Biology subjects

Hikishima, K.

Publications and source records attributed to Hikishima, K..

8 recordsLinked to original sources

bioRxiv2026

Adolescent prodromal phenotypes of psychiatric disorders: insights from a novel DISC1-perturbed monkey model

Neurodevelopmental deficits frequently lead to mild but significant adolescent social and cognitive changes, representing prodromal manifestations of adult-onset psychiatric disorders in a cross-disease manner. Although experimental medicine utilizes animal models to address the mechanisms, rodent brains lack critical structures for human higher brain functions such as the dorsolateral prefrontal cortex. To fill this translational gap, we generated monkeys with an impaired DISC1 gene locus, targeting the multifunctional protein essential for neurodevelopment and involved in transdiagnostic mental health risks. Here we analyze the F0 animals by minimizing mosaicism. At ages equivalent to human adolescence, these monkeys exhibited blunted responsiveness to social stimuli and increased internal drives, mirroring altered social behaviors in the prodromal stage in humans. Resting-state functional MRI data indicated disrupted global functional connectivity and reorganization of network topology, marked by a shift in the dominance of brain hubs from prefrontal regions to sensory areas. This primate model provides a unique platform for studying psychiatric disorders, such as schizophrenia, across the developmental trajectory.

neuroscience↗

bioRxiv2023

A whole-brain analysis of functional connectivity and immediate early gene expression revealed functional network shifts after operant learning

Previous studies of operant learning have addressed neuronal activities and network changes in specific brain areas, such as the striatum, sensorimotor cortex, prefrontal/orbitofrontal cortices, and hippocampus. However, how changes in the whole-brain network are caused by cellular-level changes remains unclear. We combine resting-state functional magnetic resonance imaging (rsfMRI) and whole-brain immunohistochemical analysis of early growth response 1 (EGR1), a marker of neural plasticity, to elucidate the spatiotemporal functional network changes and underlying cellular processes during operant learning. We used an 11.7 Tesla scanner and whole-brain immunohistochemical analysis of EGR1 in mice during the early and late stages of operant learning. In the operant training, mice received a reward when they pressed the left and right buttons alternately and were punished with a bright light when they made a mistake. Control mice spent the same time and received the same amount of reward in the same operant box. A group of mice (n = 22) underwent the first rsfMRI before behavioral sessions, the second after 3 days of sessions (early stage), and the third after 21 days of sessions (late stage). Another group of mice (n = 40) was subjected to histological analysis 15 min after the early or late stages of behavioral sessions. After the early stage of training, functional connectivity was increased between the limbic areas and thalamus or auditory cortex, and the correlations of the number of EGR1-immunopositive cells between the limbic area and auditory cortex were also increased. After the late stage of training, the increases in functional connectivity and correlations of EGR1-immunopositive cells primarily occurred between the motor cortex, somatosensory cortex, and striatum. The subcortical networks centered around the limbic areas that emerged in the early stage have been implicated in rewards, pleasures, and fears. The connectivity between the motor cortex, somatosensory cortex, and striatum that consolidated in the late stage have been implicated in motor learning. Our multimodal longitudinal study successfully revealed the temporal shifts of brain regions involved in behavioral learning together with the underlying cellular-level plasticity between these regions for the first time. Our study represents a first step toward establishing a new experimental paradigm that combines rsfMRI and immunohistochemistry for linking macroscopic and microscopic mechanisms of learning.

neuroscience↗

bioRxiv2023

Acquisition of Auditory Discrimination Mediated by Different Processes through Two Distinct Circuits Linked to the Lateral Striatum

The striatum, the central hub of cortico-basal ganglia loops, contains functionally heterogeneous subregions distinguished by the topographic patterns of structural connectivity. These subregions mediate various processes of procedural learning. However, it remains unclear when and how striatal subregions engage in the acquisition of sensory stimulus-based decision-making. A neuroimaging of regional brain activity shows that the anterior dorsolateral striatum (aDLS) and posterior ventrolateral striatum (pVLS) in rats are activated in a different temporal pattern during the acquisition phase of auditory discrimination. Chronic and transient pharmacologic manipulations show that the aDLS promotes the behavioral strategy driven by the stimulus- response association while suppressing that by the response-outcome association, and that the pVLS contributes to forming and maintaining the stimulus-response strategy. Electrophysiological recording indicates that subpopulations of aDLS neurons predominantly represent the outcome of specific behaviors at the initial period of discrimination learning, and that pVLS subpopulations encode the beginning and ending of each behavior according to the progress of learning. In addition, other subpopulations of striatal neurons indicate sustained activation after obtaining reward with distinct patterns reflecting the stimulus-response associations. Our findings demonstrate that aDLS and pVLS neurons integrate the new learning of auditory discrimination in spatiotemporally and functionally different manners.

animal behavior and cognition↗

bioRxiv2023

Chemogenetic activation of target neurons expressing insect Ionotropic Receptors in the mammalian central nervous system by systemic administration of ligand precursors

