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Fisicaro F, Cortese K, Bella R, Pennisi M, Lanza G, Yuasa K, Ugawa Y, Terao Y. Effects of off-line auricular transcutaneous vagus nerve stimulation (taVNS) on a short-term memory task: a pilot study. Front Aging Neurosci 2025; 17:1549167. [PMID: 40357230 PMCID: PMC12066449 DOI: 10.3389/fnagi.2025.1549167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction One of the commonly used indices of short-term memory (STM) is the digit span task. Prior studies have proposed pupil dilation as a measure of task engagement and as a promising biomarker of vagal activation. Transcutaneous auricular vagus nerve stimulation (taVNS) is a novel non-invasive brain stimulation technique which might be used to improve cognition and modulate pupil size through its effects on the noradrenergic release in the locus coeruleus. No previous study has investigated the effects of off-line taVNS on a digit span task. With this single-blind, sham-controlled, crossover design trial, we aimed to assess whether taVNS was able to improve the digit span score, as well as to modulate the pupillary response to cognitive load in a sample of 18 elderly Japanese volunteers with no self-reported cognitive impairments. Results Subjects were randomized to receive either real or sham taVNS during a digit span task while recording the pupil size, and then switched over to the other treatment group. We found that real stimulation significantly reduced the mean number of errors performed at span length 7, 8, and 9 (-0.83, -0.90, and -0.39, respectively compared to pre-stimulation values, and -0.71, -1.08, and -0.79, respectively, compared to sham stimulation). Additionally, real taVNS stimulation slightly but significantly increased the pupil size at all span lengths during the encoding period of the task, with larger effects for span 7-10 compared to pre-stimulation, and for span 5-10 compared to sham. No effect over the pupil size was found during the recall period. Discussion Our results suggest that taVNS might selectively improve the cognitive performance during the encoding phase of the task. Although further studies are needed to better clarify the optimal stimulation parameters, findings from this study could support the use of taVNS as a safe neuromodulation technique to improve cognitive function.
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Affiliation(s)
- Francesco Fisicaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Department of Medical Physiology, Kyorin University, Shinkawa, Tokyo, Japan
| | - Klizia Cortese
- Department of Educational Sciences, University of Catania, Catania, Italy
| | - Rita Bella
- Department of Medical and Surgical Sciences and Advanced Technologies, University of Catania, Catania, Italy
| | - Manuela Pennisi
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Giuseppe Lanza
- Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy
- Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Troina, Italy
| | - Kaoru Yuasa
- Department of Medical Physiology, Kyorin University, Shinkawa, Tokyo, Japan
| | - Yoshikazu Ugawa
- Department of Human Neurophysiology, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yasuo Terao
- Department of Medical Physiology, Kyorin University, Shinkawa, Tokyo, Japan
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Rogóż Z, Kamińska K, Lorenc-Koci E, Wąsik A. Iron administered in the neonatal period changed memory, brain monoamine levels, and BDNF mRNA expression in adult Sprague-Dawley rats. Pharmacol Rep 2024; 76:1044-1054. [PMID: 39012420 PMCID: PMC11387440 DOI: 10.1007/s43440-024-00626-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/05/2024] [Accepted: 07/07/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND Iron is one of the key microelements in the mammalian body and is the most abundant metal in the brain. Iron, a very important chemical element in the body of mammals, is the most abundant metal in the brain. It participates in many chemical reactions taking place in the central nervous system acting as a cofactor in key enzymatic reactions involved in neurotransmitter synthesis and degradation, dendritic arborization, and myelination. Moreover, iron accumulation in the brain has been implicated in the pathogenesis of neurogenerative disorders. MATERIAL AND METHODS The aim of our study was to assess the influence of iron administered orally (30 mg/kg) to rats in the neonatal period (p12-p14) by testing the performance of rats in the open field and social interaction tests, and by evaluating the recognition memory, monoamine levels in some brain structures, and BDNF mRNA expression. The behavioral and biochemical tests were performed in adult p88-p92 rats. RESULTS Iron administered to rats in the neonatal period induced long-term deficits in behavioral tests in adult rats. It reduced the exploratory activity in the open field test. In the social interaction test, it induced deficits in the parameters studied, and decreased memory retention. Moreover, iron changed the brain monoamine levels in some studied brain structures and decreased the expression of BDNF mRNA in the hippocampus. CONCLUSIONS All earlier and our present results indicated that iron administered to rats in the neonatal period induced an increase in oxidative stress which resulted in a change in the brain monoamine levels and decreased BDNF mRNA expression which may play a role in iron-induced memory impairment in adult rats.
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Affiliation(s)
- Zofia Rogóż
- Department of Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland
| | - Kinga Kamińska
- Department of Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland
| | - Elżbieta Lorenc-Koci
- Department of Neuropsychopharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland
| | - Agnieszka Wąsik
- Department of Neurochemistry, Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland.
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Boyle N, Betts S, Lu H. Monoaminergic Modulation of Learning and Cognitive Function in the Prefrontal Cortex. Brain Sci 2024; 14:902. [PMID: 39335398 PMCID: PMC11429557 DOI: 10.3390/brainsci14090902] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/09/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
Extensive research has shed light on the cellular and functional underpinnings of higher cognition as influenced by the prefrontal cortex. Neurotransmitters act as key regulatory molecules within the PFC to assist with synchronizing cognitive state and arousal levels. The monoamine family of neurotransmitters, including dopamine, serotonin, and norepinephrine, play multifaceted roles in the cognitive processes behind learning and memory. The present review explores the organization and signaling patterns of monoamines within the PFC, as well as elucidates the numerous roles played by monoamines in learning and higher cognitive function.
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Affiliation(s)
| | | | - Hui Lu
- Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA; (N.B.); (S.B.)
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Koloski MF, Terry A, Lee N, Ramanathan DS. Methylphenidate, but not citalopram, decreases impulsive choice in rats performing a temporal discounting task. Front Psychiatry 2024; 15:1385502. [PMID: 38779546 PMCID: PMC11109432 DOI: 10.3389/fpsyt.2024.1385502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/23/2024] [Indexed: 05/25/2024] Open
Abstract
Introduction Drugs targeting monoamine systems remain the most common treatment for disorders with impulse control impairments. There is a body of literature suggesting that drugs affecting serotonin reuptake and dopamine reuptake can modulate distinct aspects of impulsivity - though such tests are often performed using distinct behavioral tasks prohibiting easy comparisons. Methods Here, we directly compare pharmacologic agents that affect dopamine (methylphenidate) vs serotonin (citalopram) manipulations on choice impulsivity in a temporal discounting task where rats could choose between a small, immediate reward or a large reward delayed at either 2 or 10s. In control conditions, rats preferred the large reward at a small (2s) delay and discounted the large reward at a long (10s) delay. Results Methylphenidate, a dopamine transport inhibitor that blocks reuptake of dopamine, dose-dependently increased large reward preference in the long delay (10s) block. Citalopram, a selective serotonin reuptake inhibitor, had no effect on temporal discounting behavior. Impulsive behavior on the temporal discounting task was at least partially mediated by the nucleus accumbens shell. Bilateral lesions to the nucleus accumbens shell reduced choice impulsivity during the long delay (10s) block. Following lesions, methylphenidate did not impact impulsivity. Discussion Our results suggest that striatal dopaminergic systems modulate choice impulsivity via actions within the nucleus accumbens shell, whereas serotonin systems may regulate different aspects of behavioral inhibition/impulsivity.
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Affiliation(s)
- Miranda F. Koloski
- Mental Health, VA San Diego Medical Center, San Diego, CA, United States
- Center of Excellence for Stress and Mental Health, VA San Diego Medical Center, San Diego, CA, United States
- Department of Psychiatry, University of California-San Diego, San Diego, CA, United States
| | - Alyssa Terry
- Mental Health, VA San Diego Medical Center, San Diego, CA, United States
| | - Noelle Lee
- Mental Health, VA San Diego Medical Center, San Diego, CA, United States
| | - Dhakshin S. Ramanathan
- Mental Health, VA San Diego Medical Center, San Diego, CA, United States
- Center of Excellence for Stress and Mental Health, VA San Diego Medical Center, San Diego, CA, United States
- Department of Psychiatry, University of California-San Diego, San Diego, CA, United States
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Rebouta J, Dória L, Coelho A, Fonseca MM, Castilla-Fernández G, Pires NM, Vieira-Coelho MA, Loureiro AI. HR/MS-based lipidome analysis of rat brain modulated by tolcapone. J Pharm Biomed Anal 2024; 241:115971. [PMID: 38266454 DOI: 10.1016/j.jpba.2024.115971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 01/06/2024] [Accepted: 01/07/2024] [Indexed: 01/26/2024]
Abstract
Lipids play key roles in the body, influencing cellular regulation, function, and signalling. Tolcapone, a potent catechol-O-methyltransferase (COMT) inhibitor described to enhance cognitive performance in healthy subjects, was previously shown to impact fatty acid β-oxidation and oxidative phosphorylation. However, its impact on the brain lipidome remains unexplored. Hence, this study aimed to assess how tolcapone affects the lipidome of the rat pre-frontal cortex (PFC), a region of the brain highly relevant to tolcapone therapeutic effect, while evaluating its influence on operant behaviour. Tolcapone at 20 mg/kg was chronically administered to Wistar rats during a behavioural task and an untargeted liquid chromatography high-resolution mass spectrometry (LC-HR/MS) approach was employed to profile lipid species. The untargeted analysis identified 7227 features, of which only 33% underwent statistical analysis following data pre-processing. The results revealed an improved cognitive performance and a lipidome remodelling promoted by tolcapone. The lipidomic analysis showed 32 differentially expressed lipid species in tolcapone-treated animals (FC ≥ 1.2, p-value ≤ 0.1), and among these several triacylglycerols, cardiolipins and N-acylethanolamine (NAE 16:2) were found upregulated whereas fatty acids, hexosylceramides, and several phospholipids including phosphatidylcholines and phosphatidylethanolamines were downregulated. These preliminary findings shed light on tolcapone impact on lipid pathways within the brain. Although tolcapone improved cognitive performance and literature suggests the significance of lipids in cognition, this study did not conclusively establish that lipids directly drove or contributed to this outcome. Nevertheless, it underscores the importance of lipid modulation and encourages further exploration of tolcapone-associated mechanisms in the central nervous system (CNS).
