The development of bi-directionally coupled self-organizing neurovascular networks captures orientation-selective neural and hemodynamic cortical responses

The network of neurons in the brain is considered the primary substrate of information processing. Despite growing evidence on the possible role of cerebral blood flow in information processing, the cerebrovascular network is generally viewed as an irrigation system that ensures a timely supply of oxygen, glucose, and nutrients to the neural tissue. However, a recent study has shown that cerebral microvessels, like neurons, also exhibit tuned responses to sensory stimuli. Tuned neural responses to sensory stimuli are certainly enhanced with experience-dependent Hebbian plasticity and other forms of learning. Hence it is possible that the densely interconnected microvascular network might also be subject to some form of plasticity or competitive learning rules during early postnatal development such that its fine-scale structure becomes optimized for metabolic delivery to a given neural micro-architecture. To explore the possibility of adaptive lateral interactions and tuned responses in cerebral microvessels, we modeled the cortical neurovascular network by interconnecting two laterally connected self-organizing networks (Laterally Interconnected Synergetically Self-Organizing Map - LISSOM). The afferent and lateral connections of the LISSOM were defined by trainable weights. By varying the topology of lateral connectivity in the vascular network layer, we observed that the partial correspondence of feature selectivity between neural and hemodynamic responses could be explained by lateral coupling across local blood vessels such that the central domain receives an excitatory drive of more blood flow and a more distal surrounding region where blood flow is reduced. Critically, our simulations suggest a new role for feedback from the vascular to the neural network because the radius of vascular perfusion seems to determine whether the cortical neural map develops into a clustered and columnar vs. salt-and-pepper organization.

ANALYSIS OF THE ACTIVITIES OF "VORONEZH MATERNITY HOSPITAL №2" USING THE IDEF METHODOLOGY

Неудовлетворительное состояние здоровья населения страны в целом, ухудшающиеся показатели репродуктивного здоровья женщин лежат в основе тяжелой демографической ситуации. Такое положение в значительной мере обусловлено снижением доступности и качества медицинской помощи. В статье рассматривается деятельность родильного дома с помощью методологии IDEF0, IDEF3, дерева целей, а также проведена оценка его показателей и составлена таблица занятости медицинского персонала. Уровень оказываемой роддомом медицинской помощи напрямую влияет на здоровье рожениц и новорожденных, поэтому строгое наблюдение за его деятельностью и за соответствие всех показателей нормам необходимо. Репродуктивное здоровье женщин имеет высокую демографическую значимость, так как рождающееся потомство определяет здоровье популяции в целом, и социальную обусловленность - зависимость внутриутробного и раннего постнатального развития ребенка от качества жизни и состояния здоровья матери, обеспечивающей благополучие младенца после рождения. Для визуализации структуры организации и понятия целей ее деятельности использовались организационная структура и такой метод системного анализа как дерево целей. Для наглядного представления процессов, протекающих в роддоме, выявления взаимосвязей основных и вспомогательных элементов системы, управления и главных видов ресурсов использовалась общая модель IDEF0 и декомпозиция ее основных блоков. Диаграмма IDEF3 обеспечивает дискретность моделирования процесса, что позволяет контролировать ход выполнения работ. Основной целью моделирования деятельности родильного дома является анализ его показателей и выявление проблем, существующих в его процессах The unsatisfactory state of health of the population of the country as a whole, the deteriorating indicators of the reproductive health of women underlie the difficult demographic situation. This situation is largely due to the decline in the availability and quality of medical care. The article examines the activities of the maternity hospital using the methodology IDEF0, IDEF3, the tree of goals, as well as an assessment of its indicators and compiled a table of the employment of medical personnel. The level of medical care provided by the maternity hospital directly affects the health of women in labor and newborns, therefore, strict monitoring of its activities and the compliance of all indicators with standards is necessary. The reproductive health of women has a high demographic significance, since the offspring being born determines the health of the population as a whole, and social conditioning is the dependence of the intrauterine and early postnatal development of the child on the quality of life and the state of health of the mother, which ensures the well-being of the baby after birth. To visualize the structure of the organization and the concept of the goals of its activities, the organizational structure and such a method of system analysis as the tree of goals were used. To visualize the processes taking place in the maternity hospital, to identify the interrelationships of the main and auxiliary elements of the system, control and main types of resources, the general IDEF0 model and the decomposition of its main blocks were used. The IDEF3 diagram provides discrete process modeling, which allows you to monitor the progress of work. The main purpose of modeling the activities of a maternity hospital is to analyze its indicators and identify problems that exist in its processes. The article examines the activities of the maternity hospital using the methodology IDEF0, IDEF3, the goal tree, as well as an assessment of its indicators and compiled a table of employment of medical personnel. The level of medical care provided by the maternity hospital directly affects the health of women in labor and newborns, therefore, strict monitoring of its activities and compliance with all indicators with standards is necessary. The reproductive health of women has a high demographic significance, since the offspring born determines the health of the population as a whole, and social conditionality - the dependence of the intrauterine and early postnatal development of the child on the quality of life and the state of health of the mother, ensuring the well-being of the baby after birth. To visualize the structure of the organization and the concept of the goals of its activities, the organizational structure and such a method of system analysis as a tree of goals were used. For a visual representation of the processes taking place in the maternity hospital, to identify the interrelationships of the main and auxiliary elements of the system, management and the main types of resources, the general IDEF0 model and the decomposition of its main blocks were used. The main purpose of modeling the activities of a maternity hospital is to analyze its indicators and identify problems existing in its processes

Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods

The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.

Posttranscriptional modulation of KCNQ2 gene expression by the miR-106b microRNA family

MicroRNAs (miRNAs) have recently emerged as important regulators of ion channel expression. We show here that select miR-106b family members repress the expression of the KCNQ2 K+ channel protein by binding to the 3′-untranslated region of KCNQ2 messenger RNA. During the first few weeks after birth, the expression of miR-106b family members rapidly decreases, whereas KCNQ2 protein level inversely increases. Overexpression of miR-106b mimics resulted in a reduction in KCNQ2 protein levels. Conversely, KCNQ2 levels were up-regulated in neurons transfected with antisense miRNA inhibitors. By constructing more specific and stable forms of miR-106b controlling systems, we further confirmed that overexpression of precursor-miR-106b-5p led to a decrease in KCNQ current density and an increase in firing frequency of hippocampal neurons, while tough decoy miR-106b-5p dramatically increased current density and decreased neuronal excitability. These results unmask a regulatory mechanism of KCNQ2 channel expression in early postnatal development and hint at a role for miR-106b up-regulation in the pathophysiology of epilepsy.

Region-specific KCC2 rescue by rhIGF-1 and oxytocin in a mouse model of Rett syndrome

Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified three key frontal brain regions showing KCC2 alterations in young adult mice but not in postnatal P10 animals. We thus hypothesized that deficits in IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor (IGF-1R) and OXT receptor (OXTR) levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be the most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.

Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis

Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth.

Impact of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behaviors and BDNF mRNA expression in the adult Sprague–Dawley rats exposed to glutathione deficit during early postnatal development of the brain

Background Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. Methods In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5–p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90–92 rats were evaluated in the behavioral and biochemical tests. Results BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. Conclusion The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.

Arg1+ microglia are critical for shaping cognition in female mice

Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1+microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1+ microglia are frequently observed in close apposition to neurons and exhibit a distinct molecular signature including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2. Arg1-knockout in microglia results in a deficient cholinergic innervation along with impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, impaired long-term potentiation and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.

Erythropoietin promotes hippocampal mitochondrial function and enhances cognition in mice

Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.