Age-related decline in cognitive flexibility is associated with the levels of hippocampal neurogenesis.

Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis. We investigated the performance of 6-and 14-month-old mice (considered mature adult and late middle age, respectively) in learning and memory tasks based on the Morris water maze (MWM) and determined their levels of preceding and current neurogenesis. While both age groups successfully performed in the spatial version of MWM (sMWM), the older mice were less efficient compared to the younger mice when presented with modified versions of the MWM that required a reassessment of the previously acquired experience.

Cognitive Flexibility Is Selectively Impaired by Radiation and Is Associated with Differential Recruitment of Adult-Born Neurons.

Exposure to elevated doses of ionizing radiation, such as those in therapeutic procedures, catastrophic accidents, or space exploration, increases the risk of cognitive dysfunction. The full range of radiation-induced cognitive deficits is unknown, partly because commonly used tests may be insufficiently sensitive or may not be adequately tuned for assessing the fine behavioral features affected by radiation. Here, we asked whether γ-radiation might affect learning, memory, and the overall ability to adapt behavior to cope with a challenging environment (cognitive/behavioral flexibility).

Detection of De Novo Dividing Stem Cells In Situ through Double Nucleotide Analogue Labeling.

Tissue-specific somatic stem cells are characterized by their ability to reside in a state of prolonged reversible cell cycle arrest, referred to as quiescence. Maintenance of a balance between cell quiescence and division is critical for tissue homeostasis at the cellular level and is dynamically regulated by numerous extrinsic and intrinsic factors. Analysis of the activation of quiescent stem cells has been challenging because of a lack of methods for direct detection of de novo dividing cells.

Mesoderm-derived PDGFRA cells regulate the emergence of hematopoietic stem cells in the dorsal aorta.

Mouse haematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5), on the ventral surface of the dorsal aorta, by endothelial-to-haematopoietic transition.

Synthetic Thymidine Analog Labeling without Misconceptions.

Tagging proliferating cells with thymidine analogs is an indispensable research tool; however, the issue of the potential in vivo cytotoxicity of these compounds remains unresolved. Here, we address these concerns by examining the effects of BrdU and EdU on adult hippocampal neurogenesis and EdU on the perinatal somatic development of mice. We show that, in a wide range of doses, EdU and BrdU label similar numbers of cells in the dentate gyrus shortly after administration.

Spatiotemporal 3D image registration for mesoscale studies of brain development.

Comparison of brain samples representing different developmental stages often necessitates registering the samples to common coordinates. Although the available software tools are successful in registering 3D images of adult brains, registration of perinatal brains remains challenging due to rapid growth-dependent morphological changes and variations in developmental pace between animals. To address these challenges, we introduce CORGI (Customizable Object Registration for Groups of Images), an algorithm for the registration of perinatal brains.

Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus.

Background: Hydrocephalus (increased ventricular size due to CSF accumulation) is a common finding in human ciliopathies and in mouse models with genetic depletion of the multiciliated cell (MCC) cilia machinery. However, the contribution of MCC to CSF dynamics and, the mechanism by which impaired MCC function leads to hydrocephalus remains poorly understood. The aim of our study was to examine if defects in MCC ciliogenesis and cilia-generated CSF flow impact central nervous system (CNS) fluid homeostasis including glymphatic transport and solute waste drainage.

The bioavailability time of commonly used thymidine analogues after intraperitoneal delivery in mice: labeling kinetics in vivo and clearance from blood serum.

Detection of synthetic thymidine analogues after their incorporation into replicating DNA during the S-phase of the cell cycle is a widely exploited methodology for evaluating proliferative activity, tracing dividing and post-mitotic cells, and determining cell-cycle parameters both in vitro and in vivo. To produce valid quantitative readouts for in vivo experiments with single intraperitoneal delivery of a particular nucleotide, it is necessary to determine the time interval during which a synthetic thymidine analogue can be incorporated into newly synthesized DNA, and the time by which the nucleotide is cleared from the blood serum. To date, using a variety of methods, only the bioavailability time of tritiated thymidine and 5-bromo-2'-deoxyuridine (BrdU) have been evaluated.

nNOS regulates ciliated cell polarity, ciliary beat frequency, and directional flow in mouse trachea.

Clearance of the airway is dependent on directional mucus flow across the mucociliary epithelium, and deficient flow is implicated in a range of human disorders. Efficient flow relies on proper polarization of the multiciliated cells and sufficient ciliary beat frequency. We show that NO, produced by nNOS in the multiciliated cells of the mouse trachea, controls both the planar polarity and the ciliary beat frequency and is thereby necessary for the generation of the robust flow.

Involvement of Adult-born and Preexisting Olfactory Bulb and Dentate Gyrus Neurons in Single-trial Olfactory Memory Acquisition and Retrieval.

