Transsynaptic Degeneration of Retinal Ganglion Cells Following Lesions to Primary Visual Cortex in Marmosets.

Purpose: A lesion to primary visual cortex (V1) in primates can produce retrograde transneuronal degeneration in the dorsal lateral geniculate nucleus (LGN) and retina. We investigated the effect of age at time of lesion on LGN volume and retinal ganglion cell (RGC) density in marmoset monkeys. Methods: Retinas and LGNs were obtained about 2 years after a unilateral left-sided V1 lesion as infants (n = 7) or young adult (n = 1). Antibodies against RBPMS were used to label all RGCs, and antibodies against CaMKII or GABAA receptors were used to label nonmidget RGCs. Cell densities were compared in the left and right hemiretina of each eye. The LGNs were stained with the nuclear marker NeuN or for Nissl substance. Results: In three animals lesioned within the first 2 postnatal weeks, the proportion of RGCs lost within 5 mm of the fovea was ∼twofold higher than after lesions at 4 or 6 weeks. There was negligible loss in the animal lesioned at 2 years of age. A positive correlation between RGC loss and LGN volume reduction was evident. No loss of CaMKII-positive or GABAA receptor-positive RGCs was apparent within 2 mm of the fovea in any of the retinas investigated. Conclusions: Susceptibility of marmoset RGCs to transneuronal degeneration is high at birth and declines over the first 6 postnatal weeks. High survival rates of CaMKII and GABAA receptor-positive RGCs implies that widefield and parasol cells are less affected by neonatal cortical lesions than are midget-pathway cells.

Variability of visual field maps in human early extrastriate cortex challenges the canonical model of organization of V2 and V3.

Visual field maps in human early extrastriate areas (V2 and V3) are traditionally thought to form mirror-image representations which surround the primary visual cortex (V1). According to this scheme, V2 and V3 form nearly symmetrical halves with respect to the calcarine sulcus, with the dorsal halves representing lower contralateral quadrants, and the ventral halves representing upper contralateral quadrants. This arrangement is considered to be consistent across individuals, and thus predictable with reasonable accuracy using templates. However, data that deviate from this expected pattern have been observed, but mainly treated as artifactual. Here, we systematically investigate individual variability in the visual field maps of human early visual cortex using the 7T Human Connectome Project (HCP) retinotopy dataset. Our results demonstrate substantial and principled inter-individual variability. Visual field representation in the dorsal portions of V2 and V3 was more variable than in their ventral counterparts, including substantial departures from the expected mirror-symmetrical patterns. In addition, left hemisphere retinotopic maps were more variable than those in the right hemisphere. Surprisingly, only one-third of individuals had maps that conformed to the expected pattern in the left hemisphere. Visual field sign analysis further revealed that in many individuals the area conventionally identified as dorsal V3 shows a discontinuity in the mirror-image representation of the retina, associated with a Y-shaped lower vertical representation. Our findings challenge the current view that inter-individual variability in early extrastriate cortex is negligible, and that the dorsal portions of V2 and V3 are roughly mirror images of their ventral counterparts.

The Brain/MINDS Marmoset Connectivity Resource: An open-access platform for cellular-level tracing and tractography in the primate brain.

The primate brain has unique anatomical characteristics, which translate into advanced cognitive, sensory, and motor abilities. Thus, it is important that we gain insight on its structure to provide a solid basis for models that will clarify function. Here, we report on the implementation and features of the Brain/MINDS Marmoset Connectivity Resource (BMCR), a new open-access platform that provides access to high-resolution anterograde neuronal tracer data in the marmoset brain, integrated to retrograde tracer and tractography data. Unlike other existing image explorers, the BMCR allows visualization of data from different individuals and modalities in a common reference space. This feature, allied to an unprecedented high resolution, enables analyses of features such as reciprocity, directionality, and spatial segregation of connections. The present release of the BMCR focuses on the prefrontal cortex (PFC), a uniquely developed region of the primate brain that is linked to advanced cognition, including the results of 52 anterograde and 164 retrograde tracer injections in the cortex of the marmoset. Moreover, the inclusion of tractography data from diffusion MRI allows systematic analyses of this noninvasive modality against gold-standard cellular connectivity data, enabling detection of false positives and negatives, which provide a basis for future development of tractography. This paper introduces the BMCR image preprocessing pipeline and resources, which include new tools for exploring and reviewing the data.

