Central Regulatory Circuit Research Articles

Влияние загрязнённой радионуклидами среды на сердечный ритм детей в современных условиях

The main aim was to study the characteristics of heart rate variability in 8- and 10-year boys and girls that permanently reside in areas with an increased level of radioactive contamination. The body functions are formed by close interaction of the body and the environment. The adaptive responses of the developing organism are improved at each ontogenetic stage as its contact with the environment become more complex. We found that features of heart rate regulation depend on the area of residence. The contribution of the autonomous circuit of heart rate regulation is increased for 8- and 10-year-old girls from radio-ecologically safe areas (RESA). Based on the principle of functional antagonism this leads to a weakening of the central circuit of regulation. The shift gradient of indicators is higher for 8-year-old girls from radio-ecologically unfavorable areas (REUA) compared to 10-year-old girls. This reflects the greater sensitivity of their organism to adverse factors. The dominance of the autonomous circuit of regulation was marked for 8- and 10-year-old boys from the RESA. In contrast an imbalance in the operation of regulatory mechanisms with an increase in the central regulatory circuit was found for boys from the REUA. High centralization of cardiac control indicates that adaptation mechanisms are in a state of pronounced tension. The increase in the shift gradient for boys from REUA falls at the age of 10 years. The results of the study revealed gender differences in the regulation of heart rhythm. The obtained data is important diagnostic aspects of morphofunctional maturation of the organism for subsequent ontogenetic stages depending on environmental living conditions.

АКТИВНОСТЬ РЕГУЛЯТОРНЫХ СТРУКТУР МОЗГА ПРИ БОЕВОЙ ТРАВМЕ И ТРАВМЕ МИРНОГО ВРЕМЕНИ

Activation of the body’s regulatory systems provides adaptation to the impact of pathogenic factors. Prolonged exposure to extreme factors during combat operations can lead to the formation of a focus of pathologically increased exaltation in the central nervous system. The study aims to comparatively assess the tension of central regulatory structures in victims with battle and peacetime traumas in the acute period to develop criteria for indicating the severity of functional disorders of the central nervous system and pathogenetic treatment. Twenty servicemen who received mine-explosive trauma as a result of combat operations, twenty victims of domestic trauma, and twenty healthy males were examined. Neurophysiological and ultrasound methods of research were used to assess the functional state of the central nervous and cardiovascular systems: electroencephalography with quantitative analysis, transcranial Doppler with functional tests, electrocardiography with assessment of heart rate variability: The study assessed the index of spectral power of rhythms in alpha/theta ranges, indices of spectral power of heart rhythm (index of vagosympathetic balance; index of centralization; index of activation of subcortical structures), indices of vasodilatation/vasoconstriction reflecting reactivity of cerebral vessels to tests with hyper/hypocapnia. The following statistically significant differences were revealed between peacetime and wartime traumas: a decrease in vasodilation reserves for hypercapnia, and in some cases, their absence during battle trauma; increasing indices of centralization and activation of subcortical structures during battle trauma; decrease in the index of spectral power of rhythms in the alpha/theta ranges due to an increase in the power of the theta range during battle trauma. Based on this set of indicators, a scale of quantitative assessment of the degree of tension of regulatory subcortical structures in points was developed for early detection of patients with excessive activation of the central regulatory circuit leading to maladjustment and unfavorable course of the post-traumatic period.

The central regulatory circuit in the gene network controlling the morphogenesis of Drosophila mechanoreceptors: an <i>in silico</i> analysis

The central regulatory circuit in the gene network controlling the morphogenesis of Drosophila mechanoreceptors: an <i>in silico</i> analysis

ADAPTATION TO INTENSE MUSCULAR ACTIVITY AND PECULIARITIES OF AUTONOMIC REGULATION OF HEART RATE VARIABILITY IN ATHLETES (II MESSAGE)

