Postnatal expression and distribution of Refsum disease gene associated protein in the rat retina and visual cortex: effect of binocular visual deprivation

Previously, phytanoyl-CoA alpha-hydroxylase-associated protein 1 (PAHX-AP1) was isolated as a novel neuron-specific protein to interact with Refsum disease (RfD) gene PAHX. Its expression in the brain increased after eyelid opening, and the elevated level was maintained through adulthood. In this report, to verify the hypothesis that light could trigger this increase, we have examined the developmental distribution pattern of PAHX-AP1 in rat retina and visual cortex, and changes of its expression by binocular deprivation. Northern blot analyses demonstrated PAHX-AP1 expression reached its highest level in the visual cortex and eyeball at 4 weeks after birth, and these levels were maintained through adult life. Two weeks after visual deprivation, its expression in the eyeball and visual cortex decreased compared with the control. In situ hybridization analyses of the retina showed that PAHX-AP1 expression was limited to the ganglionic cell layer at 10 days after birth, but expressed in the inner nuclear cell layer and extended to the outer nuclear cell layer at 2 and 3 weeks after birth, respectively. Two weeks after visual deprivation, however, it decreased in the ganglionic and inner nuclear cell layer, and disappeared in the rod and cone cell layers. In the visual cortex, strong signals of PAHX-AP1 were detected in layers IV and VI, and II-VI at 10 days and 2 weeks after birth, respectively. Its expression decreased after 2 weeks of visual deprivation. These results indicate that visual stimulation is essential for the maintenance of PAHX-AP1 expressions in the retina, especially in the rod and cone cell layers, and visual cortex, and suggest that PAHX-AP1 may be involved in the developmental regulation of the photoreceptor's function.     

Maturation of GABAergic transmission and the timing of plasticity in visual cortex

During a brief postnatal critical period, excitatory connections in visual cortex can be easily modified by alterations of visual experience. Recent studies conducted in rodents, and particularly in genetically altered mice, have implicated the maturation of cortical GABAergic inhibition in the timing of the critical period. In this paper we (1) review the postnatal changes in GABAergic transmission that can have consequences for visual cortex plasticity and (2) discuss possible mechanisms by which GABAergic circuits could regulate the onset and termination of the critical period for cortical plasticity.     

Ultrastructural effects of monocular deprivation in the neuropil of nucleus rotundus in the zebra finch: a quantitative electron microscopic study

Ultrastructural effects of monocular deprivation starting at hatching have been studied in the neuropil of nucleus rotundus, the thalamic visual relay station of the tectofugal pathway in birds. Synaptic density, presynaptic terminal size, and length of postsynaptic density (PSD) have been quantified in juvenile (20-day) and adult (100-day) zebra finches. These parameters are mature in 20-day-old zebra finches when reared under normal conditions. Alterations obtained by monocular deprivation were: The synaptic density increases by 35% in the nucleus rotundus of both sides of the brain above normal values in juvenile birds. In adult birds only the deprived side maintains this hypertrophy of synaptic density (33%), the non-deprived side returns to normal values. The presynaptic terminal size remains small in the deprived nucleus of 20-day- and 100-day-old animals, whereas the non-deprived nucleus is not affected. By the age of 20 days the length of PSD in deprived and non-deprived nuclei is not reduced as much as in normally reared zebra finches. By the age of 100 days, however, the PSDs of both sides of monocularly deprived birds show a further reduction of their median length and do not differ from PSDs of zebra finches reared under normal conditions.     

Effects of monocular occlusion and diffusion on visual system development in the cat

The effects of two forms of monocular deprivation (occlusion or diffusion) on visual system development were investigated. One group of cats monocularly deprived of all form stimulation but permitted diffuse light stimulation (diffusion, n = 4) during development showed a pattern of deficits similar to those reported for monocularly sutured cats. Most cells in the visual cortex were driven exclusively by the non-deprived eye and there were eye-specific deficits in X-cell acuity, proportion of Y-cells, and cell body size (binocular and monocular segment) in the lateral geniculate nucleus (LGN). A second group of cats monocularly deprived of all form and light stimulation (occlusion, n = 4) during development showed a less severe pattern of deficits. There was no acuity loss in LGN X-cells driven by the deprived eye, and cell body shrinkage was of smaller magnitude than in diffusion reared cats and was restricted to the binocular segment. Cortical deficits and LGN Y-cell loss were similar in the two groups. The results are consistent with the idea that monocular occlusion produces only deficits due to binocular competition while monocular diffusion reflects the combined effects of binocular competition and abnormal stimulation.     

