A Critical Look at Critical Periods.

The critical period

Abnormal visual experience during a developmental critical period degrades cortical responsiveness. Yet how experience-dependent plasticity alters the response properties of individual neurons and composition of visual circuitry is unclear. Here, we measured with calcium imaging in alert mice how monocular deprivation (MD) during the developmental critical period affects tuning for binocularity, orientation, and spatial frequency for neurons in primary visual cortex. MD of the contralateral eye did not uniformly shift ocular dominance (OD) of neurons towards the fellow ipsilateral eye but reduced the number of monocular contralateral neurons and increased the number of monocular ipsilateral neurons. MD also impaired matching of preferred orientation for binocular neurons and reduced the percentage of neurons responsive at most spatial frequencies for the deprived contralateral eye. Tracking the tuning properties for several hundred neurons before and after MD revealed that the shift in OD is complex and dynamic, with many previously monocular neurons becoming binocular and binocular neurons becoming monocular. Binocular neurons that became monocular were more likely to lose responsiveness to the deprived contralateral eye if they were better matched for orientation prior to deprivation. In addition, the composition of visual circuitry changed as population of neurons more responsive to the deprived eye were exchanged for neurons with tuning properties more similar to the network of responsive neurons altered by MD. Thus, plasticity during the critical period adapts to recent experience by both altering the tuning of responsive neurons and recruiting neurons with matching tuning properties.

Restoring the “Young” Brain

Visibility Reflects Dynamic Changes of Effective Connectivity between V1 and Fusiform Cortex

The critical period of susceptibility to effects of monocular deprivation was compared in striate cortex and the lateral suprasylvian (LS) visual area of cortex. Twenty-three cats received monocular lid suture for a period of 4 weeks beginning at 4, 12, 18, 26, or 35 weeks of age or as adults. Immediately following the deprivation, single cell recordings were carried out in both cortical areas of each cat. Recordings also were made from five normally reared control cats. For both striate and LS cortex, early monocular deprivation had marked effects on neuronal ocular dominance, including an increased percentage of cells dominated by the nondeprived eye, a decreased percentage of cells dominated by the deprived eye, and a decreased percentage of binocularly driven cells. In both cortical areas, these effects were maximal in animals deprived at 4 weeks of age. Both areas then showed similar monotonic declines in effects of the deprivation following onsets from 4 to 18 weeks of age. However, in older animals there were clear differences in the effects of monocular deprivation on LS and striate cortex. In LS cortex, the monotonic decline in effects continued until 26 weeks of age, and no significant abnormalities were present in animals deprived at 26 weeks of age or older. In striate cortex, however, the effects of monocular deprivation remained relatively constant following onsets from 18 to 35 weeks of age, and significant abnormalities in all measures of ocular dominance were present when deprivation was begun as late as 35 weeks of age. Within-animal comparisons indicated that the greater effects of monocular deprivation on striate cortex than on LS cortex were present in every cat deprived at 26 or 35 weeks of age. Neither cortical area showed significant abnormalities following monocular deprivation in adult cats. These results indicate that the critical period for effects of the same regime of monocular deprivation is over sooner in LS cortex (between 18 and 26 weeks of age) than in striate cortex (after 35 weeks of age). This observation has important implications for an understanding of the sites and mechanisms of effects of visual deprivation and the mechanisms that control critical periods of development.

Vision is required for the formation of binocular neurons prior to the classical critical period

The visual thalamus serves as a critical hub for feature preprocessing in visual processing pathways. Emerging evidence demonstrates that experience-dependent plasticity can be revealed by monocular deprivation (MD) in the dorsolateral geniculate nucleus (dLGN) of the thalamus. However, whether and how this thalamic plasticity induces changes in multiple receptive field properties and the potential mechanisms remain unclear. Using in vivo electrophysiology, here we show that binocular neurons in the dLGN of 4-day MD mice starting at P28 undergo a significant ocular dominance (OD) shift during the critical period. This OD plasticity could be attributed to the potentiation of ipsilateral eye responses but not to the depression of deprived eye responses, contrasting with conventional observations in the primary visual cortex (V1). The direction and orientation selectivity of ipsilateral eye responses, but not of contralateral eye responses in these neurons, were dramatically reduced. Developmental analysis revealed pre-critical and critical period-associated changes in densities of both GABA positive neurons and GABAA receptor α1 subunit (GABRA1) positive neurons. However, early compensatory inhibition from V1 feedback in P18 MD mice maintained network stability with no changes in OD and feature selectivity. Mechanistically, pharmacological activation of GABAA receptors rescued the MD-induced OD shifts and feature selectivity impairments in critical period MD mice, operating independently of the V1 feedback. Furthermore, under different contrast levels and spatial frequencies, these critical period-associated changes in receptive field properties still indicate alterations in ipsilateral eye responses alone. Together, these findings provide novel insights into the developmental mechanisms of thalamic sensory processing, highlighting the thalamus as an active participant in experience-dependent visual plasticity rather than merely a passive relay station. The identified GABA-mediated plasticity mechanisms offer potential therapeutic targets for visual system disorders.

