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The primate prefrontal cortex (PFC) is a quintessential hub of cognitive functions. Amidst its intricate neural architecture, the interplay of distinct neuronal subtypes, notably parvalbumin (PV) and somatostatin (SST) interneurons (INs), emerge as a cornerstone in sculpting cortical circuitry and governing cognitive processes. While considerable strides have been made in elucidating the developmental trajectory of these neurons in rodent models, our understanding of their postmigration developmental dynamics in primates still needs to be studied. Disruptions to this developmental trajectory can compromise IN function, impairing signal gating and circuit modulation within cortical networks. This study examined the expression patterns of PV and SST, ion transporter KCC2, and ion channel subtypes Kv3.1b, and Nav1.1 - associated with morphophysiological stages of development in the postnatal marmoset monkey in different frontal cortical regions (granular areas 8aD, 8aV, 9, 46; agranular areas 11, 47L). Our results demonstrate that the maturation of PV+ INs extends into adolescence, characterized by discrete epochs associated with specific expression dynamics of ion channel subtypes. Interestingly, we observed a postnatal decrease in SST interneurons, contrasting with studies in rodents. This endeavor broadens our comprehension of primate cortical development and furnishes invaluable insights into the etiology and pathophysiology of neurodevelopmental disorders characterized by perturbations in PV and SST IN function.

Recent years have seen a profound resurgence of activity with nonhuman primates (NHPs) to model human brain disorders. From marmosets to macaques, the study of NHP species offers a unique window into the function of primate-specific neural circuits that are impossible to examine in other models. Examining how these circuits manifest into the complex behaviors of primates, such as advanced cognitive and social functions, has provided enormous insights to date into the mechanisms underlying symptoms of numerous neurological and neuropsychiatric illnesses. With the recent optimization of modern techniques to manipulate and measure neural activity in vivo, such as optogenetics and calcium imaging, NHP research is more well-equipped than ever to probe the neural mechanisms underlying pathological behavior. However, methods for behavioral experimentation and analysis in NHPs have noticeably failed to keep pace with these advances. As behavior ultimately lies at the junction between preclinical findings and its translation to clinical outcomes for brain disorders, approaches to improve the integrity, reproducibility, and translatability of behavioral experiments in NHPs requires critical evaluation. In this review, we provide a unifying account of existing brain disorder models using NHPs, and provide insights into the present and emerging contributions of behavioral studies to the field., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We determined the retinal ganglion cell types projecting to the medial subdivision of inferior pulvinar (PIm) and the superior colliculus (SC) in the common marmoset monkey, Callithrix jacchus. Adult marmosets received a bidirectional tracer cocktail into the PIm (conjugated to Alexa fluor 488), and the SC (conjugated to Alexa fluor 594) using an MRI-guided approach. One SC injection included the pretectum. The large majority of retrogradely labelled cells were obtained from SC injections, with only a small proportion obtained after PIm injections. Retrogradely labelled cells were injected intracellularly in vitro using lipophilic dyes (DiI, DiO). The SC and PIm both received input from a variety of ganglion cell types. Input to the PIm was dominated by broad thorny (41%), narrow thorny (24%) and large bistratified (25%) ganglion cells. Input to the SC was dominated by parasol (37%), broad thorny (24%) and narrow thorny (17%) cells. Midget ganglion cells (which make up the large majority of primate retinal ganglion cells) and small bistratified (blue-ON/yellow OFF) cells were never observed to project to SC or PIm. Small numbers of other wide-field ganglion cell types were also encountered. Giant sparse (presumed melanopsin-expressing) cells were only seen following the tracer injection which included the pretectum. We note that despite the location of pulvinar complex in dorsal thalamus, and its increased size and functional importance in primate evolution, the retinal projections to pulvinar have more in common with SC projections than they do with projections to the dorsal lateral geniculate nucleus., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Astrocytes play critical roles after brain injury, but their precise function is poorly defined. Utilizing single-nuclei transcriptomics to characterize astrocytes after ischemic stroke in the visual cortex of the marmoset monkey, we observed nearly complete segregation between stroke and control astrocyte clusters. Screening for the top 30 differentially expressed genes that might limit stroke recovery, we discovered that a majority of astrocytes expressed RTN4A/ NogoA, a neurite-outgrowth inhibitory protein previously only associated with oligodendrocytes. NogoA upregulation on reactive astrocytes post-stroke was significant in both the marmoset and human brain, whereas only a marginal change was observed in mice. We determined that NogoA mediated an anti-inflammatory response which likely contributes to limiting the infiltration of peripheral macrophages into the surviving parenchyma., (© 2021. The Author(s).)

