of emotional abnormalities following genetic disruption of the 5-HTT.

Animals↗
PubMed2006

Genetic and structural analysis of the basolateral amygdala complex in BXD recombinant inbred mice.

The amygdala integrates and coordinates emotional and autonomic responses. The genetics that underlie variation in amygdala structure may be coupled to variation in levels of aggression, fear, anxiety, and affiliated behaviors. We systematically quantified the volume and cell populations of the basolateral amygdala complex (BLAc) across 35 BXD recombinant inbred (RI) lines, the parental strains--C57BL/6J (B6) and DBA/2J (D2)--and F1 hybrids (n cases=199, bilateral analysis). Neuron number and volume vary 1.7- to 2-fold among strains (e.g., neuron number ranged from 88,000 to 170,000). Glial and endothelial populations ranged more widely (5- to 8-fold), in part because of higher technical error. A quantitative trait locus (QTL) for the BLAc size is located on chromosome (Chr) 8 near the Large gene. This locus may also influence volume of other regions including hippocampus and cerebellum. Cell populations in the BLAc appear to be modulated more weakly by loci on Chrs 11 and 13. Candidate genes were selected on the basis of correlation with BLAc traits, chromosomal location, single nucleotide polymorphism (SNP) density, and expression patterns in the Allen Brain Atlas. Neurod2, a gene shown to be significant for the formation of the BLAc by knockout studies, is among the candidates genes. Other candidates include Large, and Thra. Responses to drugs of abuse and locomotor activity were the most notable behavioral correlates of the BLAc traits.

Amygdala↗
PubMed2006

Ontogeny of fear-, anxiety- and depression-related behavior across adolescence in C57BL/6J mice.

Adolescence is characterized by behavioral traits such as emotional lability and impulsivity that are associated with increased vulnerability to affective illness and addictions. Research in rodents has found that adolescent rats and mice differ from adults on measures of anxiety-like behavior, novelty seeking and stress-responsivity. The present study sought to extend these data by evaluating fear-, anxiety- and depression-related behaviors in male C57BL/6J mice aged four (early adolescent), six (peri-adolescent) or eight (early adult) weeks of age. Age groups were compared on: Pavlovian fear conditioning and extinction, anxiety-like behavior and exploratory locomotion (using elevated plus-maze and novel open field), and depression-related behavior (via forced swim test). Results showed that early adolescent mice exhibited enhanced fear conditioning, but extinguished at a similar rate as adults. There were no major differences in anxiety-like behavior across age groups, although early adolescent and peri-adolescent mice exhibited less exploratory locomotion than adults. Depression-related immobility behavior in the forced swim test was lower in early adolescents than adult mice across three test exposures. Present findings in the C57BL/6J inbred strain add to growing evidence of changes in rodent fear- and stress-related behaviors across the developmental transition from juvenility through adulthood. Understanding the neural basis of these ontogenic changes could provide insight into the pathogenesis and treatment of affective disorders that have their origins in adolescence.

Age Factors↗
PubMed2006

Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies.

1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone. 2. We investigated here whether there might be gender differences in these consequences of combined SERT and BDNF deficiencies by extending the original studies to female mice, and also to an examination of the effects of ovariectomy and tamoxifen in these female mice, and of 21-day 17-beta estradiol implantation to male mice. 3. We found that unlike the male SERTxBDNF-deficient mice, female SERTxBDNF mice appeared protected by their gender in having significantly lesser reductions in serotonin concentrations in hypothalamus and other brain regions than males, relative to controls. Likewise, in the elevated plus maze, female SERTxBDNF-deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males. 4. Furthermore, female SERTxBDNF mice did not manifest the approximately 40% reduction in the expression of TrkB receptors or the approximately 30% reductions in dopamine and its metabolites that male SERTxBDNF did. After estradiol implantation in male SERTxBDNF mice, hypothalamic serotonin was significantly increased compared to vehicle-implanted mice. These findings support the hypothesis that estrogen may enhance BDNF function via its TrkB receptor, leading to alterations in the serotonin circuits, which modulate anxiety-like behaviors. 5. This double-mutant mouse model contributes to the knowledge base that will help in understanding genexgenexgender interactions in studies of SERT and BDNF gene polymorphisms in human genetic diseases such as anxiety disorders and depression.

