Changes In Spontaneous Activity Research Articles

No Evidence of Sensory Neuropathy in a Traditional Mouse Model of Idiopathic Parkinson’s Disease

Parkinson’s disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the Substantia nigra pars compacta and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder.

Tinnitus-related increases in single-unit activity in awake rat auditory cortex correlate with tinnitus behavior

Tinnitus is known to affect 10–15 % of the population, severely impacting 1–2 % of those afflicted. Canonically, tinnitus is generally a consequence of peripheral auditory damage resulting in maladaptive plastic changes in excitatory/inhibitory homeostasis at multiple levels of the central auditory pathway as well as changes in diverse nonauditory structures. Animal studies of primary auditory cortex (A1) generally find tinnitus-related changes in excitability across A1 layers and differences between inhibitory neuronal subtypes. Changes due to sound-exposure include changes in spontaneous activity, cross-columnar synchrony, bursting and tonotopic organization. Few studies in A1 directly correlate tinnitus-related changes in neural activity to an individual animal's behavioral evidence of tinnitus. The present study used an established condition-suppression sound-exposure model of chronic tinnitus and recorded spontaneous and driven single-unit responses from A1 layers 5 and 6 of awake Long-Evans rats. A1 units recorded from animals with behavioral evidence of tinnitus showed significant increases in spontaneous and sound-evoked activity which directly correlated to the animal's tinnitus score. Significant increases in the number of bursting units, the number of bursts/minute and burst duration were seen for A1 units recorded from animals with behavioral evidence of tinnitus. The present A1 findings support prior unit recording studies in auditory thalamus and recent in vitro findings in this same animal model. The present findings are consistent with sensory cortical studies showing tinnitus- and neuropathic pain-related down-regulation of inhibition and increased excitation based on plastic neurotransmitter and potassium channel changes. Reducing A1 deep-layer tinnitus-related hyperactivity is a potential target for tinnitus pharmacotherapy.

Altered intrinsic brain activity in patients with neuropathic pain after brachial plexus avulsion

ObjectiveThis study aimed to investigate brain activity changes in patients suffering from neuropathic pain (NP) following brachial plexus avulsion (BPA). MethodsFifteen patients with NP following BPA and eight healthy participants (HP) were recruited for this study. All participants underwent examination using resting-state functional MRI. The amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were calculated and compared between the BPA group, left-BPA subgroup, right-BPA subgroup, and the HP group using independent samples t-tests. ResultsIn the BPA group, there were notable increases in ALFF/ReHo observed in the left rolandic operculum, insula, and supramarginal gyrus, while decreases were observed in the left paracentral lobule, fusiform gyrus, calcarine fissure and surrounding cortex, lingual gyrus, precuneus, as well as the bilateral anterior/median cingulate and paracingulate gyri, supplementary motor area, and cerebellum. In the left-BPA subgroup, elevated ALFF/ReHo levels were identified in the left middle/inferior frontal gyri, rolandic operculum, and supramarginal gyrus, with corresponding decreases in the left calcarine fissure and surrounding cortex, inferior occipital gyrus, fusiform gyrus, lingual gyrus, as well as the bilateral anterior/median cingulate and paracingulate gyri, postcentral gyri, supplementary motor area, paracentral lobules, and cerebellum. The right-BPA subgroup displayed increased ALFF/ReHo in the left frontal lobe, rolandic operculum, insula, fusiform gyrus, and lingual gyrus, as well as the right cerebellum. Conversely, decreases in ALFF/ReHo were observed in the bilateral anterior/median cingulate and paracingulate gyri, calcarine fissure and surrounding cortex, cuneus, and occipital lobes. ConclusionsThe NP after BPA caused spontaneous activity changes in brain regions associated with linguistic, visual, somatosensory, and motor coordination and processing function. The majority of these abnormal areas were situated in the left cerebral hemisphere, while the effect of cingulate gyri and cerebellum seemed to be bilateral.

