多分辨率小波信号分解用于大鼠睡眠纺锤波的分析

本研究首先设计了慢波睡眠期脑电信号的合成仿真信号 ,对小波基函数进行了选择 ,结果证明Coiflet 5阶小波变换对大鼠慢波睡眠期EEG信号具有较好的分解结果。据此 ,应用多分辨率小波分析法设计了提取睡眠纺锤波的算法 ,并利用该算法对安定用药后和睡眠剥夺后大鼠慢波睡眠期纺锤波的持续时间和能量变化进行了分析 ,结果表明 :安定具有延长慢波睡眠期纺锤波持续时间的作用 ,而睡眠剥夺可以增加慢波睡眠期纺锤波的能量。这些结果说明 ,小波分析算法可以提供功率谱分析无法表现的时频信息。     

Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy

On the basis of our previous studies and the important role of the thalamo‐cortical network in states of unconsciousness, such as anaesthesia and sleep, and in sleep spindles generation, we investigated sleep spindles (SS) and high‐voltage sleep spindle (HVS) dynamics during non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep following different types of general anaesthesia in both physiological controls and in a rat model of Parkinson's disease (PD) cholinopathy, to follow the impact of anaesthesia on post‐anaesthesia sleep at the thalamo‐cortical level through an altered sleep spindle dynamics. We recorded 6 hr of spontaneous sleep in all rats, both before and 48 hr after ketamine/diazepam or pentobarbital anaesthesia, and we used 1 hr of NREM or REM sleep from each to validate visually the automatically detected SS or HVS for their extraction and analysis. In the controls, SS occurred mainly during NREM, whereas HVS occurred only during REM sleep. Ketamine/diazepam anaesthesia promoted HVS, prolonged SS during NREM, induced HVS of increased frequency during REM, and increased SS/HVS densities during REM versus NREM sleep. Pentobarbital anaesthesia decreased the frequency of SS during NREM and the HVS density during REM sleep. Although the pedunculopontine tegmental nucleus lesion prolonged SS only during NREM sleep, in these rats, ketamine/diazepam anaesthesia suppressed HVS during both sleep states, whereas pentobarbital anaesthesia promoted HVS during REM sleep. The different impacts of two anaesthetic regimens on the thalamo‐cortical regulatory network are expressed through their distinct sleep spindle generation and dynamics that are dependent on the NREM and REM state regulatory neuronal substrate.     

Artificial selection for altered male wing display inDrosophila simulans

Selection for an increase in one form of male wing display (vibration) over another (scissoring) was carried out on courting pairs of a multifemale stock ofDrosophila simulans for 17 generations. One of two lines responded to selection, and the realized heritability calculated over the first 11 generations was approximately 10% for this line. Pair matings between control and selected flies in generation 17 indicated that selection occurred primarily on males themselves, rather than indirectly on females. The trait used in selection (vibration time/wing display time) was broken down into four component traits: number of bouts of vibration, vibration bout length, number of bouts of scissoring, and scissoring bout length. Only two of these traits, number of bouts of vibration and scissoring bout length, showed a long-term response to selection.This study was supported by NSF Grant DEB 7903866.     

Night medication in rheumatoid arthritis

The efficacy of indomethacin 100 mg, diazepam 10 mg, and placebo in producing sleep, relieving night pain, and reducing the severity of morning stiffness, was compared in 18 patients in hospital with active classical or definite rheumatoid arthritis.There was no statistically significant difference in the preference of patients or sleep score among the three forms of treatment. Both indomethacin and diazepam were more effective than placebo in relieving night pain. Indomethacin decreased, but diazepam increased, morning stiffness in comparison to placebo. Neither active therapy produced significant side-effects.     

