Separation and Engagement: From Duplex Vision to the Achievement of Self-Consciousness

The world we observe and the world we act in are one and the same world, and crucially so. Dualisms are rife in cognitive science, and superficially, this paper may seem to be an exercise in splitting things in two. Neither brain structures nor cognitive aptitudes nor even modes of awareness will appear safe. Yet the core insights of this paper are guided by the above maxim of metaphysical monism, and serve to reinforce it. They will concern not differences and oppositions, but rather cooperation and complicity. To employ a prime metaphor elaborated by Brian Smith (1996), this is one story of the single dance we perform in our world, and how the two main skills we bring to bear therein – and to dig deeper, how their neural foundations – result in our important achievements as thinking creatures. Though it may traffic in popular dualisms, this is a tale of negotiation and mutual enrichment. Monisms and dualities notwithstanding, there is also a three-step hierarchy that the following argument will scale. I will begin in the trenches of neuroscience and the psychology of visual perception. This will motivate a discussion of two skills available to perceiving creatures, skills that I will subsequently claim to be central to a rather sophisticated form of self-consciousness. The main charge of this paper may be conceptualised as the task of showing that these three domains, of visual perception, of vital ways of interacting with the world, and of self-consciousness, are importantly interconnected. In what follows, I will build the case for two broad realms of embodied, embedded cognitive capability, referred to as separation and engagement in honour of Smith’s (1996) usage, being directly enabled by the functions characterising ventral stream and dorsal stream visual processing, respectively. Separation and engagement are our twin abilities to represent what is at a spatial or temporal distance from our local and present surroundings on the one hand, and to interact with our immediate, available environments, on the other. I will commence by exploring the perceptual performances made possible by the ventral and dorsal streams of the visual system. Based on empirical findings and theoretical analysis, I will draw out the relationship between ventral processing and a modest form of separation, and indeed, between dorsal processing, ecological perception, and engagement. This strictly segregated dialectic will soon begin to seem artificial. It will therefore be synthesised by way of arguments for the necessity of dorsally mediated processing for full-fledged separation, and the metaphysically indispensable position of the functions of ventral processing in engagement as we know it. Finally, I will attempt to show that full-fledged separation is what catalyses the transition from being an aware subject to being an object of self-awareness. Yet full-fledged separation cannot exist in the absence of an engaged, active life and the neural processing that supports it. Therefore, my claim will be that a sophisticated kind of self-consciousness can be traced back to the functions of the two visual streams via the interlaced achievements of separation and engagement. Prior to my closing remarks, I will advance some clarifications of this thesis and field objections as to its implications for the nature of cognition

Involvement of plasmalogens in post-natal retinal vascular development

Objective: Proper development of retinal blood vessels is essential to ensure sufficient oxygen and nutrient supplies to the retina. It was shown that polyunsaturated fatty acids (PUFAs) could modulate factors involved in tissue vascularization. A congenital deficiency in ether-phospholipids, also termed "plasmalogens'', was shown to lead to abnormal ocular vascularization. Because plasmalogens are considered to be reservoirs of PUFAs, we wished to improve our understanding of the mechanisms by which plasmalogens regulate retinal vascular development and whether the release of PUFAs by calcium-independent phospholipase A2 (iPLA2) could be involved. [br/]Methods and Results: By characterizing the cellular and molecular steps of retinal vascular development in a mouse model of plasmalogen deficiency, we demonstrated that plasmalogens modulate angiogenic processes during the early phases of retinal vascularization. They influence glial activity and primary astrocyte template formation, endothelial cell proliferation and retinal vessel outgrowth, and impact the expression of the genes involved in angiogenesis in the retina. These early defects led to a disorganized and dysfunctional retinal vascular network at adult age. By comparing these data to those obtained on a mouse model of retinal iPLA2 inhibition, we suggest that these processes may be mediated by PUFAs released from plasmalogens and further signalling through the angiopoietin/tie pathways. [br/]Conclusions: These data suggest that plasmalogens play a crucial role in retinal vascularization processes

Erythrocyte phospholipid and polyunsaturated fatty acid composition in diabetic retinopathy

Background: Long chain polyunsaturated fatty acids (LCPUFAs) including docosahexaenoic acid and arachidonic acid are suspected to play a key role in the pathogenesis of diabetes. LCPUFAs are known to be preferentially concentrated in specific phospholipids termed as plasmalogens. This study was aimed to highlight potential changes in the metabolism of phospholipids, and particularly plasmalogens, and LCPUFAs at various stages of diabetic retinopathy in humans. Methodology and Principal Findings: We performed lipidomic analyses on red blood cell membranes from controls and mainly type 2 diabetes mellitus patients with or without retinopathy. The fatty acid composition of erythrocytes was determined by gas chromatography and the phospholipid structure was determined by liquid chromatography equipped with an electrospray ionisation source and coupled with a tandem mass spectrometer (LC-ESI-MS/MS). A significant decrease in levels of docosahexaenoic acid and arachidonic acid in erythrocytes of diabetic patients with or without retinopathy was observed. The origin of this decrease was a loss of phosphatidyl-ethanolamine phospholipids esterified with these LCPUFAs. In diabetic patients without retinopathy, this change was balanced by an increase in the levels of several phosphatidyl-choline species. No influence of diabetes nor of diabetic retinopathy was observed on the concentrations of plasmalogen-type phospholipids. Conclusions and Significance: Diabetes and diabetic retinopathy were associated with a reduction of erythrocyte LCPUFAs in phosphatidyl-ethanolamines. The increase of the amounts of phosphatidyl-choline species in erythrocytes of diabetic patients without diabetic retinopathy might be a compensatory mechanism for the loss of LC-PUFA-rich phosphatidyl-ethanolamines