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Affiliation(s)
- Joana Rebouta
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, University of Porto, Porto, Portugal.
| | - Luísa Dória
- R&D department, BIAL - Portela & Cª - S.A., 4745-457 Coronado, S. Mamede e S. Romão, Portugal
| | - Ana Coelho
- R&D department, BIAL - Portela & Cª - S.A., 4745-457 Coronado, S. Mamede e S. Romão, Portugal
| | - Miguel M Fonseca
- R&D department, BIAL - Portela & Cª - S.A., 4745-457 Coronado, S. Mamede e S. Romão, Portugal
| | | | - Nuno M Pires
- R&D department, BIAL - Portela & Cª - S.A., 4745-457 Coronado, S. Mamede e S. Romão, Portugal
| | - M A Vieira-Coelho
- MedinUp - Center for Drug Discovery and Innovative Medicine, University of Porto, Porto, Portugal
| | - Ana I Loureiro
- R&D department, BIAL - Portela & Cª - S.A., 4745-457 Coronado, S. Mamede e S. Romão, Portugal
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Maximiliano JE, Ares I, Martínez M, Lopez-Torres B, Martínez-Larrañaga MR, Anadón A, Martínez MA. Dopaminergic and serotoninergic systems as preferential targets of the pyrethroid tefluthrin exposure in the rat brain. ENVIRONMENTAL RESEARCH 2024; 247:118239. [PMID: 38244974 DOI: 10.1016/j.envres.2024.118239] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 01/22/2024]
Abstract
The monoaminergic systems dopamine (DA) and serotonin (5-HT) play important roles in neuromodulation, such as motor control, cognitive, affective, and neuroendocrine functions. In the present research study, we addressed the hypothesis that exposure to Type I pyrethroid tefluthrin may specifically target the dopaminergic and serotoninergic systems. Tefluthrin could modify brain monoamine neurotransmitters, DA and 5-HT levels as well as dopaminergic and serotoninergic signaling pathways. Adult male Wistar rats were treated with tefluthrin [2.2, 4.4 and 5.5 mg/kg bw, equivalent to 1/10, 1/5 and 1/4 of the acute oral rat lethal dose 50 (LD50) value] by oral gavage, six days. After last dose of tefluthrin, DA and 5-HT and metabolites levels were determined in brain regions (striatum, hippocampus, prefrontal cortex and hypothalamus). Tefluthrin induced a decrease of DA, 5-HT and metabolites contents, in a brain regional- and dose-related manner. The major decreases in DA and 5-HT contents were observed in prefrontal cortex tissue. Here, we studied that in vivo exposure to tefluthrin may alter DA and 5-HT neurotransmission in prefrontal cortex. Transcripts related to (i) dopaminergic [dopamine transporter 1 (Dat1), tyrosine hydroxylase (TH), dopamine receptors (Drd1, Drd2)], (ii) serotoninergic [serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2), serotonin receptors (5-HT1A, 5-HT2A)] and (iii) DA and 5-HT degradation [monoamine oxidases (MAOA, MAOB)] signaling pathways were investigated. Results showed that tefluthrin induced down-regulation of transcripts responsible for the synthesis and action of DA (TH, Drd1, Drd2) and 5-HT (SERT, TPH2). In contrast, tefluthrin treatment induced up-regulation of genes involved in DA transporter (Dat1), 5-HT receptors (5-HT1A, 5-HT2A) and monoamine oxidases (MAOA, MAOB). Given the integral roles of mitochondrial dysfunction and dopaminergic and serotoninergic alterations as hallmarks of neurodegenerative diseases, our data suggest that tefluthrin may be a candidate for pesticides contributing to neurodegenerative disorders pathogenesis by causing damage to the DA and 5-HT systems.
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Affiliation(s)
- Jorge-Enrique Maximiliano
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Irma Ares
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
| | - Marta Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
| | - Bernardo Lopez-Torres
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - María-Rosa Martínez-Larrañaga
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Arturo Anadón
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - María-Aránzazu Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
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Spencer RC, Martin AJ, Devilbiss DM, Berridge CW. Cognition-enhancing and cognition-impairing doses of psychostimulants exert opposing actions on frontostriatal neural coding of delay in working memory. Neuropsychopharmacology 2024; 49:837-844. [PMID: 37741905 PMCID: PMC10948860 DOI: 10.1038/s41386-023-01738-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/25/2023]
Abstract
The prefrontal cortex (PFC) and extended frontostriatal circuitry play a critical role in executive cognitive processes that guide goal-directed behavior. Dysregulation of frontostriatal-dependent cognition is implicated in a variety of cognitive/behavioral disorders, including addiction and attention deficit hyperactivity disorder (ADHD). Psychostimulants exert dose-dependent and opposing actions on frontostriatal cognitive function. Specifically, low and clinically-relevant doses improve, while higher doses associated with abuse and addiction impair, frontostriatal-dependent cognitive function. Frontostriatal cognition is supported by the coordinated activity of neurons across this circuit. To date, the neural coding mechanisms that support the diverse cognitive actions of psychostimulants are unclear. This represents a significant deficit in our understanding of the neurobiology of frontostriatal cognition and limits the development of novel treatments for frontostriatal cognitive impairment. The current studies examined the effects of cognition-enhancing and cognition-impairing doses of methylphenidate (MPH) on the spiking activity of dorsomedial PFC (dmPFC) and dorsomedial striatal (dmSTR) neurons in 17 male rats engaged in a working memory task. Across this frontostriatal circuit, we observed opposing actions of low- and high-dose MPH on the population-based representation of delay: low-dose strengthened, while high-dose weakened, representation of this event. MPH elicited a more complex pattern of actions on reward-related signaling, that were highly dose-, region- and neuron-dependent. These observations provide novel insight into the neurophysiological mechanisms that support the cognitive actions of psychostimulants.
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Affiliation(s)
- Robert C Spencer
- Department of Psychology, University of Wisconsin-Madison, Madison, WI, 53706, USA.
| | - Andrea J Martin
- Department of Psychology, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - David M Devilbiss
- Department of Cell Biology and Neuroscience, Rowan University, 2 Medical Center Drive, SC220, Stratford, NJ, 08084, USA
| | - Craig W Berridge
- Department of Psychology, University of Wisconsin-Madison, Madison, WI, 53706, USA
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Song G, Zhao Q, Chen H, Li M, Zhang Z, Qu Z, Yang C, Lin X, Ma W, Standlee CR. Toxoplasma gondii seropositivity and cognitive functioning in older adults: an analysis of cross-sectional data of the National Health and Nutrition Examination Survey 2011-2014. BMJ Open 2024; 14:e071513. [PMID: 38448067 PMCID: PMC10916126 DOI: 10.1136/bmjopen-2022-071513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/14/2024] [Indexed: 03/08/2024] Open
Abstract
OBJECTIVES This study sought to examine the relationship between Toxoplasma gondii seropositivity and cognitive function in older adults. DESIGN An observational cross-sectional study. SETTING The National Health and Nutrition Examination Survey (NHANES) study took place at participants' homes and mobile examination centres. PARTICIPANTS A total of 2956 older adults aged 60 and above from the NHANES from 2011 to 2014 were included in the study. Exposure of interest: participants had serum Toxoplasma gondii antibody analysed in the laboratory. A value>33 IU/mL was categorised as seropositive for Toxoplasma gondii infection; <27 IU/mL was categorised as seronegative for Toxoplasma gondii infection. PRIMARY AND SECONDARY OUTCOME MEASURES Cognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest (CERAD-WL) for immediate and delayed memory, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). RESULTS About half of the 2956 participants (mean age 70.0) were female (51.0%), non-Hispanic White (48.3%), and completed some college or above (48.3%). A total of 703 participants were positive for Toxoplasma gondii infection (23.8%). Adjusted linear regression showed that compared with participants with negative Toxoplasma gondii infection, those with positive Toxoplasma gondii infection had lower CERAD-WL immediate memory (beta (β) -0.16, 95% CI -0.25 to -0.07), CERAD-WL delayed memory (β -0.15, 95% CI -0.24 to -0.06), AFT (β -0.15, 95% CI -0.24 to -0.06), DSST (β -0.34, 95% CI -0.43 to -0.26), and global cognition (β -0.24, 95% CI -0.32 to -0.16) z-scores after controlling for the covariates. CONCLUSIONS Toxoplasma gondii seropositivity is associated with worse immediate and delayed verbal learning, language proficiency, executive functioning, processing speed, sustained attention, working memory, as well as global cognition in older adults. Public health measures aiming at preventing Toxoplasma gondii infection may help preserve cognitive functioning in older adults.
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Affiliation(s)
- Ge Song
- College of Sciences and Technology, University of Houston Downtown, Houston, Texas, USA
| | - Qingxia Zhao
- School of Nursing, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongyu Chen
- School of Nursing, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meng Li
- Kentucky Department for Public Health, Infectious Disease Branch, Frankfort, Kentucky, USA
| | - Zeyu Zhang
- Institute for Hospital Management, Tsinghua University, Beijing, China
| | - Zhe Qu
- Department of Pediatric Respiratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chao Yang
- University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xuechun Lin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Weixia Ma
- Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Victor TS, Jacquet B, El Massioui F. Exploring stress response's role in executive function impairments among adults with early adverse childhood experiences. Sci Rep 2024; 14:4081. [PMID: 38374227 PMCID: PMC10876952 DOI: 10.1038/s41598-024-53819-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 02/05/2024] [Indexed: 02/21/2024] Open
Abstract
Adverse childhood experiences (ACEs) are recognised as precursors to numerous physical and mental health challenges. However, research on their impact on inhibitory control and working memory, particularly among healthy young adults, remains limited. The role played by the stress response as a moderator in these effects is likewise underexplored. Our study addresses this gap by examining cognitive impairments in non-clinical adults with early childhood trauma, specifically trauma before the age of 13 years, and by assessing the influence of the stress response on these effects. A total of 15 participants with early ACEs were compared with a control group (n = 18) using the Corsi Block Tapping Test (CBTT) and Stroop Word Colour Test (SCWT). Results showed that participants with early ACEs exhibited lower scores on the SCWT but not the CBTT. The stress response emerged as a potential factor in the relationship between early ACEs and cognitive performance. The implications of these findings are then discussed in relation to the existing literature.
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Affiliation(s)
- Taïna Steevine Victor
- Université Paris 8, UFR Psychologie, 93200, Saint-Denis, France.
- Laboratoire Cognition Humaine et Artificielle (CHArt, RNSR 200515259U), 93322, Aubervilliers, France.
| | - Baptiste Jacquet
- Université Paris 8, UFR Psychologie, 93200, Saint-Denis, France
- Laboratoire Cognition Humaine et Artificielle (CHArt, RNSR 200515259U), 93322, Aubervilliers, France
| | - Farid El Massioui
- Université Paris 8, UFR Psychologie, 93200, Saint-Denis, France
- Laboratoire Cognition Humaine et Artificielle (CHArt, RNSR 200515259U), 93322, Aubervilliers, France
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Mastwal S, Li X, Stowell R, Manion M, Zhang W, Kim NS, Yoon KJ, Song H, Ming GL, Wang KH. Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function. eLife 2023; 12:RP87414. [PMID: 37830916 PMCID: PMC10575630 DOI: 10.7554/elife.87414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023] Open
Abstract
Dopamine system dysfunction is implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive and novel paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in Arc or Disc1 to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc-/- mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in Disc1+/- mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.
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Affiliation(s)
- Surjeet Mastwal
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental HealthBethesdaUnited States
| | - Xinjian Li
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental HealthBethesdaUnited States
| | - Rianne Stowell
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester Medical CenterRochesterUnited States
| | - Matthew Manion
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental HealthBethesdaUnited States
| | - Wenyu Zhang
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental HealthBethesdaUnited States
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester Medical CenterRochesterUnited States
| | - Nam-Shik Kim
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Ki-Jun Yoon
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Hongjun Song
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Guo-Li Ming
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Kuan Hong Wang
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental HealthBethesdaUnited States
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester Medical CenterRochesterUnited States
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Mastwal S, Li X, Stowell R, Manion M, Zhang W, Kim NS, Yoon KJ, Song H, Ming GL, Wang KH. Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.03.526987. [PMID: 36778456 PMCID: PMC9915739 DOI: 10.1101/2023.02.03.526987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in the Arc or DISC1 genes to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc mutant mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in DISC1 mutant mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.
