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. Environmental enrichment (EE) commenced around birth, but not later in life, can drive a partial correction of the most mismapped retinal inputs in Ten-m3 KO mice. Here, we assess whether enrichment unlocks the capacity for microglia to selectively engulf and remove miswired circuitry, and the timing of this effect. Expression of the microglial-associated lysosomal protein CD68 showed a clear enrichment-driven, spatially restricted change which had not commenced at postnatal day (P)18, was evident at P21, more robust at P25, and had ceased by P30. This was observed specifically at the corrective pruning site and was absent at a control site. An engulfment assay at the corrective pruning site in P25 mice showed EE-driven microglial-uptake of the mismapped axon terminals. This was temporally and spatially specific, as no enrichment-driven microglial engulfment was seen in P18 KO mice, nor the control locus. The timecourse of the EE-driven corrective pruning as determined anatomically, aligned with this pattern of microglia reactivity and engulfment. Collectively, these findings show experience can drive targeted microglial engulfment of miswired neural circuitry during a restricted postnatal window. This may have important therapeutic implications for neurodevelopmental conditions involving aberrant neural connectivity.

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. Here, we describe the normal development of thalamostriatal projections arising from the parafascicular nucleus (PFN) and show a role for Ten-m3 in its formation. Ten-m3 is expressed in both the PFN and the striatum by embryonic day 17 (E17). By postnatal day 3 (P3), it had a patchy appearance in the striatum, overlaid on a high dorsal-low ventral expression gradient in both structures. In wild-type mice, axons from the PFN begin to innervate the striatum by E17. By P3, terminals had ramified but were not confined to any striatal subregion. By P7, the axons had begun to avoid striosomes. The first indication of clustering of thalamic terminals within the striatal matrix was also seen at this time point. The compartmental targeting and clustering of PFN projections became more apparent by P10. Analysis of Ten-m3 knockout mice showed that while the early developmental progression of the thalamostriatal pathway is conserved, by P10 differences emerged, with a loss of topographic precision and the absence of terminal clustering. No evidence of the involvement of EphA7 downstream of Ten-m3 was found. Overall, our results suggest that Ten-m3 plays a role in the consolidation and refinement of thalamic axons to a specific subregion of the striatal matrix.

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. Ten-m4 was found to be expressed in the retina, dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and primary visual cortex (V1) during development. Anterograde and retrograde tracing experiments in Ten-m4 knockout (KO) mice revealed a specific increase in ipsilateral retinal ganglion cells projecting to dLGN and SC. This increase was most prominent in regions corresponding to temporal retina. Consistent with this, EphB1 expression in the retina around the time of decussation was enhanced in this temporal region for KO mice, suggesting that the increased size of the ipsilateral population arises due to an increased number of retinal ganglion cells remaining ipsilaterally at the optic chiasm due to EphB1-mediated repulsion. The ectopic ipsilaterally targeted retinal ganglion cell projection observed in Ten-m4 KOs was associated with changes in response to ethologically relevant visual stimuli. Together, these data demonstrate a requirement for Ten-m4 in the establishment of ipsilateral projections from the retina, which likely acts in combination with other Ten-m members (Ten-m2 and Ten-m3) to promote the formation of functional binocular circuits.

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. Here, we reveal that with just 3.5 weeks of EE from birth, Ten-m3 KOs exhibit a partial behavioral rescue, accompanied by pruning of the most profoundly miswired retinogeniculate terminals. Analysis suggests that the pruning is underway at this time point, providing an ideal opportunity to probe potential mechanisms. With the shorter EE-period, we found a localized increase in microglial density and activation profile within the identified geniculate region where corrective pruning was observed. No comparable response to EE was found in age-matched wild-type (WT) mice. These findings identify microglia as a potential mechanistic link through which EE drives the elimination of miswired neural circuits during early postnatal development. Activity driven, atypical recruitment of microglia to prune aberrant connectivity and restore function may have important therapeutic implications for neurodevelopmental disorders such as autistic spectrum disorder.