Selection of refractory and permissive strains of Aedes triseriatus (Diptera: Culicidae) for transovarial transmission of La Crosse virus

The genetic basis of transovarial transmission of La Crosse virus in Aedes triseriatus (Say) was investigated through selection experiments on 2 mosquito strains. One strain was subject to selection for transovarial transmission refractoriness, the other for permissiveness to transovarial transmission. Response to selection for a low filial infection rate was rapid, decreasing from 18 to 3% in 3 generations. However, no response to selection for permissiveness was observed in the other strain; the average filial infection rates through 4 generations fluctuated between 25 and 40%. By contrast, the transovarial transmission rate in both strains showed a consistent response to selection in both directions. These patterns are consistent with a model in which transovarial transmission is controlled by a single genetic locus and permissiveness is conditioned by dominant alleles; whereas the filial infection rate is nongenetic and influenced by stochastic factors in the mosquito and virus.     

Selection for agonistic behavior in wild female mice

This article reports the results of 11 generations of selective breeding for isolation-induced, interfemale aggression inMus musculus. Within-family selection was used to form two high, two low, and two unselected control lines, beginning with a population of wild-trapped mice. Selection was successful in establishing the divergent lines, so that in recent generations about 50% of high-line animals attack, as do 25% of controls and 5% of lows. Realized heritabilities for eight generations of selection were 0.12 for H1, 0.14 for H2 0.34 for L1, and 0.46 for L2. Male aggression has apparently not shown a correlated response to selection for female aggression. Group housing reduces the aggression of female mice, but the order of the lines is maintained under either isolation or group housing. Practical problems encountered in this selection program are discussed.This research was supported by Grant MH28374 from NIMH to J. S. H.     

Effect of Benzodiazepine Derivatives: I. Augmentation of T Cell-Dependent Antibody Response by Diazepam in Mouse Spleen Cells

Oral administration of diazepam at doses of 5-10 mg/kg to restraint-stressed mice resulted in almost complete recovery in the stress-induced suppression of the antibody response to sheep red blood cell (SRBC). Noreover, this compound restored the suppression of antibody response to SRBC in cyclophosphamide-treated mice. Diazepam treatment also enhanced the antibody response against SRBC in normal mice only when the animals were immunized with the reduced amount of antigen. It was demonstrated that antigen specific helper T cell activity was promoted by diazepam administration in mice. Addition of diazepam augmented the in vitro anti-SRBC hemolytic plaque-forming cell (PFC) response in mouse splenocytes without altering kinetics of the response. However, the enhancing effect was observed only when the drug was added to the medium at the culture initiation. On the other hand, antibody response to T cell-independent antigens such as trinftrophenylated (TNP)-Ficoll and TNP-lipopolysaccharide were not enhanced by diazepam. Concanavalin A or LPS-induced ³H-thymidine uptake into splenocytes were not stimulated by diazepam. These results suggest that diazepam promotes the antibody response through stimulating helper T cell functions.     

Bidirectional selection for open-field activity in young chicks

A selection program for open-field activity in 2-day-old chicks was performed over eight generations. All characters measured responded to selection, and for most of them the response was symmetric in the two strains. After eight generations of selection the distribution of latencies and of measures of activity overlapped only slightly. The two exceptions were the latency to move and the percentage of birds which defecated. From an evolutionary point of view the symmetry of the two lines, the relatively high heritabilities, and the absence of heterotic effects on these characters show that open-field behavior has been subjected to a stabilizing natural selection rather than a directional one. This conclusion agrees with observations on open-field behavior in this and other species.     

Modification of actin in peritoneal macrophages after diazepam treatment

We have investigated the effect of therapeutic doses of diazepam (7 μg/mouse) on the association of actin with the macrophage cytoskeleton using cytochemical and morphological methods.

Results obtained indicated that diazepam was able to modulate the content of actin in macrophages; such an effect proved to be time-dependent. After fixation and staining for indirect immunofluorescence with actin antibody, peritoneal macrophages from mice treated for short time with diazepam, showed a fluorescent intensity increase compared to control mice. The fluorescent intensity augmented reaching peak value within 14 days of treatment. Afterwards, this value dropped below control value for mice that underwent longer treatments. In the in vitro experiments concentrations of 10^-5 M, diazepam inhibited a well cell spread and a lower amount of actin after 15 min of incubation was also revealed.