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Affiliation(s)
- Surjeet Mastwal
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental Health, Bethesda, MD 20892
| | - Xinjian Li
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental Health, Bethesda, MD 20892
| | - Rianne Stowell
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester Medical Center, Rochester, NY 14642
| | - Matthew Manion
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental Health, Bethesda, MD 20892
| | - Wenyu Zhang
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental Health, Bethesda, MD 20892
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester Medical Center, Rochester, NY 14642
| | - Nam-Shik Kim
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Ki-jun Yoon
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Hongjun Song
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Guo-li Ming
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Kuan Hong Wang
- Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental Health, Bethesda, MD 20892
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester Medical Center, Rochester, NY 14642
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12
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Amano Y, Koizumi K, Takizawa H, Hamaguchi T. Cravings for alcohol in alcohol use disorders are associated with attention deviation to alcohol: An observational study of Japanese in-patients. Medicine (Baltimore) 2023; 102:e33222. [PMID: 36897713 PMCID: PMC9997779 DOI: 10.1097/md.0000000000033222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/16/2023] [Indexed: 03/11/2023] Open
Abstract
Alcohol use disorder (AUD) may be associated with increased attentional bias (AB) toward alcohol-related information. Accordingly, our aim was to explore the relationships between alcohol-related AB, cravings, and risk of relapse among individuals with AUD after treatment. The study group included 24 in-patients with AUD who had completed alcohol withdrawal management. AB was evaluated using an image-based task, with participants asked to select the nonalcoholic image as fast and as accurately as possible and the response time (RT) measured. The intensity of the desire to drink was evaluated using a 100-mm Visual Analog Scale and the risk of relapse using the Alcohol Relapse Risk Scale. Linear regression was used to evaluate the relationship between these variables, with age, gender, duration of hospitalization, and depression score used as covariates. Intensity of cravings was significantly associated with AB RT (R2 =.625) and risk of relapse of drinking behavior (Alcohol Relapse Risk Scale score, R2 =.64). Gender and γ-GTP were significant explanatory variables of identified relationships. The main limitations of our study are a higher proportion of men than women in our study group and the absence of a control group for baseline comparison of AB RTs. This study results suggested that the desire to drink is related to AB among patients with AUD and that the intensity of the desire to drink is related to the risk of a relapse in drinking behavior after AUD treatment.
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Affiliation(s)
- Yoshifumi Amano
- Department of Rehabilitation, Graduate School of Health Science, Saitama Prefectural University, Koshigaya, Saitama, Japan
| | - Kouhei Koizumi
- Department of Rehabilitation, Graduate School of Health Science, Saitama Prefectural University, Koshigaya, Saitama, Japan
| | - Hirokazu Takizawa
- Department of Rehabilitation, Graduate School of Health Science, Saitama Prefectural University, Koshigaya, Saitama, Japan
| | - Toyohiro Hamaguchi
- Department of Rehabilitation, Graduate School of Health Science, Saitama Prefectural University, Koshigaya, Saitama, Japan
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13
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Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans. Commun Biol 2023; 6:166. [PMID: 36765261 PMCID: PMC9918528 DOI: 10.1038/s42003-023-04545-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 02/01/2023] [Indexed: 02/12/2023] Open
Abstract
Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.
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14
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Heldmann M, Mönch E, Kesseböhmer A, Brüggemann N, Münte TF, Ye Z. Pramipexole modulates fronto-subthalamic pathway in sequential working memory. Neuropsychopharmacology 2022; 48:716-723. [PMID: 36352204 PMCID: PMC10066371 DOI: 10.1038/s41386-022-01494-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 10/23/2022] [Accepted: 10/26/2022] [Indexed: 11/10/2022]
Abstract
Brain dopamine may regulate the ability to maintain and manipulate sequential information online. However, the precise role of dopamine remains unclear. This pharmacological fMRI study examined whether and how the dopamine D2/3 receptor agonist pramipexole modulates fronto-subthalamic or fronto-striatal pathways during sequential working memory. This study used a double-blind, randomized crossover design. Twenty-two healthy male volunteers completed a digit ordering task during fMRI scanning after receiving a single oral dose of 0.5-mg pramipexole or placebo. The pramipexole effects on task performance, regional activity, activity pattern similarity, and functional connectivity were analyzed. Pramipexole impaired task performance, leading to less accurate and slower responses in the digit ordering task. Also, it downregulated the maintenance-related subthalamic and dorsolateral prefrontal activity, increasing reaction times for maintaining sequences. In contrast, pramipexole upregulated the manipulation-related subthalamic and dorsolateral prefrontal activity, increasing reaction time costs for manipulating sequences. In addition, it altered the dorsolateral prefrontal activity pattern similarity and fronto-subthalamic functional connectivity. Finally, pramipexole reduced maintenance-related striatal activity, which did not affect the behavior. This study confirms the role of the fronto-subthalamic pathway in sequential working memory. Furthermore, it shows that D2 transmission can regulate sequential working memory by modulating the fronto-subthalamic pathway.
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Affiliation(s)
- Marcus Heldmann
- Department of Neurology, University of Lübeck, Lübeck, 23538, Germany.,Institute of Psychology II, University of Lübeck, Lübeck, 23538, Germany
| | - Eliana Mönch
- Department of Neurology, University of Lübeck, Lübeck, 23538, Germany
| | | | - Norbert Brüggemann
- Department of Neurology, University of Lübeck, Lübeck, 23538, Germany.,Institute of Neurogenetics, University of Lübeck, Lübeck, 23538, Germany
| | - Thomas F Münte
- Department of Neurology, University of Lübeck, Lübeck, 23538, Germany. .,Institute of Psychology II, University of Lübeck, Lübeck, 23538, Germany.
| | - Zheng Ye
- Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
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15
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Schacht JP, Yeongbin Im, Hoffman M, Voronin KE, Book SW, Anton RF. Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone. Neuropsychopharmacology 2022; 47:1953-1960. [PMID: 35523943 PMCID: PMC9073504 DOI: 10.1038/s41386-022-01335-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/25/2022] [Indexed: 11/09/2022]
Abstract
Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone's effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934.
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Affiliation(s)
- Joseph P Schacht
- Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
| | - Yeongbin Im
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Michaela Hoffman
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Konstantin E Voronin
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Sarah W Book
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Raymond F Anton
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
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16
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Armenta-Resendiz M, Assali A, Tsvetkov E, Cowan CW, Lavin A. Repeated methamphetamine administration produces cognitive deficits through augmentation of GABAergic synaptic transmission in the prefrontal cortex. Neuropsychopharmacology 2022; 47:1816-1825. [PMID: 35788684 PMCID: PMC9372065 DOI: 10.1038/s41386-022-01371-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/14/2022] [Accepted: 06/22/2022] [Indexed: 11/08/2022]
Abstract
Methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. Using PV-Cre transgenic rats that went through a METH sensitization regime or saline (SAL) followed by 7-10 days of home cage abstinence combined with cognitive tests, chemogenetic experiments, and whole-cell patch recordings on the prelimbic prefrontal cortex (PFC), we investigated the cellular and synaptic mechanisms underlying METH-induce hypofrontality. We report here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the PFC. The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, repeated METH administration increases the intrinsic excitability of parvalbumin-positive fast spiking interneurons (PV + FSIs), a key local interneuron population in PFC that contributes to the control of inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV + FSIs activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. Conversely, reducing PV + FSIs activity in the PFC of METH-exposed rats rescues METH-induced temporal order memory deficits. Together, our findings reveal that repeated METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV + FSIs activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from METH use disorder.
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Affiliation(s)
| | - Ahlem Assali
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Evgeny Tsvetkov
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Christopher W Cowan
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Antonieta Lavin
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
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17
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Rogóż Z, Lech MA, Chamera K, Wąsik A. The Effect of Glutathione Deficit During Early Postnatal Brain Development on the Prepulse Inhibition and Monoamine Levels in Brain Structures of Adult Sprague-Dawley Rats. Neurotox Res 2022; 40:733-750. [PMID: 35386024 DOI: 10.1007/s12640-022-00496-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/07/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
Abstract
Recent studies suggest that impaired glutathione synthesis and distorted dopaminergic transmission are important factors in the pathophysiology of schizophrenia. In the present study, on the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, L-buthionine-(S,R)- sulfoximine (BSO, 3.8 or 7.6 mmol/kg), and the dopamine uptake inhibitor, GBR 12,909 (5 mg/kg) alone or in combination, and prepulse inhibition of the acoustic startle response (PPI) was evaluated in adult 90-day-old rats. Moreover, the monoamine levels in the cortex and hippocampus of 16-day-old rats or 91-day-old rats were measured. The present results showed that administration of BSO at 3.8 mmol/kg led to a decreasing tendency in PPI for all tested prepulse intensities. In contrast, a combined treatment with BSO in both studied doses and GBR 12,909 did not induce significant deficits in PPI. Moreover, the results of biochemical studies indicated that treatment with BSO or GBR 12,909 alone induced a weak increase in the activity of dopaminergic, serotonergic, and noradrenergic systems in the frontal cortex and hippocampus of 16-day-old rats and 91-day-old rats. However, the combined administration of both substances allowed for maintaining the normal activity of monoaminergic systems in the rat brain. The most significant changes in the functioning of monoaminergic systems were observed in the frontal cortex of 16-day-old rats. Therefore, it seems that the frontal cortex of rat puppies is most sensitive to glutathione deficiencies resulting in increased oxidative stress in neurons. As a result, it can lead to cognitive and memory impairment.
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Affiliation(s)
- Zofia Rogóż
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Marta A Lech
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Katarzyna Chamera
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Agnieszka Wąsik
- Department of Neurochemistry, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland.
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18
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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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19
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COMT Val/Met and Psychopathic Traits in Children and Adolescents: A Systematic Review and New Evidence of a Developmental Trajectory toward Psychopathy. Int J Mol Sci 2022; 23:ijms23031782. [PMID: 35163702 PMCID: PMC8836546 DOI: 10.3390/ijms23031782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/29/2022] [Accepted: 01/31/2022] [Indexed: 12/10/2022] Open
Abstract
Psychopathic traits in youth may lead to adult criminal behaviors/psychopathy. The Val158Met polymorphism of catechol-O-methyltransferase (COMT) may influence the risk for psychopathy-related behaviors, while acting as a biomarker for predicting treatment response to dopaminergic medications. The literature shows inconsistent findings, making the interpretation of COMT's role difficult. The aims of this article are (i) to conduct a systematic review to analyze the effects of COMT Val158Met on psychopathic traits in children and adolescents, and (ii) to present new evidence on the developmental trajectory of the association of Val158Met and youth psychopathic traits. For the systematic review, a literature search was conducted using PubMed, EMBASE, OVID Medline and PsychINFO with the search terms for psychopathic traits, Val158Met and age of interest. In our genotype study, the COMT Val158Met genotype of 293 youth with European ancestry was analyzed in association with the psychopathy-related behavior scores from the Child Behavior Checklist and the Psychopathy Screening Device. To examine the potential influence of developmental changes, the sample was split into at or above and below age 13, and analyses were performed in males and females separately. The literature search yielded twenty-eight articles to be included in the systematic review, which demonstrated mixed results on the association depending on environmental factors, sex ratios, age groups and behavioral disorder diagnoses. The results from our genotype study revealed that Met homozygous youth in the below age 13 group and conversely Val carrier youth in the above age 13 group were more likely to display psychopathic traits. To our knowledge, this is the first study to systematically review the effects of COMT Val158Met on psychopathic traits in childhood and adolescence, and to provide new evidence on the changing effects of Val158Met on psychopathy-related behaviors with development. Elucidating the role of the COMT genotype in conjunction with the child versus adolescent stage of development for psychopathic traits may help predict treatment response, and may lead to early intervention and prevention strategies.