Despite the two hundred million years during which their evolutionary history was different from mammals, birds possess a central visual apparatus with surprising functional similarities to the striate cortex of cats and monkeys. The visual Wulst of the owl contains neurones which can be binocularly activated and which show precise selectivity for the orientation, direction of movement and binocular disparity of moving straight line contours, all characteristic properties of single neurones recorded from the striate cortex of cats and monkeys. We were interested to determine whether binocular neurones in the owl's Wulst are also sensitive to visual experience in the neonatal period since another important characteristic of binocular neural connections in cat and monkey visuail cortex is their extreme sensitivity to monocular deprivation during the critical period. The preliminary observations we present here, on young, monocularly-deprived owls, suggest that the functional parallel between the mammalian striate cortex and the avian Wulst extends to the phenomenon of plasticity as well.

New concepts on visual cortical plasticity: Multiple critical periods and implications for amblyopia

1. In some species, restriction of visual experience in early life may affect normal functional development of visual cortical cells. The purpose of the present study was to determine if visual deprivation during post-natal development in the hooded rat also affects the production in brain cells of certain molecular components such as tubulin, that are needed for growth and maintenance of synapses and neurites. 2. Norwegian black hooded rats were reared under a variety of conditions of visual deprivation. At various stages of development the animals were killed and the rate of synthesis of tubulin in visual and motor cortex determined. Tritiated colchicine was used to assay tubulin and L-[14C]leucine injected into the brain ventricles 2 hr before death was used to measure rate of tubulin synthesis. 3. In rats reared in normal light there is a marked elevation in visual cortex tubulin synthesis that spans the period from eye-opening (13 days) until approximately 35 days. This elevation in tubulin synthesis is absent in animals reared in darkness from birth or deprived of pattern vision by eyelid suture. Also the effect of visual deprivation on tubulin synthesis was specifically confined to visual cortex and was not found for the motor cortex. Similarly, the incorporation of L-[14C]leucine into total protein in visual cortex was unaffected by dark rearing. Hence the stimulation of tubulin synthesis by visual experience in rat visual cortex is not attributable to a general non-specific stimulation of protein synthesis. 4. Rats that were dark-reared from birth and then exposed to a lighted environment for 24 hr during a certain critical period that extends from eye-opening (13 days) until approximately 35 days, displayed a significant increase in visual cortex tubulin rats that were brought into the light later than 35 days showed no significant increase in tubulin synthesis when compared with their continuously dark-rearer controls. 5. It is suggested that the number of synapses and cytoplasmic processes that a developing cell can maintain depends on the size of the tubulin pool available to that cell. Tubulin in brain only has a half-life of about 4 days, so when the level of tubulin drops this could result in competition between different synapses for the limited supply of tubulin needed for their maintenance, a factor which may contribute to the structural plasticity of the visual cortex during the critical period.

Background The integration of segregated pathways from the two eyes first appears in V1 neurons,where it not only plays a critical role in the generation of a three-dimensional visual representation.Abnormal visual experiences in critical period usually lead to amblyopia and binocular integration defects.Objective Present study was to investigate how neurons of kitten coordinate their activity patterns in response to synchronous dichoptic stimulus inputs in striate cortex.Methods Spike rate and local field potential(LFP) gamma band(20-90Hz) power of three kitten(1-1.2Kg,8-10 weeks old) to monocular and synchronous dichoptic presented gratings were assessed for 28 binocular neurons in V1 of kitten by in vivo extracellular record method under anaesthesia and paralysis.Ocular dominance index(ODI) and binocular integration index(BII) were assessed and the correlation between these two indexes were analyzed.Results In 28 cells with binocular characteristic,the absolute value of spike-ODI was significant larger than that of LFP-ODI(t=2.606,P=0.021).A positive linear correlation between the ocular preferences of spike and LFP was found(R2=0.513,F=27.423,P=0.003).In dichotic trails,binocular facilitation with BII for spike was 2.348±0.996,showing a significant reduce in comparison with BII for LFP(3.678±1.974)(t=2.671,P=0.019).Binocular integration index for two signals were greater when monocular responses of both eyes were similar(P=0.035 and P=0.124,respectively).Conclusion Both spike rate and gamma band power of LFP exhibited binocular facilitation to synchronous presented dichotic stimuli with significant facilitation induced by balanced monocular responses.Spiking activity and LFP reflect neural activities of different spatial scales and source components. Key words: Primary cortex; Binocular integration; Local field potential; Kitten

