Cortical motor maps are the basis of voluntary movement, but they have proven difficult to understand in the context of their underlying neuronal circuits. We applied light-based motor mapping of ...Channelrhodopsin-2 mice to reveal a functional subdivision of the forelimb motor cortex based on the direction of movement evoked by brief (10 ms) pulses. Prolonged trains of electrical or optogenetic stimulation (100–500 ms) targeted to anterior or posterior subregions of motor cortex evoked reproducible complex movements of the forelimb to distinct positions in space. Blocking excitatory cortical synaptic transmission did not abolish basic motor map topography, but the site-specific expression of complex movements was lost. Our data suggest that the topography of movement maps arises from their segregated output projections, whereas complex movements evoked by prolonged stimulation require intracortical synaptic transmission.
► Optogenetic mapping reveals functional subdivision of mouse forelimb motor cortex ► Prolonged stimulation evokes distinct complex movements from different cortical areas ► Complex movements require cortical synaptic transmission, but map topography does not ► Movement representations have separate corticofugal projections
Using light to stimulate the mouse brain, Harrison et al. identify brain areas responsible for producing different types of forelimb movements and study the function of circuits within those areas by locally blocking communication between neurons.
•Created bilateral chronic windows for imaging through the intact mouse skull.•Includes a head-fixing screw for immobilizing the head during awake imaging.•Preparation is stable for awake, widefield ...imaging of neuronal activity with GCaMP6.•Functional connectivity maps were generated from awake spontaneous activity.
Craniotomy-based window implants are commonly used for microscopic imaging, in head-fixed rodents, however their field of view is typically small and incompatible with mesoscopic functional mapping of cortex.
We describe a reproducible and simple procedure for chronic through-bone wide-field imaging in awake head-fixed mice providing stable optical access for chronic imaging over large areas of the cortex for months.
The preparation is produced by applying clear-drying dental cement to the intact mouse skull, followed by a glass coverslip to create a partially transparent imaging surface. Surgery time takes about 30min. A single set-screw provides a stable means of attachment (in relation to the measured lateral and axial resolution) for mesoscale assessment without obscuring the cortical field of view.
We demonstrate the utility of this method by showing seed-pixel functional connectivity maps generated from spontaneous cortical activity of GCAMP6 signals in both awake and anesthetized mice in longitudinal studies of up to 2 months in duration.
We propose that the intact skull preparation described here may be used for most longitudinal studies that do not require micron scale resolution and where cortical neural or vascular signals are recorded with intrinsic sensors or in transgenic mice expressing genetically encoded sensors of activity.
Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering ...feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.
Aim
Clinicians mediate access to new technologies. Consequently, their views on specific devices may influence user access to diabetes technology in mainstream care. As yet, little is known about ...clinicians’ views about closed‐loop systems. This qualitative study explored clinicians’ views on the likely impacts of future closed‐loop systems in mainstream diabetes care in England.
Methods
We conducted interviews with 36 clinicians from a range of professional backgrounds in five hospital outpatient clinics (two adult, two pregnancy, one paediatric) in England to explore possible consequences of closed‐loop systems for users and clinicians. Data analysis utilized a framework approach.
Results
Clinicians reported a range of expected benefits for future users, including improved glucose control and quality of life. Expected burdens included continued need for manual input and the risk of losing basic self‐care skills. In terms of future clinical workloads, three clinicians emphasized only positive impacts, seven emphasized both positive and negative impacts, and 17 mentioned only negative impacts. Our most prominent finding, expressed by 24 clinicians, was that closed‐loop systems would generate initial challenges due to the need for staff training, user education and support, and new analytical capacities, alongside existing intra‐clinic variations in technological experience.
Conclusions
Clinicians recognize the value of closed‐loop systems in terms of health benefits, but also identify a range of concerns for both users and healthcare staff, which could impact negatively on user access. Future implementation efforts should address these concerns by providing training and support for healthcare teams, taking varied technological expertise into account.
What's new?
Clinician attitudes towards new technologies influence outcomes in mainstream care. Little is known about clinician views about the likely impacts of future closed‐loop systems in diabetes care.