Animals↗
PubMed2006

Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains.

Genetic factors and early life adversity both play a major role in the etiology of mood and anxiety disorders. Previous studies have shown that postnatal maternal separation (MS) can produce lasting abnormalities in emotion-related behavior and neuroendocrine responses to stress in rodents. The present study sought to examine the effects of repeated MS in eight different inbred strains of mice (129S1/SvImJ, 129P3/J, A/J, BALB/cJ, BALB/cByJ C57BL/6J, DBA/2J, FVB/NJ). Pups were separated from their dam and littermates for 180 min/day ('MS') or 15 min/day ('handling'), or left undisturbed ('facility-reared') from postnatal days P0-P13, and tested as adults for anxiety- and depression-related behaviors. Results demonstrated no clear and consistent effects of MS or handling on behavioral phenotypes in any of the strains tested. In all strains, MS produced an increase in maternal care on reunion with pups, which may have modified MS effects. Data demonstrate that the MS procedure employed does not provide a robust model of early life stress effects on the anxiety- and depression-related behaviors in the mouse strains tested.

Animals↗
PubMed2006

Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit.

RATIONALE: The ionotropic NMDA glutamate receptor is composed of NR1 and NR2 (NR2A-D) subunits. While there is compelling evidence that NMDA receptors modulate behavioral effects of ethanol, there is little understanding of how the subunit composition of the NMDA receptor mediates these effects. OBJECTIVES: In the current study, we assessed the relative roles of NMDA subunits via phenotypic assessment of ethanol-related behaviors in NR2A knockout (KO) mice. RESULTS: Results demonstrated that NR2A KO and heterozygous mice failed to show evidence of ethanol-induced conditioned place preference. As compared to wild-type (WT) controls, KO mice showed impaired motor coordination at baseline and, in some instances, following ethanol treatment on the accelerating rotarod, balance beam, and wire-hang tests. By contrast, open field locomotor-stimulant, sedative/hypnotic, and hypothermic responses to ethanol were not different between genotypes, nor was voluntary ethanol consumption and preference in a two-bottle choice paradigm. Blood ethanol concentrations were lower in KO than WT mice following intraperitoneal ethanol injection. CONCLUSIONS: Results suggest that the loss of NR2A subunit-containing NMDA receptors impairs the ability to form or express learned reward-related responses to ethanol and causes deficits in motor coordination. However, the loss of NR2A does not alter other measures of acute ethanol intoxication or ethanol consumption, possibly implicating other NMDA subunits in these effects. These data provide novel insight into the role of NMDA receptors in modulating the behavioral effects of ethanol.

Alcohol Drinking↗
PubMed2006

Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism.

Brain serotonin (5-HT) modulates the neural and behavioral effects of ethanol in a manner that remains poorly understood. Here we show that treatment with physiologically relevant (i.e., moderately intoxicating) doses of ethanol inhibits clearance of 5-HT from extracellular fluid in the mouse hippocampus. This finding demonstrates, in vivo, a key molecular mechanism by which ethanol modulates serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the principle means of 5-HT reuptake in the brain and an obvious candidate mechanism for the effect of ethanol to inhibit 5-HT clearance. However, our second major finding was that genetic inactivation of the 5-HTT in a knock-out mouse not only failed to prevent ethanol-induced inhibition of 5-HT clearance, but actually potentiated this effect. Ethanol-induced inhibition of 5-HT clearance was also potentiated in nonmutant mice by cotreatment with a 5-HTT antagonist. Providing a link with potential behavioral manifestations of this neural phenotype, 5-HTT knock-out mice also exhibited exaggerated sensitivity to behavioral intoxication, as assayed by the sedative/hypnotic effects of ethanol. This clearly demonstrates that the 5-HTT is not necessary for the neural and behavioral effects of ethanol observed herein and that genetic or pharmacological inactivation of the 5-HTT unmasks involvement of other principle mechanisms. These data are intriguing given growing evidence implicating the 5-HTT in the pathophysiology and treatment of alcoholism and neuropsychiatric conditions frequently comorbid with alcoholism, such as depression. The present findings provide new insights into the actions of ethanol on brain function and behavior.