Introduction. Determining the mechanisms of regulation of the cardiovascular system as an indicator of the functional state of the body, on which the effectiveness of sports activity largely depends, remains relevant in assessing the ways of adaptation of the athlete's body to various physical activities. The purpose of the study is to investigate the peculiarities of physical performance of qualified athletes with different types of autonomic regulation of heart rate based on the mathematical analysis of heart rate variability. Material and methods. The study involved 214 skilled athletes specialising in rowing, basketball, handball, athletics, hockey, triathlon, cross-country skiing, biathlon and other sports. Methods of analysis of heart rate variability features, methods of determining physical performance of qualified athletes and the reaction of the cardiorespiratory system to test loads (ergospirometric complex "Oxycon Pro", treadmill LE-200 C), mathematical and statistical methods. Results. When performing strenuous physical activity, the initial type of autonomic regulation largely determines the effectiveness of compensatory and adaptive reactions of the organism. Thus, the normotonic and moderately vagotonic type of regulation of the HR in a state of relative rest was inherent in highly skilled athletes with a high level of functional fitness. Normotonic and vagotonic types of HR regulation characterise the optimal functional state of a sportsman's organism, high functional capabilities of the organism, which ensure the preservation of vegetative homeostasis, the optimal level of regulation efficiency and the level of functioning economy, and stable regulation. The sympathicotonic type of HR regulation is also inherent in satisfactory adaptation to strenuous physical activity and sufficient functional capabilities of the sportsman's organism. However, there are already signs of dysregulation in the central regulatory circuit, a reduced level of efficiency of HR regulation, an increased level of tension in the regulatory mechanisms of adaptation. Against this background of such regulation of HR, a deterioration of the functional state of a sportsman can be noted, objective signs of fatigue appear. Prognostically unfavourable for athletes in a state of relative rest is a pronounced vagotonic type of SR regulation, as well as a sharply expressed sympathicotonic type of SR regulation - characterising reduced functional capabilities of the organism, unsatisfactory adaptation to strenuous physical activity. Conclusions. The vagotonic, normotonic and sympathicotonic types of HR regulation in a state of relative rest allow us to speak about the satisfactory adaptation of the human body to the influence of various environmental factors. The unsatisfactory adaptation of the human body to environmental factors is characterised by a pronounced vagotonic and pronounced sympathicotonic types of HR regulation in a state of relative rest.

Морфофункциональный статус студентов-первокурсников смежных поколений на рубеже веков

The aim of this work was to carry out a comparative analysis of a series of anthropometric and physiometric parameters of students who studied in the first year of three faculties of Perm State Humanitarian Pedagogical University (PSHPU) in the academic years 2004/2005 and 2022/2023, that is, students belonging to two adjacent generations. The height and body weight, the blood pressure, the type of regulatory processes, as well as indices calculated on the basis of the listed parameters were compared: body mass index, or Quetelet's index (BMI), Functional Changes Score (FCS), Centralization Index (CI), Regulatory Effort Index (REI). The last two indices are derivatives of the parameters of heart rate variability (HRV), which make it possible to as-sess the contribution of autonomous and central regulatory circuits to the body processes and to predict the adaptive resources of the body. In both samples, there were the expected differences between the male and female participants in terms of weight and height parameters, e.g. the men were taller and heavier than the women, except for those whose BMI exceeded 25 kg/m2, i.e. overweight students. However, the students surveyed in 2022 did not demonstrate any differences in the values of the height and weight from those who studied in the same faculties in 2004. The assessment of the functional parameters did not show any significant differences between the generations of the late XX, early XXI century in the heart rate (HR), in the duration of the most frequent RR interval (Mo) and in the contribution of the autonomic and central regulatory circuits to the regulatory processes. What is alarming is the higher blood pressure, especially pulse pressure, which is a kind of marker of the vascular wall abnormalities in the large arteries. It was observed in students, especially young men, of a later generation, i.e. born in 2002-2004. HRV data indicate greater resistance of the women’s body to stressing factors. This can be concluded based on the influence of central and autonomous regulation circuits on the characteristics of heart rate: in the women, the autonomous regulatory processes were more intense than in men. Moreover, this fact was reported both in the sample of 2022 and among students examined in 2004.