The middle temporal (MT) area of the extrastriate visual cortex has long been studied in adulthood for its distinctive physiological properties and function as a part of the dorsal stream, yet interestingly it possesses a similar maturation profile as the primary visual cortex (V1). Here, we examined whether an early-life lesion in MT of marmoset monkeys (six female, two male) altered the dorsal stream development and the behavioral precision of reaching-to-grasp sequences. We observed permanent changes in the anatomy of cortices associated with both reaching (parietal and medial intraparietal areas) and grasping (anterior intraparietal area), as well as in reaching-and-grasping behaviors. In addition, we observed a significant impact on the anatomy of V1 and the direction sensitivity of V1 neurons in the lesion projection zone. These findings indicate that area MT is a crucial node in the development of primate vision, affecting both V1 and areas in the dorsal visual pathway known to mediate visually guided manual behaviors. SIGNIFICANCE STATEMENT Previous studies have identified a role for the MT area of the visual cortex in perceiving motion, yet none have examined its central role in the development of the visual cortex and in the establishment of visuomotor behaviors. To address this, we used a unilateral MT lesion model in neonatal marmosets before examining the anatomic, physiological, and behavioral consequences. In adulthood, we observed perturbations in goal-orientated reach-and-grasp behavior, altered direction selectivity of V1 neurons, and changes in the cytoarchitecture throughout dorsal stream areas. This study highlights the importance of MT as a central node in visual system development and consequential visuomotor activity., (Copyright © 2021 the authors.)

Infants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adults after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was only expressed on infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged focal ischemic injury significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In rodents, innate and learned fear of predators depends on the medial hypothalamic defensive system, a conserved brain network that lies downstream of the amygdala and promotes avoidance via projections to the periaqueductal gray. Whether this network is involved in primate fear remains unknown. To address this, we provoked flight responses to a predator (moving snake) in the marmoset monkey under laboratory conditions. We combined c-Fos immunolabeling and anterograde/retrograde tracing to map the functional connectivity of the ventromedial hypothalamus, a core node in the medial hypothalamic defensive system. Our findings demonstrate that the ventromedial hypothalamus is recruited by predator exposure in primates and that anatomical connectivity of the rodent and primate medial hypothalamic defensive system are highly conserved.

Rodent models, particularly mice, have dominated the field of developmental neuroscience for decades, like they have in most fields of biomedicine research. However, with 80 million years since rodents and primates last shared a common ancestor, the use of mice to model the development of the human brain is not without many shortcomings. The human brain diverges from the mouse brain in many aspects and is comprised of novel structures as well as diversified cellular subtypes. While these newly evolved features have no equivalent in rodents, they are observed in nonhuman primates. Therefore, elucidating the cellular mechanisms underlying the development and maturation of the healthy and diseased human brain can be achieved using less complex nonhuman primates. Historically, macaques were the preferred nonhuman primate model. However, over the past decade, the New World marmoset monkey (Callithrix jacchus) has gained more importance, particularly in the field of neurodevelopment. With its small size, twin or triplet birth, and prosocial behavior, the marmoset is an ideal model to study normal brain development as well as neurodevelopmental disorders, which are often associated with abnormal social behaviors. The growing interest in the marmoset has prompted many comparative studies, all demonstrating that the marmoset brain closely resembles that of the human and is perfectly suited to model human brain development. The marmoset is thus poised to extend its influence in the field of neurodevelopment and will hopefully fill the gaps that the mouse has left in our understanding of how our brain forms and how neurodevelopmental disorders originate., (© The Author(s) 2021. Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Some patients who are considered cortically blind due to the loss of their primary visual cortex (V1) show a remarkable ability to act upon or discriminate between visual stimuli presented to their blind field, without any awareness of those stimuli. This phenomenon is often referred to as blindsight. Despite the range of spared visual abilities, the identification of the pathways mediating blindsight remains an active and contentious topic in the field. In this review, we discuss recent findings of the candidate pathways and their relative contributions to different forms of blindsight across the lifespan to illustrate the varied nature of unconscious visual processing., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The medial pulvinar (PM) is a multimodal associative thalamic nucleus, recently evolved in primates. PM participates in integrative and modulatory functions, including directed attention, and consistently exhibits alterations in disorders such as schizophrenia and autism. Despite essential cognitive functions, the cortical inputs to the PM have not been systematically investigated. To date, less than 20 cortices have been demonstrated to project to PM. The goal of this study was to establish a comprehensive map of the cortical afferents to PM in the marmoset monkey. Using a magnetic resonance imaging-guided injection approach, we reveal 62 discrete cortices projecting to the adult marmoset PM. We confirmed previously reported connections and identified further projections from discrete cortices across the temporal, parietal, retrosplenial-cingulate, prefrontal, and orbital lobes. These regions encompass areas recipient of PM efferents, demonstrating the reciprocity of the PM-cortical connectivity. Moreover, our results indicate that PM neurones projecting to distinct cortices are intermingled and form multimodal cell clusters. This microunit organization, believed to facilitate cross-modal integration, contrasts with the large functional subdivisions usually observed in thalamic nuclei. Altogether, we provide the first comprehensive map of PM cortical afferents, an essential stepping stone in expanding our knowledge of PM and its function., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Reactive astrocytes have traditionally been viewed as a significant contributor to secondary neuronal damage and repair inhibition after central nervous system (CNS) injury attributed, in large part, to their roles in glial scarring. However, more recent transcriptional evidence has uncovered the vast diversity in reactive astrocyte identity and functions that comprises both neuroprotective and -toxic characteristics. Additionally, the capacity of reactive astrocytes to shift between these activation states demonstrates a high level of environment-dependent plasticity that drives the interplay between neuroprotection and -toxicity after CNS injury. These recent findings have spawned a new field of research that seeks to identify and categorize the function of these discrete subpopulations in the context of neurotrauma, as well as identify their regulators. Therefore, this review will discuss the major and most recent advances in this field of research, with a primary emphasis on neuroprotection. This review will also discuss the major pitfalls present in the field, with a particular focus on model species and their impact on the development of novel therapies.

