Effects of different types of induced neonatal inflammation on development and behavior of C57BL/6 and BTBR mice.

Neuroinflammation in the early postnatal period can disturb trajectories of the completion of normal brain development and can lead to mental illnesses, such as depression, anxiety disorders, and personality disorders later in life. In our study, we focused on evaluating short- and long-term effects of neonatal inflammation induced by lipopolysaccharide, poly(I:C), or their combination in female and male C57BL/6 and BTBR mice. We chose the BTBR strain as potentially more susceptible to neonatal inflammation because these mice have behavioral, neuroanatomical, and physiological features of autism spectrum disorders, an abnormal immune response, and several structural aberrations in the brain.

A comparison of stress reactivity between BTBR and C57BL/6J mice: an impact of early-life stress.

Early-life stress (ELS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and can increase the risk of psychiatric disorders later in life. The aim of this study was to investigate the influence of ELS on baseline HPA axis functioning and on the response to additional stress in adolescent male mice of strains C57BL/6J and BTBR. As a model of ELS, prolonged separation of pups from their mothers (for 3 h once a day: maternal separation [MS]) was implemented.

Delayed effects of neonatal immune activation on brain neurochemistry and hypothalamic-pituitary-adrenal axis functioning.

During the postnatal period, the brain is highly sensitive to stress and inflammation, which are hazardous to normal growth and development. There is increasing evidence that inflammatory processes in the early postnatal period increase the risk of psychopathologies and cognitive impairment later in life. On the other hand, there are few studies on the ability of infectious agents to cause long-term neuroinflammation, leading to changes in the hypothalamic-pituitary-adrenal axis functioning and an imbalance in the neurotransmitter system.

Developing brain as a source of circulating norepinephrine in rats during the critical period of morphogenesis.

The development of individual organs and the whole organism is under the control by morphogenetic factors over the critical period of morphogenesis. This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ during morphogenesis, in rats during the perinatal period (Ugrumov in Neuro Chem 35:837-850, 2010). Norepinephrine, which is a morphogenetic factor, was used as a marker of the endocrine activity of the developing brain, although it is also secreted by peripheral organs.

The Role of the Brain in the Regulation of Peripheral Noradrenaline-producing Organs in Rats During Morphogenesis.

This work represents one part of our research project, in which we attempted to prove that a humoral regulation between noradrenaline-producing organs exist in the perinatal period. In this study, we used a rat model that allowed blocking the synthesis of noradrenalin in the brain and evaluated gene expression and protein levels of noradrenaline key synthesis enzymes such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) in peripheral noradrenaline-producing organs. As a result, we showed an increased gene expression of TH and DBH in adrenal glands.

Gene expression and content of enzymes of noradrenaline synthesis in the rat organ of Zuckerkandl at the critical period of morphogenesis.

Gene expression and content of the key enzymes involved in the synthesis of noradrenaline-tyrosine hydroxylase and dopamine beta-hydroxylase-was evaluated in the organ of Zuckerkandl of rats in the critical period of morphogenesis. High levels of mRNA and protein of both enzymes in the perinatal period of development and their sharp decline on day 30 of postnatal development were detected. These data indicate that the synthesis of noradrenaline in the organ of Zuckerkandl is maximum during the critical period of morphogenesis and decreases during the involution of this paraganglion.

Molecular mechanisms of synthesis of noradrenaline as an inducer of development in the adrenal glands of rats in ontogenesis.

The level of gene expression and the protein content of tyrosine hydroxylase and dopamine β-hydroxylase were determined. In the perinatal period of rats, when noradrenaline functions as a morphogenetic factor, the level of gene expression of these enzymes increased and the content of protein products of these genes was almost unchanged, indicating the difference in the regulatory mechanisms of their transcription and translation.

Plasticity of Central and Peripheral Sources of Noradrenaline in Rats during Ontogenesis.

The morphogenesis of individual organs and the whole organism occurs under the control of intercellular chemical signals mainly during the perinatal period of ontogenesis in rodents. In this study, we tested our hypothesis that the biologically active concentration of noradrenaline (NA) in blood in perinatal ontogenesis of rats is maintained due to humoral interaction between its central and peripheral sources based on their plasticity. As one of the mechanisms of plasticity, we examined changes in the secretory activity (spontaneous and stimulated release of NA) of NA-producing organs under deficiency of its synthesis in the brain.

The Effect of Dopamine Secreted by the Brain into the Systemic Circulation on Prolactin Synthesis by the Pituitary gland in Ontogenesis.

This research was aimed at studying the brain's endocrine function in ontogenesis. It has been previously shown in our laboratory that the brain serves as the source of dopamine in the systemic circulation of rats prior to the formation of the blood-brain barrier. This paper provides direct evidence that dopamine secreted by the brain directly into the systemic circulation in this period of ontogenesis has an inhibitory effect on prolactin secretion by pituitary cells.

[Reciprocal Humoral Regulation of Endocrine Noradrenaline Sources in Perinatal Development of Rats].

