Evidence for a Chromatographic Model of Olfaction

The gradient of activity produced along the olfactory mucosa by odorant stimulation was measured by the ratio (the LB/MB ratio) of the summated neural discharges recorded from two branches of the olfactory nerve, a lateral branch (LB) supplying a mucosal region near the internal naris and a medial branch (MB) supplying a region near the external naris. Twenty-four frogs "sniffed" sixteen different odorants, each odorant at four concentrations and two flow rates. Increases in concentration and flow rate produced statistically reliable increases in the ratios; the magnitude of these increases was considerably smaller than the magnitude of the statistically significant changes that could be achieved by shifting the odorants themselves. Even the small change due to concentration depended upon the odorant presented. Thus, even at the highest physiologically possible concentrations and flow rates, the general level of the activity gradient along the mucosa appeared to be determined mainly by the particular odorant used. The relative retention time of each of these 16 different odorants was measured in a gas chromatograph fitted with a Carbowax 20M column. In general, the longer the odorant's retention time the smaller its LB/MB ratio. This suggests that the different mucosal gradients of activity are established for different odorants by a chromatographic process. The data further suggest that the mucosa behaves like a polar chromatographic column.     

Chronic Powder Diet After Weaning Induces Sleep,Behavioral, Neuroanatomical,and Neurophysiological Changes in Mice

The purpose of this study is to clarify the effects of chronic powder diet feeding on sleep patterns and other physiological/anatomical changes in mice. C57BL/6 male mice were divided into two groups from weaning: a group fed with solid food (SD) and a group fed with powder food (PD), and sleep and physiological and anatomical changes were compared between the groups. PD exhibited less cranial bone structure development and a significant weight gain. Furthermore, these PD mice showed reduced number of neurogenesis in the hippocampus. Sleep analysis showed that PD induced attenuated diurnal sleep/wake rhythm, characterized by increased sleep during active period and decreased sleep during rest period. With food deprivation (FD), PD showed less enhancement of wake/locomotor activity compared to SD, indicating reduced food-seeking behavior during FD. These results suggest that powder feeding in mice results in a cluster of detrimental symptoms caused by abnormal energy metabolism and anatomical/neurological changes.     

Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.     

Neurophysiological Evidence of Compensatory Brain Mechanisms in Early-Stage Multiple Sclerosis

Multiple sclerosis (MS) is a chronic central nervous system disorder characterized by white matter inflammation, demyelination and neurodegeneration. Although cognitive dysfunction is a common manifestation, it may go unnoticed in recently-diagnosed patients. Prior studies suggest MS patients develop compensatory mechanisms potentially involving enhanced performance monitoring. Here we assessed the performance monitoring system in early-stage MS patients using the error-related negativity (ERN), an event-related brain potential (ERP) observed following behavioral errors. Twenty-seven early-stage MS patients and 31 controls were neuropsychologically assessed. Electroencephalography recordings were obtained while participants performed: a) a stop task and b) an auditory oddball task. Behavior and ERP measures were assessed. No differences in performance were found between groups in most neuropsychological tests or in behavior or ERP components in the auditory oddball task. However, the amplitude of the ERN associated with stop errors in the stop task was significantly higher in patients. ERN amplitude correlated positively with scores on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and negatively with the time since last relapse. Patients showed higher neuronal recruitment in tasks involving performance monitoring. Results suggest the development of compensatory brain mechanisms in early-stage MS and reflect the sensitivity of the ERN to detect these changes.     

Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice

ObjectiveDaily application of far-red light from the onset of diabetes mitigated diabetes-induced abnormalities in retinas of albino rats. Here, we test the hypothesis that photobiomodulation (PBM) is effective in diabetic, pigmented mice, even when delayed until weeks after onset of diabetes. Direct and indirect effects of PBM on the retina also were studied.MethodsDiabetes was induced in C57Bl/6J mice using streptozotocin. Some diabetics were exposed to PBM therapy (4 min/day; 670 nm) daily. In one study, mice were diabetic for 4 weeks before initiation of PBM for an additional 10 weeks. Retinal oxidative stress, inflammation, and retinal function were measured. In some mice, heads were covered with a lead shield during PBM to prevent direct illumination of the eye, or animals were treated with an inhibitor of heme oxygenase-1. In a second study, PBM was initiated immediately after onset of diabetes, and administered daily for 2 months. These mice were examined using manganese-enhanced MRI to assess effects of PBM on transretinal calcium channel function in vivo.ResultsPBM intervention improved diabetes-induced changes in superoxide generation, leukostasis, expression of ICAM-1, and visual performance. PBM acted in part remotely from the retina because the beneficial effects were achieved even with the head shielded from the light therapy, and because leukocyte-mediated cytotoxicity of retinal endothelial cells was less in diabetics treated with PBM. SnPP+PBM significantly reduced iNOS expression compared to PBM alone, but significantly exacerbated leukostasis. In study 2, PBM largely mitigated diabetes-induced retinal calcium channel dysfunction in all retinal layers.ConclusionsPBM induces retinal protection against abnormalities induced by diabetes in pigmented animals, and even as an intervention. Beneficial effects on the retina likely are mediated by both direct and indirect mechanisms. PBM is a novel non-pharmacologic treatment strategy to inhibit early changes of diabetic retinopathy.     

