Electrophysiological profile and monosynaptic circuitry of efferent vestibular nucleus neurons

As with other sensory modalities, the vestibular system recruits efferent circuitry to transport information from the central nervous system (CNS) to the sensory periphery. This efferent vestibular system (EVS) originates in the brainstem and terminates on vestibular hair cells and afferent fibres in the semicircular canals and otolith organs. Understanding how this central component outputs to the vestibular organs, and mediates motor and vestibular coordination, could potentially impact clinical treatment of vestibular disorders. Previous EVS work has primarily focused on the anatomy, pharmacology, synaptic mechanisms, and peripheral effects of efferent vestibular nucleus (EVN) activation. Although this work is fundamental to understanding this system and its mechanism of action, the behavioural function of the EVS is yet to be ascribed. For this, we need to appreciate the physiology of EVN neurons, and their context of activation within the CNS. In this thesis, I characterise the electrophysiological profile of EVN neurons, and trace their direct monosynaptic circuitry. My methodology includes whole-cell current- and voltage- clamp electrophysiology, and glycoproteindeficient rabies virus tracing techniques. Using these, I enrich understanding of EVN action, and hint at potential functional roles from their CNS partners. The data presented in this thesis provides novel insights into the EVS. EVN neurons are characterised with a homogeneous output, but a heterogeneous synaptic input profile. Inputs to the EVN originate from diverse areas in the brainstem and cortex. These findings suggest that the EVN modulates vestibular end organs in multiple different behavioural contexts. This work forms the basis of subsequent EVS behavioural investigations such as loss of function experiments targeting input regions via optogentic means and subsequent EVS recordings, or silencing of EVN activity and subsequent behavioural testing. Collectively, my results, these future directions, and the existing body of EVS literature, brings us closer than ever to understanding and ascribing a functional role for the EVS

Activity patterns in the septal-hippocampal network predict voluntary locomotion

In the brain of animals, locomotion is encoded and represented in multiple ways. During locomotion, the hippocampus (HC) displays characteristic activity patterns that change from asynchronous states when the animal is resting to synchronous rhythmic activity during movement. The increase in firing rates of principal neurons in CA1 and the presence of oscillations in the HC both correlate to the velocity of the animal. It has been shown previously that glutamatergic neurons in the medial septum (MS) increase their activity prior to movement onset. However, the time-course of activation of individual MS neuron types during an episode of locomotion is unknown. I investigated the MS-HC circuitry with cell-type specificity by expressing the genetically encoded calcium indicator GCaMP5G in inhibitory (PV+) and excitatory (VGluT2+) cells of the MS. I have monitored activity-dependent changes in fluorescence with a fiberoptometer coupled to an implanted fiber optic cannula in head fixed mice on a linear treadmill. In addition, I obtained CA1 local field potentials and recorded multi-unit activity in both CA1 and the MS. I aligned and correlated the recorded parameters with different phases of locomotion (onset, acceleration, deceleration, offset). My results show that there is a significant representation of locomotion in both CA1 and MS neuronal populations. I demonstrate that both glutamatergic VGluT2+ and GABAergic PV+ cells in the MS show an increase in activity several hundred milliseconds before movement. My experiments provide evidence on the single neuron activity level for CA1 and MS cellular activity that predicts movement onset. A simultaneous activation of glutamatergic and GABAergic neurons within the MS suggests the activation of an excitatory-inhibitory feedback loop controlling motion execution and HC information processing

Treatise on Hearing: The Temporal Auditory Imaging Theory Inspired by Optics and Communication

A new theory of mammalian hearing is presented, which accounts for the auditory image in the midbrain (inferior colliculus) of objects in the acoustical environment of the listener. It is shown that the ear is a temporal imaging system that comprises three transformations of the envelope functions: cochlear group-delay dispersion, cochlear time lensing, and neural group-delay dispersion. These elements are analogous to the optical transformations in vision of diffraction between the object and the eye, spatial lensing by the lens, and second diffraction between the lens and the retina. Unlike the eye, it is established that the human auditory system is naturally defocused, so that coherent stimuli do not react to the defocus, whereas completely incoherent stimuli are impacted by it and may be blurred by design. It is argued that the auditory system can use this differential focusing to enhance or degrade the images of real-world acoustical objects that are partially coherent. The theory is founded on coherence and temporal imaging theories that were adopted from optics. In addition to the imaging transformations, the corresponding inverse-domain modulation transfer functions are derived and interpreted with consideration to the nonuniform neural sampling operation of the auditory nerve. These ideas are used to rigorously initiate the concepts of sharpness and blur in auditory imaging, auditory aberrations, and auditory depth of field. In parallel, ideas from communication theory are used to show that the organ of Corti functions as a multichannel phase-locked loop (PLL) that constitutes the point of entry for auditory phase locking and hence conserves the signal coherence. It provides an anchor for a dual coherent and noncoherent auditory detection in the auditory brain that culminates in auditory accommodation. Implications on hearing impairments are discussed as well.Comment: 603 pages, 131 figures, 13 tables, 1570 reference

Visual Cortex

The neurosciences have experienced tremendous and wonderful progress in many areas, and the spectrum encompassing the neurosciences is expansive. Suffice it to mention a few classical fields: electrophysiology, genetics, physics, computer sciences, and more recently, social and marketing neurosciences. Of course, this large growth resulted in the production of many books. Perhaps the visual system and the visual cortex were in the vanguard because most animals do not produce their own light and offer thus the invaluable advantage of allowing investigators to conduct experiments in full control of the stimulus. In addition, the fascinating evolution of scientific techniques, the immense productivity of recent research, and the ensuing literature make it virtually impossible to publish in a single volume all worthwhile work accomplished throughout the scientific world. The days when a single individual, as Diderot, could undertake the production of an encyclopedia are gone forever. Indeed most approaches to studying the nervous system are valid and neuroscientists produce an almost astronomical number of interesting data accompanied by extremely worthy hypotheses which in turn generate new ventures in search of brain functions. Yet, it is fully justified to make an encore and to publish a book dedicated to visual cortex and beyond. Many reasons validate a book assembling chapters written by active researchers. Each has the opportunity to bind together data and explore original ideas whose fate will not fall into the hands of uncompromising reviewers of traditional journals. This book focuses on the cerebral cortex with a large emphasis on vision. Yet it offers the reader diverse approaches employed to investigate the brain, for instance, computer simulation, cellular responses, or rivalry between various targets and goal directed actions. This volume thus covers a large spectrum of research even though it is impossible to include all topics in the extremely diverse field of neurosciences

29th Annual Computational Neuroscience Meeting: CNS*2020

Meeting abstracts This publication was funded by OCNS. The Supplement Editors declare that they have no competing interests. Virtual | 18-22 July 202

Neurones glycinergiques et transmission inhibitrice dans les noyaux cérébelleux

The cerebellum is composed of a three-layered cortex and of nuclei and is responsible for the learned fine control of posture and movements. I combined a genetic approach (based on the use of transgenic mouse lines) with anatomical tracings, immunohistochemical stainings, electrophysiological recordings and optogenetic stimulations to establish the distinctive characteristics of the inhibitory neurons of the cerebellar nuclei and to detail their connectivity and their role in the cerebellar circuitry.We showed that the glycinergic inhibitory neurons of the cerebellar nuclei constitute a distinct neuronal population and are characterized by their mixed inhibitory GABAergic/glycinergic phenotype. Those inhibitory neurons are also distinguished by their axonal plexus which includes a local arborization with the cerebellar nuclei where they contact principal output neurons and a projection to the granular layer of the cerebellar cortex where they end onto Golgi cells dendrites. Finally, the inhibitory neurons of the cerebellar nuclei receive inhibitory afferents from Purkinje cells and may be contacted by mossy fibers or climbing fibers.We provided the first evidence of functional mixed transmission in the cerebellar nuclei and the first demonstration of a mixed inhibitory nucleo-cortical projection. Overall, our data establish the inhibitory neurons as the third cellular component of the cerebellar nuclei. Their importance in the modular organization of the cerebellum and their impact on sensory-motor integration need to be confirmed by optogenetic experiments in vivo.Le cervelet, composé d'un cortex et de noyaux, est responsable du contrôle moteur fin des mouvements et de la posture. En combinant une approche génétique (basée sur l'utilisation de lignées de souris transgéniques) avec des traçages anatomiques, des marquages immunohistochimiques et des expériences d'électrophysiologie et d'optogénétique, nous établissons les caractères distinctifs des neurones inhibiteurs des noyaux cérébelleux et en détaillons la connectivité ainsi que les fonctions dans le circuit cérébelleux. Les neurones inhibiteurs glycinergiques des noyaux profonds constituent une population de neurones distincts des autres types cellulaires identifiables par leur phénotype inhibiteur mixte GABAergique/glycinergique. Ces neurones se distinguent également par leur plexus axonal qui comporte une arborisation locale dans les noyaux cérébelleux où ils contactent les neurones principaux et une projection vers le cortex cérébelleux où ils contactent les cellules de Golgi. Ces neurones inhibiteurs reçoivent également des afférences inhibitrices des cellules de Purkinje et pourraient être contactés par les fibres moussues ou les fibres grimpantes.Nous apportons ainsi la première étude d'une transmission mixte fonctionnelle par les neurones inhibiteurs des noyaux cérébelleux, projetant à la fois dans les noyaux et le cortex cérébelleux. L'ensemble de nos données établissent les neurones inhibiteurs mixtes des noyaux cérébelleux comme la troisième composante cellulaire des noyaux profonds. Leur importance dans l'organisation modulaire du cervelet, ainsi que leur impact sur l'intégration sensori-motrice, devront être confirmés par des études optogénétiques in vivo

