Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress

In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events

Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress

When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical-genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression

Искусственный нервный проводник для направленного роста периферических нервов (кадаверное исследование)

At present, the search for effective ways of restoring peripheral nerves with anatomical damage continues. Autoplasty still remains the gold standard, which, however, is not without its drawbacks. The use of nerve implants for promoting directional axon growth is essential and promising.Objective: to study the biomechanical properties of laboratory samples of an artificial nerve conduit (NGC) made of hybrid biomaterials and to, on cadaveric material, assess the technical feasibility of using them in surgical practice to repair extended peripheral nerve defects.Material and methods. The objects of the study were three electrospun NGC samples: from synthetic material (polycaprolactone, PCL) and hybrid biomaterials (PCL + gelatin or PCL + collagen). The work compared the physical and mechanical properties of NGC: stiffness, plasticity, elasticity, brittleness, resistance to chemical attack, their ability to be impregnated with liquid media, permeability, possibility of making an anastomosis between the implant and the nerve during surgical procedure. Cadaveric material was the object of the study: we used a dissected superficial sensory branch of the human right radial nerve, 2 mm in diameter, isolated on the forearm, about 12 cm in length, because it most corresponded to the diameter of the NGC samples tested. After surgery, the echogenic features of the implants and their anastomoses with the nerve were assessed by ultrasound imaging.Results. It was found that hybrid NGC samples, based on their biomechanical properties, are fundamentally suitable for use in surgical practice, to ensure growth and replacement of a peripheral nerve defect. However, the best composition of a nerve guide can be established after comparative preclinical study of the biocompatible and functional properties of hybrid material samples.Conclusion. The physical and mechanical properties of the investigated NGC samples made of hybrid biomaterials meet the technical requirements for implantable nerve conduits for surgical application.В настоящее время продолжаются поиски эффективных способов восстановления периферических нервов при анатомическом нарушении их целостности. Золотым стандартом по-прежнему остается аутопластика, которая, однако, не лишена недостатков. Актуальным и перспективным является метод применения нервных имплантатов для направленного роста аксонов.Цель: изучить биомеханические свойства лабораторных образцов искусственного нервного проводника (ИНП) – нервного кондуита, изготовленных из гибридных биоматериалов, и на кадаверном материале оценить техническую возможность их применения в хирургической практике для восстановления протяженных дефектов периферических нервов.Материал и методы. Объектами исследования служили изготовленные методом электроспиннинга три образца ИНП: из синтетического материала – поликапролактона (ПКЛ) и гибридных биоматериалов (ПКЛ с желатином или коллагеном). В ходе работы сравнивались физические и механические свойства ИНП: жесткость, пластичность, эластичность, хрупкость, устойчивость образцов к химическому воздействию, их способность к пропитыванию жидкими средами, проницаемость, возможность наложения анастомоза между имплантатом и нервом во время хирургической операции. В качестве кадаверного материала использовали поверхностную чувствительную ветвь правого лучевого нерва человека диаметром 2 мм, выделенную на предплечье протяженностью около 12 см, как наиболее соответствующую диаметру тестируемых образцов ИНП. После хирургической операции оценивали эхогенные признаки имплантатов и их анастомозов с нервом методом ультразвуковой визуализации.Результаты. Установлено, что образцы ИНП из гибридных материалов по биомеханическим свойствам принципиально пригодны для использования в хирургической практике для обеспечения роста и замещения дефекта периферических нервов. Однако наилучший состав нервного проводника может быть установлен после проведения сравнительных доклинических исследований биосовместимых и функциональных свойств образцов из гибридных материалов.Заключение. Физические и механические свойства исследуемых образцов ИНП из гибридных биоматериалов соответствуют техническим требованиям, предъявляемым к имплантируемым нервным проводникам при их хирургическом применении

Фармакоэкономический анализ применения фоллитропина альфа при использовании вспомогательных репродуктивных технологий

Objective: to evaluate clinical-economic feasibility and impact of follitropin alfa on the state healthcare budget of the Russian Federation in the population of women with diagnosed infertility and poor ovarian response, who undergo treatment with assisted reproductive technologies (ART).Material and methods. A cost minimization analysis to evaluate clinical-economic feasibility of follitropin alfa in women with infertility and poor ovarian response who underwent ART was performed. The model of the budget impact analysis included the costs required for the ovarian stimulation of patients distributed by various variants of their management. The current practice involved the application only of fixed dose combinations (FDC) of follitropin alfa + lutropin alfa. The expected practice suggested a change in the approach by shifting 25% of patients with poor ovarian response from FDC of follitropin alfa + lutropin alfa to follitropin alfa. A time horizon of modeling was 1 year.Results. The cost minimization analysis demonstrated that the application of drug with international nonproprietary name follitropin alfa is characterized by the cost cut of 12,020 rubles (–21.56%) per patient compared with FDС of follitropin alpha + lutropin alpha. The results of budget impact analysis showed that a shift of 25% of population from FDC of follitropin alfa + lutropin alfa to follitropin alfa could cut direct medical costs by 7.96 million rubles per year (–5.39%).Conclusion. Evaluation of clinical-economic feasibility and budget impact analysis showed that the application of follitropin alfa during ovarian stimulation in women with infertility and poor ovarian response leads to a decrease in budget expenses. Цель: оценить клинико-экономическую целесообразность и влияние на бюджет государственной системы здравоохранения Российской Федерации применения лекарственного препарата фоллитропин альфа в популяции женщин с бесплодием и бедным овариальным ответом, проходящих лечение с использованием вспомогательных репродуктивных технологий (ВРТ).Материал и методы. Оценку клинико-экономической целесообразности применения фоллитропина альфа при проведении ВРТ у пациенток с бесплодием и бедным овариальным ответом выполняли с использованием анализа минимизации затрат. В модели анализа влияния на бюджет сравнивали затраты, необходимые для овариальной стимуляции пациенток, распределенных по нескольким вариантам практики их ведения. Текущая практика включала применение только фиксированной комбинации доз (ФКД) фоллитропина альфа + лутропина альфа. В ожидаемой практике предполагалось изменение подхода посредством переключения 25% пациенток с бедным овариальным ответом с ФКД фоллитропина альфа + лутропина альфа на фоллитропин альфа. Временной горизонт моделирования составил 1 год.Результаты. Анализ минимизации затрат показал, что применение лекарственного препарата с международным непатентованным наименованием фоллитропин альфа характеризуется экономией затрат в размере 12 020 руб. (–21,56%) в расчете на одну пациентку по сравнению с ФКД фоллитропина альфа + лутропина альфа. По результатам анализа влияния на бюджет определено, что перевод 25% популяции с ФКД фоллитропина альфа + лутропина альфа на фоллитропин альфа позволит сократить прямые медицинские затраты на 7,96 млн руб. в год (–5,39%).Заключение. Оценка клинико-экономической целесообразности, а также анализ влияния не бюджет показали, что использование фоллитропина альфа при проведении овариальной стимуляции в популяции женщин с бесплодием и бедным овариальным ответом приводит к экономии бюджетных средств.

