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Li Q, Cai X, Zhou H, Ma D, Li N. Maternal smoking cessation in the first trimester still poses an increased risk of attention-deficit/hyperactivity disorder and learning disability in offspring. Front Public Health 2024; 12:1386137. [PMID: 39081356 PMCID: PMC11286595 DOI: 10.3389/fpubh.2024.1386137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 07/03/2024] [Indexed: 08/02/2024] Open
Abstract
Background Studies have found maternal smoking during pregnancy was linked to attention-deficit/hyperactivity disorder (ADHD) risk. It is unclear if maternal smoking cessation during pregnancy lowers ADHD and learning disability (LD) risk in offspring. This study aimed to explore the associations between maternal smoking cessation during pregnancy and ADHD and LD risk in offspring. Methods Data from the National Health and Nutrition Examination Survey 1999-2004 (8,068 participants) were used. Logistic regression was used to analyze the associations between maternal smoking and smoking cessation during pregnancy and ADHD and LD risk in offspring. Results Compared to non-smokers' offspring, maternal smoking during pregnancy increased the risk of ADHD (odds ratios [OR] = 2.07, 95% confidence interval [CI]: 1.67-2.56) and LD (OR = 1.93, 95% CI: 1.61-2.31) in offspring, even if mothers quit smoking later (ORADHD = 1.91, 95%CIADHD: 1.38-2.65, ORLD = 1.65, 95%CILD: 1.24-2.19). Further analysis of the timing of initiation of smoking cessation during pregnancy revealed that, compared to non-smokers' offspring, maternal quitting smoking in the first trimester still posed an increased risk of ADHD (OR = 1.72, 95% CI: 1.41-2.61) and LD (OR = 1.52, 95% CI: 1.06-2.17) in offspring. Maternal quitting smoking in the second or third trimester also had a significantly increased risk of ADHD (OR = 2.13, 95% CI: 1.26-3.61) and LD (OR = 1.82, 95% CI: 1.16-2.87) in offspring. Furthermore, maternal smoking but never quitting during pregnancy had the highest risk of ADHD (OR = 2.17, 95% CI: 1.69-2.79) and LD (OR = 2.10, 95% CI: 1.70-2.58) in offspring. Interestingly, a trend toward a gradual increase in the risk-adjusted OR for ADHD and LD risk was observed among the three groups: maternal quitting smoking in the first trimester, maternal quitting smoking in the second or third trimester, and maternal smoking but never quitting. Conclusion Maternal smoking cessation in the first trimester still poses an increased risk of ADHD and LD in offspring. Furthermore, it seems that the later the mothers quit smoking during pregnancy, the higher the risk of ADHD and LD in their offspring. Therefore, early intervention of maternal smoking in preconception and prenatal care is vital for offspring neurodevelopment.
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Affiliation(s)
- Qiu Li
- Department of Rehabilitation Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China
| | - Xiaotang Cai
- Department of Rehabilitation Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China
| | - Hui Zhou
- Department of Rehabilitation Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China
| | - Dan Ma
- Department of Rehabilitation Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China
| | - Na Li
- Department of Rehabilitation Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China
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McCarthy DM, Spencer TJ, Bhide PG. Preclinical Models of Attention Deficit Hyperactivity Disorder: Neurobiology, Drug Discovery, and Beyond. J Atten Disord 2024; 28:880-894. [PMID: 38084074 DOI: 10.1177/10870547231215286] [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] [Indexed: 03/12/2024]
Abstract
OBJECTIVE We offer an overview of ADHD research using mouse models of nicotine exposure. METHOD Nicotine exposure of C57BL/6 or Swiss Webster mice occurred during prenatal period only or during the prenatal and the pre-weaning periods. Behavioral, neuroanatomical and neurotransmitter assays were used to investigate neurobiological mechanisms of ADHD and discover candidate ADHD medications. RESULTS Our studies show that norbinaltorphimine, a selective kappa opioid receptor antagonist is a candidate novel non-stimulant ADHD treatment and that a combination of methylphenidate and naltrexone has abuse deterrent potential with therapeutic benefits for ADHD. Other studies showed transgenerational transmission of ADHD-associated behavioral traits and demonstrated that interactions between untreated ADHD and repeated mild traumatic brain injury produced behavioral traits not associated with either condition alone. CONCLUSION Preclinical models contribute to novel insights into ADHD neurobiology and are valuable tools for drug discovery and translation to benefit humans with ADHD.
