Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and neurogenesis.

Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties.

Isolation of the side population from neurogenic niches enriches for endothelial cells.

In stem cell research, DNA-binding dyes offer the ability to purify live stem cells using flow cytometry as they form a low-fluorescence side population due to the activity of ABC transporters. Adult neural stem cells exist within the lateral ventricle and dentate gyrus of the adult brain yet the ability of DNA-binding dyes to identify these adult stem cells as side populations remains untested. The following experiments utilize the efflux of a DNA-binding dye, Vyrbant DyeCycle Violet (DCV), to isolate bona fide side populations in the mouse dentate gyrus and subventricular zone (SVZ), and test their sensitivity to ABC transporter inhibitors.

The Emergence of Stereotyped Kinematic Synergies when Mice Reach to Grasp Following Stroke.

Reaching tasks are commonly used in preclinical and clinical studies to assess the acquisition of fine motor skills and recovery of function following stroke. These tasks are often used to assess functional deficits in the absence of quantifying the quality of movement which requires kinematic analysis. To meet this need, this study uses a kinematic analysis in mice performing the Montoya staircase task at 5 and 14 days following a cortical photothrombosis-induced stroke.

Developmental and Interventional Plasticity of Motor Maps after Perinatal Stroke.

Within the perinatal stroke field, there is a need to establish preclinical models where putative biomarkers for motor function can be examined. In a mouse model of perinatal stroke, we evaluated motor map size and movement latency following optogenetic cortical stimulation against three factors of post-stroke biomarker utility: (1) correlation to chronic impairment on a behavioral test battery; (2) amenability to change using a skilled motor training paradigm; and (3) ability to distinguish individuals with potential to respond well to training. mice received a photothrombotic stroke at postnatal day 7 and were evaluated on a battery of motor tests between days 59 and 70.

Adult hippocampal neurogenesis occurs in the absence of Presenilin 1 and Presenilin 2.

Mutations in the presenilin genes (PS1 and PS2) are a major cause of familial-Alzheimer's disease (FAD). Presenilins regulate neurogenesis in the developing brain, with loss of PS1 inducing aberrant premature differentiation of neural progenitor cells, and additional loss of PS2 exacerbating this effect. It is unclear, however, whether presenilins are involved in adult neurogenesis, a process that may be impaired in Alzheimer's disease within the hippocampus.

Excitable Adult-Generated GABAergic Neurons Acquire Functional Innervation in the Cortex after Stroke.

Ischemic stroke enhances the proliferation of adult-generated precursor cells that ectopically migrate toward the infarct. Studies have correlated precursor cell proliferation and subsequent adult neurogenesis with enhanced stroke recovery, yet it remains unclear whether stroke can generate new neurons capable of functional integration into the injured cortex. Here, using single and bitransgenic reporter mice, we identify spatial and temporal features of a multilineage cellular response to focal ischemia.

The Multi-pronged Regulation of Adult Neurogenesis by Forkhead Box O Family Members.

In this issue of Neuron, Schäffner et al. (2018) discover multiple effects of the Forkhead Box O (FoxO) transcription factor family on the different stages of adult neurogenesis, including the genesis of dendrites and spines regulated by FoxO-dependent autophagic activity.

Autophagy and Adult Neurogenesis: Discoveries Made Half a Century Ago Yet in their Infancy of being Connected.

Within the brain, the physiological and pathological functions of autophagy in development and throughout the lifespan are being elucidated. This review summarizes recent and results that are defining the role of autophagy-related genes during the process of adult neurogenesis. We also discuss the need for future experiments to determine the molecular mechanism and functional significance of autophagy in the different neural stem cell populations and throughout the stages of adult neurogenesis.

The aPKC-CBP Pathway Regulates Post-stroke Neurovascular Remodeling and Functional Recovery.

Epigenetic modifications have emerged as attractive molecular substrates that integrate extrinsic changes into the determination of cell identity. Since stroke-related brain damage releases micro-environmental cues, we examined the role of a signaling-induced epigenetic pathway, an atypical protein kinase C (aPKC)-mediated phosphorylation of CREB-binding protein (CBP), in post-stroke neurovascular remodeling. Using a knockin mouse strain (CbpS436A) where the aPKC-CBP pathway was defective, we show that disruption of the aPKC-CBP pathway in a murine focal ischemic stroke model increases the reprogramming efficiency of ischemia-activated pericytes (i-pericytes) to neural precursors.

Loss of IRF2BP2 in Microglia Increases Inflammation and Functional Deficits after Focal Ischemic Brain Injury.

Ischemic stroke causes neuronal cell death and triggers a cascade of inflammatory signals that contribute to secondary brain damage. Microglia, the brain-resident macrophages that remove dead neurons, play a critical role in the brain's response to ischemic injury. Our previous studies showed that IRF2 binding protein 2 (IRF2BP2) regulates peripheral macrophage polarization, limits their inflammatory response and reduces susceptibility to atherosclerosis.

Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis.

Mitochondrial dysfunction is a common feature of many genetic disorders that target the brain and cognition. However, the exact role these organelles play in the etiology of such disorders is not understood. Here, we show that mitochondrial dysfunction impairs brain development, depletes the adult neural stem cell (NSC) pool and impacts embryonic and adult neurogenesis.

Holocranohistochemistry enables the visualization of α-synuclein expression in the murine olfactory system and discovery of its systemic anti-microbial effects.

Braak and Del Tredici have proposed that typical Parkinson disease (PD) has its origins in the olfactory bulb and gastrointestinal tract. However, the role of the olfactory system has insufficiently been explored in the pathogeneses of PD and Alzheimer disease (AD) in laboratory models. Here, we demonstrate applications of a new method to process mouse heads for microscopy by sectioning, mounting, and staining whole skulls ('holocranohistochemistry').