Animals↗
PubMed2006

Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice.

Extinction of conditioned fear responses is an active learning process resulting from the repeated presentation of a conditioned stimulus in the absence of the unconditioned aversive stimulus. Recent research implicates the medial prefrontal cortex (mPFC) in the mediation of fear extinction in rodents and the pathophysiology of posttraumatic stress disorder. However, there is currently little understanding of precisely how stress can impact fear extinction and the neural circuitry subserving this behavior. The present study examined the effects of brief exposure to an uncontrollable stressor on (1) fear conditioning and fear extinction, and (2) dendritic morphology of pyramidal neurons in the infralimbic (IL) and prelimbic (PL) regions of the mPFC in mice. Exposure to three episodes of stress ending 24 h before fear conditioning significantly attenuated the rate of cued fear extinction relative to nonstressed controls, but did not affect fear conditioning or cue or context recall. Analysis of Golgi-stained neurons showed that one or three exposures to daily swim stress caused significant retraction of terminal branches of apical, but not basilar, dendrites of IL neurons. In contrast, PL neuronal morphology was unaltered by stress. These data demonstrate that IL, but not PL, neurons are highly sensitive to even brief exposure to stress, and that this same form of stress impairs fear extinction. Present findings suggest that trauma may compromise the functional integrity of the mPFC with implications for the pathophysiology of certain neuropsychiatric disorders.

Animals↗
PubMed2006

Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice.

Mice are uniquely suited as experimental subjects for various approaches to the study of the molecular and genetic basis of behavior, and there has been a corresponding explosion in the use of mice in behavioral neuroscience. Rats and monkeys, however, remain the preferred species for high-order cognitive models largely due to the unavailability of valid, reliable and translatable endpoint measures of behavior in the mouse. Here we present further development and validation of a touchscreen-based operant method for measuring cognition that is comparable to methods used in other species and human patients. C57BL/6J mice were found to show good performance on visual discrimination and reversal learning using this method. Demonstrating the sensitivity of the paradigm to genetic factors, C57BL/6J and DBA/2J mice exhibited marked differences in discrimination and reversal learning. Systemic treatment with the selective D1-like agonist, SKF81297, produced an impairment in the early phase of reversal learning, but did not alter visual discrimination, in C57BL/6J mice. The same treatment impaired spatial working memory on the T-maze delayed alternation task, but did not alter control measures of behavior including motivation and locomotor activity. These data demonstrate the sensitivity of visual discrimination and reversal learning measured by this method to genetic factors and pharmacological challenge, and thereby provide an extension and further validation of the method for measuring cognition in mice. When combined with emerging molecular techniques uniquely suited to this species such as genetic engineering and RNA modification this paradigm could provide a powerful new tool for behavioral neuroscience.

Analysis of Variance↗
PubMed2006

Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1.

The transactivation of enhanced growth factor receptor (EGFR) by G protein-coupled receptor (GPCR) ligands is recognized as an important signaling mechanism in the regulation of complex biological processes, such as cancer development. Estrogen (E2), which is a steroid hormone that is intimately implicated in breast cancer, has also been suggested to function via EGFR transactivation. In this study, we demonstrate that E2-induced EGFR transactivation in human breast cancer cells is driven via a novel signaling system controlled by the lipid kinase sphingosine kinase-1 (SphK1). We show that E2 stimulates SphK1 activation and the release of sphingosine 1-phosphate (S1P), by which E2 is capable of activating the S1P receptor Edg-3, resulting in the EGFR transactivation in a matrix metalloprotease-dependent manner. Thus, these findings reveal a key role for SphK1 in the coupling of the signals between three membrane-spanning events induced by E2, S1P, and EGF. They also suggest a new signal transduction model across three individual ligand-receptor systems, i.e., "criss-cross" transactivation.

