Papers by Yuichi Takeuchi
Frontiers in Behavioral Neuroscience
Nature Communications, Jul 5, 2023
Dysregulated fear reactions can result from maladaptive processing of traumarelated memories. In ... more Dysregulated fear reactions can result from maladaptive processing of traumarelated memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., 'renewal' and 'reinstatement') and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWRtriggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders. Learning unpleasant things and remembering them is advantageous for the organism for avoiding future reoccurrences. Memories that are irrelevant to survival or adaptation tend to fade away either by graceful degradation 1,2 or by another type of learning called active extinction 3,4. Extinction learning, the process of reducing the expression of learned fear responses, is essential for adaptive behavior in response to traumatic experiences. However, in some pathological scenarios, extinction learning is often impaired, leading to persistent and maladaptive fear responses 5. For example, post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder resulting from direct or indirect exposure to stressful events, threats, or life-threatening events perceived to compromise personal physical or mental safety 6-8. Symptoms include intense feelings of unprovoked fear, panic attacks, anxiety; intrusive
ABSTRACTMaladaptive processing of trauma related memory engrams leads to dysregulated fear reacti... more ABSTRACTMaladaptive processing of trauma related memory engrams leads to dysregulated fear reactions. In post-traumatic stress disorder (PTSD), dysfunctional extinction learning prevents discretization of trauma-related memory engrams and leads to generalized fear responses. PTSD is postulated as a mnemonic-based disorder, but we lack markers or treatments targeting pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. We demonstrate that closed-loop SWRs triggered neuromodulation of the medial forebrain bundle (MFB) can enhance the consolidation of fear extinction. It modified fear memories that became resistant to induced recall (i.e., ‘renewal’ and ‘reinstatement’) and did not reemerge spontaneously as a PTSD-like phenotype. The effects are mediated by D2 receptor signaling induced synaptic remodeling in the ...
Although the etiology of major depressive disorder remains poorly understood, impairment of gamma... more Although the etiology of major depressive disorder remains poorly understood, impairment of gamma oscillations recently emerged as a potential biomarker for major depression. The olfactory bulb (OB) is a major source of brain wide gamma oscillations and bulbectomy is an animal model for depression. Here we demonstrate that chemogenetic suppression of OB neuronal activity or temporally suppressing the OB to pyriform cortex synaptic transmission decreased gamma oscillation power in multiple brain areas associated with depression-like behaviors. To assess the hypothesized link between depression and diffuse depression of gamma oscillations, we employed gamma phase-dependent closed loop neuromodulation of cortical areas, paced by the native OB output. This procedure alleviated depressive-like behaviors in animals and suggests that restoring gamma oscillations may improve depression in humans.One Sentence SummaryRole of limbic gamma oscillations in depression
Microsurgery, 2018
This study investigated the potential of collagen-coated polyglycolic acid (PGA) tube with interp... more This study investigated the potential of collagen-coated polyglycolic acid (PGA) tube with interpositional jump graft (IPJG) in rat. Materials and Methods: A total of 16 Lewis rats were used in this study. Facial nerve paralysis was created by ligating facial nerve trunk with a ligature clip. The rats were divided into 3 groups. Nerve conduit group (n 5 6) were treated by IPJG with collagen-coated PGA tubes between the facial nerve trunks and the hypoglossal nerves. Autograft group (n 5 6) were treated by IPJG with the greater auricular nerves. As the control group (n 5 4), non-treated-model rats with facial nerve paralysis were used. The number of myelinated fibers, fiber diameter, axon diameter, myelin thickness, and g-ratio, were analyzed histologically at 13 weeks after surgery. Compound muscle action potential (CMAP) and retrograde tracing were measured. Result: Although the number of myelinated fibers in autograft group (1957 6 775) had significantly higher than that of nerve conduit group (90 6 41, P < .05), the nerve conduit group showed the regeneration of myelinated nerve axons. CMAP amplitude values of the autograft (4706 6 1154 mV) and the nerve conduit groups (4119 6 1397 mV) were significantly higher than that of the control group (915 6 789 mV, P < .05). Retrograde tracing confirmed the double innervation of mimetic muscles by the facial and hypoglossal nucleus in both groups. Conclusion: This study showed histologically and physiologically the superior effectiveness of performing IPJG with a collagen-coated PGA conduit in a rat model.
