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1.
Front Psychol ; 15: 1384053, 2024.
Article in English | MEDLINE | ID: mdl-38863669

ABSTRACT

Background: Depression is one of the primary global public health issues, and there has been a dramatic increase in depression levels among young people over the past decade. The neuroplasticity theory of depression postulates that a malfunction in neural plasticity, which is responsible for learning, memory, and adaptive behavior, is the primary source of the disorder's clinical manifestations. Nevertheless, the impact of depression symptoms on associative learning remains underexplored. Methods: We used the differential fear conditioning paradigm to investigate the effects of depressive symptoms on fear acquisition and extinction learning. Skin conductance response (SCR) is an objective evaluation indicator, and ratings of nervousness, likeability, and unconditioned stimuli (US) expectancy are subjective evaluation indicators. In addition, we used associability generated by a computational reinforcement learning model to characterize the skin conductance response. Results: The findings indicate that individuals with depressive symptoms exhibited significant impairment in fear acquisition learning compared to those without depressive symptoms based on the results of the skin conductance response. Moreover, in the discrimination fear learning task, the skin conductance response was positively correlated with associability, as estimated by the hybrid model in the group without depressive symptoms. Additionally, the likeability rating scores improved post-extinction learning in the group without depressive symptoms, and no such increase was observed in the group with depressive symptoms. Conclusion: The study highlights that individuals with pronounced depressive symptoms exhibit impaired fear acquisition and extinction learning, suggesting a possible deficit in associative learning. Employing the hybrid model to analyze the learning process offers a deeper insight into the associative learning processes of humans, thus allowing for improved comprehension and treatment of these mental health problems.

2.
Transl Psychiatry ; 14(1): 190, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38622130

ABSTRACT

Drug addiction represents a multifaceted and recurrent brain disorder that possesses the capability to create persistent and ineradicable pathological memory. Deep brain stimulation (DBS) has shown a therapeutic potential for neuropsychological disorders, while the precise stimulation targets and therapeutic parameters for addiction remain deficient. Among the crucial brain regions implicated in drug addiction, the dorsal raphe nucleus (DRN) has been found to exert an essential role in the manifestation of addiction memory. Thus, we investigated the effects of DRN DBS in the treatment of addiction and whether it might produce side effects by a series of behavioral assessments, including methamphetamine priming-induced reinstatement of drug seeking behaviors, food-induced conditioned place preference (CPP), open field test and elevated plus-maze test, and examined brain activity and connectivity after DBS of DRN. We found that high-frequency DBS of the DRN significantly lowered the CPP scores and the number of active-nosepokes in the methamphetamine-primed CPP test and the self-administration model. Moreover, both high-frequency and sham DBS group rats were able to establish significant food-induced place preference, and no significant difference was observed in the open field test and in the elevated plus-maze test between the two groups. Immunofluorescence staining and functional magnetic resonance imaging revealed that high-frequency DBS of the DRN could alter the activity and functional connectivity of brain regions related to addiction. These results indicate that high-frequency DBS of the DRN effectively inhibits methamphetamine priming-induced relapse and seeking behaviors in rats and provides a new target for the treatment of drug addiction.


Subject(s)
Deep Brain Stimulation , Methamphetamine , Substance-Related Disorders , Rats , Animals , Dorsal Raphe Nucleus , Deep Brain Stimulation/methods , Drug-Seeking Behavior/physiology , Substance-Related Disorders/therapy
3.
J Neurosci Res ; 102(3): e25315, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38439584

ABSTRACT

Post-traumatic stress disorder (PTSD), a psychological condition triggered by exposure to extreme or chronic stressful events, exhibits a sex bias in incidence and clinical manifestations. Emerging research implicates the gut microbiome in the pathogenesis of PTSD and its roles in stress susceptibility. However, it is unclear whether differential gut microbiota contribute to PTSD susceptibility in male and female rats. Here, we utilized the single prolonged stress animal model and employed unsupervised machine learning to classify stressed animals into stress-susceptible subgroups and stress-resilient subgroups. Subsequently, using 16S V3-V4 rDNA sequencing, we investigated the differential gut microbiota alterations between susceptible and resilient individuals in male and female rats. Our findings revealed distinct changes in gut microbiota composition between the sexes at different taxonomic levels. Furthermore, the abundance of Parabacteroides was lower in rats that underwent SPS modeling compared to the control group. In addition, the abundance of Tenericutes in the stress-susceptible subgroup was higher than that in the control group and stress-resilient subgroup, suggesting that Tenericutes may be able to characterize stress susceptibility. What is particularly interesting here is that Cyanobacteria may be particularly associated with anti-anxiety effects in male rats. This study underscores sex-specific variations in gut microbiota composition in response to stress and sex differences should be taken into account when using macrobiotics for neuropsychiatric treatment, highlighting potential targets for PTSD therapeutic interventions.