Retinotopic specializations in the ventral visual stream, especially foveal adaptations, provide primates with high-acuity vision in the central visual field. However, visual field specializations have not been studied in the dorsal visual stream, dedicated to processing visual motion and visually guided behaviors. To investigate this, we injected retrograde neuronal tracers occupying the whole visuotopic representation of the middle temporal (MT) visual area in marmoset monkeys and studied the distribution and morphology of the afferent primary visual cortex (V1) projections. Contrary to previous reports, we found a heterogeneous population of V1-MT projecting neurons distributed in layers 3C and 6. In layer 3C, spiny stellate neurons were distributed mainly in foveal representations, while pyramidal morphologies were characteristic of peripheral eccentricities. This primate adaptation of the V1 to MT pathway is arranged in a way that we had not previously understood, with abundant stellate projection neurons in the high-resolution foveal portions, suggesting rapid relay of motion information to visual area MT. We also describe that the medial portion of the inferior pulvinar (PIm), which is the main thalamic input to area MT, shows a retinotopic organization, likely reflecting the importance of this pathway during development and the establishment of area MT topography., Competing Interests: The authors declare no competing interest.

The pulvinar is primarily referred to for its role in visual processing. However, the 'visual pulvinar' only encompasses the inferior and lateral regions of this complex thalamic nucleus. The remaining medial portion (medial pulvinar, PM) establishes distinct cortical connectivity and has been associated with directed attention, executive functions and working memory. These functions are particularly impaired in neurodevelopmental disorders, including schizophrenia and attention deficit and hyperactivity disorder (ADHD), both of which have been associated with abnormal PM architecture and connectivity. With these disorders becoming more prevalent in modern societies, we review the literature to better understand how the PM can participate in the pathophysiology of cognitive disorders and how a better understanding of the development and function of this thalamic nucleus, which is most likely exclusive to the primate brain, can advance clinical research and treatments., (© 2019 Anatomical Society.)

Throughout the primate lineage, there is a wide diversity of prehensile capacity that is thought to stem from individual species foraging patterns. While many studies have explored primates with precise hand grips, such as higher apes, few have considered primates that lack opposition movements. The New World marmoset monkey occupies an intriguing niche, displaying adept control of their hand movements yet their absence of opposable digits results in relatively imprecise grasping actions when compared with those observed in Old World monkeys, apes, and humans. The marmoset monkey offers a unique composition of ancestral primate corticospinal organization combined with skilled hand use to explore the evolution and development of visually-guided actions. In this study, four adult marmosets were trained to perform a series of visually-guided tasks, designed to assess their control over locating and retrieving objects of differing dimensions. Two of these animals received a neonatal lesion of the inferior pulvinar (unilateral), a thalamic nucleus previously demonstrated to be involved in visuomotor development. The kinematics of their reaching and grasping patterns were recorded for offline analysis. Predictive modeling revealed that maximum grip aperture, time to reach peak velocity and hand use were reliable predictors of distinguishing between cohorts. A consistent feature observed across all tasks was that they do not precisely scale their grip according to the dimensions of the target object which may be attributed to their lack of independent digit control. Therefore, the marmoset monkey represents a previously understudied position in the evolution of primate reach and grasp behavior., (© 2019 Wiley Periodicals, Inc.)

Injury to the primary visual cortex (V1, striate cortex) and the geniculostriate pathway in adults results in cortical blindness, abolishing conscious visual perception. Early studies by Larry Weiskrantz and colleagues demonstrated that some patients with an occipital-lobe injury exhibited a degree of unconscious vision and visually-guided behaviour within the blind field. A more recent focus has been the observed phenomenon whereby early-life injury to V1 often results in the preservation of visual perception in both monkeys and humans. These findings initiated a concerted effort on multiple fronts, including nonhuman primate studies, to uncover the neural substrate/s of the spared conscious vision. In both adult and early-life cases of V1 injury, evidence suggests the involvement of the Middle Temporal area (MT) of the extrastriate visual cortex, which is an integral component area of the dorsal stream and is also associated with visually-guided behaviors. Because of the limited number of early-life V1 injury cases for humans, the outstanding question in the field is what secondary visual pathways are responsible for this extraordinary capacity? Here we report for the first time a case of a child (B.I.) who suffered a bilateral occipital-lobe injury in the first two weeks postnatally due to medium-chain acyl-Co-A dehydrogenase deficiency. At 6 years of age, B.I. underwent a battery of neurophysiological tests, as well as structural and diffusion MRI and ophthalmic examination at 7 years. Despite the extensive bilateral occipital cortical damage, B.I. has extensive conscious visual abilities, is not blind, and can use vision to navigate his environment. Furthermore, unlike blindsight patients, he can readily and consciously identify happy and neutral faces and colors, tasks associated with ventral stream processing. These findings suggest significant re-routing of visual information. To identify the putative visual pathway/s responsible for this ability, MRI tractography of secondary visual pathways connecting MT with the lateral geniculate nucleus (LGN) and the inferior pulvinar (PI) were analysed. Results revealed an increased PI-MT pathway in the left hemisphere, suggesting that this pulvinar relay could be the neural pathway affording the preserved visual capacity following an early-life lesion of V1. These findings corroborate anatomical evidence from monkeys showing an enhanced PI-MT pathway following an early-life lesion of V1, compared to adults., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The current model, based on rodent data, proposes that thalamocortical afferents (TCA) innervate the subplate towards the end of cortical neurogenesis. This implies that the laminar identity of cortical neurons is specified by intrinsic instructions rather than information of thalamic origin. In order to determine whether this mechanism is conserved in the primates, we examined the growth of thalamocortical (TCA) and corticofugal afferents in early human and monkey fetal development. In the human, TCA, identified by secretagogin, calbindin, and ROBO1 immunoreactivity, were observed in the internal capsule of the ventral telencephalon as early as 7-7.5 PCW, crossing the pallial/subpallial boundary (PSB) by 8 PCW before the calretinin immunoreactive corticofugal fibers do. Furthermore, TCA were observed to be passing through the intermediate zone and innervating the presubplate of the dorsolateral cortex, and already by 10-12 PCW TCAs were occupying much of the cortex. Observations at equivalent stages in the marmoset confirmed that this pattern is conserved across primates. Therefore, our results demonstrate that in primates, TCAs innervate the cortical presubplate at earlier stages than previously demonstrated by acetylcholinesterase histochemistry, suggesting that pioneer thalamic afferents may contribute to early cortical circuitry that can participate in defining cortical neuron phenotypes., (© The Author(s) 2019. Published by Oxford University Press.)

Extraintestinal pathogenic Escherichia coli (ExPEC) cause clinical infections in humans. Understanding the evolution and dissemination of ExPEC strains via potential reservoirs is important due to associated morbidity, health care costs and mortality. To further understanding this survey has examined isolates recovered from the faeces of 221 healthy dogs and 427 healthy cats. The distribution of phylogroups varied with host species, and depended on whether the animal was living in a shelter or a home. The human associated STs 69, 73, 95, 131 and 127 were prevalent, with 30.5% of cat isolates and 10.3% of dog isolates representing these ExPEC sequence types. Resistance to the antibiotics ampicillin and tetracycline was common, but resistance to other antimicrobials was negligible., Competing Interests: The authors have declared that no competing interests exist.

The primate visual brain possesses a myriad of pathways, whereby visual information originating at the retina is transmitted to multiple subcortical areas in parallel, before being relayed onto the visual cortex. The dominant retinogeniculostriate pathway has been an area of extensive study, and Vivien Casagrande's work in examining the once overlooked koniocellular pathway of the lateral geniculate nucleus has generated interest in how alternate subcortical pathways can contribute to visual perception. Another subcortical visual relay center is the inferior pulvinar (PI), which has four subdivisions and numerous connections with other subcortical and cortical areas and is directly recipient of retinal afferents. The complexity of subcortical connections associated with the PI subdivisions has led to differing results from various groups. A particular challenge in determining the exact connectivity pattern has been in accurately targeting the subdivisions of the PI with neural tracers. Therefore, in the present study, we used a magnetic resonance imaging (MRI)-guided stereotaxic injection system to inject bidirectional tracers in the separate subdivisions of the PI, the superior layers of the superior colliculus, the retina, and the lateral geniculate nucleus. Our results have determined for the first time that the medial inferior pulvinar (PIm) is innervated by widefield retinal ganglion cells (RGCs), and this pathway is not a collateral branch of the geniculate and collicular projecting RGCs. Furthermore, our tracing data shows no evidence of collicular terminations in the PIm, which are confined to the centromedial and posterior PI., (© 2018 Wiley Periodicals, Inc.)

