An early enriched experience drives targeted microglial engulfment of miswired neural circuitry during a restricted postnatal period.

Brain function is critically dependent on correct circuit assembly. Microglia are well-known for their important roles in immunological defense and neural plasticity, but whether they can also mediate experience-induced correction of miswired circuitry is unclear. Ten-m3 knockout (KO) mice display a pronounced and stereotyped visuotopic mismapping of ipsilateral retinal inputs in their visual thalamus, providing a useful model to probe circuit correction mechanisms.

Ten-m3 plays a role in the formation of thalamostriatal projections.

The importance of the thalamostriatal pathway for a myriad of brain functions is becoming increasingly apparent. Little is known about the formation of this pathway in mice. Further, while Ten-m3, a member of the Ten-m/teneurin/Odz family, is implicated in the proper wiring of mature thalamostriatal projections, its developmental time course is unknown.

Ten-m4 plays a unique role in the establishment of binocular visual circuits.

The patterning of binocular vision requires distinct molecular pathways for inputs arising from each side of the nervous system. Recent studies have demonstrated important roles for members of the Ten-m/Odz/teneurin family in the development of ipsilateral retinal projections. Here, we further highlight the significance of this gene family in visual development by identifying a role for Ten-m4 during the formation of the ipsilateral projection in the mouse.

An Early Enriched Experience Drives an Activated Microglial Profile at Site of Corrective Neuroplasticity in Ten-m3 Knock-Out Mice.

Environmental enrichment (EE) is beneficial for brain development and function, but our understanding of its capacity to drive circuit repair, the underlying mechanisms, and how this might vary with age remains limited. Ten-m3 knock-out (KO) mice exhibit a dramatic and stereotyped mistargeting of ipsilateral retinal inputs to the thalamus, resulting in visual deficits. We have recently shown a previously unexpected capacity for EE during early postnatal life (from birth for six weeks) to drive the partial elimination of miswired axonal projections, along with a recovery of visually mediated behavior, but the timeline of this repair was unclear.

Optogenetic restoration of high sensitivity vision with bReaChES, a red-shifted channelrhodopsin.

The common final pathway to blindness in many forms of retinal degeneration is the death of the light-sensitive primary retinal neurons. However, the normally light-insensitive second- and third-order neurons persist optogenetic gene therapy aims to restore sight by rendering such neurons light-sensitive. Here, we investigate whether bReaChES, a newly described high sensitivity Type I opsin with peak sensitivity to long-wavelength visible light, can restore vision in a murine model of severe early-onset retinal degeneration.

Environmental Enrichment Rescues Visually-Mediated Behavior in Ten-m3 Knockout Mice During an Early Critical Period.

Environmental enrichment (EE) has been shown to promote neural plasticity. Its capacity to induce functional repair in models which exhibit profound sensory deficits due to aberrant axonal guidance has not been well-characterized. Ten-m3 knockout (KO) mice exhibit a highly-stereotyped miswiring of ipsilateral retinogeniculate axons and associated profound deficits in binocularly-mediated visual behavior.

Environmental Enrichment Partially Repairs Subcortical Mapping Errors in Ten-m3 Knock-Out Mice during an Early Critical Period.

Environmental enrichment (EE) has been shown to improve neural function via the regulation of cortical plasticity. Its capacity to induce functional and/or anatomical repair of miswired circuits is unknown. Ten-m3 knock-out (KO) mice exhibit a highly stereotyped and profound miswiring of ipsilateral retinogeniculate axons and associated deficits in binocularly-mediated visual behavior.

Environmental Enrichment From Birth Impacts Parvalbumin Expressing Cells and Wisteria Floribunda Agglutinin Labelled Peri-Neuronal Nets Within the Developing Murine Striatum.

Environmental enrichment can dramatically affect both the development and function of neural circuits. This is accomplished, at least in part, by the regulation of inhibitory cellular networks and related extracellular matrix glycoprotein structures known as perineuronal nets. The degree to which enhanced housing can influence brain areas involved in the planning and execution of actions is not well known.

