Topic Editors

Neuroscience Research Group, Hungarian Academy of Sciences, University of Szeged (MTA-SZTE), 6720 Szeged, Hungary
Department of Psychiatry and Forensic Medicine, Institute of Neuroscience (INc), 08193 Barcelona, Spain
1. Department of Psychology, University of Turin, Turin, Italy
2. Center for Studies and Research in Cognitive Neuroscience, Department of Psychology, University of Bologna, Bologna, Italy
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
Department of Psychology, University of Roehampton, London, UK

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods 2.0

Abstract submission deadline
closed (31 March 2023)
Manuscript submission deadline
closed (31 May 2023)
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67085

Topic Information

Dear Colleagues,

Translational research is one of the most essential but challenging areas of laboratory sciences when it comes to understanding the underlying pathomechanisms of neurological and psychiatric disorders. These challenges additionally arise when searching for new biomarkers and developing novel therapeutics. Furthermore, many branches of neuroscience can help us understand the underlying molecular factors and neural computations behind brain impairments and psychiatric disorders, as well as determining where and how to focus research and treatment. In vivo and in vitro disease models have been casting a light on the complex polygenic, multifactorial, and heterogenous disease mechanisms. Furthermore, emerging animal models are revealing the intriguing interaction of sex and aging with the pathogenesis of neuropsychiatric diseases; meanwhile, emerging research in patients has been paying closer attention to the heterogeneity of treatment responses that may help in developing personalized medicine. The diseases which translational research is applicable to include Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, infectious prion disease, sequelae, stroke, HIV infection, and psychiatric disorders—including depressive disorder, bipolar disorder, substance abuse disorder, post-traumatic stress disorder, anxiety disorder, schizophrenia, somatic symptom disorder, autism spectrum disorder, hyperactive attention deficit disorder, and rare diseases. This Special Issue highlights the most recent developments in translational research in neurologic and psychiatric diseases. We cordially invite authors to contribute original research articles focusing on—but not limited to—the following:

  • Etiology, pathogenesis, and progression mechanisms;
  • Early diagnosis, including biomarkers, bioimaging, biosensors, and neuroimaging;
  • Methodologies;
  • Biomaterial biomedical research;
  • Prophylactic, disease-modifying, and therapeutic strategies, and novel targets;
  • Novel drug discovery and development, naturally driven biomedicines, natural bioactive molecules, and vaccines;
  • Novel targets in various therapeutic areas: cardiovascular, vascular, hematology, oncology, neurology, orthopedics, dermatology, ophthalmology, and other peripheral systems;
  • Biopharmaceutical biomedicine, biologics, biosimilars, nanobiotechnology, nanosimilars, nano biosimilars;
  • Nanoscaffold implants (synthetic vascular graft);
  • Bioimaging, gene therapy, vaccine, cell therapy, and tissue engineering;
  • Predictors of clinical treatment responses;
  • Computational neuroscience and computational psychiatry.

Review articles including expert opinions, systematic analysis, metanalysis, and other statistical and analytical methods are also welcome.

Dr. Masaru Tanaka
Prof. Dr. Lydia Giménez-Llort
Dr. Simone Battaglia
Dr. Chong Chen
Dr. Piril Hepsomali
Topic Editors

Keywords

  • Alzheimer’s disease
  • Parkinson’s disease
  • mild cognitive impairment
  • multiple sclerosis
  • stroke
  • depressive disorder
  • bipolar disorder
  • post-traumatic stress disorder
  • anxiety disorder
  • schizophrenia
  • somatic symptom disorder
  • autism spectrum disorder
  • hyperactive attention deficit disorder
  • learning disabilities
  • acquired brain damage
  • altered cognitive processes
  • brain functional impairment
  • neurocognitive disorders
  • cognitive, behavioral, and functional disorders
  • trauma; brain plasticity and connectivity
  • non-invasive brain stimulation
  • altered cognition
  • rare diseases

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomedicines
biomedicines
4.7 3.7 2013 15.4 Days CHF 2600
Brain Sciences
brainsci
3.3 3.9 2011 15.6 Days CHF 2200
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700
International Journal of Molecular Sciences
ijms
5.6 7.8 2000 16.3 Days CHF 2900
Neurology International
neurolint
3.0 2.2 2009 23.3 Days CHF 1600
Pharmaceuticals
pharmaceuticals
4.6 4.7 2004 14.6 Days CHF 2900

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Published Papers (22 papers)

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14 pages, 892 KiB  
Study Protocol
Unraveling Lifelong Brain Morphometric Dynamics: A Protocol for Systematic Review and Meta-Analysis in Healthy Neurodevelopment and Ageing
by Yauhen Statsenko, Tetiana Habuza, Darya Smetanina, Gillian Lylian Simiyu, Sarah Meribout, Fransina Christina King, Juri G. Gelovani, Karuna M. Das, Klaus N.-V. Gorkom, Kornelia Zaręba, Taleb M. Almansoori, Miklós Szólics, Fatima Ismail and Milos Ljubisavljevic
Biomedicines 2023, 11(7), 1999; https://doi.org/10.3390/biomedicines11071999 - 14 Jul 2023
Cited by 3 | Viewed by 1314
Abstract
A high incidence and prevalence of neurodegenerative diseases and neurodevelopmental disorders justify the necessity of well-defined criteria for diagnosing these pathologies from brain imaging findings. No easy-to-apply quantitative markers of abnormal brain development and ageing are available. We aim to find the characteristic [...] Read more.