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Affiliation(s)
| | - Thomas J Spencer
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Pradeep G Bhide
- Florida State University College of Medicine, Tallahassee, FL, USA
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Saito H, Furukawa Y, Sasaki T, Kitajima S, Kanno J, Tanemura K. Behavioral effects of adult male mice induced by low-level acetamiprid, imidacloprid, and nicotine exposure in early-life. Front Neurosci 2023; 17:1239808. [PMID: 37662107 PMCID: PMC10469492 DOI: 10.3389/fnins.2023.1239808] [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: 06/14/2023] [Accepted: 07/28/2023] [Indexed: 09/05/2023] Open
Abstract
Introduction Acetamiprid (ACE) and imidacloprid (IMI), the neonicotinoid chemicals, are widely used as pesticides because of their rapid insecticidal activity. Although these neonicotinoids exert very low toxicity in mammals, the effects of early, low-level, chronic exposure on the adult central nervous system are largely unclear. This study investigated the effects of low-level, chronic neonicotinoids exposure in early life on the brain functions of adult mice, using environmentally relevant concentrations. Methods We exposed mice to an acceptable daily intake level of neonicotinoids in drinking water during the prenatal and postnatal periods. Additionally, we also exposed mice to nicotine (NIC) as a positive control. We then examined the effects on the central nervous system in adult male offspring. Results In the IMI and NIC exposure groups, we detected behavior that displayed impairment in learning and memory. Furthermore, immunohistochemical analysis revealed a decrease in SOX2 (as a neural stem cell marker) and GFAP (as an astrocyte marker) positive cells of the hippocampal dentate gyrus in the IMI and NIC exposure groups compared to the control group. Discussion These results suggest that exposure to neonicotinoids at low levels in early life affects neural circuit base formation and post-maturation behavior. Therefore, in the central nervous system of male mice, the effects of low-level, chronic neonicotinoids exposure during the perinatal period were different from the expected effects of neonicotinoids exposure in mature animals.
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Affiliation(s)
- Hirokatsu Saito
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Yusuke Furukawa
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Takahiro Sasaki
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Satoshi Kitajima
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Jun Kanno
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Kentaro Tanemura
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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Bakker C, Chivers E, Chia XW, Quintrell E, Wyrwoll C, Larcombe A. Switching from tobacco cigarettes in very early pregnancy: The effects of in utero e-cigarette exposure on mouse offspring neurodevelopment and behaviour. Physiol Behav 2023; 263:114118. [PMID: 36796533 DOI: 10.1016/j.physbeh.2023.114118] [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: 10/28/2022] [Revised: 01/26/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023]
Abstract
INTRODUCTION Electronic cigarettes (e-cigarettes) are often perceived to be safer than smoking, which has led to some women switching to e-cigarettes during pregnancy. However, the effects of switching from smoking to e-cigarettes on both pregnancy outcomes and the foetus are largely unknown. This study aimed to investigate the effects of switching from tobacco smoking to e-cigarette use in very early pregnancy on birth outcomes, neurodevelopment and behaviour of the offspring. METHODS Female BALB/c mice were exposed to cigarette smoke for up to two weeks before being mated. Mated dams were then allocated to one of four treatment groups: (i) continued exposure to cigarette smoke (ii) exposure to e-cigarette aerosol with nicotine, (iii) or without nicotine, or (iv) medical air. Pregnant mice were exposed for 2 h per day for the duration of pregnancy. Gestational outcomes including litter size and sex ratio were assessed, in addition to early-life markers of physical- and neuro- development. At 8 weeks of age, motor coordination, anxiety, locomotion, memory and learning of the adult offspring were assessed. RESULTS Gestational outcomes and early markers of physical- and neuro- development were unaffected by in utero exposure, as well as locomotion, anxiety-like behaviour, and object recognition memory during adulthood. However, both e-cigarette groups displayed increased spatial recognition memory compared to air exposed controls. Maternal exposure to nicotine containing e-cigarette aerosol was found to increase offspring bodyweight and impair motor skill learning. CONCLUSIONS These results suggest there may be some benefits as well as negative effects of switching to e-cigarettes in early pregnancy.
