Locomotion is a universal behaviour that provides animals with the ability to move between places. Classical experiments have used electrical microstimulation to identify brain regions that promote ...locomotion, but the identity of neurons that act as key intermediaries between higher motor planning centres and executive circuits in the spinal cord has remained controversial. Here we show that the mouse caudal brainstem encompasses functionally heterogeneous neuronal subpopulations that have differential effects on locomotion. These subpopulations are distinguishable by location, neurotransmitter identity and connectivity. Notably, glutamatergic neurons within the lateral paragigantocellular nucleus (LPGi), a small subregion in the caudal brainstem, are essential to support high-speed locomotion, and can positively tune locomotor speed through inputs from glutamatergic neurons of the upstream midbrain locomotor region. By contrast, glycinergic inhibitory neurons can induce different forms of behavioural arrest mapping onto distinct caudal brainstem regions. Anatomically, descending pathways of glutamatergic and glycinergic LPGi subpopulations communicate with distinct effector circuits in the spinal cord. Our results reveal that behaviourally opposing locomotor functions in the caudal brainstem were historically masked by the unexposed diversity of intermingled neuronal subpopulations. We demonstrate how specific brainstem neuron populations represent essential substrates to implement key parameters in the execution of motor programs.
The mesencephalic locomotor region (MLR) is a key midbrain center with roles in locomotion. Despite extensive studies and clinical trials aimed at therapy-resistant Parkinson’s disease (PD), debate ...on its function remains. Here, we reveal the existence of functionally diverse neuronal populations with distinct roles in control of body movements. We identify two spatially intermingled glutamatergic populations separable by axonal projections, mouse genetics, neuronal activity profiles, and motor functions. Most spinally projecting MLR neurons encoded the full-body behavior rearing. Loss- and gain-of-function optogenetic perturbation experiments establish a function for these neurons in controlling body extension. In contrast, Rbp4-transgene-positive MLR neurons project in an ascending direction to basal ganglia, preferentially encode the forelimb behaviors handling and grooming, and exhibit a role in modulating movement. Thus, the MLR contains glutamatergic neuronal subpopulations stratified by projection target exhibiting roles in action control not restricted to locomotion.
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•Glutamatergic mesencephalic locomotor region (MLR) neurons segregate by axonal target•MLR neurons projecting to basal ganglia output nuclei are labeled by Rbp4 transgene•Spinally projecting MLR neurons encode rearing and regulate body extension•Rbp4-MLR neurons are mostly tuned to forelimb movements and modulate behavior
The functionally diverse mesencephalic locomotor region (MLR) contains distinct subpopulations of glutamatergic neurons with different axonal targets, with activity correlated to specific behaviors beyond just locomotion.
Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct ...stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib.We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.
The objectives of the cross-sectional study were to delineate the knowledge, attitudes, and behavior among nurses regarding the prevention of central line-associated bloodstream infections (CLABSIs) ...and to identify their predisposing factors. A questionnaire was self-administered from September to November 2011 to nurses in oncology and outpatient chemotherapy units in 16 teaching and non-teaching public and private hospitals in the Campania region (Italy). The questionnaire gathered information on demographic and occupational characteristics; knowledge about evidence-based practices for the prevention of CLABSIs; attitudes towards guidelines, the risk of transmitting infections, and hand-washing when using central venous catheter (CVC); practices about catheter site care; and sources of information. The vast majority of the 335 nurses answered questions correctly about the main recommendations to prevent CLABSIs (use sterile gauze or sterile transparent semipermeable dressing to cover the catheter site, disinfect the needleless connectors before administer medication or fluid, disinfect with hydrogen peroxide the catheter insertion site, and use routinely anticoagulants solutions). Nurses aged 36 to 50 years were less likely to know these main recommendations to prevent CLABSIs, whereas this knowledge was higher in those who have received information about the prevention of these infections from courses. Nurses with lower education and those who do not know two of the main recommendations on the site's care to prevent the CLABSIs, were more likely to perceive the risk of transmitting an infection. Higher education, attitude toward the utility allow to dry antiseptic, and the need of washing hands before wearing gloves for access to port infusion were predictors of performing skin antiseptic and aseptic technique for dressing the catheter insertion site. Educational interventions should be implemented to address the gaps regarding knowledge and practice regarding the prevention of CLABSIs and to ensure that nurses use evidence-based prevention interventions.