Recent evidence demonstrates that the pulvinar nuclei play a critical role in shaping the connectivity and function of the multiple cortical areas they connect. Surprisingly, however, little is known about the development of this area, the largest corpus of the thalamic nuclei, which go on to occupy 40% of the adult thalamus in the human. It was proposed that the nonhuman primate and the human pulvinar develop according to very different processes, with a greatly reduced neurogenic period in nonhuman primate compared to human and divergent origins. In the marmoset monkey, we demonstrate that neurons populating the pulvinar are generated throughout gestation, suggesting that this aspect of development is more similar to the human than first predicted. While we were able to confirm the diencephalic source of pulvinar neurons, we provide new evidence contesting the presence of an additional niche in the telencephalon. Finally, our study defines new molecular markers that will simplify future investigations in the development and evolution of the pulvinar., (© 2018 Wiley Periodicals, Inc.)

Competing Interests: None declared

Ischemic stroke remains a leading cause of disability worldwide. Surviving patients often suffer permanent neurological impairments, and spontaneous recovery rarely occurs. However, observations that early-life brain injuries, including strokes, elicit less severe long-term functional impairments, compared to adults, continue to intrigue. While much research has focussed on neuronal changes and plasticity, less is known regarding the regulation of astrogliosis and glial scar formation after a stroke at different stages of life. Therefore, we investigated the cellular, molecular and temporal differences in chronic scar development in the infant and adult nonhuman primate (NHP) post-stroke as it bears greater clinical relevance in the close temporal and pathophysiological homology with humans. This project utilized the endothelin-1 model of focal ischemic stroke in the infant and adult primary visual cortex and investigated differences in the subacute and chronic period. We report here that the post-stroke infant neocortex generates a smaller, more discrete chronic scar, correlating to greater neuronal sparing. Reactive astrocytes that comprise the chronic scar are generated earlier in infants compared to adults, and the expression of critical markers of astrocyte reactivity differs in the subacute period between post-stroke infants and adults. Most importantly, we report that unlike adults, infant astrocyte reactivity is not dependent on several crucial regulators: signal transducer and activator of transcription 3, lipocalin2 and collagen I. Our results demonstrate that infant reactive astrocytes are not regulated by the same intrinsic and extrinsic factors that control these processes in adults, resulting in a more discrete chronic glial scar that is more permissible to neuronal sparing., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The limited capacity for the central nervous system (CNS) to repair itself was first described over 100 years ago by Spanish neuroscientist Ramon Y. Cajal. However, the exact mechanisms underlying this failure in neuronal regeneration remain unclear and, as such, no effective therapeutics yet exist. Numerous studies have attempted to elucidate the biochemical and molecular mechanisms that inhibit neuronal repair with increasing evidence suggesting that several inhibitory factors and repulsive guidance cues active during development actually persist into adulthood and may be contributing to the inhibition of repair. For example, in the injured adult CNS, there are various inhibitory factors that impede the outgrowth of neurites from damaged neurons. One of the most potent of these neurite outgrowth inhibitors is the group of proteins known as the myelin-associated inhibitors (MAIs), present mainly on the membranes of oligodendroglia. Several studies have shown that interfering with these proteins can have positive outcomes in CNS injury models by promoting neurite outgrowth and improving functional recovery. As such, the MAIs, their receptors, and downstream effectors are valid drug targets for the treatment of CNS injury. This review will discuss the current literature on MAIs in the context of CNS development, plasticity, and injury. Molecules that interfere with the MAIs and their receptors as potential candidates for the treatment of CNS injury will additionally be introduced in the context of preclinical and clinical trials.

Background and Purpose: Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke., Methods: We tested the efficacy of acute (1.5 hours) or delayed (1-3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7-14 weeks) and aged mice (20-22 months) of both sexes, as well as adult marmosets of either sex., Results: We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke., Conclusions: Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery., (© 2018 American Heart Association, Inc.)

