Brain-Derived Neurotrophic Factor Delivered Intranasally Relieves Post-Traumatic Stress Disorder Symptoms Caused by a Single Prolonged Stress in Rats.

INTRODUCTION: In our previous study, we successfully constructed the recombinant brain-derived neurotrophic factor (BDNF)-adeno-associated virus (AAV) modified by the influenza virus hemagglutinin-2 (HA2) and trans-transcriptional activator (TAT). BDNF-HA2TAT/AAV has been confirmed to have antidepression effects. BDNF-HA2TAT/AAV seems a promising therapy for post-traumatic stress disorder (PTSD) as the BDNF plays an important role in the function of the nervous system. However, the effects of BDNF-HA2TAT/AAV on PTSD caused by the single prolonged stress (SPS) model are unknown. METHODS: After the SPS model was established, BDNF-HA2TAT/AAV was administered (1 × 1011 vg per rat) through inhalation in the SPS + BDNF group for 2 weeks. Next, the rats underwent behavioral tests including an open-field test (OFT), elevated plus maze (EPM), and a forced swimming test (FST). Sera and hippocampi were obtained from the rats, and an enzyme-linked immune sorbent assay was performed to determine corticosterone concentration. Western blotting was conducted to determine BDNF, tyrosine kinase receptor B (TrkB), cAMP-response element-binding protein, and protein kinase B levels. RESULTS: BDNF-HA2TAT/AAV released anxiety-like and depression-like behaviors in OFT, EPM, and FST. BDNF-HA2TAT/AAV also results in high plasma concentrations of corticosterone, BDNF, and TrkB in the hippocampus. CONCLUSIONS: SPS is an excellent animal model to assess PTSD. BDNF-HA2TAT/AAV therapeutically effects PTSD caused by SPS, with changes seen in plasma corticosterone and BDNF-TrkB pathways within the hippocampus; therefore, BDNF-HA2TAT/AAV may be a promising treatment for patients with PTSD.

Electrical lesion of bilateral ventrolateral orbital cortex impairs fear- and space-related learning and affects subsequent choice behavior.

OBJECTIVES: Although many studies have indicated that orbitofrontal cortex plays an important role in the learning and retrieval of memory and subsequent decision-making, the role of ventrolateral orbital cortex (VLO) still remains unclear, especially related to fear and space. METHODS: Four separate cohorts of rats were used in this study. After sham surgery and electrical lesion of bilateral VLO, four cohorts received active avoidance test, passive avoidance test, Morris water maze and T maze separately. RESULTS: Firstly, data shown that electrolytic lesions of bilateral VLO of Sprague-Dawley rats shortened the latency of rats to escape to darkroom in passive avoidance test. Besides, the damage of VLO also resulted in decrease of the number of active avoidance of rats from the third day during 5 consecutive days' training in active avoidance test. What's more, the impairment of VLO significantly shortened the exploring time in the target quadrant of rats in Morris water maze. Furthermore, VLO-lesions group shown lower correct alternation percentage than sham group in T maze. CONCLUSIONS: These results indicated that not only in the learning and retrieval of fear-related memory, VLO also plays an important role in the learning and retrieval of spatial-related memory guided by visual cues.

Bibliometrics Analysis in English and Chinese Literature on Drowning in Forensic Medicine from 1991 to 2020.

OBJECTIVES: To explore the research hotspots and development trends of the field of forensic drowning from 1991 to 2020 by bibliometrics methods. METHODS: Based on Web of Science, CNKI database, Wanfang Data knowledge service platform, python 3.9.2, CiteSpace 5.8.R3, Gephi 0.9.2, etc. were used to analyze the publishing trends, countries/regions, institutions, authors and topics of the study on drowning. RESULTS: A total of 631 English literature were obtained, including 59 articles from Chinese authors, and 386 Chinese literature were obtained. The Chinese and English journals with the largest number of related literatures were Chinese Journal of Forensic Science (80 articles) and Forensic Science International (106 articles), respectively. Japan published the most articles in English, and China ranked third. Osaka City Univ (Japan, 28 articles) published the most English articles, and Guangzhou Forens Sci Inst (China, 22 articles) ranked second. Among Chinese literature, Guangzhou Forens Sci Inst (32 articles) published the most. The topic analysis of Chinese and English literature showed that diatom examination, virtual autopsy, postmortem biochemical examination, the nature of death, and postmortem submersion interval were the hot spots of current research, but English literature had more studies on new technologies and methods, while Chinese literature was more inclined to practice, application and experience summary. CONCLUSIONS: The number of literature in forensic medicine on drowning is relatively stable. The scope of international and domestic collaborations in this field is still limited. The automated examination of diatoms, the establishment of diatom DNA barcodes and virtual autopsy will be the most important research hotspots in the coming period and are expected to achieve breakthroughs in drowning diagnosis, drowning location inference, postmortem submersion interval estimation, etc.

Forensic Analysis of 9 Poisoning Death Cases Caused by Oral Administration of Diphenidol.

OBJECTIVES: To analyze the characteristics of diphenidol poisoning cases and to provide clues and technical means for the identification of such cases. METHODS: Biological samples of 9 deaths caused by diphenidol poisoning were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and the characteristics of these cases were analyzed retrospectively. RESULTS: Most of the deaths caused by diphenidol poisoning were young females. The dosage was between 60 and 300 tablets, and the mass concentration of diphenidol in the postmortem blood ranged from 0.87 to 99.00 µg/mL. There was no correlation between the dosage and the concentration of diphenidol in the blood. CONCLUSIONS: Diphenidol poisoning has the characteristics of high concealment and lethality. More attention should be paid to suicide cases, and diphenidol should be recommended as a routine detection item to avoid missing detection.

Electrolytic lesions of the bilateral ventrolateral orbital cortex not only directly reduce depression-like behavior but also decreased desperate behavior induced by chronic unpredicted mild stress in rats.

BACKGROUND: Previous studies have revealed that ventrolateral orbital cortex (VLO) may play an important role in the regulation of emotional behavior. However, it is not known what effect VLO damage will have on emotion regulation. RESULTS: Data showed that damage of VLO increased the anxiety-like behavior in open field test and elevated plus maze, and decreased the depressive behavior in forced swimming test and learned helplessness test. Besides, the impulsive aggressive behaviors were also increased while the attack latency decreased after VLO lesion. What's more, damage of VLO decreased depressive behaviors induced by chronic unpredicted mild stress in rats. CONCLUSIONS: These results suggest that the integrity of VLO plays an important role in emotional regulation, and the damage of VLO may inhibit the development of depression-like behavior.

Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice.

Accumulating evidence suggests that gut microbiota plays a role in the pathogenesis of schizophrenia via the microbiota-gut-brain axis. This study sought to investigate whether transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities. The results revealed that transplantation of fecal microbiota from schizophrenic patients into antibiotic-treated mice caused behavioral abnormalities such as psychomotor hyperactivity, impaired learning and memory in the recipient animals. These mice also showed elevation of the kynurenine-kynurenic acid pathway of tryptophan degradation in both periphery and brain, as well as increased basal extracellular dopamine in prefrontal cortex and 5-hydroxytryptamine in hippocampus, compared with their counterparts receiving feces from healthy controls. Furthermore, colonic luminal filtrates from the mice transplanted with patients' fecal microbiota increased both kynurenic acid synthesis and kynurenine aminotransferase II activity in cultured hepatocytes and forebrain cortical slices. Sixty species of donor-derived bacteria showed significant difference between the mice colonized with the patients' and the controls' fecal microbiota, highlighting 78 differentially enriched functional modules including tryptophan biosynthesis function. In conclusion, our study suggests that the abnormalities in the composition of gut microbiota contribute to the pathogenesis of schizophrenia partially through the manipulation of tryptophan-kynurenine metabolism.

The role of HINT1 protein in morphine addiction: An animal model-based study.

Drug addiction is a recurrent, chronic brain disease. The existing treatment methods have limitations, such as poor adherence and inability to completely avoid relapse. Histidine triad nucleotide-binding protein 1 (HINT1) is involved in many neuropsychiatric diseases, such as schizophrenia, pain, and drug dependence. Studies have confirmed that there is a genetic link between HINT1 and addictions such as nicotine and cocaine. However, there is no research on the role of HINT1 protein in morphine addiction at home and abroad. Thus, we designed this project by constructing different types of morphine addiction animal models, including conditioned place preference and behavioral sensitization. We comprehensively examined the participation of HINT1 protein in key brain regions associated with addiction, including prefrontal cortex, nucleus accumbens, corpus striatum, and hippocampus, in different stages of different models. In addition, we used HINT1 knockout mice to establish the above models and physical dependence model to investigate the effect of HINT1 protein deletion on morphine addiction-related behaviors. We found that HINT1 has varying degrees of involvement in different stages of multiple addictive animal models. The absence of HINT1 can attenuate morphine-mediated addictive behavior to a certain extent and can alleviate the withdrawal symptoms of morphine.

LION: a simple and rapid method to achieve CRISPR gene editing.

The RNA-guided CRISPR-Cas9 technology has paved the way for rapid and cost-effective gene editing. However, there is still a great need for effective methods for rapid generation and validation of CRISPR/Cas9 gRNAs. Previously, we have demonstrated that highly efficient generation of multiplexed CRISPR guide RNA (gRNA) expression array can be achieved with Golden Gate Assembly (GGA). Here, we present an optimized and rapid method for generation and validation in less than 1 day of CRISPR gene targeting vectors. The method (LION) is based on ligation of double-stranded gRNA oligos into CRISPR vectors with GGA followed by nucleic acid purification. Using a dual-fluorescent reporter vector (C-Check), T7E1 assay, TIDE assay and a traffic light reporter assay, we proved that the LION-based generation of CRISPR vectors are functionally active, and equivalent to CRISPR plasmids generated by traditional methods. We also tested the activity of LION CRISPR vectors in different human cell types. The LION method presented here advances the rapid functional validation and application of CRISPR system for gene editing and simplified the CRISPR gene-editing procedures.

Very Early Neurophysiological Study in Guillain-Barre Syndrome.

PURPOSE: The diagnosis of Guillain-Barre syndrome (GBS) in the very early stage may be challenging. Our aim was to report the neurophysiological abnormalities in GBS within 4 days of clinical onset. We expected that GBS will be diagnosed by the assistance of neurophysiological study in the very early stage. METHODS: We prospectively recruited patients with a diagnosis of GBS discharged from First Affiliated Hospital of Xi'an Jiaotong University and Xi Jing Hospital. Patients were classified into 3 groups according to the onset of symptoms to electromyography examination interval (OEI). The neurophysiological findings were carried out using standard procedures. All patients were examined by the same experienced neurophysiologist. RESULTS: There were not significant group differences in abnormal rate, distal motor latency (DML), motor nerve conduction velocity (MNCV), F response (FR), compound muscle action potential (CMAP), conduction block (CB), sensory nerve action potential (SNAP), and sensory nerve conduction velocity among OEI ≤4 days, 4< OEI ≤10 days, and OEI > 10 days groups. Motor nerves were more affected than sensory nerves in neurophysiological presentation in very early stage patients. The difference of motor nerves and sensory nerves was statistically significant in lower limbs, but was not in upper limbs. In motor nerve conduction studies, the abnormal rate of DML, MNCV, FR, CB was more common seen in ulnar and peroneal nerve than median and tibial nerve, the abnormal rate of CMAP was the same in ulnar, median, peroneal and tibial nerve. In sensory nerve conduction studies, the abnormal rate of ulnar nerve and median nerve was higher than the superficial peroneal nerve and sural nerve. The OEI was not correlated with the SNAP decrease rate of median (r = 0.10, p = 0.23) and ulnar (r = 0.26, p = 0.06) but was statistically correlated with sural SNAP decrease rate (r = 0.29, p = 0.04). The sural-sparing pattern phenomenon was the most commonly discovered phenomenon in very early stage patients (OEI ≤4 days), followed by patients with 4< OEI ≤10 days, ultimately found in patients with OEI > 10 days. CONCLUSIONS: We suggest performing neurophysiological examination as soon as possible for suspected GBS patients, particularly focusing on multi-spots inspection of ulnar and peroneal nerves, and paying close attention to sural-sparing patterns.

Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc.

HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator.

Although many studies have investigated the functions of histidine triad nucleotide-binding protein 1 (HINT1), its roles in neurobiological processes remain to be fully elucidated. As a member of the histidine triad (HIT) enzyme superfamily, HINT1 is distributed in almost every organ and has both enzymatic and nonenzymatic activity. Accumulating clinical and preclinical evidence suggests that HINT1 may play an important role as a neuroplastic mediator in neuropsychiatric diseases, such as schizophrenia, inherited peripheral neuropathies, mood disorders, and drug addiction. Though our knowledge of HINT1 is limited, it is believed that further research on the neuropathological functions of HINT1 would eventually benefit patients with neuropsychiatric and even psychosomatic diseases.

Emerging Roles of Histidine Triad Nucleotide Binding Protein 1 in Neuropsychiatric Diseases.

The histidine triad nucleotide binding protein1(HINT1),which belongs to the histidine triad(HIT) enzyme superfamily,exerts its enzymic activities as hydrolase or transferase. Its physiological functions are still unclear. HINT1 protein is expressed in various tissues and plays an important role in transcription and signal transduction. Earlier studies have identified HINT1 as a haplo-insufficient tumor suppressor. Other evidences indicate that HINT1 is involved in a wide variety of physiological processes,some of which are irrelevant with its basic enzymic activities. Investigations recently suggest that HINT1 is closely related to many peripheral and central nervous system diseases,and plays a vital role in some of neuropsychiatric diseases such as inherited peripheral neuropathies,schizophrenia,mood disorder,drug addiction,and Down's syndrome. In this review,the role of HINT1 in above-mentioned neuropsychiatric disorders was summarised,and the research findings of HINT1 in each of the above diseases were summarized and analyzed,in order to provide some guidance for further research on this protein.

Intranasal Delivery of Recombinant NT4-NAP/AAV Exerts Potential Antidepressant Effect.

The present study was designed to construct a recombinant adeno-associated virus (rAAV) which can express NAP in the brain and examine whether this virus can produce antidepressant effects on C57 BL/6 mice that had been subjected to open field test and forced swimming test, via nose-to-brain pathway. When the recombinant plasmid pGEM-T Easy/NT4-NAP was digested by EcoRI, 297 bp fragments can be obtained and NT4-NAP sequence was consistent with the designed sequence confirmed by DNA sequencing. When the recombinant plasmid pSSCMV/NT4-NAP was digested by EcoRI, 297 bp fragments is visible. Immunohistochemical staining of fibroblasts revealed that expression of NAP was detected in NT4-NAP/AAV group. Intranasal delivery of NT4-NAP/AAV significantly reduced immobility time when the FST was performed after 1 day from the last administration. The effects observed in the FST could not be attributed to non-specific increases in activity since intranasal delivery of NT4-NAP/AAV did not alter the behavior of the mice during the open field test. The results indicated that a recombinant AAV vector which could express NAP in cells was successfully constructed and NAP may be a potential target for therapeutic action of antidepressant treatment.

Chronic methamphetamine regulates the expression of MicroRNAs and putative target genes in the nucleus accumbens of mice.

MicroRNAs (miRNAs) are modulators of gene expression that play key regulatory roles in distinct cellular processes. Methamphetamine (METH) induces various aberrant changes in the limbic system by affecting a complex gene regulatory mechanism, yet the involvement of miRNAs in the effects of METH exposure remains unclear. This study identifies METH-responsive miRNAs and their potential effects in the nucleus accumbens (NAc) of mice. Using miRNA sequencing, we examined the expression of miRNAs in the NAc of saline- and METH-treated mice and identified 45 known miRNAs to be METH responsive. Additionally, we identified two novel miRNA candidates that were METH responsive (novel-m002C and novel-m009C). Our target prediction analysis suggested that the known METH-regulated miRNAs might target genes that are involved in cellular autophagy, cellular metabolism, and immune responses and that the novel METH-regulated miRNA candidates might target genes that are related to drug addiction. We also matched the predicted targets of METH-regulated miRNAs with the NAc messenger RNA expression profile, revealing eight putative METH-regulated target genes (Arc, Capn9, Gbp5, Lefty1, Patl2, Pde4c, Strc, and Vmn1r58). Thus, METH triggers an alteration in NAc miRNA expression, which could contribute to METH-induced changes in neuron autophagy, metabolism, and immune responses. The differential expression of putative target genes suggests their involvement following exposure to METH.

Methamphetamine induces alterations in the long non-coding RNAs expression profile in the nucleus accumbens of the mouse.

BACKGROUND: Repeated exposure to addictive drugs elicits long-lasting cellular and molecular changes. It has been reported that the aberrant expression of long non-coding RNAs (lncRNAs) is involved in cocaine and heroin addiction, yet the expression profile of lncRNAs and their potential effects on methamphetamine (METH)-induced locomotor sensitization are largely unknown. RESULTS: Using high-throughput strand-specific complementary DNA sequencing technology (ssRNA-seq), here we examined the alterations in the lncRNAs expression profile in the nucleus accumbens (NAc) of METH-sensitized mice. We found that the expression levels of 6246 known lncRNAs (6215 down-regulated, 31 up-regulated) and 8442 novel lncRNA candidates (8408 down-regulated, 34 up-regulated) were significantly altered in the METH-sensitized mice. Based on characterizations of the genomic contexts of the lncRNAs, we further showed that there were 5139 differentially expressed lncRNAs acted via cis mechanisms, including sense intronic (4295 down-regulated and one up-regulated), overlapping (25 down-regulated and one up-regulated), natural antisense transcripts (NATs, 148 down-regulated and eight up-regulated), long intergenic non-coding RNAs (lincRNAs, 582 down-regulated and five up-regulated), and bidirectional (72 down-regulated and two up-regulated). Moreover, using the program RNAplex, we identified 3994 differentially expressed lncRNAs acted via trans mechanisms. Gene ontology (GO) and KEGG pathway enrichment analyses revealed that the predicted cis- and trans- associated genes were significantly enriched during neuronal development, neuronal plasticity, learning and memory, and reward and addiction. CONCLUSIONS: Taken together, our results suggest that METH can elicit global changes in lncRNA expressions in the NAc of sensitized mice that might be involved in METH-induced locomotor sensitization and addiction.

[Histidine triad nucleotide-binding protein 1 and human diseases].

Histidine triad nucleotide-binding protein 1 (HINT1) is a member of a superfamily of histidine triad proteins named by the conserved nucleotide-binding motif histidine-x-histidine-x-histidine-xx, in which x represents hydrophobic amino acid. HINT1 is implicated in pathological progress of many human diseases including cancer and schizophrenia; however, little is known about the essential role and pathological consequences of HINT1 in cellular physiology and diseases. Therefore, we summarize the structure, distribution, and physiological function of HINT1 in cells and tissues as well as the correlation between HINT1 and human diseases.

Depression, Rumination, and Suicide Attempts in Adolescents With Mood Disorders: Sex Differences in This Relationship.

Abstract.Background: Sex differences in suicide attempts have been widely recognized across domains such as depression and rumination. The relationship between depression, rumination, and suicide attempts in mood disorders has been studied before; however, how they interact across sexes remains unclear. This study aimed to examine the sex differences in the relationship between depression, rumination, and suicide attempts in Chinese adolescents with mood disorders.Methods: We recruited 681 adolescents with mood disorders who met ICD-10 criteria for having unipolar or bipolar depression with a current depressive episode at the time of the study and collected demographic and clinical data.Results: The prevalence of suicide attempts in female adolescents with mood disorders (64.36%) was significantly higher than that in male adolescents with mood disorders (49.47%), with an odds ratio of 1.84 (95% CI, 1.31-2.59). Regression analysis showed that PHQ-9 was independently associated with suicide attempts among male adolescents with mood disorders, while in female adolescents with mood disorders, total scores of PHQ-9 and RRS-10 were independently associated with suicide attempts. Importantly, in female adolescents with mood disorders, the mediating effect of RRS-10 total score on the relationship between PHQ-9 and suicide attempts was significant (standardized ß = 0.005, P = 0.003, 95% CI, 0.002-0.008), the mediating effect accounted for 31.25% of the total effect of depressive symptoms on suicide attempts.Conclusions: Our study suggests that there are sex differences in depression, rumination, and suicide attempts and in the interaction between them in adolescents with mood disorders. These sex differences may have important clinical implications, both for improving strategies to detect suicidal behaviors and for developing better early intervention programs for this population.

Circle-seq based method for eccDNA synthesis and its application as a canonical promoter independent vector for robust microRNA overexpression.

Extrachromosomal circular DNA (eccDNA) has recently gained increasing attention due to its significant role in cancer and other pathophysiologic states. The majority of circular DNAs detected by Circle-seq are small-size eccDNAs with enigmatic functions. One major technical hurdle is to synthesize eccDNA for functional identification. Here, we describe CAES (Circle-seq based Artificial EccDNA Synthesis), a promising and reliable method for artificial eccDNA synthesis. Eight eccDNAs carrying different microRNA genes (eccMIR) found in gastric cancer tissues, ranging from 329 bp to 2189 bp in size, were created utilizing the CAES method. Exonuclease V and single restriction-endonuclease digestion identified the circular structure of synthetic eccDNAs. The DNA circularization efficiency afforded by CAES ranged from 15.6% to 31.1%, which was negatively correlated with the eccDNA length. In addition, we demonstrated that CAES-synthesized eccMIRs can express both miRNA-3p and - 5p molecules efficiently independent of a canonical promoter in human cell lines. Further assays proved that these eccMIRs were functional as they were able to repress the luciferase gene containing a miRNA-target sequence in the 3'UTR as well as the endogenous mRNA targets. Finally, kinetics study revealed that eccDNA exhibited a decay rate similar to the standard plasmids and linear DNA in cultured cells. Together, this study offers a rapid and convenient method for Circle-seq users to synthesize artificial eccDNAs. It also demonstrates the promising potential of eccMIR as a bacterial DNA-free vector for safe and robust miRNA overexpression in both basic research and therapeutic applications.

The extrachromosomal circular DNA atlas of aged and young mouse brains.

Extrachromosomal circular DNA (eccDNA) refers to a distinct class of circular DNA molecules that exist independently from linear chromosomal DNA. Extensive evidence has firmly established the significant involvement of eccDNA in cancer initiation, progression, and evolutionary processes. However, the relationship between eccDNA and brain aging remains elusive. Here, we employed extrachromosomal circular DNA sequencing (Circle-seq) to generate a comprehensive dataset of eccDNA from six brain structures of both young and naturally-aged mice, including the olfactory bulb, medial prefrontal cortex, nucleus accumbens, caudate putamen, hippocampus, and cerebellum. Furthermore, through database annotation, we characterized the properties of mouse brain eccDNA, thereby gaining insights into the potential functions of eccDNA in the mouse brain. In conclusion, our study addresses a previously unexplored area by providing a comprehensive molecular characterization of eccDNA in brain tissues. The data presented in the study can be used as a fundamental resource to associate the molecular phenotypes of eccDNA with brain aging and gain deep insights into the biological role of eccDNA in mammalian brain aging.

Ketogenic diet ameliorates attention deficit hyperactivity disorder in rats via regulating gut microbiota.

Attention deficit hyperactivity disorder (ADHD) is a common mental behavioral disorder in children. Alterations in gut microbiota composition are associated with neurological disorders. We aimed to investigate whether a ketogenic diet (KD) can be an alternative therapy for ADHD by altering the gut microbiota. Male spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were randomly allocated to the normal diet (ND), methylphenidate (MPH), and KD groups. SHR in groups KD and MPH exhibited a significant increase in behavioral characteristics of ADHD, such as distance moved and immobility time. KD and MPH treatment led to a significant elevation in concentrations of 5-HT, AC, cAMP, and NE of brain tissue and the expression of DRD1, DAT, PKA, DARPP32, and cAMP at the protein level in WKY rats and SHR. KD and MPH significantly increased the richness and diversity of gut microbiota in SHR. The abundance of Ruminococcus_gauvreauii_group, Bacteroides, Bifidobacterium, and Blautia significantly increased, whereas that of Lactobacillus, Romboutsia, Facklamia, and Turicibacter significantly declined in the KD group compared with the ND group. The gut microbiota in the KD group of SHR mainly participated in amino acid metabolism- and sugar metabolism-related pathways. KD might alleviate behavioral disorders in ADHD by regulating gut microbiota. This study provides novel insights for the use of KD in treating ADHD.