Imbalance of Pulmonary Microvascular Endothelial Cell-Expression of Metalloproteinases and Their Endogenous Inhibitors Promotes Septic Barrier Dysfunction.

Sepsis is a life-threatening disease characterized by excessive inflammation leading to organ dysfunction. During sepsis, pulmonary microvascular endothelial cells (PMVEC) lose barrier function associated with inter-PMVEC junction disruption. Matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases (ADAM), which are regulated by tissue inhibitors of metalloproteinases (TIMPs), can cleave cell-cell junctional proteins, suggesting a role in PMVEC barrier dysfunction. We hypothesize that septic PMVEC barrier dysfunction is due to a disruption in the balance between PMVEC-specific metalloproteinases and TIMPs leading to increased metalloproteinase activity. The effects of sepsis on TIMPs and metalloproteinases were assessed ex vivo in PMVEC from healthy (sham) and septic (cecal ligation and perforation) mice, as well as in vitro in isolated PMVEC stimulated with cytomix, lipopolysaccharide (LPS), and cytomix + LPS vs. PBS. PMVEC had high basal Timp expression and lower metalloproteinase expression, and septic stimulation shifted expression in favour of metalloproteinases. Septic stimulation increased MMP13 and ADAM17 activity associated with a loss of inter-PMVEC junctional proteins and barrier dysfunction, which was rescued by treatment with metalloproteinase inhibitors. Collectively, our studies support a role for metalloproteinase-TIMP imbalance in septic PMVEC barrier dysfunction, and suggest that inhibition of specific metalloproteinases may be a therapeutic avenue for septic patients.

Parvalbumin as a neurochemical marker of the primate optic radiation.

Parvalbumin (PV) is a calcium-binding protein that labels neuronal cell bodies in the magno and parvocellular layers of the primate lateral geniculate nucleus (LGN). Here we demonstrate that PV immunohistochemistry can also be used to trace the optic radiation (OR) of the marmoset monkey (Callithrix jacchus) from its LGN origin to its destinations in the primary visual cortex (V1), thus providing a high-resolution method for identification of the OR with single axon resolution. The emergence of fibers from LGN, their entire course and even the entry points to V1 were clearly defined in coronal, parasagittal, and horizontal sections of marmoset brain. In all cases, the trajectory revealed by PV staining paralleled that defined by high-resolution diffusion tensor imaging (DTI). We found that V1 was the exclusive target for the PV-containing fibers, with abrupt transitions in staining observed in the white matter at the border with area V2, and no evidence of PV-labeled axons feeding into other visual areas. Changes in the pattern of PV staining in the OR were detected following V1 lesions, demonstrating that this method can be used to assess the progress of retrograde degeneration of geniculocortical projections. These results suggest a technically simple approach to advance our understanding of a major white matter structure, which provides a cellular resolution suitable for the detection of microstructural variations during development, health and disease. Understanding the relationship between PV staining and DTI in non-human primates may also offer clues for improving the specificity and sensitivity of OR tractography for clinical purposes.

Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives.

