Nanomagnetism and spintronics are currently active areas of research, with one of the main goals being the creation of low-energy-consuming magnetic memories based on nanomagnet switching. These types of devices could also be implemented in neuromorphic computing by crafting artificial neurons (ANs) that emulate the characteristics of biological neurons, through the implementation of neuron models such as the widely used leaky integrate-and-fire (LIF) with a refractory period. In this study, we have carried out numerical simulations of a 120 nm diameter, 250 nm length ferromagnetic nanowire (NW) with the aim of exploring the design of an artificial neuron based on the creation and destruction of a Bloch-point domain wall. To replicate signal integration, we applied pulsed trains of spin-currents to the opposite faces of the ferromagnetic NW. These pulsed currents (previously studied only in the continuous form) are responsible for inducing transitions between the stable single vortex (SV) state to the metastable Bloch point domain wall (BP-DW) state. To ensure the system exhibits the leak and refractory properties, the NW was placed in an homogeneous magnetic field of the order of mT in the axial direction. The suggested configuration fulfills the requirements and characteristics of a biological neuron, potentially leading to the future creation of Artificial Neural Networks (ANNs) based on reversible changes in the topology of magnetic NWs.

The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres or as organoids are valuable to understand both neuronal and glial compartments which have contributed to reveal roles and mechanisms of transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well the recent transcriptome at the single cell level at different stages of development also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions.

Introduction: The primary objective of researchers in the biology of ageing is to gain a comprehensive understanding of the ageing process while developing practical solutions that can enhance the quality of life for older individuals. This involves a continuous effort to bridge the gap between fundamental biological research and its real-world applications. Purpose: In this narrative review, we attempt to link research findings concerning the hormetic relationship between neurons and germ cells, and translate these findings into clinically relevant concepts. Methods: We conducted a literature search using PubMed, Embase, PLOS, Digital Commons Network, Google Scholar and Cochrane Library from 2000 to 2023, analyzing studies dealing with the relationship between hormetic, cognitive, and reproductive aspects of human ageing. Results: The process of hormesis serves as a bridge between the biology of neuron-germ cell interactions on one hand, and the clinical relevance of these interactions on the other. Details concerning these processes are discussed here, emphasizing new research which strengthens the overall concept. Conclusions: This review presents a scientifically and clinically relevant argument, claiming that maintaining a cognitively active lifestyle may decrease age-related degeneration, and improve overall health in ageing.

Brain aging causes a wide variety of changes at molecular and cellular levels, leading to the decline of cognitive functions and increased vulnerability to neurodegenerative disorders. The research aimed at understanding the aging of the brain has made much progress in recent decades. Technological innovations such as single-cell RNA-sequencing (scRNA-seq), proteomic analyses, and spatial transcriptomic analyses have facilitated the research on the dynamic changes occurring within neurons, glia, and other cells along with their impacts on intercellular communication during aging. In this review, we introduce recent trends of how neurons and glia change during aging and discuss the impact of the brain microenvironment such as the blood-brain barrier (BBB).

The circadian clock is a 24-hour cycle within the body that regulates various factors, including sleep, body temperature, and hormone secretion. It allows the body to adjust to the light and dark cycle. Disruptions to the circadian rhythm are important risk factors for many diseases, including neurodegenerative illnesses. The central clock is controlled by the clock genes in the suprachiasmatic nucleus (SCN) of the brain, and one of the main functions of the circadian clock is to regulate lipid metabolism. There has been a lack of investigation on the circadian regulation of lipid metabolism-related apolipoprotein genes in the brain; thus, this study sought to summarize the rhythmic expression of clock genes and lipid metabolism-related apolipoprotein genes within the SCN of Mus musculus. Out of the 20 apolipoprotein genes that were studied by the published database, all 9 genes were highly expressed in the SCN. Most of the 6 genes showed rhythmic expression in the brain of mice, suggesting that the master clock might regulate them. The results, therefore, reveal a potential target for preventing and treating circadian disorders. We summarized most studies of lipid-related apolipoprotein genes within limited locations of the SCN and brain to further understand how disordered cerebral lipid metabolism causes multiple brain diseases and disorders. We reviewed recent studies, determined the unexplored questions, and identified a potential direction for further research.

In bilaterians organism, the signaling of pyramidal neurons (PyrNs) is linked to the relative (prevalent) molecular chirality and physiological, perceptual, cognitive, and psychological functions and dysfunctions, providing the coupling of the central nervous system downstream and upstream evolutionary and developmental processes. The most apparent and discriminating morphological specificity of PyrNs is the geometry of the cell body. However, the question "why/how PyrNs soma gains the shape of quasi-tetrahedral symmetry" has never been explicitly articulated. If the basic function of PyrNs is sensory space perception, supporting the orientation, and movement coordination, then the pyramidal shape of soma is the best evolutionary-selected geometry to perform sensory-motor coupling. In biology, the impact of chiral symmetry (handedness) is evident at all levels of biological organization, from the prevalent symmetry of biological molecules to the morphology and function of bilateral organisms. How the tetrahedral symmetry of biomolecules is linked to the morphology and functions of bilateral organisms remains a challenging question. Cell chirality represents an intermediate point connecting two poles of biochirality. In this holistic perspective, examining the PyrNs' morphology-circuitry-function link is crucial to understanding the complex interaction between genetic, epigenetic, and environmental factors in the evolution of the CNS. The predictive power of our hypothesis can be partially expressed by the statement that the most integral and reliable biomarker of the neurodegenerative (including aging) and mental (including all variants of psychiatric illness) disorders would be the detection of the hemispheric asymmetry of D-amino acids (D-AAs) level in pyramidal neurons (PyrNs).