HEART RATE VARIABILITY AND BASIC HEMODYNAMIC PARAMETERS IN MEDICAL STUDENTS IN SEASONS WITH DIFFERENT PHOTOPERIOD

One of the main external factors that contributes to the seasonal functional reorganization of the organism in the process of adaptation is seasonal photoperiodic variability. Day length is affecting not only visual function, but also all physiological and behavioural processes controlled by the circadian rhythm system. The person's ability to adapt to changes in external factors is especially important for medical students who experience significant mental overload in the process of studying at a university. The study goal was to investigate the features of the main hemodynamic parameters and heart rate variability in medical students in the spring and autumn periods, with taking into account gender differences. Materials and methods: A cross-sectional study of 304 students of the North-Ossetian State Medical Academy (Russia) comprising 233 female and 71 male subjects was performed during periods of elongation (spring) and shortening (autumn) of the photoperiod. Blood pressure (BP), pulse rate (HR), parameters of heart rate variability (HRV) were measured. Results: The students showed an increase in DBP and MBP rates within the normal range in autumn. Hemodynamic parameters of SBP, DBP, PBP, MBP in males were significantly higher than in females group, regardless of the season. Interseasonal differences in HRV parameters (LF, THF, PHF, PLF, LF/HF, IC) were revealed. From spring to autumn period, LF decreases from 980.22 (590.30; 1445.83) to 690.68 (438.81; 1170.15) ms2 against the background of a decrease in the dominant period of the high-frequency component of the spectrum (THF) from 5.40 (3 .77; 6.10) to 3.71 (3.08; 5.54) s. The contribution of the high-frequency component (PHF) to the total power of HRV fluctuations increases by 10.4%, and the low-frequency component (PLF) decreases by 6.45% as the photoperiod shortens. The centralization index (IC) also declines from 2.58 (1.42; 3.90) to 1.61 (0.97; 2.98); p=0.0076. Parameters of Mean, Mo, RMSSD, pNN50, SDNN, TP, HF, PHF in spring are lower in males in comparison with females, while parameters of HR, SI, PLF, LF/HF, VLF/HF, IC, PARS are higher in males. Conclusions: It was indicated that the change in the photoperiod trend is an important mediator of heart rate variability in the annual cycle. The lengthening of the photoperiod in the spring season is accompanied by a shift in the vegetative balance of students towards an increase in the tonus of the sympathetic division of the autonomic nervous system (ANS) together with the involvement of the central circuit of the heart rhythm regulation. In autumn, on the background of shorter daylight duration hours, parasympathetic influences are intensified and autonomic regulation circuit is most active. In the common trend of increased sympathetic activity of the ANS and activation of the central regulatory circuit in the spring, in young males these changes are indicated at greater extent.

Оценка функциональных резервов организма первокурсников северного педагогического вуза по результатам ортостатической пробы

The success of adaptation to the standard minimum load (using orthostatic test as an example) is primarily determined by the ability of the regulatory systems to restructure the activity of the cardiovascular system without involving the central regulatory circuit. Evaluation of the body’s functional reserves can provide the basis for characterization of its adaptive capabilities as a whole. The aim of this study was to assess the body’s functional reserves in first-year students of a pedagogical university in northern Russia according to the results of an orthostatic test. Materials and methods. A total of 135 first-year students of Surgut State Pedagogical University were examined, their mean age being 18.3 ± 0.33 years. Cardiointervalography (VNS-spektr device, Neurosoft, Russia) was used to assess heart rate variability at rest and during an active orthostatic test. Results. Total power, as well as absolute low frequency and very low frequency power decreased during the orthostatic test in both groups. It was found that 23 % of male and 16 % of female students had a reduced reaction to the orthostatic test. High level of adaptation reserves was observed in 30 % of first-year students. At the same time, we identified groups with a low level of adaptation reserves (8.8 % of male and 2 % of female students). The research established that the level of the body’s functional reserves in young women was higher than that in young men. In addition, female students showed a bigger contribution of the central circuit to heart rate regulation. Young men demonstrated high parasympathetic reactivity and a greater contribution of subcortical centres to heart rate regulation, compared to young women.