A high incidence and prevalence of neurodegenerative diseases and neurodevelopmental disorders justify the necessity of well-defined criteria for diagnosing these pathologies from brain imaging findings. No easy-to-apply quantitative markers of abnormal brain development and ageing are available. We aim to find the characteristic features of non-pathological development and degeneration in distinct brain structures and to work out a precise descriptive model of brain morphometry in age groups. We will use four biomedical databases to acquire original peer-reviewed publications on brain structural changes occurring throughout the human life-span. Selected publications will be uploaded to Covidence systematic review software for automatic deduplication and blinded screening. Afterwards, we will manually review the titles, abstracts, and full texts to identify the papers matching eligibility criteria. The relevant data will be extracted to a ‘Summary of findings’ table. This will allow us to calculate the annual rate of change in the volume or thickness of brain structures and to model the lifelong dynamics in the morphometry data. Finally, we will adjust the loss of weight/thickness in specific brain areas to the total intracranial volume. The systematic review will synthesise knowledge on structural brain change across the life-span. Full article
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19 pages, 1256 KiB  
Article
Unveiling the Enigma: Exploring Risk Factors and Mechanisms for Psychotic Symptoms in Alzheimer’s Disease through Electronic Medical Records with Deep Learning Models
by Peihao Fan, Oshin Miranda, Xiguang Qi, Julia Kofler, Robert A. Sweet and Lirong Wang
Pharmaceuticals 2023, 16(7), 911; https://doi.org/10.3390/ph16070911 - 21 Jun 2023
Cited by 6 | Viewed by 1402
Abstract
Around 50% of patients with Alzheimer’s disease (AD) may experience psychotic symptoms after onset, resulting in a subtype of AD known as psychosis in AD (AD + P). This subtype is characterized by more rapid cognitive decline compared to AD patients without psychosis. [...] Read more.
Around 50% of patients with Alzheimer’s disease (AD) may experience psychotic symptoms after onset, resulting in a subtype of AD known as psychosis in AD (AD + P). This subtype is characterized by more rapid cognitive decline compared to AD patients without psychosis. Therefore, there is a great need to identify risk factors for the development of AD + P and explore potential treatment options. In this study, we enhanced our deep learning model, DeepBiomarker, to predict the onset of psychosis in AD utilizing data from electronic medical records (EMRs). The model demonstrated superior predictive capacity with an AUC (area under curve) of 0.907, significantly surpassing conventional risk prediction models. Utilizing a perturbation-based method, we identified key features from multiple medications, comorbidities, and abnormal laboratory tests, which notably influenced the prediction outcomes. Our findings demonstrated substantial agreement with existing studies, underscoring the vital role of metabolic syndrome, inflammation, and liver function pathways in AD + P. Importantly, the DeepBiomarker model not only offers a precise prediction of AD + P onset but also provides mechanistic understanding, potentially informing the development of innovative treatments. With additional validation, this approach could significantly contribute to early detection and prevention strategies for AD + P, thereby improving patient outcomes and quality of life. Full article
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20 pages, 4139 KiB  
Article
Hepatic Oxi-Inflammation and Neophobia as Potential Liver–Brain Axis Targets for Alzheimer’s Disease and Aging, with Strong Sensitivity to Sex, Isolation, and Obesity
by Juan Fraile-Ramos, Anna Garrit, Josep Reig-Vilallonga and Lydia Giménez-Llort
Cells 2023, 12(11), 1517; https://doi.org/10.3390/cells12111517 - 30 May 2023
Cited by 3 | Viewed by 4556
Abstract
Research on Alzheimer’s disease (AD) has classically focused on alterations that occur in the brain and their intra- and extracellular neuropathological hallmarks. However, the oxi-inflammation hypothesis of aging may also play a role in neuroimmunoendocrine dysregulation and the disease’s pathophysiology, where the liver [...] Read more.
Research on Alzheimer’s disease (AD) has classically focused on alterations that occur in the brain and their intra- and extracellular neuropathological hallmarks. However, the oxi-inflammation hypothesis of aging may also play a role in neuroimmunoendocrine dysregulation and the disease’s pathophysiology, where the liver emerges as a target organ due to its implication in regulating metabolism and supporting the immune system. In the present work, we demonstrate organ (hepatomegaly), tissue (histopathological amyloidosis), and cellular oxidative stress (decreased glutathione peroxidase and increased glutathione reductase enzymatic activities) and inflammation (increased IL-6 and TNF𝛼) as hallmarks of hepatic dysfunction in 16-month-old male and female 3xTg-AD mice at advanced stages of the disease, and as compared to age- and sex-matched non-transgenic (NTg) counterparts. Moreover, liver–brain axis alterations were found through behavioral (increased neophobia) and HPA axis correlations that were enhanced under forced isolation. In all cases, sex (male) and isolation (naturalistic and forced) were determinants of worse hepatomegaly, oxidative stress, and inflammation progression. In addition, obesity in old male NTg mice was translated into a worse steatosis grade. Further research is underway determine whether these alterations could correlate with a worse disease prognosis and to establish potential integrative system targets for AD research. Full article
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26 pages, 3948 KiB  
Review
Deep Brain Stimulation beyond the Clinic: Navigating the Future of Parkinson’s and Alzheimer’s Disease Therapy
by Degiri Kalana Lasanga Senevirathne, Anns Mahboob, Kevin Zhai, Pradipta Paul, Alexandra Kammen, Darrin Jason Lee, Mohammad S. Yousef and Ali Chaari
Cells 2023, 12(11), 1478; https://doi.org/10.3390/cells12111478 - 25 May 2023
Cited by 8 | Viewed by 3276
Abstract
Deep brain stimulation (DBS) is a surgical procedure that uses electrical neuromodulation to target specific regions of the brain, showing potential in the treatment of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Despite similarities in disease pathology, DBS is [...] Read more.
