Yulia K. Komleva

CD38 in the nucleus accumbens and oxytocin are related to paternal behavior in mice

BackgroundMammalian sires participate in infant care. We previously demonstrated that sires of a strain of nonmonogamous laboratory mice initiate parental retrieval behavior in response to olfactory and auditory signals from the dam during isolation in a new environment. This behavior is rapidly lost in the absence of such signals when the sires are caged alone. The neural circuitry and hormones that control paternal behavior are not well-understood. CD38, a membrane glycoprotein, catalyzes synthesis of cyclic ADP-ribose and facilitates oxytocin (OT) secretion due to cyclic ADP-ribose-dependent increases in cytosolic free calcium concentrations in oxytocinergic neurons in the hypothalamus. In this paper, we studied CD38 in the nucleus accumbens (NAcc) and the role of OT on paternal pup retrieval behavior using CD38 knockout (CD38−/−) mice of the ICR strain.ResultsCD38−/− sires failed to retrieve when they were reunited with their pups after isolation together with the mate dams, but not with pup, in a novel cage for 10 min. CD38−/− sires treated with a single subcutaneous injection of OT exhibited recovery in the retrieval events when caged with CD38−/− dams treated with OT. We introduced human CD38 in the NAcc of CD38−/− sires using a lentiviral infection technique and examined the effects of local expression of CD38. Pairs of knockout dams treated with OT and sires expressing CD38 in the NAcc showed more retrieval (83% of wild-type sire levels). Complete recovery of retrieval was obtained in sires with the expression of CD38 in the NAcc in combination with OT administration. Other paternal behaviors, including pup grooming, crouching and huddling, were also more common in CD38−/− sires with CD38 expression in the NAcc compared with those in CD38−/− sires without CD38 expression in the NAcc.ConclusionsCD38 in the NAcc and OT are critical in paternal behavior.

Glycolysis-mediated control of blood-brain barrier development and function

The blood-brain barrier (BBB) consists of differentiated cells integrating in one ensemble to control transport processes between the central nervous system (CNS) and peripheral blood. Molecular organization of BBB affects the extracellular content and cell metabolism in the CNS. Developmental aspects of BBB attract much attention in recent years, and barriergenesis is currently recognized as a very important and complex mechanism of CNS development and maturation. Metabolic control of angiogenesis/barriergenesis may be provided by glucose utilization within the neurovascular unit (NVU). The role of glycolysis in the brain has been reconsidered recently, and it is recognized now not only as a process active in hypoxic conditions, but also as a mechanism affecting signal transduction, synaptic activity, and brain development. There is growing evidence that glycolysis-derived metabolites, particularly, lactate, affect barriergenesis and functioning of BBB. In the brain, lactate produced in astrocytes or endothelial cells can be transported to the extracellular space via monocarboxylate transporters (MCTs), and may act on the adjoining cells via specific lactate receptors. Astrocytes are one of the major sources of lactate production in the brain and significantly contribute to the regulation of BBB development and functioning. Active glycolysis in astrocytes is required for effective support of neuronal activity and angiogenesis, while endothelial cells regulate bioavailability of lactate for brain cells adjusting its bidirectional transport through the BBB. In this article, we review the current knowledge with regard to energy production in endothelial and astroglial cells within the NVU. In addition, we describe lactate-driven mechanisms and action of alternative products of glucose metabolism affecting BBB structural and functional integrity in developing and mature brain.

Establishment of neurogenic microenvironment in the neurovascular unit: the connexin 43 story.

Abstract Connexins (Cx) play an important role in the coordination of intercellular communication, and autocrine and paracrine regulation of cells within the neurovascular unit (NVU). Gap junctional mechanisms control proliferation and differentiation processes underlying neurogenesis and angiogenesis in the brain. Cx43 possesses some unique properties [the ability to form either intercellular channels permeable for regulatory molecules and ions or hemichannels open to the extracellular space to provide release of cell metabolites; functional coupling with nicotinamide adenine dinucleotide (NAD+)-consuming and NAD+-dependent enzymatic processes] which may be of great importance for the fate of the stem cells. Dynamic changes in Cx43 expression are associated with different stages of brain cells development either at embryonic or adult periods of ontogenesis. This review summarizes recent data on Cx43-controlled neurogenesis in the context of NVU development and functioning. Understanding the molecular mechanisms of gap junctional intercellular communication will support translational studies focused on the development of regeneration-based approaches for the therapy of central nervous system pathology.