Prefrontal cortical control of a brainstem social behavior circuit

The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior

Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression

Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP - a marker of neuronal activation - in c-fosGFP transgenic mice subjected to the learned helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing "helpless" behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing "resilient" behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses

Precise Chemical Analysis Development for Si and GaAs Surfaces

Precise chemical analysis (PCA) was developed to allow the study of non-interconnected atoms on crystalline semiconductor surfaces, such as those produced during rapid thermal processing (RTP) of silicon and electron beam lithography on gallium arsenide (GaAs). The PCA method is based on selectively dissolving the different components present on the semiconductor surface using preferential etchant solutions. After etching, the etchant solution, containing the etched component, is analyzed by a photometric technique. In this paper, we present photometric measurements of the amount of “free” (non-interconnected) atoms that remain on semiconductor surfaces following electron beam and RTP processing. In this context, “free” atoms are those presenting in any form other than crystalline GaAs or Si, for instance, those in the form of surface oxides. Using the PCA method, free Ga and As were detected on GaAs surfaces after electron beam lithography. Free silicon, boron and phosphorous atoms were found on silicon surfaces after RTP. The concentration of boron diffused into a silicon wafer during RTP was also carried out by means of slight surface etching. We estimate the accuracy of this PCA method at 2% for Ga and 5% for all other elements

MYCOBACTERIUM TUBERCULOSIS BIOLOGICAL PROPERTIES AND CHARACTERISTICS OF THE INFLAMMATORY REACTION IN PATIENTS WITH INFILTRATIVE PULMONARY TUBERCULOSIS

Host-pathogen relations were analyzed on basis of the results of examinations of 42 patients with newly diagnosed, previously untreated infiltrative pulmonary tuberculosis (IPT) with regard for the biological characteristics of Mycobacterium tuberculosis (MBT) and the biomarkers of the inflammatory reaction — the acute phase proteins (APPs). The genotypes of MBT (Beijing and the others) and the efficacy of threeonth antituberculosis therapy were used as the grouping factors. Genotype Beijing MBT patients were significantly often characterised by multiple drug resistant, had widespread pulmonary damage and association of MBT cytoxicity with the effect of therapy. The patients with the best postreatment effect had initial (pretreatment) APPs levels in the range of the referent ones. These conclusions were confirmed by analysis of the correlation pleads of the characteristics of the “host-pathogen” system and their discriminant analysis with regard for MBT genotypes and results of antituberculosis three-month therapy. It was shown that the constellation of four host’s APP characteristics (haptoglobin, ceruloplasmin, elastase and adenoaminase activities) has above 90% prognostic efficacy of treatment in spite of MBT genotype. It is suggested that in IPT patients the first component of the “host-pathogen” system reflecting the reaction of the patient’s organism to the MBT induced inflammatory process is more prognostically important

Metal trafficking for nitrogen fixation: NifQ donates molybdenum to NifEN/NifH for the biosynthesis of the nitrogenase FeMo-cofactor

The molybdenum nitrogenase, present in a diverse group of bacteria and archea, is the major contributor to biological nitrogen fixation. The nitrogenase active site contains an iron–molybdenum cofactor (FeMo-co) composed of 7Fe, 9S, 1Mo, one unidentified light atom, and homocitrate. The nifQ gene was known to be involved in the incorporation of molybdenum into nitrogenase. Here we show direct biochemical evidence for the role of NifQ in FeMo-co biosynthesis. As-isolated NifQ was found to carry a molybdenum–iron–sulfur cluster that serves as a specific molybdenum donor for FeMo-co biosynthesis. Purified NifQ supported in vitro FeMo-co synthesis in the absence of an additional molybdenum source. The mobilization of molybdenum from NifQ required the simultaneous participation of NifH and NifEN in the in vitro FeMo-co synthesis assay, suggesting that NifQ would be the physiological molybdenum donor to a hypothetical NifEN/NifH complex