Effect of brain acidification on depression-related behaviors in diabetes mellitus.

Major depressive disorder (depression) is a leading cause of disability. The severity of depression is affected by many factors, one of which being comorbidity with diabetes mellitus (DM). The comorbidity of depression with DM is a major public health concern due to the high incidence of both conditions and their mutually exacerbating pathophysiology.

Distorted neurocomputation by a small number of extra-large spines in psychiatric disorders.

Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia.

[Constructive Understanding of Multi-scale Dynamism of Neuropsychiatric Disorders].

Although synaptic abnormalities are implicated in the pathophysiology of schizophrenia, it remains unclear whether the synaptic pathology is a casual mechanism that controls the behaviors, or whether it is merely a secondary consequence of the disorder. Chaotic behavior and fluctuations in the pathophysiology of schizophrenia also make it challenging to gain a better understanding of the disorder. In this study, we focused on the disorders in a constructive and multi-scale manner, we attempt to elucidate the causal relationships across the hierarchy between schizophrenia-related genes and disease-related behaviors.

Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia.

Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions between contributory factors at different scales: susceptible gene variants (molecular scale), synaptopathies (synaptic, dendritic, and cell scales), and alterations in neuronal circuits (circuit scale), which together result in behavioral manifestations (individual scale).

Optical interrogation of multi-scale neuronal plasticity underlying behavioral learning.

Behavioral learning is driven by adaptive changes in the activation of behaviorally relevant neuronal ensembles. This learning-specific reorganization of neuronal circuits is correlated with activity-dependent modifications of synaptic dynamics. However, a definitive causal link remains to be established.

Oligodendrocyte dysfunction due to Chd8 mutation gives rise to behavioral deficits in mice.

Mutations in the gene encoding the chromatin remodeler CHD8 are strongly associated with autism spectrum disorder (ASD). CHD8 haploinsufficiency also results in autistic phenotypes in humans and mice. Although myelination defects have been observed in individuals with ASD, whether oligodendrocyte dysfunction is responsible for autistic phenotypes has remained unknown.

Near-Infrared Optogenetic Genome Engineering Based on Photon-Upconversion Hydrogels.

Photon upconversion (UC) from near-infrared (NIR) light to visible light has enabled optogenetic manipulations in deep tissues. However, materials for NIR optogenetics have been limited to inorganic UC nanoparticles. Herein, NIR-light-triggered optogenetics using biocompatible, organic TTA-UC hydrogels is reported.

Synaptic functions and their disruption in schizophrenia: From clinical evidence to synaptic optogenetics in an animal model.

The adult human brain consists of approximately a hundred billion neurons, which are connected via synapses. The pattern and strength of the synaptic connections are constantly changing (synaptic plasticity), and these changes are considered to underlie learning, memory, and personality. Many psychiatric disorders have been related to disturbances in synaptogenesis and subsequent plasticity.

Chemical Landscape for Tissue Clearing Based on Hydrophilic Reagents.

We describe a strategy for developing hydrophilic chemical cocktails for tissue delipidation, decoloring, refractive index (RI) matching, and decalcification, based on comprehensive chemical profiling. More than 1,600 chemicals were screened by a high-throughput evaluation system for each chemical process. The chemical profiling revealed important chemical factors: salt-free amine with high octanol/water partition-coefficient (logP) for delipidation, N-alkylimidazole for decoloring, aromatic amide for RI matching, and protonation of phosphate ion for decalcification.

[Optical Erasure of the Synaptic Ensemble that Underlies Learning and Memory].

Dentritic spines are small membrane protrusions. Their regulation is thought to be important for memory storage, but the links between dentric spines and memory have been largely correlational because of a luck of techniques for manipulating individual spines. To overcome this problem, we have developed a novel synaptic optoprobe, AS-PaRac1, which is unique not only because it specifically labels recently potentiated spines, but also because it becomes possible to selectively shrink spines containing AS-PaRac1.

Calcineurin knockout mice show a selective loss of small spines.

Calcineurin is required for long-term depression and activity-dependent spine shrinkage, and calcineurin mutations have been identified in patients with schizophrenia. Moreover, mice with conditional knockout of calcineurin B (CNB-KO) exhibit behavioral abnormalities suggestive of schizophrenia. Changes in the dendritic spines of these mice, however, have not been investigated.

Increased EphA4-ephexin1 signaling in the medial prefrontal cortex plays a role in depression-like phenotype.

Accumulating evidence suggests a role of the ephrin receptor EphA4 and the downstream protein ephexin1 in synaptic plasticity, which is implicated in depression. We examined whether EphA4-ephexin1 signaling plays a role in the pathophysiology of depression, and the antidepressant-like effect of EphA4 inhibitor rhynchophylline. We found increased ratios of p-EphA4/EphA4 and p-ephexin1/ephexin1 in the prefrontal cortex (PFC) and hippocampus but not in the nucleus accumbens (NAc), of susceptible mice after social defeat stress.

Synaptic Ensemble Underlying the Selection and Consolidation of Neuronal Circuits during Learning.

Memories are crucial to the cognitive essence of who we are as human beings. Accumulating evidence has suggested that memories are stored as a subset of neurons that probably fire together in the same ensemble. Such formation of cell ensembles must meet contradictory requirements of being plastic and responsive during learning, but also stable in order to maintain the memory.

Optogenetics: Applications in psychiatric research.

Recently, optogenetic techniques have emerged as a method to optically manipulate molecular and cellular events in target cells both in vitro and in vivo. Optogenetics results from the fruitful combination of optics and genetic engineering, maximizing the advantages of each discipline. These advantages are optical control through the manipulation of wavelength and light intensity on the millisecond timescale, and specific gene expression and gene product trafficking with subcellular precision.

Synapse pathology and translational applications for schizophrenia.

Schizophrenia is a chronic, severe, and disabling brain disorder, with an estimated lifetime prevalence of 0.7%. Despite its relatively low prevalence, the onset of schizophrenia usually occurs early in life, resulting in a severe lifelong disability for patients and increasing the economic and care burden on their families.

Fast 3D visualization of endogenous brain signals with high-sensitivity laser scanning photothermal microscopy.

A fast, high-sensitivity photothermal microscope was developed by implementing a spatially segmented balanced detection scheme into a laser scanning microscope. We confirmed a 4.9 times improvement in signal-to-noise ratio in the spatially segmented balanced detection compared with that of conventional detection.

Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo.

Dendritic spine generation and elimination play an important role in learning and memory, the dynamics of which have been examined within the neocortex in vivo. Spine turnover has also been detected in the absence of specific learning tasks, and is frequently exaggerated in animal models of autistic spectrum disorder (ASD). The present study aimed to examine whether the baseline rate of spine turnover was activity-dependent.

Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and β cells.

It remains unclear how readiness for Ca(2+)-dependent exocytosis depends on varying degrees of SNARE complex assembly. Here we directly investigate the SNARE assembly using two-photon fluorescence lifetime imaging (FLIM) of Förster resonance energy transfer (FRET) between three pairs of neuronal SNAREs in presynaptic boutons and pancreatic β cells in the islets of Langerhans. These FRET probes functionally rescue their endogenous counterparts, supporting ultrafast exocytosis.

Labelling and optical erasure of synaptic memory traces in the motor cortex.

Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), that can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines.

A critical time window for dopamine actions on the structural plasticity of dendritic spines.

Animal behaviors are reinforced by subsequent rewards following within a narrow time window. Such reward signals are primarily coded by dopamine, which modulates the synaptic connections of medium spiny neurons in the striatum. The mechanisms of the narrow timing detection, however, remain unknown.