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Affiliation(s)
- Chloe Bakker
- Respiratory Environmental Health, Wal-yan Respiratory Research Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia
| | - Emily Chivers
- Respiratory Environmental Health, Wal-yan Respiratory Research Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia
| | - Xian-Wen Chia
- Respiratory Environmental Health, Wal-yan Respiratory Research Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia
| | - Ebony Quintrell
- Respiratory Environmental Health, Wal-yan Respiratory Research Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia; School of Human Sciences, University of Western Australia, Nedlands, Western Australia, Australia
| | - Caitlin Wyrwoll
- School of Human Sciences, University of Western Australia, Nedlands, Western Australia, Australia
| | - Alexander Larcombe
- Respiratory Environmental Health, Wal-yan Respiratory Research Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia; Occupation, Environment and Safety, School of Population Health, Curtin University, Perth, Western Australia.
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5
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Archie SR, Sifat AE, Zhang Y, Villalba H, Sharma S, Nozohouri S, Abbruscato TJ. Maternal e-cigarette use can disrupt postnatal blood-brain barrier (BBB) integrity and deteriorates motor, learning and memory function: influence of sex and age. Fluids Barriers CNS 2023; 20:17. [PMID: 36899432 PMCID: PMC9999561 DOI: 10.1186/s12987-023-00416-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/17/2023] [Indexed: 03/12/2023] Open
Abstract
Electronic nicotine delivery systems (ENDS), also commonly known as electronic cigarettes (e-cigs) are considered in most cases as a safer alternative to tobacco smoking and therefore have become extremely popular among all age groups and sex. It is estimated that up to 15% of pregnant women are now using e-cigs in the US which keeps increasing at an alarming rate. Harmful effects of tobacco smoking during pregnancy are well documented for both pregnancy and postnatal health, however limited preclinical and clinical studies exist to evaluate the long-term effects of prenatal e-cig exposure on postnatal health. Therefore, the aim of our study is to evaluate the effect of maternal e-cig use on postnatal blood-brain barrier (BBB) integrity and behavioral outcomes of mice of varying age and sex. In this study, pregnant CD1 mice (E5) were exposed to e-Cig vapor (2.4% nicotine) until postnatal day (PD) 7. Weight of the offspring was measured at PD0, PD7, PD15, PD30, PD45, PD60 and PD90. The expression of structural elements of the BBB, tight junction proteins (ZO-1, claudin-5, occludin), astrocytes (GFAP), pericytes (PDGFRβ) and the basement membrane (laminin α1, laminin α4), neuron specific marker (NeuN), water channel protein (AQP4) and glucose transporter (GLUT1) were analyzed in both male and female offspring using western blot and immunofluorescence. Estrous cycle was recorded by vaginal cytology method. Long-term motor and cognitive functions were evaluated using open field test (OFT), novel object recognition test (NORT) and morris water maze test (MWMT) at adolescence (PD 40-45) and adult (PD 90-95) age. In our study, significantly reduced expression of tight junction proteins and astrocyte marker were observed in male and female offspring until PD 90 (P < 0.05). Additionally, prenatally e-cig exposed adolescent and adult offspring showed impaired locomotor, learning, and memory function compared to control offspring (P < 0.05). Our findings suggest that prenatal e-cig exposure induces long-term neurovascular changes of neonates by disrupting postnatal BBB integrity and worsening behavioral outcomes.