The production of new neurons and their incorporation into preexisting neuronal circuits occur throughout adulthood in the olfactory bulb and the hippocampal dentate gyrus of the mammalian brain. To determine whether the adult-born neurons are engaged in the acquisition and retrieval of olfactory associative memory, we developed and validated a single-trial olfactory fear conditioning protocol in mice which allows to detect activation of newborn neurons during a specific episode of memory acquisition. Using c-Fos mapping of neuronal activity, we then examined the activation of new and preexisting neurons during training and testing sessions.

Modes of division and differentiation of neural stem cells.

Hippocampal neurogenesis presents an unorthodox form of neuronal plasticity and may be relevant for the normal or abnormal functioning of the human and animal brain. As production of new neurons decreases after birth, purposefully activating stem cells to create additional new neurons may augment brain function or slow a disease's progression. Here, we describe current models of hippocampal stem cell maintenance and differentiation, and emphasize key features of neural stem cells' turnover that may define hippocampal neurogenesis enhancement attempts' long-term consequences.

Slowly Reducible Genetically Encoded Green Fluorescent Indicator for In Vivo and Ex Vivo Visualization of Hydrogen Peroxide.

Hydrogen peroxide (HO) plays an important role in modulating cell signaling and homeostasis in live organisms. The HyPer family of genetically encoded indicators allows the visualization of HO dynamics in live cells within a limited field of view. The visualization of HO within a whole organism with a single cell resolution would benefit from a slowly reducible fluorescent indicator that integrates the HO concentration over desired time scales.

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer's Disease Model.

Adult hippocampal neurogenesis has been reported to be decreased, increased, or not changed in Alzheimer's disease (AD) patients and related transgenic mouse models. These disparate findings may relate to differences in disease stage, or the presence of seizures, which are associated with AD and can stimulate neurogenesis. In this study, we investigate a transgenic mouse model of AD that exhibits seizures similarly to AD patients and find that neurogenesis is increased in early stages of disease, as spontaneous seizures became evident, but is decreased below control levels as seizures recur.

A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate.

Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification. However, it remains unknown how this supply is maintained throughout childhood growth. Chondroprogenitors in the resting zone are thought to be gradually consumed as they supply cells for longitudinal growth, but this model has never been proved.

Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus.

While irradiation can effectively treat brain tumors, this therapy also causes cognitive impairments, some of which may stem from the disruption of hippocampal neurogenesis. To study how radiation affects neurogenesis, we combine phenotyping of subpopulations of hippocampal neural stem and progenitor cells with double- and triple S-phase labeling paradigms. Using this approach, we reveal new features of division, survival, and differentiation of neural stem and progenitor cells after exposure to gamma radiation.

Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis.

Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin.

NTnC-like genetically encoded calcium indicator with a positive and enhanced response and fast kinetics.

The NTnC genetically encoded calcium indicator has an advantageous design because of its smaller size, GFP-like N- and C-terminal ends and two-fold reduced number of calcium binding sites compared with widely used indicators from the GCaMP family. However, NTnC has an inverted and modest calcium response and a low temporal resolution. By replacing the mNeonGreen fluorescent part in NTnC with EYFP, we engineered an NTnC-like indicator, referred to as YTnC, that had a positive and substantially improved calcium response and faster kinetics.

Noninvasive Tracking of Anesthesia Neurotoxicity in the Developing Rodent Brain.

Background: Potential deleterious effect of multiple anesthesia exposures on the developing brain remains a clinical concern. We hypothesized that multiple neonatal anesthesia exposures are more detrimental to brain maturation than an equivalent single exposure, with more pronounced long-term behavioral consequences. We designed a translational approach using proton magnetic resonance spectroscopy in rodents, noninvasively tracking the neuronal marker N-acetyl-aspartate, in addition to tracking behavioral outcomes.

Spatial geometry of stem cell proliferation in the adult hippocampus.

The modes of stem cell divisions (e.g., symmetric vs.

Triple S-Phase Labeling of Dividing Stem Cells.

Marking replicating DNA with multiple labels presents the possibility of revealing new features and mechanisms of DNA synthesis and cell division; however, progression beyond double labeling has been hampered by cross-reactivity of label detection and scarcity of appropriate labels. Here, we present a method for triple S-phase labeling of the dividing cells, with a fourth label used to mark cells actively engaged in cell-cycle progression (e.g.

DALMATIAN: An Algorithm for Automatic Cell Detection and Counting in 3D.

Current 3D imaging methods, including optical projection tomography, light-sheet microscopy, block-face imaging, and serial two photon tomography enable visualization of large samples of biological tissue. Large volumes of data obtained at high resolution require development of automatic image processing techniques, such as algorithms for automatic cell detection or, more generally, point-like object detection. Current approaches to automated cell detection suffer from difficulties originating from detection of particular cell types, cell populations of different brightness, non-uniformly stained, and overlapping cells.

Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in is mediated by the epigenetic chromatin modifiers.

Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR's target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway.