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1.
Neuron ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34875233

RESUMO

The regenerative capacity of neurons is limited in the central nervous system (CNS), with irreversible neuronal loss upon insult. In contrast, microglia exhibit extraordinary capacity for repopulation. Matsuda et al. (2019) recently reported NeuroD1-induced microglia-to-neuron conversion, aiming to provide an "unlimited" source to regenerate neurons. However, the extent to which NeuroD1 can exert cross-lineage reprogramming of microglia (myeloid lineage) to neurons (neuroectodermal lineage) is unclear. In this study, we unexpectedly found that NeuroD1 cannot convert microglia to neurons in mice. Instead, NeuroD1 expression induces microglial cell death. Moreover, lineage tracing reveals non-specific leakage of similar lentiviruses as previously used for microglia-to-neuron conversion, which confounds the microglia-to-neuron observation. In summary, we demonstrated that NeuroD1 cannot induce microglia-to-neuron cross-lineage reprogramming. We here propose rigid principles for verifying glia-to-neuron conversion. This Matters Arising paper is in response to Matsuda et al. (2019), published in Neuron.

2.
iScience ; 24(12): 103429, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34901788

RESUMO

It has been 40 years since the report of long-term synaptic plasticity on the rodent brain. Transcranial ultrasound stimulation (TUS) shows advantages in spatial resolution and penetration depth when compared with electrical or magnetic stimulation. The repetitive TUS (rTUS) can induce cortical excitability alteration on animals, and persistent aftereffects were observed. However, the effects of rTUS on synaptic plasticity in humans remain unelucidated. In the current study, we applied a 15-min rTUS protocol to stimulate left primary motor cortex (l-M1) in 24 male healthy participants. The single-pulsed transcranial magnetic stimulation-evoked motor evoked potential and Stop-signal task was applied to measure the rTUS aftereffects. Here, we report that conditioning the human motor cortex using rTUS may produce long-lasting and statistically significant effects on motor cortex excitability as well as motor behavior, without harmful side effects observed. These findings suggest a considerable potential of rTUS in cortical plasticity modulation and clinical intervention for impulsivity-related disorders.

4.
Schizophr Res ; 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34916095

RESUMO

BACKGROUND: Accumulating evidence suggests that the pathology of some psychiatric symptoms may relate to autoantibodies against various neuronal surface antigens, such as NMDA receptors (NMDARs) or inhibitory GABAA receptors (GABAARs). However, it is unclear whether the plasma of patients with schizophrenia contains autoantibodies targeting to NMDARs or GABAARs. METHODS: Serum samples of 293 patients with schizophrenia were analyzed using a combination of live-cell-based assay (CBA) and immunostaining on primary neurons to quantify the positive rate of autoantibodies targeting NMDARs or GABAARs. RESULTS: Only one sample was found positive for anti-NMDAR autoantibodies, and no surface autoantibodies against GABAARs were found. No obvious difference in clinical manifestations was observed between the patients with positive and negative anti-NMDAR autoantibodies. CONCLUSIONS: Our results suggest that autoantibodies against NMDARs or GABAARs may affect only a small group of patients with schizophrenia, and the rates of these autoantibodies are lower than reported in prior work. It would be interesting to perform studies with psychotic disorder instead of schizophrenia to determine whether NMDAR or GABAAR autoantibody can be used as a biomarker to provide a new avenue for immunomodulatory therapy.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34705652

RESUMO

Although the spatiotemporal complexity and network connectivity are clarified to be disrupted during the general anesthesia (GA) induced unconsciousness, it remains to be difficult to exactly monitor the fluctuation of consciousness clinically. In this study, to track the loss of consciousness (LOC) induced by GA, we first developed the multi-channel cross fuzzy entropy method to construct the time-varying networks, whose temporal fluctuations were then explored and quantitatively evaluated. Thereafter, an algorithm was further proposed to detect the time onset at which patients lost their consciousness. The results clarified during the resting state, relatively stable fuzzy fluctuations in multi-channel network architectures and properties were found; by contrast, during the LOC period, the disrupted frontal-occipital connectivity occurred at the early stage, while at the later stage, the inner-frontal connectivity was identified. When specifically exploring the early LOC stage, the uphill of the clustering coefficients and the downhill of the characteristic path length were found, which might help resolve the propofol-induced consciousness fluctuation in patients. Moreover, the developed detection algorithm was validated to have great capacity in exactly capturing the time point (in seconds) at which patients lost consciousness. The findings demonstrated that the time-varying cross-fuzzy networks help decode the GA and are of great significance for developing anesthesia depth monitoring technology clinically.


Assuntos
Estado de Consciência , Propofol , Anestesia Geral , Encéfalo , Eletroencefalografia , Entropia , Humanos , Inconsciência
7.
BMC Psychiatry ; 21(1): 522, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686178

RESUMO

BACKGROUND: Individuals with psychiatric disorders perceive the world differently. Previous studies indicated impaired color vision and weakened color discrimination ability in psychotic patients. Examining the paintings from psychotic patients can measure the visual-motor function. However, few studies examined the potential changes in the color painting behavior in these individuals. The current study aims to discriminate schizophrenia patients from healthy controls (HCs) and predict PANSS scores of schizophrenia patients according to their paintings. METHODS: In the present study, we retrospectively analyzed the paintings colored by 281 chronic schizophrenia patients and 35 HCs. The images were scanned and processed using series of computational analyses. RESULTS: The results showed that schizophrenia patients tend to use less color and exhibit different strokes compared to HCs. Using a deep learning residual neural network (ResNet), we were able to discriminate patients from HCs with over 90% accuracy. Further, we developed a novel convolutional neural network to predict PANSS positive, negative, general psychopathology, and total scores. The Root Mean Square Error (RMSE) of the prediction was low, which indicates higher accuracy of prediction. CONCLUSION: In conclusion, the deep learning paradigm showed the large potential to discriminate schizophrenia patients from HCs based on color paintings. Besides, this color painting-based paradigm can effectively predict clinical symptom severity for chronic schizophrenia patients. The color paintings by schizophrenia patients show potential as a tool for clinical diagnosis and prognosis. These findings show potential as a tool for clinical diagnosis and prognosis among schizophrenia patients.

8.
Mol Psychiatry ; 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686765

RESUMO

Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novo protein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.

9.
Int J Psychophysiol ; 170: 133-155, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34687811

RESUMO

The impairment of inhibitory control and reward system is the core feature underlying substance use disorder (SUD). Previous studies suggested that it can be regarded as impaired response inhibition and salience attribution syndrome (iRISA). The neural substrates of the two deficit functions were widely investigated in neuroimaging studies, and the impaired prefrontal cortex, limbic-orbitofrontal network, and fronto-insular-parietal network were observed. Previous Event-related potential (ERP) studies were also conducted to explore EEG indexes related to abnormal brain function. In the current meta-analysis, we aimed to explore the consistency of ERP indexes that can reflect the two aberrant processes: P300/slow potential (SP) for salience attribution and Error-related negativity (ERN)/Nogo-N200/Nogo-P300 for inhibitory control and conflict monitoring. Subgroup analyses for drug type and drug use conditions were also conducted. According to the 60 research studies, we found significantly enhanced drug-cue-induced P300 amplitude and attenuated Nogo-N200 amplitude in SUD individuals relative to Healthy control (HC), which supports the dual model. Moreover, the drug-cue-induced P300 displayed time-dependence recovery, suggesting a potential index for treatment evaluation. In conclusion, drug-cue-induced P300 and Nogo-N200 demonstrated high consistency, and the drug-cue-induced P300 can be used to track the changes of functional recovery for SUD. The integration of the two ERP components could be regarded as a potential biomarker for SUD, which may provide a new insight for clinical treatment and investigation.

10.
Natl Sci Rev ; 8(9): nwab004, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34691732

RESUMO

Synaptic associativity, a feature of Hebbian plasticity wherein coactivation of two inputs onto the same neuron produces synergistic actions on postsynaptic activity, is a primary cellular correlate of associative learning. However, whether and how synaptic associativity are implemented into context-dependent relapse of extinguished memory (i.e. fear renewal) is unknown. Here, using an auditory fear conditioning paradigm in mice, we show that fear renewal is determined by the associativity between convergent inputs from the auditory cortex (ACx) and ventral hippocampus (vHPC) onto the lateral amygdala (LA) that reactivate ensembles engaged during learning. Fear renewal enhances synaptic strengths of both ACx to LA and the previously unknown vHPC to LA monosynaptic inputs. While inactivating either of the afferents abolishes fear renewal, optogenetic activation of their input associativity in the LA recapitulates fear renewal. Thus, input associativity underlies fear memory renewal.

11.
Front Psychiatry ; 12: 719782, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484007

RESUMO

Background: The cue-induced craving by addiction related materials is commonly employed in addiction research; however, no existing standardized picture database based on the expectation model of craving has been developed. We prepared and validated a Pictures Library of Smoking Cravings (PLSC) in this study. Methods: We captured pictures 366 smoking and 406 control pictures (matched in content). We selected 109 smoking pictures and 115 control pictures and asked participants to provide ratings of craving, familiarity, valence, and arousal induced in them. Participants were divided into three groups: non-smokers (n = 211), light smokers (n = 504), and heavy smokers (n = 101). Results: The results showed that smoking pictures evoked a greater craving, familiarity, and arousal than control pictures in smokers (ps < 0.01). In addition, craving caused by smoking pictures was positively associated with the Fagerström test for nicotine dependence score in dependent smokers. Conclusions: Overall, the contemporary results showed that PLSC is effective and can be used in smoking-related studies.

12.
Mol Psychiatry ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561611

RESUMO

Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a "two-hit" stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.

13.
Mol Psychiatry ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385601

RESUMO

Previous studies both in laboratory animals and humans have reported that abstinence induces incubation of cue-induced drug craving for nicotine, alcohol, cocaine, and methamphetamine. However, current experimental procedures utilized to study incubation of methamphetamine craving do not incorporate the temporal dynamics of neuropsychological measures and electrophysiological activities associated with this incubation process. This study utilized the high-density electroencephalogram (EEG) signals as a rapid, inexpensive, and noninvasive measure of cue-induced craving potential. A total of 156 male individuals with methamphetamine use disorder (MUD) enrolled in this multisite, cross-sectional study. Structured clinical interview data, self-report questionnaires (cued craving, quality of sleep, impulsivity, anxiety, and depression) and resting-state, eye-closed 128 high-density channel EEG signals were collected at 5 abstinence duration time points (<1, 1-3, 3-6, 6-12, and 12-24 months) to track the neuropsychological and neurophysiological signatures. Cue-induced craving was higher after 1-3 months than after the other time points. This incubation effect was also observed for sleep quality but not for anxiety, depression, and impulsivity symptoms, along with exhibited decreased power spectrum for theta (5.5-8 Hz) and alpha (8-13 Hz), and increased in beta (16.5-26.5 Hz) frequency band. Source reconstructed resting-state EEG analysis showed increased synchronization of medial prefrontal cortex (MPFC) for the beta frequency band in 1-3 months abstinent MUD group, and associated with the incubation of craving. Remarkably, the robust incubation-related abnormalities may be driven by beta-band source space connectivity between MPFC and bilateral orbital gyrus (ORB). Our findings suggest the enhancement of beta activity in the incubation period most likely originates from a dysfunction involving frontal brain regions. This neurophysiological signature of incubation of craving can be used to identify individuals who might be most susceptible to relapse, providing a potential insight into future therapeutic interventions for MUD via neuromodulation of beta activity.

14.
Psychopharmacology (Berl) ; 238(9): 2515-2524, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34291307

RESUMO

RATIONALE: The use of methcathinone (MCAT), a psychostimulant drug that can lead to long-term health risks and executive dysfunction, increased to an alarming rate in recent years. Impairments in low-level executive function have been reported in substance use disorder. However, little empirical evidence is available regarding high-level executive function (e.g., problem solving), which may act as a risk factor for relapse. OBJECTIVES: The present study aimed to investigate whether the problem-solving ability was altered in abstinent individuals with methcathinone use disorder (MCUD). Here, we tested fifty male MCUD individuals (short-term MCUD group: twenty-nine patients with MCAT use less than 3 years, long-term MCUD group: twenty-one patients with MCAT use longer than 3 years, which were split by medium years of drug use) and twenty-four well-matched healthy controls (HC) in the Tower of Hanoi task (TOH) to assess the impact of task difficulty on drug-related changes in problem-solving performance. We used several measures to characterize problem-solving performance: the number of mistakes made, the completion time of the task, and the thinking time before the first move. RESULTS: In the low task difficulty condition, the MCUD group and HC group showed similar levels of mistakes and completion time, while in the high task difficulty condition, the MCUD group reported more mistakes (the mean number of mistakes in each trial: 1.41 ± 1.15 vs 0.79 ± 0.76, P = 0.019, Cohen's d = 0.635) and longer completion time in the task (the mean completion time in each trial: 45.83 ± 20.51 s vs 33.40 ± 15.10 s, P = 0.010, Cohen's d = 0.690) than the HC group. The thinking time before the first move did not differ significantly between groups (P = 0.257). We further found that the long-term (more than 3 years) MCUD group made more mistakes than the short-term MCUD group and HC group, mainly in the highly difficult subtasks. The longer time than HCs was reported in the long-term MCUD group among high task difficulty of subtasks. In addition, there was a positive correlation between years of MCAT use and the number of mistakes made in high task difficulty TOH task (r = 0.326, P = 0.021). CONCLUSIONS: Chronic methcathinone use was associated with deficits in problem-solving performance, which depended on the degree of task difficulty. The impairment was more evident in the long-term (> 3 years) MCAT group.


Assuntos
Disfunção Cognitiva , Resolução de Problemas , Função Executiva , Humanos , Masculino , Testes Neuropsicológicos , Propiofenonas
15.
Psychophysiology ; 58(10): e13896, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34231226

RESUMO

It is crucial for humans to coordinate between behavioural tendencies that can lead to reward but are in conflict with each other. This response conflict can be measured in a reward-modulated Simon task, in which a discriminative response to the identity of a lateral target is required and the target is associated with either high- or low-reward. Critically, the lateral target is presented either congruent or incongruent with the location of the responding hand. It has been shown that relative to the low-reward target, the high-reward target induced a larger response conflict when the target was incongruent with the position of the task-required, reward-obtaining hand. Here we investigated how this response conflict is resolved by acquiring 24 healthy participants' electromyography (EMG) signals from both the task-required responding hand (i.e., goal-directed effector) and the alternative hand (i.e., inappropriate effector). During the coping with the response conflict, motor inhibition (indexed by reduction in EMG signals between conditions) was observed not only at the inappropriate effector but also at the goal-directed effector. Individuals who showed stronger inhibition on the inappropriate effector suffered less from the inhibition on the goal-directed effector, and had more efficient implementation of the reward-obtaining response. Our findings suggest a global motor inhibition that may function to increase the signal-noise ratio in the motor system so as to implement reward-guided behavior.

16.
Elife ; 102021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34313218

RESUMO

Sleep is essential in maintaining physiological homeostasis in the brain. While the underlying mechanism is not fully understood, a 'synaptic homeostasis' theory has been proposed that synapses continue to strengthen during awake and undergo downscaling during sleep. This theory predicts that brain excitability increases with sleepiness. Here, we collected transcranial magnetic stimulation measurements in 38 subjects in a 34 hr program and decoded the relationship between cortical excitability and self-report sleepiness using advanced statistical methods. By utilizing a combination of partial least squares regression and mixed-effect models, we identified a robust pattern of excitability changes, which can quantitatively predict the degree of sleepiness. Moreover, we found that synaptic strengthen occurred in both excitatory and inhibitory connections after sleep deprivation. In sum, our study provides supportive evidence for the synaptic homeostasis theory in human sleep and clarifies the process of synaptic strength modulation during sleepiness.


Assuntos
Encéfalo/fisiologia , Excitabilidade Cortical/fisiologia , Eletroencefalografia , Sono/fisiologia , Estimulação Magnética Transcraniana , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Privação do Sono , Sonolência , Adulto Jovem
17.
Front Cell Neurosci ; 15: 654521, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093130

RESUMO

Region-specific plasticity in the striatal circuit plays an important role in the development and long-term maintenance of skills and sequential movement procedures. Studies investigating the molecular substrates that contribute to the plasticity changes during motor skill processes have documented a transition in expression from the dorsomedial striatum (DMS) to the dorsolateral striatum (DLS); however, few studies have explored the expression pattern of molecular substrates in the dorsal striatum during progression of instrumental learning. To address this issue, the activity-regulated cytoskeleton-associated protein (Arc) expressions in the subregional dorsal striatum were analyzed during the early and late learning phases of the 10-day sucrose self-administration process. We found that Arc protein is primarily detected in the DMS only in the initial learning stage; however, it is expressed in the DLS during both early and late learning stages. Moreover, Arc expression in the DMS correlated with the number of rewards received later in the training. These data indicated that the Arc expression in subregions of the dorsal striatum shows region-specific transfer and that Arc expression in the DMS contributes to obtaining reward in later learning stage during the process of instrumental learning.

18.
Mol Neurobiol ; 58(9): 4666-4681, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34164760

RESUMO

Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes.

19.
20.
Psychoneuroendocrinology ; 128: 105211, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33812228

RESUMO

Increased expression of the Nod-like receptor pyrin containing 3 (NLRP3) inflammasome and proinflammatory cytokines is associated with depressive behaviors. This study aimed to explore potential differences in neuroinflammation associated with stress resilience, as well as associated changes in autophagy, in a mouse model of chronic unpredictable mild stress (CUMS). Animals were classified as CUMS resilient or CUMS susceptible based on performance on behavioral tests following the CUMS protocol. Then the expression levels of NLRP3 inflammasome-related proteins, interleukin-1 beta (IL-1ß), and Beclin 1 in stress-related brain regions (e.g., prefrontal cortex and hippocampus) were determined. Results showed that stress exposure triggered significant NLRP3 inflammasome increase in CUMS susceptible mice but not in CUMS resilient mice. These changes were accompanied by altered IL-1ß and Beclin 1 expression levels. These findings indicate that stress resilience is associated with reduced pro-inflammatory signaling and autophagy activation, and suggest that therapeutically targeting these pathways might promote stress resilience.

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