Cannabidiol (CBD) improves survival and behavioural comorbidities of Dravet syndrome in mice

Background and Purpose Dravet syndrome is a severe, genetic form of paediatric epilepsy associated with premature mortality and comorbidities such as anxiety, depression, autism, motor dysfunction, and memory deficits. Cannabidiol is an approved anticonvulsive drug in USA and Europe for seizures associated with Dravet syndrome therapy in patients 2 years of age and older; we investigated its potential to prevent premature mortality and improve associated comorbidities. Experimental Approach The efficacy of sub-chronic cannabidiol administration in two mouse models which reproduce characteristics of Dravet syndrome was investigated. The effect of cannabidiol on neonatal welfare and survival was studied using Scn1a-/- mice. We then used a hybrid, heterozygote Scn1a+/- mouse model to study the effect of cannabidiol on survival and behavioural comorbidities; motor deficits (rotarod and static-beam test), gait abnormality (gait test), social anxiety (social interaction test), anxiety-like (elevated plus maze) and depressive-like behaviours (sucrose preference test) and cognitive impairment (radial arm maze test). Key Results In Scn1a-/- mice, cannabidiol increased survival and delayed worsening of neonatal welfare. In Scn1a+/- mice chronic cannabidiol administration did not show any adverse effect on motor function and gait, reduced premature mortality, improved social behaviour and memory function, and reduced anxiety-like and depressive-like behaviours. Conclusion and Implications We are the first to demonstrate a potential disease-modifying effect of cannabidiol in animal models of Dravet syndrome. cannabidiol treatment reduced premature mortality and improved several behavioural comorbidities in Dravet syndrome mice. These crucial findings may be translated into human therapy to address behavioural comorbidities associated with Dravet syndrome

Dynamic expression of the mouse orthologue of the human amyotropic lateral sclerosis associated gene <i>C9orf72</i> during central nervous system development and neuronal differentiation

The hexanucleotide repeat in the first intron of the C9orf72 gene is the most significant cause of amyotropic lateral sclerosis as well as some forms of fronto‐temporal dementia. The C9orf72 protein has been previously reported to be expressed in post‐mortem human brain as well as in late embryonic and some postnatal stages in mice. Herein, we present a detailed study of the distribution of C9orf72 protein in the embryonic, postnatal and adult mouse brain, spinal cord as well as during the differentiation of P19 embryonal carcinoma cells to neurons including motor neurons. We show that the expression levels of the C9orf72 transcripts in the developing and adult mouse brain as well as in differentiating neurons, are dynamic. Besides the strong expression in the cerebellum and motor cortex reported previously, we show for the first time that C9orf72 is expressed strongly in the olfactory bulb and also in the hippocampus. Our immunostaining data also reveal a hitherto unreported switch in the cellular distribution of C9orf72 from a predominantly cytoplasmic to a nucleo‐cytoplasmic distribution during corticogenesis. This switch in distribution was also observed during differentiation of the pluripotent embryonal carcinoma P19 cell line to mature neurons. Our findings have implications for interpreting the pathophysiology caused by the repeat expansions in C9orf72 in mouse models

Dynamic expression of the mouse orthologue of the human amyotropic lateral sclerosis associated gene <i>C9orf72</i> during central nervous system development and neuronal differentiation

The hexanucleotide repeat in the first intron of the C9orf72 gene is the most significant cause of amyotropic lateral sclerosis as well as some forms of fronto-temporal dementia. The C9orf72 protein has been previously reported to be expressed in post-mortem human brain as well as in late embryonic and some postnatal stages in mice. Herein, we present a detailed study of the distribution of C9orf72 protein in the embryonic, postnatal and adult mouse brain, spinal cord as well as during the differentiation of P19 embryonal carcinoma cells to neurons including motor neurons. We show that the expression levels of the C9orf72 transcripts in the developing and adult mouse brain as well as in differentiating neurons, are dynamic. Besides the strong expression in the cerebellum and motor cortex reported previously, we show for the first time that C9orf72 is expressed strongly in the olfactory bulb and also in the hippocampus. Our immunostaining data also reveal a hitherto unreported switch in the cellular distribution of C9orf72 from a predominantly cytoplasmic to a nucleo-cytoplasmic distribution during corticogenesis. This switch in distribution was also observed during differentiation of the pluripotent embryonal carcinoma P19 cell line to mature neurons. Our findings have implications for interpreting the pathophysiology caused by the repeat expansions in C9orf72 in mouse models.</p

Determination and biological activity of active fatty acids in foods (with special emphasis in dairy products) as well as their importance and role in human health

