A Thalamic Reticular Circuit for Head Direction Cell Tuning and Spatial Navigation.

As we navigate in space, external landmarks and internal information guide our movement. Circuit and synaptic mechanisms that integrate these cues with head-direction (HD) signals remain, however, unclear. We identify an excitatory synaptic projection from the presubiculum (PreS) and the multisensory-associative retrosplenial cortex (RSC) to the anterodorsal thalamic reticular nucleus (TRN), so far classically implied in gating sensory information flow. In vitro, projections to TRN involve AMPA/NMDA-type glutamate receptors that initiate TRN cell burst discharge and feedforward inhibition of anterior thalamic nuclei. In vivo, chemogenetic anterodorsal TRN inhibition modulates PreS/RSC-induced anterior thalamic firing dynamics, broadens the tuning of thalamic HD cells, and leads to preferential use of allo- over egocentric search strategies in the Morris water maze. TRN-dependent thalamic inhibition is thus an integral part of limbic navigational circuits wherein it coordinates external sensory and internal HD signals to regulate the choice of search strategies during spatial navigation

Development of quality metrics for ambulatory pediatric cardiology: Chest pain

ObjectiveAs part of the American College of Cardiology Adult Congenital and Pediatric Cardiology Section effort to develop quality metrics (QMs) for ambulatory pediatric practice, the chest pain subcommittee aimed to develop QMs for evaluation of chest pain.DesignA group of 8 pediatric cardiologists formulated candidate QMs in the areas of history, physical examination, and testing. Consensus candidate QMs were submitted to an expert panel for scoring by the RAND‐UCLA modified Delphi process. Recommended QMs were then available for open comments from all members.PatientsThese QMs are intended for use in patients 5–18 years old, referred for initial evaluation of chest pain in an ambulatory pediatric cardiology clinic, with no known history of pediatric or congenital heart disease.ResultsA total of 10 candidate QMs were submitted; 2 were rejected by the expert panel, and 5 were removed after the open comment period. The 3 approved QMs included: (1) documentation of family history of cardiomyopathy, early coronary artery disease or sudden death, (2) performance of electrocardiogram in all patients, and (3) performance of an echocardiogram to evaluate coronary arteries in patients with exertional chest pain.ConclusionsDespite practice variation and limited prospective data, 3 QMs were approved, with measurable data points which may be extracted from the medical record. However, further prospective studies are necessary to define practice guidelines and to develop appropriate use criteria in this population.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140026/1/chd12509.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140026/2/chd12509_am.pd

A lack of GluN2A-containing NMDA receptors confers a vulnerability to redox dysregulation: Consequences on parvalbumin interneurons, and their perineuronal nets.

The GluN2A subunit of NMDA receptors (NMDARs) plays a critical role during postnatal brain development as its expression increases while Glun2B expression decreases. Mutations and polymorphisms in GRIN2A gene, coding for GluN2A, are linked to developmental brain disorders such as mental retardation, epilepsy, schizophrenia. Published data suggest that GluN2A is involved in maturation and phenotypic maintenance of parvalbumin interneurons (PVIs), and these interneurons suffer from a deficient glutamatergic neurotransmission via GluN2A-containing NMDARs in schizophrenia. In the present study, we find that although PVIs and their associated perineuronal nets (PNNs) appear normal in anterior cingulate cortex of late adolescent/young adult GRIN2A KO mice, a lack of GluN2A delays PNN maturation. GRIN2A KO mice display a susceptibility to redox dysregulation as sub-threshold oxidative stress and subtle alterations in antioxidant systems are observed in their prefrontal cortex. Consequently, an oxidative insult applied during early postnatal development increases oxidative stress, decreases the number of parvalbumin-immunoreactive cells, and weakens the PNNs in KO but not WT mice. These effects are long-lasting, but preventable by the antioxidant, N-acetylcysteine. The persisting oxidative stress, deficit in PVIs and PNNs, and reduced local high-frequency neuronal synchrony in anterior cingulate of late adolescent/young adult KO mice, which have been challenged by an early-life oxidative insult, is accompanied with microglia activation. Altogether, these indicate that a lack of GluN2A-containing NMDARs alters the fine control of redox status, leading to a delayed maturation of PNNs, and conferring vulnerability for long-term oxidative stress, microglial activation, and PVI network dysfunction

Quantifying Infra-slow Dynamics of Spectral Power and Heart Rate in Sleeping Mice.

Three vigilance states dominate mammalian life: wakefulness, non-rapid eye movement (non-REM) sleep, and REM sleep. As more neural correlates of behavior are identified in freely moving animals, this three-fold subdivision becomes too simplistic. During wakefulness, ensembles of global and local cortical activities, together with peripheral parameters such as pupillary diameter and sympathovagal balance, define various degrees of arousal. It remains unclear the extent to which sleep also forms a continuum of brain states-within which the degree of resilience to sensory stimuli and arousability, and perhaps other sleep functions, vary gradually-and how peripheral physiological states co-vary. Research advancing the methods to monitor multiple parameters during sleep, as well as attributing to constellations of these functional attributes, is central to refining our understanding of sleep as a multifunctional process during which many beneficial effects must be executed. Identifying novel parameters characterizing sleep states will open opportunities for novel diagnostic avenues in sleep disorders. We present a procedure to describe dynamic variations of mouse non-REM sleep states via the combined monitoring and analysis of electroencephalogram (EEG)/electrocorticogram (ECoG), electromyogram (EMG), and electrocardiogram (ECG) signals using standard polysomnographic recording techniques. Using this approach, we found that mouse non-REM sleep is organized into cycles of coordinated neural and cardiac oscillations that generate successive 25-s intervals of high and low fragility to external stimuli. Therefore, central and autonomic nervous systems are coordinated to form behaviorally distinct sleep states during consolidated non-REM sleep. We present surgical manipulations for polysomnographic (i.e., EEG/EMG combined with ECG) monitoring to track these cycles in the freely sleeping mouse, the analysis to quantify their dynamics, and the acoustic stimulation protocols to assess their role in the likelihood of waking up. Our approach has already been extended to human sleep and promises to unravel common organizing principles of non-REM sleep states in mammals

Thalamic reticular control of local sleep in mouse sensory cortex.

