Lactate:a prospective target for therapeutic intervention in psychiatric disease

Although antipsychotics that act via monoaminergic neurotransmitter modulation have considera ble therapeutic effect,they cannot completely relieve clinical symptoms in patients suffering from psychiatric disorde rs.This may be attributed to the limited range of neurotransmitters that are regulated by psychotropic drugs.Recent findings indicate the need for investigation of psychotropic medications that target less-studied neurotransmitte rs.Among these candidate neurotransmitters,lactate is developing from being a waste metabolite to a glial-neuronal signaling molecule in recent years.Previous studies have suggested that cerebral lactate levels change considerably in numerous psychiatric illnesses;animal experiments have also shown that the supply of exogenous la ctate exerts an antidepressant effect.In this review,we have described how medications targeting newer neurotransmitte rs offer promise in psychiatric diseases;we have also summarized the advances in the use of lactate(and its corresponding signaling pathways)as a signaling molecule.In addition,we have described the alterations in brain lactate levels in depression,anxiety,bipolar disorder,and schizophrenia and have indicated the challenges that need to be overcome before brain lactate can be used as a therapeutic target in psychopharmacology.

Brain expression quantitative trait locus mapping informs genetic studies of psychiatric diseases

Genome-wide association study（GWAS） can be used to identify genes that increase the risk of psychiatric diseases.However,much of the disease heritability is still unexplained,suggesting that there are genes to be discovered.Functional annotation of the genetic variants may increase the power of GWAS to identify disease genes,by providing prior information that can be used in Bayesian analysis or in reducing the number of tests.Expression quantitative trait loci（eQTLs） are genomic loci that regulate gene expression.Genetic mapping of eQTLs can help reveal novel functional effects of thousands of single nucleotide polymorphisms（SNPs）.The present review mainly focused on the current knowledge on brain eQTL mapping,and discussed some major methodological issues and their possible solutions.The frequently ignored problems of batch effects,covariates,and multiple testing were emphasized,since they can lead to false positives and false negatives.The future application of eQTL data in GWAS analysis was also discussed.

Brain organoids are new tool for drug screening of neurological diseases

At the level of in vitro drug screening,the development of a phenotypic analysis system with highcontent screening at the core provides a strong platform to support high-throughput drug screening.There are few systematic reports on brain organoids,as a new three-dimensional in vitro model,in terms of model stability,key phenotypic fingerprint,and drug screening schemes,and particula rly rega rding the development of screening strategies for massive numbers of traditional Chinese medicine monomers.This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases.The paper also highlights the prospects from model stability,induction criteria of brain organoids,and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.

Stereotactic multi-target limbic leucotomy for treating intractable psychiatric disease in 30 patients Three-year follow-up of memory, intelligence, and psychiatric symptoms

BACKGROUND： The biochemical hypothesis of dopamine hyperfunction in the brain can explain the pathological mechanisms of schizophrenia. Surgery is performed based on limbic system circuit theory correspondence to above-mentioned hypothesis. Stereotactic surgery for the treatment of mental disorders is related to stereotactic surgery that influences the Papez circuit. OBJECTIVE： To observe the effects of stereotactic multi-target limbic leucotomy on the improvements in memory, intelligence and psychiatric symptoms in the treatment of intractable psychiatric disease. DESIGN： Self-control case analysis and follow-up of therapeutic effects. SETTING： Department of Neurosurgery, First Hospital, Hebei Medical University. PARTICIPANTS： Thirty patients with intractable psychiatric disease, who received stereotactic surgery in the Department of Neurosurgery, First Hospital, Hebei Medical University between July 2002 and August 2005, were included in this study. The patients, 21 males and 9 females, all met the diagnostic criteria of intractable psychiatric disease, determined by the national psychosurgery cooperation team in 1998. Informed consents for surgery and clinical follow-up exams were obtained from patients and/or patients＇ relatives （guardians）. METHODS： In 30 patients with intractable psychiatric disease, limbic leucotomy was performed by stereotactic technique. Multi-target radiofrequency hyperthermia was performed in the intracranial amygdaloid nucleus, anterior limb of internal capsule, callosal gyrus, among other regions. The therapeutic effects of patients were evaluated by Brief Psychiatric Rating Scale （BPRS） before surgery, and 6 months, 1, and 3 years after surgery. The Wechsler Adult Intelligence Scale （WAIS） and Clinical Memory Scale （CMS） were used to assess memory and intelligence before and after surgery. MAIN OUTCOME MEASURES： Memory, intelligence, and psychiatric symptoms of patients before and after operation. RESULTS： Thirty patients were included in the final analysis. （1） Memory and intelligence changes of patients： CMS and WAIS showed there were no significant differences in the changes of brain functions before and after operation （P 〉 0.05）. （2） Improved degree of symptoms： 5 patients were cured, 8 patients significantly improved, 8 patients improved, 3 patients had no changes, and 6 patients had recurrent symptoms. CONCLUSION： Stereotactic multi-target limbic leucotomy can improve the symptoms of patients with intractable psychiatric disease. Follow-up results showed that memory and intelligence were not noticeably improved after surgery.

Triggering of Major Brain Disorders by Protons and ATP:The Role of ASICs and P2X Receptors

Adenosine triphosphate(ATP)is well-known as a universal source of energy in living cells.Less known is that this molecule has a variety of important signaling func-tions:it activates a variety of specific metabotropic(P2Y)and ionotropic(P2X)receptors in neuronal and non-neu-ronal cell membranes.So,a wide variety of signaling func-tions well fits the ubiquitous presence of ATP in the tissues.Even more ubiquitous are protons.Apart from the unspe-cific interaction of protons with any protein,many physi-ological processes are affected by protons acting on specific ionotropic receptors--acid-sensing ion channels(ASICs).Both protons(acidification)and ATP are locally elevated in various pathological states.Using these fundamentally important molecules as agonists,ASICs and P2X receptors signal a variety of major brain pathologies.Here we briefly outline the physiological roles of ASICs and P2X receptors,focusing on the brain pathologies involving these receptors.