Visual performance and synapses in the visual cortex of rabbits

The density of synaptic connections, the length of the contact zones and the number of synaptic vesicles are quantitatively studied in the left and right hemisphere of a group of rabbits a number of which showed marked ocular dominance. No systematic differences in the parameters studied could be observed in the visual cortex between symmetric animals, indicating that the ocular dominance cannot be explained by hemispheric differences in density of synapses.     

Effects of strabismus and monocular deprivation on the eye preference of neurons in the visual claustrum of the cat

Visual response properties of neurons in the dorsocaudal claustrum were studied in two cats reared with convergent strabismus and three cats reared with monocular lid-suture. In the normal claustrum, most cells respond about equally well to stimulation of either eye (Sherk and LeVay, '81). In the strabismic animals, there was a partial breakdown of binocularity: most cells remained binocular but were influenced more strongly by one eye (usually the contralateral eye) than the other. The loss of binocularity was less extreme in the claustrum than in area 17 of the same animals. In the monocularly deprived cats, claustral cells responded exclusively to the experienced eye. We interpret the changes observed in the claustrum as reflecting changes in the ocular dominance of cortical inputs to the claustrum, rather than as evidence for plasticity within the claustrum itself. Autoradiography was used to study the return projection from claustrum to cortex in monocular deprivation. The cortical labeling pattern resembled that seen in normal cats. To examine whether this return projection might be involved in reducing cortical responsiveness to the deprived eye, recordings were made from area 17 of a monocularly deprived cat before and after ablation of the ipsilateral claustrum by injection of kainic acid. Following ablation, there was no unmasking of cortical responses to the deprived eye. Thus the cortico-claustral loop does not appear to suppress cortical responses to the deprived eye.     

The effects of visual deprivation on functional and structural organization of the human brain

Early onset blindness allows one to investigate how the human brain adapts to sensory experience in infancy and early childhood. Over the past decade, lesion, functional and structural imaging studies have accumulated evidence that severe perturbations to visual experience alter the functional and structural organization of the human brain. Visual deprivation can induce plastic changes not only in the visual system, but also in the remaining intact sensory–motor system, secondary to altered experience using these spared modalities. In particular, occipital, usually visual, areas are reorganized and recruited by the remaining senses and higher cognitive tasks primarily through cortico-cortical connectivity. Importantly, these plastic changes vary as a function of timing and are most pronounced in early onset blindness. Thus, sensory experience shapes functional and structural brain organization during sensitive periods in neurodevelopment.     

Paradoxical sleep deprivation of the mother enhances DNA synthesis in fetal rat brain: Autoradiographic and biochemical evidence

Pregnant rats were deprived of paradoxical sleep for 3 days starting on the 18th gestational day. The condition of PS-D was imposed by confinement on a small platform surrounded by water or by daily injections of clomipramine. Four hours before the killing rats received a s.c. injection of [3H]-thymidine. The amount of radioactive DNA determined by autoradiography in several regions of fetal brain was found to be markedly increased under both experimental conditions in comparison with the control fetal brain. Considerably more limited effects were observed in kidney. Comparable changes of lower magnitude were obtained by comparing the specific radioactivity of DNA samples purified by chlorophorm extraction and digestion with RNase and proteinase K. The results fully confirm our previous data obtained under similar experimental conditions but based on the analysis of an acid-washed DNA fraction.     

The role of the pulvinar in resolving competition between memory and visual selection: a functional connectivity study

Memory and attention interact. Information held in working memory (WM) can bias visual selection toward matching stimuli in a subsequent search display, while a search target that is different from the memory stimulus can interfere with its subsequent recognition. In recent fMRI studies, the pulvinar has been consistently shown to have an enhanced response when an item in WM matches a search target and a reduced response when the WM item matches a distracter in search. Here we used Granger causality analysis to help understand the role of the pulvinar in resolving competition between memory and selection processes. Across three experiments the results showed increased coupling between the pulvinar and the ipsilateral superior frontal gyrus, contralateral temporal-parietal junction (TPJ) and calcarine sulcus when a visual search distracter matched the item held in memory. This connection pattern suggests that the pulvinar suppresses visual responses to the target when a contralateral distracter contains information held in working memory. We propose that this suppression acts to protect the memory item from interference arising from information associated with the search target. Consistent with this proposal we showed that the strength of the thalamus-to-visual connection predicted performance on a subsequent memory test. The data therefore suggest that the thalamus modulates bottom up processing in sensory cortex to minimize interference to WM content.     

Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain

The cytological organization and the timetable of emergence and dissolution of the transient subplate zone subjacent to the developing visual and somatosensory cortex were studied in a series of human and monkey fetal brains. Cerebral walls processed with Nissl, Golgi, electron-microscopic, and histochemical methods show that this zone consists of migratory and postmigratory neurons, growth cones, loosely arranged axons, dendrites, synapses, and glial cells. In both species the subplate zone becomes visible at the beginning of the mid-third of gestation as a cell-poor/fiber-rich layer situated between the intermediate zone and the developing cortical plate. The subplate zone appears earlier in the somatosensory than in the visual area and reaches maximal width at the beginning of the last third of gestation in both regions. At the peak of its size the ratio between the width of the subplate zone and cortical plate in the somatosensory cortex is 2:1 in monkey and 4:1 in man while in the occipital lobe these structures have about equal width in both species. The dissolution of the subplate zone begins during the last third of gestation with degeneration of some subplate neurons and the relocation of fiber terminals into the cortex. The subplate zone disappears faster in the visual than in the somatosensory area. The present results together with our previous findings support the hypothesis that the subplate zone may serve as a "waiting" compartment for transient cellular interactions and a substrate for competition, segregation, and growth of afferents originated sequentially from the brain stem, basal forebrain, thalamus, and from the ipsi- and contralateral cerebral hemisphere. After a variable and partially overlapping time period, these fibers enter the cortical plate while the subplate zone disappears leaving only a vestige of cells scattered throughout the subcortical white matter. A comparison between species indicates that the size and duration of the subplate zone increases during mammalian evolution and culminates in human fetuses concomitantly with an enlargement of cortico-cortical fiber systems. The regional difference in the size, pattern, and resolution of the subplate zone correlates also with the pattern of cerebral convolutions. Our findings indicate that, contrary to prevailing notions, the subplate may not be a vestige of the phylogenetically old network but a transient embryonic structure that expanded during evolution to subserve the increasing number of its connections.     

Evaluating a split fovea model of visual word recognition: effects of case alternation in the two visual fields and in the left and right halves of words presented at the fovea

Two experiments are reported exploring the effect of cAsE aLtErNaTiOn on lexical decisions to words and nonwords presented laterally or centrally. In line with previous research, Experiment 1 found that case alternation slowed lexical decision responses to words more in the right visual field (RVF) than in the left visual field (LVF). In Experiment 2, the words and nonwords were all presented centrally. There were three conditions, a condition in which the word and nonwords were presented in lower case letters, a condition in which the letters to the left of the central fixation were case alternated (e.g., aMbItion, mOdLants) and a condition in which the letters to the right of fixation were case alternated (e.g., collApSe, pireNtOl). Alternating the case of letters to the right of fixation slowed lexical decision responses more than alternating letter case to the left of fixation. The results provide further support for a split fovea account of visual word recognition according to which those letters of a centrally-fixated word that fall to the left of fixation are processed initially by the right cerebral hemisphere while those letters that fall to the right of fixation are processed initially by the left cerebral hemisphere, with the characteristics of the left and right hemispheres being revealed in the processing of initial and final letters in centrally presented words.     

Midsagittal transection of the optic chiasm and the corpus callosum induces visual split brain in cats: the effect on ocular dominance and responsiveness to cells in the visual cortex

The geniculocortical pathways from the contralateral eye and the callosal pathway were interrupted in cats in order to study how cortical cells are influenced by changes induced in the interhemispheric transfer of visual information. Unit recording was carried out from areas 17 and 18 boundary, the callosal projection zone. The ocular dominance distribution of cortical cells showed absence of interhemispheric interaction. The visual areas in the two sides of the brain thus functioned independently, presenting a condition of visual split brain. This also has been reflected by the absence of compensatory visual inputs via an alternative commissural pathway. Furthermore, remarkable diminution in the excitability level was found as indicated by the reduction in the proportion of visually responsive cells. Finally, the results of the split brain cat reflect the condition of the individual operations from which it is composed.     

小鼠神经胶质细胞培养上清IL-6水平与脑不对称性的关系

目的　 通过体外培养小鼠大脑皮层神经胶质细胞 ,探讨该细胞分泌IL 6与脑不对称性的关系。 方法　分别取新生小鼠左、右两侧大脑皮层胶质细胞培养于 2 4孔板内 ;俟细胞长满孔底后 ,用细菌脂多糖 (LPS)刺激 ,培养 2 4h后收集上清并测定IL 6水平。结果　正常对照组胶质细胞培养上清中可检测出较低水平的IL 6 ,其趋势为右侧高于左侧 ,但统计学上无显著性差别 (P >0 .0 5 ) ;LPS刺激组IL 6水平明显增高 (P <0 .0 5 ) ,且右侧IL 6水平明显高于左侧 (P <0 .0 5 )。结论　 左、右两侧大脑皮层胶质细胞对LPS刺激的反应性存在差异 ,右侧显著高于左侧 ,这种异质性可能部分介导了脑不对称对免疫功能的影响     