Neural and Behavioral Evidence for an Intrinsic Cost of Self-Control

The capacity for self-control is critical to adaptive functioning, yet our knowledge of the underlying processes and mechanisms is presently only inchoate. Theoretical work in economics has suggested a model of self-control centering on two key assumptions: (1) a division within the decision-maker between two ‘selves’ with differing preferences; (2) the idea that self-control is intrinsically costly. Neuroscience has recently generated findings supporting the ‘dual-self’ assumption. The idea of self-control costs, in contrast, has remained speculative. We report the first independent evidence for self-control costs. Through a neuroimaging meta-analysis, we establish an anatomical link between self-control and the registration of cognitive effort costs. This link predicts that individuals who strongly avoid cognitive demand should also display poor self-control. To test this, we conducted a behavioral experiment leveraging a measure of demand avoidance along with two measures of self-control. The results obtained provide clear support for the idea of self-control costs.     

Behavioral Perturbation and Sleep in Healthy and Virus-Infected Inbred Mice

Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that has been studied extensively in terms of host immune responses to herpesviruses during acute infection, latency, and reactivation from latency. Although herpesvirus infections in people can be associated with fatigue and excessive sleepiness during both acute and latent infection, MuGHV has not been assessed extensively as a model for studying the behavioral consequences of chronic latent herpesvirus infections. To assess MuGHV infection as a model for evaluating fatigue and assessing potential mechanisms that underlie the exacerbation of fatigue during chronic viral disease, we evaluated sleep, temperature, and activity after exposure of healthy and latently MuGHV-infected mice to sleep fragmentation and social interaction. Neither treatment nor infection significantly affected temperature. However, at some time points, latently infected mice that underwent sleep fragmentation had less locomotor activity and more slow-wave sleep than did mice exposed to social interaction. In addition, delta-wave amplitude during slow-wave sleep was lower in infected mice exposed to sleep fragmentation compared with uninfected mice exposed to the same treatment. Both reduced locomotor activity and increased time asleep could indicate fatigue in infected mice after sleep fragmentation; reduced delta-wave amplitude during slow-wave sleep indicates a light plane of sleep from which subjects would be aroused easily. Identifying the mechanisms that underlie sleep responses of mice with chronic latent MuGHV infection may increase our understanding of fatigue during infections and eventually contribute to improving the quality of life for people with chronic viral infections.Abbreviations: CFS, chronic fatigue syndrome; DWA, delta-wave amplitude; EBV, Epstein–Barr virus; MuGHV, murine γ-herpesvirus; REMS, rapid-eye-movement sleep; SF, sleep fragmentation; SI, social interaction; SWS, slow-wave sleepEpstein–Barr virus (EBV) is a ubiquitous human γ-herpesvirus that causes acute disease, establishes life-long latency and is associated with the common syndrome of infectious mononucleosis. Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that provides an experimental animal model for studying the pathophysiology of an EBV-like gammaherpesvirus.^10,27 A comparison of MuGHV strain 68 (MuGHV68) infection in bank voles (a natural host) and laboratory mice (Mus musculus) using in vivo luciferase imaging and classic virologic methods showed that the 2 host species have quantitative differences in the magnitude of the infection yet exhibit comparable patterns of viral replication and sites of viral latency.¹² These findings support using MuGHV68 and Mus musculus for the study of gammaherpesvirus pathogenesis. Although MuGHV has been studied extensively with regard to host immune responses to herpesviruses during acute infection, latency, and reactivation from latency,^10,27 it has not been assessed extensively as a model for the study of the behavioral consequences of chronic latent herpesvirus infections.EBV infection in humans is often associated with fatigue and excessive sleepiness during both acute and latent phases of infection.^{1,16,19,38,43,44} Many people similarly experience fatigue in association with other chronic medical conditions that have either specific viral etiologies (for example, hepatitis C, HIV) or symptoms suggestive of viral infections (for example, chronic fatigue syndrome (CFS), fibromyalgia syndrome).^3,21,23 Acute viral infections, persistent viral infections, and reactivation of latent virus may trigger or exacerbate fatigue.^15,29,35 Furthermore, exacerbation of fatigue in response to various physiologic and psychologic challenges is prominent in many disease conditions associated with chronic fatigue. For example, exercise is reported to precipitate or exacerbate fatigue or malaise in persons with CFS,^2,26 and CFS both reduces activity and blunts the circadian rhythm of activity in patients.⁴² In addition, stressful life events are reported to precipitate CFS and to exacerbate fatigue in persons with CFS,^6,37and stress can be a factor in reactivation of latent EBV and other herpesviruses.¹⁵ Fatigue, like other so-called ‘sickness behaviors’ (for example, anorexia, anhedonia, reduced social interaction), has been linked causally to various cytokines that are facets of the immune response.⁷ Therefore, the host immune response to chronic infection or inflammation is likely to create a powerful and unrelenting stimulus for fatigue.Human fatigue can be viewed as continued performance of essential activities (for example, employment, care-giving) with curtailment of nonessential, voluntary, or recreational activities.³² Similarly, fatigue in mice can be defined operationally as a reduction in voluntary activity (that is, wheel running) as compared with essential activity (that is, locomotion in the cage to obtain food and water).^28,30,33 Problems with sleep can either reflect or contribute to fatigue. For example, excessive sleep may reflect fatigue associated with other causes, whereas poor sleep or inadequate amounts of sleep may cause fatigue.Mice inoculated with MuGHV develop changes in sleep and activity that may indicate fatigue. On days 7 through 11 after inoculation (that is, at times associated with the peak lytic infection and its resolution), infected mice show hypothermia, increased somnolence, and reduced running-wheel activity during the dark (active) phase of the diurnal cycle as well as reduced food intake and body weight.²⁸ These measures all return to normal during days 11 through 30 after inoculation, as the virus enters the latent phase.²⁸ After this time, these behavioral indicators of fatigue can again be elicited by challenging mice with LPS. In uninfected mice, LPS administration induces modest and relatively transient (that is, less than 18 h) hypothermia, reduced running-wheel activity, and alterations in sleep.²⁸ In contrast, mice with latent MuGHV infection develop prolonged hypothermia, hypoactivity, hypersomnolence, and fragmented sleep, all of which persist for as long as 5 d after LPS administration.²⁸ This duration is consistent with the time reported for viral reactivation from latency in MuGHV-infected mice treated with LPS.¹⁴ Therefore, as compared with uninfected mice, mice with latent infections appear to show a greater magnitude and duration of LPS-induced behavioral perturbations that may reflect fatigue, perhaps in association with virus reactivation.To further assess MuGHV infection as a model system for evaluation of fatigue and assessment of potential mechanisms that underlie exacerbation of fatigue during chronic viral disease, we extended our previous work^28,40 by evaluating sleep, temperature, and activity after exposure of uninfected and latently infected mice to sleep fragmentation (SF) and social interaction (SI), both of which are likely to create behavioral stress.     

