Annotated dataset for training deep learning models to detect astrocytes in human brain tissue.

Astrocytes, a type of glial cell, significantly influence neuronal function, with variations in morphology and density linked to neurological disorders. Traditional methods for their accurate detection and density measurement are laborious and unsuited for large-scale operations. We introduce a dataset from human brain tissues stained with aldehyde dehydrogenase 1 family member L1 (ALDH1L1) and glial fibrillary acidic protein (GFAP). The digital whole slide images of these tissues were partitioned into 8730 patches of 500 × 500 pixels, comprising 2323 ALDH1L1 and 4714 GFAP patches at a pixel size of 0.5019/pixel, furthermore 1382 ADHD1L1 and 311 GFAP patches at 0.3557/pixel. Sourced from 16 slides and 8 patients our dataset promotes the development of tools for glial cell detection and quantification, offering insights into their density distribution in various brain areas, thereby broadening neuropathological study horizons. These samples hold value for automating detection methods, including deep learning. Derived from human samples, our dataset provides a platform for exploring astrocyte functionality, potentially guiding new diagnostic and treatment strategies for neurological disorders.

Upper cortical layer-driven network impairment in schizophrenia.

Schizophrenia is one of the most widespread and complex mental disorders. To characterize the impact of schizophrenia, we performed single-nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. In addition, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most marked in upper-layer GABAergic neurons, including down-regulation in energy metabolism and up-regulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Last, Visium spatial transcriptomics further corroborated upper-layer neuron vulnerability in schizophrenia. Overall, our results point toward general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology.

The spatiotemporal dynamics of microglia across the human lifespan.

Microglia, the brain's resident macrophages, shape neural development and are key neuroimmune hubs in the pathological signatures of neurodevelopmental disorders. Despite the importance of microglia, their development has not been carefully examined in the human brain, and most of our knowledge derives from rodents. We aimed to address this gap in knowledge by establishing an extensive collection of 97 post-mortem tissues in order to enable quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing waves in microglial density across gestation, infancy, and childhood, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNA-seq and single-cell RNA-seq datasets. This study provides a detailed insight into the spatiotemporal dynamics of microglia across the human lifespan and serves as a foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

D-Aspartate consumption selectively promotes intermediate-term spatial memory and the expression of hippocampal NMDA receptor subunits.

D-Aspartate (D-Asp) and D-serine (D-Ser) have been proposed to promote early-phase LTP in vitro and to enhance spatial memory in vivo. Here, we investigated the behavioural effects of chronic consumption of D-Asp and D-Ser on spatial learning of mice together with the expression of NMDA receptors. We also studied the alterations of neurogenesis by morphometric analysis of bromo-deoxyuridine incorporating and doublecortin expressing cells in the hippocampus. Our results specify a time period (3-4 h post-training), within which the animals exposed to D-Asp (but not D-Ser) show a more stable memory during retrieval. The cognitive improvement is due to elimination of transient bouts of destabilization and reconsolidation of memory, rather than to enhanced acquisition. D-Asp also protracted reversal learning probably due to reduced plasticity. Expression of GluN1 and GluN2A subunits was elevated in the hippocampus of D-Asp (but not D-Ser) treated mice. D-Asp or D-Ser did not alter the proliferation of neuronal progenitor cells in the hippocampus. The observed learning-related changes evoked by D-Asp are unlikely to be due to enhanced proliferation and recruitment of new neurones. Rather, they are likely associated with an upregulation of NMDA receptors, as well as a reorganization of receptor subunit assemblies in existing hippocampal/dentate neurons.

Evidence for Decreased Density of Calretinin-Immunopositive Neurons in the Caudate Nucleus in Patients With Schizophrenia.