Listening to Npas4: a transcription factor is the prescription for restoring youthful plasticity in the mature brain

Objective To explore the effect of enriched environment on the level of NR2A and NR2B subunits of N-mehyl-D-aspartate (NMDA) receptors which belong to glutamate receptors with excitability at the 17th area of the visual cortex in amblyopia rats after the critical period, and to understand the possible mechanism of synaptic plasticity of the visual cortex in adult amblyopia rats. Methods Eighty Wistar rats were divided into normal group and experimental group by random number table.Right eyelids of all rats were sutured through the whole critical period in order to establish monocular deprivation (MD) amblyopia model.The rats in experimental group were divided into the amblyopia group, standard environment (SE) group and environmental enrichment (EE) group on P45 in random.The sutured right eyelids were opened on P46 in the SE group and EE group.All rats were sacrificed to get the 17th area of the left visual cortex on P60, P75 and P105.Three rats were used at different time points from each group.The Ⅰ-Ⅵ layers of the visual cortex area 17 were observed by using hematoxylin-eosin staining.The expression of NMDA-NR2A and NMDA-NR2B was detected by immunohistochemistry.Integrated optical density of NMDA-NR2A and NMDA-NR2B was detected by using special image analysis software (Image-Pro Plus 6.0). The use of animals complied with Regulation on the Managenment Experimental Ainimals from Shandong Eye Institute and Association for Research in Vision and Ophthalmology (ARVO). Results The positive expression of NMDA-NR2A and NMDA-NR2B were observed in the visual cortex.The positive cells were mostly round or elliptical and mainly expressed in cell membrane.The expression of NMDA-NR2A in P60, P75 and P105 from four groups had statistical differences (all at P 0.05). Conclusions The plasticity of visual cortex exists not only in the critical period but also after the critical period of visual development.EE, as a non-invasion method, can improve and recover the synaptic plasticity in visual cortex of adult rats by the expression of NMDA-NR2A and NMDA-NR2B. Key words: Amblyopia; Visual cortex; Synapse; Enriched environment; N-mehyl-D-aspartate receptors

Brain-derived neurotrophic factor (BDNF) reverses the effects of rapid eye movement sleep deprivation (REMSD) on developmentally regulated, long-term potentiation (LTP) in visual cortex slices

BackgroundIn cat visual cortex, critical period neuronal plasticity is minimal until approximately 3 postnatal weeks, peaks at 5 weeks, gradually declines to low levels at 20 weeks, and disappears by 1 year of age. Dark rearing slows the entire time course of this critical period, such that at 5 weeks of age, normal cats are more plastic than dark reared cats, whereas at 20 weeks, dark reared cats are more plastic. Thus, a stringent criterion for identifying genes that are important for plasticity in visual cortex is that they show differences in expression between normal and dark reared that are of opposite direction in young versus older animals.ResultsThe present study reports the identification by differential display PCR of a novel gene, α-chimaerin, as a candidate visual cortex critical period plasticity gene that showed bidirectional regulation of expression due to age and dark rearing. Northern blotting confirmed the bidirectional expression and 5'RACE sequencing identified the gene. There are two alternatively-spliced α-chimaerin isoforms: α1 and α2. Western blotting extended the evidence for bidirectional regulation of visual cortex α-chimaerin isoform expression to protein in cats and mice. α1- and α2-Chimaerin were elevated in dark reared compared to normal visual cortex at the peak of the normal critical period and in normal compared to dark reared visual cortex at the nadir of the normal critical period. Analysis of variance showed a significant interaction in both cats and mice for both α-chimaerin isoforms, indicating that the effect of dark rearing depended on age. This differential expression was not found in frontal cortex.ConclusionsChimaerins are RhoGTPase-activating proteins that are EphA4 effectors and have been implicated in a number of processes including growth cone collapse, axon guidance, dendritic spine development and the formation of corticospinal motor circuits. The present results identify α-chimaerin as a candidate molecule for a role in the postnatal critical period of visual cortical plasticity.