Accurate motor-task execution relies on continuous comparison of planned and performed actions. Motor-output pathways establish internal circuit collaterals for this purpose. Here we focus on motor ...collateral organization between spinal cord and upstream neurons in the brainstem. We used a newly developed mouse genetic tool intersectionally with viruses to uncover the connectivity rules of these ascending pathways by capturing the transient expression of neuronal subpopulation determinants. We reveal a widespread and diverse network of spinal dual-axon neurons, with coincident input to forelimb motor neurons and the lateral reticular nucleus (LRN) in the brainstem. Spinal information to the LRN is not segregated by motor pool or neurotransmitter identity. Instead, it is organized according to the developmental domain origin of the progenitor cells. Thus, excerpts of most spinal information destined for action are relayed to supraspinal centers through exquisitely organized ascending connectivity modules, enabling precise communication between command and execution centers of movement.
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•Mouse-limb premotor neurons project to select brainstem areas•Ascending projections to LRN derive from functionally diverse spinal neurons•Lack of segregation of LRN input by motor pool or neurotransmitter identity•Spinal progenitor-domain origin reveals connection specificity to LRN
A comprehensive circuit of dual-axon neurons, organized by their developmental origins, mediates communication between the brainstem centers that command motion and the motor neuron centers that execute it.
To evaluate the effect of sleep deprivation on time-based prospective memory performance, that is, realizing delayed intentions at an appropriate time in the future (e.g., to take a medicine in 30 ...minutes).
Between-subjects experimental design. The experimental group underwent 24 h of total sleep deprivation, and the control group had a regular sleep-wake cycle. Participants were tested at 08:00.
Laboratory.
Fifty healthy young adults (mean age 22 ± 2.1, 31 female).
24 h of total sleep deprivation.
Participants were monitored by wrist actigraphy for 3 days before the experimental session. The following cognitive tasks were administered: one time-based prospective memory task and 3 reasoning tasks as ongoing activity. Objective and subjective vigilance was assessed by the psychomotor vigilance task and a visual analog scale, respectively. To measure the time-based prospective memory task we assessed compliance and clock checking behavior (time monitoring). Sleep deprivation negatively affected time-based prospective memory compliance (P < 0.001), objective vigilance (mean RT: P < 0.001; slowest 10% RT: P < 0.001; lapses: P < 0.005), and subjective vigilance (P < 0.0001). Performance on reasoning tasks and time monitoring behavior did not differ between groups.
The results highlight the potential dangerous effects of total sleep deprivation on human behavior, particularly the ability to perform an intended action after a few minutes. Sleep deprivation strongly compromises time-based prospective memory compliance but does not affect time check frequency. Sleep deprivation may impair the mechanism that allows the integration of information related to time monitoring with the prospective intention.
Abstract
The gene encoding for the protein SE translocation (SET) was identified for the first time 30 years ago as part of a chromosomal translocation in a patient affected by leukemia. Since then, ...accumulating evidence have linked overexpression of SET, aberrant SET splicing, and cellular localization to cancer progression and development of neurodegenerative tauopathies such as Alzheimer’s disease. Molecular biology tools, such as targeted genetic deletion, and pharmacological approaches based on SET antagonist peptides, have contributed to unveil the molecular functions of SET and its implications in human pathogenesis. In this review, we provide an overview of the functions of SET as inhibitor of histone and non-histone protein acetylation and as a potent endogenous inhibitor of serine–threonine phosphatase PP2A. We discuss the role of SET in multiple cellular processes, including chromatin remodelling and gene transcription, DNA repair, oxidative stress, cell cycle, apoptosis cell migration and differentiation. We review the molecular mechanisms linking SET dysregulation to tumorigenesis and discuss how SET commits neurons to progressive cell death in Alzheimer’s disease, highlighting the rationale of exploiting SET as a therapeutic target for cancer and neurodegenerative tauopathies.