Cell Line, Tumor↗
PubMed2006

Vulnerability to mild predator stress in serotonin transporter knockout mice.

Effect of predator stress on rat and mouse anxiety-like behavior may model aspects of post traumatic stress disorder (PTSD). A single cat exposure of wild type (C57, CFW) mice can produce lasting anxiety-like effects in the elevated plus maze, light/dark box tests and startle. In addition, female but not male C57 mice are made more anxious in the plus maze by exposure to predator odors alone, suggesting differential vulnerability to predator stressors of differing intensity. There is a link between genetic variation in the serotonin (5-HT) transporter (SERT) and anxiety in humans. This prompted the generation of SERT knockout mice [see Holmes A, Murphy DL, Crawley, JN. Biol Psychiatry 2003;54(10):953-9]. Present work used these mice to determine if there was a link between vulnerability to the anxiogenic effects of predator odors and abnormalities of 5-HT transmission induced by a life long reduction in 5-HT reuptake. Wild type (WT, C57 background), heterozygous (SERT +/-, HET) mice and homozygous knockout (SERT -/-, KO) were assigned to handled control groups or groups exposed for 10 min to a large testing room rich in cat odor. One week after handling or room exposure, anxiety testing took place in the dark phase of the light/dark cycle, in red light. Predator odor exposure was selectively anxiogenic in the plus maze and light/dark box tests in SERT -/- mice. Exposure to predator odor did not potentiate startle. Findings suggest a role for abnormalities in 5-HT transmission in vulnerability to some of the lasting anxiogenic effects of species relevant stressors and possibly in vulnerability to PTSD.

Animals↗
PubMed2006

Genetics of emotional regulation: the role of the serotonin transporter in neural function.

Identifying biological mechanisms through which genes lead to individual differences in emotional behavior is paramount to our understanding of how such differences confer risk for neuropsychiatric illness. The emergence of techniques such as in vivo imaging of brain function in humans and genetic engineering in rodents has provided important new insights into the impact of serotonin (5-HT), a key modulator of emotional behavior, on neural systems subserving anxiety and depression. A major finding has been the discovery of genetic variation in a crucial regulatory molecule within the 5-HT system, the 5HT transporter (5-HTT), and its influence on emotional traits. The study of the 5-HTT provides a new foundation for understanding the neurobiological and genetic basis of emotional regulation and affective illness.

Amygdala↗
PubMed2006

Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice.

There is growing evidence implicating the glutamate system in the pathophysiology and treatment of mood and anxiety disorders. Glutamatergic neurotransmission is mediated by several receptor subfamilies including multiple NMDA receptor subunits (NR2A-D). However, little is currently understood about the specific roles of NMDA subunits in the mediation of emotional behavior due to a lack of subunit-specific ligands. In the present study, we employed a mouse gene-targeting approach to examine the role of the NR2A subunit in the mediation of anxiety- and depressive-related behaviors. Results showed that NR2A knockout (KO) mice exhibit decreased anxiety-like behavior relative to wild-type littermates (WT) across multiple tests (elevated plus maze, light-dark exploration test, novel open field). NR2A KO mice showed antidepressant-like profiles in the forced swim test and tail suspension test, as compared to WT controls. Locomotor activity in the nonaversive environments of the home cage or a familiar open field were normal in the NR2A KO mice, as were gross neurological and sensory functions, including prepulse inhibition of startle. Taken together, these data demonstrate a selective and robust reduction in anxiety- and depression-related behavior in NMDA receptor NR2A subunit KO mice. Present results support a role for the NR2A subunit in the modulation of emotional behaviors in rodents and provide insight into the role of glutamate in the pathophysiology and treatment of mood and anxiety disorders.

Analysis of Variance↗
PubMed2006

The acute intoxicating effects of ethanol are not dependent on the vasopressin 1a or 1b receptors.