On the use of integral indicators of the functional state of the children’s body as criteria for realizing the risk of adverse effects of environmental factors

Special attention is always paid to the health of children associated with the influence of environmental factors in scientific research. This is due to the fact that environmental factors play an important role in determining the health and well-being of children. Of particular importance is the search for informative integral indicators that characterize the impact of various degrees of anthropogenic load on the health of the child population. The article presents the results of a study of integral indicators of the health status of 315 children aged 4–6 years living in the territory with a high (group 1) and low (group 2) level of anthropogenic load, such as the stability of the nervous reaction, the stress index of regulatory systems, the index of vegetative equilibrium, the vegetative rhythm indicator, the indicator of the adequacy of regulatory processes. The obtained data indicate that a high level of anthropogenic load has an adverse effect on the integral indicators of the functional state of the central nervous, autonomic and cardiovascular systems. This is characterized by a decrease in the stability index of the nervous reaction, an increase in the sympathetic activity of the central nervous system, depletion of the central regulatory circuits due to prolonged activation of non-economic mechanisms for regulating the high tone of the sympathetic nervous system. At the same time, the adverse effects increase with an increase in the age of children from 4 to 6 years old living in an area with a high level of anthropogenic load. The established facts of changes in integral indicators represent a scientific justification for the use of these indicators in the development of mathematical models for managing risks to children’s health under the influence of anthropogenic factors.

Deletion of the Feeding-Induced Hepatokine TSK Ameliorates the Melanocortin Obesity Syndrome.

Work in recent decades has established that metabolic hormones released by endocrine cells and diverse other cell types serve to regulate nutrient intake and energy homeostasis. Tsukushi (TSK) is a leucine-rich repeat-containing protein secreted primarily by the liver that exerts an inhibitory effect on brown fat sympathetic innervation and thermogenesis. Despite this, physiological regulation of TSK and the mechanisms underlying its effects on energy balance remain poorly understood. Here we show that hepatic expression and plasma concentrations of TSK are induced by feeding and regulated by melanocortin-4 receptor (MC4R) signaling. We generated TSK and MC4R-double-knockout mice to elucidate the nature of cross talk between TSK and the central regulatory circuit of energy balance. Remarkably, TSK inactivation restores energy balance, ameliorates hyperphagia, and improves metabolic health in MC4R-deficient mice. TSK ablation enhances thermogenic gene expression in brown fat, dampens obesity-association inflammation in the liver and adipose tissue, and protects MC4R-null mice from diet-induced nonalcoholic steatohepatitis. At the cellular level, TSK deficiency augments feeding-induced c-Fos expression in the paraventricular nucleus of the hypothalamus. These results illustrate physiological cross talk between TSK and the central regulatory circuit in maintaining energy balance and metabolic homeostasis.

Mathematical and numerical models of the central regulatory circuit of the morphogenesis system of Drosophila

Mathematical and numerical models of the central regulatory circuit of the morphogenesis system of Drosophila

Mathematical and Numerical Models of the Central Regulatory Circuit of the Morphogenesis System of Drosophila

The results are presented of mathematical and computer simulation of the functioning of the central regulatory circuit (CRC) which is the system integrator of the gene networks of morphogenesis of Drosophila mechanoreceptors. The main element of the CRC is represented by the complex of Achaete-Scute (AS-C) genes, the main genes of the mechanoreceptor morphogenesis. The content level of the proteins encoded by the AS-C genes is a determining factor for initiating the development of a mechanoreceptor. We carried out a comparative study of the CRC behavior under normal conditions and in the presence of mutational changes in the Achaete-Scute complex. The results of simulation are in good accord with the available biological data.

Гестаційний процес та пологова діяльність у вагітних з різними типами вегетативної регуляції