The goal of the present study was to verify our hypothesis of humoral interaction between the norepinephrine secreting organs in the perinatal period of ontogenesis that is aimed at the sustaining of physiologically active concentration of norepinephrine in blood. The objects of the study were the transitory organs, such as brain, organ of Zuckerkandl, and adrenals, the permanent endocrine organ of rats that releases norepinephrine into the bloodstream. To reach this goal, we assessed the adrenal secretory activity (norepinephrine level) and activity of the Zuckerkandl’s organ under the conditions of destructed noradrenergic neurons of brain caused by (1) their selective death induced by introduction of a hybrid molecular complex, which consisted of antibodies against dopamine-β-hydroxylase (DBH) conjugated with saporin cytotoxin (anti-DBH-saporin) into the lateral brain ventricles of neonatal rats; and (2) microsurgical in utero destruction of embryo’s brain (in utero encephalectomy).

Signal molecules during the organism development: Central and peripheral sources of noradrenaline in rat ontogenesis.

Using the method of high performance liquid chromatography with electrochemical detection, the age dynamics of the content of noradrenaline (NA) in the brain, adrenal gland, and the organ of Zuckerkandl in prenatal (18th and 21st days of embryogenesis) and early postnatal (3, 7, 15, and 30th days) periods of development was studied. The potential contribution of these organs to the formation of physiologically active concentration of noradrenalin in the blood was also assessed. The results suggest that, during the development of the organism, the activity of the sources of noradrenaline in the general circulation changes, which gives a reason to assume the existence of humoral interaction between NA-producing organs in the perinatal period of ontogenesis.

Role of Adenohypophysotropic Neurohormones in Endocrine Paraadenohypophysial Regulation of Peripheral Target Organs in Rat Ontogeny.

We tested the hypothesis that brain-derived chemical stimuli contribute to direct endocrine regulation of peripheral organs during ontogeny before blood-brain barrier closure. Dopamine and gonadotropin-releasing hormone present in high concentration in peripheral blood only before blood-brain barrier closure were chosen as the chemical stimuli. It was shown than dopamine in concentrations equal to its level in the peripheral blood inhibits prolactin secretion in organotypic culture of the pituitary gland from newborn rats via specific receptors.

Neurons expressing individual enzymes of dopamine synthesis in the mediobasal hypothalamus of adult rats: functional significance and topographic interrelations.

Besides dopaminergic (DA-ergic) neurons having all enzymes of DA synthesis, tyrosine hydroxylase (TH) and aromatic l-amino acid decarboxylase (AADC), "monoenzymatic" neurons expressing only one of them were found in the brain, mostly in the mediobasal hypothalamus (MBH). The aim of this study was to test our hypothesis that DA is synthesized by monoenzymatic neurons, i.e.

Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature.

Background: Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology?

Discussion: Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases.

Developing brain as an endocrine organ: secretion of dopamine.

This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ before the establishment of the blood-brain barrier (BBB), in rats up to the first postnatal week. Dopamine (DA) was selected as a marker of the brain endocrine activity. The hypothesis was supported by the observations in rats of: (i) the physiological concentration of DA in peripheral blood of fetuses and neonates, before the BBB establishment, and its drop by prepubertal period, after the BBB development; (ii) a drop of the DA concentration in the brain for 54% and in blood for 74% on the 3rd postnatal day after the intraventricular administration of 50 μg of α-methyl-p-tyrosine, an inhibitor of DA synthesis, with no changes in the DA metabolism in peripheral DA-producing organs.

[Development of serotonergic neurons of dorsal raphe nuclei in mice with knockout of monoamine oxidase A and 5-HT1A and 5-HT1B autoreceptor].

The morphological changes in the development of serotonergic neurons of the dorsal raphe nuclei in the medulla oblongata was studied by immunocytochemistry in mice with knockout of 1A and 1B serotonin autoreceptors as well as monoamine oxidase A. Serotonin autoreceptors regulate electric activity of serotonergic neurons as well as the synthesis and release of the neurotransmitter, while monoamine oxidase A catalyzes its degradation. These genetic modifications proved to have no effect on the number of serotonergic neurons in the medulla oblongata but induced morphofunctional changes.

[Development of central and peripheral serotonin-producing systems in rats in ontogenesis].

The work deals with study of development of central and peripheral serotonin-producing systems in rat ontogenesis before and after formation of the blood-brain barrier. By the method of highly efficient liquid chromatography it has been shown that the serotonin level in peripheral blood before formation of the blood-brain barrier (in fetuses and neonatal rats) is sufficiently high for realization of physiological effect on target cells and organs. At the period of formation of the blood-brain barrier the serotonin level in brain sharply rises, whereas the serotonin concentration and amount in plasma and duodenum increase insignificantly.

[Brain is a source of blood serotonin in rats during perinatal development].

The aim of this study was to test our hypothesis that the brain functions as an endocrine organ before the blood-brain barrier is formed. A model of drug-inhibited serotonin synthesis in the brain using a single stereotactic administration of p-chlorophenylalanine, an inhibitor of serotonin synthesis, was developed. The inhibitor dose inducing the maximum effect in the brain and no effect on serotonin synthesis in the periphery was experimentally selected.