Pediatric acute-onset neuropsychiatric syndrome (PANS) features a heterogeneous constellation of acute obsessive-compulsive disorder (OCD), eating restriction, cognitive, behavioral and/or affective symptoms, often followed by a chronic course with cognitive deterioration. An immune-mediated etiology is advocated in which the CNS is hit by different pathogen-driven (auto)immune responses. This narrative review focused on recent clinical (ie, diagnostic criteria, pre-existing neurodevelopmental disorders, neuroimaging) and pathophysiological (ie, CSF, serum, genetic and autoimmune findings) aspects of PANS. We also summarized recent points to facilitate practitioners with the disease management. Relevant literature was obtained from PubMed database which included only English-written, full-text clinical studies, case reports, and reviews. Among a total of 1005 articles, 205 were pertinent to study inclusion. Expert opinions are converging on PANS as the effect of post-infectious events or stressors leading to "brain inflammation", as it is well-established for anti-neuronal psychosis. Interestingly, differentiating PANS from either autoimmune encephalitides and Sydenham's chorea or from alleged "pure" psychiatric disorders (OCD, tics, Tourette's syndrome), reveals several overlaps and more analogies than differences. Our review highlights the need for a comprehensive algorithm to help both patients during their acute distressing phase and physicians during their treatment decision. A full agreement on the hierarchy of each therapeutical intervention is missing owing to the limited number of randomized controlled trials. The current approach to PANS treatment emphasizes immunomodulation/anti-inflammatory treatments in association with both psychotropic and cognitive-behavioral therapies, while antibiotics are suggested when an active bacterial infection is established. A dimensional view, taking into account the multifactorial origin of psychiatric disorders, should suggest neuro-inflammation as a possible shared substrate of different psychiatric phenotypes. Hence, PANS and PANS-related disorders should be considered as a conceptual framework describing the etiological and phenotypical complexity of many psychiatric disorders.

Robotic-assisted distal pancreatectomy with splenectomy in a paediatric patient for solid pseudopapillary tumour.

Solid pseudopapillary tumour is a rare low-grade malignant potential carcinoma of the pancreas that typically occurs in females in their third decade. It most commonly occurs in the tail of the pancreas, although any site can be affected. Surgical resection is the standard treatment and offers an excellent prognosis. We report a case of a 17-year-old female with an acute onset abdominal pain and a radiological diagnosis of a cystic lesion in the distal pancreas. A robotic-assisted distal pancreatectomy with splenectomy was performed. Robotic-assisted surgery is an emerging technique for the treatment of pancreatic neoplasms. This approach can be considered for younger patients, thanks to the potential advantages of the robotic Da Vinci Xi System.

A spiking computational model for striatal cholinergic interneurons.

Cholinergic interneurons in the striatum, also known as tonically active interneurons or TANs, are thought to have a strong effect on corticostriatal plasticity and on striatal activity and outputs, which in turn play a critical role in modulating downstream basal ganglia activity and movement. Striatal TANs can exhibit a variety of firing patterns and responses to synaptic inputs; furthermore, they have been found to display various surges and pauses in activity associated with sensory cues and reward delivery in learning as well as with motor tic production. To help explain the factors that contribute to TAN activity patterns and to provide a resource for future studies, we present a novel conductance-based computational model of a striatal TAN. We show that this model produces the various characteristic firing patterns observed in recordings of TANs. With a single baseline tuning associated with tonic firing, the model also captures a wide range of TAN behaviors found in previous experiments involving a variety of manipulations. In addition to demonstrating these results, we explain how various ionic currents in the model contribute to them. Finally, we use this model to explore the contributions of the acetylcholine released by TANs to the production of surges and pauses in TAN activity in response to strong excitatory inputs. These results provide predictions for future experimental testing that may help with efforts to advance our understanding of the role of TANs in reinforcement learning and in motor disorders such as Tourette's syndrome.

An integrated resource for functional and structural connectivity of the marmoset brain.

Comprehensive integration of structural and functional connectivity data is required to model brain functions accurately. While resources for studying the structural connectivity of non-human primate brains already exist, their integration with functional connectivity data has remained unavailable. Here we present a comprehensive resource that integrates the most extensive awake marmoset resting-state fMRI data available to date (39 marmoset monkeys, 710 runs, 12117 mins) with previously published cellular-level neuronal tracing data (52 marmoset monkeys, 143 injections) and multi-resolution diffusion MRI datasets. The combination of these data allowed us to (1) map the fine-detailed functional brain networks and cortical parcellations, (2) develop a deep-learning-based parcellation generator that preserves the topographical organization of functional connectivity and reflects individual variabilities, and (3) investigate the structural basis underlying functional connectivity by computational modeling. This resource will enable modeling structure-function relationships and facilitate future comparative and translational studies of primate brains.