Deep brain stimulation (DBS) is a surgical procedure that uses electrical neuromodulation to target specific regions of the brain, showing potential in the treatment of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Despite similarities in disease pathology, DBS is currently only approved for use in PD patients, with limited literature on its effectiveness in AD. While DBS has shown promise in ameliorating brain circuits in PD, further research is needed to determine the optimal parameters for DBS and address any potential side effects. This review emphasizes the need for foundational and clinical research on DBS in different brain regions to treat AD and recommends the development of a classification system for adverse effects. Furthermore, this review suggests the use of either a low-frequency system (LFS) or high-frequency system (HFS) depending on the specific symptoms of the patient for both PD and AD. Full article
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18 pages, 5080 KiB  
Article
Evaluation of the Autologous Genetically Enriched Leucoconcentrate on the Lumbar Spinal Cord Morpho-Functional Recovery in a Mini Pig with Thoracic Spine Contusion Injury
by Ravil Garifulin, Maria Davleeva, Andrei Izmailov, Filip Fadeev, Vage Markosyan, Roman Shevchenko, Irina Minyazeva, Tagir Minekayev, Igor Lavrov and Rustem Islamov
Biomedicines 2023, 11(5), 1331; https://doi.org/10.3390/biomedicines11051331 - 30 Apr 2023
Cited by 2 | Viewed by 1509
Abstract
Background: Pathological changes associated with spinal cord injury (SCI) can be observed distant, rostral, or caudal to the epicenter of injury. These remote areas represent important therapeutic targets for post-traumatic spinal cord repair. The present study aimed to investigate the following in relation [...] Read more.
Background: Pathological changes associated with spinal cord injury (SCI) can be observed distant, rostral, or caudal to the epicenter of injury. These remote areas represent important therapeutic targets for post-traumatic spinal cord repair. The present study aimed to investigate the following in relation to SCI: distant changes in the spinal cord, peripheral nerve, and muscles. Methods: The changes in the spinal cord, the tibial nerve, and the hind limb muscles were evaluated in control SCI animals and after intravenous infusion of autologous leucoconcentrate enriched with genes encoding neuroprotective factors (VEGF, GDNF, and NCAM), which previously demonstrated a positive effect on post-traumatic restoration. Results: Two months after thoracic contusion in the treated mini pigs, a positive remodeling of the macro- and microglial cells, expression of PSD95 and Chat in the lumbar spinal cord, and preservation of the number and morphological characteristics of the myelinated fibers in the tibial nerve were observed and were aligned with hind limb motor recovery and reduced soleus muscle atrophy. Conclusion: Here, we show the positive effect of autologous genetically enriched leucoconcentrate-producing recombinant neuroprotective factors on targets distant to the primary lesion site in mini pigs with SCI. These findings open new perspectives for the therapy of SCI. Full article
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18 pages, 6157 KiB  
Article
Morphofunctional Improvement of the Facial Nerve and Muscles with Repair Using Heterologous Fibrin Biopolymer and Photobiomodulation
by Cleuber Rodrigo de Souza Bueno, Maria Clara Cassola Tonin, Daniela Vieira Buchaim, Benedito Barraviera, Rui Seabra Ferreira Junior, Paulo Sérgio da Silva Santos, Carlos Henrique Bertoni Reis, Cláudio Maldonado Pastori, Eliana de Souza Bastos Mazuqueli Pereira, Dayane Maria Braz Nogueira, Marcelo Augusto Cini, Geraldo Marco Rosa Junior and Rogerio Leone Buchaim
Pharmaceuticals 2023, 16(5), 653; https://doi.org/10.3390/ph16050653 - 27 Apr 2023
Cited by 7 | Viewed by 1468
Abstract
Peripheral nerve injuries impair the patient’s functional capacity, including those occurring in the facial nerve, which require effective medical treatment. Thus, we investigated the use of heterologous fibrin biopolymer (HFB) in the repair of the buccal branch of the facial nerve (BBFN) associated [...] Read more.
Peripheral nerve injuries impair the patient’s functional capacity, including those occurring in the facial nerve, which require effective medical treatment. Thus, we investigated the use of heterologous fibrin biopolymer (HFB) in the repair of the buccal branch of the facial nerve (BBFN) associated with photobiomodulation (PBM), using a low-level laser (LLLT), analyzing the effects on axons, muscles facials, and functional recovery. This experimental study used twenty-one rats randomly divided into three groups of seven animals, using the BBFN bilaterally (the left nerve was used for LLLT): Control group—normal and laser (CGn and CGl); Denervated group—normal and laser (DGn and DGl); Experimental Repair Group—normal and laser (ERGn and ERGl). The photobiomodulation protocol began in the immediate postoperative period and continued for 5 weeks with a weekly application. After 6 weeks of the experiment, the BBFN and the perioral muscles were collected. A significant difference (p < 0.05) was observed in nerve fiber diameter (7.10 ± 0.25 µm and 8.00 ± 0.36 µm, respectively) and axon diameter (3.31 ± 0.19 µm and 4.07 ± 0.27 µm, respectively) between ERGn and ERGl. In the area of muscle fibers, ERGl was similar to GC. In the functional analysis, the ERGn and the ERGI (4.38 ± 0.10) and the ERGI (4.56 ± 0.11) showed parameters of normality. We show that HFB and PBM had positive effects on the morphological and functional stimulation of the buccal branch of the facial nerve, being an alternative and favorable for the regeneration of severe injuries. Full article
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25 pages, 725 KiB  
Review
Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges
by Jiafeng Chen, Lijuan Huang, Yue Yang, Wei Xu, Qingchun Qin, Rongxing Qin, Xiaojun Liang, Xinyu Lai, Xiaoying Huang, Minshan Xie and Li Chen
Brain Sci. 2023, 13(3), 524; https://doi.org/10.3390/brainsci13030524 - 22 Mar 2023
Cited by 2 | Viewed by 2901
Abstract
Nervous system diseases present significant challenges to the neuroscience community due to ethical and practical constraints that limit access to appropriate research materials. Somatic cell reprogramming has been proposed as a novel way to obtain neurons. Various emerging techniques have been used to [...] Read more.
