Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature.

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD).

Development and Application of Technology for Neural Circuit Visualization - Secondary Publication.

The dynamics of neurite extension and synaptic connections are central issues in neural circuit research. The development of technologies for labeling purified cytoskeletal proteins with fluorescent dyes and introducing them into living neurons using microinjection greatly facilitated our understanding of cytoskeletal dynamics in neuronal axons. Imaging data showed that the cytoskeleton repeatedly polymerized and depolymerized within the axon, and elongation was driven by the new cytoskeleton formed at the axon tip.

In vivo imaging of the phagocytic dynamics underlying efficient clearance of adult-born hippocampal granule cells by ramified microglia.

The phagocytosis of dead cells by microglia is essential in brain development and homeostasis. However, the mechanism underlying the efficient removal of cell corpses by ramified microglia remains poorly understood. Here, we investigated the phagocytosis of dead cells by ramified microglia in the hippocampal dentate gyrus, where adult neurogenesis and homeostatic cell clearance occur.

Three-dimensional mouse cochlea imaging based on the modified Sca/eS using confocal microscopy.

The three-dimensional stria vascularis (SV) and cochlear blood vessel structure is essential for inner ear function. Here, modified Sca/eS, a sorbitol-based optical-clearing method, was reported to visualize SV and vascular structure in the intact mouse cochlea. Cochlear macrophages as well as perivascular-resident macrophage-like melanocytes were detected as GFP-positive cells of the CX3CR1 mice.

Necl2/3-mediated mechanism for tripartite synapse formation.

Ramified, polarized protoplasmic astrocytes interact with synapses via perisynaptic astrocyte processes (PAPs) to form tripartite synapses. These astrocyte-synapse interactions mutually regulate their structures and functions. However, molecular mechanisms for tripartite synapse formation remain elusive.

Simultaneous Imaging of Microglial Dynamics and Neuronal Activity in Awake Mice.

Since brain functions are under the continuous influence of the signals derived from peripheral tissues, it is critical to elucidate how glial cells in the brain sense various biological conditions in the periphery and transmit the signals to neurons. Microglia, immune cells in the brain, are involved in synaptic development and plasticity. Therefore, the contribution of microglia to neural circuit construction in response to the internal state of the body should be tested critically by intravital imaging of the relationship between microglial dynamics and neuronal activity.

In vivo Chronic Two-Photon Imaging of Microglia in the Mouse Hippocampus.

Microglia, the only immune cells resident in the brain, actively participate in neural circuit maintenance by modifying synapses and neuronal excitability. Recent studies have revealed the differential gene expression and functional heterogeneity of microglia in different brain regions. The unique functions of the hippocampal neural network in learning and memory may be associated with the active roles of microglia in synapse remodeling.

Imaging neural circuit pathology of autism spectrum disorders: autism-associated genes, animal models and the application of in vivo two-photon imaging.

Recent advances in human genetics identified genetic variants involved in causing autism spectrum disorders (ASDs). Mouse models that mimic mutations found in patients with ASD exhibit behavioral phenotypes consistent with ASD symptoms. These mouse models suggest critical biological factors of ASD etiology.

Advanced Technologies for Local Neural Circuits in the Cerebral Cortex.

The neural network in the brain can be viewed as an integrated system assembled from a large number of local neural circuits specialized for particular brain functions. Activities of neurons in local neural circuits are thought to be organized both spatially and temporally under the rules optimized for their roles in information processing. It is well perceived that different areas of the mammalian neocortex have specific cognitive functions and distinct computational properties.

Neuroscience20 (BRAIN20, SPINE20, and MENTAL20) Health Initiative: A Global Consortium Addressing the Human and Economic Burden of Brain, Spine, and Mental Disorders Through Neurotech Innovations and Policies.

Neurological disorders significantly impact the world's economy due to their often chronic and life-threatening nature afflicting individuals which, in turn, creates a global disease burden. The Group of Twenty (G20) member nations, which represent the largest economies globally, should come together to formulate a plan on how to overcome this burden. The Neuroscience-20 (N20) initiative of the Society for Brain Mapping and Therapeutics (SBMT) is at the vanguard of this global collaboration to comprehensively raise awareness about brain, spine, and mental disorders worldwide.

Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications.

Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear.

Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice.

Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear.

The role of molecular diffusion within dendritic spines in synaptic function.

Spines are tiny nanoscale protrusions from dendrites of neurons. In the cortex and hippocampus, most of the excitatory postsynaptic sites reside in spines. The bulbous spine head is connected to the dendritic shaft by a thin membranous neck.

Imaging of spine synapses using super-resolution microscopy.

Neuronal circuits in the neocortex and hippocampus are essential for higher brain functions such as motor learning and spatial memory. In the mammalian forebrain, most excitatory synapses of pyramidal neurons are formed on spines, which are tiny protrusions extending from the dendritic shaft. The spine contains specialized molecular machinery that regulates synaptic transmission and plasticity.

Geometry and the Organizational Principle of Spine Synapses along a Dendrite.

Precise information on synapse organization in a dendrite is crucial to understanding the mechanisms underlying voltage integration and the variability in the strength of synaptic inputs across dendrites of different complex morphologies. Here, we used focused ion beam/scanning electron microscope (FIB/SEM) to image the dendritic spines of mice in the hippocampal CA1 region, CA3 region, somatosensory cortex, striatum, and cerebellum (CB). Our results show that the spine geometry and dimensions differ across neuronal cell types.

Regulation of actin dynamics in dendritic spines: Nanostructure, molecular mobility, and signaling mechanisms.

Dendritic spines are major sites of excitatory synaptic connection in pyramidal neurons of the forebrain, and their functional regulation underlies the development of functional neuronal circuits and experience-dependent circuit plasticity. Dendritic spines contain a large amount of actin filaments, and their organization and dynamics control both the morphology and function of dendritic spines. New optical technologies, including super-resolution microscopy, fluorescence lifetime imaging, and fluorescence correlation measurements, have helped gather further information about the nanoscale features of spine structure and cytoskeletal organization, together with the molecular interactions and mobility within spines.

Recent advances in computational methods for measurement of dendritic spines imaged by light microscopy.

Dendritic spines are small protrusions that receive most of the excitatory inputs to the pyramidal neurons in the neocortex and the hippocampus. Excitatory neural circuits in the neocortex and hippocampus are important for experience-dependent changes in brain functions, including postnatal sensory refinement and memory formation. Several lines of evidence indicate that synaptic efficacy is correlated with spine size and structure.

Impaired actin dynamics and suppression of Shank2-mediated spine enlargement in cortactin knockout mice.

Cortactin regulates actin polymerization and stabilizes branched actin network. In neurons, cortactin is enriched in dendritic spines that contain abundant actin polymers. To explore the function of cortactin in dendritic spines, we examined spine morphology and dynamics in cultured neurons taken from cortactin knockout (KO) mice.

Vasodilator-stimulated phosphoprotein (VASP) is recruited into dendritic spines via G-actin-dependent mechanism and contributes to spine enlargement and stabilization.

Actin organization and dynamics are modulated by diverse actin regulators during dendritic spine development. To understand the molecular network that regulates actin organization and spine morphology, it is important to investigate dynamic redistribution of actin regulators during spine development. One of the actin regulators, vasodilator-stimulated phosphoprotein (VASP), has multiple functions in actin regulation and is known to regulate spine morphology.

Temporal Sequences of Synapse Disintegration Triggered by Afferent Axon Transection, Time-Lapse Imaging Study of Presynaptic and Postsynaptic Molecules.

Traumatic brain injury (TBI) is one of the major causes of death and disability. Multiple animal models have been developed to explore therapeutic targets for TBI. However, heterogeneity of pathophysiology obstructs discovery of therapeutic targets.

Neonatal social isolation increases the proportion of the immature spines in the layer 2/3 pyramidal neurons of the somatosensory cortex.

Social isolation during the juvenile period is postulated to leave specific sequelae, such as attention deficits and emotion recognition. Miswiring of the cortical neuronal circuit during postnatal development may underlie such behavioral impairments, but the details of the circuit-level impairment associated with social isolation have not yet been clarified. In this study, we evaluated the possibility that environmental factors may induce alternation in spine characteristics and dynamics.