Subject(s)
Gastrointestinal Microbiome , Resilience, Psychological , Female , Male , Animals , Rats , Sex Characteristics , Bacteroidetes , Models, Animal
4.
Mol Biol Rep ; 51(1): 415, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38472517

ABSTRACT

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.


Subject(s)
Autism Spectrum Disorder , Depressive Disorder, Major , Humans , Female , Male , Autism Spectrum Disorder/genetics , Sex Characteristics , Depressive Disorder, Major/metabolism , Estrogens/metabolism , Synapses/metabolism , Emotions
5.
Int J Mol Sci ; 25(6)2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38542386

ABSTRACT

The extracellular matrix (ECM) within the brain possesses a distinctive composition and functionality, influencing a spectrum of physiological and pathological states. Among its constituents, perineuronal nets (PNNs) are unique ECM structures that wrap around the cell body of many neurons and extend along their dendrites within the central nervous system (CNS). PNNs are pivotal regulators of plasticity in CNS, both during development and adulthood stages. Characterized by their condensed glycosaminoglycan-rich structures and heterogeneous molecular composition, PNNs not only offer neuroprotection but also participate in signal transduction, orchestrating neuronal activity and plasticity. Interfering with the PNNs in adult animals induces the reactivation of critical period plasticity, permitting modifications in neuronal connections and promoting the recovery of neuroplasticity following spinal cord damage. Interestingly, in the adult brain, PNN expression is dynamic, potentially modulating plasticity-associated states. Given their multifaceted roles, PNNs have emerged as regulators in the domains of learning, memory, addiction behaviors, and other neuropsychiatric disorders. In this review, we aimed to address how PNNs contribute to the memory processes in physiological and pathological conditions.


Subject(s)
Brain , Central Nervous System , Animals , Central Nervous System/physiology , Brain/metabolism , Neurons/metabolism , Memory/physiology , Extracellular Matrix/metabolism , Neuronal Plasticity/physiology
6.
Sci Adv ; 10(12): eadk9484, 2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38507477

ABSTRACT

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin-brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.


Subject(s)
Electroencephalography , Epilepsy , Animals , Humans , Seizures/etiology , Sirolimus , TOR Serine-Threonine Kinases , Mammals
7.
Pharmaceutics ; 16(1)2024 Jan 08.
Article in English | MEDLINE | ID: mdl-38258095

ABSTRACT

Addiction, particularly in relation to psychostimulants and opioids, persists as a global health crisis with profound social and economic ramifications. Traditional interventions, including medications and behavioral therapies, often encounter limited success due to the chronic and relapsing nature of addictive disorders. Consequently, there is significant interest in the development of innovative therapeutics to counteract the effects of abused substances. In recent years, vaccines have emerged as a novel and promising strategy to tackle addiction. Anti-drug vaccines are designed to stimulate the immune system to produce antibodies that bind to addictive compounds, such as nicotine, cocaine, morphine, methamphetamine, and heroin. These antibodies effectively neutralize the target molecules, preventing them from reaching the brain and eliciting their rewarding effects. By obstructing the rewarding sensations associated with substance use, vaccines aim to reduce cravings and the motivation to engage in drug use. Although anti-drug vaccines hold significant potential, challenges remain in their development and implementation. The reversibility of vaccination and the potential for combining vaccines with other addiction treatments offer promise for improving addiction outcomes. This review provides an overview of anti-drug vaccines, their mechanisms of action, and their potential impact on treatment for substance use disorders. Furthermore, this review summarizes recent advancements in vaccine development for each specific drug, offering insights for the development of more effective and personalized treatments capable of addressing the distinct challenges posed by various abused substances.

8.
Mol Psychiatry ; 29(3): 730-741, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38221548

ABSTRACT

Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.


