Prion Disorders: Creutzfeldt-Jakob Disease and Related Disorders

Prion disorders, or transmissible spongiform encephalopathies (TSEs), are universally fatal human and animal diseases that cause rapid degeneration of brain neurons by way of a conformational change in the prion protein that autocatalyzes further conformational change and selective neuronal toxicity. TSEs may occur sporadically, be inherited, or, least frequently, spread like an infectious agent. Mounting evidence suggests that degenerative proteinopathies such as Alzheimer disease and Parkinson disease may also involve prionlike spread of abnormal proteins between neurons but not between organisms as in the prion disorders discussed in this chapter.

Global DNA Methylation Of Brain Neurons In Acute Poisoning With Clozapine And Its Combination With Alcohol: An Experimental Study

Background — Acute poisoning with atypical neuroleptic clozapine is characterized by rapid progression, high risk of death and severe neurological manifestations. Neurotoxic effects of this pharmaceutical drug have also been reported at therapeutic doses. The pathogenesis of brain damage in acute clozapine poisoning is not fully understood. Changes in DNA methylation level may play an important role in the mechanisms of drug neurotoxicity. The available data on the effect of clozapine on brain cell DNA provide a rationale for studying the epigenetic aspects of the pathogenesis of acute poisoning with this neuroleptic agent. The objective of our study was to evaluate the global DNA methylation level in rat brain neurons in acute poisoning with clozapine and its combination with ethanol. Material and methods — Clozapine – 150 mg/kg in 2.0 ml of normal saline solution, or clozapine – 150 mg/kg in 2.0 ml of 40% ethanol were administered via a gastric tube to adult male Wistar rats (n=21) under anesthesia with sevoflurane. In the control group, saline was administered via a gastric tube. Animals were euthanized four hours after drug administration. Autopsy was performed with the collection of brain samples for histochemical examination and determination of the DNA methylation level using the fluorometric method. To detect DNA in sections of paraffin-embedded tissue, we used the Feulgen staining. The TUNEL method was employed to detect DNA fragmentation. Results — An increase in the level of global DNA methylation in brain neurons was found in the clozapine and clozapine+ethanol groups. The average level of methylated DNA in the clozapine+ethanol group was higher than in the control group or clozapine group (2.56±0.31 vs. 1.35±0.1, p=0.007 and 1.70±0.33, p=0.044, respectively). An increase in the mean optical density of the cortical neuron nuclei was observed in the clozapine+ethanol group compared with the control group and clozapine group. DNA fragmentation was not detected in any experimental group. Conclusion — Acute poisoning with clozapine in combination with alcohol caused an increase in the global DNA methylation level in brain neurons, which may have played a significant role in the pathogenesis of acute clozapine poisoning and could be an important factor in the neurotoxicity of this medication.

Adult brain neurons require continual expression of the schizophrenia-risk gene Tcf4 for structural and functional integrity

The schizophrenia-risk gene Tcf4 has been widely studied in the context of brain development using mouse models of haploinsufficiency, in utero knockdown and embryonic deletion. However, Tcf4 continues to be abundantly expressed in adult brain neurons where its functions remain unknown. Given the importance of Tcf4 in psychiatric diseases, we investigated its role in adult neurons using cell-specific deletion and genetic tracing in adult animals. Acute loss of Tcf4 in adult excitatory neurons in vivo caused hyperexcitability and increased dendritic complexity of neurons, effects that were distinct from previously observed effects in embryonic-deficiency models. Interestingly, transcriptomic analysis of genetically traced adult-deleted FACS-sorted Tcf4-knockout neurons revealed that Tcf4 targets in adult neurons are distinct from those in the embryonic brain. Meta-analysis of the adult-deleted neuronal transcriptome from our study with the existing datasets of embryonic Tcf4 deficiencies revealed plasma membrane and ciliary genes to underlie Tcf4-mediated structure-function regulation specifically in adult neurons. The profound changes both in the structure and excitability of adult neurons upon acute loss of Tcf4 indicates that proactive regulation of membrane-related processes underlies the functional and structural integrity of adult neurons. These findings not only provide insights for the functional relevance of continual expression of a psychiatric disease-risk gene in the adult brain but also identify previously unappreciated gene networks underpinning mature neuronal regulation during the adult lifespan.

A Conserved MTMR Lipid Phosphatase Increasingly Suppresses Autophagy in Brain Neurons During Aging

Aging is driven by the progressive, lifelong accumulation of cellular damage. Autophagy (cellular self-eating) functions as a major cell clearance mechanism to degrade such damages, and its capacity declines with age. Despite its physiological and medical significance, it remains largely unknown why autophagy becomes incapable of effectively eliminating harmful cellular materials at advanced ages. Here we show that age-associated defects in autophagic degradation occur at both early and late stages of the process. Furthermore, in the fruit fly Drosophila melanogaster, the myotubularin-related (MTMR) lipid phosphatase EDTP (egg-derived tyrosine phosphatase) known as an autophagy repressor gradually accumulates in brain neurons during the adult life span. The age-related increase in EDTP activity is associated with a growing DNA N6-adenine methylation at EDTP locus. MTMR14, the human counterpart of EDTP, also tends to accumulate with age in brain neurons. Thus, EDTP, and presumably MTMR14, promotes brain aging by increasingly suppressing autophagy throughout adulthood. We propose that EDTP and MTMR14 phosphatases operate as endogenous pro-aging factors setting the rate at which neurons age largely independently of environmental factors, and that autophagy is influenced by DNA N6-methyladenine levels.

Classical Soliton Theory for Studying the Dynamics and Evolution of in Network

This paper presents the dynamic model ofthe soliton. Based on this model, it is supposed to study the state of the network. The term neural networks refersto the networks of neurons in the mammalian brain. Neurons are its main units of computation. In the brain, they are connected together in a network to process data. This can be a very complex task, and so the dynamics of neural networks in the mammalian brain in response to external stimuli can be quite complex. The inputs and outputs of each neuron change as a function of time, in the form of so-called spike chains, but the network itself also changes. We learn and improve our data processing capabilities by establishing reconnections between neurons.

Piezo2, A Pressure Sensitive Channel Is Expressed in Select Neurons of the Mouse Brain: a Putative Mechanism for Synchronizing Neural Networks by Transducing Intracranial Pressure Pulses

Piezo2 expression in mouse brain was examined using an anti-PIEZO2 antibody (Ab) generated against a C-terminal fragment of the human PIEZO2 protein. As a positive control for Ab staining of mouse neurons, the Ab stained a majority of mouse dorsal root ganglion (DRG) neurons, consistent with recent in situ hybridization and single cell RNA sequencing studies of Piezo2 expression. As a negative control and test for specificity, the Ab failed to stain human erythrocytes, which selectively express PIEZO1. In brain slices isolated from the same mice as the DRG, the Ab displayed high selectivity in staining specific neuron types, including pyramidal neurons in the neocortex and hippocampus, Purkinje cells in the cerebellar cortex and mitral cells in the olfactory bulb. Given the demonstrated role of Piezo2 channels in peripheral neurons as a low-threshold pressure sensor (i.e., ≤ 5 mm Hg) critical for the regulation of breathing and blood pressure, its expression in select brain neurons has interesting implications. In particular, we hypothesize that Piezo2 provides select brain neurons with an intrinsic resonance enabling their entrainment by the normal intracranial pressure (ICP) pulses (~ 5 mm Hg) associated with breathing and cardiac cycles. This mechanism could serve to increase the robustness of respiration-entrained oscillations previously reported across widely distributed neuronal networks in both rodent and human brains. This idea of a “global brain rhythm” has previously been thought to arise from the effect of nasal airflow activating mechanosensitive neurons within the olfactory epithelium, which then synaptically entrain mitral cells within the olfactory bulb and through their projections, neural networks in other brain regions, including the hippocampus and neocortex. Our proposed, non-synaptic, intrinsic mechanism in which Piezo2 tracks the “metronome-like” ICP pulses would have the advantage that spatially separated brain networks could also be synchronized by a physical force that is rapidly transmitted throughout the brain.

Radiation-Induced Changes in Nucleic Acids of Brain Neurons

Purpose: Study of radiation-induced changes in the content of nucleic acids in neurons of the brain after exposure to ionizing radiation in doses of 0.1 – 1.0 Gy. Material and methods. The study was carried out in compliance with the rules of bioethics on 240 white outbred male rats at the age of 4 months. by the beginning of the experiment, exposed to a single exposure to γ-radiation of 60Co in doses of 0.1–1.0 Gy. Neuromorphological methods were used to assess morphometric and tinctorial parameters of nerve cells, as well as the dynamics of changes in the content of nucleic acids in neurons during the entire life span of animals. Statistical processing of the results was carried out using the Statistica 6.1 software packages, using parametric criteria. Results: In control and irradiated animals throughout their life, there are undulating changes in the content of nucleic acids in the neurons of the brain with a gradual decrease in indicators by the end of the experiment. At the same time, changes in the level of DNA in the nuclei and RNA in the nucleoli are usually associated with changes in the size of the structures of their localization, and the RNA content in the cytoplasm is apparently associated with changes in the physiological state of neurons (rest, excitation, inhibition) and the corresponding structural and functional rearrangement of nerve cells. Nucleic acid changes do not have a linear dose and time dependence on the factors investigated. At the end of the experiment, when death of both irradiated and control animals is observed, the content of nucleic acids in neurons is statistically significantly reduced in all groups, and to a greater extent in irradiated animals. Conclusion: No functionally significant radiation-induced changes in the content and topochemistry of the products of histochemical reactions were revealed in the detection of nucleic acids in the structures of brain neurons. However, in some periods of observation, the content of nucleic acids in neurons in irradiated animal’s changes to a greater extent than in animals of age control.