Neurons In Brain Research Articles

Rational fusion design inspired by cell-penetrating peptide: SS31/S-14 G Humanin hybrid peptide with amplified multimodal efficacy and bio-permeability for the treatment of Alzheimer's disease

Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14 G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Aβ affinity greatly inhibited Aβ oligomerization/fibrillation, and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ. In 3× Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.

Expansion of learning capacity elicited by interspecific hybridization.

Learned behavior, a fundamental adaptive trait in fluctuating environments, is shaped by species-specific constraints. This phenomenon is evident in songbirds, which acquire their species-specific songs through vocal learning. To explore the neurogenetic mechanisms underlying species-specific song learning, we generated F1 hybrid songbirds by crossing Taeniopygia guttata with Aidemosyne modesta. These F1 hybrids demonstrate expanded learning capacities, adeptly mimicking songs from both parental species and other heterospecific songs more extensively than their parental counterparts. Despite the conserved size of brain regions and neuron numbers in the neural circuits for song learning and production, single-cell transcriptomics reveals distinctive transcriptional characteristics in the F1 hybrids, especially in vocal-motor projection neurons. These neurons exhibit enrichment for nonadditively expressed genes, particularly those related to ion channel activity and cell adhesion, which are associated with the degree of song learning among F1 individuals. Our findings provide insights into the emergence of altered learning capabilities through hybridization, linked to cell type-specific transcriptional changes.

Pathomorphological parameters of sepsis-associated encephalopathy in deceased septic patients without purulent lesions to the brain

Sepsis-associated encephalopathy (SAE) clinically manifests by delirium and decreased consciousness less than 15 points on Glasgow Coma Scale. SAE pathophysiology includes neuroinflammation, ischemic-hypoxic and dysmetabolic mechanisms. Despite the high frequency and the important role in thanatogenesis, pathomorphological criteria of SAE remain to be defined. The aim of the study was to specify the key pathomorphological parameters of sepsis-associated encephalopathy in deceased septic patients without purulent lesions to the brain by defining the changes of neurogliovascular unit and the level of tissue ammonia. Material and methods. Using pathohistological, histochemical, and immunohistochemical methods we studied cerebral cortex and white matter, hippocampus, thalamus, and cerebellum of 35 deceased septic patients with SAE in comparison with the control group, which included 30 patients who died from acute cardiovascular failure without CNS pathology. Results. In SAE, small foci of encephalolysis due to thrombosis of microvessels, ischemic-hypoxic and apoptotic changes in neurons are associated with the following parameters that are reliably (p < 0.05) different from the control group: higher (up to 199.48 %) level of tissue ammonia and increased number (up to 316.07 %) of caspase-3+ apoptotic neurons in the cortex, hippocampus, thalamus, and cerebellum; in all studied brain regions, an increased expression level of astrocytic glial fibrillary acidic protein (up to 192.69 %), glutamine synthetase (up to 134.41 %) and aquaporin-4 (up to 400.8 %); significant (up to 947.01 %) expansion of perivascular and pericellular “edematous” spaces, increased (up to 479.58 %) immunopositive area of extravascular CD68+ microgliocytes and increased (up to 374.43 %) proportion of CD68+ ameboid microgliocytes, increased (up to 3.66 times) number of Alzheimer type 2 astrocytes in cerebral cortex, thalamus, and cerebellum; increased (up to 2 times) number of amyloid bodies in the thalamus and cerebellum. Conclusions. The obtained data indicate that the delirious state, loss of consciousness and other manifestations of SAE are associated with ischemic-hypoxic and ammonia-induced ischemic and apoptotic changes of the brain neurones; small foci of encephalolysis; adaptive remodeling and dystrophic changes of astrocytes; microglial reactiveness with increased proportion of phagocytic microgliocytes; brain edema and dysfunctional glymphatics.

Transcriptional pathobiology and multi-omics predictors for Parkinson's disease.

Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal p < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes IKBIP, CXCR2, and NFKBIB. Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction.