Neuro-Navigated rTMS Improves Sleep and Cognitive Impairment via Regulating Sleep-Related Networks' Spontaneous Activity in AD Spectrum Patients.

By examining spontaneous activity changes of sleep-related networks in patients with the Alzheimer's disease (AD) spectrum with or without insomnia disorder (ID) over time via neuro-navigated repetitive transcranial magnetic stimulation (rTMS), we revealed the effect and mechanism of rTMS targeting the left-angular gyrus in improving the comorbidity symptoms of the AD spectrum with ID. A total of 34 AD spectrum patients were recruited in this study, including 18 patients with ID and the remaining 16 patients without ID. All of them were measured for cognitive function and sleep by using the cognitive and sleep subscales of the neuropsychiatric inventory. The amplitude of low-frequency fluctuation changes in sleep-related networks was revealed before and after neuro-navigated rTMS treatment between these two groups, and the behavioral significance was further explored. Affective auditory processing and sensory-motor collaborative sleep-related networks with hypo-spontaneous activity were observed at baseline in the AD spectrum with ID group, while substantial increases in activity were evident at follow-up in these subjects. In addition, longitudinal affective auditory processing, sensory-motor and default mode collaborative sleep-related networks with hyper-spontaneous activity were also revealed at follow-up in the AD spectrum with ID group. In particular, longitudinal changes in sleep-related networks were associated with improvements in sleep quality and episodic memory scores in AD spectrum with ID patients. We speculated that left angular gyrus-navigated rTMS therapy may enhance the memory function of AD spectrum patients by regulating the spontaneous activity of sleep-related networks, and it was associated with memory consolidation in the hippocampus-cortical circuit during sleep. The study was registered at the Chinese Clinical Trial Registry, registration ID: ChiCTR2100050496, China.

Resting-state functional magnetic resonance imaging in bipolar affective disorder. A systematized umbrella review

Bipolar affective disorder (BD) is a complex mental illness that presents diagnostic challenges due to its heterogeneous nature. As a result, identifying potential markers for the disorder is crucial for effective diagnosis and treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) is a promising non-invasive technique that provides a window into the pathophysiological characteristics of psychiatric and neurological diseases in vivo. The amount of data accumulated in the scientific community regarding changes in spontaneous activity and functional connectivity of brain regions in BD necessitates a comprehensive synthesis to determine the spectrum of disorders. Accordingly, a systematic review of reviews was conducted to summarize the changes characteristic of patients with BD as measured by fMRI. Qualitative synthesis of results of nine systematic reviews and six meta-analyses has allowed the definition of changes in spontaneous activity and functional connectivity most characteristic for BD, confirming the unity of functional disturbances of this nosological unit. The findings of the review indicate that the manic state in BD is often associated with increased activity of the amygdala and decreased functional connectivity between the amygdala and frontal regions. Conversely, the depressive phase is characterized by abnormalities of functional connectivity within the default mode network, particularly in relation to the posterior cingulate cortex. Changes in functional connectivity during periods of euthymia may reflect residual manifestations of one of the exacerbation phases or may be associated with a history of a psychotic episode. Furthermore, a comparative analysis of possible methods of quantitative fMRI data synthesis has been conducted for the first time in Russia, which is a valuable contribution to the field.

Abnormal spontaneous brain activity in females with autism spectrum disorders.

