Cochlear function and audiogenic seizures: developmental covariance in the LP/J mouse

Innate susceptibility to audiogenic seizures develops and declines at varying rates and ages, depending upon genotype and environmental conditions. Auditory dysfunctions have been experimentally produced which induce susceptibility in otherwise nonsusceptible mouse strains. In order to more closely correlate cochlear functions and audiogenic seizures in genetically susceptible mice, both measures were obtained from LP/J mice, at ages ranging from 8 to 120 days. Susceptibility to sound-produced convulsions was first noted at 12 days, was maximal from 18 to 32 days, declined rapidly by 40 days, and disappeared by 120 days of age. Cochlear nerve-evoked potential thresholds were very high at 12 days, were lowest between 18 and 32 days and increased thereafter. The correlation between susceptibility and cochlear thresholds was greatest for high frequencies (r = -.93), intermediate for midfrequency (r = -.77), and poorest for low frequencies (r = -.56). It was concluded that either genetic or environmental factors which produce an intermediate level of high frequency cochlear damage in the young mouse will produce susceptibility to audiogenic seizures.     

Albinism and auditory function in the laboratory mouse. I. Effects of single-gene substitutions on auditory physiology,audiogenic seizures,and developmental processes

The effects of single-gene albino (c/c) mutations on auditory behavior and physiology were examined in congenic C57BL/6J mice. At 16 days of age, thec gene was additively associated with both reduced auditory functioning and lower body weight; 16-day-oldc/c mice had higher auditory evoked potential (AEP) thresholds than +/c mice, which, in turn, had higher thresholds than +/+ mice; +/c mice were also intermediate with regard to body weight. Since these differences had nearly disappeared by 21 days of age, it was concluded that thec genes worked in an additive fashion to delay development during the period previously (Henry, 1967) found critical for inducing susceptibility to audiogenic seizures. At 16 days of age, albino mice (c/c) displayed susceptibility to audiogenic seizures, but nonalbino genotypes (+/c and +/+) were immune to the convulsive effects of sound. This behavior appeared to be a recessive trait at this age. But 5 days later, the behavioral phenotype exhibited incomplete dominance, with the +/c genotype displaying audiogenic seizures intermediate to those seen in the susceptiblec/c and the nonsusceptible +/+ genotypes. These behaviors were compared to the thresholds and peak-to-peak amplitudes of the AEP, as seen in the input-output functions. It is suggested that differential development of the auditory systems in these genotypes is causally related to susceptibility to audiogenic seizures.     

Sources of energy for the brain and susceptibility to audiogenic seizures.

The onset of susceptibility to audiogenic seizures (AGS) coincides with the draining of the ear canal at about 14 to 16 days of age. This is also when the mouse brain has almost attained its maximal size and weight, and also about the time of weaning from the dam's high-fat milk to the beginning of dietary self-sufficiency. During suckling, the brain is primarily dependent on ketone-body utilization as a source for brain energy; weaned mice use glucose. It is suggested that in AGS-prone mice, there may be a developmental lag in the onset of a sufficient rate of glycolysis in brain to provide adequate immediately available energy reserves to last through a brief period of an external-stimulus-induced large energy expediture until energy repletion processes can begin. As a results, ATP levels might fall below an hypothesized lower limit to subserve organized neural activity in some inhibitory area of the brain, resulting in the onset of an AGS.     

Noise priming and the effects of different cochlear centrifugal pathways on loud-sound-induced hearing loss