Development of Neuroscience-Based Biology Learning Media to Increase Learning Motivation and Cognitive Learning Outcomes of Tenggarong High School Students

Neuroscience-based learning is a field of neuroscience study that focuses on studying educational concepts from the perspective of the brain's working system. It turns out that teachers and parents still rarely pay attention to this field of study, which has led to the emergence of a learning atmosphere that is passive and not optimal in stimulating nerve cells in the human brain. The results of initial observations carried out on 22-28 April 2021 on high school teachers and students in Tenggarong (SMA Negeri 1 Tenggarong, SMA Negeri 2 Tenggarong, SMA Negeri 3 Tenggarong) showed that there were still many (85%) It was found that teachers still relied on verbal language, image/animation media, PowerPoint and only a few (15%) were varied in their use of biology learning media, although based on interviews they said they understood audio, visual and audiovisual media well enough. Likewise with learning with neuroscience-based media, from the interview results, generally (85%) were not familiar with biology learning with neuroscience-based media and only a few (15%) were familiar with and had implemented it in biology learning. The same thing applies to students' cognitive learning outcomes from interviews that I found that students' abilities were generally moderate and low. This is because students think that biology is a rote subject and are less motivated when learning. This research method is Research and Development (R&amp;D) Sivasailam Thiagarajan. The main objective of this development research method is to produce products and determine the feasibility of products developed in the form of neuroscience-based learning videos which are limited to the circulatory system. The research subjects included four validator experts, namely media experts, materials experts, language experts and learning tools experts. Class XI students as the research sample consisted of two classes, namely the control class and the experimental class. The results of the research show that the validity of learning media is in the valid category (79.95%), the practicality of learning media is in the very good category (83.37%), and also the effectiveness of neuroscience-based learning media in providing a high increase in learning motivation (Gain score = 0 .73) and t test analysis (t count &lt; 0.05) via the SPSS application.

Tubulin-binding region alters tau-lipid interactions and changes toxicity of tau fibrils formed in the presence of phosphatidylserine lipids.

Alzheimer's disease is the fastest-growing neurodegenerative disease that affects over six million Americans. The abnormal aggregation of amyloid β peptide and Tau protein is the expected molecular cause of the loss of neurons in brains of AD patients. A growing body of evidence indicates that lipids can alter the aggregation rate of amyloid β peptide and modify the toxicity of amyloid β aggregates. However, the role of lipids in Tau aggregation remains unclear. In this study, we utilized a set of biophysical methods to determine the extent to which phospatidylserine (PS) altered the aggregation properties of Tau isoforms with one (1N4R) and two (2N4R) N terminal inserts that enhance the binding of Tau to tubulin. We found that the length and saturation of fatty acids (FAs) in PS altered the aggregation rate of 2N4R isoform, while no changes in the aggregation rate of 1N4R were observed. These results indicate that N terminal inserts play an important role in protein-lipid interactions. We also found that PS could change the toxicity of 1N4R and 2N4R Tau fibrils, as well as alter molecular mechanisms by which these aggregates exert cytotoxicity to neurons. Finally, we found that although Tau fibrils formed in the presence and absence of PS endocytosed by cells, only fibril species that were formed in the presence of PS exert strong impairment of the cell mitochondria.

New Pharmacological Therapies in the Treatment of Epilepsy in the Pediatric Population.

Epilepsy is a disorder characterized by abnormal brain neuron activity, predisposing individuals to seizures. The International League Against Epilepsy (ILAE) categorizes epilepsy into the following groups: focal, generalized, generalized and focal, and unknown. Infants are the most vulnerable pediatric group to the condition, with the cause of epilepsy development being attributed to congenital brain developmental defects, white matter damage, intraventricular hemorrhage, perinatal hypoxic-ischemic injury, perinatal stroke, or genetic factors such as mutations in the Sodium Channel Protein Type 1 Subunit Alpha (SCN1A) gene. Due to the risks associated with this condition, we have investigated how the latest pharmacological treatments for epilepsy in children impact the reduction or complete elimination of seizures. We reviewed literature from 2018 to 2024, focusing on the age group from 1 month to 18 years old, with some studies including this age group as well as older individuals. The significance of this review is to present and compile research findings on the latest antiseizure drugs (ASDs), their effectiveness, dosing, and adverse effects in the pediatric population, which can contribute to selecting the best drug for a particular patient. The medications described in this review have shown significant efficacy and safety in the studied patient group, outweighing the observed adverse effects. The main aim of this review is to provide a comprehensive summary of the current state of knowledge regarding the newest pharmacotherapy for childhood epilepsy.