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20
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Beals N, Farhath MM, Kharel P, Croos B, Mahendran T, Johnson J, Basu S. Rationally designed DNA therapeutics can modulate human TH expression by controlling specific GQ formation in its promoter. Mol Ther 2022; 30:831-844. [PMID: 33992806 PMCID: PMC8822133 DOI: 10.1016/j.ymthe.2021.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 05/05/2021] [Accepted: 05/11/2021] [Indexed: 02/04/2023] Open
Abstract
Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the catecholamine (CA) biosynthesis pathway, making TH a molecular target for controlling CA production, specifically dopamine. Dysregulation of dopamine is correlated with neurological diseases such as Parkinson's disease (PD) and post-traumatic stress disorder (PTSD), among others. Previously, we showed that a 49-nucleotide guanine (G)-rich sequence within the human TH promoter adopts two different sets of G-quadruplex (GQ) structures (5'GQ and 3'GQ), where the 5'GQ uses G-stretches I, II, IV, and VI in TH49, which enhances TH transcription, while the 3'GQ utilizes G-stretches II, IV, VI, and VII, which represses transcription. Herein, we demonstrated targeted switching of these GQs to their active state using rationally designed DNA GQ Clips (5'GQ and 3'GQ Clips) to modulate endogenous TH gene expression and dopamine production. As a translational approach, we synthesized a targeted nanoparticle delivery system to effectively deliver the 5'GQ Clip in vivo. We believe this strategy could potentially be an improved approach for controlling dopamine production in a multitude of neurological disorders, including PD.
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Affiliation(s)
- Nathan Beals
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA,Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA
| | - Mohamed M. Farhath
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA,Department of Chemical Sciences, Faculty of Applied Sciences, South Eastern University of Sri Lanka, Oluvil, Sri Lanka
| | - Prakash Kharel
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA,Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA,Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Brintha Croos
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA
| | - Thulasi Mahendran
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA
| | - John Johnson
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Soumitra Basu
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA,Corresponding author: Soumitra Basu, Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA.
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21
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Physical Stress Attenuates Cognitive Inhibition: An fNIRS Examination. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1395:29-33. [PMID: 36527609 DOI: 10.1007/978-3-031-14190-4_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
This study aimed to assess the haemodynamics in the prefrontal cortex (PFC) and salivary α-amylase (sAA) response during acute physical stress. Acute stress was induced using the cold pressor task (CPT). The haemodynamics in the prefrontal cortex was measured using functional near-infrared spectroscopy (fNIRS). The Stroop test was performed and the sAA levels were measured before and after the task. The accuracy rate (%) of the Stroop test decreased significantly in the stress group (t = 2.80, p = 0.008) but not the control group (t = -1.05, p = 0.298). The results showed that oxyHb activation in the mid-left and mid-right regions of PFC after the CPT. The sAA levels significantly increased during and after the CPT in the stress group (U/ml, 2527.58 ± 437.54, mean ± SD, n = 26) but not the control group (U/ml, 1506.92 ± 291.05, n = 23). Our data showed that the acute stress exposure attenuated cognitive inhibition, which may be due to changes of scalp blood flow and/or cerebral haemodynamics near the mid-left PFC and mid-right PFC following acute stress.
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22
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Sex differences in methylphenidate-induced dopamine increases in ventral striatum. Mol Psychiatry 2022; 27:939-946. [PMID: 34707237 PMCID: PMC9043036 DOI: 10.1038/s41380-021-01294-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 08/16/2021] [Accepted: 09/08/2021] [Indexed: 12/02/2022]
Abstract
Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [11C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).
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Nosjean A, Granon S. Brain Adaptation to Acute Stress: Effect of Time, Social Buffering, and Nicotinic Cholinergic System. Cereb Cortex 2021; 32:3990-4011. [PMID: 34905774 DOI: 10.1093/cercor/bhab461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 11/13/2022] Open
Abstract
Both social behavior and stress responses rely on the activity of the prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) and on cholinergic transmission. We previously showed in adult C57BL/6J (B6) mice that social interaction has a buffering effect on stress-related prefrontal activity, depending on the β2-/- cholinergic nicotinic receptors (nAChRs, β2-/- mice). The latency for this buffer to emerge being short, we question here whether the associated brain plasticity, as reflected by regional c-fos protein quantification and PFC-BLA functional connectivity, is modulated by time. Overall, we show that time normalized the stress-induced PFC hyperactivation in B6 mice and PFC hypo-activation in β2-/- mice, with no effect on BLA. It also triggered a multitude of functional links between PFC subareas, and between PFC and BLA in B6 mice but not β2-/- mice, showing a central role of nAChRs in this plasticity. Coupled with social interaction and time, stress led to novel and drastic diminution of functional connectivity within the PFC in both genotypes. Thus, time, emotional state, and social behavior induced dissociated effects on PFC and BLA activity and important cortico-cortical reorganizations. Both activity and plasticity were under the control of the β2-nAChRs.
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Affiliation(s)
- Anne Nosjean
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay (NeuroPSI), 91400 Saclay, France
| | - Sylvie Granon
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay (NeuroPSI), 91400 Saclay, France
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de Haan L, Sutterland AL, Schotborgh JV, Schirmbeck F, de Haan L. Association of Toxoplasma gondii Seropositivity With Cognitive Function in Healthy People: A Systematic Review and Meta-analysis. JAMA Psychiatry 2021; 78:1103-1112. [PMID: 34259822 PMCID: PMC8281022 DOI: 10.1001/jamapsychiatry.2021.1590] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPORTANCE The parasite Toxoplasma gondii has been associated with behavioral alterations and psychiatric disorders. Studies investigating neurocognition in people with T gondii infection have reported varying results. To systematically analyze these findings, a meta-analysis evaluating cognitive function in healthy people with and without T gondii seropositivity is needed. OBJECTIVE To assess whether and to what extent T gondii seropositivity is associated with cognitive function in otherwise healthy people. DATA SOURCES A systematic search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. A systematic search of PubMed, MEDLINE, Web of Science, PsycInfo, and Embase was performed to identify studies from database inception to June 7, 2019, that analyzed cognitive function among healthy participants with available data on T gondii seropositivity. Search terms included toxoplasmosis, neurotoxoplasmosis, Toxoplasma gondii, cognition disorder, neuropsychological, and psychomotor performance. STUDY SELECTION Studies that performed cognitive assessment and analyzed T gondii seroprevalence among otherwise healthy participants were included. DATA EXTRACTION AND SYNTHESIS Two researchers independently extracted data from published articles; if needed, authors were contacted to provide additional data. Quantitative syntheses were performed in predefined cognitive domains when 4 independent data sets per domain were available. Study quality, heterogeneity, and publication bias were assessed. MAIN OUTCOMES AND MEASURES Performance on neuropsychological tests measuring cognitive function. RESULTS The systematic search yielded 1954 records. After removal of 533 duplicates, an additional 1363 records were excluded based on a review of titles and abstracts. A total of 58 full-text articles were assessed for eligibility (including reference list screening); 45 articles were excluded because they lacked important data or did not meet study inclusion or reference list criteria. The remaining 13 studies comprising 13 289 healthy participants (mean [SD] age, 46.7 [16.0] years; 6586 men [49.6%]) with and without T gondii seropositivity were included in the meta-analysis. Participants without T gondii seropositivity had favorable functioning in 4 cognitive domains: processing speed (standardized mean difference [SMD], 0.12; 95% CI, 0.05-0.19; P = .001), working memory (SMD, 0.16; 95% CI, 0.06-0.26; P = .002), short-term verbal memory (SMD, 0.18; 95% CI, 0.09-0.27; P < .001), and executive functioning (SMD, 0.15; 95% CI, 0.01-0.28; P = .03). A meta-regression analysis found a significant association between older age and executive functioning (Q = 6.17; P = .01). Little suggestion of publication bias was detected. CONCLUSIONS AND RELEVANCE The study's findings suggested that T gondii seropositivity was associated with mild cognitive impairment in several cognitive domains. Although effect sizes were small, given the ubiquitous prevalence of this infection globally, the association with cognitive impairment could imply a considerable adverse effect at the population level. Further research is warranted to investigate the underlying mechanisms of this association.
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Affiliation(s)
- Lies de Haan
- Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Arjen L. Sutterland
- Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Jasper V. Schotborgh
- Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Frederike Schirmbeck
- Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Lieuwe de Haan
- Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
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25
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Johnny M, Goodarzi N, Bazm MA. Histological, transmission electron microscopic, and immunohistochemical study of the adrenal gland in the Persian squirrel (Sciurus anomalus). Microsc Res Tech 2021; 85:738-747. [PMID: 34553804 DOI: 10.1002/jemt.23945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/17/2021] [Accepted: 09/13/2021] [Indexed: 11/12/2022]
Abstract
This research was aimed to present the histological and ultrastructure properties of the adrenal gland in the Persian squirrel. Two male and female animals were included in the study. The adrenal gland was bean-shaped and located on the cranial pole of kidney. The enveloping capsule was dense connective tissue that reacted positively with Periodic-Acid Schiff (PAS) and Masson trichrome stainings. The parenchyma of the gland consisted of two-part, namely cortex and medulla; the cortex had three layers: zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR). The cells of the ZG were mainly spherical and ovoid with circular arrangement and few lipid droplets in TEM micrographs. The cells of the ZF were columnar and spherical that were arranged in cord-like rows. Transmission electron microscopy (TEM) indicated conspicuous lipid droplets and mitochondria in this zone. The cells of the ZR were arranged in a tangled networks and were almost similar to those in the ZF. TEM images showed fewer lipid vesicles in the ZR compared to the ZF and ZG. Chromaffin cells were located in the medulla of the adrenal gland in two layers. TEM images showed that some of them were smaller and contained fewer secretory granules; other cells were larger and contained more electron-dense secretory granules. Immunofluorescence staining showed that steroidogenic factor 1 (SF1) expressed from cortex to the corticomedullary junction (CMJ) and tyrosine hydroxylase (TH) expressed in the medulla. In conclusion, the results indicated both similarities and differences between the adrenal gland of the Persian squirrel and other animals such as mammals and rodents.
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Affiliation(s)
- Mahshid Johnny
- Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Nader Goodarzi
- Department of Basic Sciences and Pathobiology, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Mohsen Akbari Bazm
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Kosillo P, Bateup HS. Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models. Front Neural Circuits 2021; 15:700968. [PMID: 34366796 PMCID: PMC8343025 DOI: 10.3389/fncir.2021.700968] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by altered social interaction and communication, and repetitive, restricted, inflexible behaviors. Approximately 1.5-2% of the general population meet the diagnostic criteria for ASD and several brain regions including the cortex, amygdala, cerebellum and basal ganglia have been implicated in ASD pathophysiology. The midbrain dopamine system is an important modulator of cellular and synaptic function in multiple ASD-implicated brain regions via anatomically and functionally distinct dopaminergic projections. The dopamine hypothesis of ASD postulates that dysregulation of dopaminergic projection pathways could contribute to the behavioral manifestations of ASD, including altered reward value of social stimuli, changes in sensorimotor processing, and motor stereotypies. In this review, we examine the support for the idea that cell-autonomous changes in dopaminergic function are a core component of ASD pathophysiology. We discuss the human literature supporting the involvement of altered dopamine signaling in ASD including genetic, brain imaging and pharmacologic studies. We then focus on genetic mouse models of syndromic neurodevelopmental disorders in which single gene mutations lead to increased risk for ASD. We highlight studies that have directly examined dopamine neuron number, morphology, physiology, or output in these models. Overall, we find considerable support for the idea that the dopamine system may be dysregulated in syndromic ASDs; however, there does not appear to be a consistent signature and some models show increased dopaminergic function, while others have deficient dopamine signaling. We conclude that dopamine dysregulation is common in syndromic forms of ASD but that the specific changes may be unique to each genetic disorder and may not account for the full spectrum of ASD-related manifestations.
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Affiliation(s)
- Polina Kosillo
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States
| | - Helen S. Bateup
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States
- Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, United States
- Chan Zuckerberg Biohub, San Francisco, CA, United States
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27
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Urbin MA, Lafe CW, Simpson TW, Wittenberg GF, Chandrasekaran B, Weber DJ. Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans. Brain Stimul 2021; 14:990-1001. [PMID: 34154980 DOI: 10.1016/j.brs.2021.06.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 06/01/2021] [Accepted: 06/07/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Transcutaneous stimulation of the external ear is thought to recruit afferents of the auricular vagus nerve, providing a means to activate noradrenergic pathways in the central nervous system. Findings from human studies examining the effects of auricular stimulation on noradrenergic biomarkers have been mixed, possibly relating to the limited and variable parameter space explored to date. OBJECTIVE We tested the extent to which brief pulse trains applied to locations of auricular innervation (canal and concha) elicit acute pupillary responses (PRs) compared to a sham location (lobe). Pulse amplitude and frequency were varied systematically to examine effects on PR features. METHODS Participants (n = 19) underwent testing in three separate experiments, each with stimulation applied to a different external ear location. Perceptual threshold (PT) was measured at the beginning of each experiment. Pulse trains (∼600 ms) consisting of different amplitude (0.0xPT, 0.8xPT, 1.0xPT, 1.5xPT, 2.0xPT) and frequency (25 Hz, 300 Hz) combinations were administered during eye tracking procedures. RESULTS Stimulation to all locations elicited PRs which began approximately halfway through the pulse train and peaked shortly after the final pulse (≤1 s). PR size and incidence increased with pulse amplitude and tended to be greatest with canal stimulation. Higher pulse frequency shortened the latency of PR onset and peak dilation. Changes in pupil diameter elicited by pulse trains were weakly associated with baseline pupil diameter. CONCLUSION (s): Auricular stimulation elicits acute PRs, providing a basis to synchronize neuromodulator release with task-related neural spiking which preclinical studies show is a critical determinant of therapeutic effects. Further work is needed to dissociate contributions from vagal and non-vagal afferents mediating activation of the biomarker.
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Affiliation(s)
- Michael A Urbin
- Human Engineering Research Laboratories, VA RR&D Center of Excellence, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Rehabilitation Neural Engineering Laboratories, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Charles W Lafe
- Human Engineering Research Laboratories, VA RR&D Center of Excellence, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Rehabilitation Neural Engineering Laboratories, University of Pittsburgh, Pittsburgh, PA, USA
| | - Tyler W Simpson
- Rehabilitation Neural Engineering Laboratories, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA
| | - George F Wittenberg
- Human Engineering Research Laboratories, VA RR&D Center of Excellence, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Rehabilitation Neural Engineering Laboratories, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bharath Chandrasekaran
- Department of Communication Science and Disorders, University of Pittsburgh, Pittsburgh, PA, USA
| | - Douglas J Weber
- Rehabilitation Neural Engineering Laboratories, University of Pittsburgh, Pittsburgh, PA, USA; Department of Mechanical Engineering and the Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA
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Choi JY, Jang HJ, Ornelas S, Fleming WT, Fürth D, Au J, Bandi A, Engel EA, Witten IB. A Comparison of Dopaminergic and Cholinergic Populations Reveals Unique Contributions of VTA Dopamine Neurons to Short-Term Memory. Cell Rep 2020; 33:108492. [PMID: 33326775 PMCID: PMC8038523 DOI: 10.1016/j.celrep.2020.108492] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 09/18/2020] [Accepted: 11/17/2020] [Indexed: 10/22/2022] Open
Abstract
We systematically compare the contributions of two dopaminergic and two cholinergic ascending populations to a spatial short-term memory task in rats. In ventral tegmental area dopamine (VTA-DA) and nucleus basalis cholinergic (NB-ChAT) populations, trial-by-trial fluctuations in activity during the delay period relate to performance with an inverted-U, despite the fact that both populations have low activity during that time. Transient manipulations reveal that only VTA-DA neurons, and not the other three populations we examine, contribute causally and selectively to short-term memory. This contribution is most significant during the delay period, when both increases and decreases in VTA-DA activity impair short-term memory. Our results reveal a surprising dissociation between when VTA-DA neurons are most active and when they have the biggest causal contribution to short-term memory, and they also provide support for classic ideas about an inverted-U relationship between neuromodulation and cognition.
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Affiliation(s)
- Jung Yoon Choi
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA; Department of Psychology, Princeton University, Princeton, NJ 08544, USA
| | - Hee Jae Jang
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA
| | - Sharon Ornelas
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA
| | - Weston T Fleming
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA
| | - Daniel Fürth
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Jennifer Au
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA
| | - Akhil Bandi
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA
| | - Esteban A Engel
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA
| | - Ilana B Witten
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA; Department of Psychology, Princeton University, Princeton, NJ 08544, USA.
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Injury during adolescence leads to sex-specific executive function deficits in adulthood in a pre-clinical model of mild traumatic brain injury. Behav Brain Res 2020; 402:113067. [PMID: 33333110 DOI: 10.1016/j.bbr.2020.113067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 12/01/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022]
Abstract
Adolescents are more likely than adults to develop chronic symptoms, such as impulsivity and difficulty concentrating, following a mild traumatic brain injury (mTBI) which may relate to disruption of pre-frontal cortex (PFC development). During adolescence the PFC is undergoing extensive remodelling, driving maturation of executive functions incorporating attention, motivation and impulse control. In part maturation of the PFC is driven by outgrowth of dopaminergic neurons to the PFC under the guidance of specific axonal targeting cues, including netrin-1. How a mTBI in adolescence may alter the expression of these axonal targeting cues, and the influence on PFC development is not yet known. As such the effects of mTBI in mid-adolescence on executive functioning in adulthood (12 weeks) were examined via the 5-choice serial reaction task in both male and female Sprague Dawley rats. Animals at p35 (n = 12-16 per group) were injured via weight drop (100 g from 0.75 m) and injury confirmed by a significant increase in righting reflex. Interestingly, while a mid-adolescence mTBI in females led to significantly higher omissions and decreased accuracy when task difficulty was high (stimulus duration 1 s), males had significantly increased premature response rate when the intertrial interval was varied. Examination of levels of TH, as a reflection of dopaminergic innervation, found no difference in either gender post-TBI in the PFC, but a significant increase in the limbic system (nucleus accumbens) in males, but not females, chronically post-TBI, suggesting an imbalance between the regions. The increase in TH was accompanied by a chronic reduction in netrin-1 within the nucleus accumbens in males only. Taken together, these results indicate that mTBI in adolescence leads to sex specific effects in different domains of PFC function in adulthood, which may relate to subtle alterations in the developmental trajectory of the mesocortical limbic pathway in males only.
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30
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Lee M, Mueller A, Moore T. Differences in Noradrenaline Receptor Expression Across Different Neuronal Subtypes in Macaque Frontal Eye Field. Front Neuroanat 2020; 14:574130. [PMID: 33328901 PMCID: PMC7732642 DOI: 10.3389/fnana.2020.574130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/16/2020] [Indexed: 11/14/2022] Open
Abstract
Cognitive functions such as attention and working memory are modulated by noradrenaline receptors in the prefrontal cortex (PFC). The frontal eye field (FEF) has been shown to play an important role in visual spatial attention. However, little is known about the underlying circuitry. The aim of this study was to characterize the expression of noradrenaline receptors on different pyramidal neuron and inhibitory interneuron subtypes in macaque FEF. Using immunofluorescence, we found broad expression of noradrenaline receptors across all layers of the FEF. Differences in the expression of different noradrenaline receptors were observed across different inhibitory interneuron subtypes. No significant differences were observed in the expression of noradrenaline receptors across different pyramidal neuron subtypes. However, we found that putative long-range projecting pyramidal neurons expressed all noradrenaline receptor subtypes at a much higher proportion than any of the other neuronal subtypes. Nearly all long-range projecting pyramidal neurons expressed all types of noradrenaline receptor, suggesting that there is no receptor-specific machinery acting on these long-range projecting pyramidal neurons. This pattern of expression among long-range projecting pyramidal neurons suggests a mechanism by which noradrenergic modulation of FEF activity influences attention and working memory.
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Affiliation(s)
- Max Lee
- Department of Neurobiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - Adrienne Mueller
- Department of Neurobiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - Tirin Moore
- Department of Neurobiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, United States
- Department of Neurobiology, Stanford University, Stanford, CA, United States
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Karalija N, Jonassson L, Johansson J, Papenberg G, Salami A, Andersson M, Riklund K, Nyberg L, Boraxbekk CJ. High long-term test-retest reliability for extrastriatal 11C-raclopride binding in healthy older adults. J Cereb Blood Flow Metab 2020; 40:1859-1868. [PMID: 31506011 PMCID: PMC7446562 DOI: 10.1177/0271678x19874770] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal 11C-raclopride binding potential (BPND) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64-78 years). Mean 11C-raclopride BPND values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal 11C-raclopride measurements represent a true D2 signal.
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Affiliation(s)
- Nina Karalija
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Lars Jonassson
- Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Jarkko Johansson
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Goran Papenberg
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Alireza Salami
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.,Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.,Wallenberg Centre for Molecular Medicine, Lund, Sweden
| | - Micael Andersson
- Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Katrine Riklund
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Lars Nyberg
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Carl-Johan Boraxbekk
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Danish Research Center for Magnetic Resonance, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
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Mäki-Marttunen V, Hagen T, Laeng B, Espeseth T. Distinct Neural Mechanisms Meet Challenges in Dynamic Visual Attention due to Either Load or Object Spacing. J Cogn Neurosci 2020; 32:65-84. [DOI: 10.1162/jocn_a_01469] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Abstract
When engaged in dynamic visuospatial tasks, the brain copes with perceptual and cognitive processing challenges. During multiple-object tracking (MOT), the number of objects to be tracked (i.e., load) imposes attentional demands, but so does spatial interference from irrelevant objects (i.e., close encounters). Presently, it is not clear whether the effect of load on accuracy solely depends on the number of close encounters. If so, the same cognitive and physiological mechanisms deal with increasing load by preparing for and dealing with spatial interference. However, this has never been directly tested. Such knowledge is important to understand the neurophysiology of dynamic visual attention and resolve conflicting views within visual cognition concerning sources of capacity limitations. We varied the processing challenge in MOT task in two ways: the number of targets and the minimum spatial proximity between targets and distractors. In a first experiment, we measured task-induced pupil dilations and saccades during MOT. In a separate cohort, we measured fMRI activity. In both cohorts, increased load and close encounters (i.e., close spatial proximity) led to reduced accuracy in an additive manner. Load was associated with pupil dilations, whereas close encounters were not. Activity in dorsal attentional areas and frequency of saccades were proportionally larger both with higher levels of load and close encounters. Close encounters recruited additionally ventral attentional areas that may reflect orienting mechanisms. The activity in two brainstem nuclei, ventral tegmental area/substantia nigra and locus coeruleus, showed clearly dissociated patterns. Our results constitute convergent evidence indicating that different mechanisms underlie processing challenges due to load and object spacing.
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33
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Swann AC, Lijffijt M, O'Brien B, Mathew SJ. Impulsivity and Suicidal Behavior. Curr Top Behav Neurosci 2020; 47:179-195. [PMID: 32472429 DOI: 10.1007/7854_2020_144] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Suicide is the leading cause of injury mortality in the United States and the second-leading cause of death in people aged 10-34 years. While many long-term risk factors are known, the short-term prediction of suicidal behavior remains elusive. Many characteristics of suicidal behavior cut across diagnoses, but suicide is increased in recurrent psychiatric disorders, addictive disorders, and trauma-related disorders. Suicide results from the interaction of short-term and long-term behavioral regulation. The shorter the time-course of the mechanism, the closer it is to actual suicidal behavior, and the harder it is to prevent. We will discuss the manner in which impulsivity, a major determinant of short-term suicide risk, interacts with longer-term risk factors, especially sensitization to addictive or traumatic stimuli. Impulsivity predisposes to sensitization; in turn, impulsivity is a prominent component of sensitized behavior. Impulsivity can be described as a general pattern of behavior ("trait" impulsivity), as responses that are not conformed to their context (action-impulsivity), or as inability to delay reward or to take future consequences into account (choice-impulsivity). Each of these contributes to suicidal behavior. The neural mechanisms of impulsivity and sensitization are analogous, and sensitization can produce rapidly fluctuating patterns of impulsive behavior, arousal, and anhedonia. In order to recognize and prevent suicidal behavior, it is necessary to identify factors associated with susceptibility to bouts of impulsive behavior in people at elevated long-term risk.
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Affiliation(s)
- Alan C Swann
- Mental Health Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA. .,Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
| | - Marijn Lijffijt
- Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.,Research Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Brittany O'Brien
- Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
| | - Sanjay J Mathew
- Mental Health Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.,Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
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Pro-cognitive effect of 1MeTIQ on recognition memory in the ketamine model of schizophrenia in rats: the behavioural and neurochemical effects. Psychopharmacology (Berl) 2020; 237:1577-1593. [PMID: 32076746 PMCID: PMC7239818 DOI: 10.1007/s00213-020-05484-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/12/2020] [Indexed: 01/07/2023]
Abstract
RATIONALE Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. OBJECTIVES In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. METHODS We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. RESULTS Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. CONCLUSIONS 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia.
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Lövdén M, Karalija N, Andersson M, Wåhlin A, Axelsson J, Köhncke Y, Jonasson LS, Rieckman A, Papenberg G, Garrett DD, Guitart-Masip M, Salami A, Riklund K, Bäckman L, Nyberg L, Lindenberger U. Latent-Profile Analysis Reveals Behavioral and Brain Correlates of Dopamine-Cognition Associations. Cereb Cortex 2019; 28:3894-3907. [PMID: 29028935 DOI: 10.1093/cercor/bhx253] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 09/07/2017] [Indexed: 01/14/2023] Open
Abstract
Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64-68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D2/3R availability (probed with 11C-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny.
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Affiliation(s)
- Martin Lövdén
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Nina Karalija
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Micael Andersson
- Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Anders Wåhlin
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Jan Axelsson
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Ylva Köhncke
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Lars S Jonasson
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Center for Aging and Demographic Research, CEDAR, Umeå University, Umeå, Sweden
| | - Anna Rieckman
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Goran Papenberg
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Douglas D Garrett
- Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany.,Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
| | - Marc Guitart-Masip
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Alireza Salami
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Katrine Riklund
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Lars Bäckman
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Lars Nyberg
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Ulman Lindenberger
- Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany.,Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.,European University Institute, San Domenico di Fiesole (FI), Italy
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Weinberg RP, Koledova VV, Subramaniam A, Schneider K, Artamonova A, Sambanthamurthi R, Hayes KC, Sinskey AJ, Rha C. Palm Fruit Bioactives augment expression of Tyrosine Hydroxylase in the Nile Grass Rat basal ganglia and alter the colonic microbiome. Sci Rep 2019; 9:18625. [PMID: 31819070 PMCID: PMC6901528 DOI: 10.1038/s41598-019-54461-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 11/12/2019] [Indexed: 01/07/2023] Open
Abstract
Tyrosine hydroxylase (TH) catalyzes the hydroxylation of L-tyrosine to L-DOPA. This is the rate-limiting step in the biosynthesis of the catecholamines - dopamine (DA), norepinephrine (NE), and epinephrine (EP). Catecholamines (CA) play a key role as neurotransmitters and hormones. Aberrant levels of CA are associated with multiple medical conditions, including Parkinson's disease. Palm Fruit Bioactives (PFB) significantly increased the levels of tyrosine hydroxylase in the brain of the Nile Grass rat (NGR), a novel and potentially significant finding, unique to PFB among known botanical sources. Increases were most pronounced in the basal ganglia, including the caudate-putamen, striatum and substantia nigra. The NGR represents an animal model of diet-induced Type 2 Diabetes Mellitus (T2DM), exhibiting hyperglycemia, hyperinsulinemia, and insulin resistance associated with hyperphagia and accelerated postweaning weight gain induced by a high-carbohydrate diet (hiCHO). The PFB-induced increase of TH in the basal ganglia of the NGR was documented by immuno-histochemical staining (IHC). This increase in TH occurred equally in both diabetes-susceptible and diabetes-resistant NGR fed a hiCHO. PFB also stimulated growth of the colon microbiota evidenced by an increase in cecal weight and altered microbiome. The metabolites of colon microbiota, e.g. short-chain fatty acids, may influence the brain and behavior significantly.
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Affiliation(s)
- Robert P Weinberg
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA.
- Biomaterials Science and Engineering Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA.
| | - Vera V Koledova
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
- Biomaterials Science and Engineering Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
| | | | - Kirsten Schneider
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
- Biomaterials Science and Engineering Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
| | - Anastasia Artamonova
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
- Biomaterials Science and Engineering Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
| | - Ravigadevi Sambanthamurthi
- Advanced Biotechnology and Breeding Centre, Malaysian Palm Oil Board, 6, Persiaran Institusi, Bandar Baru Bangi, 43000, Kajang, Selangor, Malaysia
| | - K C Hayes
- Department of Biology, Brandeis University, Waltham, Massachusetts 02453, USA
| | - Anthony J Sinskey
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
- Biomaterials Science and Engineering Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
| | - ChoKyun Rha
- Biomaterials Science and Engineering Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA.
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Leyrer‐Jackson JM, Thomas MP. Dopaminergic D1 receptor effects on commissural inputs targeting layer V pyramidal subtypes of the mouse medial prefrontal cortex. Physiol Rep 2019; 7:e14256. [PMID: 31650716 PMCID: PMC6813257 DOI: 10.14814/phy2.14256] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 11/28/2022] Open
Abstract
In humans, prefrontal cortical areas are known to support goal-directed behaviors, mediating a variety of functions that render behavior more flexible in the face of changing environmental demands. In mice, these functions are mediated by homologous regions within medial prefrontal cortex (mPFC) and rely heavily on proper dopaminergic tone. Comprised of two major subtypes, pyramidal tract (PT) and intratelencephalic (IT), layer V pyramidal cells serve as the major outputs of the mPFC, targeting brainstem nuclei and the contralateral hemisphere, respectively. However, it remains relatively unknown how cortical inputs targeting these subtypes are integrated. We explored how layer V pyramidal cell subtypes integrate commissural inputs, which integrate information flow between the hemispheres. An optogenetic approach was used to elicit commissural fiber activation onto PT and IT cells and the effects of D1 receptor activation on elicited EPSPs were explored. We showed that commissural inputs into PT and IT cells elicit facilitating and depressing EPSP patterns, respectively. D1 receptor activation increased the initial EPSP amplitude, enhanced EPSP facilitation, and prolonged EPSP decay time constant in PT cells. In IT cells, D1 receptor activation increased commissural-evoked initial EPSP amplitude but did not affect facilitation or EPSP shape. Furthermore, D1 receptor activation elicited burst firing in a subset of PT cells in response to commissural fiber activation. Combined, these results lend insight into the role of dopamine in promoting persistent firing and temporal integration in PT and IT cells, respectively, that in turn may contribute to working memory functions.
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Affiliation(s)
- Jonna M. Leyrer‐Jackson
- School of PsychologyPsychology Department – Behavioral NeuroscienceArizona State UniversityTempeArizona
| | - Mark P. Thomas
- School of Biological SciencesUniversity of Northern ColoradoGreeleyColorado
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Attentional blink and putative noninvasive dopamine markers: Two experiments to consolidate possible associations. COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2019; 19:1444-1457. [PMID: 31396846 PMCID: PMC6861702 DOI: 10.3758/s13415-019-00717-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Adaptive behavioral control involves a balance between top-down persistence and flexible updating of goals under changing demands. According to the metacontrol state model (MSM), this balance emerges from the interaction between the frontal and the striatal dopaminergic system. The attentional blink (AB) task has been argued to tap into the interaction between persistence and flexibility, as it reflects overpersistence—the too-exclusive allocation of attentional resources to the processing of the first of two consecutive targets. Notably, previous studies are inconclusive about the association between the AB and noninvasive proxies of dopamine including the spontaneous eye blink rate (sEBR), which allegedly assesses striatal dopamine levels. We aimed to substantiate and extend previous attempts to predict individual sizes of the AB in two separate experiments with larger sample sizes (N = 71 & N = 65) by means of noninvasive behavioral and physiological proxies of dopamine (DA), such as sEBR and mood measures, which are likely to reflect striatal dopamine levels, and color discrimination, which has been argued to tap into the frontal dopamine levels. Our findings did not confirm the prediction that AB size covaries with sEBR, mood, or color discrimination. The implications of this inconsistency with previous observations are discussed.
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Dumontheil I, Kilford EJ, Blakemore SJ. Development of dopaminergic genetic associations with visuospatial, verbal and social working memory. Dev Sci 2019; 23:e12889. [PMID: 31336006 PMCID: PMC7064996 DOI: 10.1111/desc.12889] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 06/05/2019] [Accepted: 07/11/2019] [Indexed: 01/10/2023]
Abstract
Dopamine transmission in the prefrontal cortex (PFC) supports working memory (WM), the temporary holding, processing and manipulation of information in one's mind. The gene coding the catechol-O-methyltransferase (COMT) enzyme, which degrades dopamine, in particular in the PFC, has a common single nucleotide polymorphism leading to two versions of the COMT enzyme which vary in their enzymatic activity. The methionine (Met) allele has been associated with higher WM performance and lower activation of the PFC in executive function tasks than the valine (Val) allele. In a previous study, COMT genotype was associated with performance on verbal and visuospatial WM tasks in adults, as well as with performance on a novel social WM paradigm that requires participants to maintain and manipulate information about the traits of their friends or family over a delay. Here, data collected in children and adolescents (N = 202) were compared to data from the adult sample (N = 131) to investigate possible age differences in genetic associations. Our results replicate and extend previous work showing that the pattern of superior WM performance observed in Met/Met adults emerges during development. These findings are consistent with a decrease in prefrontal dopamine levels during adolescence. Developmentally moderated genetic effects were observed for both visuospatial and social WM, even when controlling for non-social WM performance, suggesting that the maintenance and manipulation of social information may also recruit the dopamine neurotransmitter system. These findings show that development should be considered when trying to understand the impact of genetic polymorphisms on cognitive function.
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Affiliation(s)
- Iroise Dumontheil
- Department of Psychological Sciences, Centre for Brain and Cognitive Development, Birkbeck, University of London, London, UK
| | - Emma J Kilford
- Institute of Cognitive Neuroscience, University College London, London, UK
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40
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Karalija N, Papenberg G, Wåhlin A, Johansson J, Andersson M, Axelsson J, Riklund K, Lövdén M, Lindenberger U, Bäckman L, Nyberg L. C957T-mediated Variation in Ligand Affinity Affects the Association between 11C-raclopride Binding Potential and Cognition. J Cogn Neurosci 2019; 31:314-325. [DOI: 10.1162/jocn_a_01354] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with 11C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64–68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of 11C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that 11C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between 11C-raclopride BP and cognitive performance. In accordance with previous findings, we show that 11C-raclopride BP was increased in T-homozygotes. Importantly, 11C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest 11C-raclopride BP–cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and 11C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Ulman Lindenberger
- Max Planck Institute for Human Development
- Max Planck UCL Centre for Computational Psychiatry and Ageing Research
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Weele CMV, Siciliano CA, Tye KM. Dopamine tunes prefrontal outputs to orchestrate aversive processing. Brain Res 2018; 1713:16-31. [PMID: 30513287 DOI: 10.1016/j.brainres.2018.11.044] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 11/25/2018] [Accepted: 11/30/2018] [Indexed: 01/06/2023]
Abstract
Decades of research suggest that the mesocortical dopamine system exerts powerful control over mPFC physiology and function. Indeed, dopamine signaling in the medial prefrontal cortex (mPFC) is implicated in a vast array of processes, including working memory, stimulus discrimination, stress responses, and emotional and behavioral control. Consequently, even slight perturbations within this delicate system result in profound disruptions of mPFC-mediated processes. Many neuropsychiatric disorders are associated with dysregulation of mesocortical dopamine, including schizophrenia, depression, attention deficit hyperactivity disorder, post-traumatic stress disorder, among others. Here, we review the anatomy and functions of the mesocortical dopamine system. In contrast to the canonical role of striatal dopamine in reward-related functions, recent work has revealed that mesocortical dopamine fine-tunes distinct efferent projection populations in a manner that biases subsequent behavior towards responding to stimuli associated with potentially aversive outcomes. We propose a framework wherein dopamine can serve as a signal for switching mPFC states by orchestrating how information is routed to the rest of the brain.
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Affiliation(s)
- Caitlin M Vander Weele
- The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Cody A Siciliano
- The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Kay M Tye
- The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis. NPJ SCHIZOPHRENIA 2018; 4:22. [PMID: 30361502 PMCID: PMC6202388 DOI: 10.1038/s41537-018-0064-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 09/13/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022]
Abstract
Cognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and is, therefore, a treatment target in itself. Yet, literature on efficacy of different pharmaco-therapeutic options is inconsistent. This quantitative review provides an overview of studies that investigated potential cognitive enhancers in schizophrenia. We included pharmacological agents, which target different neurotransmitter systems and evaluated their efficacy on overall cognitive functioning and seven separate cognitive domains. In total, 93 studies with 5630 patients were included. Cognitive enhancers, when combined across all different neurotransmitter systems, which act on a large number of different mechanisms, showed a significant (yet small) positive effect size of 0.10 (k = 51, p = 0.023; 95% CI = 0.01 to 0.18) on overall cognition. Cognitive enhancers were not superior to placebo for separate cognitive domains. When analyzing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small significant effect on overall cognition (k = 29, Hedges’ g = 0.19, p = 0.01), as well as on working memory (k = 20, Hedges’ g = 0.13, p = 0.04). A sub-analysis of cholinesterase inhibitors (ChEI) showed a small effect on working memory (k = 6, Hedges’ g = 0.26, p = 0.03). Other sub-analyses were positively nonsignificant, which may partly be due to the low number of studies we could include per neurotransmitter system. Overall, this meta-analysis showed few favorable effects of cognitive enhancers for patients with schizophrenia, partly due to lack of power. There is a lack of studies involving agents acting on other than glutamatergic and cholinergic systems, especially of those targeting the dopaminergic system.
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Tye KM. Neural Circuit Motifs in Valence Processing. Neuron 2018; 100:436-452. [PMID: 30359607 PMCID: PMC6590698 DOI: 10.1016/j.neuron.2018.10.001] [Citation(s) in RCA: 172] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/24/2018] [Accepted: 09/28/2018] [Indexed: 01/07/2023]
Abstract
How do our brains determine whether something is good or bad? How is this computational goal implemented in biological systems? Given the critical importance of valence processing for survival, the brain has evolved multiple strategies to solve this problem at different levels. The psychological concept of "emotional valence" is now beginning to find grounding in neuroscience. This review aims to bridge the gap between psychology and neuroscience on the topic of emotional valence processing. Here, I highlight a subset of studies that exemplify circuit motifs that repeatedly appear as implementational systems in valence processing. The motifs I identify as being important in valence processing include (1) Labeled Lines, (2) Divergent Paths, (3) Opposing Components, and (4) Neuromodulatory Gain. Importantly, the functionality of neural substrates in valence processing is dynamic, context-dependent, and changing across short and long timescales due to synaptic plasticity, competing mechanisms, and homeostatic need.
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Affiliation(s)
- Kay M Tye
- Picower Institute for Learning and Memory, Dept of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Salk Institute for Biological Sciences, La Jolla, CA 92037, USA.
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Ishii K, Liang N, Asahara R, Takahashi M, Matsukawa K. Feedforward- and motor effort-dependent increase in prefrontal oxygenation during voluntary one-armed cranking. J Physiol 2018; 596:5099-5118. [PMID: 30175404 DOI: 10.1113/jp276956] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 08/31/2018] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Some cortical areas are believed to transmit a descending signal in association with motor intention and/or effort that regulates the cardiovascular system during exercise (termed central command). However, there was no evidence for the specific cortical area responding prior to arbitrary motor execution and in proportion to the motor effort. Using a multichannel near-infrared spectroscopy system, we found that the oxygenation of the dorsolateral and ventrolateral prefrontal cortices on the right side increases in a feedforward- and motor effort-dependent manner during voluntary one-armed cranking with the right arm. This finding may suggest a role of the dorsolateral and ventrolateral prefrontal cortices in triggering off central command and may help us to understand impaired regulation of the cardiovascular system in association with lesion of the prefrontal cortex. ABSTRACT Output from higher brain centres (termed central command) regulates the cardiovascular system during exercise in a feedforward- and motor effort-dependent manner. This study aimed to determine a cortical area responding prior to arbitrarily started exercise and in proportion to the effort during exercise. The oxygenation responses in the frontal and frontoparietal areas during one-armed cranking with the right arm were measured using multichannel near-infrared spectroscopy, as indexes of regional blood flow responses, in 20 subjects. The intensity of voluntary exercise was 30% and 60% of the maximal voluntary effort (MVE). At the start period of both voluntary cranking tasks, the oxygenation increased (P < 0.05) only in the lateral and dorsal part of the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC) and sensorimotor cortices. Then, the oxygenation increased gradually in all cortical areas during cranking at 60% MVE, while oxygenation increased only in the frontoparietal area and some of the frontal area during cranking at 30% MVE. The rating of perceived exertion to the cranking tasks correlated (P < 0.05) with the oxygenation responses on the right side of the lateral-DLPFC (r = 0.46) and VLPFC (r = 0.48) and the frontopolar areas (r = 0.47-0.49). Motor-driven passive one-armed cranking decreased the oxygenation in most cortical areas, except the contralateral frontoparietal areas. Accordingly, the lateral-DLPFC and VLPFC on the right side would respond in a feedforward- and motor effort-dependent manner during voluntary exercise with the right arm. Afferent inputs from mechanosensitive afferents may decrease the cortical oxygenation.
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Affiliation(s)
- Kei Ishii
- Department of Integrative Physiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Automotive Human Factors Research Centre, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Nan Liang
- Department of Integrative Physiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryota Asahara
- Department of Integrative Physiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Makoto Takahashi
- Department of Biomechanics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kanji Matsukawa
- Department of Integrative Physiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Gálosi R, Petykó Z, Kállai V, Tóth A, Ollmann T, Péczely L, Kovács A, Berta B, Lénárd L. Destruction of noradrenergic terminals increases dopamine concentration and reduces dopamine metabolism in the medial prefrontal cortex. Behav Brain Res 2018; 344:57-64. [PMID: 29454007 DOI: 10.1016/j.bbr.2018.02.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 02/13/2018] [Accepted: 02/13/2018] [Indexed: 01/01/2023]
Abstract
Effects of destroyed noradrenergic (NE) innervation in the medial prefrontal cortex (mPFC) were examined on dopamine (DA) content and metabolism. Six-hydroxy-DOPA (6-OHDOPA) or 6-hydroxy-dopamine (6-OHDA) in combination with a potent DA reuptake inhibitor GBR 12935 or 6-OHDA were injected bilaterally into the mPFC in separate groups of animals. In addition, GBR 12935 or vehicle was injected into the mPFC in two other groups of animals as control experiments. NE and DA concentrations from postmortem tissue of the mPFC were measured using HPLC with electrochemical detection. In addition, extracellular NE, DA and DOPAC levels were determined using in vivo microdialysis after the 6-OHDA lesion in combination with GBR 12935 pretreatment in the mPFC. Using reverse microdialysis of alpha-2-adrenoreceptor antagonist yohimbine, we tested the remaining activity of NE innervation and the extracellular concentration of DA and DOPAC. NE and DA concentrations from postmortem tissue of the mPFC showed that 6-OHDOPA lesion reduced NE concentration to 76%, which was a non-significant alteration, however it enhanced significantly DA concentration to 186% compared to vehicle. After 6-OHDA lesion with GBR 12935 pretreatment, concentration of NE significantly decreased to 51% and DA level increased to 180%. 6-OHDA lesion without GBR 12635 pretreatment decreased NE concentration to 23% and DA concentration to 67%. In the microdialysis experiment, after 6-OHDA lesion with GBR 12935 pretreatment, extracellular NE levels were not detectable, whereas extracellular DA levels were increased and DOPAC levels were decreased compared to controls. Reverse microdialysis of yohimbine demonstrated that the residual NE innervation was able to increase NE level and DA levels, but DOPAC concentration remained low after lesion of the NE terminals. These findings suggest that the damage of NE innervation in the mPFC may alter extracellular DA level due to a reduced DA clearance.
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Affiliation(s)
- Rita Gálosi
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary.
| | - Zoltán Petykó
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary; Molecular Neuroendocrinology Research Group, University of Pécs, Szentágothai Research Center, Pécs, Hungary
| | - Veronika Kállai
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary
| | - Attila Tóth
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary
| | - Tamás Ollmann
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary
| | - László Péczely
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary
| | - Anita Kovács
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary
| | - Beáta Berta
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary
| | - László Lénárd
- Institute of Physiology, University of Pécs Medical School, Pécs, Hungary; Molecular Neuroendocrinology Research Group, University of Pécs, Szentágothai Research Center, Pécs, Hungary
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Reed JL, D’Ambrosio E, Marenco S, Ursini G, Zheutlin AB, Blasi G, Spencer BE, Romano R, Hochheiser J, Reifman A, Sturm J, Berman KF, Bertolino A, Weinberger DR, Callicott JH. Interaction of childhood urbanicity and variation in dopamine genes alters adult prefrontal function as measured by functional magnetic resonance imaging (fMRI). PLoS One 2018; 13:e0195189. [PMID: 29634738 PMCID: PMC5892884 DOI: 10.1371/journal.pone.0195189] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 03/13/2018] [Indexed: 12/29/2022] Open
Abstract
Brain phenotypes showing environmental influence may help clarify unexplained associations between urban exposure and psychiatric risk. Heritable prefrontal fMRI activation during working memory (WM) is such a phenotype. We hypothesized that urban upbringing (childhood urbanicity) would alter this phenotype and interact with dopamine genes that regulate prefrontal function during WM. Further, dopamine has been hypothesized to mediate urban-associated factors like social stress. WM-related prefrontal function was tested for main effects of urbanicity, main effects of three dopamine genes-catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), and dopamine receptor D2 (DRD2)-and, importantly, dopamine gene-by-urbanicity interactions. For COMT, three independent human samples were recruited (total n = 487). We also studied 253 subjects genotyped for DRD1 and DRD2. 3T fMRI activation during the N-back WM task was the dependent variable, while childhood urbanicity, dopamine genotype, and urbanicity-dopamine interactions were independent variables. Main effects of dopamine genes and of urbanicity were found. Individuals raised in an urban environment showed altered prefrontal activation relative to those raised in rural or town settings. For each gene, dopamine genotype-by-urbanicity interactions were shown in prefrontal cortex-COMT replicated twice in two independent samples. An urban childhood upbringing altered prefrontal function and interacted with each gene to alter genotype-phenotype relationships. Gene-environment interactions between multiple dopamine genes and urban upbringing suggest that neural effects of developmental environmental exposure could mediate, at least partially, increased risk for psychiatric illness in urban environments via dopamine genes expressed into adulthood.
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Affiliation(s)
- Jessica L. Reed
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
- Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, United States of America
- Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Enrico D’Ambrosio
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, United States of America
- Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Stefano Marenco
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Gianluca Ursini
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, United States of America
- Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Amanda B. Zheutlin
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Giuseppe Blasi
- Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Barbara E. Spencer
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Raffaella Romano
- Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Jesse Hochheiser
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Ann Reifman
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Justin Sturm
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Karen F. Berman
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Alessandro Bertolino
- Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Daniel R. Weinberger
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, United States of America
- Departments of Psychiatry, Neurology, Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Joseph H. Callicott
- Clinical and Translational Neuroscience Branch, Division of Intramural Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
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Nemmi F, Nymberg C, Darki F, Banaschewski T, Bokde A, Büchel C, Flor H, Frouin V, Garavan H, Gowland P, Heinz A, Martinot JL, Nees F, Paus T, Smolka M, Robbins T, Schumann G, Klingberg T, the IMAGEN consortium. Interaction between striatal volume and DAT1 polymorphism predicts working memory development during adolescence. Dev Cogn Neurosci 2018; 30:191-199. [PMID: 29567584 PMCID: PMC6969124 DOI: 10.1016/j.dcn.2018.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 02/26/2018] [Accepted: 03/10/2018] [Indexed: 12/03/2022] Open
Abstract
There is considerable inter-individual variability in the rate at which working memory (WM) develops during childhood and adolescence, but the neural and genetic basis for these differences are poorly understood. Dopamine-related genes, striatal activation and morphology have been associated with increased WM capacity after training. Here we tested the hypothesis that these factors would also explain some of the inter-individual differences in the rate of WM development. We measured WM performance in 487 healthy subjects twice: at age 14 and 19. At age 14 subjects underwent a structural MRI scan, and genotyping of five single nucleotide polymorphisms (SNPs) in or close to the dopamine genes DRD2, DAT-1 and COMT, which have previously been associated with gains in WM after WM training. We then analyzed which biological factors predicted the rate of increase in WM between ages 14 and 19. We found a significant interaction between putamen size and DAT1/SLC6A3 rs40184 polymorphism, such that TC heterozygotes with a larger putamen at age 14 showed greater WM improvement at age 19. The effect of the DAT1 polymorphism on WM development was exerted in interaction with striatal morphology. These results suggest that development of WM partially share neuro-physiological mechanism with training-induced plasticity.
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Affiliation(s)
- F. Nemmi
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - C. Nymberg
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - F. Darki
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - T. Banaschewski
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - A.L.W. Bokde
- Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland
| | - C. Büchel
- University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - H. Flor
- Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany
| | - V. Frouin
- NeuroSpin, CEA, Université Paris-Saclay, Gif-sur-Yvette, France
| | - H. Garavan
- Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA
| | - P. Gowland
- Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham,University Park, Nottingham, United Kingdom
| | - A. Heinz
- Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - J.-L. Martinot
- Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 “Neuroimaging & Psychiatry”, University Paris Sud − Paris Saclay, University Paris Descartes, Service Hospitalier Frédéric Joliot, Orsay; and Maison de Solenn, Paris, France
| | - F. Nees
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - T. Paus
- Rotman Research Institute, Baycrest and Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - M.N. Smolka
- Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany
| | - T.W. Robbins
- Department of Psychology, Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
| | - G. Schumann
- Medical Research Council − Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, United Kingdom
| | - T. Klingberg
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Dopamine-dependent social information processing in non-human primates. Psychopharmacology (Berl) 2018; 235:1141-1149. [PMID: 29332256 PMCID: PMC5869898 DOI: 10.1007/s00213-018-4831-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 01/03/2018] [Indexed: 01/21/2023]
Abstract
RATIONALE Dopamine (DA) is a neurotransmitter whose roles have been suggested in various aspects of brain functions. Recent studies in rodents have reported its roles in social function. However, how DA is involved in social information processing in primates has largely remained unclear. OBJECTIVES We investigated prefrontal cortical (PFC) activities associated with social vs. nonsocial visual stimulus processing. METHODS Near-infrared spectroscopy (NIRS) was applied to Japanese macaques, along with pharmacological manipulations of DA transmission, while they were gazing at social and nonsocial visual stimuli. RESULTS Oxygenated (oxy-Hb) and deoxygenated (deoxy-Hb) hemoglobin changes as well as functional connectivity based on such Hb changes within the PFC network which were distinct between social and nonsocial stimuli were observed. Administration of both D1 and D2 receptor antagonists affected the Hb changes associated with social stimuli, whereas D1, but not D2, receptor antagonist affected the Hb changes associated with nonsocial stimuli. CONCLUSIONS These results suggest that mesocortical DA transmission in the PFC plays significant roles in social information processing, which involves both D1 and D2 receptor activation, in nonhuman primates. However, D1 and D2 receptor signaling in the PFC mediates different aspects of social vs. nonsocial information processing.
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50
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Rosenquist AH, Høyer BB, Julvez J, Sunyer J, Pedersen HS, Lenters V, Jönsson BAG, Bonde JP, Toft G. Prenatal and Postnatal PCB-153 and p, p'-DDE Exposures and Behavior Scores at 5–9 Years of Age among Children in Greenland and Ukraine. ENVIRONMENTAL HEALTH PERSPECTIVES 2017; 125:107002. [PMID: 28974479 PMCID: PMC5933308 DOI: 10.1289/ehp553] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 08/29/2017] [Accepted: 08/29/2017] [Indexed: 05/06/2023]
Abstract
BACKGROUND Studies have reported some evidence of adverse effects of organochlorine exposures on child development, but the results have been inconsistent, and few studies have evaluated associations with child behavior. OBJECTIVE We investigated the association between prenatal and early-life exposures to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE) and behaviors in children between 5 and 9 y of age. METHODS In the Biopersistent organochlorines in diet and human fertility: Epidemiologic studies of time to pregnancy and semen quality in Inuit and European populations (INUENDO) cohort, consisting of mother-child pairs from Greenland and Ukraine (n=1,018), maternal serum PCB-153 and p,p'-DDE concentrations were measured during pregnancy, and cumulative postnatal exposures during the first 12 months after delivery were estimated using a pharmacokinetic model. Parents completed the Strengths and Difficulties Questionnaire (SDQ), and children's behaviors were dichotomized as abnormal (high) versus normal/borderline for five SDQ subscales and the total difficulties score. RESULTS The total difficulties score, an overall measure of abnormal behavior, was not clearly associated with pre- or postnatal exposures to PCB-153 or to p,p'-DDE. However, pooled adjusted odds ratios (ORs) for high conduct problem scores with a doubling of exposure were 1.19 (95% CI: 0.99, 1.42) and 1.16 (95% CI: 0.96, 1.41) for pre- and postnatal PCB-153, respectively, and 1.25 (95% CI: 1.04, 1.51) and 1.24 (95% CI: 1.01, 1.51) for pre- and postnatal p,p'-DDE, respectively. Corresponding ORs for high hyperactivity scores were 1.24 (95% CI: 0.94, 1.62) and 1.08 (95% CI: 0.81, 1.45) for pre- and postnatal PCB-153, respectively, and 1.43 (95% CI: 1.06, 1.92) and 1.27 (95% CI: 0.93, 1.73) for pre- and postnatal p,p'-DDE, respectively. CONCLUSION Prenatal and early postnatal exposures to p,p'-DDE and PCB-153 were associated with a higher prevalence of abnormal scores for conduct and hyperactivity at 5–9 y of age in our study population. These findings provide further support for the importance of minimizing organochlorine exposures to young children and to women of childbearing age. https://doi.org/10.1289/EHP553.
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Affiliation(s)
- Aske Hess Rosenquist
- Department of Clinical Epidemiology, Aarhus University Hospital , Aarhus, Denmark
| | - Birgit Bjerre Høyer
- Department of Occupational and Environmental Medicine, Copenhagen University Hospital , Copenhagen, Denmark
- Department of Clinical Epidemiology, Aarhus University Hospital , Aarhus, Denmark
| | - Jordi Julvez
- ISGlobal, Centre for Research in Environmental Epidemiology (CREAL) , Barcelona, Catalonia, Spain
| | - Jordi Sunyer
- ISGlobal, Centre for Research in Environmental Epidemiology (CREAL) , Barcelona, Catalonia, Spain
| | | | - Virissa Lenters
- Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University , Utrecht, Netherlands
| | - Bo A G Jönsson
- Division of Occupational and Environmental Medicine, Lund University , Lund, Sweden
| | - Jens Peter Bonde
- Department of Occupational and Environmental Medicine, Copenhagen University Hospital , Copenhagen, Denmark
| | - Gunnar Toft
- Department of Clinical Epidemiology, Aarhus University Hospital , Aarhus, Denmark
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