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Affiliation(s)
- Sabrina Rahman Archie
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA
| | - Ali Ehsan Sifat
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA
| | - Yong Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA
| | - Heidi Villalba
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA
| | - Sejal Sharma
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA
| | - Saeideh Nozohouri
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA
| | - Thomas J Abbruscato
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
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Chen Z, Chen W, Li Y, Moos M, Xiao D, Wang C. Single-nucleus chromatin accessibility and RNA sequencing reveal impaired brain development in prenatally e-cigarette exposed neonatal rats. iScience 2022; 25:104686. [PMID: 35874099 PMCID: PMC9304611 DOI: 10.1016/j.isci.2022.104686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/13/2022] [Accepted: 06/24/2022] [Indexed: 11/03/2022] Open
Abstract
Although emerging evidence reveals that vaping alters the function of the central nervous system, the effects of maternal vaping on offspring brain development remain elusive. Using a well-established in utero exposure model, we performed single-nucleus ATAC-seq (snATAC-seq) and RNA sequencing (snRNA-seq) on prenatally e-cigarette-exposed rat brains. We found that maternal vaping distorted neuronal lineage differentiation in the neonatal brain by promoting excitatory neurons and inhibiting lateral ganglionic eminence-derived inhibitory neuronal differentiation. Moreover, maternal vaping disrupted calcium homeostasis, induced microglia cell death, and elevated susceptibility to cerebral ischemic injury in the developing brain of offspring. Our results suggest that the aberrant calcium signaling, diminished microglial population, and impaired microglia-neuron interaction may all contribute to the underlying mechanisms by which prenatal e-cigarette exposure impairs neonatal rat brain development. Our findings raise the concern that maternal vaping may cause adverse long-term brain damage to the offspring.
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Affiliation(s)
- Zhong Chen
- Center for Genomics, School of Medicine, Loma Linda University, 11021 Campus St., Loma Linda, CA 92350, USA
| | - Wanqiu Chen
- Center for Genomics, School of Medicine, Loma Linda University, 11021 Campus St., Loma Linda, CA 92350, USA
| | - Yong Li
- Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Malcolm Moos
- Center for Biologics Evaluation and Research & Division of Cellular and Gene Therapies, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
| | - Daliao Xiao
- Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Charles Wang
- Center for Genomics, School of Medicine, Loma Linda University, 11021 Campus St., Loma Linda, CA 92350, USA
- Division of Microbiology & Molecular Genetics, Department of Basic Science, School of Medicine, Loma Linda University, 11021 Campus St., Loma Linda, CA 92350, USA
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7
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McCarthy DM, Zhang L, Wilkes BJ, Vaillancourt DE, Biederman J, Bhide PG. Nicotine and the developing brain: Insights from preclinical models. Pharmacol Biochem Behav 2022; 214:173355. [PMID: 35176350 PMCID: PMC9063417 DOI: 10.1016/j.pbb.2022.173355] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 11/26/2022]
Abstract
Use of tobacco products during pregnancy is associated with increased risk for neurodevelopmental disorders in the offspring. Preclinical models of developmental nicotine exposure have offered valuable insights into the neurobiology of nicotine's effects on the developing brain and demonstrated lasting effects of developmental nicotine exposure on brain structure, neurotransmitter signaling and behavior. These models have facilitated discovery of novel compounds as candidate treatments for attention deficit hyperactivity disorder, a neurodevelopmental disorder associated with prenatal nicotine exposure. Using these models the significance of heritability of behavioral phenotypes from the nicotine-exposed pregnant female or adult male to multiple generations of descendants has been demonstrated. Finally, research using the preclinical models has demonstrated synergistic interactions between developmental nicotine exposure and repetitive mild traumatic brain injury that contribute to "worse" outcomes from the injury in individuals with attention deficit hyperactivity disorder associated with developmental nicotine exposure.
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Affiliation(s)
- Deirdre M McCarthy
- Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL 32306, United States of America
| | - Lin Zhang
- Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL 32306, United States of America
| | - Bradley J Wilkes
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, United States of America
| | - David E Vaillancourt
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, United States of America
| | - Joseph Biederman
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States of America
| | - Pradeep G Bhide
- Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL 32306, United States of America.
