Effect of prenatal emotional-pain stress on the status of interphase chromatin in neurons of the rat developing brain with various excitation of the nervous system

A short-term emotional-painful stress, experienced by pregnant rat females differing in threshold of excitability of their nervous system, was used to assess the state of interphase condensed chromatin and C-heterochromatin of neuron nuclei in developing brains of 16-17 day old embryos. To reveal relationships between the genetically determined excitability of rats and the state of interphase chromatin in their neuron nuclei a computer information system has been used that enabled us to classify the neuronal nuclei according to their specific DNA image cytometry features. The results indicate an obvious relationship between excitability of the nervous system and structural-functional state of the neuronal interphase chromatin.     

Structural-functional and metabolic changes in the nervous system in low- and high-excitable rats deprived of paradoxical sleep

Studying of the influence of 24-hour deprivation of paradoxical sleep phase (PSPh) on rats with different genetically determined levels of excitability of the nervous system allowed to establish: 1) significant changes in functional state of the central part of the nervous system responsible for elaboration and preservation of defensive conditioned reflexes; 2) considerable lowering of functional state of the peripheral nervous system expressed both in a decrease of tibial nerve excitability thresholds and in changing of morpho-tinctorial characteristics of the studied nerve receptor parameters. The degree of the observed effects of PSPh deprivation is dependent on animal line belonging.     

The open-field behavior of neuroticized rats]

A detailed study has been carried out of the behaviour in the open field of the lines of rats with different functional state of the nervous system after prolonged neurotization in dependence on the phase of circadian rhythm and terms after the end of the influence. Significant changes have been shown by the amplitude of circadian rhythms of emotionality and motor activity. It is established that the reaction of the rats lines to prolonged neuroticizing action depends on the phase of the circadian rhythm, the time after its termination and on genetically determined level of excitability of the nervous system.     

The differential sensitivity to a neurotigenic exposure of rat strains differing by the threshold of nervous system excitability]

The influence was studied of 15-days stressing on the appearance of stable neurosis-like state of rats lines, selected by the excitability of the nervous system. Unconditioned and conditioned components of behaviour were tested: pain sensitivity, behaviour in the open field, level of "anxiety", passive and active defensive avoidance. Differential reactivity was shown of the rats lines to prolonged stressing, depending on the genetically determined level of the nervous system functional state. Interlinear differences in dynamics of the development of neurosis-like state were established.     

Systemic control of the molecular,cell, and epigenetic mechanisms of long-lasting consequences of stress

Based on M.E. Lobashev’s views of the systemic control of genetic and cytogeneitc processes and a substantial effect of excitability on plastic changes in the central nervous system (CNS), the effect of prolonged emotional and pain stress (PEPS) on the molecular, cell, and epigenetic mechanisms of injury memory was studied in rat strains bred for a certain excitability of the nervous system. PEPS was for the first time found to cause long-lasting (2 months) morphological alterations of the CA3 region of the hippocampus and to modify the genome activity of its pyramidal neurons. The two phenomena were potentiated by a genetically determined low functional state of the CNS. The post-stress regulation of the genome function in hippocampal neurons was mediated by changes in heterochromatin conformation, activation of methyl-CpG-binding protein (MeCP2) synthesis, and subsequent changes in acetylation of histone H4. Genetically determined high excitability of the nervous system proved to be a risk factor that affects the specifics and time course of the observed molecular, cell, and genetic transformations of neurons. The results provide for a better understanding of the epigenetic mechanisms of injury memory, which forms a pathogenetic basis for posttraumatic stress disorder and other human psychogenic conditions characterized by a prolonged duration.     

The relationship between the formation of trace reactions and the functional state of rats of different genetic lines]

The level of excitability of the nervous system was enhanced in rats of the Krushinsky--Molodkina (K--M) and Wistar (W) lines by means of dynamic and static physical loads and injections of different doses of al-amphetamine. It was shown that a higher level of excitability of the central nervous system produced in both lines of rats improved memory and increased the rate of formation of a conditioned active aboidance reflex (CAAR). A greater physical load or dose of the stimulant drug in the K-M line of rats resulted in a decrease of all parameters characterizing CAAR, while in the other line they rose in progression. The data obtained are believed to be related to a different genetically conditioned initial level of excitability in the indicated lines of rats--a higher one in the K--M line animals as compared with the W line rats, which determines a different norm of the nervous system responsiveness in the indicated groups of animals.     

Effect of NMDA receptor activity on histone H3 methylation and its asymmetry in the hippocampal pyramidal neurons of rats with different excitability thresholds under normal and stress conditions

Process of methylation of histone H3 for lysine 4 (H3K4) was studied in hippocampal pyramidal neurons of rats—intact and submitted to emotional-pain stress with active and inactivated channels of NMDA-receptors with taking into account the interhemisphere lateralization and in connection with the genetically determined level of excitability of the animals’ nervous system. There were revealed interstrain differences in the basal level of the H3K4 methylation whose direction depends on structural-functional peculiarities of hippocampal fields and lateralization. Under action of stress the direction of the observed changes in the degree of the H3K4 methylation depended on the functional states of channels of NMDA-receptors. On the background of active receptors the proportion of immunopositive cells predominantly increased. In the CA1 field this change was not connected with excitability and lateralization, whereas in the CA3 field it had a complex character and depended on these two factors. At inactivation of channels of NMDA-receptors the portion of immunopositive nuclei as a result of the stress action, on the contrary, predominantly decreased; interstrain specificity of these changes was connected with lateralization, while its direction in different hippocampal fields was different. Action of the short-time emotional-pain stress did not lead to a change of shape of interhemisphere at active state of receptors, whereas at inactivation of receptors it changes depending on the structural-functional organization of hippocampus and on excitability of the nervous system.     

Genetic relationship between the neurological (excitability thresholds) and the behavioral characteristics of mouse strains and their hybrids

The comparative genetic analysis of 16 inbred mouse strains was carried out for excitability thresholds of peripherical parts of the nervous system, viability to learning, short-term memory and exploratory activity in different experimental conditions. The high positive correlation was shown between excitability thresholds of different parts of the peripherical nervous system, the high negative correlation being established between excitability thresholds, viability to learning, short-term memory and exploratory activity. The data led to the conclusion about the existence of the pleiotropic effect of genes controlling the excitability thresholds, on peculiarities of behaviour. This was confirmed by the findings obtained in the study of various hybrids, which point to the similar way of inheritance of excitability thresholds and behavioural patterns.     

Control of neuronal excitability by GSK-3beta: Epilepsy and beyond

Glycogen synthase kinase 3beta (GSK-3β) is an enzyme with a variety of cellular functions in addition to the regulation of glycogen metabolism. In the central nervous system, different intracellular signaling pathways converge on GSK-3β through a cascade of phosphorylation events that ultimately control a broad range of neuronal functions in the development and adulthood. In mice, genetically removing or increasing GSK-3β cause distinct functional and structural neuronal phenotypes and consequently affect cognition. Precise control of GSK-3β activity is important for such processes as neuronal migration, development of neuronal morphology, synaptic plasticity, excitability, and gene expression. Altered GSK-3β activity contributes to aberrant plasticity within neuronal circuits leading to neurological, psychiatric disorders, and neurodegenerative diseases. Therapeutically targeting GSK-3β can restore the aberrant plasticity of neuronal networks at least in animal models of these diseases. Although the complete repertoire of GSK-3β neuronal substrates has not been defined, emerging evidence shows that different ion channels and their accessory proteins controlling excitability, neurotransmitter release, and synaptic transmission are regulated by GSK-3β, thereby supporting mechanisms of synaptic plasticity in cognition. Dysregulation of ion channel function by defective GSK-3β activity sustains abnormal excitability in the development of epilepsy and other GSK-3β-linked human diseases.     

Primary afferent depolarization of C fibres in the spinal cord of the cat

The excitability of primary afferent terminals of cutaneous C fibres was tested in the spinal cord of decerebrated cats. C fibre terminal excitability was decreased in the spinal state, and increased by conditioning volleys that activated only A fibres of another cutaneous nerve and by stimulating hair mechanically. It is suggested that C fibre input and therefore nociceptive information to the central nervous system is susceptible to presynaptic control by segmental and suprasegmental mechanisms.     

Open-field behavior of rats with different levels of nervous system excitability

The dependence was studied of characteristics of organization of orienting-investigating behaviour in the open field test on the level of nervous system excitability in rats selected by the threshold of excitability of the peripheral nervous system. It is established that the studied rats lines can be divided into groups according to entropy level of their behaviour. Rats of highly excitable line build their behaviour in highly probable stereotypes as compared with the animals of low-excitable line, which organize their behaviour with more plasticity, diversity. Differences in the nervous system excitability influence first of all the organization of animals behaviour.     

Neurotransmitter abnormalities in genetically epileptic rodents

A growing body of evidence supports a pathophysiological role for norepinephrine (NE) and serotonin in the regulation of seizures in the genetically epilepsy-prone rat (GEPR). Other evidence indicates that gamma-aminobutyric acid (GABA) and taurine may also participate in the seizure regulation process. Innate deficits in NE and serotonin appear to be causes of the genetically determined seizure-prone states of the GEPR, whereas abnormalities in GABAergic systems and taurine metabolism may represent inadequate attempts of the central nervous system to compensate for the seizure-prone state in these rats. In audiogenic seizure-susceptible (AGS) mice, evidence suggests a role for dopamine as well as GABA and possibly serotonin. NE may contribute to the regulation of seizures in AGS mice, but consistent evidence for a primary role for this monoamine is lacking. It is suggested that there is no single common neurotransmitter abnormality underlying genetic seizure disorders in humans or other animals and that the GEPR and the AGS mouse may both serve as good models for study of the neurochemical abnormalities that underlie the different human epilepsies.     

pH-sensitive, Ca2+/calmodulin-dependent phosphorylation of unique protein in molluscan nervous system

Intracellular pH and Ca2+ are prominent co-regulators of neuron excitability that act on ion channels. In looking for a possible mechanism of their action, we tested their combinatorial effect on the phosphorylation state of nervous system proteins. 32PO4 labelling in endogenous phosphorylation reactions of homogenates of nervous tissue of the sea-slug Pleurobranchaea showed steep pH sensitivity in protein migrating at a molecular mass of 108 kDa with pI 6.9-7.0 (pp108). Phosphorylation of pp108 was highest below reaction pH 7.0 and declined steeply as pH rose to 7.4 pp108 phosphorylation was Ca2+/calmodulin-dependent. pp108 constituted a significant part of the total protein (0.15%) and phosphoprotein (8.9%) of the nervous system. The specifically and uniquely combinatorial pH and Ca2+ sensitivity of the phosphorylation of pp108, and its relative abundance, suggest that it could mediate integrated actions of H+ and Ca2+ in the molluscan neuron.     

Neuroplasticity in nucleus tractus solitarius neurons after episodic ozone exposure in infant primates.

Acute ozone exposure evokes adverse respiratory responses, particularly in children. With repeated ozone exposures, however, despite the persistent lung inflammation and increased sensory nerve excitability, the central nervous system reflex responses, i.e., rapid shallow breathing and decreased lung function, adapt, suggesting changes in central nervous system signaling. We determined whether repeated ozone exposures altered the behavior of nucleus tractus solitarius (NTS) neurons where reflex respiratory motor outputs are first coordinated. Whole cell recordings were performed on NTS neurons in brain stem slices from infant monkeys exposed to filtered air or ozone (0.5 ppm, 8 h/day for 5 days every 14 days for 11 episodes). Although episodic ozone exposure depolarized the membrane potential, increased the membrane resistance, and increased neuronal spiking responses to depolarizing current injections (P < 0.05), it decreased the excitability to vagal sensory fiber activation (P < 0.05), suggesting a diminished responsiveness to sensory transmission, despite overall increases in excitability. Substance P, implicated in lung and NTS signaling, contributed to the increased responsiveness to current injections but not to the diminished sensory transmission. The finding that NTS neurons undergo plasticity with repeated ozone exposures may help to explain the adaptation of the respiratory motor responses.     

The genetic control aspects of the development of the autonomic nervous system

This article provides a review of current views about the role of cell genetic machinery in the control of development of neurons of the autonomous nervous system. Some of the genes defining migration and specification of these neurons are described. We give a schematic presentation of the genetically determined organization of the neuronal networks, which are a basis of the intramural nervous machinery and sympathetic ganglia. We describe the distribution of neurons with different transmitter specificity in the cell populations comprising the neuronal networks.     

Genetics of the human electroencephalogram (EEG) and event-related brain potentials (ERPs): a review

Twin and family studies of normal variation in the human electroencephalogram (EEG) and event related potentials (ERPs) are reviewed. Most of these studies are characterized by small sample sizes. However, by summarizing these studies in one paper, we may be able to gain some insight into the genetic influences on individual differences in central nervous system functioning that may mediate genetically determined differences in behavior. It is clear that most EEG parameters are to a large extent genetically determined. The results for ERPs are based on a much smaller number of studies and suggest medium to large heritability.     

Aspects of the genetic control of development of the autonomous nervous system

This article provides a review of current views about the role of cell genetic machinery in the control of development of neurons of the autonomous nervous system. Some of the genes defining migration and specification of these neurons are described. We give a schematic presentation of the genetically determined organization of the neuronal networks, which are a basis of the intramural nervous machinery and sympathetic ganglia. We describe the distribution of neurons with different transmitter specificity in the cell populations comprising the neuronal networks. To the memory of my friend Aleksandr Neifakh, an outstanding Russian embryologist