Schizophrenia (SCH) and autism spectrum disorder (ASD) share several common aetiological and symptomatic features suggesting they may be included in a common spectrum. For example, recent results suggest that excitatory/inhibitory imbalance is relevant in the etiology of SCH and ASD. Numerous studies have investigated this imbalance in regions like the ventromedial and dorsolateral prefrontal cortex (DLPFC). However, relatively little is known about neuroanatomical changes that could reduce inhibition in subcortical structures, such as the caudate nucleus (CN), in neuropsychiatric disorders. We recently showed a significant decrease in calretinin-immunopositive (CR-ip) interneuronal density in the CN of patients with ASD without significant change in the density of neuropeptide Y-immunopositive (NPY-ip) neurons. These subtypes together constitute more than 50% of caudate interneurons and are likely necessary for maintaining excitatory/inhibitory balance. Consequently, and since SCH and ASD share characteristic features, here we tested the hypothesis, that the density of CR-ip neurons in the CN is decreased in patients with SCH. We used immunohistochemistry and qPCR for CR and NPY in six patients with schizophrenia and six control subjects. As expected, small, medium and large CR-ip interneurons were detected in the CN. We found a 38% decrease in the density of all CR-ip interneurons (P < 0.01) that was driven by the loss of the small CR-ip interneurons (P < 0.01) in patients with SCH. The densities of the large CR-ip and of the NPY-ip interneurons were not significantly altered. The lower density detected could have been due to inflammation-induced degeneration. However, the state of microglial activation assessed by quantification of ionized calcium-binding adapter molecule 1 (Iba1)- and transmembrane protein 119 (TMEM119)-immunopositive cells showed no significant difference between patients with SCH and controls. Our results warrant further studies focussing on the role of CR-ip neurons and on the striatum being a possible hub for information selection and regulation of associative cortical fields whose function have been altered in SCH.

Galectin-3 modulates postnatal subventricular zone gliogenesis.

Postnatal subventricular zone (SVZ) neural stem cells generate forebrain glia, namely astrocytes and oligodendrocytes. The cues necessary for this process are unclear, despite this phase of brain development being pivotal in forebrain gliogenesis. Galectin-3 (Gal-3) is increased in multiple brain pathologies and thereby regulates astrocyte proliferation and inflammation in injury. To study the function of Gal-3 in inflammation and gliogenesis, we carried out functional studies in mouse. We overexpressed Gal-3 with electroporation and using immunohistochemistry surprisingly found no inflammation in the healthy postnatal SVZ. This allowed investigation of inflammation-independent effects of Gal-3 on gliogenesis. Loss of Gal-3 function via knockdown or conditional knockout reduced gliogenesis, whereas Gal-3 overexpression increased it. Gal-3 overexpression also increased the percentage of striatal astrocytes generated by the SVZ but decreased the percentage of oligodendrocytes. These novel findings were further elaborated with multiple analyses demonstrating that Gal-3 binds to the bone morphogenetic protein receptor one alpha (BMPR1α) and increases bone morphogenetic protein (BMP) signaling. Conditional knockout of BMPR1α abolished the effect of Gal-3 overexpression on gliogenesis. Gain-of-function of Gal-3 is relevant in pathological conditions involving the human forebrain, which is particularly vulnerable to hypoxia/ischemia during perinatal gliogenesis. Hypoxic/ischemic injury induces astrogliosis, inflammation and cell death. We show that Gal-3 immunoreactivity was increased in the perinatal human SVZ and striatum after hypoxia/ischemia. Our findings thus show a novel inflammation-independent function for Gal-3; it is necessary for gliogenesis and when increased in expression can induce astrogenesis via BMP signaling.

Neuroserpin expression during human brain development and in adult brain revealed by immunohistochemistry and single cell RNA sequencing.

Neuroserpin is a serine-protease inhibitor mainly expressed in the CNS and involved in the inhibition of the proteolytic cascade. Animal models confirmed its neuroprotective role in perinatal hypoxia-ischaemia and adult stroke. Although neuroserpin may be a potential therapeutic target in the treatment of the aforementioned conditions, there is still no information in the literature on its distribution during human brain development. The present study provides a detailed description of the changing spatiotemporal patterns of neuroserpin focusing on physiological human brain development. Five stages were distinguished within our examined age range which spanned from the 7th gestational week until adulthood. In particular, subplate and deep cortical plate neurons were identified as the main sources of neuroserpin production between the 25th gestational week and the first postnatal month. Our immunohistochemical findings were substantiated by single cell RNA sequencing data showing specific neuronal and glial cell types expressing neuroserpin. The characterization of neuroserpin expression during physiological human brain development is essential for forthcoming studies which will explore its involvement in pathological conditions, such as perinatal hypoxia-ischaemia and adult stroke in human.