These results suggest that administration of diazepam in vivo plays a role in both the nonspecific and specific immune response, producing in the macrophages a reorganization process of microfilaments.     

Effect of Benzodiazepine Derivatives: I. Augmentation of T Cell-Dependent Antibody Response by Diazepam in Mouse Spleen Cells

Abstract

Oral administration of diazepam at doses of 5–10 mg/kg to restraint-stressed mice resulted in almost complete recovery in the stress-induced suppression of the antibody response to sheep red blood cell (SRBC). Noreover, this compound restored the suppression of antibody response to SRBC in cyclophosphamide-treated mice. Diazepam treatment also enhanced the antibody response against SRBC in normal mice only when the animals were immunized with the reduced amount of antigen. It was demonstrated that antigen specific helper T cell activity was promoted by diazepam administration in mice. Addition of diazepam augmented the in vitro anti-SRBC hemolytic plaque-forming cell (PFC) response in mouse splenocytes without altering kinetics of the response. However, the enhancing effect was observed only when the drug was added to the medium at the culture initiation. On the other hand, antibody response to T cell-independent antigens such as trinftrophenylated (TNP)-Ficoll and TNP-lipopolysaccharide were not enhanced by diazepam. Concanavalin A or LPS-induced ³H-thymidine uptake into splenocytes were not stimulated by diazepam. These results suggest that diazepam promotes the antibody response through stimulating helper T cell functions.     

The effect of diazepam upon local cerebral glucose use in the conscious rat

The effects of diazepam (0.1-1.0 mg/kg i.v.) upon local cerebral glucose utilization, were analysed in 61 anatomically discrete areas of the conscious rat brain using [14C]-2-deoxyglucose quantitative autoradiography. The administration of diazepam resulted in significant reductions in the rate of glucose use in every region investigated. The regional pattern of alterations in glucose utilization was rather homogeneous, with the majority of brain regions analysed showing reductions of between 20 and 40% in response to 0.3 mg/kg diazepam. Only two regions of the central nervous system differed significantly from the widespread, homogeneous reductions. In the mammillary body, the rate of glucose utilization was more sensitive to depression than elsewhere in the brain (55% reductions following 0.3 mg/kg diazepam), whilst in the lateral amygdala, the rate of glucose use was less sensitive (8% reductions following 0.3 mg/kg diazepam). The effects of diazepam were compared to those elicited by i.v. injection of the gamma-aminobutyric acid (GABA) agonists, muscimol and tetrahydroisoxazolopyridinol (THIP), as reported previously by the authors. Although muscimol and THIP, like diazepam, reduced glucose use in every region of the brain, visual inspection of the autoradiograms suggested that whilst the patterns of regional responsiveness to the two GABA agonists were almost identical, they were different to the pattern of response evoked by diazepam. A rigorous system of analysis was devised making use of the dose-response profiles in each of the 61 brain areas to construct a regional hierarchy of responsiveness to the three drugs and allowing comparison of their effects on the brain as a whole. This critical form of data evaluation revealed that there was a more regionally homogeneous response to diazepam than to either muscimol or THIP, and whilst the regional hierarchy of responses to the GABA agonists was very similar, both differed from diazepam. It would appear that whilst benzodiazepines may interact with the GABA receptor, their effects upon the integrated functional activity of the brain as a whole differs markedly from that evoked by putative GABA receptor agonists.     

Genetics of antibody responsiveness to bovine serum albumin and rabbit gamma-globulin. II. Evidence for a partially common genetic regulation of response to bovine serum albumin and rabbit gamma-globulin

In order to measure the reciprocal nonspecific effect of the genetic regulation of antibody responsiveness to bovine serum albumin (BSA) and rabbit gamma-globulin (RGG), two independent bidirectional selective breedings for responses to these two antigens were carried out: selection V/BSA and selection V/RGG respectively. The total interline separation at selection limit (RT) was 5.3 log2 for selection V/BSA and 2.6 log2 for selection V/RGG. The sum of these two values (7.9 log2) is similar to the RT in selection V carried out by alternating these two antigens in consecutive generations. In selection V/BSA, the nonspecific effect for responsiveness to RGG was 72%. In selection V/RGG, the nonspecific effect for BSA responsiveness was 135%. The F1 hybrids between homologous lines of selection V/BSA and selection V/RGG presented a larger difference in antibody response to both antigens than their parental lines. This demonstrates an additive effect of the loci controlling the two responses.     