The objective: is to analyze the frequency of gestational complications and labor abnormalities in pregnant women with different types of vegetative regulation disorders. Materials and methods. 129 women were examined. The type of vegetative regulation was determined by recording the time and spectral parameters of heart rate variability by computer cardiointervalography with use of CardioLab Bebicard diagnostic system. The main group consisted of 66 pregnant women with established vegetative regulation disorders. 63 patients with a normal vegetative state, a balanced level of sympathetic and parasympathetic activity formed a control group. To assess the status of the mother–placenta–fetus, an ultrasound examination with doplerometry was performed. Results. A significant increase of the central regulatory circuit activity in pregnant women with vegetative dysfunction was established. The cardiointervalography indicate a balanced activity of the vegetative nervous system in the control group. The gestational complications were significantly more frequent in women of the main group in the context of detected vegetative dysfunction than in the control group. Labor anomalies were more common in pregnant women of the main group. Women with high parasympathetic astivity noted an increased frequency of labor dystocia. In patients with a superiority of sympathetic and humoral regulation, an increased frequency of weakness of labour activity was observed. The fast deliveries often determined in pregnant women with decreased activity of both departments of autonomic nervous system. The incidence of urgent caesarian deliveries was significantly higher in the main group, including due to the ineffectiveness of the medical correction of labor abnormalities. Conclusions. The cardiointervalography is informative for the diagnosis of vegetative regulation and adaptive disorders, which may be the prerequisites for the gestational complications and labor abnormalities development. Using the heart rate variability analysis in pregnant women will improve the early prediction of gestational pathology and pathological birth process, reduce the risk of obstetric and perinatal complications. Key words: heart rate variability, vegetative regulation, gestational complications, labor activity abnormalities.

GPR88 is a critical regulator of feeding and body composition in mice

GPR88 is an orphan G-protein-coupled receptor with predominant expression in reward-related areas in the brain. While the lack of GPR88 has been demonstrated to induce behavioral deficits, the potential function of the receptor in the control of food intake and energy balance remains unexplored. In this work, the role of GPR88 in energy homeostasis was investigated in Gpr88−/− mice fed either standard chow or high fat diet (HFD). Gpr88−/− mice showed significantly reduced adiposity accompanied with suppressed spontaneous food intake, particularly pronounced under HFD treatment. While energy expenditure was likewise lower in Gpr88−/− mice, body weight gain remained unchanged. Furthermore, deregulation in glucose tolerance and insulin responsiveness in response to HFD was attenuated in Gpr88−/− mice. On the molecular level, distinct changes in the hypothalamic mRNA levels of cocaine-and amphetamine-regulated transcript (Cartpt), a neuropeptide involved in the control of feeding and reward, were observed in Gpr88−/− mice. In addition, GPR88 deficiency was associated with altered expressions of the anorectic Pomc and the orexigenic Npy in the arcuate nucleus, especially under HFD condition. Together, our results indicate that GPR88 signalling is not only important for reward processes, but also plays a role in the central regulatory circuits for energy homeostasis.

Gene network controlling the morphogenesis of D. melanogaster macrochaetes: An expanded model of the central regulatory circuit

The drosophila macrochaetes act as mechanoreceptors, the sensory organs of the peripheral nervous system. Each mechanoreceptor consists of four specialized cells, namely, the shaft, socket, neuron, and sheath. All these cells develop from a single cell referred to as the sensory organ precursor (SOP) cell. The SOP cell segregates from the surrounding cells of imaginal disc, thereby launching multistage sensory organ development. A characteristic feature of the SOP cell is the highest content of the proneural proteins Achaete and Scute (ASC) as compared with the surrounding cells. The pattern of changes in the content of proneural proteins in the SOP cell is determined by a gene network with the achaete-scute (AS-C) gene complex as its key component. The activity of this complex is controlled by the central regulatory circuit (CRC), containing the genes hairy, senseless (sens), charlatan (chn), scratch (scrt), daughterless (da), extramacrochaete (emc), and groucho (gro), encoding the transcription factors involved in the system of feedforwards and feedbacks and implementing the activation–repression of CRC components, as well as the gene phyllopod (phyl), an adaptor protein that controls the degradation of ASC proteins. A mathematical model describing the CRC functioning in the SOP cell as a regulator of the content of ASC proneural proteins is proposed.