Although classically considered a relay station for basal ganglia (BG) output, the anatomy, connectivity, and function of the mesencephalic locomotor region (MLR) were redefined during the last two ...decades. In striking opposition to what was initially thought, MLR and BG are actually reciprocally and intimately interconnected. New viral-based, optogenetic, and mapping technologies revealed that cholinergic, glutamatergic, and GABAergic neurons coexist in this structure, which, in addition to extending descending projections, send long-range ascending fibers to the BG. These MLR projections to the BG convey motor and non-motor information to specific synaptic targets throughout different nuclei. Moreover, MLR efferent fibers originate from precise neuronal subpopulations located in particular MLR subregions, defining independent anatomo-functional subcircuits involved in particular aspects of animal behavior such as fast locomotion, explorative locomotion, posture, forelimb- related movements, speed, reinforcement, among others. In this review, we revised the literature produced during the last decade linking MLR and BG. We conclude that the classic framework considering the MLR as a homogeneous output structure passively receiving input from the BG needs to be revisited. We propose instead that the multiple subcircuits embedded in this region should be taken as independent entities that convey relevant and specific ascending information to the BG and, thus, actively participate in the execution and tuning of behavior.
A recent study has functionally disentangled the hitherto enigmatic mesencephalic locomotor region of the brain on the basis of cell type diversity and identified differential upstream regulatory ...pathways.
A recent study has functionally disentangled the hitherto enigmatic mesencephalic locomotor region of the brain on the basis of cell type diversity and identified differential upstream regulatory pathways.
Brain-wide neural circuits enable bi- and quadrupeds to express adaptive locomotor behaviors in a context- and state-dependent manner, e.g., in response to threats or rewards. These behaviors include ...dynamic transitions between initiation, maintenance and termination of locomotion. Advances within the last decade have revealed an intricate coordination of these individual locomotion phases by complex interaction of multiple brain circuits. This review provides an overview of the neural basis of state-dependent modulation of locomotion initiation, maintenance and termination, with a focus on insights from circuit-centered studies in rodents. The reviewed evidence indicates that a brain-wide network involving excitatory circuit elements connecting cortex, midbrain and medullary areas appears to be the common substrate for the initiation of locomotion across different higher-order states. Specific network elements within motor cortex and the mesencephalic locomotor region drive the initial postural adjustment and the initiation of locomotion. Microcircuits of the basal ganglia, by implementing action-selection computations, trigger goal-directed locomotion. The initiation of locomotion is regulated by neuromodulatory circuits residing in the basal forebrain, the hypothalamus, and medullary regions such as locus coeruleus. The maintenance of locomotion requires the interaction of an even larger neuronal network involving motor, sensory and associative cortical elements, as well as defined circuits within the superior colliculus, the cerebellum, the periaqueductal gray, the mesencephalic locomotor region and the medullary reticular formation. Finally, locomotor arrest as an important component of defensive emotional states, such as acute anxiety, is mediated via a network of survival circuits involving hypothalamus, amygdala, periaqueductal gray and medullary premotor centers. By moving beyond the organizational principle of functional brain regions, this review promotes a circuit-centered perspective of locomotor regulation by higher-order states, and emphasizes the importance of individual network elements such as cell types and projection pathways. The realization that dysfunction within smaller, identifiable circuit elements can affect the larger network function supports more mechanistic and targeted therapeutic intervention in the treatment of motor network disorders.
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