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. Intravitreal injection of an adeno-associated viral vector carrying the sequence for bReaChES downstream of the calcium calmodulin kinase IIα promoter resulted in sustained retinal expression of bReaChES. Retinal ganglion cells (RGCs) expressing bReaChES generated action potentials at light levels consistent with bright indoor lighting (from 13.6 log photons cm-2 s-1). They could also detect flicker at up to 50 Hz, which approaches the upper temporal limit of human photopic vision. Topological response maps of bReaChES-expressing RGCs suggest that optogenetically activated RGCs may demonstrate similar topographical responses to RGCs stimulated by photoreceptor activation. Furthermore, treated dystrophic mice displayed restored cortical neuronal activity in response to light and rescued behavioral responses to a looming stimulus that simulated an aerial predator. Finally, human surgical retinal explants exposed to the bReaChES treatment vector demonstrated transduction. Together, these findings suggest that intravitreal gene therapy to deliver bReaChES to the retina may restore vision in human retinal degeneration in vivo at ecologically relevant light levels with spectral and temporal response characteristics approaching those of normal human photopic vision.

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. We determined whether, and when, EE can drive functional recovery by analyzing Ten-m3 KO and wildtype (WT) mice that were enriched for 6 weeks from adulthood, weaning or birth in comparison to standard-housed controls. EE initiated from birth, but not later, rescued the response of Ten-m3 KOs to the "looming" stimulus (expanding disc in dorsal visual field), suggesting improved visual function. EE can thus induce recovery of visual behavior, but only during an early developmentally-restricted time-window.

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. We examined the effect of enriching mice from birth on parvalbumin expression and perineuronal net formation in developing and adult striatum. This input nucleus of the basal ganglia consists of topographically discernible regions that serve different functions, providing a means of simultaneously examining the influence of environmental factors on discrete, but related networks. Greater densities of striatal parvalbumin positive cells and wisteria floribunda agglutinin labelled perineuronal nets were present in enriched pups during the second postnatal week, primarily within the lateral portion of the nucleus. Housing conditions continued to have an impact into adulthood, with enriched mice exhibiting higher parvalbumin positive cell densities in both medial and lateral striatum. Curiously, no differences due to housing conditions were detected in striatal perineuronal net densities of mature animals. The degree of overlap between striatal parvalbumin expression and perineuronal net formation was also increased, suggesting that heightened neural activity associated with enrichment may have contributed to greater engagement of networks affiliated with cells that express the calcium binding protein. Brain derived neurotrophic factor, an important regulator of inhibitory network maturation, is also subtly, but significantly affected within the striatum of enriched cohorts. Together, these findings suggest that environmental enrichment can exert cell specific effects within different divisions of an area vital for the regulation of action.

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. We determined whether, and when, EE can drive the repair of subcortical wiring deficits by analyzing Ten-m3 KO and wild-type (WT) mice that were enriched for six weeks from adulthood, weaning or birth in comparison to standard-housed (SE) controls. Six weeks of EE initiated from birth, but not later, induced a significant reduction in the area occupied by ipsilateral retinogeniculate terminals in KOs. No EE-induced correction of mistargeted axons was observed at postnatal day (P)7, indicating that this intervention impacts pruning rather than initial targeting of axons. This reduction was most prominent in the ventrolateral region of the dorsal lateral geniculate nucleus (dLGN), suggesting a preferential pruning of the most profoundly mistargeted axons. EE can thus partially repair a specific, subcortical axonal wiring deficit, but only during an early, developmentally-restricted time window.

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. These observations, together with biochemical and over-expression studies, led to the hypothesis that homophilic interactions between teneurins on afferent and target cells may help to guide the assembly of neural circuits. This review will focus on insights gained on teneurin function in vivo in mammals using mouse knockout models. These studies provide support for the hypothesis that homophilic interactions between teneurin molecules can guide the formation of neural connections with largely consistent results obtained in hippocampal and striatal circuits. Mapping changes obtained in the mouse visual pathway, however, suggest additional roles for these glycoproteins in the formation and specification of circuits which subserve binocular vision.

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. This approach allowed us to compare animals raised in either enriched or standard laboratory housing conditions on a number of measures, including the acquisition of a complex discrimination task, temporal sequence recall accuracy (i.e., the ability to accurately recall a sequences of events) and acuity (i.e., the ability to resolve past events that occurred in close temporal proximity), as well as cognitive flexibility tested in the style of a rule reversal and an Intra-Dimensional Shift (IDS). We found that enrichment accelerated the acquisition of the temporal order discrimination task, although neither accuracy nor acuity was affected at asymptotic performance levels. Further, while a subtle enhancement of overall performance was detected for both rule reversal and IDS versions of the task, accelerated performance recovery could only be attributed to the shift-like contingency change. These findings suggest that EE can affect specific elements of complex, multi-faceted cognitive processes.