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8
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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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9
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Zhang L, Levenson CW, Salazar VC, Biederman J, Zafonte R, Bhide PG. Repetitive Mild Traumatic Brain Injury in an Awake, Unanesthetized Mouse Model of Perinatal Nicotine Exposure Produces Transient Novelty-Seeking and Depression-Like Behaviors. J Neurotrauma 2022; 39:954-963. [PMID: 34913733 DOI: 10.1089/neu.2021.0268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) can be a risk factor for repetitive mild traumatic brain injury (mTBI) or concussions such as those that can occur in contact sports. Individuals with ADHD also appear to have a higher risk of poor neurocognitive outcomes after repetitive mTBI. Findings from clinical studies examining the interactions between ADHD and repetitive mTBI vary, likely because of variabilities in experimental design and outcome measures. We used a mouse model of perinatal nicotine exposure (PNE), which displays behavioral, neuroanatomical, and neurotransmitter features consistent with ADHD and subjected the mice to repetitive mTBI. We used a closed head model of mTBI in awake, unanesthetized mice to mimic concussions in humans. The mTBI was repeated three times daily for seven days. The mice in the PNE-mTBI group took longer to regain consciousness after the mTBI and showed transient novelty-seeking and depression-like behaviors. Before the repetitive mTBI, the mice in the PNE group showed attention deficit, which persisted after the mTBI. The mice in the control (non-PNE) group showed a transient attention deficit after the repetitive mTBI but not any of the other behavioral changes seen in the PNE-mTBI group. These findings from an unanesthetized mouse model with a pre-existing condition show that ADHD and repetitive mTBI together contribute to transient novelty-seeking and depression-like behavior supporting the notion that untreated ADHD may be a risk factor for poor neurocognitive outcomes after concussions.
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Affiliation(s)
- Lin Zhang
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Cathy W Levenson
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Valentina Cea Salazar
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ross Zafonte
- Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Brigham and Women's Hospital, and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Pradeep G Bhide
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
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10
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Zhou L, Tao X, Pang G, Mu M, Sun Q, Liu F, Hu Y, Tao H, Li B, Xu K. Maternal Nicotine Exposure Alters Hippocampal Microglia Polarization and Promotes Anti-inflammatory Signaling in Juvenile Offspring in Mice. Front Pharmacol 2021; 12:661304. [PMID: 34045967 PMCID: PMC8144443 DOI: 10.3389/fphar.2021.661304] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/26/2021] [Indexed: 12/15/2022] Open
Abstract
Accumulating evidence reveal that maternal smoking or perinatal nicotine replacement therapy impairs hippocampal neurogenesis, neural development, and cognitive behaviors in the offspring. Microglia is a source of non-neural regulation of neuronal development and postnatal neurogenesis. In this study, we explored the impact of nicotine on the microglia during the development of hippocampus. Developmental nicotine exposure in a mouse model was conducted by supplementing nicotine in the drinking water to mother mice during gestation and lactation period. We found that juvenile offspring with maternal nicotine exposure presented physical and neurobehavioral development delay and an increase in anxiety-like behavior in the open field test on postnatal day (PND) 20. To further detect possible developmental neurotoxic effects of nicotine in offspring and underlying mechanism, whole genome microarray analysis of the expression profile of the hippocampus was performed on postnatal day 20. Significant alterations in the expression of genes related to inflammatory, neurotransmitter, and synapsis were observed in the hippocampus after maternal nicotine exposure, as compared to the vehicle control. Concurrently, an increase in microglial markers and the presence of M2 polarity state in the hippocampus of the nicotine offspring were observed by histological analysis and confocal z-stacking scanning. The M2 microglial polarization state was further confirmed with in vitro primary microglia culture by cytokine array, and double-positive expression of BDNF/Iba1 in microglia by immunohistochemical staining in the juvenile offspring hippocampus was visualized. We also found that nicotine offspring showed an increase of neurite length in the molecular layer and CA1 by Tuj1 staining, as well as an increase in the expression of synapse associated protein, PSD95, but the expression of NeuroD1 in CA1 and CA3 reduced. In summary, maternal nicotine exposure dysregulates immune-related genes expression by skewing the polarity of M2 microglia in the hippocampus, which may cause abnormal cognitive and behavioral performance in the offspring.