Regeneration of specific nerve cells in lesioned visual cortex of the human brain: An indirect evidence after constant stimulation with different spots of light

The defective parts of the visual field of two braininjured patients were stimulated with different spots of light. There is evidence for at least five independent visual functions which can be restored due to constant stimulation of the blind part of the visual field: (1) The constant stimulation of the blind part of the visual field with spots of white light leads to an increase of the visual field for the perception of white light only. (2) The constant stimulation with spots of light of different wavelengths leads to an increase of the visual field for different color perception. To enlarge the visual field for the perception of the color red, a light stimulus with the wavelength of 656 nanometers (nm) was used; for the visual field for the perception of the color green 525 nm; for yellow 578 nm; and for blue 450 nm. (3) The constant stimulation of the blind visual field with black and white light bars of different orientations and constellations leads to an increase of the foveal acuity and an improvement of form perception in the periphery of the visual field. The results suggest that the recovery of visual functions, different color perception and form perception, may depend upon neuronal regeneration in the human visual cortex; regeneration occurs with adequate and constant stimulation of its specific neurons. © 1995 Wiley-Liss, Inc.     

Cellular expression of connexins in the rat brain: neuronal localization, effects of kainate-induced seizures and expression in apoptotic neuronal cells

The identification of connexins (Cxs) expressed in neuronal cells represents a crucial step for understanding the direct communication between neurons and between neuron and glia. In the present work, using a double-labelling method combining in situ hybridization for Cx mRNAs with immunohistochemical detection for neuronal markers, we provide evidence that, among cerebral connexins (Cx26, Cx32, Cx36, Cx37, Cx40, Cx43, Cx45 and Cx47), only Cx45 and Cx36 mRNAs are localized in neuronal cells in both developing and adult rat brain. In order to establish whether connexin expression is influenced in vivo by abnormal neuronal activity, we examined the short-term effects of kainate-induced seizures. The results revealed an unexpected expression of Cx26 and Cx45 mRNA in neuronal cells undergoing apoptotic cell death in the CA3-CA4, in the hilus of the hippocampus and in other brain regions involved in seizure-induced lesion. However, the expression of Cx26 and Cx45 mRNAs was not associated with detectable expression of corresponding proteins as evaluated by immunohistochemistry with specific antibodies. Moreover, in the same brain regions Cx32 and Cx43 were up-regulated in non-neruronal cells whereas the neuronal Cx36 was down-regulated. Taken together the present results provide novel information regarding the specific subpopulation of neurons expressing Cx45 and raise the question of the meaning of connexin mRNA expression in the neuronal apoptotic process.     

In vivo imaging of brain incorporation of fatty acids and of 2-deoxy-d-glucose demonstrates functional and structural neuroplastic effects of chronic unilateral visual deprivation in rats

Regional cerebral ‘incorporation coefficients’k^* of each of 3 labeled long-chain fatty acids — [9,10-³H]palmitate ([³H]PA), [1-¹⁴C]arachidonate ([¹⁴C]AA) and [1-¹⁴C]docosahexaenoate ([¹⁴C]DHA) — were measured using quantitative autoradiography in 11 bilateral brain visual areas of 3.5-month-old awake, hooded, Long-Evans rats, and were compared with regional cerebral metabolic rates for glucose (rCMR_glc). The rats, which had undergone unilateral orbital enucleation at 15 days of age, were studied either in the dark with eyelids of the intact eye sutured, or when stimulated in a light ? with the intact eye open. rCMR_glc did not differ between homologous contralateral and ipsilateral visual areas in the dark or during stimulation, but was elevated bilaterally by 25% or more in many visual areas during stimulation compared with dark. Contralateral compared with ipsilateralk^* was lower for each fatty acid tracer in superficial gray of the superior colliculus (in dark and during stimulation) and dorsal nucleus of lateral geniculate body (during stimulation). In the dark,k^* for [³H]PA was correlated significantly with rCMR_glc for the 22 visual areas studied, whereas during stimulationk^* for [¹⁴C]AA was correlated with rCMR_glc. These results suggest that central neuroplastic changes following chronic unilateral enucleation are accompanied by reduced incorporation of [³H]PA, [¹⁴C]AA and [¹⁴C]DHA into contralateral brain areas that normally receive crossed retinofugal fibers, and by symmetry of rCMR_glc in the dark but increased bilateral symmetrical responsiveness of rCMR_glc to visual stimulation of the intact eye.     