Establishment of the Diagnostic Signature of Ferroptosis Genes in Multiple Sclerosis.

Ferroptosis is a novel form of membrane-dependent cell death that differs from other cell death modalities such as necrosis, apoptosis, and autophagy. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system primarily affecting brain and spinal cord neurons. Although the pathogenesis of these two conditions may seem unrelated, recent studies have indicated a connection between ferroptosis and multiple sclerosis. In fact, ferroptosis plays a significant role in the development of MS, as evidenced by the presence of elevated iron levels and iron metabolism abnormalities in the brains, spinal cords, and other neurons of MS patients. These abnormalities disrupt iron homeostasis within cells, leading to the occurrence of ferroptosis. However, there is currently a lack of research on the diagnostic value of ferroptosis-related genes in multiple sclerosis. In this study, we employed bioinformatics methods to identify ferroptosis-related genes (ATM, GSK3B, HMGCR, KLF2, MAPK1, NFE2L1, NRAS, PCBP1, PIK3CA, RPL8, VDAC3) associated with the diagnosis of multiple sclerosis and constructed a diagnostic model. The results demonstrated that the diagnostic model accurately identified the patients' condition. Subsequently, subgroup analysis was performed based on the expression levels of ferroptosis-related genes, dividing patients into high and low expression groups. The results showed differences in immune function and immune cell infiltration between the two groups. Our study not only confirms the correlation between ferroptosis and multiple sclerosis but also demonstrates the diagnostic value of ferroptosis-related genes in the disease. This provides guidance for clinical practice and direction for further mechanistic research.

Exploration of Solving Methods and Applications of Neural Network Models in Optimization Problems

With the booming growth of artificial intelligence (AI) technology, machine learning (ML) as its core component has shown enormous potential and application value in solving optimization problems. Among numerous ML algorithms, neural networks (NN) have become one of the preferred tools for handling optimization problems due to their high flexibility and powerful learning ability. This article focuses on the application of NN in the field of image recognition, exploring its solution methods and application exploration. Image recognition, as an important branch in the field of AI, aims to recognize and understand information in images through computer algorithms. NN can automatically learn features in images and construct complex classification models by simulating the connections and working modes of human brain neurons. By applying the NN model, the performance of the image recognition system has been significantly improved. NN can accurately recognize objects, scenes, and text information in images, providing strong technical support for fields such as intelligent security, autonomous driving, and medical diagnosis. With the continuous progress of technology and the expansion of application scenarios, NN will play an important role in more fields, promoting the rapid growth of AI technology.

Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins.

Recent advances in neuroscience tools for single-cell molecular profiling of brain neurons have revealed an enormous spectrum of neuronal subpopulations within the neuroendocrine hypothalamus, highlighting the remarkable molecular and cellular heterogeneity of this brain area. Neuronal diversity in the hypothalamus reflects the high functional plasticity of this brain area, where multiple neuronal populations flexibly integrate a variety of physiological outputs, including energy balance, stress and fertility, through crosstalk mechanisms with peripheral hormones. Intrinsic functional heterogeneity is also observed within classically 'defined' subpopulations of neuroendocrine neurons, including subtypes with distinct neurochemical signatures, spatial organisation and responsiveness to hormonal cues. The aim of this review is to critically evaluate past and current research on the functional diversity of hypothalamic neuroendocrine neurons and their plasticity. It focuses on how this neuronal plasticity in this brain area relates to metabolic control, feeding regulation and interactions with stress and fertility-related neural circuits. Our analysis provides an original framework for improving our understanding of the hypothalamic regulation of hormone function and the development of neuroendocrine diseases.

Deafness causing neuroplastin missense variants fail to promote plasma membrane Ca2+-ATPase levels and Ca2+ transient regulation in brain neurons

Hearing, the ability to sense sounds, and the processing of auditory information are important for perception of the world. Mice lacking expression of neuroplastin (Np), a type-1 transmembrane glycoprotein, display deafness, multiple cognitive deficiencies, and reduced expression of plasma membrane calcium (Ca2+) ATPases (PMCAs) in cochlear hair cells and brain neurons. In this study, we transferred the deafness causing missense mutations pitch (C315S) and audio-1 (I122N) into human Np (hNp) constructs and investigated their effects at the molecular and cellular level. Computational molecular dynamics show that loss of the disulfide bridge in hNppitch causes structural destabilization of immunoglobulin-like domain (Ig) III and that the novel asparagine in hNpaudio-1 results in steric constraints and an additional N-glycosylation site in IgII. Additional N-glycosylation of hNpaudio-1 was confirmed by PNGaseF treatment. In comparison to hNpWT, transfection of hNppitch and hNpaudio-1 into HEK293T cells resulted in normal mRNA levels but reduced the Np protein levels and their cell surface expression due to proteasomal/lysosomal degradation. Furthermore, hNppitch and hNpaudio-1 failed to promote exogenous PMCA levels in HEK293T cells. In hippocampal neurons, expression of additional hNppitch or hNpaudio-1 was less efficient than hNpWT to elevate endogenous PMCA levels and to accelerate the restoration of basal Ca2+ levels after electrically-evoked Ca2+ transients. We propose that mutations leading to pathological Np variants, as exemplified here by the deafness causing Np mutants, can affect Np-dependent Ca2+ regulatory mechanisms and may potentially cause intellectual and cognitive deficits in humans.

Robust variability of grid cell properties within individual grid modules enhances encoding of local space.

Although grid cells are one of the most well studied functional classes of neurons in the mammalian brain, the assumption that there is a single grid orientation and spacing per grid module has not been carefully tested. We investigate and analyze a recent large-scale recording of medial entorhinal cortex to characterize the presence and degree of heterogeneity of grid properties within individual modules. We find evidence for small, but robust, variability and hypothesize that this property of the grid code could enhance the ability of encoding local spatial information. Performing analysis on synthetic populations of grid cells, where we have complete control over the amount heterogeneity in grid properties, we demonstrate that variability, of a similar magnitude to the analyzed data, leads to significantly decreased decoding error, even when restricted to activity from a single module. Our results highlight how the heterogeneity of the neural response properties may benefit coding and opens new directions for theoretical and experimental analysis of grid cells.

Age-dependent increase of perineuronal nets in the human hippocampus and precocious aging in epilepsy.

Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age-dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age-matched post-mortem control subjects and to compare PNN-related changes with memory impairment observed in our patient cohort. Sixty-six formalin-fixed and paraffin-embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty-nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age-matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p < 0.05). Our results were compatible with age-dependent ECM specialization in the human hippocampus and its precocious aging in the epileptic condition. These observations confirm recent experimental animal models and also support the notion that PNN play a role in memory formation in the human brain. "Perineuronal nets" (PNN) are a specialized compartment of the extracellular matrix (ECM), especially surrounding highly active neurons of the mammalian brain. There is evidence that PNN play a role in memory formation, brain maturation, and in some pathologies like Alzheimer's disease, schizophrenia or epilepsy. In this study, we investigated the role of PNN in patients suffering from drug-resistant focal epilepsy compared to controls. We found that with increasing age, more neurons are surrounded by PNN. Similarly, all epilepsy patients but especially patients with better memory performance also had more PNN. This study raises further interest in studying ECM molecules in the human brain under physiological and pathophysiological conditions.

Investigation of Resistance Switching and Synaptic Properties of VO x for Neuromorphic Applications.

The taking run on artificial intelligence in the last decades is based on the von Neumann architecture where memory and computation units are separately located from each other. This configuration causes a large amount of energy and time to be dissipated during data transfer between these two units, in contrast to synapses in biological neurons. A new paradigm has been proposed inspired by biological neurons in human brains, known as neuromorphic computing. Due to the unusual current-voltage characteristic of memristor devices such as pinched hysteresis loops, memristors are considered a key element of neuromorphic architecture. In this study, we report the basic current-voltage characteristic of the memristor devices in the form of Si/SiO2/Pt(30 nm)/VO x (3, 13, 25 nm)/Pt (30 nm) sandwich structure. Synaptic functions such as spike-time-dependent plasticity (STDP), paired-pulse facilitation (PPF), long-term potentiation (LTP), and long-term depression (LTD) of memristor devices were examined in detail. The oxide layer VO x has been grown by using the VO2 target in a pulsed laser deposition (PLD) chamber. The composition and oxidation states of the oxide layer were examined using the X-ray photoelectron spectroscopy (XPS) technique. The status of oxygen vacancies, which play an active role in the operation of the devices, was examined with a photoluminescence (PL) technique. The experimental results showed that the thickness of the oxide layer can significantly influence the synaptic and resistive switching properties of the devices.

Involvement of Endolysosomes and Aurora Kinase A in the Regulation of Amyloid β Protein Levels in Neurons.

Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer's disease (AD) brain samples, but little is known about the role of AURKA in AD pathogenesis. Here, we demonstrate that AURKA is expressed in primary cultured rat neurons, neurons from adult mouse brains, and neurons in postmortem human AD brains. AURKA phosphorylation, which positively correlates with its activity, is reduced in human AD brains. In SH-SY5Y cells, pharmacological activation of AURKA increased AURKA phosphorylation, acidified endolysosomes, decreased the activity of amyloid beta protein (Aβ) generating enzyme β-site amyloid precursor protein cleaving enzyme (BACE-1), increased the activity of the Aβ degrading enzyme cathepsin D, and decreased the intracellular and secreted levels of Aβ. Conversely, pharmacological inhibition of AURKA decreased AURKA phosphorylation, de-acidified endolysosomes, decreased the activity of cathepsin D, and increased intracellular and secreted levels of Aβ. Thus, reduced AURKA activity in AD may contribute to the development of intraneuronal accumulations of Aβ and extracellular amyloid plaque formation.

An Update on Parkinson's Disease and its Neurodegenerative Counterparts.

Neurodegenerative disorders are a group of diseases that cause nerve cell degeneration in the brain, resulting in a variety of symptoms and are not treatable with drugs. Parkinson's disease (PD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinal cerebral dyskinesia (SCA), spinal muscle atrophy (SMA), multiple system atrophy, Alzheimer's disease (AD), spinocerebellar ataxia (SCA) (ALS), pantothenate kinase-related neurodegeneration, and TDP-43 protein disorder are examples of neurodegenerative diseases. Dementia is caused by the loss of brain and spinal cord nerve cells in neurodegenerative diseases. Even though environmental and genetic predispositions have also been involved in the process, redox metal abuse plays a crucial role in neurodegeneration since the preponderance of symptoms originates from abnormal metal metabolism. Hence, this review investigates several neurodegenerative diseases that may occur symptoms similar to Parkinson's disease to understand the differences and similarities between Parkinson's disease and other neurodegenerative disorders based on reviewing previously published papers. Based on the findings, the aggregation of alpha-synuclein occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Other neurodegenerative diseases occur with different protein aggregation or mutations. We can conclude that Parkinson's disease, Multiple system atrophy, and Dementia with Lewy bodies are closely related. Therefore, researchers must distinguish among the three diseases to avoid misdiagnosis of Multiple System Atrophy and Dementia with Lewy bodies with Parkinson's disease symptoms.

PROJECT PROPOSAL: REJUVENATION OF BRAIN NEURONS USING QUANTUM ENTANGLEMENT IN NUCLEOTIDES AND CRYPTOCHROMES

In this paper, we propose a novel and futuristic theoretical framework aimed at rejuvenating and repairing human brain neurons through the application of quantum entanglement. We hypothesize that by inducing atomic entanglement in nucleotides and photonic entanglement in cryptochromes, and subsequently reinjecting these entangled particles into brain neurons, we can exploit the unique properties of quantum entanglement to enhance neuronal repair and regeneration. Our study delves into the underlying quantum mechanisms, presents detailed mathematical formulations, and outlines comprehensive experimental protocols for achieving neuronal rejuvenation. Additionally, we explore the potential amplification of these effects by exposing entangled particles to the space environment, leveraging factors such as microgravity, cosmic radiation, vacuum conditions, temperature extremes, and electromagnetic isolation. This approach is specifically tailored for brain neurons, as other cells in the body do not process and transmit information in a manner that would benefit from quantum entanglement. Furthermore, we discuss the potential application of this method in treating blindness and neurodegenerative diseases such as Alzheimers disease.

CRISPR knockout of HRE sequences in the C9orf72 gene to treat ALS, FTD, and HDL2

Amyotrophic lateral sclerosis (ALS), familial frontotemporal dementia (FTD), and phenotypic Huntington syndrome-like disease (HDL2) have in common multiple hexanucleotide repeat expansions (HREs), in the C9orf72 gene. The C9orf72 protein aids in sending and receiving signals in multiple neurons. The C9orf72 protein is found primarily expressed in the brain and specific neurons, especially in the cerebral cortex. In ALS, FTD, and HDL2, the gene has a repeat sequence GGGGCC that is found in many patients with familial neurodegenerative conditions, resulting in the loss of function of many patients' motor neurons. The repeat sequence causes reduced production of the C9orf72 protein, called haploinsufficiency, and simultaneously a gain-of-function mutation by producing toxic dipeptide proteins, and excess RNA foci (RNA toxicity) in the brain. Different gene editing techniques in vitro and in vivo have shown the successful knockout of genes in the brain as well as on the C9orf72 gene and the connection to ALS, FTD, and Huntington-like syndrome in mice. CRISPR is a gene-editing tool used to target HREs. This review will focus on knocking down/out the HREs of the C9orf72 gene using various delivery strategies. Targeting the C9orf72 gene HREs, it would be expected that a decrease in protein aggregations that affect motor neurons, be able to prevent protein haploinsufficiency and prevent RNA toxicity, which are the main factors of these three neurodegenerative diseases. Using gene editing, treatment may be possible for patients with familial ALS, FTD, and HDL2 with the HRE sequences in the C9orf72 gene.

Neuronal autosis is Na+/K+-ATPase alpha 3-dependent and involved in hypoxic-ischemic neuronal death

Macroautophagy (hereafter called autophagy) is an essential physiological process of degradation of organelles and long-lived proteins. The discovery of autosis, a Na+/K+-ATPase (ATP1)-dependent type of autophagic cell death with specific morphological and biochemical features, has strongly contributed to the acceptance of a pro-death role of autophagy. However, the occurrence and relevance of autosis in neurons has never been clearly investigated, whereas we previously provided evidence that autophagy mechanisms could be involved in neuronal death in different in vitro and in vivo rodent models of hypoxia-ischemia (HI) and that morphological features of autosis were observed in dying neurons following rat perinatal cerebral HI. In the present study, we demonstrated that neuronal autosis could occur in primary cortical neurons using two different stimulations enhancing autophagy flux and neuronal death: a neurotoxic concentration of Tat-BECN1 (an autophagy-inducing peptide) and a hypoxic/excitotoxic stimulus (mimicking neuronal death induced by cerebral HI). Both stimulations induce autophagic neuronal death (dependent on canonical autophagic genes and independent on apoptotic, necroptotic or ferroptotic pathways) with all morphological and biochemical (ATP1a-dependent) features of autosis. However, we demonstrated that autosis is not dependent on the ubiquitous subunit ATP1a1 in neurons, as in dividing cell types, but on the neuronal specific ATP1a3 subunit. We also provided evidence that, in different in vitro and in vivo models where autosis is induced, ATP1a3-BECN1 interaction is increased and prevented by cardiac glycosides treatment. Interestingly, an increase in ATP1a3-BECN1 interaction is also detected in dying neurons in the autoptic brains of human newborns with severe hypoxic-ischemic encephalopathy (HIE). Altogether, these results suggest that ATP1a3-BECN1-dependent autosis could play an important role in neuronal death in HI conditions, paving the way for the development of new neuroprotective strategies in hypoxic-ischemic conditions including in severe case of human HIE.

Compensatory enhancement of input maintains aversive dopaminergic reinforcement in hungry Drosophila

Hungry animals need compensatory mechanisms to maintain flexible brain function, while modulation reconfigures circuits to prioritize resource seeking. In Drosophila, hunger inhibits aversively reinforcing dopaminergic neurons (DANs) to permit the expression of food-seeking memories. Multitasking the reinforcement system for motivation potentially undermines aversive learning. We find that chronic hunger mildly enhances aversive learning and that satiated-baseline and hunger-enhanced learning require endocrine adipokinetic hormone (AKH) signaling. Circulating AKH influences aversive learning via its receptor in four neurons in the ventral brain, two of which are octopaminergic. Connectomics revealed AKH receptor-expressing neurons to be upstream of several classes of ascending neurons, many of which are presynaptic to aversively reinforcing DANs. Octopaminergic modulation of and output from at least one of these ascending pathways is required for shock- and bitter-taste-reinforced aversive learning. We propose that coordinated enhancement of input compensates for hunger-directed inhibition of aversive DANs to preserve reinforcement when required.