To date, most studies on autism spectrum disorder (ASD) have focused on sample sets that were primarily or entirely composed of males; brain spontaneous activity changes in females remain unclear. The purpose of this study was to explore changes in the brain spontaneous neural activity in females with ASD. In this study, resting-state functional magnetic resonance images (rs-fMRI) of 41 females with ASD and 41 typically developing (TD) controls were obtained from the ABDIE database. The amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) of the two groups were calculated to detect the regional brain activity. A two independent sample t-test was used to analyze differences between the ASD and TD groups and a p-value <0.05 was considered statistically significant after false discovery rate (FDR) correction. Pearson correlation analysis was conducted between social responsiveness scale (SRS) scores and the local activity of significantly different brain regions. Compared with the typically developing (TD) group, the values of ALFF and ReHo were significantly increased in the left superior temporal gyrus (STG), while the values of ReHo were significantly decreased in the left superior frontal gyrus (SFG), left middle occipital gyrus (MOG), bilateral superior parietal lobule (SPL), and bilateral precuneus in the females with ASD group. Correlation analysis showed that the ReHo of the right precuneus was positively correlated to the total SRS, social communication, and autistic mannerisms. Spontaneous activity changes in females with ASD involved multiple brain regions and were related to clinical characteristics. Our results may provide some help for further exploring the neurobiological mechanism of females with ASD.

Abnormal cerebral blood flow and brain function in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) lead to impaired cerebral blood perfusion, which leads to changes in brain function and affects the cognitive function of patients. In this study, cerebral blood flow (CBF) was used to evaluate the effect of T2DM on cerebral perfusion, and functional connectivity (FC) analysis was further used to explore whether the FC between the abnormal CBF region and the whole brain was changed. In addition, amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were used to investigate the changes in spontaneous activity and connectivity strength of the brain network. We recruited 40 T2DM patients and 55 healthy controls (HCs). They underwent 3D-T1WI, rs-fMRI, arterial spin labeling (ASL) sequence scans and a series of cognitive tests. Cognitive test scores and brain imaging indicators were compared between the two groups, and the relationships among laboratory indicators, cognitive test scores, and brain imaging indicators were explored in the T2DM group. Compared to HCs, The CBF values of Calcarine_L and Precuneus_R in the T2DM group were lower. The DC value of Paracentral_Lobule_L and Precuneus_L, and the ALFF value of Hippocampus_L in the T2DM group were higher. In addition, the CBF values of Calcarine_L was negatively correlated with fasting insulin and HOMA_IR. This study found that there were regions of cerebral hypoperfusion in T2DM patients, which are associated with insulin resistance. In addition, we found abnormally elevated brain activity and enhanced functional connectivity in T2DM patients, which we speculated was the compensatory mechanism of brain neural activity.

Nicotine addiction and overweight affect intrinsic neural activity and neurotransmitter activity: A fMRI study of interaction effects.

Nicotine addiction and overweight often co-exist, but the neurobiological mechanism of their co-morbidity remains to be clarified. In this study, we explore how nicotine addiction and overweight affect intrinsic neural activity and neurotransmitter activity. This study included 54 overweight people and 54 age-, sex-, and handedness-matched normal-weight individuals, who were further divided into four groups based on nicotine addiction. We used a two-way factorial design to compare intrinsic neural activity (calculated by the fALFF method) in four groups based on resting-state functional magnetic resonance images (rs-fMRI). Furthermore, the correlation between fALFF values and PET- and SPECT-derived maps to examine specific neurotransmitter system changes underlying nicotine addiction and overweight. Nicotine addiction and overweight affect intrinsic neural activity by themselves. In combination, they showed antagonistic effects in the interactive brain regions (left insula and right precuneus). Cross-modal correlations displayed that intrinsic neural activity changes in the interactive brain regions were related to the noradrenaline system (NAT). Due to the existence of interaction, nicotine partially restored the changes of spontaneous activity in the interactive brain regions of overweight people. Therefore, when studying one factor alone, the other should be used as a control variable. Besides, this work links the noradrenaline system with intrinsic neural activity in overweight nicotine addicts. By examining the interactions between nicotine addiction and overweight from neuroimaging and molecular perspectives, this study provides some ideas for the treatment of both co-morbidities.

Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder

BackgroundMethylphenidate, a first-line treatment for attention-deficit/hyperactivity disorder (ADHD), is thought to influence dopaminergic neurotransmission in the nucleus accumbens (NAc) and its associated brain circuitry, but this hypothesis has yet to be systematically tested. MethodsWe conducted a randomized, placebo-controlled, double-blind crossover trial including 27 children with ADHD. Children with ADHD were scanned twice with resting-state functional magnetic resonance imaging under methylphenidate and placebo conditions, along with assessment of sustained attention. We examined spontaneous neural activity in the NAc and the salience, frontoparietal, and default mode networks and their links to behavioral changes. Replicability of methylphenidate effects on spontaneous neural activity was examined in a second independent cohort. ResultsMethylphenidate increased spontaneous neural activity in the NAc and the salience and default mode networks. Methylphenidate-induced changes in spontaneous activity patterns in the default mode network were associated with improvements in intraindividual response variability during a sustained attention task. Critically, despite differences in clinical trial protocols and data acquisition parameters, the NAc and the salience and default mode networks showed replicable patterns of methylphenidate-induced changes in spontaneous activity across two independent cohorts. ConclusionsWe provide reproducible evidence demonstrating that methylphenidate enhances spontaneous neural activity in NAc and cognitive control networks in children with ADHD, resulting in more stable sustained attention. Our findings identified a novel neural mechanism underlying methylphenidate treatment in ADHD to inform the development of clinically useful biomarkers for evaluating treatment outcomes.

Resting state electroretinography: An innovative approach to intrinsic retinal function monitoring.

The electroretinogram (ERG) represents the biopotential evoked by the retina in response to a light stimulus. The flash evoked ERG (fERG) is the ERG modality most frequently used clinically to diagnose and monitor retinal disorders. We hereby present a new method to record spontaneous retinal activity, without the use of a flash stimulus, that we named the resting-state ERG (rsERG). The recordings were done in normal subjects under light- and dark-adaptation and with different background light conditions (i.e., variations of wavelength and intensity). Additionally, rsERG recordings were obtained in five patients with retinopathies. The signals were subsequently analyzed in the frequency domain, extracting both periodic (i.e., frequency peaks) and aperiodic (i.e., background trend) components of the signal. The later was further assessed through a multifractal analysis using Wavelet Leaders. Results show that, irrespective of the recording conditions used, the rsERG always includes the same 90 Hz component; a frequency component also present in the fERG response, suggesting a retinally-intrinsic origin. However, in addition, the fERGs also includes a low-frequency component which is absent in the rsERGs, a finding supporting a retinally-induced origin. Comparing rsERGs with fERGs in selected patients with various retinal disorders indicates that the two retinal signals are not always similarly affected (either as a result of underlying retinal pathology or otherwise), suggesting an added value in the assessment of retinal function. Thus, the rsERG could have a similar role in clinical visual electrophysiology as that of the resting-state EEG in neurology namely, to quantify changes in spontaneous activity that result from a given disease processes.

Altered Brain Activity in Strabismic Amblyopic Children as Determined by Regional Homogeneity: A Resting-State Functional Magnetic Resonance Imaging Study.

ObjectiveEarlier research has determined that amblyopia or strabismus may cause remarkable brain anatomical and functional variations. Nonetheless, thus far, the spontaneous changes in brain activity in children with strabismus amblyopia (SA) remain unclear. The purpose of this study was to determine the association between abnormal brain activity in children with SA and its behavioral manifestations.Patients and Methods?A total of 24 children with SA (10 male and 14 female children) as well as 24 healthy controls (HCs), including 10 male and 14 female children were closely matched in sex and age, and examined using resting-state functional magnetic resonance imaging (fMRI). The regional homogeneity (ReHo) technique was applied to evaluate spontaneous cerebral activity variations in children with SA and HCs. Moreover, associations between altered ReHo values in distinct cerebral areas and the degree of strabismus were assessed using Pearson correlation analysis.ResultsRemarkably increased ReHo values were observed in the right lingual, right superior frontal medial, bilateral superior parietal, and right inferior parietal gyri of children with SA compared with HCs. In contrast, mean ReHo values in children with SA were lower in the right cerebellum, left superior frontal gyrus, and left putamen nucleus. Furthermore, esotropia showed a positive correlation with ReHo values of the left putamen.ConclusionThe anomalous spontaneous activity changes in several brain areas that are caused by SA may indicate neuropathologic mechanisms of visual deficits and oculomotor disorders in children with SA.