Alongside benefits and burdens for users, clinicians expect closed‐loop systems to generate health service challenges due to heightened needs for training, user support and analytical capacities.
Clinicians identify a range of concerns for both users and staff, which could impact negatively on user access. Future implementation efforts should address these concerns by providing training and support for healthcare teams.
Motor cortical plasticity contributes to spontaneous recovery after incomplete spinal cord injury (SCI), but the pathways underlying this remain poorly understood. We performed optogenetic mapping of ...motor cortex in channelrhodopsin-2 expressing mice to assess the capacity of the cortex to re-establish motor output longitudinally after a C3/C4 dorsal column SCI that bilaterally ablated the dorsal corticospinal tract (CST) containing ∼96% of corticospinal fibers but spared ∼3% of CST fibers that project via the dorsolateral funiculus. Optogenetic mapping revealed extensive early deficits, but eventual reestablishment of motor cortical output maps to the limbs at the same latency as preoperatively by 4 weeks after injury. Analysis of skilled locomotion on the horizontal ladder revealed early deficits followed by partial spontaneous recovery by 6 weeks after injury. To dissociate between the contributions of injured dorsal projecting versus spared dorsolateral projecting corticospinal neurons, we established a transient silencing approach to inactivate spared dorsolaterally projecting corticospinal neurons specifically by injecting adeno-associated virus (AAV)-expressing Cre-dependent DREADD (designer receptor exclusively activated by designer drug) receptor hM4Di in sensorimotor cortex and AAV-expressing Cre in C7/C8 dorsolateral funiculus. Transient silencing uninjured dorsolaterally projecting corticospinal neurons via activation of the inhibitory DREADD receptor hM4Di abrogated spontaneous recovery and resulted in a greater change in skilled locomotion than in control uninjured mice using the same silencing approach. These data demonstrate the pivotal role of a minor dorsolateral corticospinal pathway in mediating spontaneous recovery after SCI and support a focus on spared corticospinal neurons as a target for therapy.
Spontaneous recovery can occur after incomplete spinal cord injury (SCI), but the pathways underlying this remain poorly understood. We performed optogenetic mapping of motor cortex after a cervical SCI that interrupts most corticospinal transmission but results in partial recovery on a horizontal ladder task of sensorimotor function. We demonstrate that the motor cortex can reestablish output to the limbs longitudinally. To dissociate the roles of injured and uninjured corticospinal neurons in mediating recovery, we transiently silenced the minor dorsolateral corticospinal pathway spared by our injury. This abrogated spontaneous recovery and resulted in a greater change in skilled locomotion than in uninjured mice using the same approach. Therefore, uninjured corticospinal neurons substantiate remarkable motor cortical plasticity and partial recovery after SCI.
N-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic ...targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice.
► Synaptic NMDA receptor activity is normal in neurons of presymptomatic HD mice ► Extrasynaptic NMDA receptor activity is greatly augmented in the same cells ► Nonsynaptic NR2B subunits are elevated and nuclear CREB activation is reduced ► Ex-NMDAR blockade (memantine) reverses CREB signaling and motor learning deficits
Recovery from stroke is hypothesized to involve the reorganization of surviving cortical areas. To study the functional organization of sensorimotor cortex at multiple time points before and after ...stroke, we performed longitudinal light-based motor mapping of transgenic mice expressing light-sensitive channelrhodopsin-2 in layer 5 cortical neurons.
Pulses of light stimulation were targeted to an array of cortical points, whereas evoked forelimb motor activity was recorded using noninvasive motion sensors. Intrinsic optical signal imaging produced maps of the forelimb somatosensory cortex. The resulting motor and sensory maps were repeatedly generated for weeks before and after small (0.2 mm3) photothrombotic infarcts were targeted to forelimb motor or sensory cortex.
Infarcts targeted to forelimb sensory or motor areas caused decreased motor output in the infarct area and spatial displacement of sensory and motor maps. Strokes in sensory cortex caused the sensory map to move into motor cortex, which adopted a more diffuse structure. Stroke in motor cortex caused a compensatory increase in peri-infarct motor output, but did not affect the position or excitability of sensory maps.
