Tau load in select brainstem neurons predicts the severity and nature of balance deficits in the absence of cell death.

Patients with tauopathies present with profoundly different clinical symptoms , even within the same disorder . A central hypothesis in the field, well-supported by biomarker studies and post-mortem pathology , is that clinical heterogeneity reflects differential degeneration of vulnerable neuronal populations responsible for specific neurological functions. Recent work has revealed mechanisms underlying susceptibility of particular cell types , but relating tau load to disrupted behavior - es- pecially before cell death - requires a targeted circuit-level approach.

The Vestibulospinal Nucleus Is a Locus of Balance Development.

Mature vertebrates maintain posture using vestibulospinal neurons that transform sensed instability into reflexive commands to spinal motor circuits. Postural stability improves across development. However, due to the complexity of terrestrial locomotion, vestibulospinal contributions to postural refinement in early life remain unexplored.

Transgenic tools targeting the basal ganglia reveal both evolutionary conservation and specialization of neural circuits in zebrafish.

The cortico-basal ganglia circuit mediates decision making. Here, we generated transgenic tools for adult zebrafish targeting specific subpopulations of the components of this circuit and utilized them to identify evolutionary homologs of the mammalian direct- and indirect-pathway striatal neurons, which respectively project to the homologs of the internal and external segment of the globus pallidus (dorsal entopeduncular nucleus [dEN] and lateral nucleus of the ventral telencephalic area [Vl]) as in mammals. Unlike in mammals, the Vl mainly projects to the dEN directly, not by way of the subthalamic nucleus.

The vestibulospinal nucleus is a locus of balance development.

Mature vertebrates maintain posture using vestibulospinal neurons that transform sensed instability into reflexive commands to spinal motor circuits. Postural stability improves across development. However, due to the complexity of terrestrial locomotion, vestibulospinal contributions to postural refinement in early life remain unexplored.

Molecular blueprints for spinal circuit modules controlling locomotor speed in zebrafish.

The flexibility of motor actions is ingrained in the diversity of neurons and how they are organized into functional circuit modules, yet our knowledge of the molecular underpinning of motor circuit modularity remains limited. Here we use adult zebrafish to link the molecular diversity of motoneurons (MNs) and the rhythm-generating V2a interneurons (INs) with the modular circuit organization that is responsible for changes in locomotor speed. We show that the molecular diversity of MNs and V2a INs reflects their functional segregation into slow, intermediate or fast subtypes.

A gene regulatory network combining Pax3/7, Sox10 and Mitf generates diverse pigment cell types in medaka and zebrafish.

Neural crest cells generate numerous derivatives, including pigment cells, and are a model for studying how fate specification from multipotent progenitors is controlled. In mammals, the core gene regulatory network for melanocytes (their only pigment cell type) contains three transcription factors, Sox10, Pax3 and Mitf, with the latter considered a master regulator of melanocyte development. In teleosts, which have three to four pigment cell types (melanophores, iridophores and xanthophores, plus leucophores e.

Biomechanics and neural circuits for vestibular-induced fine postural control in larval zebrafish.

Land-walking vertebrates maintain a desirable posture by finely controlling muscles. It is unclear whether fish also finely control posture in the water. Here, we showed that larval zebrafish have fine posture control.

Deficiency in the cell-adhesion molecule impairs hypothalamic CRH neuron development and perturbs normal neuroendocrine stress axis function.

The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified () as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function.

shox2 is required for vestibular statoacoustic neuron development.

Homeobox genes act at the top of genetic hierarchies to regulate cell specification and differentiation during embryonic development. We identified the short stature homeobox domain 2 (shox2) transcription factor that is required for vestibular neuron development. shox2 transcripts are initially localized to the otic placode of the developing inner ear where neurosensory progenitors reside.

Tiltable objective microscope visualizes selectivity for head motion direction and dynamics in zebrafish vestibular system.

Spatio-temporal information about head orientation and movement is fundamental to the sense of balance and motion. Hair cells (HCs) in otolith organs of the vestibular system transduce linear acceleration, including head tilt and vibration. Here, we build a tiltable objective microscope in which an objective lens and specimen tilt together.

Voltage-sensing phosphatase (Vsp) regulates endocytosis-dependent nutrient absorption in chordate enterocytes.

Voltage-sensing phosphatase (Vsp) is a unique membrane protein that translates membrane electrical activities into the changes of phosphoinositide profiles. Vsp orthologs from various species have been intensively investigated toward their biophysical properties, primarily using a heterologous expression system. In contrast, the physiological role of Vsp in native tissues remains largely unknown.

A viral toolbox for conditional and transneuronal gene expression in zebrafish.

The zebrafish is an important model in systems neuroscience but viral tools to dissect the structure and function of neuronal circuitry are not established. We developed methods for efficient gene transfer and retrograde tracing in adult and larval zebrafish by herpes simplex viruses (HSV1). HSV1 was combined with the Gal4/UAS system to target cell types with high spatial, temporal, and molecular specificity.