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Affiliation(s)
- Li Zhou
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China
| | - Xinrong Tao
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Control and Occupational Health, Ministry of Education, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety, Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China.,Engineering Laboratory of Occupational Safety and Health, Anhui Province, Anhui University of Science and Technology, Huainan, China
| | - Gang Pang
- College of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Min Mu
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Control and Occupational Health, Ministry of Education, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety, Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China.,Engineering Laboratory of Occupational Safety and Health, Anhui Province, Anhui University of Science and Technology, Huainan, China
| | - Qixian Sun
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China
| | - Fei Liu
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China
| | - Yuting Hu
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China
| | - Huihui Tao
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Control and Occupational Health, Ministry of Education, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety, Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China.,Engineering Laboratory of Occupational Safety and Health, Anhui Province, Anhui University of Science and Technology, Huainan, China
| | - Bing Li
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China
| | - Keyi Xu
- Center for Medical Research, School of Medicine, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Control and Occupational Health, Ministry of Education, Anhui University of Science and Technology, Huainan, China.,Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety, Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China.,Engineering Laboratory of Occupational Safety and Health, Anhui Province, Anhui University of Science and Technology, Huainan, China
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11
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Zhang L, Levenson CW, Salazar VC, McCarthy DM, Biederman J, Zafonte R, Bhide PG. Repetitive Mild Traumatic Brain Injury in a Perinatal Nicotine Exposure Mouse Model of Attention Deficit Hyperactivity Disorder. Dev Neurosci 2021; 43:63-72. [PMID: 33849015 DOI: 10.1159/000515198] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/11/2021] [Indexed: 11/19/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) increases the risk for concussion or mild traumatic brain injury (mTBI). At the same time, recommendations for the management of ADHD include participation in sports and other organized physical activities, including those that carry an increased risk of mTBI. Very little work has been done to determine the extent to which untreated ADHD adversely impacts behavioral outcomes of repeated mild concussions. Here, we used a perinatal nicotine exposure (PNE) mouse model of ADHD combined with a closed-head, repetitive mTBI model. The PNE mouse model carries significant construct, face, and predictive validity as a preclinical model of ADHD. Two-month-old PNE and control mice were subjected to closed-head repetitive mTBI or sham procedure once daily for 5 days. Object-based attention, novel object recognition memory, spatial working memory, and depression-like behavior were analyzed 1 day and 2 weeks following repeated mTBI. Consistent with our previous reports, mice in the PNE group showed significant deficits in object-based attention and working memory prior to mTBI. These deficits persisted following the repeated mTBI. Repeated mTBI produced a transient attention deficit in the control group but did not exacerbate the attention deficit that is characteristic of the PNE group. Although neither PNE nor repetitive mTBI alone influenced immobility in the tail suspension test, when PNE mice were subjected to mTBI, there was a transient increase in this measurement suggesting a synergistic effect of ADHD and mTBI on depression-like behavior. Thus, our data using the PNE mouse model suggest that ADHD may be a risk factor for transient depression following repeated mTBI and that repeated mTBI may be a risk factor for transient attention deficit.
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Affiliation(s)
- Lin Zhang
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Cathy W Levenson
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Valentina Cea Salazar
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Deirdre M McCarthy
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ross Zafonte
- Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General hospital, Brigham and Women's Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Pradeep G Bhide
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
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12
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Zhang L, McCarthy DM, Eskow Jaunarajs KL, Biederman J, Spencer TJ, Bhide PG. Frontal Cortical Monoamine Release, Attention, and Working Memory in a Perinatal Nicotine Exposure Mouse Model Following Kappa Opioid Receptor Antagonism. Cereb Cortex 2021; 31:483-496. [PMID: 32869057 DOI: 10.1093/cercor/bhaa238] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 02/27/2024] Open
Abstract
Perinatal nicotine exposure (PNE) produces frontal cortical hypo-dopaminergic state and attention and working memory deficits consistent with neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD). Methylphenidate alleviates ADHD symptoms by increasing extracellular dopamine and noradrenaline. Kappa opioid receptor (KOR) antagonism may be another mechanism to achieve the same results because KOR activation inhibits frontal cortical dopamine release. We administered the selective KOR antagonist norbinaltorphimine (norBNI) (20 mg/kg; intraperitoneal) or methylphenidate (0.75 mg/kg; intraperitoneal) to PNE mouse model and examined frontal cortical monoamine release, attention, and working memory. Both compounds increased dopamine and noradrenaline release but neither influenced serotonin release. Both compounds improved object-based attention and working memory in the PNE group, with norBNI's effects evident at 2.5 h and 5.5 h but absent at 24 h. Methylphenidate's effects were evident at 0.5 h but not at 2.5 h. norBNI's effects temporally coincided with frontal cortical c-Jun N-terminal kinase phosphorylation. norBNI did not alter tissue dopamine content in the nucleus accumbens, offering preliminary support for lack of reinforcement.