Perinatal stroke: modelling and the potential of neurovisualization

Perinatal stroke (PS), characterized by sudden disappearance or impairment of brain functions, is a socially significant form of pathology that leads to the death and/or disability of children. Depending on the extent of the lesion, the severity of the consequences of a PS varies from a slight lag in learning to lifelong disability and inability to independently take care of yourself. The most common complications are cerebral palsy and epilepsy. Since the possibilities of diagnosis and therapy in the acute period are extremely limited, the efforts of health care providers and scientists are aimed at improving approaches to the rehabilitation of such patients. The authors presented an overview of modern methods of modelling PS in various experimental conditions. It is established that the modelling of PS is continuously being improved, new ways of forming ischemic brain damage are being created, each of which is necessary for the development of new scientific criteria for its early diagnosis and prediction of outcomes in standardized conditions. It is shown that a special place in the diagnosis of ischemic brain damage is occupied by wide-field optical visualization, which allows determining the formation of neural networks and functional maps of the cortex of the developing brain, provides an opportunity to analyze the spatiotemporal activity of neurons in large areas of the cerebral cortex and the processes of restoring cortical functions in the post-traumatic period. With the advent of genetically encoded ion sensor proteins and technologies for obtaining transgenic animal lines that specifically express sensors directly in neurons, opportunities have been created for optical registration of neural activity by analyzing changes in spontaneous activity of calcium signals and other mechanisms, which allows us to study brain neuroplasticity at a new level and create new ways to correct ischemic brain damage.

P430. Developmental Refinement of Spontaneous Activity Varies Across Sensorimotor and Association Cortices

Spontaneous activity refines cortical circuits in the developing brain. In animals, spontaneous activity in sensory regions evolves from globally synchronized to decorrelated as the cortex transitions from plastic to mature. Here, we leverage the fact that synchronized bursts in intrinsic activity are a functional hallmark of plastic cortices to characterize the unfolding of activity-indexed plasticity in youth. We hypothesized that age-related changes in spontaneous activity would differ between early-maturing sensorimotor cortices and late-maturing association cortices.

Nitroxyl Delivered by Angeli's Salt Causes Short-Lasting Activation Followed by Long-Lasting Deactivation of Meningeal Afferents in Models of Headache Generation.

The role of TRPA1 receptor channels in meningeal nociception underlying the generation of headaches is still unclear. Activating as well as inhibitory effects of TRPA1 agonists have been reported in animal models of headache. The aim of the present study was to clarify the effect of the TRPA1 agonist nitroxyl (HNO) delivered by Angeli’s salt in two rodent models of meningeal nociception. Single fibre recordings were performed using half-skull preparations of mice (C57BL/6) in vitro. Angeli’s salt solution (AS, 300 µM) caused short-lasting vigorous increases in neuronal activity of primary meningeal afferents, followed by deactivation and desensitisation. These effects were similar in TRPA1 knockout and even more pronounced in TRPA1/TRPV1 double-knockout mice in comparison to wild-type mice. The activity of spinal trigeminal neurons with afferent input from the dura mater was recorded in vivo in anesthetised rats. AS (300 µM) or the TRPA1 agonist acrolein (100 and 300 µM) was applied to the exposed dura mater. AS caused no significant changes in spontaneous activity, while the mechanically evoked activity was reduced after acrolein application. These results do not confirm the assumption that activation of trigeminal TRPA1 receptor channels triggers the generation of headaches or contributes to its aggravation. Instead, there is evidence that TRPA1 activation may have an inhibitory function in the nociceptive trigeminal system.

Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs-Donnan Forces, Namely Spreading Depolarization.

Neuronal cytotoxic edema is the morphological correlate of the near-complete neuronal battery breakdown called spreading depolarization, or conversely, spreading depolarization is the electrophysiological correlate of the initial, still reversible phase of neuronal cytotoxic edema. Cytotoxic edema and spreading depolarization are thus different modalities of the same process, which represents a metastable universal reference state in the gray matter of the brain close to Gibbs–Donnan equilibrium. Different but merging sections of the spreading-depolarization continuum from short duration waves to intermediate duration waves to terminal waves occur in a plethora of clinical conditions, including migraine aura, ischemic stroke, traumatic brain injury, aneurysmal subarachnoid hemorrhage (aSAH) and delayed cerebral ischemia (DCI), spontaneous intracerebral hemorrhage, subdural hematoma, development of brain death, and the dying process during cardio circulatory arrest. Thus, spreading depolarization represents a prime and simultaneously the most neglected pathophysiological process in acute neurology. Aristides Leão postulated as early as the 1940s that the pathophysiological process in neurons underlying migraine aura is of the same nature as the pathophysiological process in neurons that occurs in response to cerebral circulatory arrest, because he assumed that spreading depolarization occurs in both conditions. With this in mind, it is not surprising that patients with migraine with aura have about a twofold increased risk of stroke, as some spreading depolarizations leading to the patient percept of migraine aura could be caused by cerebral ischemia. However, it is in the nature of spreading depolarization that it can have different etiologies and not all spreading depolarizations arise because of ischemia. Spreading depolarization is observed as a negative direct current (DC) shift and associated with different changes in spontaneous brain activity in the alternating current (AC) band of the electrocorticogram. These are non-spreading depression and spreading activity depression and epileptiform activity. The same spreading depolarization wave may be associated with different activity changes in adjacent brain regions. Here, we review the basal mechanism underlying spreading depolarization and the associated activity changes. Using original recordings in animals and patients, we illustrate that the associated changes in spontaneous activity are by no means trivial, but pose unsolved mechanistic puzzles and require proper scientific analysis.

Necrostatin-1 Against Sevoflurane-Induced Cognitive Dysfunction Involves Activation of BDNF/TrkB Pathway and Inhibition of Necroptosis in Aged Rats.

Postoperative cognitive dysfunction (POCD) induced by anesthesia or surgery has become a common complication in the aged population. Sevoflurane, a clinical inhalation anesthetic, could stimulate calcium overload and necroptosis to POCD. In addition, necroptosis inhibitor necrostatin-1 (Nec-1) alleviated cognitive impairment caused by multiple causes, including postoperative cognitive impairment. However, whether Nec-1 exerts a neuroprotective effect on POCD via calcium and necroptosis remains unclear. We anesthetized Sprague-Dawley rats with sevoflurane to construct the POCD model and to explore the mechanism underlying neuroprotective effects of Nec-1 in POCD. Rats were treated with Nec-1 (6.25mg/kg) 1h prior to anesthesia. Open field test and Morris water maze were employed to detect the cognitive function. In this study, rats exposed to sevoflurane displayed cognitive dysfunction without changes in spontaneous activity; however, the sevoflurane-induced POCD could be relieved by Nec-1 pretreatment. Nec-1 decreased sevoflurane-induced calcium overload and calpain activity in the hippocampus. In addition, Nec-1 alleviated the expression of p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL and MLKL. Furthermore, Nec-1 remarkably increased BDNF and p-TrkB/TrkB expression in the hippocampus of aged rats. Ultimately, our research manifests evidence that Nec-1 may play a neuroprotective role against sevoflurane-induced cognitive impairment via the increase of BDNF/TrkB and suppression of necroptosis-related pathway.