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. Deletion of Ten-m3 causes profound disruption of binocular visual alignment and function. Surprisingly, one of the most apparent neuroanatomical changes-dramatic mismapping of ipsilateral, but not contralateral, retinal axons along the representation of the nasotemporal retinal axis-does not correlate well with Ten-m3's expression pattern, raising questions regarding mechanism. The aim of this study was to further our understanding of the molecular interactions which enable the formation of functional binocular visual circuits. METHODS: Anterograde tracing, gene expression studies and protein pull-down experiments were performed. Statistical significance was tested using a Kolmogorov-Smirnov test, pairwise-fixed random reallocation tests and univariate ANOVAs. RESULTS: We show that the ipsilateral retinal axons in Ten-m3 knockout mice are mismapped as a consequence of early axonal guidance defects. The aberrant invasion of the ventral-most region of the dorsal lateral geniculate nucleus by ipsilateral retinal axons in Ten-m3 knockouts suggested changes in the expression of other axonal guidance molecules, particularly members of the EphA-ephrinA family. We identified a consistent down-regulation of EphA7, but none of the other EphA-ephrinA genes tested, as well as an up-regulation of ipsilateral-determinants Zic2 and EphB1 in visual structures. We also found that Zic2 binds specifically to the intracellular domain of Ten-m3 in vitro. CONCLUSION: Our findings suggest that Zic2, EphB1 and EphA7 molecules may work as effectors of Ten-m3 signalling, acting together to enable the wiring of functional binocular visual circuits.

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. Here, we investigated a potential role for Ten-m3 in striatal circuit formation. In situ hybridisation revealed a patchy distribution of Ten-m3 mRNA expression superimposed on a high-dorsal to low-ventral gradient in a subregion of the striatal matrix. A survey of afferent/efferent structures associated with the matrix identified the parafascicular thalamic nucleus (PF) as a potential locus of action. Ten-m3 was also found to be expressed in a high-dorsal to low-ventral gradient in the PF, corresponding topographically to its expression in the striatum. Further, a subset of thalamic terminal clusters overlapped with Ten-m3-positive domains within the striatal matrix. Studies in wild-type (WT) and Ten-m3 knockout (KO) mice revealed no differences in overall striatal or PF structure. Thalamostriatal terminals in KOs, however, while still confined to the matrix subregion, lost their clustered appearance. Topography was also altered, with terminals from the lateral PF projecting ectopically to ventral and medial striatum, rather than remaining confined dorsolaterally as in WTs. Behaviorally, Ten-m3 KOs displayed delayed motor skill acquisition. This study demonstrates that Ten-m3 plays a key role in directing the formation of thalamostriatal circuitry, the first molecular candidate reported to regulate connectivity within this pathway.

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. Particularly important roles have been demonstrated in the visual, olfactory and motor systems. This review attempts to relate new insights into the complex biology of these molecules to their roles in the establishment of functional neural circuits.

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. Further, there is no straightforward manner in which the effects of environmental enrichment can be assessed: most methods require either fairly complicated behavioral paradigms and/or postmortem anatomical/physiological analyses. This protocol describes the use of a simple and inexpensive behavioral assay, the Puzzle Box (5-7) as a robust means of determining the efficacy of increased social, sensory and motor stimulation on mice compared to cohorts raised in standard laboratory conditions. This simple problem solving task takes advantage of a rodent's innate desire to avoid open enclosures by seeking shelter. Cognitive ability is assessed by adding increasingly complex impediments to the shelter's entrance. The time a given subject takes to successfully remove the obstructions and enter the shelter serves as the primary metric for task performance. This method could provide a reliable means of rapidly assessing the efficacy of different enrichment protocols on cognitive function, thus paving the way for systematically determining the role specific environmental factors play in delaying the onset of neurodevelopmental and neurodegenerative disease.

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-m2 expression was observed in the retina, dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and primary visual cortex (V1) of the developing mouse. Anterograde and retrograde tracing experiments in Ten-m2 knock-out (KO) mice revealed a specific decrease in ipsilateral retinal ganglion cells projecting to dLGN and SC. This reduction was most prominent in regions corresponding to ventral retina. No change in the topography of ipsilateral or contralateral projections was observed. While expression of a critical ipsilateral fate determinant, Zic2, appeared unaltered, a notable reduction in one of its downstream targets, EphB1, was observed in ventral retina, suggesting that Ten-m2 may interact with this molecular pathway. Immunohistochemistry for c-fos, a neural activity marker, revealed that the area of V1 driven by ipsilateral inputs was reduced in KOs, while the ratio of ipsilateral-to-contralateral responses contributing to binocular activation during visually evoked potential recordings was also diminished. Finally, a novel two-alternative swim task revealed specific deficits associated with dorsal visual field. These data demonstrate a requirement for Ten-m2 in the establishment of ipsilateral projections, and thus the generation of binocular circuits, critical for mammalian visual function.