Japanese Journal of Applied Physics, 2020
A neural probe with six micro-light-emitting diodes (MicroLEDs) and 15 neural electrodes was fabr... more A neural probe with six micro-light-emitting diodes (MicroLEDs) and 15 neural electrodes was fabricated for optogenetic application. Local field potentials, which provide information about the neural activity, were successfully recorded using the neural probe, indicating the effectiveness of the neural electrodes. The MicroLEDs on the probe exhibited highly consistent current–voltage characteristics and sufficient light output of 20 mW mm−2 at 1 mA to manipulate neural activity. The light distribution in brain tissue was simulated to estimate the optical stimulation area and a number of optically stimulated neurons. The increase in LED temperature, i.e. ΔT, was investigated because high temperatures can damage brain tissue. A curve illustrating the relationship between ΔT and the wall-plug efficiency was derived. The wall-plug efficiency was increased 1.8 times by installing an Ag mirror on the back of a MicroLED. These results suggest that the MicroLED neural probe would significan...
Science Advances, 2021
In the red-haired background, altered pain thresholds exist and are explained by distinct OPRM1/M... more In the red-haired background, altered pain thresholds exist and are explained by distinct OPRM1/MC4R signaling.
The first release on 2018/04/18.
Igor Pro GUI which enables averaging, analyses, and figure preparation of evoked potentials. The ... more Igor Pro GUI which enables averaging, analyses, and figure preparation of evoked potentials. The latest version will be available in GitHub page below.
Matlab GUI for controlling NI data acquisition boards
Igor Pro GUI which offers a spike sorting environment for extracellular recordings.
Matlab GUI for automatic action potential detection of membrane potential recordings.
Frontiers in Neural Circuits, 2021
The medial septum (MS), as part of the basal forebrain, supports many physiological functions, fr... more The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of...
Neuroscience Research, 2020
Oscillatory brain activities support many physiological functions from motor control to cognition... more Oscillatory brain activities support many physiological functions from motor control to cognition. Disruptions of the normal oscillatory brain activities are commonly observed in neurological and psychiatric disorders including epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, anxiety/trauma-related disorders, major depressive disorders, and drug addiction. Therefore, these disorders can be considered as common oscillation defects despite having distinct behavioral manifestations and genetic causes. Recent technical advances of neuronal activity recording and analysis have allowed us to study the pathological oscillations of each disorder as a possible biomarker of symptoms. Furthermore, recent advances in brain stimulation technologies enable timeand space-targeted interventions of the pathological oscillations of both neurological disorders and psychiatric disorders as possible targets for regulating their symptoms.
PLOS ONE, 2019
The metabotropic glutamate receptor subtype 1 (mGluR1) is a major subtype of group I mGluRs, whic... more The metabotropic glutamate receptor subtype 1 (mGluR1) is a major subtype of group I mGluRs, which contributes to the development and plasticity of synapses in the brain. In the sensory thalamus, the thalamocortical neuron receives sensory afferents and massive feedback input from corticothalamic (CT) fibers. Notably, mGluR1 is more concentrated in CT synapses in the sensory thalamus. In the visual thalamus, mGluR1 maintains mature afferent synaptic connectivity. However, it is unknown whether mGluR1 contributes to strengthening of immature synapses or weakening of excess synapses during development and whether mGluR1 at CT synapses heterosynaptically regulates the development or refinement of afferent synapses. Here we investigated the effects of knocking out the gene encoding mGluR1 or pharmacologically blocking cortical activity on the development and maintenance of lemniscal synapses, i.e., the somatosensory afferent synapses, in the ventral posteromedial somatosensory thalamus. mGluR1-knockout (KO) mice exhibited delayed developmental strengthening as well as incomplete elimination and remodeling after maturation of lemniscal synapses. Similar to the phenotypes exhibited by mGluR1-KO mice, pharmacological blockade of somatosensory cortical activity from P12 or P21 for 1 week in wild-type mice perturbed elimination or maintenance of lemniscal synapses, respectively. The same manipulation in mGluR1-KO mice failed to induce additional abnormalities in lemniscal synaptic connectivity. These results suggest that activation of mGluR1, driven by CT input, regulates multiple stages of the development of lemniscal synapses, including strengthening, refinement, and maintenance in the somatosensory thalamus.