Benzodiazepine Receptor Agonists Cause Drug-Specific and State-Specific Alterations in EEG Power and Acetylcholine Release in Rat Pontine Reticular Formation

Study Objectives:

Benzodiazepine (BDZ) and non-benzodiazepine (NBDZ) hypnotics enhance GABAergic transmission and are widely used for the treatment of insomnia. In the pontine reticular formation (PRF), GABA inhibits rapid eye movement (REM) sleep and acetylcholine (ACh) release. No previous studies have characterized the effects of BDZ and NBDZ hypnotics on ACh release in the PRF. This study tested 2 hypotheses: (1) that microdialysis delivery of zolpidem, eszopiclone, and diazepam to rat PRF alters ACh release in PRF and electroencephalographic (EEG) delta power and (2) that intravenous (IV) administration of eszopiclone to non-anesthetized rat alters ACh release in the PRF, sleep, and EEG delta power.

Design:

A within- and between-groups experimental design.

Setting:

University of Michigan.

Patients or Participants:

Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 57).

Interventions:

In vivo microdialysis of the PRF in rats anesthetized with isoflurane was used to derive the concentration-response effects of zolpidem, eszopiclone, and diazepam on ACh release. Chronically instrumented rats were used to quantify the effects of eszopiclone (3 mg/kg, IV) on ACh release in the PRF, sleep-wake states, and cortical EEG power.

Measurements and Results:

ACh release was significantly increased by microdialysis delivery to the PRF of zolpidem and eszopiclone but not diazepam. EEG delta power was increased by zolpidem and diazepam but not by eszopiclone administered to the PRF. Eszopiclone (IV) decreased ACh release in the PRF of both anesthetized and non-anesthetized rats. Eszopiclone (IV) prevented REM sleep and increased EEG delta power.

Conclusion:

The concentration-response data provide the first functional evidence that multiple GABA_A receptor subtypes are present in rat PRF. Intravenously administered eszopiclone prevented REM sleep, decreased ACh release in the PRF, and increased EEG delta power. The effects of eszopiclone are consistent with evidence that ACh release in the PRF is lower during NREM sleep than during REM sleep, and with data showing that cholinergic stimulation of the PRF activates the cortical EEG.

Citation:

Hambrecht-Wiedbusch VS; Gauthier EA; Baghdoyan HA; Lydic R. Benzodiazepine receptor agonists cause drug-specific and state-specific alterations in EEG power and acetylcholine release in rat pontine reticular formation. SLEEP 2010;33(7):909-918.     

A biometrical genetic analysis of ethanol response in selectively bred Long-Sleep and Short-Sleep mice

A classical Mendelian cross was derived from Long-Sleep (LS) and Short-Sleep (SS) mice, lines selectively bred for differences in response to hypnotic doses of ethanol (ETOH). Biometrical genetic procedures applied to the selection phenotype, namely, duration of the ETOH-induced loss of the righting reflex, suggest that a simple additive genetic system controls this depressant response. Sex differences were present in the Mendelian cross generations that had the longest duration responses. An estimate of the number of loci differentiated by the selection was nine. Blood ethanol levels at the time of regaining the righting reflex in the seven genotypes of the Mendelian cross showed that the selection operated solely by changing tissue sensitivity to ethanol.This work was supported by a grant from the SUNY Research Foundation.     

A sequential double-blind controlled study of moclobemide and diazepam in patients with atypical depression

A double-blind controlled study comparing moclobemide and diazepam in patients with atypical depression was carried out. Statistical comparison of the 14 pairs completing 4 weeks showed that significant reductions in depressive symptomatology as measured by the Hamilton and Carroll depression rating scales occurred in both drug groups, and that diazepam was significantly better than moclobemide. A separate analysis of the 10 pairs completing 8 weeks treatment showed that significant decreases in depression ratings occurred in both drug groups but that by week 8 there was no significant difference between the two drugs for depression scores. Side-effects were minimal, and the most common side-effects emerging for both drugs were sleep disturbance and physical tiredness.     

