Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice.

Stress induces aversive memory overgeneralization, a hallmark of many psychiatric disorders. Memories are encoded by a sparse ensemble of neurons active during an event (an engram ensemble). We examined the molecular and circuit processes mediating stress-induced threat memory overgeneralization in mice.

Gamma-protocadherins regulate dendrite self-recognition and dynamics to drive self-avoidance.

Neurons form cell-type-specific morphologies that are shaped by cell-surface molecules and their cellular events governing dendrite growth. One growth rule is dendrite self-avoidance, whereby dendrites distribute uniformly within a neuron's territory by avoiding sibling branches. In mammalian neurons, dendrite self-avoidance is regulated by a large family of cell-recognition molecules called the clustered protocadherins (cPcdhs).

Pten regulates endocytic trafficking of cell adhesion and Wnt signaling molecules to pattern the retina.

The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and tensin homolog (Pten) controls starburst amacrine cell spacing by modulating vesicular trafficking of cell adhesion molecules and Wnt proteins. Single-cell transcriptomics and double-mutant analyses revealed that Pten and Down syndrome cell adhesion molecule Dscam) are co-expressed and function additively to pattern starburst amacrine cell mosaics.

Combining the Nurse Intuition Patient Deterioration Scale with the National Early Warning Score provides more Net Benefit in predicting serious adverse events: A prospective cohort study in medical, surgical, and geriatric wards.

Objectives: This prospective cohort study aimed to assess the predictive value of the Nurse Intuition Patient Deterioration Scale (NIPDS) combined with the National Early Warning Score (NEWS) for identifying serious adverse events in patients admitted to diverse hospital wards.

Research Methodology/design: Data was collected between December 2020 and February 2021 in a 350-bed acute hospital near Brussels, Belgium. The study followed a prospective cohort design, employing NIPDS alongside NEWS for risk assessment.

The Role of Protocadherin γ in Adult Sensory Neurons and Skin Reinnervation.

The clustered protocadherins (cPcdhs) play a critical role in the patterning of several CNS axon and dendritic arbors, through regulation of homophilic self and neighboring interactions. While not explored, primary peripheral sensory afferents that innervate the epidermis may require similar constraints to convey spatial signals with appropriate fidelity. Here, we show that members of the γ-Pcdh (Pcdhγ) family are expressed in both adult sensory neuron axons and in neighboring keratinocytes that have close interactions during skin reinnervation.

Sticking to your side: A niche for the development of ipsilateral retinal projections.

Visual impairments in albinism result from decreased ipsilateral retinal projections. In this issue of Neuron, Slavi, Balasubramanian, and colleagues demonstrate how low CyclinD2 in the ciliary marginal zone perturbs generation of ipsilaterally projecting RGCs and that restoring CyclinD2 improves vision in albino mice.

PV-IRES-Cre mouse line targets excitatory granule neurons in the cerebellum.

Parvalbumin-expressing inhibitory neurons (PV-INs) are critical for the balance and fine-tuning of complex neuronal circuits. Studies of PV-IN biology require tools for their specific labeling, targeting and manipulation. Among these, the Cre/LoxP system is the most popular in mice, with the two commonly used PV-Cre lines cited over 5600 times.

Morphological pseudotime ordering and fate mapping reveal diversification of cerebellar inhibitory interneurons.

Understanding how diverse neurons are assembled into circuits requires a framework for describing cell types and their developmental trajectories. Here we combine genetic fate-mapping, pseudotemporal profiling of morphogenesis, and dual morphology and RNA labeling to resolve the diversification of mouse cerebellar inhibitory interneurons. Molecular layer interneurons (MLIs) derive from a common progenitor population but comprise diverse dendritic-, somatic-, and axon initial segment-targeting interneurons.

Time-Lapse Imaging of Neuronal Arborization using Sparse Adeno-Associated Virus Labeling of Genetically Targeted Retinal Cell Populations.

Discovering mechanisms that pattern dendritic arbors requires methods to visualize, image, and analyze dendrites during development. The mouse retina is a powerful model system for the investigation of cell type-specific mechanisms of neuronal morphogenesis and connectivity. The organization and composition of retinal subtypes are well-defined, and genetic tools are available to access specific types during development.

Molecular mechanisms that mediate dendrite morphogenesis.

Neurons develop dendritic morphologies that bear cell type-specific features in dendritic field size and geometry, branch placement and density, and the types and distributions of synaptic contacts. Dendritic patterns influence the types and numbers of inputs a neuron receives, and the ways in which neural information is processed and transmitted in the circuitry. Even subtle alterations in dendritic structures can have profound consequences on neuronal function and are implicated in neurodevelopmental disorders.

The γ-Protocadherins Regulate the Survival of GABAergic Interneurons during Developmental Cell Death.

Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the neocortex, inhibitory network formation occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The cell surface molecules that select interneurons to survive or die are unknown.

Human iPSC-derived Down syndrome astrocytes display genome-wide perturbations in gene expression, an altered adhesion profile, and increased cellular dynamics.

Down syndrome (DS), caused by the triplication of human chromosome 21, leads to significant alterations in brain development and is a major genetic cause of intellectual disability. While much is known about changes to neurons in DS, the effects of trisomy 21 on non-neuronal cells such as astrocytes are poorly understood. Astrocytes are critical for brain development and function, and their alteration may contribute to DS pathophysiology.

Loss of OcaB Prevents Age-Induced Fat Accretion and Insulin Resistance by Altering B-Lymphocyte Transition and Promoting Energy Expenditure.