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Affiliation(s)
- Lin Zhang
- Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | - Deirdre M McCarthy
- Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | | | - Joseph Biederman
- Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Thomas J Spencer
- Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Pradeep G Bhide
- Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
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13
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Eliasen JN, Krall J, Frølund B, Kohlmeier KA. Sex-specific alterations in GABA receptor-mediated responses in laterodorsal tegmentum are associated with prenatal exposure to nicotine. Dev Neurobiol 2020; 80:178-199. [PMID: 32628361 DOI: 10.1002/dneu.22772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/23/2020] [Accepted: 06/23/2020] [Indexed: 12/14/2022]
Abstract
Smoking during pregnancy is associated with deleterious physiological and cognitive effects on the offspring, which are likely due to nicotine-induced alteration in the development of neurotransmitter systems. Prenatal nicotine exposure (PNE) in rodents is associated with changes in behaviors controlled in part by the pontine laterodorsal tegmentum (LDT), and LDT excitatory signaling is altered in a sex and age-dependent manner by PNE. As effects on GABAergic LDT signaling are unknown, we used calcium imaging to evaluate GABAA receptor- (GABAA R as well as GABAA -ρ R) and GABAB receptor (GABAB R)-mediated calcium responses in LDT brain slices from female and male PNE mice in two different age groups. Overall, in older PNE females, changes in calcium induced by stimulation of GABAA R and GABAB R, including GABAA -ρ R were shifted toward calcium rises. In both young and old males, PNE was associated with alterations in calcium mediated by all three receptors; however, the GABAA R was the most affected. These results show for the first time that PNE is associated with alterations in GABAergic transmission in the LDT in a sex- and age-dependent manner, and these data are the first to show PNE-associated alterations in functionality of GABA receptors in any nucleus. PNE-associated alterations in LDT GABAergic transmission within the LDT would be expected to alter output to target regions and could play a role in LDT-implicated, negative behavioral outcomes following gestational exposure to smoking. Accordingly, our data provide further supportive evidence of the importance of eliminating the consumption of nicotine during pregnancy.
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Affiliation(s)
- Jannik Nicklas Eliasen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jacob Krall
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bente Frølund
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristi A Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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14
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McCarthy DM, Lowe SE, Morgan TJ, Cannon EN, Biederman J, Spencer TJ, Bhide PG. Transgenerational transmission of behavioral phenotypes produced by exposure of male mice to saccharin and nicotine. Sci Rep 2020; 10:11974. [PMID: 32686722 PMCID: PMC7371742 DOI: 10.1038/s41598-020-68883-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 06/30/2020] [Indexed: 12/12/2022] Open
Abstract
The use of non-nutritive sweeteners such as saccharin is widely prevalent. Although saccharin is considered safe for human consumption, it produces behavioral changes in experimental animals. We report that saccharin’s behavioral effects are much more pervasive than currently recognized. In a mouse model, saccharin exposure produced motor impulsivity not only in the saccharin-exposed males but also in their offspring. In addition, the offspring showed locomotor hyperactivity and working memory deficit not observed in fathers. Spermatazoal DNA was hypermethylated in the saccharin-exposed fathers, especially at dopamine receptor promoter regions, suggesting that epigenetic modification of germ cell DNA may mediate transgenerational transmission of behavioral phenotypes. Dopamine’s role in hyperactivity was further highlighted by the finding that the stimulant drug methylphenidate mitigated the hyperactivity. Nicotine is another substance that is widely used. Its use via smokeless tobacco products, some of which contain saccharin, is on the rise contributing to concerns about adverse outcomes of co-exposure to saccharin and nicotine. We found that co-exposure of male mice to saccharin and nicotine produced significant behavioral impairment in their offspring. Thus, our data point to potential adverse neurobehavioral consequences of exposure to saccharin alone or saccharin and nicotine for the exposed individuals and their descendants.
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Affiliation(s)
- Deirdre M McCarthy
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Sarah E Lowe
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Thomas J Morgan
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA.,School of Physician Assistant Practice, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Elisa N Cannon
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Thomas J Spencer
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Pradeep G Bhide
- Biomedical Sciences and Center for Brain Repair, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL, 32306, USA.
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15
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Mamiya T, Tanase S, Takeuchi S, Kato S, Ito A, Hiramatsu M, Nabeshima T. Galantamine improves enhanced impulsivity, impairments of attention and long-term potentiation induced by prenatal nicotine exposure to mice. Biochem Pharmacol 2020; 180:114139. [PMID: 32652142 DOI: 10.1016/j.bcp.2020.114139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 12/21/2022]
Abstract
Prenatal nicotine exposure (PNE) causes behavioral abnormalities in offspring, such as an enhancement of impulsivity and decrease in attention at adolescence. Here we examined the effects of galantamine (GAL) on the behavioral and electrophysiological changes induced by PNE in mice. Pregnant C57BL/6J mice were exposed to nicotine (0.2 mg/mL) dissolved in sweetened (2% saccharin) drinking water during gestational day 14 and perinatal day 0 (P0). At the ages of postnatal days 42-49 (P42-P49), female offspring displayed impulsivity in the cliff avoidance test and impairment of visual attention in the object-based attention test. Decrease of long-term potentiation (LTP) and extracellular glutamate levels were observed in the prefrontal cortex of PNE mice. Systemic treatment with GAL (1 mg/kg, s.c.), an allosteric potentiating ligand for the nicotinic acetylcholine receptor (nAChR) and a weak cholinesterase inhibitor, attenuated the enhancement of impulsivity and impairment of attention induced by PNE in mice. Further, GAL reversed the impairment of LTP induced by PNE in the prefrontal cortex of mice, although it failed to attenuate the decrease of extracellular glutamate levels. The effects of GAL were blocked by an α 7 nAChR antagonist, methyllycaconitine (1 mg/kg, i.p.). These results suggest that PNE during cortex development affects nicotinic cholinergic-dependent plasticity and formation of impulsivity and attention. Furthermore, GAL could be a useful drug for cognitive impairments-related to attention deficit hyperactivity disorder.
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Affiliation(s)
- Takayoshi Mamiya
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan.
| | - Shota Tanase
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Shino Takeuchi
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Shunsuke Kato
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Ai Ito
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Masayuki Hiramatsu
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Graduate School of Health Sciences, Fujita Health University, Toyoake, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
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16
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Polli FS, Scharff MB, Ipsen TH, Aznar S, Kohlmeier KA, Andreasen JT. Prenatal nicotine exposure in mice induces sex-dependent anxiety-like behavior, cognitive deficits, hyperactivity, and changes in the expression of glutamate receptor associated-genes in the prefrontal cortex. Pharmacol Biochem Behav 2020; 195:172951. [PMID: 32439454 DOI: 10.1016/j.pbb.2020.172951] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/29/2022]
Abstract
In rodents, prenatal nicotine exposure (PNE) has been associated with increased risk for development of cognitive and emotional disturbances, but the findings are somewhat conflicting. Lack of behavioral alterations following PNE could be due to the variety of methods available for nicotine delivery, exposure time and species used, with inbred strains being mostly employed. Such differences suggest the need to investigate the behavioral phenotype in each PNE model available if we are to find models with enhanced translational value. In this study, we assessed sex-dependent effects of PNE on ADHD-related behaviors and on the levels of mRNA coding for glutamate receptor subunits within the prefrontal cortex in the outbred NMRI mice exposed to nicotine via maternal drinking water during gestation. Cotinine levels were assessed in newborn pups. Behaviors related to anxiety, compulsivity, working memory, and locomotion were evaluated in both sexes of young adult offspring using the elevated zero maze, marble burying, spontaneous alternation behavior, and locomotor activity tests. Expression of mRNA coding for different glutamate receptors subunits within the prefrontal cortex (PFC) was measured using RT-qPCR. Cotinine levels in the serum of newborns confirmed fetal nicotine exposure. Both male and female offspring showed ADHD-like behaviors, such as deficit in the SAB test and hyperactivity. In addition, PNE male mice displayed anxiety- and compulsive-like behaviors, effects that were absent in female offspring. