Cell biology of the neuron: ARC goes viral
Cell biology of the neuron: ARC goes viral, Published online: 01 February 2018; doi:10.1038/nrn.2018.9Two recent papers reveal that the activity-regulated cytoskeleton-associated proteins ARC and Drosophila melanogaster dArc1 auto-assemble into mRNA-containing, virus-like capsids that are released by neurons in exosomal vesicles and that can be endocytosed at the postsynaptic compartment.
Spatial processing: An 'other' kind of place cell
Spatial processing: An 'other' kind of place cell, Published online: 01 February 2018; doi:10.1038/nrn.2018.12'Social place cells' of the dorsal hippocampal CA1 region in bats and in rats encode the position of an observed conspecific.
Neural development: 'Enhancing' human cognition
Neural development: 'Enhancing' human cognition, Published online: 01 February 2018; doi:10.1038/nrn.2018.11Human-gained enhancers (regulatory elements in the human genome that are more active in the human lineage) are shown to regulate progenitor proliferation in the outer subventricular zone, an area that is substantially larger in humans compared with other primates.
Medial preoptic circuit induces hunting-like actions to target objects and prey
Medial preoptic circuit induces hunting-like actions to target objects and prey, Published online: 29 January 2018; doi:10.1038/s41593-018-0072-xThis study finds the key neurons that respond to 3D objects in the medial preoptic area (MPA). Their photostimulation induces hunting-like behaviors towards toys and prey, showing how the brain organizes behaviors to acquire useful resources.
Insular cortex mediates approach and avoidance responses to social affective stimuli
Insular cortex mediates approach and avoidance responses to social affective stimuli, Published online: 29 January 2018; doi:10.1038/s41593-018-0071-yDetermining how to respond to others in distress is central to social cognition. In a new model, male rats approach stressed juveniles but avoid stressed adults; these behaviors require excitatory action of oxytocin within the insular cortex.
Objective: Although gamma-glutamyl transferase (GGT) is generally regarded as an alternative biomarker for alcohol consumption, its independent role in vascular diseases emerged recently. However, its role in stroke remains unknown. The aim of this study is to clarify the impact of GGT on stroke in a large-sized, national, standardized population cohort in Korea.
Methods: In Korea, the National Health Insurance Service (NHIS) provides full-coverage health insurance service for all citizens. Using data from the NHIS, the NHIS-National Sample Cohort (NHIS-NSC) was designed by randomly selecting 2% of Koreans, carefully considering demographic characteristics. We analyzed eligible individuals from this standardized cohort. The Cox proportional hazards model was used for the longitudinal study investigating the relationship between GGT and stroke.
Results: Among the 456,100 eligible participants, 7,459 patients (1.64%) developed stroke as follows: 5,789 ischemic strokes, 1,046 intracerebral hemorrhages (ICHs), and 624 subarachnoid hemorrhages. GGT was independently correlated with increased risk of stroke after adjustment for alcohol consumption and stroke risk factors (hazard ratio (HR), 1.39; 95% confidence interval (CI), 1.29–1.51). The risks of both ischemic stroke (HR, 1.45; 95% CI, 1.32–1.58) and ICH (HR, 1.46; 95% CI, 1.18–1.80) were significantly elevated with increasing GGT. Despite some effect modifications by sex, age and alcohol, the risk of total stroke and ischemic stroke in association with GGT remained significant in all subgroups.
Interpretation: In a standard Korean population, GGT was a novel biomarker predicting stroke risk, independently from alcohol consumption and other risk factors. This article is protected by copyright. All rights reserved.
Objective: Internal globus pallidus (GPi) deep brain stimulation (DBS) relieves symptoms in dystonia patients. However, the physiological effects produced by GPi DBS are not fully understood. In particular, how a single-pulse GPi DBS changes cortical circuits has never been investigated. We studied the modulation of motor cortical excitability and plasticity with single-pulse GPi DBS in dystonia patients with bilateral implantation of GPi DBS.
Methods: The cortical evoked potentials from DBS were recorded with electroencephalography. Transcranial magnetic stimulation with a conditioning-test paired-pulse paradigm was used to investigate the effect of GPi DBS on the primary motor cortex. How GPi DBS might modulate the motor cortical plasticity was tested using a paired associative stimulation paradigm with repetitive pairs of GPi DBS and motor cortical stimulation at specific time intervals.
Results: GPi stimulation produced two peaks of cortical evoked potentials with latencies of ∼10 and ∼25 ms in the motor cortical area. Cortical facilitation was observed at ∼10 ms after single-pulse GPi DBS and cortical inhibition was observed at ∼25 ms interval. Repetitive pairs of GPi stimulation with cortical stimulation at these two time intervals produced long term potentiation-like effects in the motor cortex.
Interpretation: Single-pulse DBS modulates cortical excitability and plasticity at specific time intervals. These effects may be related to the mechanism of action of DBS. Combination of DBS with cortical stimulation at appropriate timing has therapeutic potential and could be explored in the future as a method to enhance the effects of neuromodulation for neurological and psychiatric diseases. This article is protected by copyright. All rights reserved.
To assess the association between incident Parkinson's disease (PD) and subsequent incident epileptic seizures.
We conducted a retrospective cohort study with a nested case-control analysis using data from the UK Clinical Practice Research Datalink. We identified patients aged ≥40 years with an incident diagnosis of PD between 1995 and 2016 and a matched comparison group of PD-free individuals. We calculated crude incidence rates (IRs) with 95% confidence intervals (CIs) of epileptic seizures in PD patients and the PD-free comparison group, and corresponding crude incidence rate ratios (IRRs). In the nested case-control analysis, we calculated adjusted odds ratios (adj. ORs) of incident PD among cases with incident epileptic seizures and seizure-free controls overall and stratified by various, seizure-provoking comorbidities.