The influence of chlorpromazine, diazepam and imipramine on the central action of ethanol

In experiments with white rats, chlorpromazine, diazepam and imirpramine injected intraperitoneally in the dose of 20 mg/kg and imipramine and diazepam in the dose of 50 mg/kg did not enhance the acute toxicity of ethanol expressed as LD50. Only chlorpromazine in the dose of 50 mg/kg i.p. increased toxicity of ethanol. However, the aforementioned drugs intensified the central action of ethanol by prolonging (except imipramine) duration of narcotic sleep and motor incoordination, and potential ethanol-induced hypothermia.     

The Bethlem lines: Genetic selection for high and low rearing activity in rats

A foundation population derived from nine different rat strains was subjected to genetic selection for high and low rearing activity. A rapid response to selection was demonstrated, the two selected lines showing virtually no overlap in scores after 10 generations. Heritability estimates were assessed from parent-offspring regressions in the unselected control line and from comparisons of the achieved response with the selection pressure applied in the selected lines. Overall, the heritability of rearing activity in the rat was assessed to be about 0.25. In addition, a major gene effect was revealed, albinism being associated with low rearing activity scores.This investigation was supported by a grant from the Bethlem-Maudsley Research Fund.     

Bidirectional selection for susceptibility to ethanol withdrawal seizures inMus musculus

Using within-family selection from a genetically heterogeneous population of HS/Ibg mice, lines and replicates have been selected for high (withdrawal seizure prone; WSP) and low (withdrawal seizure resistant; WSR) susceptibility to convulsions after withdrawal from chronic exposure to ethanol. Two nonselected control lines (withdrawal-seizure control; WSC) have also been maintained. The response was bidirectional in both replicates across 11 selected generations, WSP and WSR lines differing approximately 10-fold in seizure severity after an identical regimen of chronic exposure to ethanol. Realized heritability was found to be approximately 0.28. The phenotype appears to be polygenic in nature. The relatively low amount of inbreeding in these lines and the large response to selection should make them useful for examining the physiological basis of physical dependence on ethanol.     

Female Remating in Drosophila ananassae: Bidirectional Selection for Remating Speed

In Drosophila ananassae, artificial selection was carried out for fast and slow remating speed for 10 generations. Response to selection resulted in rapid divergence in remating time in each of two replicates of both fast and slow lines. There were significant differences in mean remating time in females among fast, slow, and control lines. Regression coefficients for both fast and slow lines are significantly different from zero. The realized heritability over 10 generations of selection is from 0.26 to 0.33 for two replicates of fast line and from 0.23 to 0.27 for two replicates of slow line. These findings suggest that female remating time in D. ananassae is under polygenic control. Remating frequency of females showed a correlated response in both fast and slow lines. At generation 10, correlated response to selection was also investigated. Mating propensity of D. ananassae of fast and slow lines was observed in an Elens-Wattiaux mating chamber. Fifteen pairs per test showed that on the average, the fast lines (11.20, 11.60) were more successful in mating than those of slow (6.40, 5.60) and control (8.00) lines. Productivity of once-mated females was measured in terms of number of progeny produced per female and the results of productivity analysis indicate that females of fast lines (157.83, 130.83) produced more progeny compared with slow (72.70, 85.83) and control (109.23) lines.     

Effects of Variations in Time and Dose of Diazepam Injection On Delayed Hypersensitivity

Administration of diazepam was suggested to exert immuno-suppressive properties in mice. In the present study, we explored the time and dose-dependence of diazepam effects on delayed hypersensitivity to sheep erythrocytes in Balb/c mice. DTH response was only depressed when diazepam was injected shortly after immunization and this effect on DTH induction was found with doses of 4 and 8 mg/kg ip while lower doses (0,5, 1 and 2 mg/kg) remained ineffective.