The pulvinar and the mediodorsal (MDN) nuclei of the thalamus are higher order nuclei which have been implicated in directed effort and corollary discharge systems. We used seed-based resting fMRI to examine functional connectivity to bilateral pulvinar and MDN in 24 schizophrenic patients (SZ), 24 major depressive disorder patients (MDD), and 24 age-matched healthy controls. SZ had less connectivity than controls between the left pulvinar and precuneus, left ventral-lateral prefrontal cortex (vlPFC), and superior and medial-frontal regions, between the right pulvinar and right frontal pole, and greater connectivity between the right MDN and left dorsolateral prefrontal cortex (dlPFC). SZ had less connectivity than MDD between the left pulvinar and ventral anterior cingulate (vACC), left vlPFC, anterior insula, posterior cingulate cortex (PCC), and right hippocampus, between the right pulvinar and right PCC, and between the right MDN and right dorsal anterior cingulate (dACC). This is the first study to measure the functional connectivity to the higher order nuclei of the thalamus in both SZ and MDD. We observed less connectivity in SZ than MDD between pulvinar and emotional encoding regions, a directed effort region, and a region involved in representation and salience, and between MDN and a directed effort region., (Copyright © 2017 Elsevier B.V. All rights reserved.)

An evolutionary hallmark of anthropoid primates, including humans, is the use of vision to guide precise manual movements. These behaviors are reliant on a specialized visual input to the posterior parietal cortex. Here, we show that normal primate reaching-and-grasping behavior depends critically on a visual pathway through the thalamic pulvinar, which is thought to relay information to the middle temporal (MT) area during early life and then swiftly withdraws. Small MRI-guided lesions to a subdivision of the inferior pulvinar subnucleus (PIm) in the infant marmoset monkey led to permanent deficits in reaching-and-grasping behavior in the adult. This functional loss coincided with the abnormal anatomical development of multiple cortical areas responsible for the guidance of actions. Our study reveals that the transient retino-pulvinar-MT pathway underpins the development of visually guided manual behaviors in primates that are crucial for interacting with complex features in the environment., Competing Interests: The authors declare no conflict of interest.

The development of the neocortex requires co-ordination between proliferation and differentiation, as well as the precise orchestration of neuronal migration. Eph/ephrin signaling is crucial in guiding neurons and their projections during embryonic development. In adult ephrin-A2 knockout mice we consistently observed focal patches of disorganized neocortical laminar architecture, ranging in severity from reduced neuronal density to a complete lack of neurons. Loss of ephrin-A2 in the pre-optic area of the diencephalon reduced the migration of neocortex-bound interneurons from this region. Furthermore, ephrin-A2 participates in the creation of excitatory neurons by inhibiting apical progenitor proliferation in the ventricular zone, with the disruption of ephrin-A2 signaling in these cells recapitulating the abnormal neocortex observed in the knockout. The disturbance to the architecture of the neocortex observed following deletion of ephrin-A2 signaling shares many similarities with defects found in the neocortex of children diagnosed with autism spectrum disorder.

Throughout evolution, the neocortex has undergone a dramatic expansion providing the substrate for increasingly complex cognitive abilities, culminating with humans. The enlargement of the neocortex did not affect its' basic organization, which is remarkably conserved from rodents to primates. The mouse has thus proven an advantageous model to decipher the molecular and cellular mechanisms supporting neocortical development. However, it is of limited benefit when studying the mechanisms leading to the inclusion of higher order association areas, which form the largest fraction of the primate neocortex. In the quest for a suitable nonhuman primate model to study the developmental mechanism of neocortical patterning and expansion, researchers focussed on the Old World macaque, routinely employed in functional and behavioral studies. However, the species has many limitations making studies difficult and/or impractical. Therefore, in the past couple of decades, the New World common marmoset (Callithrix jacchus) has drawn much attention and become an accepted model. The marmoset has the advantage of a smooth neocortical sheet, enabling the direct correspondence between developing cortices and the comprehensive map established for the adult, with a significant amount of cortical maturation occurring during the postnatal period. This review presents the contributions of recent marmoset studies to our understanding of the mechanisms regulating corticogenesis in a complex species, the molecular control of neocortical patterning and the sequential maturation of visual cortical areas while commenting on the future of the species in the field. Furthermore, while these new findings are relevant to developmental biology, in order to understand how new cortical areas have emerged to expand cognitive abilities, they also represent a foundation for the better understanding of developmental cognitive disorders. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 263-272, 2017., (© 2016 Wiley Periodicals, Inc.)

The pulvinar is the largest of the thalamic nuclei in the primates, including humans. In the primates, two of the three major subdivisions, the lateral and inferior pulvinar, are heavily interconnected with a significant proportion of the visual association cortex. However, while we now have a better understanding of the bidirectional connectivity of these pulvinar subdivisions, its functions remain somewhat of an enigma. Over the past few years, researchers have started to tackle this problem by addressing it from the angle of development and visual cortical lesions. In this review, we will draw together literature from the realms of studies in nonhuman primates and humans that have informed much of the current understanding. This literature has been responsible for changing many long-held opinions on the development of the visual cortex and how the pulvinar interacts dynamically with cortices during early life to ensure rapid development and functional capacity Furthermore, there is evidence to suggest involvement of the pulvinar following lesions of the primary visual cortex (V1) and geniculostriate pathway in early life which have far better functional outcomes than identical lesions obtained in adulthood. Shedding new light on the pulvinar and its role following lesions of the visual brain has implications for our understanding of visual brain disorders and the potential for recovery.