Directional Reaching for Water as a Cortex-Dependent Behavioral Framework for Mice

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小鼠脑缺血神经功能障碍行为学评价的研究进展

在脑缺血及脑缺血-再灌注损伤的研究中,小鼠的可逆性大脑中动脉阻塞（middle cerebral artery occlusion,MCAO）模型应用广泛。除了测量脑梗死体积外,神经功能缺损的行为学评价也是判定脑缺血严重程度的重要指标。其评价指标大多移植于大鼠的评价体系,方法较多,没有统一的评价标准,本文对小鼠脑缺血后神经功能损伤的行为学评价方法及各自的优缺点及侧重点做一综述。     

Evidence for Pervasive Adaptive Protein Evolution in Wild Mice

The relative contributions of neutral and adaptive substitutions to molecular evolution has been one of the most controversial issues in evolutionary biology for more than 40 years. The analysis of within-species nucleotide polymorphism and between-species divergence data supports a widespread role for adaptive protein evolution in certain taxa. For example, estimates of the proportion of adaptive amino acid substitutions (α) are 50% or more in enteric bacteria and Drosophila. In contrast, recent estimates of α for hominids have been at most 13%. Here, we estimate α for protein sequences of murid rodents based on nucleotide polymorphism data from multiple genes in a population of the house mouse subspecies Mus musculus castaneus, which inhabits the ancestral range of the Mus species complex and nucleotide divergence between M. m. castaneus and M. famulus or the rat. We estimate that 57% of amino acid substitutions in murids have been driven by positive selection. Hominids, therefore, are exceptional in having low apparent levels of adaptive protein evolution. The high frequency of adaptive amino acid substitutions in wild mice is consistent with their large effective population size, leading to effective natural selection at the molecular level. Effective natural selection also manifests itself as a paucity of effectively neutral nonsynonymous mutations in M. m. castaneus compared to humans.     

