Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice.

Introduction: Neuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals.

AAV8 vector induced gliosis following neuronal transgene expression.

Introduction: Expression of light sensitive ion channels by selected neurons has been achieved by viral mediated transduction with gene constructs, but for this to have therapeutic uses, for instance in treating epilepsy, any adverse effects of viral infection on the cerebral cortex needs to be evaluated. Here, we assessed the impact of adeno-associated virus 8 (AAV8) carrying DNA code for a soma targeting light activated chloride channel/FusionRed (FR) construct under the CKIIa promoter.

Methods: Viral constructs were harvested from transfected HEK293 cells and purified.

Is there a consensus on the location and composition of the human subplate?

Cortical wall of human fetal cerebral cortex (early second trimester immunostained for a synaptic marker [red]) revealing the extent of the subplate, which is considerably wider than the cortical plate at this developmental stage.

Expression of the schizophrenia associated gene in the early developing fetal human forebrain.

Introduction: The protein fasciculation and elongation zeta-1 (FEZ1) is involved in axon outgrowth but potentially interacts with various proteins with roles ranging from intracellular transport to transcription regulation. Gene association and other studies have identified as being directly, or indirectly, implicated in schizophrenia susceptibility. To explore potential roles in normal early human forebrain neurodevelopment, we mapped expression by region and cell type.

Altered synaptic connectivity in an in vitro human model of STXBP1 encephalopathy.

Early infantile developmental and epileptic encephalopathies are devastating conditions, generally of genetic origin, but the pathological mechanisms often remain obscure. A major obstacle in this field of research is the difficulty of studying cortical brain development in humans, at the relevant time period in utero. To address this, we established an in vitro assay to study the impact of gene variants on the developing human brain by using living organotypic cultures of the human subplate and neighbouring cortical regions, prepared from ethically sourced, 14-17 post-conception week brain tissue (www.

Closed-loop optogenetic control of the dynamics of neural activity in non-human primates.

Electrical neurostimulation is effective in the treatment of neurological disorders, but associated recording artefacts generally limit its applications to open-loop stimuli. Real-time and continuous closed-loop control of brain activity can, however, be achieved by pairing concurrent electrical recordings and optogenetics. Here we show that closed-loop optogenetic stimulation with excitatory opsins enables the precise manipulation of neural dynamics in brain slices from transgenic mice and in anaesthetized non-human primates.

Reduced placental size and increased apoptosis are associated with prenatal nicotine exposure in rats.

Objective: Smoking during pregnancy has been linked to a variety of negative embryonic and neonatal consequences. Nicotine is the major constituent of tobacco smoke, which was associated with adverse impacts on histological and functional features of the placenta. This study aims to investigate the potential influence of nicotine exposure on the rat placenta and fetus.

Tyramide signal amplification coupled with multiple immunolabeling and RNAScope in situ hybridization in formaldehyde-fixed paraffin-embedded human fetal brain.

Several strategies have been recently introduced to improve the practicality of multiple immunolabeling and RNA in situ hybridization protocols. Tyramide signal amplification (TSA) is a powerful method used to improve the detection sensitivity of immunohistochemistry. RNAScope is a novel commercially available in situ hybridization assay for the detection of RNA expression.

Increased hippocampal excitability in miR-324-null mice.

MicroRNAs are non-coding RNAs that act to downregulate the expression of target genes by translational repression and degradation of messenger RNA molecules. Individual microRNAs have the ability to specifically target a wide array of gene transcripts, therefore allowing each microRNA to play key roles in multiple biological pathways. miR-324 is a microRNA predicted to target thousands of RNA transcripts and is expressed far more highly in the brain than in any other tissue, suggesting that it may play a role in one or multiple neurological pathways.

Creative Destruction: A Basic Computational Model of Cortical Layer Formation.

One of the most characteristic properties of many vertebrate neural systems is the layered organization of different cell types. This cytoarchitecture exists in the cortex, the retina, the hippocampus, and many other parts of the central nervous system. The developmental mechanisms of neural layer formation have been subject to substantial experimental efforts.

Multimodal Three-Dimensional Visualization Enhances Novice Learner Interpretation of Basic Cross-Sectional Anatomy.

While integrated delivery of anatomy and radiology can support undergraduate anatomical education, the interpretation of complex three-dimensional spatial relationships in cross-sectional and radiological images is likely to be demanding for novices. Due to the value of technology-enhanced and multimodal strategies, it was hypothesized that simultaneous digital and physical learning could enhance student understanding of cross-sectional anatomy. A novel learning approach introduced at a United Kingdom university medical school combined visualization table-based thoracic cross-sections and digital models with a three-dimensional printed heart.

Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein.

Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice.

Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.

Background: Joubert syndrome and related disorders (JSRD) and Jeune syndrome are multisystem ciliopathy disorders with overlapping phenotypes. There are a growing number of genetic causes for these rare syndromes, including the recently described genes ARL3 and CEP120.

Methods: We sought to explore the developmental expression patterns of ARL3 and CEP120 in humans to gain additional understanding of these genetic conditions.

Multiple Origins of Secretagogin Expressing Cortical GABAergic Neuron Precursors in the Early Human Fetal Telencephalon.

Secretagogin (SCGN) which acts as a calcium signaling sensor, has previously been shown to be expressed by a substantial population of cortical GABAergic neurons at mid-gestation in humans but not in mice. The present study traced SCGN expression in cortical GABAergic neurons in human fetal forebrain from earlier stages than previously studied. Multiple potential origins of SCGN-expressing neurons were identified in the caudal ganglionic eminence (CGE) lateral ganglionic eminence (LGE) septum and preoptic area; these cells largely co-expressed SP8 but not the medial ganglionic eminence marker LHX6.

Selective Expression of Nicotinic Receptor Sub-unit mRNA in Early Human Fetal Forebrain.

Increasing evidence from animal and human studies indicate that exposure to nicotine during development, separated from the effects of smoking tobacco, can contribute to dysregulation of brain development including behavioral deficits. An RNAseq study of human fetal cerebral cortex demonstrated that 9 out of 16 genes for human nicotinic acetylcholine (ACh) receptor subunits are selectively expressed between 7.5 and 12 post-conceptional weeks (PCW).

Embryonic and foetal expression patterns of the ciliopathy gene CEP164.

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited genetic disorders that share a defect in the formation, maintenance or functioning of the primary cilium complex, causing progressive cystic kidney disease and other clinical manifestations. Mutations in centrosomal protein 164 kDa (CEP164), also known as NPHP15, have been identified as a cause of NPHP-RC. Here we have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) to perform immunohistochemistry studies on human embryonic and foetal tissues to determine the expression patterns of CEP164 during development.

Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome.

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify (alias ) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a -deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of in the parental mouse strain phenocopied the severe cystic kidney phenotype.

New insights into the development of the human cerebral cortex.

The cerebral cortex constitutes more than half the volume of the human brain and is presumed to be responsible for the neuronal computations underlying complex phenomena, such as perception, thought, language, attention, episodic memory and voluntary movement. Rodent models are extremely valuable for the investigation of brain development, but cannot provide insight into aspects that are unique or highly derived in humans. Many human psychiatric and neurological conditions have developmental origins but cannot be studied adequately in animal models.

Expression of ventral telencephalon transcription factors ASCL1 and DLX2 in the early fetal human cerebral cortex.

In rodent ventral telencephalon, diffusible morphogens induce expression of the proneural transcription factor ASCL1, which in turn induces expression of the transcription factor DLX2 that controls differentiation of cortical interneuron precursors and their tangential migration to the cerebral cortex. RNAseq analysis of human fetal samples of dorsal telencephalon revealed consistently high cortical expression of ASCL1 and increasing expression of DLX2 between 7.5 and 17 post-conceptional weeks (PCW).

Thalamocortical Afferents Innervate the Cortical Subplate much Earlier in Development in Primate than in Rodent.

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.

Human neural stem cells dispersed in artificial ECM form cerebral organoids when grafted in vivo.

Human neural stem cells (hNSC) derived from induced pluripotent stem cells can be differentiated into neurons that could be used for transplantation to repair brain injury. In this study we dispersed such hNSC in a three-dimensional artificial extracellular matrix (aECM) and compared their differentiation in vitro and following grafting into the sensorimotor cortex (SMC) of postnatal day (P)14 rat pups lesioned by localised injection of endothelin-1 at P12. After 10-43 days of in vitro differentiation, a few cells remained as PAX6 neuroprogenitors but many more resembled post-mitotic neurons expressing doublecortin, β-tubulin and MAP2.