In the past decade, the New World common marmoset (Callithrix jacchus) has taken a seminal position in neurobiological research, fueled in part by its smooth cortical sheet, which allows cortical areas to be easily accessed by current technologies on the dorsal surface of the brain. In this protocol, we describe a method for the precision placement of agents (e.g., tracers or neurotoxins) into small brain regions of the infant and adult marmoset, using an MRI-guided approach. This strategy uses a protocol for prolonged anesthesia without the need for intubation that we have recently developed, alongside appropriate analgesia and monitoring. The protocol can be readily adapted to be used together with advanced research techniques, such as two-photon microscopy and optical imaging. Including a 5-d postoperative care plan, this protocol takes 7 d to complete. The protocol requires a team of personnel experienced in marmoset care and handling, and small-animal neurosurgery; an assistant for monitoring the animal and assisting with anesthesia; and an MRI technician.

Rodents have been the principal model to study brain anatomy and function due to their well-mapped brain architecture, rapid reproduction and amenability to genetic modification. However, there are clear limitations, for example their simpler neocortex, necessitating the need to adopt a model that is closer to humans in order to understand human cognition and brain conditions. Nonhuman primates (NHPs) are ideally suited as they are our closest relatives in the animal kingdom but in vivo imaging technologies to study brain structure and function in these species can be challenging. With the surge in NHP research in recent years, scientists have begun adapting imaging technologies, such as two-photon microscopy, for these species. Here we review the various NHP models that exist as well as their use in advanced microscopic and mesoscopic studies. We discuss the challenges in the field and investigate the opportunities that lie ahead., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The New World marmoset monkey (Callithrix jacchus) has a relatively short gestational period compared with other primates but possesses a retina at a similar stage of maturation by birth. Previous studies have highlighted that the complex fovea of the marmoset undergoes a more rapid postnatal development in comparison with the Macaca monkey, reaching a mature stage earlier than these species. In this current study, we examined the prenatal proliferation profile of cells in the entire retina employing the thymidine analogs and also determined their phenotype by double-label immunocytochemistry using type-specific markers. Akin to other primate species, we demonstrate a centroperipheral gradient in the emergence of both neurons and Müller glia with cones, ganglion cells, and horizontal cells generated first in the fovea at fetal day (Fd)70-74 and with the last generated at the retinal edge at Fd115. Rods, bipolar cells, amacrine cells, displaced amacrine cells, and Müller glia were generated between Fd76 and Fd135 along the same gradient. Similar to foveal development, marmoset neuronal generation was rapid, only taking 51% of gestation whereas in Macaca this takes 81%., (© 2015 Wiley Periodicals, Inc.)

The pulvinar is the largest thalamic nucleus in primates and one of the most mysterious. Endeavors to understand its role in vision have focused on its abundant connections with the visual cortex. While its connectivity mapping in the cortex displays a broad topographic organization, its projections are also marked by considerable convergence and divergence. As a result, the pulvinar is often regarded as a central forebrain hub. Moreover, new evidence suggests that its comparatively modest input from structures such as the retina and superior colliculus may critically shape the functional organization of the visual cortex, particularly during early development. Here we review recent studies that cast fresh light on how the many convergent pathways through the pulvinar contribute to visual cognition., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Traditional "textbook" theory suggests that the development and maturation of visual cortical areas occur as a wave from V1. However, more recent evidence would suggest that this is not the case, and the emergence of extrastriate areas occurs in a non-hierarchical fashion. This proposition comes from both physiological and anatomical studies but the actual developmental sequence of extrastriate areas remains unknown. In the current study, we examined the development and maturation of the visual cortex of the marmoset monkey, a New World simian, from embryonic day 130 (15 days prior to birth) through to adulthood. Utilizing the well-described expression characteristics of the calcium-binding proteins calbindin and parvalbumin, and nonphosphorylated neurofilament for the pyramidal neurons, we were able to accurately map the sequence of development and maturation of the visual cortex. To this end, we demonstrated that both V1 and middle temporal area (MT) emerge first and that MT likely supports dorsal stream development while V1 supports ventral stream development. Furthermore, the emergence of the dorsal stream-associated areas was significantly earlier than ventral stream areas. The difference in the temporal development of the visual streams is likely driven by a teleological requirement for specific visual behavior in early life.