Among 23,086 incident PD patients and 92,343 PD-free individuals, we identified 898 patients with incident epileptic seizures. The crude IR of epileptic seizures in PD patients was 266.7/100,000 person years (95% CI 235.6-297.7), and in PD-free individuals 112.4/100,000 person years (95% CI 103.5-121.3) [IRR: 2.37, 95% CI 2.06-2.37]. The adj. OR of epileptic seizures was 1.68 [95% CI 1.43-1.98]) in PD patients compared with PD-free individuals. PD patients with comorbid brain disorders (adj. OR 12.36 [95% CI 8.74-17.48]) or with >1 seizure-provoking comorbidity (adj. OR 13.24 [95% CI 10.15-17.25]) were at the highest risk of epileptic seizures compared with PD-free individuals with no seizure-provoking comorbidities.
This study suggests that incident PD is associated with an increased risk of incident epileptic seizures. This article is protected by copyright. All rights reserved.
Objective: Recent studies have underlined the effect of systemic inflammation on the pathophysiology of Alzheimer's disease. Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation if not tightly regulated. The aim of our study was to fully characterize human circulating neutrophils at different disease stages in Alzheimer's disease.
Methods: We analyzed neutrophil phenotypes and functions in forty-two patients with Alzheimer's disease (sixteen with mild cognitive impairment and twenty-six with dementia), and compared them with twenty-two age-matched healthy subjects. This study was performed directly in whole blood to avoid issues with data interpretation related to cell isolation procedures.
Results: Blood samples from Alzheimer's diseases patients with dementia revealed neutrophil hyperactivation associated with increased reactive oxygen species production and increased levels of intravascular neutrophil extravascular traps. The homeostasis of circulating neutrophils in these patients also changed: the ratio between the harmful hyperreactive CXCR4high/CD62Llow senescent and the CD16bright/CD62Ldim immunosuppressive neutrophil subsets rose in the later stage of the disease. These abnormalities were greater in fast-decliner than in slow-decliner patients.
Interpretation: Our results indicate that the inflammatory properties of circulating neutrophils shift as the percentage of aged neutrophils expands in patients with Alzheimer's disease — changes that may play an instrumental role in establishing systemic chronic inflammation. Most important, our data strongly suggest that the neutrophil phenotype may be associated with the rate of cognitive decline and may thus constitute an innovative and prognostic blood biomarker in patients with Alzheimer's disease. This article is protected by copyright. All rights reserved.
Objective: Lysosomal Storage Disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of Metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement.
Methods: MT-1 over-expressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and in the manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models.
Results: Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5-10% increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT- LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to the brains by systemic AAV gene transfer.
Interpretation: MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS. This article is protected by copyright. All rights reserved.
Objective: CD16+/CD163+ macrophages (MΦ)s and microglia accumulate in the brains of patients with HIV encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders (HAND), HIV-associated dementia (HIV-D). Recently, we found that some parenchymal microglia in brain of HIV+ subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE, HIV/noE, and HIV- controls.
Methods: Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163+, CD16+ or CD68+ MΦs/microglia per case, using terminal continuation (TC) RNA amplification and a custom-designed array platform.
Results: Several classes of microglial transcripts in HIVE and HIV/noE, were altered, relative to HIV- subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors are reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE.
Interpretation: Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as ascertain alterations in specific pathways, genes, and, ostensibly, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain. This article is protected by copyright. All rights reserved.
Skip the salt: your brain might thank you
Skip the salt: your brain might thank you, Published online: 25 January 2018; doi:10.1038/s41593-018-0068-6Excessive dietary salt can impair cerebral blood flow regulation, resulting in cognitive dysfunction in mice. A ‘gut–brain’ pathway is implicated that links expansion of TH17 lymphocytes in small intestine to elevated bloodstream interleukin-17, which impairs brain perfusion by decreasing nitric oxide production in brain vascular endothelium.
Grid cells map the visual world
Grid cells map the visual world, Published online: 25 January 2018; doi:10.1038/s41593-017-0062-4Neuroimaging studies of human entorhinal cortex activity revealed 60-degree spatial periodicity, a hallmark of grid cells, as gaze movements were made throughout the visual field. This activity may serve as a framework for organizing visuospatial memory.
Pamela Sklar 1959–2017
Pamela Sklar 1959–2017, Published online: 25 January 2018; doi:10.1038/s41593-017-0067-zPamela Sklar, Chair of the Department of Genetics and Genomic Sciences and endowed Professor of Psychiatric Genetics at the Icahn School of Medicine at Mount Sinai in New York City, died 20 November 2017 after a long illness.
John Lisman 1944–2017
John Lisman 1944–2017, Published online: 25 January 2018; doi:10.1038/s41593-018-0069-5On 20 October 2017, John Lisman passed away at the age of 73. Neuroscience lost a great luminary.
Integrating new findings and examining clinical applications of pattern separation
Integrating new findings and examining clinical applications of pattern separation, Published online: 25 January 2018; doi:10.1038/s41593-017-0065-1The authors review the latest evidence on hippocampal pattern separation, survey recent data from cognitive tasks testing pattern separation and their application to clinical studies, and evaluate the assumptions that guide studies in the area.
Same path, different beginnings
Same path, different beginnings, Published online: 25 January 2018; doi:10.1038/s41593-017-0063-3An extensive single-cell transcriptomic collection of over 30,000 cells of the developing hippocampus shows that adult hippocampal neurogenesis follows the same differentiation path as embryonic neurogenesis, but the cell of origin differs. This work provides an invaluable resource with important implications for neuronal regeneration.