Studies of the role of vasopressin (Avp) in mediating the effects of ethanol have focused on Avp's role in altering kidney function via its action through the vasopressin 2 receptor. However, alcohol consumption also has central effects that are poorly understood. There is evidence that Avp may mediate ethanol consumption as well as some of ethanol's behavioral effects. Centrally only two Avp receptor subtypes are expressed: the 1a receptor (Avpr1a) and the 1b receptor (Avpr1b). To determine the extent to which these receptors mediate the behavioral effects of alcohol, we used mice with targeted disruptions of either their Avpr1a or Avpr1b gene. We examined the effects of genotype on the acute intoxicating effects of ethanol as well as on voluntary ethanol consumption. Surprisingly, our findings indicate that there is no interaction between either the Avpr1a or Avpr1b and ethanol on motor coordination, hypothermia, mood, or voluntary ethanol consumption.

Alcohol Drinking↗
PubMed2006

Ethanol-related behaviors in serotonin transporter knockout mice.

BACKGROUND: Increasing evidence supports a role for 5-hydroxytryptamine (5-HT) and the 5-HT transporter (5-HTT) in modulating the neural and behavioral actions of ethanol (EtOH) and other drugs of abuse. METHODS: We used a 5-HTT knockout (KO) mouse model to further study this relationship. 5-Hydroxytryptamine transporter KO mice were tested for the sedative/hypnotic, hypothermia-inducing, motor-incoordinating (via accelerating rotarod), and depression-related (via tail suspension test) effects of acute EtOH administration. Reward-related effects of EtOH were assessed in 5-HTT KO mice using the conditioned place preference (CPP) paradigm. 5-Hydroxytryptamine transporter KO mice were tested for voluntary consumption of EtOH in a modified 2-bottle choice test that measured the temporal organization of drinking over the circadian cycle via "lickometers." RESULTS: Replicating previous findings, 5-HTT KO mice exhibited significantly increased sensitivity to EtOH-induced sedation/hypnosis relative to wild-type controls. Additionally, 5-HTT KO mice showed motor-coordination deficits at baseline and in response to EtOH. Hypothermic, pro-depressive-like, and reward-related effects of EtOH were no different across genotypes. Gross EtOH consumption was modestly reduced in 5-HTT KO mice, due to significantly lesser consumption during the peak period of drinking in the early dark phase. CONCLUSIONS: Data extend the finding that loss of 5-HTT gene function alters certain neural and behavioral effects of EtOH, with implications for better understanding the pathophysiology and treatment of alcoholism.

Alcohol Drinking↗
PubMed2006

Effects of repeated maternal separation on prepulse inhibition of startle across inbred mouse strains.

A growing body of research implicates genetic factors and childhood trauma in the etiology of neuropsychiatric diseases such as schizophrenia. However, there remains little understanding of how genetic variation influences early life stress to affect later disease susceptibility. Studies in rats have shown that postnatal maternal separation (MS) results in later deficits in prepulse inhibition of the acoustic startle response (PPI), an impairment in sensorimotor gating found in schizophrenic patients. In the present study, genetic differences in the effects of repeated MS on PPI were examined in eight inbred strains of mice (129S1/SvImJ, 129P3/J, A/J, BALB/cJ, BALB/cByJ C57BL/6J, DBA/2J and FVB/NJ). Mice were assigned to either MS (180 min/day on postnatal days P0-P13), 'handling' (15 min/day, P0-P13) or facility-reared conditions and tested for PPI at 12 weeks of age. Results demonstrated major strain differences in the production of viable offspring irrespective of MS, leading to the exclusion of 129P3/J, A/J and BALB/cJ from the study. Pups from the five remaining strains exhibited marked differences in the acoustic startle response and PPI, confirming previous strain comparisons. However, MS produced no significant effects on PPI in any of the strains tested. A second form of postnatal stress (repeated footshock) also failed to alter PPI in the one strain studied, C57BL/6J. Present results demonstrate that the form of MS studied herein does not provide a robust model of early life stress effects on PPI in the mouse strains tested. The development and validation of a reliable mouse model of early life stress remains an important research goal.

Acoustic Stimulation↗