Synaptic and Intrinsic Activation of GABAergic Neurons in the Cardiorespiratory Brainstem Network

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca2+ currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration

Functional contribution of the mesencephalic locomotor region to locomotion

Parce qu'il est naturel et facile de marcher, il peut sembler que cet acte soit produit aussi facilement qu'il est accompli. Au contraire, la locomotion nécessite une interaction neurale complexe entre les neurones supraspinaux, spinaux et périphériques pour obtenir une locomotion fluide et adaptée à l'environnement. La région locomotrice mésencéphalique (MLR) est un centre locomoteur supraspinal situé dans le tronc cérébral qui a notamment pour rôle d'initier la locomotion et d'induire une transition entre les allures locomotrices. Cependant, bien que cette région ait initialement été identifiée comme le noyau cunéiforme (CnF), un groupe de neurones glutamatergiques, et le noyau pédonculopontin (PPN), un groupe de neurones glutamatergiques et cholinergiques, son corrélat anatomique est encore un sujet de débat. Et alors qu'il a été prouvé que, que ce soit lors d’une stimulation de la MLR ou pour augmenter la vitesse locomotrice, la plupart des quadrupèdes présentent un large éventail d'allures locomotrices allant de la marche, au trot, jusqu’au galop, la gamme exacte des allures locomotrices chez la souris est encore inconnue. Ici, en utilisant l'analyse cinématique, nous avons d'abord décidé d'identifier d’évaluer les allures locomotrices des souris C57BL / 6. Sur la base de la symétrie de la démarche et du couplage inter-membres, nous avons identifié et caractérisé 8 allures utilisées à travers un continuum de fréquences locomotrices allant de la marche au trot puis galopant avec différents sous-types d'allures allant du plus lent au plus rapide. Certaines allures sont apparues comme attractrices d’autres sont apparues comme transitionnelles. En utilisant une analyse graphique, nous avons également démontré que les transitions entre les allures n'étaient pas aléatoires mais entièrement prévisibles. Nous avons ensuite décidé d'analyser et de caractériser les contributions fonctionnelles des populations neuronales de CnF et PPN au contrôle locomoteur. En utilisant des souris transgéniques exprimant une opsine répondant à la lumière dans les neurones glutamatergiques (Glut) ou cholinergiques (CHAT), nous avons photostimulé (ou photo-inhibé) les neurones glutamatergiques du CnF ou du PPN ou les neurones cholinergiques du PPN. Nous avons découvert que les neurones glutamatergiques du CnF initient et modulent l’allure locomotrice et accélèrent le rythme, tandis que les neurones glutamatergiques et cholinergiques du PPN le ralentissent. En initiant, modulant et en accélérant la locomotion, notre étude identifie et caractérise des populations neuronales distinctes de la MLR. Définir et décrire en profondeur la MLR semble d’autant plus urgent qu’elle est devenue récemment une cible pour traiter les symptômes survenant après une lésion de la moelle épinière ou liés à la maladie de Parkinson.Because it is natural and easy to walk, it could seem that this act is produced as easily as it is accomplished. On the contrary, locomotion requires an intricate and complex neural interaction between the supraspinal, spinal and peripheric neurons to obtain a locomotion that is smooth and adapted to the environment. The Mesencephalic Locomotor Region (MLR) is a supraspinal brainstem locomotor center that has the particular role of initiating locomotion and inducing a transition between locomotor gaits. However, although this region was initially identified as the cuneiform nucleus (CnF), a cluster of glutamatergic neurons, and the pedunculopontine nucleus (PPN), a cluster of glutamatergic and cholinergic neurons, its anatomical correlate is still a matter of debate. And while it is proven that, either under MLR stimulation or in order to increase locomotor speed, most quadrupeds exhibit a wide range of locomotor gaits from walk, to trot, to gallop, the exact range of locomotor gaits in the mouse is still unknown. Here, using kinematic analysis we first decided to identify to assess locomotor gaits C57BL/6 mice. Based on the symmetry of the gait and the inter-limb coupling, we identified and characterized 8 gaits during locomotion displayed through a continuum of locomotor frequencies, ranging from walk to trot and then to gallop with various sub-types of gaits at the slowest and highest speeds that appeared as attractors or transitional gaits. Using graph analysis, we also demonstrated that transitions between gaits were not random but entirely predictable. Then we decided to analyze and characterize the functional contributions of the CnF and PPN’s neuronal populations to locomotor control. Using transgenic mice expressing opsin in either glutamatergic (Glut) or cholinergic (CHAT) neurons, we photostimulated (or photoinhibited) glutamatergic neurons of the CnF or PPN or cholinergic neurons of the PPN. We discovered that glutamatergic CnF neurons initiate and modulate the locomotor pattern, and accelerate the rhythm, while glutamatergic and cholinergic PPN neurons decelerate it. By initiating, modulating, and accelerating locomotion, our study identifies and characterizes distinct neuronal populations of the MLR. Describing and defining thoroughly the MLR seems all the more urgent since it has recently become a target for spinal cord injury and Parkinson’s disease treatment

Deep Brain Stimulation (DBS) Applications

The issue is dedicated to applications of Deep Brain Stimulation and, in this issue, we would like to highlight the new developments that are taking place in the field. These include the application of new technology to existing indications, as well as ‘new’ indications. We would also like to highlight the most recent clinical evidence from international multicentre trials. The issue will include articles relating to movement disorders, pain, psychiatric indications, as well as emerging indications that are not yet accompanied by clinical evidence. We look forward to your expert contribution to this exciting issue