Sex-specific Gene Expression in Flupirtine-Treated Cln3Δex7/8 Mouse Brain

Gene expression is a powerful tool to understand structure-function relationships in the nervous system. This study reports global gene expression changes induced by flupirtine in brain of male and female Cln3Δex7/8 mice, exposing potential flupirtine targets at the molecular level. Gene expression analysis of male and female Cln3Δex7/8 mouse brain was determined following oral administration of flupirtine for 14 weeks, using Mouse Genome 430 2.0 array Chips and an Affymetrix platform. Fifty-six genes in males and 79 in females were differentially expressed in flupirtine- versus vehicle-treated Cln3Δex7/8 mouse brain. Flupirtine altered several pathways in Cln3Δex7/8 mouse brain: apoptosis, the complement cascade, NF-kB, and p38α MAPK signaling pathways. Gene-gene network analysis highlighted networks and processes functionally pertinent to flupirtine treatment. These encompassed neurodegeneration, neuro-inflammation, and implicated neurological disorders such as Alzheimer and Parkinson disease. Flupirtine mediates its action in males and females through distinctive actionable targets in the same pathways. This work consolidates the groundwork for considering flupirtine as a treatment option in human CLN3 disease

Exogenous Flupirtine as Potential Treatment for CLN3 Disease

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3Δex7/8 mice. WT/Cln3Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in Cln3Δex7/8 mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in Cln3Δex7/8 mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female Cln3Δex7/8 mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in Cln3Δex7/8 mice, paving the way for potential therapies for CLN3 disease

The impact of the COVID-19 pandemic on the mental health of healthcare workers:study protocol for the COVID-19 HEalth caRe wOrkErS (HEROES) study

BACKGROUND: Preliminary country-specific reports suggest that the COVID-19 pandemic has a negative impact on the mental health of the healthcare workforce. In this paper, we summarize the protocol of the COVID-19 HEalth caRe wOrkErS (HEROES) study, an ongoing, global initiative, aimed to describe and track longitudinal trajectories of mental health symptoms and disorders among health care workers at different phases of the pandemic across a wide range of countries in Latin America, Europe, Africa, Middle-East, and Asia. METHODS: Participants from various settings, including primary care clinics, hospitals, nursing homes, and mental health facilities, are being enrolled. In 26 countries, we are using a similar study design with harmonized measures to capture data on COVID-19 related exposures and variables of interest during two years of follow-up. Exposures include potential stressors related to working in healthcare during the COVID-19 pandemic, as well as sociodemographic and clinical factors. Primary outcomes of interest include mental health variables such as psychological distress, depressive symptoms, and posttraumatic stress disorders. Other domains of interest include potentially mediating or moderating influences such as workplace conditions, trust in the government, and the country’s income level. RESULTS: As of August 2021, ~ 34,000 health workers have been recruited. A general characterization of the recruited samples by sociodemographic and workplace variables is presented. Most participating countries have identified several health facilities where they can identify denominators and attain acceptable response rates. Of the 26 countries, 22 are collecting data and 2 plan to start shortly. CONCLUSIONS: This is one of the most extensive global studies on the mental health of healthcare workers during the COVID-19 pandemic, including a variety of countries with diverse economic realities and different levels of severity of pandemic and management. Moreover, unlike most previous studies, we included workers (clinical and non-clinical staff) in a wide range of settings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00127-021-02211-9

Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ?-amyloid (A?) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than A? plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble A? species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, A? peptide expression and neuroinflammation). Administration of anti-IL17 for 5?months, starting at the age of 7?months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and A?1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.This study was supported by the Jerome Lejeune Foundation, Fundación Tatiana Pérez de Guzmán el Bueno, the Spanish Ministry of Economy and Competitiveness (PSI-2016-76194-R, SAF2014-55088-R, SAF2016-75195-R, AEI/FEDER, EU) and Luchamos por la Vida Foundatio