Subject(s)
Basolateral Nuclear Complex , Cocaine , Memory Consolidation , Neurons , Prefrontal Cortex , Animals , Memory Consolidation/drug effects , Memory Consolidation/physiology , Cocaine/pharmacology , Male , Rats , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiology , Basolateral Nuclear Complex/drug effects , Basolateral Nuclear Complex/metabolism , Neurons/metabolism , Neurons/drug effects , Memory, Long-Term/drug effects , Memory, Long-Term/physiology , Cues , Rats, Sprague-Dawley , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Self Administration , Dendritic Spines/drug effects , Dendritic Spines/metabolism , Dendritic Spines/physiology , Cocaine-Related Disorders/metabolism , Cocaine-Related Disorders/physiopathology , Memory/drug effects , Memory/physiology
9.
Heliyon ; 10(1): e23748, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38205315

ABSTRACT

Objective: Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that can develop after experiencing or witnessing a traumatic event. Exposure therapy is a common treatment for PTSD, but it has varying levels of efficacy depending on sex. In this study, we aimed to compare the sexual dimorphism in brain activation during the extinction of fear conditioning in male and female rats by detecting the c-fos levels in the whole brain. Methods: Thirty-two rats (Male: n = 16; Female: n = 16) were randomly separated into the extinction group as well as the non-extinction group, and fear conditioning was followed by extinction and non-extinction, respectively. Subsequently, brain sections from the sacrificed animal were performed immunofluorescence and the collected data were analyzed by repeated two-way ANOVAs as well as Pearson Correlation Coefficient. Results: Our findings showed that most brain areas activated during extinction were similar in both male and female rats, except for the reuniens thalamic nucleus and ventral hippocampi. Furthermore, we found differences in the correlation between c-fos activation levels and freezing behavior during extinction between male and female rats. Specifically, in male rats, c-fos activation in the anterior cingulate cortex was negatively correlated with the freezing level, while c-fos activation in the retrosplenial granular cortex was positively correlated with the freezing level; but in female rats did not exhibit any correlation between c-fos activation and freezing level. Finally, the functional connectivity analysis revealed differences in the neural networks involved in extinction learning between male and female rats. In male rats, the infralimbic cortex and insular cortex, anterior cingulate cortex and retrosplenial granular cortex, and dorsal dentate gyrus and dCA3 were strongly correlated after extinction. In female rats, prelimbic cortex and basolateral amygdala, insular cortex and dCA3, and anterior cingulate cortex and dCA1 were significantly correlated. Conclusion: These results suggest divergent neural networks involved in extinction learning in male and female rats and provide a clue for improving the clinical treatment of exposure therapy based on the sexual difference.

10.
Front Neurosci ; 17: 1281401, 2023.
Article in English | MEDLINE | ID: mdl-38116070

ABSTRACT

Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to traumatic events or fear. PTSD is characterized by re-experiencing, avoidance behavior, hyperarousal, negative emotions, insomnia, personality changes, and memory problems following exposure to severe trauma. However, the biological mechanisms and symptomatology underlying this disorder are still largely unknown or poorly understood. Considerable evidence shows that PTSD results from a dysfunction in highly conserved brain systems involved in regulating stress, anxiety, fear, and reward circuitry. This review provides a contemporary update about PTSD, including new data from the clinical and preclinical literature on stress, PTSD, and fear memory consolidation and extinction processes. First, we present an overview of well-established laboratory models of PTSD and discuss their clinical translational value for finding various treatments for PTSD. We then highlight the research progress on the neural circuits of fear and extinction-related behavior, including the prefrontal cortex, hippocampus, and amygdala. We further describe different molecular mechanisms, including GABAergic, glutamatergic, cholinergic, and neurotropic signaling, responsible for the structural and functional changes during fear acquisition and fear extinction processes in PTSD.

11.
Front Endocrinol (Lausanne) ; 14: 1178396, 2023.
Article in English | MEDLINE | ID: mdl-37908752

ABSTRACT

Sleep disorders affect mental and physical health. Infertile women undergoing assisted reproductive technology (ART) treatment are prone to sleep disorders. Sleep condition, its influencing factors, and the association between sleep condition and ART treatment outcomes before treatment have not been explored within a population with a large sample size. Therefore, we investigated the sleep characteristics of 1002 Chinese infertile women before ovulation induction and investigated the influencing factors (negative and positive psychological factors, demographics, and fertility characteristics). We also examined whether sleep conditions before treatment predicted reproductive outcomes. We found that 24.1% of participants reported poor sleep quality. Women with primary infertility reported poorer sleep than women with secondary infertility. Negative psychological factors, including depression, anxiety, and perceived stress were associated with poor sleep, whereas positive affect was linked with good sleep. Adverse sleep characteristics, including poor subjective sleep quality, sleep disturbances, and poor sleep efficiency, decreased the quantity and quality of oocytes retrieved, fertilization rates, and clinical pregnancy rates. This study indicates that before ART treatment, a large number of females with infertility suffer from sleep problems, which are affected by psychological factors and infertility type, and unhealthy sleep characteristics may impair treatment outcomes. Our findings highlight the importance of screening and treatment for sleep disorders before the enrollment of ART treatment in infertile women.


Subject(s)
Infertility, Female , Sleep Wake Disorders , Pregnancy , Humans , Female , Infertility, Female/therapy , Infertility, Female/etiology , Prospective Studies , East Asian People , Reproductive Techniques, Assisted/adverse effects , Sleep , Sleep Wake Disorders/complications , Sleep Wake Disorders/epidemiology , Sleep Wake Disorders/therapy
12.
Funct Integr Genomics ; 23(4): 309, 2023 Sep 22.
Article in English | MEDLINE | ID: mdl-37735249

ABSTRACT

Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders.


Subject(s)
Cysteine , Transcriptome , Humans , Animals , Female , Rats , Estrogens , Estrus , Hippocampus
13.
Front Psychiatry ; 14: 1247714, 2023.
Article in English | MEDLINE | ID: mdl-37692297

ABSTRACT

The experience of traumatic stress can engender lasting memories associated with the trauma, often resulting in post-traumatic stress disorder (PTSD). However, only a minority of individuals develop PTSD symptoms upon exposure. The neurobiological mechanisms underlying the pathology of PTSD are poorly understood. Utilizing a rat model of PTSD, the Single Prolonged Stress (SPS) paradigm, we were able to differentiate between resilient and susceptible individuals. Fourteen days after the SPS exposure, we conducted the behavioral analyses using Elevated Plus Maze (EPM) and Open Field (OF) tests to identify male rats as trauma resilient or susceptible. We focused on the microRNA (miRNA) profiles of the infralimbic (IL) and prelimbic (PL) cortical regions, known to be crucial in regulating the stress response. Our investigation of stressed rats exposed to the SPS procedure yielded divergent response, and differential expression microRNAs (DEmiRs) analysis indicated significant differences in the IL and PL transcriptional response. In the IL cortex, the GO analysis revealed enriched GO terms in the resilient versus control comparison, specifically related to mitogen-activated protein kinase and MAP kinase signaling pathways for their molecular functions as well as cytosol and nucleoplasm for the biological process. In the susceptible versus resilient comparison, the changes in molecular functions were only manifested in the functions of regulation of transcription involved in the G1/S transition of the mitotic cell cycle and skeletal muscle satellite cell activation. However, no enriched GO terms were found in the susceptible versus control comparison. In the PL cortex, results indicated that the DEmiRs were enriched exclusively in the cellular component level of the endoplasmic reticulum lumen in the comparison between resilient and control rats. Overall, our study utilized an animal model of PTSD to investigate the potential correlation between stress-induced behavioral dysfunction and variations in miRNA expression. The aforementioned discoveries have the potential to pave the way for novel therapeutic approaches for PTSD, which could involve the targeted regulation of transcriptome expression.

14.
Front Neurosci ; 17: 1200701, 2023.
Article in English | MEDLINE | ID: mdl-37496741

ABSTRACT

Introduction: Emotional disorders are essential manifestations of many neurological and psychiatric diseases. Nowadays, researchers try to explore bi-directional brain-computer interface techniques to help the patients. However, the related functional brain areas and biological markers are still unclear, and the dynamic connection mechanism is also unknown. Methods: To find effective regions related to different emotion recognition and intervention, our research focuses on finding emotional EEG brain networks using spiking neural network algorithm with binary coding. We collected EEG data while human participants watched emotional videos (fear, sadness, happiness, and neutrality), and analyzed the dynamic connections between the electrodes and the biological rhythms of different emotions. Results: The analysis has shown that the local high-activation brain network of fear and sadness is mainly in the parietal lobe area. The local high-level brain network of happiness is in the prefrontal-temporal lobe-central area. Furthermore, the α frequency band could effectively represent negative emotions, while the α frequency band could be used as a biological marker of happiness. The decoding accuracy of the three emotions reached 86.36%, 95.18%, and 89.09%, respectively, fully reflecting the excellent emotional decoding performance of the spiking neural network with self- backpropagation. Discussion: The introduction of the self-backpropagation mechanism effectively improves the performance of the spiking neural network model. Different emotions exhibit distinct EEG networks and neuro-oscillatory-based biological markers. These emotional brain networks and biological markers may provide important hints for brain-computer interface technique exploration to help related brain disease recovery.

15.
Mol Psychiatry ; 28(4): 1415-1429, 2023 04.
Article in English | MEDLINE | ID: mdl-36646901

ABSTRACT

In 1986, Gawin and Kleber reported a progressive increase in cue-induced drug craving in individuals with cocaine use disorders during prolonged abstinence. After years of controversy, as of 2001, this phenomenon was confirmed in rodent studies using self-administration model, and defined as the incubation of drug craving. The intensification of cue-induced drug craving after withdrawal exposes abstinent individuals to a high risk of relapse, which urged us to develop effective interventions to prevent incubated craving. Substantial achievements have been made in deciphering the neural mechanisms, with potential implications for reducing drug craving and preventing the relapse. The present review discusses promising drug targets that have been well investigated in animal studies, including some neurotransmitters, neuropeptides, neurotrophic factors, and epigenetic markers. We also discuss translational exploitation and challenges in the field of the incubation of drug craving, providing insights into future investigations and highlighting the potential of pharmacological interventions, environment-based interventions, and neuromodulation techniques.


Subject(s)
Cocaine , Substance-Related Disorders , Animals , Craving , Pharmaceutical Preparations , Substance-Related Disorders/drug therapy , Self Administration , Recurrence , Cues , Cocaine/pharmacology , Drug-Seeking Behavior
16.
Sci Adv ; 8(51): eabq5745, 2022 12 23.
Article in English | MEDLINE | ID: mdl-36563158

ABSTRACT

Compulsive drug use, a cardinal symptom of drug addiction, is characterized by persistent substance use despite adverse consequences. However, little is known about the neural circuit mechanisms behind this behavior. Using a footshock-punished cocaine self-administration procedure, we found individual variability of rats in the process of drug addiction, and rats with compulsive cocaine use presented increased neural activity of the anterior insular cortex (aIC) compared with noncompulsive rats. Chemogenetic manipulating activity of aIC neurons, especially aIC glutamatergic neurons, bidirectionally regulated compulsive cocaine intake. Furthermore, the aIC received inputs from the orbitofrontal cortex (OFC), and the OFC-aIC circuit was enhanced in rats with compulsive cocaine use. Suppression of the OFC-aIC circuit switched rats from punishment resistance to sensitivity, while potentiation of this circuit increased compulsive cocaine use. In conclusion, our results found that aIC glutamatergic neurons and the OFC-aIC circuit gated the shift from controlled to compulsive cocaine use, which could serve as potential therapeutic targets for drug addiction.


Subject(s)
Cocaine-Related Disorders , Cocaine , Rats , Animals , Insular Cortex , Prefrontal Cortex , Cocaine/pharmacology , Compulsive Behavior
17.
Nature ; 610(7932): 562-568, 2022 10.
Article in English | MEDLINE | ID: mdl-36261549

ABSTRACT

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1-5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.


Subject(s)
Bacteria , Intestines , Nicotine , Non-alcoholic Fatty Liver Disease , Tobacco Smoking , Animals , Humans , Mice , Bacteria/drug effects , Bacteria/metabolism , Ceramides/biosynthesis , Nicotine/adverse effects , Nicotine/metabolism , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/microbiology , Sphingomyelin Phosphodiesterase/metabolism , Tobacco Smoking/adverse effects , Tobacco Smoking/metabolism , Intestines/drug effects , Intestines/microbiology , AMP-Activated Protein Kinases/metabolism , Disease Progression
18.
EBioMedicine ; 85: 104283, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36182773

ABSTRACT

BACKGROUND: Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP. METHODS: In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate. FINDINGS: Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01). INTERPRETATION: The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse. FUNDING: National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800).


Subject(s)
Opioid-Related Disorders , Substance Withdrawal Syndrome , Humans , Male , Animals , Rats , Methadone/pharmacology , Methadone/therapeutic use , Heroin/adverse effects , Narcotics/adverse effects , Substance Withdrawal Syndrome/drug therapy , Substance Withdrawal Syndrome/psychology , Substance Withdrawal Syndrome/rehabilitation , Neoplasm Recurrence, Local/drug therapy , Opioid-Related Disorders/drug therapy
19.
Biol Psychiatry ; 92(10): 800-814, 2022 11 15.
Article in English | MEDLINE | ID: mdl-36008159

ABSTRACT

BACKGROUND: Impairment of synaptic plasticity is closely correlated with a range of pathological conditions, such as cognitive deficits. However, how synaptic efficacy is regulated remains incompletely understood. Here, we report that the epigenetic factor JADE2 was indispensable for the maintenance of hippocampal synaptic plasticity and cognitive functions in mice. METHODS: We used the Morris water maze and the fear conditioning test to examine learning-related behaviors. In addition, Western blotting, viral-mediated JADE2 manipulations, RNA sequencing, and electrophysiological recordings were used to address our questions. RESULTS: JADE2 expression is increased upon enhanced neuronal activity in vitro and in vivo. Knockdown or genetic deletion of Jade2 in hippocampal CA1 results in impaired structural and functional synaptic plasticity, leading to memory impairment, whereas overexpression of JADE2 in CA1 neurons facilitates hippocampal-dependent learning and memory. Mechanistically, our data show that JADE2 modulates synaptic functions mainly by transcriptional activation of cytoskeletal regulator Rac1, and this activity is dependent on its interaction with histone acetyltransferase HBO1. Finally, we demonstrate that restoring RAC1 expression in Jade2 knockout mice could rescue the deficits in synaptic plasticity and learning-related behaviors. CONCLUSIONS: Our findings reveal that JADE2 plays a critical role in regulating synaptic plasticity and memory formation, suggesting that activity-dependent epigenetic regulation is an important molecular mechanism in controlling synaptic plasticity.


Subject(s)
Epigenesis, Genetic , Neuronal Plasticity , Mice , Animals , Neuronal Plasticity/physiology , Hippocampus/metabolism , Cognition/physiology , Mice, Knockout , Histone Acetyltransferases
20.
Mol Psychiatry ; 27(10): 4009-4022, 2022 10.
Article in English | MEDLINE | ID: mdl-35732696

ABSTRACT

Methamphetamine (METH), a widely abused stimulant drug, induces psychosis in approximately half of abusers; this effect is becoming a major concern for society. Although the Notch1 signalling pathway has been shown to play a part in the pathogenesis of some psychiatric disorders, its role in METH-induced psychosis (MIP) is still unknown. Here, the METH-induced locomotor sensitization model in rodents is considered to represent the underlying neurochemical changes driving psychoses. We found that the Notch1 signalling was downregulated in the medial prefrontal cortex (mPFC) in sensitized mice. Direct genetic and pharmacological manipulations of Notch1 signalling bidirectionally altered METH-induced locomotor sensitization and other MIP-related behaviours through governing neuronal activity in the mPFC. Moreover, Notch1 signalling negatively regulated GABAB1 receptor expression in the mPFC of METH-sensitized mice through Hes1, a transcriptional repressor in Notch1 signalling. Further, we show that Hes1 can directly bind to the GABAB1 receptor promoter. Notably, pharmacological regulation of the GABAB receptor in the mPFC reversed the changes in METH-induced locomotor sensitization caused by the dysfunction of Notch1 signalling. Together, our findings uncover a previously unrecognised Notch1-Hes1-GABAB1 receptor-dependent mechanism involved in regulating mPFC neuronal activity and behavioural phenotypes in MIP. Our work provides mechanistic insight into the aetiology and pathophysiology of MIP.


Subject(s)
Central Nervous System Stimulants , Methamphetamine , Psychotic Disorders , Receptors, GABA-B , Receptors, Notch , Transcription Factor HES-1 , Animals , Mice , Central Nervous System Stimulants/pharmacology , Methamphetamine/pharmacology , Motor Activity , Prefrontal Cortex/metabolism , Psychotic Disorders/metabolism , Receptors, GABA-B/genetics , Receptors, GABA-B/metabolism , Transcription Factor HES-1/genetics , Transcription Factor HES-1/metabolism , Receptors, Notch/genetics , Receptors, Notch/metabolism
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