Abstract 13939: Triiodothyronine and Dexamethasone Enhances Electrophysiological Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Background: Human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) technology opens new avenues for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes. Objective: To improve the electrophysiological maturation of hiPSC-CMs. Methods and Results: Day 16 th hiPSC-CMs were treated with vehicle or 100 nmol/L triiodothyronine (T3) and 1 μmol/L Dexamethasone (Dex) for 14 days. On day 30 th , hiPSC-CMs were dissociated and replated as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3+Dex-treated hiPSC-CMs. T3+Dex-treated hiPSC-CMs had a slower spontaneous beating rate (vehicle 17 ± 0.8 vs . T3+Dex 12 ± 0.8 beats/min, P &lt; 0.01), more hyperpolarized resting membrane potential (vehicle -65.04 ± 1.20 vs. T3+Dex -72.00 ± 1.10 mV, P &lt; 0.01), faster maximal upstroke velocity (vehicle 86.08 ± 8.12 vs. T3+Dex 131.78 ± 8.49 mV/ms, P &lt; 0.01), and shorter action potential duration at 90% repolarization (APD 90 , vehicle 550.44 ± 39.54 vs. T3+Dex 418.59 ± 21.58 ms, P &lt; 0.01) compared to the vehicle. Changes in spontaneous activity and AP were mediated by decreasing the funny current (I f , vehicle -12.20 ± 2.15 vs. T3+Dex -6.98 ± 0.89 pA/pF at -120 mV, P &lt; 0.05) and increasing the inward rectifier potassium current (I K1 , vehicle -4.62 ± 0.59 pA/pF vs . T3+Dex -18.79 ± 1.98 pA/pF at -120 mV, P &lt; 0.01), the sodium current (I Na , vehicle -9.8 ± 1.86 vs. T3+Dex -44.9 ± 7.10 pA/pF at -30 mV, P &lt; 0.01), and the rapidly and slowly activating delayed rectifier potassium currents (I Kr , 0.81 ± 0.07 vs. T3+Dex: 1.35 ± 0.19 pA/pF at 20 mV, P &lt; 0.01; I Ks , vehicle 0.38 ± 0.06 vs. T3+Dex 0.72 ± 0.17 pA/pF at 40 mV, P &lt; 0.05). Furthermore, T3+Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter APD than the vehicle. Inhibition of I K1 by 100 μM BaCl 2 significantly slowed conduction velocity and prolonged APD in T3+Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the important role of I K1 for conduction velocity and APD. Conclusion: T3+Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.

The habenula clock influences response to a stressor

The response of an animal to a sensory stimulus depends on the nature of the stimulus and on expectations, which are mediated by spontaneous activity. Here, we ask how circadian variation in the expectation of danger, and thus the response to a potential threat, is controlled. We focus on the habenula, a mediator of threat response that functions by regulating neuromodulator release, and use zebrafish as the experimental system. Single cell transcriptomics indicates that multiple clock genes are expressed throughout the habenula, while quantitative in situ hybridization confirms that the clock oscillates. Two-photon calcium imaging indicates a circadian change in spontaneous activity of habenula neurons. To assess the role of this clock, a truncated clocka gene was specifically expressed in the habenula. This partially inhibited the clock, as shown by changes in per3 expression as well as altered day-night variation in dopamine, serotonin and acetylcholine levels. Behaviourally, anxiety-like responses evoked by an alarm pheromone were reduced. Circadian effects of the pheromone were disrupted, such that responses in the day resembled those at night. Behaviours that are regulated by the pineal clock and not triggered by stressors were unaffected. We suggest that the habenula clock regulates the expectation of danger, thus providing one mechanism for circadian change in the response to a stressor.

Facial Expression Recognition and ReHo Analysis in Major Depressive Disorder.

