Intact in vivo visualization of telencephalic microvasculature in medaka using optical coherence tomography

To date, various human disease models in small fish—such as medaka (Oryzias lapties)--have been developed for medical and pharmacological studies. Although genetic and environmental homogeneities exist, disease progressions can show large individual differences in animal models. In this study, we established an intact in vivo angiographic approach and explored vascular networks in the telencephalon of wild-type adult medaka using the spectral-domain optical coherence tomography. Our approach, which required neither surgical operations nor labeling agents, allowed to visualize blood vessels in medaka telencephala as small as about 8 µm, that is, almost the size of the blood cells of medaka. Besides, we could show the three-dimensional microvascular distribution in the medaka telencephalon. Therefore, the intact in vivo imaging via optical coherence tomography can be used to perform follow-up studies on cerebrovascular alterations in metabolic syndrome and their associations with neurodegenerative disease models in medaka

Psychological resilience is correlated with dynamic changes in functional connectivity within the default mode network during a cognitive task

Resilience is a dynamic process that enables organisms to cope with demanding environments. Resting-state functional MRI (fMRI) studies have demonstrated a negative correlation between resilience and functional connectivities (FCs) within the default mode network (DMN). Considering the on-demand recruitment process of resilience, dynamic changes in FCs during cognitive load increases may reflect essential aspects of resilience. We compared DMN FC changes in resting and task states and their association with resilience. Eighty-nine healthy volunteers completed the Connor–Davidson Resilience Scale (CD-RISC) and an fMRI with an auditory oddball task. The fMRI time series was divided into resting and task periods. We focused on FC changes between the latter half of the resting period and the former half of the task phase (switching), and between the former and latter half of the task phase (sustaining). FCs within the ventral DMN significantly increased during “switching” and decreased during “sustaining”. For FCs between the retrosplenial/posterior cingulate and the parahippocampal cortex, increased FC during switching was negatively correlated with CD-RISC scores. In individuals with higher resilience, ventral DMN connectivities were more stable and homeostatic in the face of cognitive demand. The dynamic profile of DMN FCs may represent a novel biomarker of resilience

GPCR-mediated calcium and cAMP signaling determines psychosocial stress susceptibility and resiliency

ストレスに強い脳と弱い脳のメカニズム解明 --うつ病の脳のしくみ解明へ前進--. 京都大学プレスリリース. 2023-04-06.Chronic stress increases the risk of developing psychiatric disorders, including mood and anxiety disorders. Although behavioral responses to repeated stress vary across individuals, the underlying mechanisms remain unclear. Here, we perform a genome-wide transcriptome analysis of an animal model of depression and patients with clinical depression and report that dysfunction of the Fos-mediated transcription network in the anterior cingulate cortex (ACC) confers a stress-induced social interaction deficit. Critically, CRISPR-Cas9–mediated ACC Fos knockdown causes social interaction deficits under stressful situation. Moreover, two classical second messenger pathways, calcium and cyclic AMP, in the ACC during stress differentially modulate Fos expression and regulate stress-induced changes in social behaviors. Our findings highlight a behaviorally relevant mechanism for the regulation of calcium- and cAMP-mediated Fos expression that has potential as a therapeutic target for psychiatric disorders related to stressful environments

Functional relevance of the precuneus in verbal politeness.

Non-competitive and non-threatening aspects of social hierarchy, such as politeness, are universal among human cultures, and might have evolved from ritualized submission in primates; however, these behaviors have rarely been studied. Honorific language is a type of polite linguistic communication that plays an important role in human social interactions ranging from everyday conversation to international diplomacy. Here, functional magnetic resonance imaging (fMRI) revealed selective precuneus activation during a verbal politeness judgment task, but not other linguistic-judgment or social-status recognition tasks. The magnitude of the activation was correlated with the task performance. Functional suppression of the activation using cathodal transcranial direct-current stimulation reduced performance in the politeness task. These results suggest that the precuneus is an essential hub of the verbal politeness judgment

Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex

[Background] A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. [Methods] We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. [Results] Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non–monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. [Conclusions] These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience

Dopamine error signal to actively cope with lack of expected reward

目標に向けて努力し続けられる脳の仕組みを解明 --期待外れを乗り越えるためのドーパミン機能--. 京都大学プレスリリース. 2023-03-13.Dope defense against disappointment: Neurons in rats increase dopamine immediately after setbacks. 京都大学プレスリリース. 2023-06-20.To obtain more of a particular uncertain reward, animals must learn to actively overcome the lack of reward and adjust behavior to obtain it again. The neural mechanisms underlying such coping with reward omission remain unclear. Here, we developed a task in rats to monitor active behavioral switch toward the next reward after no reward. We found that some dopamine neurons in the ventral tegmental area exhibited increased responses to unexpected reward omission and decreased responses to unexpected reward, following the opposite responses of the well-known dopamine neurons that signal reward prediction error (RPE). The dopamine increase reflected in the nucleus accumbens correlated with behavioral adjustment to actively overcome unexpected no reward. We propose that these responses signal error to actively cope with lack of expected reward. The dopamine error signal thus cooperates with the RPE signal, enabling adaptive and robust pursuit of uncertain reward to ultimately obtain more reward

Disorganization of Semantic Brain Networks in Schizophrenia Revealed by fMRI

OBJECTIVES: Schizophrenia is a mental illness that presents with thought disorders including delusions and disorganized speech. Thought disorders have been regarded as a consequence of the loosening of associations between semantic concepts since the term "schizophrenia" was first coined by Bleuler. However, a mechanistic account of this cardinal disturbance in terms of functional dysconnection has been lacking. To evaluate how aberrant semantic connections are expressed through brain activity, we characterized large-scale network structures of concept representations using functional magnetic resonance imaging (fMRI). STUDY DESIGN: We quantified various concept representations in patients' brains from fMRI activity evoked by movie scenes using encoding modeling. We then constructed semantic brain networks by evaluating the similarity of these semantic representations and conducted graph theory-based network analyses. STUDY RESULTS: Neurotypical networks had small-world properties similar to those of natural languages, suggesting small-worldness as a universal property in semantic knowledge networks. Conversely, small-worldness was significantly reduced in networks of schizophrenia patients and was correlated with psychological measures of delusions. Patients' semantic networks were partitioned into more distinct categories and had more random within-category structures than those of controls. CONCLUSIONS: The differences in conceptual representations manifest altered semantic clustering and associative intrusions that underlie thought disorders. This is the first study to provide pathophysiological evidence for the loosening of associations as reflected in randomization of semantic networks in schizophrenia. Our method provides a promising approach for understanding the neural basis of altered or creative inner experiences of individuals with mental illness or exceptional abilities, respectively

Neural Correlates of Non-clinical Internet Use in the Motivation Network and Its Modulation by Subclinical Autistic Traits

Background: Increasing evidence regarding the neural correlates of excessive or pathological internet use (IU) has accumulated in recent years, and comorbidity with depression and autism has been reported in multiple studies. However, psychological and neural correlates of non-clinical IU in healthy individuals remain unclear.Objectives: The aim of the current study was to investigate the relationships between non-clinical IU and functional connectivity (FC), focusing on the brain’s motivation network. We sought to clarify the influence of depression and autistic traits on these relationships in healthy individuals.Methods: Resting-state functional magnetic resonance imaging (fMRI) was performed in 119 healthy volunteers. IU, depression, and autistic traits were assessed using the Generalized Problematic Internet Use Scale 2 (GPIUS2), Beck Depression Inventory-II (BDI-II), and the autism spectrum quotient (AQ) scale, respectively. Correlational analyses were performed using CONN-software within the motivation-related network, which consisted of 22 brain regions defined by a previous response-conflict task-based fMRI study with a reward cue. We also performed mediation analyses via the bootstrap method.Results: Total GPIUS2 scores were positively correlated with FC between the (a) left middle frontal gyrus (MFG) and bilateral medial prefrontal cortex; (b) left MFG and right supplementary motor area (SMA); (c) left MFG and right anterior insula, and (d) right MFG and right insula. The “Mood Regulation” subscale of the GPIUS2 was positively correlated with FC between left MFG and right SMA. The “Deficient Self-Regulation” subscale was positively correlated with FC between right MFG and right anterior insula (statistical thresholds, FDR < 0.05). Among these significant correlations, those between GPIUS2 (total and “Mood Regulation” subscale) scores and FC became stronger after controlling for AQ scores (total and “Attention Switching” subscale), indicating significant mediation by AQ (95% CI < 0.05). In contrast, BDI-II had no mediating effect.Conclusion: Positive correlations between IU and FC in the motivation network may indicate health-promoting effects of non-clinical IU. However, this favorable association is attenuated in individuals with subclinical autistic traits, suggesting the importance of a personalized educational approach for these individuals in terms of adequate IU