Priming/conditioning the cochlea with moderately loud sound can reduce damage caused by subsequent loud sound. This study examined immediate effects of short-term priming with monaural broadband noise on temporary threshold shifts (TTSs) in hearing caused by a subsequent loud high-frequency tone and the role of centrifugal olivocochlear pathways. Priming caused delay-dependent changes in tone-induced TTSs, particularly or only at frequencies higher than the peak tone-affected frequency, through two general effects: a short-lasting increase in cochlear susceptibility to loud sound and longer-lasting complex end effects of centrifugal pathways. The results indicated the following points. Priming noise had "pure" cochlear effects, outlasting its presentation and declining with delay, that exacerbated tone-induced TTSs at frequencies higher than the peak tone-affected frequency. The centrifugal uncrossed medial olivocochlear system (UMOCS) could prevent this noise exacerbation and as this noise effect declined, could even reduce tone-induced TTSs below those to the unprimed tone. For longer delays, when priming noise no longer had any exacerbative "pure" cochlear effects on TTSs, UMOCS exacerbated TTSs above those to the unprimed tone. The crossed medial olivocochlear system (CMOCS) appeared to show a gradual "build-up" of effects postpriming. A parallel study showed it exercised no end effect on TTSs when noise and tone were concurrent. With priming, CMOCS effects were observed. For the shortest priming delay, the CMOCS blocked a UMOCS effect preventing noise exacerbation of tone-induced TTSs. For longer delays, CMOCS end effects, when present, reduced tone-induced TTSs below those to the unprimed tone. The CMOCS may oscillate between producing these effects and exerting no end-effect. With increasing delay CMOCS protection occurred in a greater proportion of animals. Finally, with a delay of 600 s between primer and loud tone, all these systems appeared to have reset to normal so that TTSs were similar to those in the unprimed condition. Thus the effects of short-term priming are not simple and do not suggest that centrifugal pathways act automatically as a protective system during such priming.     

Reversal of the physiological effects of monocular deprivation in kittens: further evidence for a sensitive period

1. It was confirmed that suturing the lids of one eye (monocular deprivation), until only 5 weeks of age, leaves virtually every neurone in the kitten's visual cortex entirely dominated by the other eye. On the other hand, deprivation of both eyes causes no change in the normal ocular dominance of cortical neurones, most cells being clearly binocularly driven.2. Kittens were monocularly deprived until various ages, from 5 to 14 weeks, at which time reverse suturing was performed: the initially deprived right eye was opened and the left eye closed for a further 9 weeks before recording from the visual cortex.3. Reverse suturing at 5 weeks caused a complete switch in ocular dominance: every cell was dominated by the initially deprived right eye. Reverse suturing at 14 weeks, however, had almost no further effect on ocular dominance: most cells were still driven solely by the left eye. Animals reverse sutured at intermediate ages had cortical neurones strongly dominated by one eye or the other, and they were organized into clear columnar groups according to ocular dominance.4. Thus, between 5 weeks and 4 months of age, there is a period of declining sensitivity to both the effects of an initial period of monocular deprivation and the reversal of those effects by reverse suturing.5. The small proportion of binocular cells in reverse sutured kittens (which have never had simultaneous binocular vision) often differed considerably in their receptive field properties in the two eyes. In particular, if the cells were orientation selective in both eyes the two preferred orientations could differ by up to 70 degrees .6. The relative importance of innate and environmental contributions to the properties of cortical cells is discussed.     

Inhibition of the substantia nigra suppresses absences and clonic seizures in audiogenic rats, but not tonic seizures: evidence for seizure specificity of the nigral control

GABAergic inhibition of the substantia nigra pars reticulata has been shown to suppress seizures in most models of epilepsy involving forebrain networks, such as absences or clonic seizures. No such antiepileptic effects were observed, however, in genetically audiogenic rats exhibiting tonic seizures generated in the brainstem. This suggests a constitutive dysfunction of the nigral GABAergic neurotransmission in this strain of rat or a selective action of the nigral control on specific networks. In the present study, we first confirmed that bilateral injection of muscimol (700 pmol/side) in the substantia nigra had no effect in Wistar rats with audiogenic seizures (Wistar AS). [3H]Muscimol autoradiography suggested a 40% reduced density of GABA(A) receptors in the substantia nigra of Wistar AS, whereas no change was observed in the cortex and the superior colliculus (superficial and intermediate layers), as compared to control animals. In Wistar AS where 40 repetitions of audiogenic stimulations progressively induced generalised convulsive seizures with both tonic and clonic components, bilateral injection of muscimol (350 pmol/side) in the substantia nigra suppressed the clonic component but had no effect on tonic seizures. In hybrid rats issued from cross-breeding between Wistar AS and rats with spontaneous absence seizures, bilateral injection of muscimol (18 pmol/side) in the substantia nigra abolished cortical spike-and-wave discharges, but had no effect on tonic audiogenic seizures at doses up to 700 pmol/side. These results show that despite a decreased number of GABA(A) receptors in the substantia nigra, inhibition of this structure in Wistar AS still leads to inhibition of seizures involving forebrain structures. These results confirm that GABAergic inhibition of the substantia nigra has antiepileptic effects through the control of forebrain circuits. They suggest that this control mechanism has no inhibitory effect on circuits underlying audiogenic tonic seizures.     