Objective: To explore the characteristics of expression recognition and spontaneous activity of the resting state brain in major depressive disorder (MDD) patients to find the neural basis of expression recognition and emotional processing.Methods: In this study, two of the six facial expressions (happiness, sadness, anger, fear, aversion, and surprise) were presented in quick succession using a short expression recognition test. The differences in facial expression recognition between MDD patients and healthy people were compared. Further, the differences in ReHo values between the two groups were compared using a resting-state functional magnetic resonance imaging (fMRI) scan to investigate the characteristics of spontaneous brain activity in the resting state and its relationship with clinical symptoms and the accuracy of facial expression recognition in patients with MDD.Results: (1) The accuracy of facial expression recognition in patients with MDD was lower than that of the HC group. There were differences in facial expression recognition between the two groups in sadness-anger (p = 0.026), surprise-aversion (p = 0.038), surprise-happiness (p = 0.014), surprise-sadness (p = 0.019), fear-happiness (p = 0.027), and fear-anger (p = 0.009). The reaction time for facial expression recognition in the patient group was significantly longer than that of the HC group. (2) Compared with the HC group, the ReHo values decreased in the left parahippocampal gyrus, left thalamus, right putamen, left putamen, and right angular gyrus, and increased in the left superior frontal gyrus, left middle temporal gyrus, left medial superior frontal gyrus, and right medial superior frontal gyrus in the patient group. (3) Spearman correlation analysis showed no statistical correlation between ReHo and HAMD-17 scores in MDD patients (p > 0.05). The ReHo value of the left putamen was negatively correlated with the recognition of fear-surprise (r = −0.429, p = 0.016), the ReHo value of the right angular gyrus was positively correlated with the recognition of sadness-anger (r = 0.367, p = 0.042), and the ReHo value of the right medial superior frontal gyrus was negatively correlated with the recognition of fear-anger (r = −0.377, p = 0.037).Conclusion: In view of the different performance of patients with MDD in facial expression tasks, facial expression recognition may have some suggestive effect on the diagnosis of depression and has clinical guiding significance. Many brain regions, including the frontal lobe, temporal lobe, striatum, hippocampus, and thalamus, in patients with MDD show extensive ReHo abnormalities in the resting state. These brain regions with abnormal spontaneous neural activity are important components of LCSPT and LTC circuits, and their dysfunctional functions cause disorder of emotion regulation. The changes in spontaneous activity in the left putamen, right angular gyrus, and right medial superior frontal gyrus may represent the abnormal pattern of spontaneous brain activity in the neural circuits related to emotion perception and may be the neural basis of facial expression recognition.

Triiodothyronine and dexamethasone alter potassium channel expression and promote electrophysiological maturation of human-induced pluripotent stem cell-derived cardiomyocytes

BackgroundHuman-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising tool for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes. ObjectiveTo improve the electrophysiological maturation of hiPSC-CMs. Methods and resultsOn day 16 of cardiac differentiation, hiPSC-CMs were treated with 100 nmol/L triiodothyronine (T3) and 1 μmol/L Dexamethasone (Dex) or vehicle for 14 days. On day 30, vehicle- and T3 + Dex-treated hiPSC-CMs were dissociated and replated either as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3 + Dex-treated hiPSC-CMs. Compared to vehicle, T3 + Dex-treated hiPSC-CMs had a slower spontaneous beating rate, more hyperpolarized resting membrane potential, faster maximal upstroke velocity, and shorter action potential duration. Changes in spontaneous activity and action potential were mediated by decreased hyperpolarization-activated current (If) and increased inward rectifier potassium currents (IK1), sodium currents (INa), and the rapidly and slowly activating delayed rectifier potassium currents (IKr and IKs, respectively). Furthermore, T3 + Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter action potential duration than the vehicle. Inhibition of IK1 by 100 μM BaCl2 significantly slowed conduction velocity and prolonged action potential duration in T3 + Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the importance of IK1 for conduction velocity and action potential duration. ConclusionT3 + Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.