Endothelial Progenitor Cells Physiology and Metabolic Plasticity in Brain Angiogenesis and Blood-Brain Barrier Modeling

Currently, there is a considerable interest to the assessment of blood-brain barrier (BBB) development as a part of cerebral angiogenesis developmental program. Embryonic and adult angiogenesis in the brain is governed by the coordinated activity of endothelial progenitor cells, brain microvascular endothelial cells, and non-endothelial cells contributing to the establishment of the BBB (pericytes, astrocytes, neurons). Metabolic and functional plasticity of endothelial progenitor cells controls their timely recruitment, precise homing to the brain microvessels, and efficient support of brain angiogenesis. Deciphering endothelial progenitor cells physiology would provide novel engineering approaches to establish adequate microfluidically-supported BBB models and brain microphysiological systems for translational studies.

H2S- and NO-Signaling Pathways in Alzheimer's Amyloid Vasculopathy: Synergism or Antagonism?

Alzheimers type of neurodegeneration dramatically affects H2S and NO synthesis and interactions in the brain, which results in dysregulated vasomotor function, brain tissue hypoperfusion and hypoxia, development of perivascular inflammation, promotion of Aβ deposition, and impairment of neurogenesis/angiogenesis. H2S- and NO-signaling pathways have been described to offer protection against Alzheimers amyloid vasculopathy and neurodegeneration. This review describes recent developments of the increasing relevance of H2S and NO in Alzheimers disease (AD). More studies are however needed to fully determine their potential use as therapeutic targets in Alzheimers and other forms of vascular dementia.

Astroglial control of neuroinflammation: TLR3-mediated dsRNA-sensing pathways are in the focus.

Abstract Neuroinflammation is as an important component of pathogenesis in many types of brain pathology. Immune mechanisms regulate neuroplasticity, memory formation, neurogenesis, behavior, brain development, cognitive functions, and brain metabolism. It is generally believed that essential homeostatic functions of astrocytes – astroglia-neuron metabolic coupling, gliovascular control, regulation of proliferation, and migration of cells in the neurogenic niches – are compromised in neuroinflammation resulting in excitotoxicity, neuronal and glial cell death, and alterations of intercellular communication. Viral neuroinfection, release of non-coding RNAs from the cells at the sites of brain injury or degeneration, and application of siRNA or RNA aptamers as therapeutic agents would require dsRNA-sensing pathways in the cells of neuronal and non-neuronal origin. In this review, we analyze the data regarding the role of astrocytes in dsRNA-initiated innate immune response in neuroinflammation and their contribution to progression of neurodegenerative and neurodevelopmental pathology.

Designing in vitro Blood-Brain Barrier Models Reproducing Alterations in Brain Aging

Blood-brain barrier (BBB) modeling in vitro is a huge area of research covering study of intercellular communications and development of BBB, establishment of specific properties that provide controlled permeability of the barrier. Current approaches in designing new BBB models include development of new (bio) scaffolds supporting barriergenesis/angiogenesis and BBB integrity; use of methods enabling modulation of BBB permeability; application of modern analytical techniques for screening the transfer of metabolites, bio-macromolecules, selected drug candidates and drug delivery systems; establishment of 3D models; application of microfluidic technologies; reconstruction of microphysiological systems with the barrier constituents. Acceptance of idea that BBB in vitro models should resemble real functional activity of the barrier in different periods of ontogenesis and in different (patho) physiological conditions leads to proposal that establishment of BBB in vitro model with alterations specific for aging brain is one of current challenges in neurosciences and bioengineering. Vascular dysfunction in the aging brain often associates with leaky BBB, alterations in perivascular microenvironment, neuroinflammation, perturbed neuronal and astroglial activity within the neurovascular unit, impairments in neurogenic niches where microvascular scaffold plays a key regulatory role. The review article is focused on aging-related alterations in BBB and current approaches to development of “aging” BBB models in vitro.