The hairless gene of the mouse: relationship of phenotypic effects with expression profile and genotype.

Various mutations of the hairless (hr) gene of mice result in hair loss and other integument defects. To examine the role of the hr gene in mouse development, the expression profile of hr has been determined by in situ hybridisation and correlated to the nature of genetic changes and morphological abnormalities in different mutant animals. Four variant alleles have been characterised at the molecular level. hr/hr mice produce reduced, but significant, levels of hr mRNA whereas other alleles contain mutations which would be expected to preclude the synthesis of functional product, demonstrating a correlation between allelic variation at the hr locus and phenotypic severity. hr expression was shown to be widespread and temporally regulated. It was identified in novel tissues such as cartilage, developing tooth, inner ear, retina, and colon as well as in skin and brain. Analysis of mice homozygous for the rhino allele of hairless revealed that, although no morphological defects were detectable in many tissues normally expressing hr, previously undescribed abnormalities were present in several tissues including inner ear, retina, and colon. These findings indicate that the hairless gene product plays a wider role in development than previously suspected. Dev Dyn 1999;216:113-126.     

Delimitation of a sensitive period for the effects of early life undernutrition on social behaviour of adult male rats

In a previous experiment undernutrition during the suckling period, but not during gestation, was found to have lasting effects on the social behaviour of male rats. To establish whether the sensitive period for this effect extends beyond weaning, rats were undernourished in the present experiment from 30 to 55 days of age. To control for the possibility of competition between the underfed rats for food, one group was caged in pairs and the other singly to obviate competition. All rats were fed ad lib from 55 days and testing began at 100 days. There were no significant effects of nutritional treatment or of method of housing on any aspect of social behaviour. This result, together with that of the previous experiment, indicates that the sensitive period for the undernutrition effect is the suckling period.     

Intergenerational arsenic exposure on the mouse epigenome and metabolic physiology

Inorganic arsenic (iAs) is one of the largest toxic exposures to impact humanity worldwide. Exposure to iAs during pregnancy may disrupt the proper remodeling of the epigenome of F1 developing offspring and potentially their F2 grand-offspring via disruption of fetal primordial germ cells (PGCs). There is a limited understanding between the correlation of disease phenotype and methylation profile within offspring of both generations and whether it persists to adulthood. Our study aims to understand the intergenerational effects of in utero iAs exposure on the epigenetic profile and onset of disease phenotypes within F1 and F2 adult offspring, despite the lifelong absence of direct arsenic exposure within these generations. We exposed F0 female mice (C57BL6/J) to the following doses of iAs in drinking water 2 weeks before pregnancy until the birth of the F1 offspring: 1, 10, 245, and 2300 ppb. We found sex- and dose-specific changes in weight and body composition that persist from early time to adulthood within both generations. Fasting blood glucose challenge suggests iAs exposure causes dysregulation of glucose metabolism, revealing generational, exposure, and sex-specific differences. Toward understanding the mechanism, genome-wide DNA methylation data highlights exposure-specific patterns in liver, finding dysregulation within genes associated with cancer, T2D, and obesity. We also identified regions containing persistently differentially methylated CpG sites between F1 and F2 generations. Our results indicate the F1 developing embryos and their PGCs, which will result in F2 progeny, retain epigenetic damage established during the prenatal period and are associated with adult metabolic dysfunction.     