The IR-mediated neuronal activation (IRNA) technology allows stimulation of neurons in the brain that heterologously-express members of the insect chemosensory IR repertoire in response to their cognate ligands. In the current protocol, a ligand against the complex consisting of IR84a and IR8a subunits, phenylacetic acid (PhAc), is locally injected into a brain region, because of a low efficiency of PhAc for the delivery into the brain across the blood-brain barrier. To circumvent this invasive injection, here we developed a strategy for activation of target neurons in the brain through peripheral administration with a precursor of PhAc, methyl ester of PhAc (PhAcM), which is efficiently transferred into the brain and converted to the mature ligand by endogenous esterase activities. Peripheral administration of with PhAcM activated IR84a/IR8a-expressing neurons in the locus coeruleus of mice and increased the release of neurotransmitters in their nerve terminal regions. (S)-2-phenylpropionic acid ((S)-PhPr) was newly identified as a ligand for IR84a/IR8a, and peripheral administration with the methyl ester of PhPr with the S-configuration [(S)-PhPrM] caused similar effects on the target neurons. In addition, cell-type specific expression of IR84a/IR8a complex in the striatum of rats was unilaterally induced with a viral vector based on the Cre-loxP system. Peripheral administration with PhAcM or (S)-PhPrM stimulated the neurotransmitter release in the ipsilateral terminal regions of the vector-injected striatum, and PhAcM administration resulted in rotational behavior. Finally, we demonstrated that the metabolites of the peripherally administered-radiolabeled (S)-PhPrM accumulated in the IR84a/IR8a-expressing region in the striatum of the vector-injected rats. These results demonstrate that the systemic IRNA technique provides a powerful strategy for remote manipulation of diverse types of target neurons in the mammalian central nervous system.

neuroscience↗

bioRxiv2023

Dentate neurogenesis mediates cognitive flexibility via modulation of the hippocampal longitudinal-axis network

Adult neurogenesis endows the hippocampus with unparalleled neural plasticity, essential for intricate cognitive functions. However, the manner in which sparse newborn neurons (NBNs) modulate neural activities and subsequently shape behavior remains enigmatic. Utilizing a newly engineered NBN-Tetanus Toxin mouse model, we non-invasively silenced NBNs and confirmed their crucial role in cognitive flexibility, as demonstrated through reversal learning in the Morris water maze and the Go/Nogo task in operant learning. Pairing task-based functional MRI (tb-fMRI) with operant learning revealed a dorsal hippocampal hyperactivation during Nogo task, implying that hippocampal hyperexcitability might underlie the observed behavioral deficits. Notably, resting-state fMRI (rs-fMRI) revealed enhanced functional connectivity between the dorsal and ventral dentate gyrus following NBN silencing. Further exploration of PV+ interneurons and mossy cells activities highlighted NBNs integral part in preserving the excitation/inhibition balance within the hippocampus. Our findings emphasize how the neural plasticity driven by NBNs extensively modulates the hippocampus, sculpting cognitive flexibility.

neuroscience↗

bioRxiv2022

A novel micro-ECoG recording method for recording multisensory neural activity from the parietal to temporal cortexes in mice

Characterization of inter-regional interactions in brain is essential for understanding the mechanism relevant to normal brain function and neurological disease. The recently developed flexible micro ()-electrocorticography (ECoG) device is one prominent method used to examine large-scale cortical activity across multiple regions. The sheet-shaped ECoG electrodes arrays can be placed on a relatively wide area of cortical surface beneath the skull by inserting the device into the space between skull and brain. Although rats and mice are useful tools for neuroscience, current ECoG recording methods in these animals are limited to the parietal region of cerebral cortex. Recording cortical activity from the temporal region of cortex in mice has proven difficult because of surgical barriers created by the skull and surrounding temporalis muscle anatomy. Here, we developed a sheet-shaped 64-channel ECoG device that allows access to the mouse temporal cortex, and we determined the factor determining the appropriate bending stiffness for the ECoG electrode array. We also established a surgical technique to implant the electrode arrays into the epidural space over a wide area of cerebral cortex covering from the barrel field to olfactory (piriform) cortex, which is the deepest region of the cerebral cortex. Using histology and computed tomography (CT) images, we confirmed that the tip of the ECoG device reached to the most ventral part of cerebral cortex without causing noticeable damage to the brain surface. Moreover, the device simultaneously recorded somatosensory and odor stimulus-evoked neural activity from dorsal and ventral parts of cerebral cortex in awake and anesthetized mice. These data indicate that our ECoG device and surgical techniques enable the recording of large-scale cortical activity from the parietal to temporal cortex in mice, including somatosensory and olfactory cortices. This system will provide more opportunities for the investigation of physiological functions from wider areas of the mouse cerebral cortex than those currently available with existing ECoG techniques.

neuroscience↗

bioRxiv2019

Enhanced emotional memory retrieval by chemogenetic activation of locus coeruleus norepinephrine neurons

The ability to retrieve memory store in response to the environment is essential for animal behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. In this study, we developed a neural chemogenetic activation strategy using insect olfactory Ionotropic Receptors (IRs), and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons resulted in enhancement of the retrieval process of conditioned taste aversion, which was mediated through at least partly adrenergic receptors in the amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdalar pathway is required and sufficient for enhancing the recall of taste associative memory.

neuroscience↗

bioRxiv2017

The Brain/MINDS 3D digital marmoset brain atlas

We present a new 3D digital brain atlas of the non-human primate, common marmoset monkey (Callithrix jacchus), with MRI and coregistered Nissl histology data. To the best of our knowledge this is the first comprehensive digital 3D brain atlas of the common marmoset having normalized multi-modal data, cortical and sub-cortical segmentation, and in a common file format (NIfTI). The atlas can be registered to new data, is useful for connectomics, functional studies, simulation and as a reference.\n\nThe atlas was based on previously published work but we provide several critical improvements to make this release valuable for researchers. Nissl histology images were processed to remove illumination and shape artifacts and then normalized to the MRI data. Brain region segmentation is provided for both hemispheres. The data is in the NIfTI format making it easy to integrate into neuroscience pipelines, whereas the previous atlas was in an inaccessible file format. We also provide cortical, mid-cortical and white matter boundary segmentations useful for visualization and analysis.

neuroscience↗