Ipsilateral corticocortical projections to the primary and middle temporal visual areas of the primate cerebral cortex: area-specific variations in the morphology of connectionally identified pyramidal cells

We quantified the morphology of over 350 pyramidal neurons with identified ipsilateral corticocortical projections to the primary (V1) and middle temporal (MT) visual areas of the marmoset monkey, following intracellular injection of Lucifer Yellow into retrogradely labelled cells. Paralleling the results of studies in which randomly sampled pyramidal cells were injected, we found that the size of the basal dendritic tree of connectionally identified cells differed between cortical areas, as did the branching complexity and spine density. We found no systematic relationship between dendritic tree structure and axon target or length. Instead, the size of the basal dendritic tree increased roughly in relation to increasing distance from the occipital pole, irrespective of the length of the connection or the cortical layer in which the neurons were located. For example, cells in the second visual area had some of the smallest and least complex dendritic trees irrespective of whether they projected to V1 or MT, while those in the dorsolateral area (DL) were among the largest and most complex. We also observed that systematic differences in spine number were more marked among V1-projecting cells than MT-projecting cells. These data demonstrate that the previously documented systematic differences in pyramidal cell morphology between areas cannot simply be attributed to variable proportions of neurons projecting to different targets, in the various areas. Moreover, they suggest that mechanisms intrinsic to the area in which neurons are located are strong determinants of basal dendritic field structure.     

The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting

For half a century, the human brain was believed to contain about 100 billion neurons and one trillion glial cells, with a glia:neuron ratio of 10:1. A new counting method, the isotropic fractionator, has challenged the notion that glia outnumber neurons and revived a question that was widely thought to have been resolved. The recently validated isotropic fractionator demonstrates a glia:neuron ratio of less than 1:1 and a total number of less than 100 billion glial cells in the human brain. A survey of original evidence shows that histological data always supported a 1:1 ratio of glia to neurons in the entire human brain, and a range of 40–130 billion glial cells. We review how the claim of one trillion glial cells originated, was perpetuated, and eventually refuted. We compile how numbers of neurons and glial cells in the adult human brain were reported and we examine the reasons for an erroneous consensus about the relative abundance of glial cells in human brains that persisted for half a century. Our review includes a brief history of cell counting in human brains, types of counting methods that were and are employed, ranges of previous estimates, and the current status of knowledge about the number of cells. We also discuss implications and consequences of the new insights into true numbers of glial cells in the human brain, and the promise and potential impact of the newly validated isotropic fractionator for reliable quantification of glia and neurons in neurological and psychiatric diseases. J. Comp. Neurol. 524:3865–3895, 2016. © 2016 Wiley Periodicals, Inc.     

Relationships between β- and α2-adrenoceptors and G coupling proteins in the human brain: effects of age and suicide

Interactions between brain α₂- and β-adrenoceptors are of interest in physiological (aging) and pathological (major depression) processes involving both receptors. In this study, total β-adrenoceptors and β_1/2-subtypes were quantitated in postmortem human brains to investigate their relationships with α_2A-adrenoceptors and specific G proteins during the process of aging and in brains of suicide victims. Analysis of [³H]CGP12177 binding, in the presence of CGP20712A (β₁-antagonist), indicated that the predominant β-adrenoceptor in the frontal cortex is the β₁-subtype (65–75%). The density of total β- (r=−0.60, n=44) or β₁-adrenoceptors (r=−0.78, n=22), but not the β₂-subtype, declined with aging (3–80 years). The density of total β- or β₁-adrenoceptors, but not the β₂-subtype, correlated with the number of α₂-adrenoceptors quantitated in the same brains with the agonist [³H]UK14304 (r=0.71–0.81) or the antagonist [³H]RX821002 (r=0.61–0.66). Interestingly, the ratios α₂/β- or α₂/β₁-adrenoceptors did not correlate with the age of the subject at death, indicating that the proportion of α₂/β-adrenoceptors in brain remains rather constant during the process of aging. The density of β-adrenoceptors correlated with the immunodensity of Gαs (r=0.55) and Gβ (r=0.61) proteins, and that of α₂-adrenoceptors with those of Gαi_1/2 (r=0.88) and Gβ (r=0.65). In brains of suicides, compared to controls, the ratio between α₂- and β- or β₁-adrenoceptors (α₂-full agonist sites/β-sites) was greater (1.3- to 2.0-fold; P<0.05). The results demonstrate a close interdependence between brain α₂- and β-adrenoceptors during aging, and in brains of suicides. The quantitation of the α_2A/β-adrenoceptor ratio could represent a relevant neurochemical index in the study of brain pathologies in which both receptors are involved.