Sleep affects brain activity globally, but many cortical sleep waves are spatially confined. Local rhythms serve cortical area-specific sleep needs and functions; however, mechanisms controlling locality are unclear. We identify the thalamic reticular nucleus (TRN) as a source for local, sensory-cortex-specific non-rapid-eye-movement sleep (NREMS) in mouse. Neurons in optogenetically identified sensory TRN sectors showed stronger repetitive burst discharge compared to non-sensory TRN cells due to higher activity of the low-threshold Ca <sup>2+</sup> channel Ca <sub>V</sub> 3.3. Major NREMS rhythms in sensory but not non-sensory cortical areas were regulated in a Ca <sub>V</sub> 3.3-dependent manner. In particular, NREMS in somatosensory cortex was enriched in fast spindles, but switched to delta wave-dominated sleep when Ca <sub>V</sub> 3.3 channels were genetically eliminated or somatosensory TRN cells chemogenetically hyperpolarized. Our data indicate a previously unrecognized heterogeneity in a powerful forebrain oscillator that contributes to sensory-cortex-specific and dually regulated NREMS, enabling local sleep regulation according to use- and experience-dependence

Coordinated infraslow neural and cardiac oscillations mark fragility and offline periods in mammalian sleep.

Rodents sleep in bouts lasting minutes; humans sleep for hours. What are the universal needs served by sleep given such variability? In sleeping mice and humans, through monitoring neural and cardiac activity (combined with assessment of arousability and overnight memory consolidation, respectively), we find a previously unrecognized hallmark of sleep that balances two fundamental yet opposing needs: to maintain sensory reactivity to the environment while promoting recovery and memory consolidation. Coordinated 0.02-Hz oscillations of the sleep spindle band, hippocampal ripple activity, and heart rate sequentially divide non-rapid eye movement (non-REM) sleep into offline phases and phases of high susceptibility to external stimulation. A noise stimulus chosen such that sleeping mice woke up or slept through at comparable rates revealed that offline periods correspond to raising, whereas fragility periods correspond to declining portions of the 0.02-Hz oscillation in spindle activity. Oscillations were present throughout non-REM sleep in mice, yet confined to light non-REM sleep (stage 2) in humans. In both species, the 0.02-Hz oscillation predominated over posterior cortex. The strength of the 0.02-Hz oscillation predicted superior memory recall after sleep in a declarative memory task in humans. These oscillations point to a conserved function of mammalian non-REM sleep that cycles between environmental alertness and internal memory processing in 20- to 25-s intervals. Perturbed 0.02-Hz oscillations may cause memory impairment and ill-timed arousals in sleep disorders

Detecting carotid stenosis from skin vibrations using Laser Doppler Vibrometry - An in vitro proof-of-concept.

Early detection of asymptomatic carotid stenosis may help identifying individuals at risk of stroke. We explore a new method based on laser Doppler vibrometry (LDV) which could allow the non-contact detection of stenosis from neck skin vibrations due to stenosis-induced flow disturbances. Experimental fluid dynamical tests were performed with water on a severely stenosed patient-specific carotid bifurcation model. Measurements were taken under various physiological flow regimes both in a compliant and stiff-walled version of the model, at 1 to 4 diameters downstream from the stenosis. An inter-arterial pressure catheter was positioned as reference. Increasing flow led to corresponding increase in power spectral density (PSD) of pressure and LDV recordings in the 0-500 Hz range. The stiff model lead to higher PSD. PSD of the LDV signal was less dependent on the downstream measurement location than pressure. The strength of the association between PSD and flow level, model material and measuring location was highest in the 0-50 Hz range, however useful information was found up to 200 Hz. This proof-of-concept suggests that LDV has the potential to detect stenosis-induced disturbed flow. Further computational and clinical validation studies are ongoing to assess the sensitivity and specificity of the technique for clinical screening.EU H2020 644798 gran

Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries

OBJECTIVES: The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. METHODS: Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the 'tumour location' of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. RESULTS: ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. CONCLUSIONS: There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made

A case–control study of risk of leukaemia in relation to mobile phone use

Background Mobile phone use is now ubiquitous, and scientific reviews have recommended research into its relation to leukaemia risk, but no large studies have been conducted.Methods In a case-control study in South East England to investigate the relation of acute and non-lymphocytic leukaemia risk to mobile phone use, 806 cases with leukaemia incident 2003-2009 at ages 18-59 years (50% of those identified as eligible) and 585 non-blood relatives as controls (provided by 392 cases) were interviewed about mobile phone use and other potentially aetiological variables.Results No association was found between regular mobile phone use and risk of leukaemia (odds ratio (OR)=1.06, 95% confidence interval (CI)=0.76, 1.46). Analyses of risk in relation to years since first use, lifetime years of use, cumulative number of calls and cumulative hours of use produced no significantly raised risks, and there was no evidence of any trends. A non-significantly raised risk was found in people who first used a phone 15 or more years ago (OR=1.87, 95% CI=0.96, 3.63). Separate analyses of analogue and digital phone use and leukaemia subtype produced similar results to those overall.Conclusion This study suggests that use of mobile phones does not increase leukaemia risk, although the possibility of an effect after long-term use, while biologically unlikely, remains open