Novelty and Dopaminergic Modulation of Memory Persistence:A Tale of Two Systems

Adaptation to the ever-changing world is critical for survival, and our brains are particularly tuned to remember events that differ from previous experiences. Novel experiences induce dopamine release in the hippocampus, a process which promotes memory persistence. While axons from the ventral tegmental area (VTA) were generally thought to be the exclusive source of hippocampal dopamine, recent studies have demonstrated that noradrenergic neurons in the locus coeruleus (LC) co-release noradrenaline and dopamine in the hippocampus, and that their dopamine release boost memory retention as well. Here, we propose that the projections originating from the VTA and the LC belong to two distinct systems that enhance memory of novel events. Novel experiences that share some commonality with past ones (‘common novelty’) activate the VTA and promotes semantic memory formation via systems memory consolidation. In contrast, experiences that bear only minimal relationship to past experiences (‘distinct novelty’) activate the LC to trigger strong initial memory consolidation in the hippocampus resulting in vivid and long-lasting episodic memories

Metabolism of plasmalogens in neuronal tissues : involvment in retinal vascular development through calcium independant phospholipase A2 (iPLA2)

Les complications vasculaires rétiniennes constituent des évènements qui peuvent être observés au cours de rétinopathies pouvant être à l’origine d’une cécité à tous les stades de la vie. Ces complications concernent particulièrement la rétinopathie du prématuré, la rétinopathie diabétique et la dégénérescence maculaire liée à l’âge. Les lipides offrent de nombreuses possibilités pour prévenir et éventuellement freiner le développement de ces rétinopathies. Parmi eux, la classe des plasmalogènes est particulièrement riche en acides gras poly-insaturés (AGPI), qui sont libérés par une phospholipase indépendante du calcium (iPLA2) et qui sont précurseurs de métabolites biologiquement actifs. Certains de ces métabolites sont connus pour être impliqués dans la modulation de l’angiogenèse rétinienne. L’objectif de ce travail de thèse a été d’évaluer l’implication des plasmalogènes dans le développement vasculaire rétinien par l’intermédiaire de la libération des AGPI par la iPLA2. Pour vérifier cette hypothèse, nous avons caractérisé les évènements cellulaires et moléculaires du développement vasculaire rétinien postnatal chez un modèle animal d’inhibition de la iPLA2 rétinienne que nous avons préalablement développé, ceci de manière comparative avec un modèle de déficience totale en plasmalogènes. Nous avons également tenté de mettre en évidence de potentielles altérations du métabolisme des plasmalogènes chez au cours d’une rétinopathie à composante vasculaire chez l’homme, la rétinopathie diabétique. Nos résultats ont suggéré que les plasmalogènes sont indispensables pour le développement physiologique des vaisseaux rétiniens. Ils seraient impliqués dans le contrôle de la formation de la trame astrocytaire et la mise en place du réseau endothélial par l’intermédiaire des AGPI libérés par la iPLA2. Les mécanismes moléculaires impliqueraient la voie des Angiopoïétines-Tie sans affecter celle du VEGF. Chez l’homme, nous avons noté une réduction des AGPI circulants, en particulier l’acide docosaexanéïque et l’acide arachidonique, sur les phosphatidyl-éthanolamines chez tous les patients diabétiques avec ou sans rétinopathie diabétique, sans implication des formes plasmalogènes. Nos résultats suggèrent une implication du métabolisme des plasmalogènes dans le contrôle du développement vasculaire en période péri-natale mais pas au cours de la rétinopathie diabétique. Ce contrôle serait exercé par l’intermédiaire des AGPI libérés par la iPLA2.Retinal vascular complications are secondary events of several retinopathies that result in blindness at all ages. Such complications can be observed in retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. Lipids, and particularly polyunsaturated fatty acids (PUFAs), display beneficial properties in the prevention of such retinopathies. Among the different lipid classes, the plasmalogen subclass is particularly interesting since it is known to be rich in PUFAs. These PUFAs are known to be released by a calcium-independent phospholipase (iPLA2) and further converted into biologically active metabolites. Some of these metabolites are known to be involved in the modulation of retinal angiogenesis. The aim of this work was to evaluate the involvement of plasmalogens in retinal vascular development through PUFA release by iPLA2. To check this hypothesis, we have comparatively characterized cellular and molecular mechanisms of postnatal retinal vascular development in an animal model of retinal iPLA2 inhibition as well as in a model of plasmalogens deficiency. On the other hand, we have attempted to identify potential alterations in plasmalogen metabolism in diabetic retinopathy. Our results suggest that plasmalogens are essential for the physiological development of retinal vessels. They are involved in the control of astrocyte template formation and the development of the primary vascular network through PUFA released by iPLA2. Molecular mechanisms by which PUFAs from plasmalogens control retinal vascular development involve Angiopoietin-Tie pathways, without affecting those involving VEGF. In the human study, we have observed a decrease in the bioavailability of circulating PUFAs, and especially docosaexaneic acid and arachidonic acid binded to phosphatidyl-ethanolamine in all diabetic patients with or without diabetic retinopathy. Plasmalogens were not involved in these modifications. Our results suggest that plasmalogen metabolism is involved in the control of primary vascular growth during retinal development but not in diabetic retinopathy. Plasmalogens may control early steps of retinal vascular development through the release of PUFAs by iPLA2