Microbiota: ‘bugging’ insights into metabolic regulation

The advent of e omics technologies has renewed longstanding interest in understanding the symbiotic relationship between gutresident microbiota and the physiological integrity of the host. A flurry of mostly explorative studies has revealed an intimate, bidirectional exchange of information between the microbiota and the host, indicating mutual dependencies, particularly with respect to human health and in the context of human diseases. Emerging data capture and classify major microbial populations and elucidate the signaling molecules and/or metabolites mediating direct microbial effects on the host’s intestinal epithelium. Further research has assessed the propensity of bacterial signals/compounds to pass the intestinal barrier and has begun to unravel how such compounds affect a variety of metabolic organs, their lines of communication, and their respective central regulatory circuit(s). That said, we have only just begun to understand how post-industrialization changes to diet, lifestyle, and the physical and chemical components of our environments affect the composition and biological activity of individual human microbiomes. Understanding the complexity of host-microbiome interactions at the molecular level, therefore, holds great potential for tackling significant global health problems, such as obesity, diabetes, and metabolic syndrome, as well as shedding new light on poorly understood multifactorial diseases, such as non-alcoholic fatty liver disease. At Molecular Metabolism, we appreciate the fast-paced and global reach of modern research. With our commitment to emerging trends in diabetes and metabolism research, we are delighted to introduce our special issue entitled Microbiota & Metabolism: how microbes affect metabolic balance. We hope that the contributions solicited for this special issue offer a much needed overview on this exciting field and that our expert authors inspire you and open new directions for future research. Starting with an anthropologic approach, Suzanne Devkota & Josiane Broussard suggest that post-industrialization changes to diet in conjunction with physical environments contribute to the rise in chronic inflammatory and metabolic diseases. Their evolutionary take on (gut-) microbial selection due to Western diet and our self-inflicted restriction to mostly indoor-habitats and life-style choices create physical barriers for bacterial exposure. This review offers a general

Glutamatergic drive facilitates synaptic inhibition of dorsal vagal motor neurons after experimentally induced diabetes in mice.

The role of central regulatory circuits in modulating diabetes-associated glucose dysregulation has only recently been under rigorous investigation. One brain region of interest is the dorsal motor nucleus of the vagus (DMV), which contains preganglionic parasympathetic motor neurons that regulate subdiaphragmatic visceral function. Previous research has demonstrated that glutamatergic and GABAergic neurotransmission are independently remodeled after chronic hyperglycemia/hypoinsulinemia. However, glutamatergic circuitry within the dorsal brain stem impinges on GABAergic regulation of the DMV. The present study investigated the role of glutamatergic neurotransmission in synaptic GABAergic control of DMV neurons after streptozotocin (STZ)-induced hyperglycemia/hypoinsulinemia by using electrophysiological recordings in vitro. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was elevated in DMV neurons from STZ-treated mice. The effect was abolished in the presence of the ionotropic glutamate receptor blocker kynurenic acid or the sodium channel blocker tetrodotoxin, suggesting that after STZ-induced hyperglycemia/hypoinsulinemia, increased glutamatergic receptor activity occurs at a soma-dendritic location on local GABA neurons projecting to the DMV. Although sIPSCs in DMV neurons normally demonstrated considerable amplitude variability, this variability was significantly increased after STZ-induced hyperglycemia/hypoinsulinemia. The elevated amplitude variability was not related to changes in quantal release, but rather correlated with significantly elevated frequency of sIPSCs in these mice. Taken together, these findings suggest that GABAergic regulation of central vagal circuitry responsible for the regulation of energy homeostasis undergoes complex functional reorganization after several days of hyperglycemia/hypoinsulinemia, including both glutamate-dependent and -independent forms of plasticity.

A model study of the morphogenesis of D. melanogaster mechanoreceptors: the central regulatory circuit.

Macrochaetes (large bristles) are sensor organs of the Drosophila peripheral nervous system with a function of mechanoreceptors. An adult mechanoreceptor comprises four specialized cells: shaft (trichogen), socket (tormogen), neuron, and glial cell (thecogen). All these cells originate from a single cell, the so-called sensor organ precursor (SOP) cell. Separation of the SOP cell from the encompassing cells of the imaginal disc initiates a multistage process of sensory organ development. A characteristic feature of the SOP cell is the highest amount of the proneural proteins AS-C as compared with the encompassing ectodermal cells. The accumulation of proneural proteins and maintenance of their amount in the SOP cell at a necessary level is provided by the gene network with the achaete-scute gene complex (AS-C) as its key component. The activity of this complex is controlled by the central regulatory circuit (CRC). The CRC comprises the genes hairy, senseless (sens), charlatan (chn), scratch (scrt), daughterless (da), extramacrochaete (emc), and groucho (gro), coding for the transcription factors involved in the system of direct links and feedbacks and implementation of activation-repression relationships between the CRC components. The gene phyllopod (phyl), involved in degradation of the AS-C proteins, is also associated with the CRC functioning. In this paper, we propose a mathematical model for the CRC functioning as a regulator of the amount of proneural AS-C proteins in the SOP cell taking into account their degradation. The modeling has demonstrated that a change in the amount of proneural proteins in the SOP cell is stepwise rather than strictly monotonic. This prediction can be tested experimentally.