Behavioral and Neurotransmitter Abnormalities in Mice Deficient for Parkin,DJ-1 and Superoxide Dismutase

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by loss of neurons in the substantia nigra that project to the striatum and release dopamine. The cause of PD remains uncertain, however, evidence implicates mitochondrial dysfunction and oxidative stress. Although most cases of PD are sporadic, 5-10% of cases are caused by inherited mutations. Loss-of-function mutations in Parkin and DJ-1 were the first to be linked to recessively inherited Parkinsonism. Surprisingly, mice bearing similar loss-of-function mutations in Parkin and DJ-1 do not show age-dependent loss of nigral dopaminergic neurons or depletion of dopamine in the striatum. Although the normal cellular functions of Parkin and DJ-1 are not fully understood, we hypothesized that loss-of-function mutations in Parkin and DJ-1 render cells more sensitive to mitochondrial dysfunction and oxidative stress. To test this hypothesis, we crossed mice deficient for Parkin and DJ-1 with mice deficient for the mitochondrial antioxidant protein Mn-superoxide dismutase (SOD2) or the cytosolic antioxidant protein Cu-Zn-superoxide dismutase (SOD1). Aged Parkin ^-/- DJ-1 ^-/- and Mn-superoxide dismutase triple deficient mice have enhanced performance on the rotorod behavior test. Cu/Zn-superoxide dismutase triple deficient mice have elevated levels of dopamine in the striatum in the absence of nigral cell loss. Our studies demonstrate that on a Parkin/DJ-1 null background, mice that are also deficient for major antioxidant proteins do not have progressive loss of dopaminergic neurons but have behavioral and striatal dopamine abnormalities.     

鼻内镜下低温等离子刀鼻后神经切断术与鼻内镜下鼻后神经切断术对中重度变应性鼻炎的近远期疗效及安全性分析

摘要 目的：探讨鼻内镜下低温等离子刀鼻后神经切断术与鼻内镜下鼻后神经切断术对中重度变应性鼻炎的近远期疗效及安全性。方法：选择2019年3月到2021年3月来我院诊治的变应性鼻炎患者90例,将其随机分为对照组与观察组,对照组中48例,观察组42例,对照组给予鼻内镜下鼻后神经切断术治疗,观察组给予鼻内镜下低温等离子刀鼻后神经切断术治疗。对比两组患者术前、术后3个月及术后1年的喷嚏、鼻塞、鼻痒、流涕临床症状评分、临床疗效、生活质量评分、血清血管活性肠肽5水平,对比两组并发症发生率。结果：术后3个月及术后1年,两组临床症状评分降低,且观察组较对照组低（P<0.05）;术后3个月,两组的临床症状评分低于同组间术后1年,但对比无差异（P>0.05）。术后3个月及术后1年,观察组的治疗有效率均较高（P<0.05）。术后3个月及术后1年,两组生活质量评分降低,且观察组较对照组低（P<0.05）;术后3个月,两组的生活质量评分高于同组间术后1年,但对比无差异（P>0.05）。术后3个月及术后1年,两组血清血管活性肠肽5水平降低,且观察组较对照组低（P<0.05）;术后3个月,两组的血清血管活性肠肽5水平低于同组间术后1年,但对比无差异（P>0.05）。观察组的并发症发生率较对照组低（P<0.05）。结论：与鼻内镜下鼻后神经切断术相比,鼻内镜下低温等离子刀鼻后神经切断术可提高中重度变应性鼻炎的近远期疗效,且安全性较好。     

No Evidence for Cardiac Dysfunction in Kif6 Mutant Mice

A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function.     

帕金森病小鼠模型行为学检测方法的比较研究

目的比较目前常用的5种帕金森病(PD)小鼠模型行为学检测方法在PD研究中的作用。方法用MPTP建立C57BL小鼠PD模型,通过行为学检测(自主活动计数、滚轴实验、游泳实验、爬杆实验、悬挂实验)、免疫组织化学和荧光分光光度法,对比5种行为学检测方法的平均数与变异系数,观察MPTP对PD小鼠模型的行为学、黑质多巴胺(DA)神经元和纹状体酪氨酸羟化酶免疫反应阳性(TH-ir)神经纤维以及纹状体DA水平的影响。结果给与MPTP后,小鼠行为学计数降低,爬杆实验未能得到检测结果,悬挂实验变异系数很高,结果有明显的偶然性,滚轴实验结果变异系数中等,平均数呈现一定的上升趋势,自主活动计数中移动与站立和游泳实验的平均数则呈现明显的下降趋势,变异系数很低,而黑质DA神经元数目减少约58%,纹状体TH-ir神经纤维密度减低,纹状体DA水平明显降低约88%,两组相比差异有显著性(P<0.01)。结论MPTP所致的C57BL小鼠的神经病理、生化改变与PD患者近似,自主活动计数和游泳实验优于其他行为学检测方法。