Nervous system diseases present significant challenges to the neuroscience community due to ethical and practical constraints that limit access to appropriate research materials. Somatic cell reprogramming has been proposed as a novel way to obtain neurons. Various emerging techniques have been used to reprogram mature and differentiated cells into neurons. This review provides an overview of somatic cell reprogramming for neurological research and therapy, focusing on neural reprogramming and generating different neural cell types. We examine the mechanisms involved in reprogramming and the challenges that arise. We herein summarize cell reprogramming strategies to generate neurons, including transcription factors, small molecules, and microRNAs, with a focus on different types of cells.. While reprogramming somatic cells into neurons holds the potential for understanding neurological diseases and developing therapeutic applications, its limitations and risks must be carefully considered. Here, we highlight the potential benefits of somatic cell reprogramming for neurological disease research and therapy. This review contributes to the field by providing a comprehensive overview of the various techniques used to generate neurons by cellular reprogramming and discussing their potential applications. Full article
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19 pages, 705 KiB  
Review
Efficacy, Tolerability, and Safety of Toludesvenlafaxine for the Treatment of Major Depressive Disorder—A Narrative Review
by Octavian Vasiliu
Pharmaceuticals 2023, 16(3), 411; https://doi.org/10.3390/ph16030411 - 08 Mar 2023
Cited by 6 | Viewed by 4916
Abstract
The estimated rate of treatment-resistant major depressive disorder (TRD) remains higher than 30%, even after the discovery of multiple classes of antidepressants in the last 7 decades. Toludesvenlafaxine (ansofaxine, LY03005, or LPM570065) is a first-in-class triple monoaminergic reuptake inhibitor (TRI) that has reached [...] Read more.
The estimated rate of treatment-resistant major depressive disorder (TRD) remains higher than 30%, even after the discovery of multiple classes of antidepressants in the last 7 decades. Toludesvenlafaxine (ansofaxine, LY03005, or LPM570065) is a first-in-class triple monoaminergic reuptake inhibitor (TRI) that has reached clinical use. The objective of this narrative review was to summarize clinical and preclinical evidence about the efficacy, tolerability, and safety of toludesvenlafaxine. Based on the results of 17 reports retrieved in the literature, the safety and tolerability profiles of toludesvenlafaxine were good in all clinical trials, and the pharmacokinetic parameters were well described in the phase 1 trials. The efficacy of toludesvenlafaxine was demonstrated in one phase 2 and one phase 3 trial, both on primary and secondary outcomes. In conclusion, this review highlights the favorable clinical results of toludesvenlafaxine in only two short-term trials that enrolled patients with major depressive disorder (MDD) (efficacy and tolerability were good for up to eight weeks), indicating the need for more good quality, larger-sample, and longer-term trials. Exploring new antidepressants, such as TRI, can be considered a priority for clinical research due to the high rates of TRD, but also due to the significant percentages of relapse in patients with MDD. Full article
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19 pages, 1144 KiB  
Review
Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles
by Hans O. Kalkman
Biomedicines 2023, 11(3), 806; https://doi.org/10.3390/biomedicines11030806 - 07 Mar 2023
Cited by 7 | Viewed by 2811
Abstract
Depression is a major public health concern. Unfortunately, the present antidepressants often are insufficiently effective, whilst the discovery of more effective antidepressants has been extremely sluggish. The objective of this review was to combine the literature on depression with the pharmacology of antidepressant [...] Read more.
Depression is a major public health concern. Unfortunately, the present antidepressants often are insufficiently effective, whilst the discovery of more effective antidepressants has been extremely sluggish. The objective of this review was to combine the literature on depression with the pharmacology of antidepressant compounds, in order to formulate a conceivable pathophysiological process, allowing proposals how to accelerate the discovery process. Risk factors for depression initiate an infection-like inflammation in the brain that involves activation microglial Toll-like receptors and glycogen synthase kinase-3β (GSK3β). GSK3β activity alters the balance between two competing transcription factors, the pro-inflammatory/pro-oxidative transcription factor NFκB and the neuroprotective, anti-inflammatory and anti-oxidative transcription factor NRF2. The antidepressant activity of tricyclic antidepressants is assumed to involve activation of GS-coupled microglial receptors, raising intracellular cAMP levels and activation of protein kinase A (PKA). PKA and similar kinases inhibit the enzyme activity of GSK3β. Experimental antidepressant principles, including cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine and electrical stimulation of the Vagus nerve, all activate microglial pathways that result in GSK3β-inhibition. An in vitro screen for NRF2-activation in microglial cells with TLR-activated GSK3β activity, might therefore lead to the detection of totally novel antidepressant principles with, hopefully, an improved therapeutic efficacy. Full article
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16 pages, 3440 KiB  
Article
Weak Ultrasound Contributes to Neuromodulatory Effects in the Rat Motor Cortex
by Po-Chun Chu, Chen-Syuan Huang, Pi-Kai Chang, Rou-Shayn Chen, Ko-Ting Chen, Tsung-Hsun Hsieh and Hao-Li Liu
Int. J. Mol. Sci. 2023, 24(3), 2578; https://doi.org/10.3390/ijms24032578 - 30 Jan 2023
Cited by 5 | Viewed by 2390
Abstract
Transcranial focused ultrasound (tFUS) is a novel neuromodulating technique. It has been demonstrated that the neuromodulatory effects can be induced by weak ultrasound exposure levels (spatial-peak temporal average intensity, ISPTA < 10 mW/cm2) in vitro. However, fewer studies have examined [...] Read more.