Postnatal dietary fatty acid composition permanently affects the structure of hypothalamic pathways controlling energy balance in mice

We previously reported that dietary lipid quality during early life can have long-lasting effects on metabolic health and adiposity. Exposure to a postnatal diet with low dietary omega-6 (n-6) or high omega-3 (n-3) fatty acid (FA) content resulted in reduced body fat accumulation when challenged with a moderate Western-style diet (WSD) beginning in adolescence. We determined whether this programming effect is accompanied by changes in hypothalamic neural projections or modifications in the postnatal leptin surge, which would indicate the altered development of hypothalamic circuits that control energy balance. Neonatal mice were subjected to a control diet (CTR) or experimental diet with altered relative n-6 and n-3 FA contents [ie, a diet with a relative reduction in n-6 fatty acid (LOW n-6) or a diet with a relative increase in n-3 fatty acid (HIGH n-3) compared with the CTR from postnatal day (PN) 2 to 42]. Compared with CTR mice, mice fed a LOW n-6 or HIGH n-3 during postnatal life showed significant reductions in the density of both orexigenic and anorexigenic neural projections to the paraventricular nucleus of the hypothalamus at PN 28. These impairments persisted into adulthood and were still apparent after the WSD challenge between PNs 42 and 98. However, the neuroanatomical changes were not associated with changes in the postnatal leptin surge. Although the exact mechanism remains to be elucidated, our data indicate that the quality of dietary FA during postnatal life affects the development of the central regulatory circuits that control energy balance and may do so through a leptin-independent mechanism.

VirF-Independent Regulation of Shigella virB Transcription is Mediated by the Small RNA RyhB

Infection of the human host by Shigella species requires the coordinated production of specific Shigella virulence factors, a process mediated largely by the VirF/VirB regulatory cascade. VirF promotes the transcription of virB, a gene encoding the transcriptional activator of several virulence-associated genes. This study reveals that transcription of virB is also regulated by the small RNA RyhB, and importantly, that this regulation is not achieved indirectly via modulation of VirF activity. These data are the first to demonstrate that the regulation of virB transcription can be uncoupled from the master regulator VirF. It is also established that efficient RyhB-dependent regulation of transcription is facilitated by specific nucleic acid sequences within virB. This study not only reveals RyhB-dependent regulation of virB transcription as a novel point of control in the central regulatory circuit modulating Shigella virulence, but also highlights the versatility of RyhB in controlling bacterial gene expression.

Hypothalamic Y2 receptors regulate bone formation.

Neuropeptide Y (NPY) is a downstream modulator of leptin action, possibly at the level of the arcuate nucleus where NPY neurons are known to express both leptin receptors and Y2 receptors. In addition to the well-described role of NPY and leptin in energy balance and obesity, intracerebroventricular administration of NPY or leptin also causes bone loss. Here we show that Y2 receptor-deficient mice have a twofold increase in trabecular bone volume as well as greater trabecular number and thickness compared with control mice. We also demonstrate that central Y2 receptors are crucial for this process, since selective deletion of hypothalamic Y2 receptors in mature conditional Y2 knockout mice results in an identical increase in trabecular bone volume within 5 weeks. This hypothalamus-specific Y2 receptor deletion stimulates osteoblast activity and increases the rate of bone mineralization and formation, with no effect on osteoblast or osteoclast surface measurements. The lack of any changes in plasma total calcium, leptinemia, or hypothalamo-pituitary-corticotropic, -thyrotropic, -somatotropic, or -gonadotropic output suggests that Y2 receptors do not modulate bone formation by humoral mechanisms, and that alteration of autonomic function through hypothalamic Y2 receptors may play a key role in a major central regulatory circuit of bone formation.