Teneurins: Mediators of Complex Neural Circuit Assembly in Mammals.

The teneurins (Ten-m/Odz) are a family of evolutionarily ancient transmembrane molecules whose complex and multi-faceted roles in the generation of mammalian neural circuits are only beginning to be appreciated. In mammals there are four family members (Ten-m1-4). Initial expression studies in vertebrates revealed intriguing expression patterns in interconnected populations of neurons.

Environmental Enrichment Expedites Acquisition and Improves Flexibility on a Temporal Sequencing Task in Mice.

Environmental enrichment (EE) via increased opportunities for voluntary exercise, sensory stimulation and social interaction, can enhance the function of and behaviours regulated by cognitive circuits. Little is known, however, as to how this intervention affects performance on complex tasks that engage multiple, definable learning and memory systems. Accordingly, we utilised the Olfactory Temporal Order Discrimination (OTOD) task which requires animals to recall and report sequence information about a series of recently encountered olfactory stimuli.

Downstream mediators of Ten-m3 signalling in the developing visual pathway.

Background: The formation of visuotopically-aligned projections in the brain is required for the generation of functional binocular circuits. The mechanisms which underlie this process are unknown. Ten-m3 is expressed in a broad high-ventral to low-dorsal gradient across the retina and in topographically-corresponding gradients in primary visual centres.

The use of the puzzle box as a means of assessing the efficacy of environmental enrichment.

Environmental enrichment can dramatically influence the development and function of neural circuits. Further, enrichment has been shown to successfully delay the onset of symptoms in models of Huntington's disease (1-4), suggesting environmental factors can evoke a neuroprotective effect against the progressive, cellular level damage observed in neurodegenerative disorders. The ways in which an animal can be environmentally enriched, however, can vary considerably.

The glycoprotein Ten-m3 mediates topography and patterning of thalamostriatal projections from the parafascicular nucleus in mice.

The striatum is the key input nucleus of the basal ganglia, and is implicated in motor control and learning. Despite the importance of striatal circuits, the mechanisms associated with their development are not well established. Previously, Ten-m3, a member of the Ten-m/teneurin/odz family of transmembrane glycoproteins, was found to be important in the mapping of binocular visual pathways.

The teneurins: new players in the generation of visual topography.

A functionally critical feature of the nervous system is the precision of its connectivity. An emerging molecular mediator of this process is the teneurin/ten-m/odz family of transmembrane proteins. A number of recent studies have provided compelling evidence that teneurins have homophilic adhesive properties which, together with their corresponding expression patterns in interconnected groups of neurons, enables them to promote appropriate patterns of connectivity.

Ten-m2 is required for the generation of binocular visual circuits.

Functional binocular vision requires that inputs arising from the two retinae are integrated and precisely organized within central visual areas. Previous studies have demonstrated an important role for one member of the Ten-m/Odz/teneurin family, Ten-m3, in the mapping of ipsilateral retinal projections. Here, we have identified a distinct role for another closely related family member, Ten-m2, in the formation of the ipsilateral projection in the mouse visual system.

Ten-m3 is required for the development of topography in the ipsilateral retinocollicular pathway.

Background: The alignment of ipsilaterally and contralaterally projecting retinal axons that view the same part of visual space is fundamental to binocular vision. While much progress has been made regarding the mechanisms which regulate contralateral topography, very little is known of the mechanisms which regulate the mapping of ipsilateral axons such that they align with their contralateral counterparts.

Results: Using the advantageous model provided by the mouse retinocollicular pathway, we have performed anterograde tracing experiments which demonstrate that ipsilateral retinal axons begin to form terminal zones (TZs) in the superior colliculus (SC), within the first few postnatal days.

Deletion of Ten-m3 induces the formation of eye dominance domains in mouse visual cortex.