In recent years, artificial neural networks (ANNs) have won numerous contests in pattern recognition, machine learning, and artificial intelligence. The basic unit of an ANN is to mimic neurons in the brain. Neuron in ANNs is expressed as f (wx+b) or f (wx). This structure does not consider the information processing capabilities of dendrites. However, recently, studies shown that dendrites participate in pre-calculation in the brain. Concretely, biological dendrites play a role in the pre-processing to the interaction information of input data. Therefore, it is time to perfect the neuron of the neural network. This paper, add dendrite processing section, presents a novel artificial neuron, according to our previous studies (CR-PNN or Gang transform). The dendrite processing section can be expressed as . Because I perfected the basic unit of ANNs— neuron, there are so many networks to try. This article gives the basic architecture for reference in future research.

The highly specialized structure and function of neurons depend on a sophisticated organization of the cytoskeleton, which supports a similarly sophisticated system to traffic organelles and cargo vesicles. Mitochondria sustain crucial functions by providing energy and buffering calcium where is needed. Accordingly, the distribution of mitochondria is not even in neurons and is regulated by a dynamic balance between active transport and stable docking events. This system is finely tuned to respond to changes in environmental conditions and neuronal activity. In this review, we summarize the mechanisms by which mitochondria are selectively transported in different compartments taking into account the structure of the cytoskeleton, the molecular motors and the metabolism of neurons. Remarkably, the motor proteins driving the mitochondrial transport in axons have been shown to mediate also their transfer between cells. This so-named intercellular transport of mitochondria is opening new exciting perspectives in the treatment of multiple diseases.

Growing evidence suggests a possible involvement of the intestinal microbiota in generating new neurons, but a detailed breakdown of the microbiota composition is lacking. In this report, we systematically reviewed preclinical rodent reports addressing the connection between the composition of the intestinal microbiota and neurogenesis and neurogenesis-affecting neurotrophins in the hippocampus. Various changes in bacterial composition from low taxonomic resolution at the phylum level to high taxonomic resolution at the species level were identified. As for neurogenesis, studies predominantly used doublecortin (DCX) as a marker of newly formed neurons or bromodeoxyuridine (BrdU) as a marker of proliferation. Brain-derived neurotrophic factor (BDNF) was the only neurotrophin found researched in relation to the intestinal microbiota. Phylum Actinobacteria, genus Bifidobacterium and genus Lactobacillus found the strongest positive while phylum Firmicutes, phylum Bacteroidetes and family Enterobacteriaceae as well as germ-free status, showed the strongest negative correlation towards neurogenesis or BDNF mRNA expression. Age, short-chain fatty acids (SCFA), obesity and chronic stress were recurring topics in all studies identified. Overall, these findings add to the existing evidence of a connection between microbiota and processes in the brain. To better understand this interaction, further investigation based on analyses of higher taxonomic resolution and clinical studies would be a gain to the matter.

The most common and taught membrane theory assumes that the membrane behaves as a kind of electrical capacitance that is exposed to an electrical current generated by an ionic flow. If this statement is verifiable, it can be confirmed by the laws of physics, mathematics and in particular electricity. We will demonstrate that this hypothesis is not verified and that it is necessary to modify biophysics according to already established and experimentally verified principles of physics.

Chronic pain has increasingly become a significant health challenge, not just as a symptomatic manifestation but also as a pathological condition with profound socioeconomic implications. Despite the expansion of medical interventions, the prevalence of chronic pain remains remarkably persistent, prompting a turn towards non-pharmacological treatments, such as therapeutic education, exercise and cognitive-behavioral therapy. With the advent of cognitive neuroscience, pain is often presented as a primary output derived from the brain, aligning with Engel's Biopsychosocial Model which views disease not solely from a biological perspective but also considering psychological and social factors. This paradigm shift, brings forward potential misconceptions and over-simplifications. The current review delves into the intricacies of nociception and pain perception. It questions long-standing beliefs like the cerebral-centric view of pain, the forgotten role of the peripheral nervous system in pain chronification, misconceptions around central sensitization syndromes, the controversy about the existence of a dedicated pain neuromatrix, the consciousness of the pain experience and the possible oversight of factors beyond the nervous system. In re-evaluating these aspects, the review emphasizes the critical need for understanding the complexity of pain, urging the scientific and clinical community to move beyond reductionist perspectives and consider the multifaceted nature of this phenomenon.

Nervous systems evolved around 560 million years ago to coordinate and empower animal bodies. Ctenophores – one of the earliest-branching lineages – are thought to share few neuronal genes with bilaterians and may have evolved neurons convergently. Here we review our current understanding of the evolution of neuronal molecules in non-bilaterians. We also reanalyse single-cell sequencing data in light of new cell-cluster identities from a ctenophore and uncover evidence supporting the homology of one ctenophore neuron-type with neurons in Bilateria. The specific coexpression of the presynaptic proteins Unc13 and RIM with voltage-gated channels, neuropeptides and homeobox genes pinpoint a spiking sensory-peptidergic cell in the ctenophore mouth. Similar Unc13-RIM neurons may have been present in the first eumetazoans to rise to dominance only in stem Bilateria. We hypothesize that the Unc13-RIM lineage ancestrally innervated the mouth and conquered other parts of the body with the rise of macrophagy and predation during the Cambrian explosion.

Cisplatin induces early-onset ototoxicity, resulting in hearing loss. The exact mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase(RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in animal models. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were was measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H-E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. H-E stains outlined necroptotic changes in the organ of Cortis (OCs) and spiral ganglion neurons (SGNs). Additionally, immunohistochemistry and western blot analysis showed overexpression of RIP3 in the OCs and SGNs that were treated with cisplatin. These results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.