Rejuvenating effects of 10-week underfeeding period on estrous cycles in young and old rats

The effects of providing 50% of normal feed intake for 10 weeks followed by 16 weeks of ad lib feeding on estrous cycles and mammary tumor incidence were studied in female rats initially 4 months and 15-16 months old. Initially all young rats exhibited regular or irregular estrous cycles and only about 41% of the older rats cycled regularly or irregularly; the remainder of the older rats did not cycle. During underfeeding, both the young and older rats lost body weight and ceased to cycle. After refeeding 100% of both young and old rats resumed cycling, the young rats for a much longer period than the old rats, and more of both groups continued to cycle than their ad lib-fed controls. Upon refeeding, the young and old rats reached the body weights of the ad lib-fed controls in about 3 weeks. Mammary tumors were initially present only in old rats and regressed during underfeeding; they rapidly reached control size upon refeeding. Plasma PRL levels declined during underfeeding but rebounded to higher than control values upon refeeding in both young and old rats. In young but not in old rats, plasma LH levels fell during underfeeding but returned to control values upon refeeding. These results demonstrate that a relatively short period of underfeeding, followed by refeeding, can delay the decline in reproductive cycles in young rats and reinitiate estrous cycles in older rats. These effects appear to be mediated via the neuroendocrine system.     

Reelin-immunoreactivity in the hippocampal formation of 9-month-old wildtype mouse: effects of APP/PS1 genotype and ovariectomy

Reelin, an extracellular matrix protein has an important role in the migration, correct positioning and maturation of neurons during development. Though it is generally down-regulated in the postnatal period, expression of this large glycoprotein continues in the adult brain in some cell populations. In the present study, we examined the distribution of reelin-immunoreactivity (-ir) in the hippocampal formation of 9-month-old wildtype mice (WT). Then, reelin-ir in normal mice was compared to that of transgenic mice (APP/PS1) carrying mutated human APP and PS1 genes, which are linked to the familial form of Alzheimer's disease (AD). The APP/PS1 mice were additionally burdened with a second risk factor for AD, namely depletion of circulating gonadal hormones by ovariectomy (APP/PS1 + OVX). The analyses revealed that in adult WT reelin-ir is expressed by Cajal-Retzius cells and a subgroup of interneurons throughout the hippocampal formation. In addition, layer II projection neurons in the lateral entorhinal subfields are reelin-ir. Interestingly, ovariectomy decreases the number of reelin-ir cells in the hilus in WT mice, whereas AD-related genotype alone induces only a non-significant reduction. Unexpectedly, additional stress, e.g., depletion of gonadal hormones, does not aggravate the slight reduction in the reelin cell number in the APP/PS1 mice. We propose that the changes in normal reelin-ir are linked to disturbances in repair mechanisms in which APP/PS1 and gonadal hormones are involved and which are perturbed in neurodegenerative conditions, namely AD.     

Effect of generalized seizures on the structure of the sleep-waking cycle and the EEG in rats with an inherited predisposition to audiogenic convulsions

Data are presented on the effects of generalized tonic-clonic seizures on the structure of the one-day sleep-waking cycle in Krushinskii-Molodkina (KM) rats, which have a genetic predisposition to audiogenic convulsions. Spectral and correlation analysis of EEG activity in the hippocampus, caudate nucleus, medial central nucleus of the thalamus, and in the somatosensory, visual, and auditory regions of the cortex of these animals was carried out for time intervals before and after convulsions. After seizures, rats showed a prolonged (up to 3.5 h) reduction in fast-wave sleep (FWS) with no subsequent compensatory increase in this shase in the sleep-waking cycle, while a disturbance in slow-wave sleep (SWS) was minor and short-lived (not more than 2 h). It is suggested that generalized paroxysmal attacks predominantly involve disorganization of the function of the systems regulating FWS, while the synchronizing mechanisms of the brain, responsible for SWS, are affected to a lesser extent. Laboratory of the Evolution of Sleep and Waking (Director G. A. Oganesyan), I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 81, No. 10, pp. 1–8, October, 1995.     

羚羊角与钩藤联合用药抑制热性惊厥大鼠脑损伤作用机制研究

目的:探讨羚羊角与钩藤联合用药对热性惊厥所致发育期大鼠脑损伤的保护作用及其作用机制。方法:采用热水浴建立热性惊厥大鼠模型,实验分为5 组,空白对照组、模型组、羚羊角组、钩藤组、羚羊角与钩藤联合用药组(简称联用组),每组10 只,共50 只。通过HE 染色法观察组织病理情况;ELISA 法检测各组大鼠脑组织TNF-α、IL-1β、Glu 及Asp 含量;免疫组化法检测大鼠海马区TNF-α、IL-1β表达情况。结果:联用组、羚羊角组、钩藤组脑组织Asp、Glu、TNF-α及IL-1β及海马区TNF-α、IL-1β含量显著低于模型组(P<0.01,P<0.05)。联用组脑组织Asp、TNF-α及IL-1β含量较钩藤组显著降低(P<0.05)。联用组海马区TNF-α较羚羊角组、钩藤组显著降低(P<0.05),IL-1β较钩藤组表达显著降低(P<0.05)。结论:羚羊角与钩藤联合用药抑制热性惊厥所致大鼠脑损伤,效果优于羚羊角及钩藤单用,其作用机制可能与其抑制促炎症因子TNF-α、IL-1β及兴奋性氨基酸Asp、Glu 表达有关。     

Effects of lambing induction on the sensitive period for the establishment of maternal behaviour in sheep

The existence and length of the sensitive period for the establishment of maternal behaviour was investigated in aged, thus presumably multiparous, merino ewes as well as the possible effects of inducing parturition on this component of maternal behaviour. While a few dams still showed spontaneous maternal behaviour after a 24 hr mother-young separation starting at parturition, maternal responsiveness had faded in most cases after 4 to 12 hr of such a separation. When realized two to four days after lambing, a 24 hr separation was of little consequence on maternal behaviour. Ewes which eventually accepted their lambs, either spontaneously or after human intervention, all established a discriminative behaviour at suckling. Inducing parturition by an IM injection of 15 mg of dexamethasone did not affect the length of the sensitive period. By constrast inducing lambing with 20 mg of oestradiol benzoate IM resulted in a significant lengthening of the sensitive period. Possible roles of oestrogens and prolactin are discussed in this respect.     

Distribution of dynorphin B and methionine-enkephalin in the mouse hippocampus: influence of genotype

Immunohistochemical techniques were used to localize dynorphin B and methionine-enkephalin in the mouse hippocampus. Methionine-enkephalin-like immunoreactivity was found within the somata of interneurons distributed mainly in and around the CA1 stratum pyramidale and stratum granulosum as well as in the mossy fibers. Dynorphin B appeared to be confined to the mossy fiber pathway. In addition, we observed a difference between the inbred mouse strains DBA/2 and C57BL/6 with regard to the areas of the dynorphinergic mossy fiber projections: the intra- and infrapyramidal terminal fields were larger in the latter group.     

A sensitive period for shibboleths: the long tail and changing goals of speech perception over the course of development

It is clear that the ability to learn new speech contrasts changes over development, such that learning to categorize speech sounds as native speakers of a language do is more difficult in adulthood than it is earlier in development. There is also a wealth of data concerning changes in the perception of speech sounds during infancy, such that infants quite rapidly progress from language-general to more language-specific perceptual biases. It is often suggested that the perceptual narrowing observed during infancy plays a causal role in the loss of plasticity observed in adulthood, but the relationship between these two phenomena is complicated. Here I consider the relationship between changes in sensitivity to speech sound categorization over the first 2 years of life, when they appear to reorganize quite rapidly, to the "long tail" of development throughout childhood, in the context of understanding the sensitive period for speech perception.