After stroke in motor cortex, decreased motor output from the infarcted area was offset by peri-infarct excitability. Sensory stroke caused a new sensory map to form in motor cortex, which maintained its center position, despite becoming more diffuse. These data suggest that surviving regions of cortex are able to assume functions from stroke-damaged areas, although this may come at the cost of alterations in map structure.
Aim
Excessive gestational weight gain increases risk of gestational diabetes mellitus (GDM) but it remains unclear whether weight control after GDM diagnosis improves outcomes. We assessed whether: ...(1) total gestational weight gain during pregnancy (0–36 weeks); (2) early gestational weight gain (0–28 weeks, before GDM diagnosis); or (3) late gestational weight gain (28–36 weeks, after diagnosis) are associated with maternal–fetal outcomes.
Methods
Some 546 women with GDM who delivered viable singleton infants at a single UK obstetric centre (October 2014 to March 2017) were included in this retrospective observational study.
Results
Higher total gestational weight gain was associated with Caesarean section n = 376; odds ratio (OR) 1.05; confidence intervals (CI) 1.02–1.08, P < 0.001 and large for gestational age (OR 1.08; CI 1.03–1.12, P < 0.001). Higher late gestational weight gain (28–36 weeks; n = 144) was associated with large for gestational age (OR 1.17; CI 1.01–1.37, P < 0.05), instrumental deliveries (OR 1.26; CI 1.03–1.55, P < 0.01), higher total daily insulin doses (36 weeks; beta coefficient 4.37; CI 1.92–6.82, P < 0.001), and higher post‐partum 2‐h oral glucose tolerance test concentrations (beta coefficient 0.12; CI 0.01–0.22, P < 0.05). Women who avoided substantial weight gain after GDM diagnosis had 0.7 mmol/l lower postnatal 2‐h glucose and needed half the amount of insulin/day at 36 weeks compared with women with substantial weight gain after diagnosis. There were no significant associations between early gestational weight gain (0–28 weeks) and pregnancy outcomes.
Conclusions
These findings suggest that controlling gestational weight gain should be a priority following GDM diagnosis to optimize pregnancy outcomes and improve maternal postnatal glucose homeostasis. The period after diagnosis of GDM (often 28 weeks gestation) is not too late to offer lifestyle advice or intervention to improve weight management and pregnancy outcomes.
What's new?
Gestational diabetes is associated with pre‐pregnancy obesity and excessive gestational weight gain.
However, there is no clear evidence to guide weight management after diagnosis of gestational diabetes (at 28 weeks).
In this study, excessive gestational weight gain was strongly associated with fetal growth and difficult deliveries in women with gestational diabetes.
Women who gained weight after diagnosis needed higher insulin doses and had higher postnatal glucose concentrations.
Keeping weight stable after diagnosis of gestational diabetes should be a priority to improve outcomes for both mother and child; 28 weeks is not too late to offer advice or intervention.
A clinical trial to guide weight management in women with gestational diabetes would be extremely useful to confirm these findings and provide clear targets for weight gain after diagnosis.
Recently revised public health guidelines acknowledge the health benefits of regular intermittent bouts of vigorous intensity incidental physical activity done as part of daily living, such as ...carrying shopping bags, walking uphill, and stair climbing. Despite this recognition and the advantages such lifestyle physical activity has over continuous vigorous intensity structured exercise, a scoping review we conducted revealed that current research in this area is, at best, rudimentary. Key gaps include the absence of an empirically-derived dose specification (e.g., minimum duration of lifestyle physical activity required to achieve absolute or relative vigorous intensity), lack of acceptable measurement standards, limited understanding of acute and chronic (adaptive) effects of intermittent vigorous bouts on health, and paucity of essential information necessary to develop feasible and scalable interventions (e.g., acceptability of this kind of physical activity by the public). To encourage collaboration and research agenda alignment among groups interested in this field, we propose a research framework to further understanding of vigorous intermittent lifestyle physical activity (VILPA). This framework comprises four pillars aimed at the development of: (a) an empirical definition of VILPA, (b) methods to reliably and accurately measure VILPA, (c) approaches to examine the short and long-term dose–response effects of VILPA, and (d) scalable and acceptable behavioural VILPA-promoting interventions.
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