The cytostatic agent hydroxyurea (HU) has proven to be beneficial for a variety of conditions in the disciplines of oncology, hematology, infectious disease and dermatology. It disrupts the S-phase of the cell cycle by inhibiting the ribonucleotide reductase enzyme, thus blocking the transformation of ribonucleotides into deoxyribonucleotides, a rate limiting step in DNA synthesis. HU is listed as an essential medicine by the World Health Organization. Several studies have indicated that HU is well tolerated and safe in pregnant women and very young pediatric patients. To our knowledge, only a few controlled studies about the adverse effects of HU therapy have been done in humans. Despite this, the prevalence of central nervous system abnormalities, including ischemic lesions and stenosis have been reported. This review will summarize and present the effects of HU-exposure on the prenatal and perinatal development of the rat cerebellar cortex and deep cerebellar nuclei neurons. Our results call for the necessity to better understand HU effects and define the administration of this drug to gestating women and young pediatric patients.

Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads from lower motor neuron involvement to progressive muscle atrophy, weakness, fasciculations for the upper motor neuron involvement to spasticity. Muscle atrophy in ALS is caused by a dysregulation in the molecular network controlling fast and slow muscle fibres. Denervation and reinnervation processes in skeletal muscle occur in the course of ALS and are modulated by rehabilitation. MicroRNAs (miRNAs) are small non-coding RNAs that modulate a wide range of biological functions under various pathophysiological conditions. MiRNAs can be secreted by various cell types and they are markedly stable in body fluids. MiR-1, miR-133 a, miR-133b, and miR-206 are called “myomiRs” and are considered markers of myogenesis during muscle regeneration and neuromuscular junction stabilization or sprouting. We observed a positive effect of a standard aerobic exercise rehabilitative protocol conducted for six weeks in 18 ALS patients during hospitalization in our center. We correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, myomiRNAs were down-regulated, suggesting an active proliferation of satellite cells in muscle and increased neuromuscular junctions. Our data suggest that circulating miRNAs modulate during skeletal muscle recovery in response to physical rehabilitation in ALS.

Forensic hospitals throughout the country house individuals with severe mental illness and history of criminal violations. Insomnia affects 67.4% of hospitalized patients with chronic neuropsychiatric disorders, indicating that these conditions may hijack human somnogenic pathways. Conversely, somnolence is a common adverse effect of many antipsychotic drugs, further highlighting a common etiopathogenesis. The role of dysfunctional mitochondria in psychopathology is well-established, however, the association of these organelles with sleep physiology is novel. Indeed, reducing neuronal oxidative stress by importing mitochondria from astrocytes, may be the purpose of human slumber. This model may explain mitochondrial dysfunction during anesthesia as well as in the rare genetic disease, fatal familial insomnia. In this narrative review, we focus on the salience network of the brain, a common denominator for insomnia, neuropsychiatric and neurodegenerative disorders. We also discuss mitochondria-protecting strategies, including membrane lipid replacement, natural and synthetic phenazine and phenothiazine derivatives.

This research investigates the implementation of complex exponential-based neurons in FPGA, which can pave the way for implementing bio-inspired spiking neural networks to compensate for the existing computational constraints in conventional artificial neural networks. The increasing use of extensive neural networks and the complexity of models in handling big data lead to higher power consumption and delays. Hence, finding solutions to reduce computational complexity is crucial for addressing power consumption challenges. The complex exponential form effectively encodes oscillating features like frequency, amplitude, and phase shift, streamlining the demanding calculations typical of conventional artificial neurons through levering simple phase addition of complex exponential functions. The article implements such a two-neuron and a multi-neuron neural model using Xilinx system generator and Vivado design suite, employing 8-bit, 16-bit, and 32-bit fixed-point data format representations. The study evaluates the accuracy of the proposed neuron model across different FPGA implementations while also providing a detailed analysis of operating frequency, power consumption, and resource usage for the hardware implementations. BRAM-based Vivado designs outperformed Simulink regarding speed, power, and resource efficiency. Specifically, the Vivado BRAM-based approach supported up to 128 neurons, showcasing optimal LUT and FF resource utilization. Such outcomes accommodate choosing the optimal design procedure for implementing spiking neural networks on FPGAs.

In network analysis, links depict the connections between each pair of network nodes. However, such pairwise connections fail to consider the interactions among more agents, which may be indirectly connected. Such non-pairwise or higher-order connections can be signified by involving simplicial complexes. The higher-order connections become even more noteworthy when it comes to neuronal network synchronization, an emerging phenomenon responsible for the many biological processes in real-world phenomena. However, involving higher-order interactions may considerably increase the computational costs. To confound this issue, map-based models are more suitable since they are faster, simpler, more flexible, and computationally more optimal. Therefore, this paper addresses the impact of pairwise and non-pairwise neuronal interactions on the synchronization state of 10 coupled memristive Hindmarsh-Rose neuron maps. To this aim, electrical, inner linking, and chemical synaptic functions are considered as 2- and 3-body interactions in three homogenous and two non-homogenous cases. The results show that through chemical pairwise and non-pairwise synapses, the neurons achieve synchrony with the weakest coupling strengths.

Working memory refers to the capability of the nervous system to selectively retain short-term memories in an active state. The long-standing viewpoint is that neurons play an indispensable role and working memory is encoded by synaptic plasticity. Furthermore, some recent studies have shown that calcium signaling assists the memory processes and the working memory might be affected by the astrocyte density. Over the last few decades, growing evidence has also revealed that astrocytes exhibit diverse coverage of synapses which are considered to participate in neuronal activities. However, very little effort has yet been made to attempt to shed light on the potential correlations between these observations. Hence, in this article we will leverage a computational neuron-astrocyte model to study the short-term memory performance subject to various astrocytic coverage and we will demonstrate that the short-term memory is susceptible to this factor. Our model may also provide plausible hypotheses for the various sizes of calcium events as they are reckoned to be correlated with the astrocytic coverage.

For more than 70 years, biologists and biophysicists have been trying to unravel the mystery that exists regarding the saltatory conduction of so-called myelinated neurons. Albert Einstein used the train metaphor to explain the theory of relativity. It is possible to use a similar metaphor to better understand this transient functioning of the neuron: the action potential. We will, once again, use a train to demonstrate unequivocally that the action potential does not jump from node of Ranvier to node of Ranvier (noR) as we thought it would. It is possible to describe that the neuron uses an elegant method to increase the speed of transmission of the neural message. It is also important to conclude that this increase in speed, contrary to the common idea, has a certain energy cost that is proportional to speed and in accordance with thermodynamics.

With the explosion of the generation, transmission and sharing of image data over the Internet and other unsecured networks, the need and significance for the development of novel image encryption algorithms is unprecedented. In this research work, we propose a novel framework for image encryption that is based on two hyperchaotic maps, utilized in conjunction with the single neuron model (SNM). The framework entails three successive stages, where in every stage, a substitution box (S-box) is applied, then XORing with an encryption key is carried out. The S-boxes and the encryption keys are generated from the numerical solutions of the hyperchaotic maps and the SNM. The performance of the proposed framework is gauged through a number of metrics, reflecting superior performance and complete asymmetry between the plain images and their encrypted versions. However, the main advantages of this work are: (1) The attained width of the key space; and (2) The achieved efficiency in software implementation. The superior key space of 2^{2551} is the result of employing the two hyperchaotic maps, while the improved efficiency, resulting in an average encryption rate of 8.54 Mbps, is the result of the utilization of the single neuron model, as well as the employment of optimized parallel processing techniques. In addition, the proposed encryption framework is shown to output encrypted images that pass the NIST SP 800 suite.

Long-term potentiation (LTP) is a molecular basis of memory formation. Here, we demonstrate that LTP critically depends on muscle fructose 1,6-bisphosphatase 2 (Fbp2) – a glyconeogenic enzyme and moonlighting protein protecting mitochondria against stress. We show that LTP induction regulates Fbp2 association with neuronal mitochondria and Camk2, and that the Fbp2-Camk2 interaction correlates with Camk2 autophosphorylation. Silencing of Fbp2 expression or simultaneous inhibition and tetramerization of the enzyme with a synthetic effector mimicking the action of physiological inhibitors (NAD⁺ and AMP) abolishes Camk2 autoactivation and blocks formation of the early phase of LTP and expression of the late phase LTP markers. Astrocyte-derived lactate reduces NAD⁺/NADH ratio in neurons and thus, diminishes the pool of tetrameric and increases the fraction of dimeric Fbp2. We therefore hypothesize that this NAD⁺-level-dependent increase of the Fbp2 dimer/tetramer ratio might be a crucial mechanism in which astrocyte-neuron lactate shuttle stimulates LTP formation.

Cellular therapies have started an important new therapeutic direction for Autistic Spectrum Disease (ASD), and the ample diversity of ASD pathophysiology and the different types of cell therapies need an equally ample effort for studying the applicable ASD causes and the specific benefits of cell therapies via clinical studies.CORDUS Clinical Study is a crossover study in which autologous cord blood was administered intravenously to 56 patients between January 2019 and July 2023, and has compared its efficacy versus an individualized combination of supplements; both treatments were administered in a different sequence to all participants. Treatment efficacy was evaluated pre- and post- treatments by an independent psychotherapist with ATEC, Q-CHAT and a 16-item comparative table score, after interviews with the children’s parents and therapists.Cord blood was beneficial in the group of 3–7-year-old children (n=28; 3 out of 4 children – 78.57% - improved scores), but was much less effective in kids older than 8 years or with body weight of more than 35 kg (n=28; 1 out of 10 children improved scores). Individualized supplements were more efficacious than cord blood in 5 cases out of 28, while in 23 kids cord blood brought more improvement than supplements; 6 kids registered minor or no improvement. Statistically significant improvements were seen after cord blood infusion on areas such as verbalization and social interaction, but not on irritability or aggressive behavior; also ample individual differences were noted. No serious adverse reactions were noted during and after cord blood or supplement administration.

Abstract: Objectives: To establish the expression profile of N6-methyladenosine(m6A) modifications in the hippocampus of mice with diabetic cognitive impairment (DCI) and elucidate the potential regulatory mechanism. Methods: A DCI model was established by feeding a high-fat diet to C57BL/6J mice. m6A and RNA sequencing was conducted to profile the m6A-tagged transcripts in the hippocampus. Results: Methylated RNA immunoprecipitation with next-generation sequencing and RNA sequencing analyses yielded differentially m6A-modified and expressed genes in the hippocampus of DCI mice, which were enriched in pathways involving synaptic transmission and axonal guidance. Mechanistic analyses revealed a remarkable change in m6A modification levels through alteration of the mRNA expression of m6A methyltransferases (METTL3 and METTL14) and demethylase (FTO) in the hippocampus of DCI mice. Conclusions: We identified a co-mediated specific RNA regulatory strategy that broadens the epigenetic regulatory mechanism of RNA-induced neurodegenerative disorders associated with metabolic and endocrine diseases.

Recent biotechnological innovations make feasible the new paradigm of creating biological neural circuits de novo. With advances in protein, cell and tissue engineering techniques, as well as cellular reprogramming methods, we are entering an era where the construction of neural circuits can open completely new ways for studying nervous systems and for treating nervous system disorders. I explore here three technologies, namely cellular engraftment, neuronal reprogramming and transsynaptic molecule engineering, and delineate how they are being used in a variety of basic research and translational medicine contexts. In basic neuroscience, neural circuit construction methods are enabling ways to study causality in neural development (e.g. neural precursor differentiation and migration) and circuit function (e.g. excitation/inhibition balance, neural population dynamics). In translational neuroscience, they are providing opportunities for the targeted correction of circuit malfunction in brain disorders, both psychiatric (e.g. schizophrenia) and neurological (e.g. Parkinson’s, Huntington’s and Alzheimer’s disease, as well as epilepsy). I discuss the challenges that these methods currently face, such as targeting specificity and cell survival, and outline future paths and opportunities to realize the full potential of technologies for creating new biological neural circuits.

The receptor tyrosine kinase Ret plays a critical role in regulating enteric nervous system (ENS) development. Ret is important for proliferation, migration, and survival of enteric progenitor cells (EPCs). Ret also promotes neuronal fate, but its role during neuronal differentiation and in the adult ENS is less well understood. Inactivating RET mutations are associated with ENS diseases, e.g. Hirschsprung Disease, in which distal bowel lacks ENS cells. Zebrafish is an established model system for studying ENS development and modeling human ENS diseases. One advantage of the zebrafish model system is that their embryos are transparent allowing visualization of developmental phenotypes in live animals. However, we lack tools to monitor Ret expression in live zebrafish. Here, we developed a new BAC transgenic line that expresses GFP under the ret promoter. We find that EPCs and the majority of ENS neurons express ret:GFP during ENS development. In the adult ENS, GFP+ neurons are equally present in female and male. In homozygous mutants of ret and sox10 – another important ENS developmental regulator gene – GFP+ ENS cells are absent. In summary, we characterize a ret:GFP transgenic line as a new tool to visualize and study the Ret signaling pathway from early development through adulthood.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Oxidative stress is known to be critically implicated in the pathophysiology of several neurological disorders, including Alzheimer’s disease and ischemic stroke. The remarkable neurotrophic activity of Gelidium amansii, has been reported consistently in a series of our previous studies, inspired us to investigate whether this popular agarophyte could protect against hypoxia/reoxygenation (H/R)-induced oxidative injury in hippocampal neurons. The primary culture of hippocampal neurons challenged with H/R suffered from a significant loss of cell survival, accompanied by apoptosis and necrosis, DNA damage, generation of reactive oxygen species (ROS), and dissipation of mitochondrial membrane potential (MMP) which were successfully attenuated when the neuronal cultures were preconditioned with GAE, an optimized ethanolic extract of G. amansii. Moreover, the expression of N-methyl-D-acetate receptor subunit 2B (GluN2B), an extrasynaptic glutamate receptor, was significantly repressed in GAE-treated neurons as compared to those without GAE intervention. Together, this study demonstrates that GAE attenuated H/R-induced oxidative injury in hippocampal neurons through, at least in part, a potential neuroprotective mechanism that involves inhibition of GluN2B-mediated excitotoxicity and suppression of ROS production, and suggest that this edible seaweed could be a potential source of bioactive metabolites having therapeutic significance against oxidative stress-related neurodegeneration, including ischemic stroke and neurodegenerative diseases.

Key features of glycogen metabolism in excitable tissues are not well-explained by current concepts. Glycogen stores in brain and skeletal muscle are generally considered to function as local glucose reserves, to be utilized during transient mismatches between glucose supply and demand; however, quantitative measures show that blood glucose supply is likely never rate-limiting for energy metabolism in either brain or muscle under physiological conditions. These tissues nevertheless do normally utilize glycogen during intervals of increased energy demand, despite the availability of free glucose, and despite the ATP cost of cycling glucose through glycogen polymer. This seemingly wasteful shunt can be explained by considering the effect of glycogenolysis on the amount of energy derived from ATP (ΔG’ATP). ΔG’ATP is diminished by elevations in Pi, such as occur at sites of rapid ATP hydrolysis and net phosphocreatine consumption. Glycogen utilization counters this effect by sequestering Pi in glycolytic metabolites (glycogen_n + Pi → glycogen_n-1 + glucose-1-phosphate → phosphorylated glycolytic intermediates), and thereby maintains the amount of energy obtained from ATP at sites of rapid ATP consumption. This thermodynamic effect may be particularly important in the narrow, spatially constricted astrocyte processes that ensheath neuronal synapses. This effect can also explain the co-localization of glycogen and cytosolic phosphocreatine in brain astrocytes, glycolytic super-compensation in brain when glycogen is not available, and aspects of exercise physiology in muscle glycogen phosphorylase deficiency (McArdle’s disease).

Human induced pluripotent stem cell (hiPSC)-derived neural cells have been used at the preclinical stage of drug development. As previously reported, hiPSC-derived neurons exhibit greater tolerance to excitotoxicity than that of primary cultures of rodent neurons; however, the underlying mechanisms remain unknown. We therefore investigated the functions of L-glutamate (L-Glu) transporters, the most important machinery used to maintain low extracellular L-Glu concentrations, in hiPSC-derived neural cells. We also clarified the contribution of each L-Glu transporter subtype. At 63 days in vitro (DIV), we detected neuronal circuit functions in hiPSC-derived neural cells by a microelectrode array system (MEA). Exposure to 100 μM L-Glu for 24 hrs did not affect the viability of these 63 DIV neural cells. Pharmacological inhibition of excitatory amino acid transporter 1 (EAAT1) and EAAT2 blocked almost 100% of L-Glu uptake. In this condition, L-Glu exposure dramatically decreased cell viability. These results suggest that in hiPSC-derived neural cells, EAAT1 and EAAT2 are predominant L-Glu transporters, and their uptake potentials are stronger than those of primary cultures of rodent neurons. Furthermore, hiPSC-derived neural cells may be useful for screening drugs that target L-Glu transporters.

The effects of hypothermia on neonatal encephalopathy may vary regionally, spatially, and cytopathologically in the gyrencephalic neocortex with manifestations potentially influenced by seizures that alter the severity and distribution of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia with continuous encephalographic (cEEG) monitoring for seizures to study injury in neocortex. Neonatal piglets were randomized to naïve, HI-normothermia (NT), overnight hypothermia (HT) initiated 2 hours after HI, sham-NT, or sham-HT treatments. Some piglets within sham and HI groups received cEEG monitoring during recovery. Survival was 2-7 days (piglets were unmedicated and those with poor recovery and unresolving seizures were euthanized early); there was no differences in survival among groups (p>0.078). Neuropathology was assessed by hematoxylin and eosin staining and immunohistochemistry for RNA Binding FOX-1 Homolog 3 (Rbfox3/NeuN). Normal and ischemic-necrotic neurons were counted (layers II-VI collectively) in somatosensory, motor, and prefrontal cortices, identified by cytoarchitecture and connectomics, and in inferior parietal cortex by layer. Seizure burden was determined. HI-NT piglets had reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to naïve, sham-NT, and sham-HT piglets in anterior and posterior motor and somatosensory cortices. Frontal cortex was vulnerable in the prefrontal lateral bank after HI-NT with ischemic-necrosis. HI-HT piglets had higher normal/total neuron ratios and lower ischemic-necrotic/total neuron ratios than HI-NT piglets in anterior/posterior motor and somatosensory cortices. Total normal neuron density in layer III of inferior parietal cortex was reduced in HI-NT piglets compared to sham piglets and was protected by HT. Laminar analysis of Rbfox3 in somatosensory cortex revealed three types of neurons: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT. Cortical neuron Rbfox3-depletion was partly rescued by HT. Seizure burden was more severe in HI piglets compared to sham piglets, but HI-NT and HI-HT piglets were similar. We conclude that 1) the neonatal piglet neocortex has a suprasylvian spatial vulnerability to HI and seizures; 2) HT protects against neuropathology in functionally different regions of the neonatal gyrencephalic neocortex; 3) neurons in neonatal neocortex have a limited cytopathology repertoire seen by H&E staining; 4) higher seizure burden correlates with more ischemic-necrotic neurons in somatosensory cortex; 5) seizure presence associates with damage spread to inferior parietal cortex; 6) seizure presence is insensitive to HT, and 7) Rbfox3 immunophenotyping identifies a novel neuronal RNA splicing protein nuclear-depletion pathology that appears reversible by HT. This work demonstrates that HT protection of neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores depleted neuronal RNA splicing factor.

The mechanism of brain information processing unfolds within spatial and temporal domains inherently linked to the concept of symmetry. Biological evolution, beginning with the prevalent molecular chirality, results in the handedness of cognitive and psychological functions (the phenomena known as biochirality). The key element in the chain of chirality transfer from the downstream to upstream processes is the pyramidal neuron (PyrN) morphology-function paradigm (archetype). The most apparent landmark of PyrN is the geometry of the cell soma. However, “why/how PyrN soma gains the shape of quasi-tetrahedral symmetry” has never been explicitly articulated. Resolving the above inquiry is only possible based on the broad-view assumption that encoding 3D-space requires specific 3D-geometry of the neuronal detector and corresponding network. Accordingly, our hypothesis states that if the primary function of PyrNs, at the organism level, is sensory space perception, then the pyramidal shape of soma is the best evolutionary-selected geometry to support sensory-motor coupling.

Autistic spectrum disease (ASD) is an increasingly common diagnosis nowadays with a prevalence of 1-2% in most countries. Its complex causality – a combination of genetic, immune, metabolic and environmental factors - is translated into pleiomorphic developmental disorders of various severity, which have in common two main aspects: repetitive, restrictive behaviors, and difficulties in social interaction varying from awkward habits and verbalization to complete lack of interest from the ASD child for the outside world. The wide variety of ASD causes also makes it very difficult to find a common denominator – a disease biomarker and medication – and currently there is no commonly used diagnostic and therapeutic strategy besides clinical evaluation and psychotherapy.It is known that inflammation is present in a majority of ASD children, and blood inflammatory markers, together with metabolic, electrophysiological markers and imagistics are useful for ASD diagnostic validation and treatment; however, they tend to leave out a sizeable proportion of ASD kids who do not have such modifications. Genetic testing – whole exome sequencing or targeted profiling on about 500 ASD-linked genes- may also provide good insight into pathophysiology, however many times its results are more restrictive rather than offering additional therapeutic options.Here we describe a new biomarker for ASD - the neuron-specific enolase (NSE) - which was elevated above the normal clinical range (less than 16.3 ng/mL) in the vast majority of ASD kids tested in our study (40 of 41, or 97.5%). This finding opens up a new direction for diagnostic confirmation, dynamic evaluation and therapeutic intervention for ASD kids.

Activation Functions are crucial parts of the Deep Learning Artificial Neural Networks. From the Biological point of view, a neuron is just a node with many inputs and one output. A neural network consists of many interconnected neurons. It is a “simple” device that receives data at the input and provides a response. The function of neurons is to process and transmit information; the neuron is the basic unit in the nervous system. Carly Vandergriendt (2018) stated the human brain at birth consists of an estimated 100 billion Neurons. The ability of a machine to mimic human intelligence is called Machine Learning. Deep Learning Artificial Neural Networks was designed to work like a human brain with the aid of arbitrary choice of Non-linear Activation Functions. Currently, there is no rule of thumb on the choice of Activation Functions, “Try out different things and see what combinations lead to the best performance”, however, sincerely; the choice of Activation Functions should not be Trial and error. Jamilu (2019) proposed that Activation Functions shall be emanated from AI-ML-Purified Data Set and its choice shall satisfy Jameel’s ANNAF Stochastic and or Deterministic Criterion. The objectives of this paper are to propose instances where Deep Learning Artificial Neural Networks are SUPERINTELLIGENT. Using Jameel’s ANNAF Stochastic and or Deterministic Criterion, the paper proposed four classes where Deep Learning Artificial Neural Networks are Superintelligent namely; Stochastic Superintelligent, Deterministic Superintelligent, and Stochastic-Deterministic 1^st and 2^nd Levels Superintelligence. Also, a Normal Probabilistic-Deterministic case was proposed.

This paper is about to estimate the suspended sediment transport amount in the streams flowing into the Sapanca Lake Basin. There are 12 subsidiary streams flowing into the Sapanca Lake Basin. With the aim of estimating the suspended sediment transport in 2012-204 in these subsidiary streams, measurements belonging the parameters such as level, cross sectioning, flow rate, temperature and suspended sediment were made monthly. Along the measurement period, weather conditions were above seasonal normal and precipitations decreased. In order to estimate the suspended sediment amount by using results of the measurement obtained, Artificial Neuron Network (ANN), Sediment Rating Curve (SRC) and Multiple Linear Regression (MLR) models were used for different scenarios. It was seen that artificial neuron networks yielded the most accurate results among the models.

Recurrent neural networks (RNNs) transmit information over time through recurrent connections. In contrast, biological neural networks use many other temporal processing mechanisms. One of these mechanisms is the inter-neuron delays caused by varying axon properties. Recently, this feature was implemented in echo state networks (ESNs), a type of RNN, by assigning spatial locations to neurons and introducing distance-dependent inter-neuron delays. These delays were shown to significantly improve ESN task performance. However, thus far it is still unclear why distance-based delay networks (DDNs) perform bettern than ESNs. In this paper, we show that by optimizing inter-node delays, the memory capacity of the network matches the memory requirements of the task. As such, networks concentrate their memory capabilities to the points in the past which contain the most information for the task at hand. Moreover, we show that DDNs have more total linear memory capacity, with the same amount of non-linear processing power.

Amyotrophic lateral sclerosis (ALS) is also called "motor neuron disease”. In this review, we propose that ALS is not just a neuromotor disorder, but begins as a disorder of P53-modulated skeletal muscle metabolism, leading to failures at the energy state of the cells, incorrect redox states, motor denervation, and a loss of muscle fibers. Motoneurons die as a consequence of the lack of muscular feedback, and the oligomeric TDP43 aggregates progressively and relentlessly lead to mistakes in peripheral immune self-tolerance sustained over time. An effective treatment has not been found for this devastating pathology, as for 152 years the target has not been accurately defined. Scientists and doctors should consider new knowledge regarding ALS and consider immunomodulatory therapies that, based on genetic analysis and symptoms, can be combined with compounds that regulate metabolism and promote the elimination of useless organelles and cells. What if ALS could be cured as a result of seeing motor neuron disease differently? This review aims to develop that goal and change the paradigm of our understanding of ALS.

Wingless-type MMTV integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation, axonal extension, synapse formation, neurogenesis and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional β-catenin protein which is a potent co-activator of transcription factors such as Lymphoid Enhancer Factor (LEF) and T Cell Factor (TCF). Accumulating evidence points to dysregulation of Wnt/β-catenin signaling in major neurodegenerative disorders. Here I focus on a “Wnt/β-catenin-glial connection” in Parkinson’s disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. I will summarize the work of the last decade documenting that Wnt/β-catenin signaling in partnership with glial cells is critically involved in each step and at every levels in the regulation of nigrostriatal DAergic neuronal health, protection and regeneration in the MPTP mouse model of PD, focusing on Wnt/β-catenin signaling to boost a full neurorestorative program in PD.

Abstract The relationship between cancer and neurodegeneration has spurred extensive scientific discourse, challenging their historical classification as distinct disorders. While cancer signifies uncontrolled cellular proliferation and neurodegeneration marks progressive neuronal loss, recent insights highlight intriguing interconnections between these seemingly disparate conditions. Cancer entails perpetual signaling for growth, evasion of growth inhibitors, resistance to cell death, acquisition of replicative immortality, stimulation of blood vessel growth (angiogenesis), and initiation of invasion and metastasis. Conversely, investigations emphasize disrupted cellular energy regulation and evasion of immune surveillance as key traits arising from genome instability, mutations, and inflammation driving tumorigenesis. Neurodegeneration involves neuronal malfunction and depletion, synaptic impairment, and protein abnormalities aggregations contributing to muscle atrophy and cognitive deficits. Varied clinical studies underscore contrasting correlations between cancer and neurodegeneration, hinting at mirrored molecular pathways that foster cell resilience or vulnerability. Research explores cellular signaling in tumorigenesis, shared with neurodegenerative disorders. Aberrant expression or mutations in crucial genes implicated in neurodegeneration also surface in cancer contexts. Debates persist on the nature of the relationship between cancer and neurodegeneration, contemplating inverse associations or shared pathways. Understanding their complex interplay, encompassing genetics, cellular mechanisms, and environmental influences, remains pivotal in unraveling their connections. This review explores the intriguing perspective that neurodegeneration and cancer might share fundamental genetic links, delving into potential implications for their onset and progression.

Anterior-tooth (ANT) contacts induce short latency reflex inhibition of human jaw-closing muscles. The jaw is a rigid class 1 lever for pinpoint-targeting muscle force into a single bite-point, the pivoting food particle. See-saw reflex movements around the food particle fulcrum multiply the food-crushing force. Unpredictable jolts of reaction force caused by food-crushing are subjected to the rostral ANT and caudally to the two articulate ends of the jaw triangle. Compression/distraction strains of food-crushing must be monitored and inhibited by withdrawal reflexes. The mesencephalic ganglion (Vmes), neural myelin sheath, and muscle stretch receptors evolved subsequently to the advent of jaws to improve the velocity of proprioceptive and withdrawal reflexes. In mammalians, the spindles of the taut motor units, stretched by the food-fulcrum send excitatory monosynaptic feedback for the efferent neurons of the respective ipsilateral muscle units, via Vmes. In the Vmes, the spindle-input-mediating afferent neurons are coupled with another source of afferent feedback, which is also excitatory, from the back-tooth (BAT) mechanoreceptors. The two sources of excitatory pulses are summated and targeted for the efferent neurons to boost the stretched and taut motor units. Likewise, the afferent feedback from ANT mechanoreceptors is also coupled in the Vmes with concomitant feedback from spindles. The ANT output, however, is inhibitory to negate the excitatory feedback from the stretched jaw-muscle units. The inhibitory feed from ANT temporarily blocks the excitatory potential of masticatory motor efferent neurons to protect the ANT and jaw-joints from inadvertent strains. The inhibitory inputs from ANT alternate with the excitatory inputs from BAT to determine which jaw-closing muscle units are activated or inhibited at any given instant of food-crushing. The Vmes exists in all jawed vertebrates, and its’ evolution was probably motivated by demands for the control of bite force. The monosynaptic unilateral food-crushing excitatory and inhibitory reflexes (UFCR) override the coexisting bilaterally executed feed for jaw muscles from the central nervous system. Hypothesis: The Vmes-mediated UFCR combine neural inputs from tooth contacts with concomitant feedback from muscle stretch receptors for the control of mammalian food-crushing bite force.

Microglial cells, the resident macrophages of the CNS, exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell damaging factors they get transformed to an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia has a number of important physiological functions in the CNS; they e.g. shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures and clear surplus synapses during development. In neurodegenerative illnesses they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, A3, and being targets for endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5’-nucleotidase enzymes to the weak adenosine agonist inosine as an end-product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins and decrease levels of toxic proteins. ASOs are being developed for the treatment of several diseases, including motor neuron diseases (MNDs), a group of neurodegenerative disorders characterised by the loss of motor neurons, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MND, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macro-phages and reactive M1 microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in a the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlight the time-dependent transformation of reactive mi-croglia (M1) and astrocytes (A1) into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide sug-gestions on how to increase functional outcome after SCI and discuss key therapeutic approaches.

Consciousness is a special type of interaction between subjects exchanging by lingua quanta (phonemes). A set of lingua quanta composes a thesaurus placed on the edge of chaos. Its library is a memory, modification of which is due to tuning of memristive neural elements scattered in the brain volume. The memristive neural model takes into consideration two types of neurons - excitatory and inhibitory and the current leakage, all at the body temperature, T = 309 K. At such temperatures only heavy ions like hydrogen ions - protons can pass robustly through the water medium of the brain. The robust ion transport is proton water wires supported by the Grotthuss mechanism. Final aims of the ions are the gap junctions (electric synapses) linking nearest neurons. Following these observations, a model of excitable nervous tissue is constructed. Namely, a difference mapping on the basis of sigmoid curves can reproduce chaotic modes of neural activity proved by positive values of the Lyapunov exponent. The edge of chaos is placed near the bifurcation boundary dividing the chaos and the periodic convulsive activity typical at the epileptic discharges. In this region the self-sustained spiral waves occur. An intermittent activity of the competing excitatory and inhibitory neurons is observed on the edge of chaos. The intermittent electrical activity of neural tissues is demonstrated by records both from different literature issues and records made by the author together with DR. A. Dudkin on slices of CA1 field of the hippocampus.

Understanding brain function is one of the most important problems in human history. At present, there is no concrete theory for how the brain works. Here, a theory is presented that provides a detailed mechanistic biological account of the brain's capacities, including motor control, functional states, language, and thinking. Brain function is managed by a well-defined response (R) process that is generally similar to the process underlying the immune system. The R process is strongly reflected in the brain's anatomy, physiology, and external interactions. Different R process stages are supported by distinct excitatory networks located in different cortical layers, hippocampal fields, and bagal ganglia paths, by distinct coordination networks comprised of GABAergic interneurons, and by distinct molecular agents. The roles of norepinephrine, serotonin, dopamine and acetylcholine is to promote the alert, planning, goal-setting and execution R process modes, respectively. Opioids and oxytocin promote termination by success, failure, fight or run, while glucocorticoids and cannabinoids suppress acute responses to protect cells. The R process has two instances occurring at different time scales. The millisecond-scale Quax process implements the execution of hierarchical sequences of movements and thoughts, in which the selection of the next action is determined via interaction between top-down predictions and sensory inputs. The slower Need process controls the satisfaction of internal and external needs. The theory differs from the existing standard accounts in many of the major topics (e.g., the basal ganglia, dopamine, language), and shows how cognition results from biological processes.