Absence of neurogenic response following robust predator-induced stress response.

Traumatic events contribute to a variety of neuropsychiatric disorders including post-traumatic stress disorder (PTSD). Identifying the neural mechanisms that affect the stress response may improve treatment for stress-related disorders. Neurogenesis, the production of neurons, occurs within the adult brain and disturbances in neurogenesis in the subgranular zone (SGZ) of the hippocampus have been linked to mood and anxiety disorders.

RB regulates the production and the survival of newborn neurons in the embryonic and adult dentate gyrus.

In mammals, hippocampal dentate gyrus granule cells (DGCs) constitute a particular neuronal population produced both during embryogenesis and adult life, and play key roles in neural plasticity and memory. However, the molecular mechanisms regulating neurogenesis in the dentate lineage throughout development and adulthood are still not well understood. The Retinoblastoma protein (RB), a transcriptional repressor primarily involved in cell cycle control and cell death, plays crucial roles during cortical development but its function in the formation and maintenance of DGCs remains unknown.

Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program.

Regulated mechanisms of stem cell maintenance are key to preventing stem cell depletion and aging. While mitochondrial morphology plays a fundamental role in tissue development and homeostasis, its role in stem cells remains unknown. Here, we uncover that mitochondrial dynamics regulates stem cell identity, self-renewal, and fate decisions by orchestrating a transcriptional program.

Pannexin 1 Differentially Affects Neural Precursor Cell Maintenance in the Ventricular Zone and Peri-Infarct Cortex.

Unlabelled: We demonstrated previously that Pannexin 1 (Panx1), an ion and metabolite channel, promotes the growth and proliferation of ventricular zone (VZ) neural precursor cells (NPCs) in vitro. To investigate its role in vivo, we used floxed Panx1 mice in combination with viruses to delete Panx1 in VZ NPCs and to track numbers of Panx1-null and Panx1-expressing VZ NPCs over time. Two days after virus injection, Panx1-null cells were less abundant than Panx1-expressing cells, suggesting that Panx1 is required for the maintenance of VZ NPCs.

Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice.

Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models.

Doublecortin (DCX) is not Essential for Survival and Differentiation of Newborn Neurons in the Adult Mouse Dentate Gyrus.

In the adult brain, expression of the microtubule-associated protein Doublecortin (DCX) is associated with neural progenitor cells (NPCs) that give rise to new neurons in the dentate gyrus. Many studies quantify the number of DCX-expressing cells as a proxy for the level of adult neurogenesis, yet no study has determined the effect of removing DCX from adult hippocampal NPCs. Here, we use a retroviral and inducible mouse transgenic approach to either knockdown or knockout DCX from adult NPCs in the dentate gyrus and examine how this affects cell survival and neuronal maturation.

Bcl-2 is required for the survival of doublecortin-expressing immature neurons.

In the adult brain only a small proportion of the neural stem and progenitor cells (NPCs) and their progeny survive to become mature neurons in the hippocampus. Recent studies have elucidated the roles for members of the B-cell lymphoma-2 (Bcl-2) family of proteins in regulating the survival of NPCs and their progeny at different stages of maturation, yet the requirement of Bcl-2 during this process remains unknown. Here we report that inducible removal of Bcl-2 from nestin-expressing neural stem/progenitor cells and their progeny resulted in a reduction in the survival of doublecortin-expressing cells in the absence of changing the number of radial-glial stem cells or dividing NPCs.

CDK5 phosphorylates DRP1 and drives mitochondrial defects in NMDA-induced neuronal death.

Defects in mitochondrial fission and cyclin dependent kinase 5 (CDK5) activation are early events that precede neuronal loss following NMDA-induced neuronal death. Here, we report that the cytoplasmic CDK5 tightly regulates mitochondrial morphology defects associated with NMDA-induced neuronal injury via regulation of the mitochondrial fission protein, dynamin-related protein 1 (DRP1). We show that DRP1 is a direct target of CDK5.

Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling.

Collapse of endocannabinoid (eCB) signaling in the amygdala contributes to stress-induced anxiety, but the mechanisms of this effect remain unclear. eCB production is tied to the function of the glutamate receptor mGluR5, itself dependent on tyrosine phosphorylation. Herein, we identify a novel pathway linking eCB regulation of anxiety through phosphorylation of mGluR5.

A longitudinal study of stress-induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat.

Hippocampal shrinkage is a commonly found neuroanatomical change in stress-related mood disorders such as depression and post-traumatic stress disorders (PTSD). Since the onset and severity of these disorders have been found to be closely related to stressful life events, and as stress alone has been shown to reduce hippocampal volume in animal studies, vulnerability to mood disorders may be related to a susceptibility to stress-induced hippocampal shrinkage. However, a smaller hippocampal volume before stress exposure has also been suggested to confer vulnerability of stressed individuals to PTSD or depression.

Developmental and adult GAP-43 deficiency in mice dynamically alters hippocampal neurogenesis and mossy fiber volume.

Growth-associated protein-43 (GAP-43) is a presynaptic protein that plays key roles in axonal growth and guidance and in modulating synapse formation. Previous work has demonstrated that mice lacking one allele of this gene (GAP-43+/- mice) exhibit hippocampal structural abnormalities, impaired spatial learning and stress-induced behavioral withdrawal and anxiety, behaviors that are dependent on proper hippocampal circuitry and function. Given the correlation between hippocampal function, synaptic connectivity and neurogenesis, we tested if behaviorally naïve GAP-43+/- mice had alterations in either neurogenesis or synaptic connectivity in the hippocampus during early postnatal development and young adulthood, and following behavior testing in older adults.