The aim of the present thesis was to study Conjugate linoleic Acid (Conjugated Linoleic Acid- CLA) and all other fatty acids of traditional Greek yogurts and of the popular Greek Feta cheese during various stages of its preparation. CLA is a mixture of geometric and positional isomers of linoleic acid (Linoleic Acid-LA) with conjugated double bonds, which in recent decades has been studied by many researchers because of its potential health benefits, which mainly concern the inhibition of carcinogenesis and tumourigenesis, body fat content reduction and improvement of plasma cholesterol and triacylglycerol metabolism. Firstly, the research has been focused on the fatty acid and CLA content determination, as well as the chemical characteristics of various traditional yogurts from different milk and geographical origins of Greece that are commercially available in the Greek market. After that, traditional Greek yogurts were manufactured in the laboratory from cow and sheep milk in order to determine whether the 14 - day storage time at 5 oC affects their overall chemical and fatty acid composition, and especially the CLA concentration. Besides yogurts, the most popular Greek cheese (Feta Cheese) was studied during the first stages of manufacturing, but also during the ripening and aging process in order to determine the way they affect the fatty acid and especially the CLA content. Finally, in an effort to reduce the time required for determining the fatty acids in milk products, a direct method was applied to various dairy products for the determination of fatty acids without prior lipid extraction and was compared to a conventional one that involved lipid extraction followed by transesterification.Σκοπός της διατριβής ήταν η μελέτη του Συζυγούς Λινελαϊκού Οξέος (Conjugated Linoleic Acid - CLA) αλλά και όλων των υπόλοιπων λιπαρών οξέων σε ελληνικά παραδοσιακά γιούρτια καθώς και στο δημοφιλές ελληνικό τυρί Φέτα κατά τα διάφορα στάδια της παρασκευής αυτού. Το CLA είναι ένα μίγμα γεωμετρικών ισομερών και ισομερών θέσεως του Λινελαϊκού Οξέος (Linoleic Acid-LA) με συζυγείς διπλούς δεσμούς, το οποίο τις τελευταίες δεκαετίες μελετήθηκε από πολλούς ερευνητές λόγω των ευεργετικών επιδράσεων για την υγεία που φαίνεται να εμφανίζει. Αυτές αφορούν κυρίως την αναστολή της καρκινογένεσης και της δημιουργίας όγκων, τη μείωση του σωματικού λίπους και τη βελτίωση του μεταβολισμού της χοληστερόλης του πλάσματος και των τριακυλογλυκερολών. Αρχικά, προσδιορίστηκαν τα λιπαρά οξέα, το CLA και τα χημικά χαρακτηριστικά διαφόρων παραδοσιακών γιαουρτιών που παράγονται από διαφορετικό είδος γάλακτος, προερχόμενο από διάφορες γεωγραφικές περιοχές της Ελλάδας, και διατίθενται στην ελληνική αγορά. Στη συνέχεια, παρασκευάστηκαν στο εργαστήριο παραδοσιακά γιαούρτια από αγελαδινό και πρόβειο γάλα προκειμένου να διερευνηθεί αν η διάρκεια συντήρησης υπό ψύξη (5 οC / 14 ημέρες) επηρεάζει τη χημική τους σύσταση, τη σύνθεση των λιπαρών οξέων, και ιδίως τη συγκέντρωση του CLA. Σε μία τρίτη φάση, μελετήθηκε το πιο δημοφιλές ελληνικό τυρί (η Φέτα) κατά τη διάρκεια των πρώτων σταδίων της παραγωγής, της ωρίμανσης και της παλαίωσης, προκειμένου να προσδιοριστεί το πώς οι διάφορες αυτές φάσεις επηρεάζουν τη συγκέντρωση των λιπαρών οξέων και κυρίως το περιεχόμενο CLA. Τέλος, σε μια προσπάθεια να μειωθεί ο απαιτούμενος χρόνος προσδιορισμού των λιπαρών οξέων σε γαλακτοκομικά προϊόντα, εφαρμόστηκε μια απευθείας μέθοδος για τον προσδιορισμό των λιπαρών οξέων, η οποία δεν απαιτεί προηγούμενη εκχύλιση του λίπους, και συγκρίθηκε με μια συμβατική μέθοδο η οποία περιελάμβανε εκχύλιση του λίπους και στη συνέχεια μετεστεροποίησή του σε διάφορα γαλακτοκομικά προϊόντα

The potential contribution of bloggers to change lifestyle and reduce plastic use and pollution: A small data approach

Awareness raising and public engagement are key steps towards the reduction of demand, use and pollution related to plastic in everyday life. However, people not already active in this respect, nor seeking information about, may remain excluded from the main information flow. We therefore involved a professional blogger-posting on family lifestyle and travel with children- in the preparation of six thematic posts, each one dealing with a specific plastic-related topic. Given the size and the target of the initiative, results were considered in a small data approach: social-media parameters such as reaches and engagements overall aligned with blog followers' expected response in terms of engagement rates. However, high fluctuations were recorded, depending on the post topic. Such potential to reach blog readers and to highlight gaps at fine scale is encouraging the collaborations of professional bloggers with thematic campaigns, developed together with specialists of the topics considered

Heterogeneous progenitor cell behaviors underlie the assembly of neocortical cytoarchitecture

The cerebral cortex contains multiple hierarchically organized areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have quantitatively investigated the neuronal output of individual progenitor cells in the ventricular zone of the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. We found that individual cortical progenitor cells show a high degree of stochasticity and generate pyramidal cell lineages that adopt a wide range of laminar configurations. Mathematical modelling these lineage data suggests that a small number of progenitor cell populations, each generating pyramidal cells following different stochastic developmental programs, suffice to generate the heterogenous complement of pyramidal cell lineages that collectively build the complex cytoarchitecture of the neocortex

Dataset for "Input-specific control of interneuron numbers in nascent striatal networks" by Sreenivasan et al., 2022

This dataset contains raw imaging data along with the MATLAB analysis files for all animals that were analysed in Figures 1 to 5 of the original publication

Input-specific control of interneuron numbers in nascent striatal networks

The assembly of functional neuronal circuits requires appropriate numbers of distinct classes of neurons, but the mechanisms through which their relative proportions are established remain poorly defined. Investigating the mouse striatum, we found that the two most prominent subtypes of striatal interneurons, parvalbumin-expressing (PV+) GABAergic and cholinergic (ChAT+) interneurons, undergo extensive programmed cell death between the first and second postnatal weeks. Remarkably, the survival of PV+ and ChAT+ interneurons is regulated by distinct mechanisms mediated by their specific afferent connectivity. While long-range cortical inputs control PV+ interneuron survival, ChAT+ interneuron survival is regulated by local input from the medium spiny neurons. Our results identify input-specific circuit mechanisms that operate during the period of programmed cell death to establish the final number of interneurons in nascent striatal networks.</p