Blood-brain barrier-supported neurogenesis in healthy and diseased brain

Abstract Adult neurogenesis is one of the most important mechanisms contributing to brain development, learning, and memory. Alterations in neurogenesis underlie a wide spectrum of brain diseases. Neurogenesis takes place in highly specialized neurogenic niches. The concept of neurogenic niches is becoming widely accepted due to growing evidence of the important role of the microenvironment established in the close vicinity to stem cells in order to provide adequate control of cell proliferation, differentiation, and apoptosis. Neurogenic niches represent the platform for tight integration of neurogenesis and angiogenesis supported by specific properties of cerebral microvessel endothelial cells contributing to establishment of partially compromised blood-brain barrier (BBB) for the adjustment of local conditions to the current metabolic needs of stem and progenitor cells. Here, we review up-to-date data on microvascular dynamics in activity-dependent neurogenesis, specific properties of BBB in neurogenic niches, endothelial-driven mechanisms of clonogenic activity, and future perspectives for reconstructing the neurogenic niches in vitro.

Differential Roles of Environmental Enrichment in Alzheimer’s Type of Neurodegeneration and Physiological Aging

Impairment of hippocampal adult neurogenesis in aging or degenerating brain is a well-known phenomenon caused by the shortage of brain stem cell pool, alterations in the local microenvironment within the neurogenic niches, or deregulation of stem cell development. Environmental enrichment (EE) has been proposed as a potent tool to restore brain functions, to prevent aging-associated neurodegeneration, and to cure neuronal deficits seen in neurodevelopmental and neurodegenerative disorders. Here, we report our data on the effects of environmental enrichment on hippocampal neurogenesis in vivo and neurosphere-forming capacity of hippocampal stem/progenitor cells in vitro. Two models – Alzheimer’s type of neurodegeneration and physiological brain aging – were chosen for the comparative analysis of EE effects. We found that environmental enrichment greatly affects the expression of markers specific for stem cells, progenitor cells and differentiated neurons (Pax6, Ngn2, NeuroD1, NeuN) in the hippocampus of young adult rats or rats with Alzheimer’s disease (AD) model but less efficiently in aged animals. Application of time-lag mathematical model for the analysis of impedance traces obtained in real-time monitoring of cell proliferation in vitro revealed that EE could restore neurosphere-forming capacity of hippocampal stem/progenitor cells more efficiently in young adult animals (fourfold greater in the control group comparing to the AD model group) but not in the aged rats (no positive effect of environmental enrichment at all). In accordance with the results obtained in vivo, EE was almost ineffective in the recovery of hippocampal neurogenic reserve in vitro in aged, but not in amyloid-treated or young adult, rats. Therefore, EE-based neuroprotective strategies effective in Aβ-affected brain could not be directly extrapolated to aged brain.

Oxytocin and excitation/inhibition balance in social recognition

Social recognition is the sensitive domains of complex behavior critical for identification, interpretation and storage of socially meaningful information. Social recognition develops throughout childhood and adolescent, and is affected in a wide variety of psychiatric disorders. Recently, new data appeared on the molecular mechanisms of these processes, particularly, the excitatory-inhibitory (E/I) ratio which is modified during development, and then E/I balance is established in the adult brain. While E/I imbalance has been proposed as a mechanism for schizophrenia, it also seems to be the common mechanism in autism spectrum disorder (ASD). In addition, there is a strong suggestion that the oxytocinergic system is related to GABA-mediated E/I control in the context of brain socialization. In this review, we attempt to summarize the underpinning molecular mechanisms of E/I balance and its imbalance, and related biomarkers in the brain in healthiness and pathology. In addition, because there are increasing interest on oxytocin in the social neuroscience field, we will pay intensive attention to the role of oxytocin in maintaining E/I balance from the viewpoint of its effects on improving social impairment in psychiatric diseases, especially in ASD.