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. Significantly, ipsilateral projections are expanded in the dorsal lateral geniculate nucleus and are not aligned with contralateral projections in Ten-m3 knockout (KO) mice. Here, we demonstrate the impact of altered retinogeniculate mapping on the organization and function of V1. Transneuronal tracing and c-fos immunohistochemistry demonstrate that the subcortical expansion of ipsilateral input is conveyed to V1 in Ten-m3 KOs: Ipsilateral inputs are widely distributed across V1 and are interdigitated with contralateral inputs into eye dominance domains. Segregation is confirmed by optical imaging of intrinsic signals. Single-unit recording shows ipsilateral, and contralateral inputs are mismatched at the level of single V1 neurons, and binocular stimulation leads to functional suppression of these cells. These findings indicate that the medial expansion of the binocular zone together with an interocular mismatch is sufficient to induce novel structural features, such as eye dominance domains in rodent visual cortex.

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. These appear mature by postnatal day 11. Importantly, TZs formed by ipsilaterally-projecting retinal axons are spatially offset from those of contralaterally-projecting axons arising from the same retinotopic location from the outset. This pattern is consistent with that required for adult visuotopy. We further demonstrate that a member of the Ten-m/Odz/Teneurin family of homophilic transmembrane glycoproteins, Ten-m3, is an essential regulator of ipsilateral retinocollicular topography. Ten-m3 mRNA is expressed in a high-medial to low-lateral gradient in the developing SC. This corresponds topographically with its high-ventral to low-dorsal retinal gradient. In Ten-m3 knockout mice, contralateral ventrotemporal axons appropriately target rostromedial SC, whereas ipsilateral axons exhibit dramatic targeting errors along both the mediolateral and rostrocaudal axes of the SC, with a caudal shift of the primary TZ, as well as the formation of secondary, caudolaterally displaced TZs. In addition to these dramatic ipsilateral-specific mapping errors, both contralateral and ipsilateral retinocollicular TZs exhibit more subtle changes in morphology. CONCLUSIONS: We conclude that important aspects of adult visuotopy are established via the differential sensitivity of ipsilateral and contralateral axons to intrinsic guidance cues. Further, we show that Ten-m3 plays a critical role in this process and is particularly important for the mapping of the ipsilateral retinocollicular 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. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.

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. These cells exhibit distinct dendritic morphologies from the earliest postnatal time points examined. Furthermore, our data show that the dendritic arbors of these neurons change in length, branch points, diameter and tortuosity, regardless of morphological type. The increase in dendritic length is accompanied by a decrease in the number of branch points that occur in different, but consistent, parts of the dendritic arbor. All of these changes are most pronounced during the second postnatal week, coinciding with a number of developmental events considered important for consolidating circuitry within the striatal matrix. Our results further support the critical importance of this early postnatal period in striatal development.

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. METHODOLOGY/PRINCIPAL FINDINGS: Mice were raised in standard or enriched housing from birth. For animals assessed as adults, half of the mice had their rearing condition reversed at weaning to enable the examination of the effects of pre- versus post-weaning enrichment. We found that exclusively pre-weaning enrichment significantly improved performance on the Morris water maze compared to non-enriched mice. The effects of early enrichment on the emergence of motor programs were assessed by performing behavioural tests at postnatal day 10. Enriched mice traversed a significantly larger region of the test arena in an open-field test and had improved swimming ability compared to non-enriched cohorts. A potential cellular correlate of these changes was investigated using Wisteria-floribunda agglutinin (WFA) staining to mark chondroitin-sulfate proteoglycans (CSPGs). We found that the previously reported transition of CSPG staining from striosome-associated clouds to matrix-associated perineuronal nets (PNNs) is accelerated in enriched mice. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration that the early emergence of exploratory as well as coordinated movement is sensitive to experience. These behavioural changes are correlated with an acceleration of the emergence of striatal PNNs suggesting that they may consolidate the neural circuits underlying these behaviours. Finally, we confirm that pre-weaning experience can lead to life long changes in the learning ability of mice.