Neuronal density and expression of calcium-binding proteins across the layers of the superior colliculus in the common marmoset (Callithrix jacchus).

The superior colliculus (SC) is a layered midbrain structure with functions that include polysensory and sensorimotor integration. Here, we describe the distribution of different immunohistochemically identified classes of neurons in the SC of adult marmoset monkeys (Callithrix jacchus). Neuronal nuclei (NeuN) staining was used to determine the overall neuronal density in the different SC layers. In addition, we studied the distribution of neurons expressing different calcium-binding proteins (calbindin [CB], parvalbumin [PV] and calretinin [CR]). Our results indicate that neuronal density in the SC decreases from superficial to deep layers. Although the neuronal density within the same layer varies little across the mediolateral axis, it tends to be lower at rostral levels, compared to caudal levels. Cells expressing different calcium-binding proteins display differential gradients of density according to depth. Both CB- and CR-expressing neurons show markedly higher densities in the stratum griseum superficiale (SGS), compared to the stratum opticum and intermediate and deep layers. However, CR-expressing neurons are twice as common as CB-expressing neurons outside the SGS. The distribution of PV-expressing cells follows a shallow density gradient from superficial to deep layers. When normalized relative to total neuronal density, the proportion of CR-expressing neurons increases between the superficial and intermediate layers, whereas that of CB-expressing neurons declines toward the deep layers. The proportion of PV-expressing neurons remains constant across layers. Our data provide layer-specific and accurate estimates of neuronal density, which may be important for the generation of biophysical models of how the primate SC transforms sensory inputs into motor signals.

The marmoset as a model for investigating the neural basis of social cognition in health and disease.

Social-cognitive processes facilitate the use of environmental cues to understand others, and to be understood by others. Animal models provide vital insights into the neural underpinning of social behaviours. To understand social cognition at even deeper behavioural, cognitive, neural, and molecular levels, we need to develop more representative study models, which allow testing of novel hypotheses using human-relevant cognitive tasks. Due to their cooperative breeding system and relatively small size, common marmosets (Callithrix jacchus) offer a promising translational model for such endeavours. In addition to having social behavioural patterns and group dynamics analogous to those of humans, marmosets have cortical brain areas relevant for the mechanistic analysis of human social cognition, albeit in simplified form. Thus, they are likely suitable animal models for deciphering the physiological processes, connectivity and molecular mechanisms supporting advanced cognitive functions. Here, we review findings emerging from marmoset social and behavioural studies, which have already provided significant insights into executive, motivational, social, and emotional dysfunction associated with neurological and psychiatric disorders.

Dimension of visual information interacts with working memory in monkeys and humans.

Humans demonstrate behavioural advantages (biases) towards particular dimensions (colour or shape of visual objects), but such biases are significantly altered in neuropsychological disorders. Recent studies have shown that lesions in the prefrontal cortex do not abolish dimensional biases, and therefore suggest that such biases might not depend on top-down prefrontal-mediated attention and instead emerge as bottom-up processing advantages. We hypothesised that if dimensional biases merely emerge from an enhancement of object features, the presence of visual objects would be necessary for the manifestation of dimensional biases. In a specifically-designed working memory task, in which macaque monkeys and humans performed matching based on the object memory rather than the actual object, we found significant dimensional biases in both species, which appeared as a shorter response time and higher accuracy in the preferred dimension (colour and shape dimension in humans and monkeys, respectively). Moreover, the mnemonic demands of the task influenced the magnitude of dimensional bias. Our findings in two primate species indicate that the dichotomy of top-down and bottom-up processing does not fully explain the emergence of dimensional biases. Instead, dimensional biases may emerge when processed information regarding visual object features interact with mnemonic and executive functions to guide goal-directed behaviour.

Remodeling of lateral geniculate nucleus projections to extrastriate area MT following long-term lesions of striate cortex.

Here, we report on a previously unknown form of thalamocortical plasticity observed following lesions of the primary visual area (V1) in marmoset monkeys. In primates, lateral geniculate nucleus (LGN) neurons form parallel pathways to the cortex, which are characterized by the expression of different calcium-binding proteins. LGN projections to the middle temporal (MT) area only originate in the koniocellular layers, where many neurons express calbindin. In contrast, projections to V1 also originate in the magnocellular and parvocellular layers, where neurons express parvalbumin but not calbindin. Our results demonstrate that this specificity is disrupted following long-term (1 to 3 y) unilateral V1 lesions, indicating active rearrangement of the geniculocortical circuit. In lesioned animals, retrograde tracing revealed MT-projecting neurons scattered throughout the lesion projection zone (LPZ, the sector of the LGN that underwent retrograde degeneration following a V1 lesion). Many of the MT-projecting neurons had large cell bodies and were located outside the koniocellular layers. Furthermore, we found that a large percentage of magno- and parvocellular neurons expressed calbindin in addition to the expected parvalbumin expression and that this coexpression was present in many of the MT-projecting neurons within the LPZ. These results demonstrate that V1 lesions trigger neurochemical and structural remodeling of the geniculo-extrastriate pathway, leading to the emergence of nonkoniocellular input to MT. This has potential implications for our understanding of the neurobiological bases of the residual visual abilities that survive V1 lesions, including motion perception and blindsight, and reveals targets for rehabilitation strategies to ameliorate the consequences of cortical blindness.

Structural Attributes and Principles of the Neocortical Connectome in the Marmoset Monkey.

The marmoset monkey has become an important primate model in Neuroscience. Here, we characterize salient statistical properties of interareal connections of the marmoset cerebral cortex, using data from retrograde tracer injections. We found that the connectivity weights are highly heterogeneous, spanning 5 orders of magnitude, and are log-normally distributed. The cortico-cortical network is dense, heterogeneous and has high specificity. The reciprocal connections are the most prominent and the probability of connection between 2 areas decays with their functional dissimilarity. The laminar dependence of connections defines a hierarchical network correlated with microstructural properties of each area. The marmoset connectome reveals parallel streams associated with different sensory systems. Finally, the connectome is spatially embedded with a characteristic length that obeys a power law as a function of brain volume across rodent and primate species. These findings provide a connectomic basis for investigations of multiple interacting areas in a complex large-scale cortical system underlying cognitive processes.

Afferent Connections of Cytoarchitectural Area 6M and Surrounding Cortex in the Marmoset: Putative Homologues of the Supplementary and Pre-supplementary Motor Areas.

Cortical projections to the caudomedial frontal cortex were studied using retrograde tracers in marmosets. We tested the hypothesis that cytoarchitectural area 6M includes homologues of the supplementary and pre-supplementary motor areas (SMA and pre-SMA) of other primates. We found that, irrespective of the injection sites' location within 6M, over half of the labeled neurons were located in motor and premotor areas. Other connections originated in prefrontal area 8b, ventral anterior and posterior cingulate areas, somatosensory areas (3a and 1-2), and areas on the rostral aspect of the dorsal posterior parietal cortex. Although the origin of afferents was similar, injections in rostral 6M received higher percentages of prefrontal afferents, and fewer somatosensory afferents, compared to caudal injections, compatible with differentiation into SMA and pre-SMA. Injections rostral to 6M (area 8b) revealed a very different set of connections, with increased emphasis on prefrontal and posterior cingulate afferents, and fewer parietal afferents. The connections of 6M were also quantitatively different from those of the primary motor cortex, dorsal premotor areas, and cingulate motor area 24d. These results show that the cortical motor control circuit is conserved in simian primates, indicating that marmosets can be valuable models for studying movement planning and control.

Volume reduction without neuronal loss in the primate pulvinar complex following striate cortex lesions.

Lesions in the primary visual cortex (V1) cause extensive retrograde degeneration in the lateral geniculate nucleus, but it remains unclear whether they also trigger any neuronal loss in other subcortical visual centers. The inferior (IPul) and lateral (LPul) pulvinar nuclei have been regarded as part of the pathways that convey visual information to both V1 and extrastriate cortex. Here, we apply stereological analysis techniques to NeuN-stained sections of marmoset brain, in order to investigate whether the volume of these nuclei, and the number of neurons they comprise, change following unilateral long-term V1 lesions. For comparison, the medial pulvinar nucleus (MPul), which has no connections with V1, was also studied. Compared to control animals, animals with lesions incurred either 6 weeks after birth or in adulthood showed significant LPul volume loss following long (> 11 months) survival times. However, no obvious areas of neuronal degeneration were observed. In addition, estimates of neuronal density in lesioned hemispheres were similar to those in the non-lesioned hemispheres of same animals. Our results support the view that, in marked contrast with the geniculocortical projection, the pulvinar pathway is largely spared from the most severe long-term effects of V1 lesions, whether incurred in early postnatal or adult life. This difference can be linked to the more divergent pattern of pulvinar connectivity to the visual cortex, including strong reciprocal connections with extrastriate areas. The results also caution against interpretation of volume loss in brain structures as a marker for neuronal degeneration.

Metabolomic Characterization of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).

INTRODUCTION: PANS is a controversial clinical entity, consisting of a complex constellation of psychiatric symptoms, adventitious changes, and expression of various serological alterations, likely sustained by an autoimmune/inflammatory disease. Detection of novel biomarkers of PANS is highly desirable for both diagnostic and therapeutic management of affected patients. Analysis of metabolites has proven useful in detecting biomarkers for other neuroimmune-psychiatric diseases. Here, we utilize the metabolomics approach to determine whether it is possible to define a specific metabolic pattern in patients affected by PANS compared to healthy subjects. DESIGN: This observational case-control study tested consecutive patients referred for PANS between June 2019 to May 2020. A PANS diagnosis was confirmed according to the PANS working criteria (National Institute of Mental Health [NIMH], 2010). Healthy age and sex-matched subjects were recruited as controls. METHODS: Thirty-four outpatients referred for PANS (mean age 9.5 years; SD 2.9, 71% male) and 25 neurotypical subjects matched for age and gender, were subjected to metabolite analysis. Serum samples were obtained from each participant and were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy. Subsequently, multivariate and univariate statistical analyses and Receiver Operator Curves (ROC) were performed. RESULTS: Separation of the samples, in line with the presence of PANS diagnosis, was observed by applying a supervised model (R2X = 0.44, R2Y = 0.54, Q2 = 0.44, p-value < 0.0001). The significantly altered variables were 2-Hydroxybutyrate, glycine, glutamine, histidine, tryptophan. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan metabolism, as well as glutamine and glutamate metabolism, exhibited the largest deviations from neurotypical controls. CONCLUSION: We found a unique plasma metabolic profile in PANS patients, significantly differing from that of healthy children, that suggests the involvement of specific patterns of neurotransmission (tryptophan, glycine, histamine/histidine) as well as a more general state of neuroinflammation and oxidative stress (glutamine, 2-Hydroxybutyrate, and tryptophan-kynurenine pathway) in the disorder. This metabolomics study offers new insights into biological mechanisms underpinning the disorder and supports research of other potential biomarkers implicated in PANS.

Claustral Input to the Macaque Medial Posterior Parietal Cortex (Superior Parietal Lobule and Adjacent Areas).

The projections from the claustrum to cortical areas within and adjacent to the superior parietal lobule were studied in 10 macaque monkeys, using retrograde tracers, computerized reconstructions, and quantitative methods. In contrast with the classical view that posterior parietal areas receive afferents primarily from the dorsal and posterior regions of the claustrum, we found that these areas receive more extensive projections, including substantial afferents from the anterior and ventral regions of the claustrum. Moreover, our findings uncover a previously unsuspected variability in the precise regions of the claustrum that originate the projections, according to the target areas. For example, areas dominated by somatosensory inputs for control of body movements tend to receive most afferents from the dorsal-posterior claustrum, whereas those which also receive significant visual inputs tend to receive more afferents from the ventral claustrum. In addition, different areas within these broadly defined groups differ in terms of quantitative emphasis in the origin of projections. Overall, these results argue against a simple model whereby adjacency in the cortex determines adjacency in the sectors of claustral origin of projections and indicate that subnetworks defined by commonality of function may be an important factor in defining claustrocortical topography.