The visual system is characterized by precise retinotopic mapping of each eye, together with exquisitely matched binocular projections. In many species, the inputs that represent the eyes are segregated into ocular dominance columns in primary visual cortex (V1), whereas in rodents, this does not occur. Ten-m3, a member of the Ten-m/Odz/Teneurin family, regulates axonal guidance in the retinogeniculate pathway.

Perineuronal nets play a role in regulating striatal function in the mouse.

The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait.

Medium spiny neurons of the neostriatal matrix exhibit specific, stereotyped changes in dendritic arborization during a critical developmental period in mice.

In mice, the matrix compartment of the striatum (caudate/putamen) undergoes major developmental changes during the second postnatal week, including the establishment of corticostriatal and nigrostriatal afferents, the maturation of parvalbumin-positive interneurons and the appearance of perineuronal nets. It is not known if any of these events influence the dendritic structure of medium spiny neurons, the principal output cells of the striatum. To determine whether any measurable changes in the dendrites of matrix medium spiny neurons occur during this important developmental period, we labeled individual cells at different time points flanking the second postnatal week.

Enrichment from birth accelerates the functional and cellular development of a motor control area in the mouse.

Background: There is strong evidence that sensory experience in early life has a profound influence on the development of sensory circuits. Very little is known, however, about the role of experience in the early development of striatal networks which regulate both motor and cognitive function. To address this, we have investigated the influence of early environmental enrichment on motor development.

Rapid reversal of chondroitin sulfate proteoglycan associated staining in subcompartments of mouse neostriatum during the emergence of behaviour.

Background: The neostriatum, the mouse homologue of the primate caudate/putamen, is the input nucleus for the basal ganglia, receiving both cortical and dopaminergic input to each of its sub-compartments, the striosomes and matrix. The coordinated activation of corticostriatal pathways is considered vital for motor and cognitive abilities, yet the mechanisms which underlie the generation of these circuits are unknown. The early and specific targeting of striatal subcompartments by both corticostriatal and nigrostriatal terminals suggests activity-independent mechanisms, such as axon guidance cues, may play a role in this process.

Ten_m3 regulates eye-specific patterning in the mammalian visual pathway and is required for binocular vision.

Binocular vision requires an exquisite matching of projections from each eye to form a cohesive representation of the visual world. Eye-specific inputs are anatomically segregated, but in register in the visual thalamus, and overlap within the binocular region of primary visual cortex. Here, we show that the transmembrane protein Ten_m3 regulates the alignment of ipsilateral and contralateral projections.

Differential gene expression between sensory neocortical areas: potential roles for Ten_m3 and Bcl6 in patterning visual and somatosensory pathways.

Adult neocortical areas are characterized by marked differences in cytoarchitecture and connectivity that underlie their functional roles. The molecular determinants of these differences are largely unknown. We performed a microarray analysis to identify molecules that define the somatosensory and visual areas during the time when afferent and efferent projections are forming.

Two functional channels from primary visual cortex to dorsal visual cortical areas.

Relationships between the M and P retino-geniculo-cortical visual pathways and "dorsal" visual areas were investigated by measuring the sources of local excitatory input to individual neurons in layer 4B of primary visual cortex. We found that contributions of the M and P pathways to layer 4B neurons are dependent on cell type. Spiny stellate neurons receive strong M input through layer 4Calpha and no significant P input through layer 4Cbeta.

Chiral discrimination with regioselectively substituted cellulose esters as chiral stationary phases.

Four kinds of cellulose derivatives, including two regioselectively substituted cellulose esters (6-O-acetyl-2,3-di-O-benzoyl cellulose and 2,3-di-O-acetyl-6-O-benzoyl cellulose), were synthesized so that the effects of their functional group distribution on their chiral discrimination ability could be examined. The degree of substitution by functional groups appeared to have a critical effect on the separation in most cases, but the type of the functional group at the C-6 position also significantly influenced chiral discrimination when a series of neutral arylalcohol derivatives were used as racemates. Copyright 2000 Wiley-Liss, Inc.