Martial Arts “Kendo” and the Motivation Network During Attention Processing: An fMRI Study

Japanese martial arts, Budo, have been reported to improve cognitive function, especially attention. However, the underlying neural mechanisms of the effect of Budo on attention processing has not yet been investigated. Kendo, a type of fencing using bamboo swords, is one of the most popular forms of Budo worldwide. We investigated the difference in functional connectivity (FC) between Kendo players (KPs) and non-KPs (NKPs) during an attention-related auditory oddball paradigm and during rest. The analyses focused on the brain network related to “motivation.” Resting-state functional magnetic resonance imaging (rs-fMRI) and task-based fMRI using the oddball paradigm were performed in healthy male volunteers (14 KPs and 11 NKPs). Group differences in FC were tested using CONN-software within the motivation network, which consisted of 22 brain regions defined by a previous response-conflict task-based fMRI study with a reward cue. Daily general physical activities were assessed using the International Physical Activity Questionnaire (IPAQ). We also investigated the impact of major confounders, namely, smoking habits, alcohol consumption, IPAQ score, body mass index (BMI), and reaction time (RT) in the oddball paradigm. Resting-state fMRI revealed that KPs had a significantly lower FC than NKPs between the right nucleus accumbens and right frontal eye field (FEF) within the motivation network. Conversely, KPs exhibited a significantly higher FC than NKPs between the left intraparietal sulcus (IPS) and the left precentral gyrus (PCG) within the network during the auditory oddball paradigm [statistical thresholds, False Discovery Rate (FDR) < 0.05]. These results remained significant after controlling for major covariates. Our results suggest that attenuated motivation network integrity at rest together with enhanced motivation network integrity during attentional demands might underlie the instantaneous concentration abilities of KPs

Neuroimaging at 7 Tesla: a pictorial narrative review

Neuroimaging using the 7-Tesla (7T) human magnetic resonance (MR) system is rapidly gaining popularity after being approved for clinical use in the European Union and the USA. This trend is the same for functional MR imaging (MRI). The primary advantages of 7T over lower magnetic fields are its higher signal-to-noise and contrast-to-noise ratios, which provide high-resolution acquisitions and better contrast, making it easier to detect lesions and structural changes in brain disorders. Another advantage is the capability to measure a greater number of neurochemicals by virtue of the increased spectral resolution. Many structural and functional studies using 7T have been conducted to visualize details in the white matter and layers of the cortex and hippocampus, the subnucleus or regions of the putamen, the globus pallidus, thalamus and substantia nigra, and in small structures, such as the subthalamic nucleus, habenula, perforating arteries, and the perivascular space, that are difficult to observe at lower magnetic field strengths. The target disorders for 7T neuroimaging range from tumoral diseases to vascular, neurodegenerative, and psychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, major depressive disorder, and schizophrenia. MR spectroscopy has also been used for research because of its increased chemical shift that separates overlapping peaks and resolves neurochemicals more effectively at 7T than a lower magnetic field. This paper presents a narrative review of these topics and an illustrative presentation of images obtained at 7T. We expect 7T neuroimaging to provide a new imaging biomarker of various brain disorders