Background: Conscious vision is believed to depend upon an intact primary visual cortex (V1), although injury in early life is often accompanied by the preservation of visual capacity, unlike in adulthood. The middle temporal area (MT) receives input from the retinorecipient koniocellular layers of the lateral geniculate nucleus (LGN) and the more recently described medial subdivision of the inferior pulvinar (PIm) of the thalamus, pathways that potentially contribute to preservation of vision after early damage to V1., Results: We examined the potential of these pathways to the long-term preservation of vision after permanent lesions of primate V1 in early and adult life by using a combination of neural tracing and diffusion MRI. We show that early-life V1 lesions lead to less pruning of the retina-pulvinar-MT pathway than is observed in control or adult lesion animals., Conclusions: These findings suggest that sustained visual input through the pulvinar to MT following a lesion of V1 in early life has the capacity to afford improved visual outcomes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Retrograde transneuronal degeneration (RTD) of retinal ganglion cells and dorsal lateral geniculate (LGN) neurons are well described following a lesion of the primary visual cortex (V1) in both Old World monkeys and humans. Based on previous studies of New World monkeys and prosimians, it was suggested that these species displayed no RTD following a lesion of V1. In this study of the New World marmoset monkey, 1 year after a unilateral V1 lesion either in adults or at 14 days after birth, we observed ~20 % ganglion cell (GC) loss in adult but ~70 % in infants. This finding is similar to the RTD previously described for Old World Macaca monkeys. Furthermore, in infants we find a similar amount of RTD at 3 weeks and 1 year following lesion, demonstrating that RTD is very rapid in neonates. This highlights the importance of trying to prevent the rapid onset of RTD following a lesion of V1 in early life as a strategy for improved functional recovery. Despite differences in GC loss, there was little difference between LGN degeneration in infant versus adult lesions. A wedge on the horizontal meridian corresponding to the LGN foveal representation revealed extensive neuronal loss. Retinal afferent input was labeled by cholera toxin B subunit. Input to the degenerated parvocellular layers was difficult to detect, while input to magnocellular and koniocellular layers was reduced but still apparent. Our demonstration that the New World marmoset monkey shares many of the features of neuroplasticity with Old World Macaca monkeys and humans emphasizes the opportunity and benefit of marmosets as models of visual cortical injury.

The visual cortex is organized into discrete domains characterized by their specific function, connectivity, chemoarchitecture, and cytoarchitecture. Gradients of transcription factors across the anteroposterior and mediolateral axes of the neocortex have previously been demonstrated to specify the main sensory regions. However, they do not account for the establishment of multiple areas in the primate visual cortex, which occupies approximately 50% of the neocortical surface. We demonstrate that the guidance molecule Semaphorin3A (Sema3A) is initially secreted in the cortical plate of the embryonic marmoset monkey and acts as an intrinsic cue to control the migration of subpopulations of neuronal progenitors and projection neurons expressing the receptor Neuropilin 1 (Npn1). During the first 2 postnatal weeks, Sema3A expression becomes primarily associated with ventral visual cortical areas, leading to the specific migration of Npn1+ neurons in the late maturing visual areas. In the mouse, Sema3A distribution is not arealized, but Npn1 expression becomes restricted to the posterior neocortex at embryonic day 16.5. The selective reduction in the striate cortex we observe in Sema3A-/- animals potentially results from the differential distribution of Npn1+ cells. Therefore, the Sema3A/Npn1 pathway participates to the parcellation of the visual neocortex in both the mouse and the marmoset, however, through different regulatory processes., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischaemic lesion rapidly die and other neuronal populations in the ischaemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischaemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischaemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischaemia and are dissecting the functional importance of this regenerative mechanism following brain injury. This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Models of ischemic brain injury in the nonhuman primate (NHP) are advantageous for investigating mechanisms of central nervous system (CNS) injuries and testing of new therapeutic strategies. However, issues of reproducibility and survivability persist in NHP models of CNS injuries. Furthermore, there are currently no pediatric NHP models of ischemic brain injury. Therefore, we have developed a NHP model of cortical focal ischemia that is highly reproducible throughout life to enable better understanding of downstream consequences of injury. Posterior cerebral arterial occlusion was induced through intracortical injections of endothelin-1 in adult (n = 5) and neonatal (n = 3) marmosets, followed by magnetic resonance imaging (MRI), histology and immunohistochemistry. MRI revealed tissue hyperintensity at the lesion site at 1-7 days followed by isointensity at 14-21 days. Peripheral macrophage and serum albumin infiltration was detected at 1 day, persisting at 21 days. The proportional loss of total V1 as a result of infarction was consistent in adults and neonates. Minor hemorrhagic transformation was detected at 21 days at the lesion core, while neovascularization was detected in neonates, but not in adults. We have developed a highly reproducible and survivable model of focal ischemia in the adult and neonatal marmoset primary visual cortex, demonstrating similar downstream anatomical and cellular pathology to those observed in post-ischemic humans., (© 2014 International Society of Neuropathology.)