Hearing Loss

Authored by 17 international researchers and research teams, the book provides up-to-date insights on topics in five different research areas related to normal hearing and deafness. Techniques for assessment of hearing and the appropriateness of the Mongolian gerbil as a model for age-dependent hearing loss in humans are presented. Parental attitudes to childhood deafness and role of early intervention for better treatment of hearing loss are also discussed. Comprehensive details are provided on the role of different environmental insults including injuries in causing deafness. Additionally, many genes involved in hearing loss are reviewed and the genetics of recessively inherited moderate to severe and progressive deafness is covered for the first time. The book also details established and evolving therapies for treatment of deafness

Immunohistochemical and electrophysiological investigation of E/I balance alterations in animal models of frontotemporal dementia

Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterised by changes in behaviour. Apathy, behavioural disinhibition and stereotyped behaviours are the first symptoms to appear and all have a basis in reward and pleasure deficits. The ventral striatum and ventral regions of the globus pallidus are involved in reward and pleasure. It is therefore reasonable to suggest alterations in these regions may underpin bvFTD. One postulated contributory factor is alteration in E/I balance in striatal regions. GABAergic interneurons play a role in E/I balance, acting as local inhibitory brakes, they are therefore a rational target for research investigating early biological predictors of bvFTD. To investigate this, we will carry out immunohistochemical staining for GABAergic interneurons (parvalbumin and neuronal nitric oxide synthase) in striatal regions of brains taken from CHMP2B mice, a validated animal model of bvFTD. We hypothesise that there will be fewer GABAergic interneurons in the striatum which may lead to ‘reward-seeking’ behaviour in bvFTD. This will also enable us to investigate any preclinical alterations in interneuron expression within this region. Results will be analysed using a mixed ANOVA and if significant, post hoc t-tests will be used. The second part of our study will involve extracellular recordings from CHMP2B mouse brains using a multi-electrode array (MEA). This will enable us to determine if there are alterations in local field potentials (LFP) in preclinical and symptomatic animals. We will also be able to see if neuromodulators such as serotonin and dopamine effect LFPs after bath application. We will develop slice preparations to preserve pathways between the ventral tegmental area and the ventral pallidum, an output structure of the striatum, and the dorsal raphe nucleus and the VP. Using the MEA we will stimulate an endogenous release of dopamine and serotonin using the slice preparations as described above. This will enable us to see if there are any changes in LFPs after endogenous release of neuromodulators. We hypothesise there will be an increase in LFPs due to loss of GABAergic interneurons

The 1989-1990 NASA space biology accomplishments

Individual technical summaries of research projects on NASA's Space Biology Program for research conducted during the period May 1989 to April 1990 are presented. This program is concerned with using the unique characteristics of the space environment, particularly microgravity, as a tool to advance the following: (1) knowledge in the biological sciences; (2) understanding of how gravity has shaped and affected life on the Earth; and (3) understanding of how the space environment affects both plants and animals. The summaries for each project include a description of the research, a list of accomplishments, an explanation of the significance of the accomplishments, and a list of publications

Towards an understanding of the role of Connexin26 in breathing

Connexin26 (Cx26) hemichannels expressed in glia at the ventral medullary surface (VMS) have been proposed to play a role in respiratory chemoreception, although this is disputed. At the VMS Cx26 hemichannels open in response to CO2 directly, causing ATP release that is capable of increasing respiratory drive. The main aim of this work was to establish a genetic strategy that can be used in vivo to elegantly remove Cx26 CO2- sensitivity from chemosensitive areas of the VMS, and to thereby investigate the role that Cx26 CO2 sensitivity plays in the chemoreception of awake mice. Using Forster resonance energy transfer and dye loading studies a Cx26 mutant (Cx26DN) was found to coassemble with Cx26WT subunits (forming heteromeric connexon hemichannels) and to remove CO2-induced hemichannel opening from cells stably expressing Cx26WT. In mice aged 12-18 weeks, bilateral lentivirus injections were used to express Cx26DN in GFAP+ cells at the VMS, as a means of removing CO2-induced Cx26 hemichannel opening and subsequent ATP release. As determined by whole-body plethysmography, expression of Cx26DN in the retrotrapezoid nucleus (RTN) had no effect on the hypercapnic ventilatory response in mice. Accidental Cx26DN expression in the caudal chemosensitive area resulted in reduced tidal volume 3 weeks post-transduction, however this was not well supported statistically. Such an auspicious result from suboptimal caudal expression warrants this to be repeated in order to validate these results. The work performed in this thesis outlines the first use of a highly novel genetic tool to remove the CO2-sensitivity property of Cx26 from specific cells, without removing the protein from the system. The results shed light on our understanding of central respiratory chemoreception, suggesting that Cx26 plays no role in chemoreception in the RTN but is likely to play a role in caudal areas of the VMS. Such a tool could aid research into the virtually unexplored role that Cx26 CO2 gating has in the body