Transcranial focused ultrasound (tFUS) is a novel neuromodulating technique. It has been demonstrated that the neuromodulatory effects can be induced by weak ultrasound exposure levels (spatial-peak temporal average intensity, ISPTA < 10 mW/cm2) in vitro. However, fewer studies have examined the use of weak tFUS to potentially induce long-lasting neuromodulatory responses in vivo. The purpose of this study was to determine the lower-bound threshold of tFUS stimulation for inducing neuromodulation in the motor cortex of rats. A total of 94 Sprague–Dawley rats were used. The sonication region aimed at the motor cortex under weak tFUS exposure (ISPTA of 0.338–12.15 mW/cm2). The neuromodulatory effects of tFUS on the motor cortex were evaluated by the changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In addition to histology analysis, the in vitro cell culture was used to confirm the neuromodulatory mechanisms following tFUS stimulation. In the results, the dose-dependent inhibitory effects of tFUS were found, showing increased intensities of tFUS suppressed MEPs and lasted for 30 min. Weak tFUS significantly decreased the expression of excitatory neurons and increased the expression of inhibitory GABAergic neurons. The PIEZO-1 proteins of GABAergic neurons were found to involve in the inhibitory neuromodulation. In conclusion, we show the use of weak ultrasound to induce long-lasting neuromodulatory effects and explore the potential use of weak ultrasound for future clinical neuromodulatory applications. Full article
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13 pages, 2116 KiB  
Article
Buffy Coat Score as a Biomarker of Treatment Response in Neuronal Ceroid Lipofuscinosis Type 2
by Siyamini Sivananthan, Laura Lee, Glenn Anderson, Barbara Csanyi, Ruth Williams and Paul Gissen
Brain Sci. 2023, 13(2), 209; https://doi.org/10.3390/brainsci13020209 - 27 Jan 2023
Cited by 2 | Viewed by 1753
Abstract
The introduction of intracerebroventricular (ICV) enzyme replacement therapy (ERT) for treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease has produced dramatic improvements in disease management. However, assessments of therapeutic effect for ICV ERT are limited to clinical observational measures, namely the CLN2 [...] Read more.
The introduction of intracerebroventricular (ICV) enzyme replacement therapy (ERT) for treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease has produced dramatic improvements in disease management. However, assessments of therapeutic effect for ICV ERT are limited to clinical observational measures, namely the CLN2 Clinical Rating Scale, a subjective measure of motor and language performance. There is a need for an objective biomarker to enable assessments of disease progression and response to treatment. To address this, we investigated whether the proportion of cells with abnormal storage inclusions on electron microscopic examination of peripheral blood buffy coats could act as a biomarker of disease activity in CLN2 disease. We conducted a prospective longitudinal analysis of six patients receiving ICV ERT. We demonstrated a substantial and continuing reduction in the proportion of abnormal cells over the course of treatment, whereas symptomatic scores revealed little or no change over time. Here, we proposed the use of the proportion of cells with abnormal storage as a biomarker of response to therapy in CLN2. In the future, as more tissue-specific biomarkers are developed, the buffy coats may form part of a panel of biomarkers in order to give a more holistic view of a complex disease. Full article
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24 pages, 868 KiB  
Review
The Role of Arginine-Vasopressin in Stroke and the Potential Use of Arginine-Vasopressin Type 1 Receptor Antagonists in Stroke Therapy: A Narrative Review
by Karol Chojnowski, Mikołaj Opiełka, Jacek Gozdalski, Jakub Radziwon, Aleksandra Dańczyszyn, Andrew Vieira Aitken, Vinicia Campana Biancardi and Paweł Jan Winklewski
Int. J. Mol. Sci. 2023, 24(3), 2119; https://doi.org/10.3390/ijms24032119 - 20 Jan 2023
Cited by 2 | Viewed by 3009
Abstract
Stroke is a life-threatening condition in which accurate diagnoses and timely treatment are critical for successful neurological recovery. The current acute treatment strategies, particularly non-invasive interventions, are limited, thus urging the need for novel therapeutical targets. Arginine vasopressin (AVP) receptor antagonists are emerging [...] Read more.
Stroke is a life-threatening condition in which accurate diagnoses and timely treatment are critical for successful neurological recovery. The current acute treatment strategies, particularly non-invasive interventions, are limited, thus urging the need for novel therapeutical targets. Arginine vasopressin (AVP) receptor antagonists are emerging as potential targets to treat edema formation and subsequent elevation in intracranial pressure, both significant causes of mortality in acute stroke. Here, we summarize the current knowledge on the mechanisms leading to AVP hyperexcretion in acute stroke and the subsequent secondary neuropathological responses. Furthermore, we discuss the work supporting the predictive value of measuring copeptin, a surrogate marker of AVP in stroke patients, followed by a review of the experimental evidence suggesting AVP receptor antagonists in stroke therapy. As we highlight throughout the narrative, critical gaps in the literature exist and indicate the need for further research to understand better AVP mechanisms in stroke. Likewise, there are advantages and limitations in using copeptin as a prognostic tool, and the translation of findings from experimental animal models to clinical settings has its challenges. Still, monitoring AVP levels and using AVP receptor antagonists as an add-on therapeutic intervention are potential promises in clinical applications to alleviate stroke neurological consequences. Full article
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29 pages, 1991 KiB  
Review
The Role of Alpha Oscillations among the Main Neuropsychiatric Disorders in the Adult and Developing Human Brain: Evidence from the Last 10 Years of Research
by Giuseppe Ippolito, Riccardo Bertaccini, Luca Tarasi, Francesco Di Gregorio, Jelena Trajkovic, Simone Battaglia and Vincenzo Romei
Biomedicines 2022, 10(12), 3189; https://doi.org/10.3390/biomedicines10123189 - 08 Dec 2022
Cited by 47 | Viewed by 4771
Abstract
Alpha oscillations (7–13 Hz) are the dominant rhythm in both the resting and active brain. Accordingly, translational research has provided evidence for the involvement of aberrant alpha activity in the onset of symptomatological features underlying syndromes such as autism, schizophrenia, major depression, and [...] Read more.
Alpha oscillations (7–13 Hz) are the dominant rhythm in both the resting and active brain. Accordingly, translational research has provided evidence for the involvement of aberrant alpha activity in the onset of symptomatological features underlying syndromes such as autism, schizophrenia, major depression, and Attention Deficit and Hyperactivity Disorder (ADHD). However, findings on the matter are difficult to reconcile due to the variety of paradigms, analyses, and clinical phenotypes at play, not to mention recent technical and methodological advances in this domain. Herein, we seek to address this issue by reviewing the literature gathered on this topic over the last ten years. For each neuropsychiatric disorder, a dedicated section will be provided, containing a concise account of the current models proposing characteristic alterations of alpha rhythms as a core mechanism to trigger the associated symptomatology, as well as a summary of the most relevant studies and scientific contributions issued throughout the last decade. We conclude with some advice and recommendations that might improve future inquiries within this field. Full article
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18 pages, 4618 KiB  
Article
The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease
by Ksenia Skobeleva, Alexey Shalygin, Elena Mikhaylova, Irina Guzhova, Maria Ryazantseva and Elena Kaznacheyeva
Int. J. Mol. Sci. 2022, 23(23), 14810; https://doi.org/10.3390/ijms232314810 - 26 Nov 2022
Cited by 6 | Viewed by 2003
Abstract
Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are [...] Read more.
Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry mediated by VGC channels in 5xFAD neurons was dependent on STIM2 but not STIM1 protein in cells with replete Ca2+ stores. The result gives new evidence on the VGC channel modulation by STIM2. Overall, the data demonstrate the changes in calcium signaling of hippocampal neurons of the AD mouse model, which precede amyloid plaque accumulation or other signs of pathology manifestation. Full article
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11 pages, 1958 KiB  
Article
NGFR Gene and Single Nucleotide Polymorphisms, rs2072446 and rs11466162, Playing Roles in Psychiatric Disorders
by Longyou Zhao, Binyin Hou, Lei Ji, Decheng Ren, Fan Yuan, Liangjie Liu, Yan Bi, Fengping Yang, Shunying Yu, Zhenghui Yi, Chuanxin Liu, Bo Bai, Tao Yu, Changqun Cai, Lin He, Guang He, Yi Shi, Xingwang Li and Shaochang Wu
Brain Sci. 2022, 12(10), 1372; https://doi.org/10.3390/brainsci12101372 - 09 Oct 2022
Cited by 6 | Viewed by 1779
Abstract
Psychiatric disorders are a class of complex disorders characterized by brain dysfunction with varying degrees of impairment in cognition, emotion, consciousness and behavior, which has become a serious public health issue. The NGFR gene encodes the p75 neurotrophin receptor, which regulates neuronal growth, [...] Read more.
Psychiatric disorders are a class of complex disorders characterized by brain dysfunction with varying degrees of impairment in cognition, emotion, consciousness and behavior, which has become a serious public health issue. The NGFR gene encodes the p75 neurotrophin receptor, which regulates neuronal growth, survival and plasticity, and was reported to be associated with depression, schizophrenia and antidepressant efficacy in human patient and animal studies. In this study, we investigated its association with schizophrenia and major depression and its role in the behavioral phenotype of adult mice. Four NGFR SNPs were detected based on a study among 1010 schizophrenia patients, 610 patients with major depressive disorders (MDD) and 1034 normal controls, respectively. We then knocked down the expression of NGFR protein in the hippocampal dentate gyrus of the mouse brain by injection of shRNA lentivirus to further investigate its behavioral effect in mice. We found significant associations of s2072446 and rs11466162 for schizophrenia. Ngfr knockdown mice showed social and behavioral abnormalities, suggesting that it is linked to the etiology of neuropsychiatric disorders. We found significant associations between NGFR and schizophrenia and that Ngfr may contribute to the social behavior of adult mice in the functional study, which provided meaningful clues to the pathogenesis of psychiatric disorders. Full article
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18 pages, 1736 KiB  
Article
Accuracy of EEG Biomarkers in the Detection of Clinical Outcome in Disorders of Consciousness after Severe Acquired Brain Injury: Preliminary Results of a Pilot Study Using a Machine Learning Approach
by Francesco Di Gregorio, Fabio La Porta, Valeria Petrone, Simone Battaglia, Silvia Orlandi, Giuseppe Ippolito, Vincenzo Romei, Roberto Piperno and Giada Lullini
Biomedicines 2022, 10(8), 1897; https://doi.org/10.3390/biomedicines10081897 - 05 Aug 2022
Cited by 41 | Viewed by 4350
Abstract
Accurate outcome detection in neuro-rehabilitative settings is crucial for appropriate long-term rehabilitative decisions in patients with disorders of consciousness (DoC). EEG measures derived from high-density EEG can provide helpful information regarding diagnosis and recovery in DoC patients. However, the accuracy rate of EEG [...] Read more.
Accurate outcome detection in neuro-rehabilitative settings is crucial for appropriate long-term rehabilitative decisions in patients with disorders of consciousness (DoC). EEG measures derived from high-density EEG can provide helpful information regarding diagnosis and recovery in DoC patients. However, the accuracy rate of EEG biomarkers to predict the clinical outcome in DoC patients is largely unknown. This study investigated the accuracy of psychophysiological biomarkers based on clinical EEG in predicting clinical outcomes in DoC patients. To this aim, we extracted a set of EEG biomarkers in 33 DoC patients with traumatic and nontraumatic etiologies and estimated their accuracy to discriminate patients’ etiologies and predict clinical outcomes 6 months after the injury. Machine learning reached an accuracy of 83.3% (sensitivity = 92.3%, specificity = 60%) with EEG-based functional connectivity predicting clinical outcome in nontraumatic patients. Furthermore, the combination of functional connectivity and dominant frequency in EEG activity best predicted clinical outcomes in traumatic patients with an accuracy of 80% (sensitivity = 85.7%, specificity = 71.4%). These results highlight the importance of functional connectivity in predicting recovery in DoC patients. Moreover, this study shows the high translational value of EEG biomarkers both in terms of feasibility and accuracy for the assessment of DoC. Full article
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15 pages, 3119 KiB  
Article
ERK1/2 Signalling Pathway Regulates Tubulin-Binding Cofactor B Expression and Affects Astrocyte Process Formation after Acute Foetal Alcohol Exposure
by Yin Zheng, Jiechao Huo, Mei Yang, Gaoli Zhang, Shanshan Wan, Xiaoqiao Chen, Bingqiu Zhang and Hui Liu
Brain Sci. 2022, 12(7), 813; https://doi.org/10.3390/brainsci12070813 - 22 Jun 2022
Cited by 2 | Viewed by 1958
Abstract
Foetal alcohol spectrum disorders (FASDs) are a spectrum of neurological disorders whose neurological symptoms, besides the neuronal damage caused by alcohol, may also be associated with neuroglial damage. Tubulin-binding cofactor B (TBCB) may be involved in the pathogenesis of FASD. To understand the [...] Read more.
Foetal alcohol spectrum disorders (FASDs) are a spectrum of neurological disorders whose neurological symptoms, besides the neuronal damage caused by alcohol, may also be associated with neuroglial damage. Tubulin-binding cofactor B (TBCB) may be involved in the pathogenesis of FASD. To understand the mechanism and provide new insights into the pathogenesis of FASD, acute foetal alcohol exposure model on astrocytes was established and the interference experiments were carried out. First, after alcohol exposure, the nascent astrocyte processes were reduced or lost, accompanied by the absence of TBCB expression and the disruption of microtubules (MTs) in processes. Subsequently, TBCB was silenced with siRNA. It was severely reduced or lost in nascent astrocyte processes, with a dramatic reduction in astrocyte processes, indicating that TBCB plays a vital role in astrocyte process formation. Finally, the regulating mechanism was studied and it was found that the extracellular signal-regulated protease 1/2 (ERK1/2) signalling pathway was one of the main pathways regulating TBCB expression in astrocytes after alcohol injury. In summary, after acute foetal alcohol exposure, the decreased TBCB in nascent astrocyte processes, regulated by the ERK1/2 signalling pathway, was the main factor leading to the disorder of astrocyte process formation, which could contribute to the neurological symptoms of FASD. Full article
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16 pages, 2727 KiB  
Article
Safety of Special Waveform of Transcranial Electrical Stimulation (TES): In Vivo Assessment
by Muhammad Adeel, Chun-Ching Chen, Bor-Shing Lin, Hung-Chou Chen, Jian-Chiun Liou, Yu-Ting Li and Chih-Wei Peng
Int. J. Mol. Sci. 2022, 23(12), 6850; https://doi.org/10.3390/ijms23126850 - 20 Jun 2022
Cited by 5 | Viewed by 2333
Abstract
Intermittent theta burst (iTBS) powered by direct current stimulation (DCS) can safely be applied transcranially to induce neuroplasticity in the human and animal brain cortex. tDCS-iTBS is a special waveform that is used by very few studies, and its safety needs to be [...] Read more.
Intermittent theta burst (iTBS) powered by direct current stimulation (DCS) can safely be applied transcranially to induce neuroplasticity in the human and animal brain cortex. tDCS-iTBS is a special waveform that is used by very few studies, and its safety needs to be confirmed. Therefore, we aimed to evaluate the safety of tDCS-iTBS in an animal model after brain stimulations for 1 h and 4 weeks. Thirty-one Sprague Dawley rats were divided into two groups: (1) short-term stimulation for 1 h/session (sham, low, and high) and (2) long-term for 30 min, 3 sessions/week for 4 weeks (sham and high). The anodal stimulation applied over the primary motor cortex ranged from 2.5 to 4.5 mA/cm2. The brain biomarkers and scalp tissues were assessed using ELISA and histological analysis (H&E staining) after stimulations. The caspase-3 activity, cortical myelin basic protein (MBP) expression, and cortical interleukin (IL-6) levels increased slightly in both groups compared to sham. The serum MBP, cortical neuron-specific enolase (NSE), and serum IL-6 slightly changed from sham after stimulations. There was no obvious edema or cell necrosis seen in cortical histology after the intervention. The short- and long-term stimulations did not induce significant adverse effects on brain and scalp tissues upon assessing biomarkers and conducting histological analysis. Full article
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15 pages, 3153 KiB  
Article
The Establishment of a Mouse Model of Recurrent Primary Dysmenorrhea
by Fang Hong, Guiyan He, Manqi Zhang, Boyang Yu and Chengzhi Chai
Int. J. Mol. Sci. 2022, 23(11), 6128; https://doi.org/10.3390/ijms23116128 - 30 May 2022
Cited by 8 | Viewed by 3088
Abstract
Primary dysmenorrhea is one of the most common reasons for gynecologic visits, but due to the lack of suitable animal models, the pathologic mechanisms and related drug development are limited. Herein, we establish a new mouse model which can mimic the periodic occurrence [...] Read more.
Primary dysmenorrhea is one of the most common reasons for gynecologic visits, but due to the lack of suitable animal models, the pathologic mechanisms and related drug development are limited. Herein, we establish a new mouse model which can mimic the periodic occurrence of primary dysmenorrhea to solve this problem. Non-pregnant female mice were pretreated with estradiol benzoate for 3 consecutive days. After that, mice were injected with oxytocin to simulate menstrual pain on the 4th, 8th, 12th, and 16th days (four estrus cycles). Assessment of the cumulative writhing score, uterine tissue morphology, and uterine artery blood flow and biochemical analysis were performed at each time point. Oxytocin injection induced an equally severe writhing reaction and increased PGF accompanied with upregulated expression of COX-2 on the 4th and 8th days. In addition, decreased uterine artery blood flow but increased resistive index (RI) and pulsatility index (PI) were also observed. Furthermore, the metabolomics analysis results indicated that arachidonic acid metabolism; linoleic acid metabolism; glycerophospholipid metabolism; valine, leucine, and isoleucine biosynthesis; alpha-linolenic acid metabolism; and biosynthesis of unsaturated fatty acids might play important roles in the recurrence of primary dysmenorrhea. This new mouse model is able to mimic the clinical characteristics of primary dysmenorrhea for up to two estrous cycles. Full article
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14 pages, 26214 KiB  
Article
Intraoperative Hypothermia Induces Vascular Dysfunction in the CA1 Region of Rat Hippocampus
by Tianjia Li, Guangyan Xu, Jie Yi and Yuguang Huang
Brain Sci. 2022, 12(6), 692; https://doi.org/10.3390/brainsci12060692 - 27 May 2022
Cited by 2 | Viewed by 2158
Abstract
Intraoperative hypothermia is very common and leads to memory decline. The hippocampus is responsible for memory formation. As a functional core area, the cornu ammonis 1 (CA1) region of the hippocampus contains abundant blood vessels and is susceptible to ischemia. The aim of [...] Read more.
Intraoperative hypothermia is very common and leads to memory decline. The hippocampus is responsible for memory formation. As a functional core area, the cornu ammonis 1 (CA1) region of the hippocampus contains abundant blood vessels and is susceptible to ischemia. The aim of the study was to explore vascular function and neuronal state in the CA1 region of rats undergoing intraoperative hypothermia. The neuronal morphological change and activity-regulated cytoskeleton-associated protein (Arc) expression were evaluated by haematoxylin-eosin staining and immunofluorescence respectively. Histology and immunohistochemistry were used to assess vascular function. Results showed that intraoperative hypothermia inhibited the expression of vascular endothelial growth factor and endothelial nitric oxide synthase, and caused reactive oxygen species accumulation. Additionally, the phenotype of vascular smooth muscle cells was transformed from contractile to synthetic, showing a decrease in smooth muscle myosin heavy chain and an increase in osteopontin. Ultimately, vascular dysfunction caused neuronal pyknosis in the CA1 region and reduced memory-related Arc expression. In conclusion, neuronal disorder in the CA1 region was caused by intraoperative hypothermia-related vascular dysfunction. This study could provide a novel understanding of the effect of intraoperative hypothermia in the hippocampus, which might identify a new research target and treatment strategy. Full article
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15 pages, 1392 KiB  
Article
The Cost of Imagined Actions in a Reward-Valuation Task
by Manuela Sellitto, Damiano Terenzi, Francesca Starita, Giuseppe di Pellegrino and Simone Battaglia
Brain Sci. 2022, 12(5), 582; https://doi.org/10.3390/brainsci12050582 - 29 Apr 2022
Cited by 9 | Viewed by 2996
Abstract
Growing evidence suggests that humans and other animals assign value to a stimulus based not only on its inherent rewarding properties, but also on the costs of the action required to obtain it, such as the cost of time. Here, we examined whether [...] Read more.
Growing evidence suggests that humans and other animals assign value to a stimulus based not only on its inherent rewarding properties, but also on the costs of the action required to obtain it, such as the cost of time. Here, we examined whether such cost also occurs for mentally simulated actions. Healthy volunteers indicated their subjective value for snack foods while the time to imagine performing the action to obtain the different stimuli was manipulated. In each trial, the picture of one food item and a home position connected through a path were displayed on a computer screen. The path could be either large or thin. Participants first rated the stimulus, and then imagined moving the mouse cursor along the path from the starting position to the food location. They reported the onset and offset of the imagined movements with a button press. Two main results emerged. First, imagery times were significantly longer for the thin than the large path. Second, participants liked significantly less the snack foods associated with the thin path (i.e., with longer imagery time), possibly because the passage of time strictly associated with action imagery discounts the value of the reward. Importantly, such effects were absent in a control group of participants who performed an identical valuation task, except that no action imagery was required. Our findings hint at the idea that imagined actions, like real actions, carry a cost that affects deeply how people assign value to the stimuli in their environment. Full article
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18 pages, 2750 KiB  
Article
Memory Enhancement with Kynurenic Acid and Its Mechanisms in Neurotransmission
by Diána Martos, Bernadett Tuka, Masaru Tanaka, László Vécsei and Gyula Telegdy
Biomedicines 2022, 10(4), 849; https://doi.org/10.3390/biomedicines10040849 - 05 Apr 2022
Cited by 57 | Viewed by 5867
Abstract
Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric [...] Read more.
Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric disorders such as depression and autism spectrum disorders, whereas a higher level of KYNA is associated with the pathogenesis of schizophrenia. Little is known about the optimal concentration for neuroprotection and the threshold for neurotoxicity. In this study the effects of KYNA on memory functions were investigated by passive avoidance test in mice. Six different doses of KYNA were administered intracerebroventricularly to previously trained CFLP mice and they were observed for 24 h. High doses of KYNA (i.e., 20–40 μg/2 μL) significantly decreased the avoidance latency, whereas a low dose of KYNA (0.5 μg/2 μL) significantly elevated it compared with controls, suggesting that the low dose of KYNA enhanced memory function. Furthermore, six different receptor blockers were applied to reveal the mechanisms underlying the memory enhancement induced by KYNA. The series of tests revealed the possible involvement of the serotonergic, dopaminergic, α and β adrenergic, and opiate systems in the nootropic effect. This study confirmed that a low dose of KYNA improved a memory component of cognitive domain, which was mediated by, at least in part, four systems of neurotransmission in an animal model of learning and memory. Full article
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