Long descending commissural V0v neurons ensure coordinated swimming movements along the body axis in larval zebrafish.

Developmental maturation occurs in slow swimming behavior in larval zebrafish; older larvae acquire the ability to perform slow swimming while keeping their head stable in the yaw dimension. A class of long-distance descending commissural excitatory V0v neurons, called MCoD neurons, are known to develop in a later phase of neurogenesis, and participate in slow swimming in older larvae. We hypothesized that these MCoD neurons play a role in coordinating the activities of trunk muscles in the diagonal dimension (e.

Generation of knock-in lampreys by CRISPR-Cas9-mediated genome engineering.

The lamprey represents the oldest group of living vertebrates and has been a key organism in various research fields such as evolutionary developmental biology and neuroscience. However, no knock-in technique for this animal has been established yet, preventing application of advanced genetic techniques. Here, we report efficient generation of F knock-in lampreys by CRISPR-Cas9-mediated genome editing.

Central Vestibular Tuning Arises from Patterned Convergence of Otolith Afferents.

As sensory information moves through the brain, higher-order areas exhibit more complex tuning than lower areas. Though models predict that complexity arises via convergent inputs from neurons with diverse response properties, in most vertebrate systems, convergence has only been inferred rather than tested directly. Here, we measure sensory computations in zebrafish vestibular neurons across multiple axes in vivo.

Transient activation of the Notch-her15.1 axis plays an important role in the maturation of V2b interneurons.

In the vertebrate ventral spinal cord, p2 progenitors give rise to two interneuron subtypes: excitatory V2a interneurons and inhibitory V2b interneurons. In the differentiation of V2a and V2b cells, Notch signaling promotes V2b fate at the expense of V2a fate. Later, V2b cells extend axons along the ipsilateral side of the spinal cord and express the inhibitory transmitter GABA.

Neuronal Circuits That Control Rhythmic Pectoral Fin Movements in Zebrafish.

The most basic form of locomotion in limbed vertebrates consists of alternating activities of the flexor and extensor muscles within each limb coupled with left/right limb alternation. Although larval zebrafish are not limbed, their pectoral fin movements exhibit the following fundamental aspects of this basic movement: abductor/adductor alternation (corresponding to flexor/extensor alternation) and left/right fin alternation. Because of the simplicity of their movements and the compact neural organization of their spinal cords, zebrafish can serve as a good model to identify the neuronal networks of the central pattern generator (CPG) that controls rhythmic appendage movements.

Functional Diversity of Glycinergic Commissural Inhibitory Neurons in Larval Zebrafish.

Commissural inhibitory neurons in the spinal cord of aquatic vertebrates coordinate left-right body alternation during swimming. Their developmental origin, however, has been elusive. We investigate this by comparing the anatomy and function of two commissural inhibitory neuron types, dI6dmrt3a and V0d, derived from the pd6 and p0 progenitor domains, respectively.

Associative conditioning remaps odor representations and modifies inhibition in a higher olfactory brain area.

Intelligent behavior involves associations between high-dimensional sensory representations and behaviorally relevant qualities such as valence. Learning of associations involves plasticity of excitatory connectivity, but it remains poorly understood how information flow is reorganized in networks and how inhibition contributes to this process. We trained adult zebrafish in an appetitive odor discrimination task and analyzed odor representations in a specific compartment of the posterior zone of the dorsal telencephalon (Dp), the homolog of mammalian olfactory cortex.

Spinal V2b neurons reveal a role for ipsilateral inhibition in speed control.

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction.

Regulation of locomotor speed and selection of active sets of neurons by V1 neurons.

During fast movements in vertebrates, slow motor units are thought to be deactivated due to the mechanical demands of muscle contraction, but the associated neuronal mechanisms for this are unknown. Here, we perform functional analyses of spinal V1 neurons by selectively killing them in larval zebrafish, revealing two functions of V1 neurons. The first is the long-proposed role of V1 neurons: they play an important role in shortening the cycle period during swimming by providing in-phase inhibition.

Behavioral Role of the Reciprocal Inhibition between a Pair of Mauthner Cells during Fast Escapes in Zebrafish.

During many behaviors in vertebrates, the CNS generates asymmetric activities between the left and right sides to produce asymmetric body movements. For asymmetrical activations of the CNS, reciprocal inhibition between the left and right sides is believed to play a key role. However, the complexity of the CNS makes it difficult to identify the reciprocal inhibition circuits at the level of individual cells and the contribution of each neuron to the asymmetric activity.

Highly efficient generation of knock-in transgenic medaka by CRISPR/Cas9-mediated genome engineering.

Background: Medaka () is a popular animal model used in vertebrate genetic analysis. Recently, an efficient (~ 30%) knock-in system via non-homologous end joining (NHEJ) was established in zebrafish using the CRISPR/Cas9 system. If the same technique were applicable in medaka, it would greatly expand the usefulness of this model organism.