PLoS biology, 2018
Evolutionary development of vision has provided us with the capacity to detect moving objects. Co... more Evolutionary development of vision has provided us with the capacity to detect moving objects. Concordant shifts of visual features suggest movements of the observer, whereas discordant changes are more likely to be indicating independently moving objects, such as predators or prey. Such distinction helps us to focus attention, adapt our behavior, and adjust our motor patterns to meet behavioral challenges. However, the neural basis of distinguishing self-induced and self-independent visual motions is not clarified in unrestrained animals yet. In this study, we investigated the presence and origin of motion-related visual information in the striatum of rats, a hub of action selection and procedural memory. We found that while almost half of the neurons in the dorsomedial striatum are sensitive to visual motion congruent with locomotion (and that many of them also code for spatial location), only a small subset of them are composed of fast-firing interneurons that could also perceive...
MethodsX, 2018
Compound muscle action potential (CMAP) recording via reconstructed or regenerated motor axons is... more Compound muscle action potential (CMAP) recording via reconstructed or regenerated motor axons is a critical examination to evaluate newly developed surgical and regeneration techniques. However, there is currently no documentation on technical aspects of CMAP recordings via reconstructed or regenerated facial nerves. We have studied new techniques of plastic surgery and nerve regeneration using a rat facial nerve defect model for years, standardizing an evaluation pipeline using CMAP recordings. Here we describe our CMAP recording procedure in detail as a package including surgical preparation, data acquisition, analysis and troubleshooting. Each resource is available in public repositories and is maintained as a version control system. In addition, we demonstrate that our analytical pipeline can not only be applied to rats, but also mice. Finally, we show that CMAP recordings can be practically combined with other behavioral and anatomical examinations. For example, retrograde motor neuron labeling provides anatomical evidence for physical routes between the facial motor nucleus and its periphery through reconstructed or regenerated facial nerves, in addition to electrophysiological evidence by CMAP recordings from the same animal. Standardized surgical, recording and analytical procedures for the functional evaluation of reconstructed or regenerated facial nerves of rats, extended to mice. The functional evaluation can be combined with anatomical evaluations. The methods described here are maintained in public repositories as version control systems.
Nature communications, Feb 2, 2018
Transcranial electric stimulation is a non-invasive tool that can influence brain activity; howev... more Transcranial electric stimulation is a non-invasive tool that can influence brain activity; however, the parameters necessary to affect local circuits in vivo remain to be explored. Here, we report that in rodents and human cadaver brains, ~75% of scalp-applied currents are attenuated by soft tissue and skull. Using intracellular and extracellular recordings in rats, we find that at least 1 mV/mm voltage gradient is necessary to affect neuronal spiking and subthreshold currents. We designed an 'intersectional short pulse' stimulation method to inject sufficiently high current intensities into the brain, while keeping the charge density and sensation on the scalp surface relatively low. We verify the regional specificity of this novel method in rodents; in humans, we demonstrate how it affects the amplitude of simultaneously recorded EEG alpha waves. Our combined results establish that neuronal circuits are instantaneously affected by intensity currents that are higher than t...
Plastic and reconstructive surgery. Global open, 2015
Interpositional jump graft (IPJG) is a nerve graft axonally supercharged from the hypoglossal ner... more Interpositional jump graft (IPJG) is a nerve graft axonally supercharged from the hypoglossal nerve. However, for using the technique, an autologous nerve, which should contain the great auricular and sural nerves, must be obtained. Depending on the donor site, unavoidable issues such as nerve disorders and postoperative scarring may appear. To reduce the issues, in this study, the authors developed an end-to-side neurorrhaphy technique with the recipient nerve and an artificial nerve conduit and investigated the efficacy of an IPJG with an artificial nerve conduit in a rat facial nerve paresis model. A ligature clip was used to crush the facial nerve trunk, thereby creating a partial facial nerve paresis model. An artificial nerve conduit was then prepared with a 10-mm-long silicone tube containing 10 μL type I collagen and used to create an IPJG between the facial nerve trunk and the hypoglossal nerve (the silicone tube group). Thirteen weeks after the surgery, the outcome was his...
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Papers by Yuichi Takeuchi