The current demographic shift toward an aging population has led to a robust increase in the prevalence of age-associated metabolic disorders. Recent studies have demonstrated that the etiology of obesity-related insulin resistance that develops with aging differs from that induced by high-calorie diets. Whereas the role of adaptive immunity in changes in energy metabolism driven by nutritional challenges has recently gained attention, its impact on aging remains mostly unknown.

Combinatorial Effects of Alpha- and Gamma-Protocadherins on Neuronal Survival and Dendritic Self-Avoidance.

The clustered protocadherins (Pcdhs) comprise 58 cadherin-related proteins encoded by three tandemly arrayed gene clusters, -α, -β, and -γ (, , and , respectively). Pcdh isoforms from different clusters are combinatorially expressed in neurons. They form multimers that interact homophilically and mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, axonal tiling, and dendritic self-avoidance.

Neuronal territory formation by the atypical cadherins and clustered protocadherins.

Spatial patterns of neuronal connectivity are critical for neural circuit function and information processing. For many neuron types, the development of stereotyped dendritic and axonal territories involves reiterative contacts between neurites and successive re-calibration of branch outgrowth and directionality. Here I review emerging roles for members of the atypical cadherins (Fmi/Celsrs) and the clustered Protocadherins (Pcdhs) in neurite patterning.

Leukotriene B₄ Metabolism and p70S6 Kinase 1 Inhibitors: PF-4708671 but Not LY2584702 Inhibits CYP4F3A and the ω-Oxidation of Leukotriene B₄ In Vitro and In Cellulo.

LTB4 is an inflammatory lipid mediator mainly biosynthesized by leukocytes. Since its implication in inflammatory diseases is well recognized, many tools to regulate its biosynthesis have been developed and showed promising results in vitro and in vivo, but mixed results in clinical trials. Recently, the mTOR pathway component p70S6 kinase 1 (p70S6K1) has been linked to LTC4 synthase and the biosynthesis of cysteinyl-leukotrienes.

Vaccine efficacy and T helper cell differentiation change with aging.

Influenza and pneumonia are leading causes of death in elderly populations. With age, there is an increased inflammatory response and slower viral clearance during influenza infection which increases the risk of extended illness and mortality. Here we employ a preclinical murine model of influenza infection to examine the protective capacity of vaccination with influenza nucleoprotein (NP).

Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses.

T follicular helper (TFH) cell responses are essential for generation of protective humoral immunity during influenza infection. Aging has a profound impact on CD4(+) T cell function and humoral immunity, yet the impact of aging on antigen specific TFH responses remains unclear. Influenza specific TFH cells are generated in similar numbers in young and aged animals during infection, but TFH cells from aged mice exhibit significant differences, including reduced expression of ICOS and elevated production of IL-10 and IFNγ, which potentially impairs interaction with cognate B cells.

Development of dendritic form and function.

The nervous system is populated by numerous types of neurons, each bearing a dendritic arbor with a characteristic morphology. These type-specific features influence many aspects of a neuron's function, including the number and identity of presynaptic inputs and how inputs are integrated to determine firing properties. Here, we review the mechanisms that regulate the construction of cell type-specific dendrite patterns during development.

Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites.

2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids.

Dendrite self-avoidance requires cell-autonomous slit/robo signaling in cerebellar purkinje cells.

Dendrites from the same neuron usually develop nonoverlapping patterns by self-avoidance, a process requiring contact-dependent recognition and repulsion. Recent studies have implicated homophilic interactions of cell surface molecules, including Dscams and Pcdhgs, in self-recognition, but repulsive molecular mechanisms remain obscure. Here, we report a role for the secreted molecule Slit2 and its receptor Robo2 in self-avoidance of cerebellar Purkinje cells (PCs).

A straight neutrophil path to healthy aging?

In this issue of Blood, Sapey et al. report that the human polymorphonuclear neutrophil leukocyte (or neutrophil) undergoes an age-related loss of its ability to migrate up chemotactic gradients, a functional defect that seems causally related to alterations in the polyphosphoinositide pathway.

Cooperative role of endogenous leucotrienes and platelet-activating factor in ischaemia-reperfusion-mediated tissue injury.

Insufficient oxygen delivery to organs leads to tissue dysfunction and cell death. Reperfusion, although vital to organ survival, initiates an inflammatory response that may both aggravate local tissue injury and elicit remote organ damage. Polymorphonuclear neutrophil (PMN) trafficking to remote organs following ischaemia/reperfusion (I/R) is associated with the release of lipid mediators, including leucotriene (LT) B4 , cysteinyl-LTs (CysLTs) and platelet-activating factor (PAF).

Acute Plasmodium chabaudi infection dampens humoral responses to a secondary T-dependent antigen but enhances responses to a secondary T-independent antigen.

High rates of coinfection occur in malaria endemic regions, leading to more severe disease outcomes. Understanding how coinfecting pathogens influence the immune system is important in the development of treatment strategies that reduce morbidity and mortality. Using the Plasmodium chabaudi mouse model of malaria and immunization with model Ags that are either T-dependent (4-hydroxy-3-nitrophenyl [NP]-OVA) or T-independent (NP-Ficoll), we analyzed the effects of acute malaria on the development of humoral immunity to secondary Ags.

Inhibition of dehydroepiandosterone sulfate action in androgen-sensitive tissues by EM-1913, an inhibitor of steroid sulfatase.

Steroid sulfatase (STS) plays an important role in the formation of estrogens and androgens by allowing the conversion of inactive circulating sulfated steroids into active hormones. These steroids support the development and growth of a number of hormone-dependent cancers, including prostate cancer. Here, we tested a non-estrogenic and non-androgenic inhibitor of steroid STS, namely EM-1913, with special attention to its potential use in the treatment of prostate cancer.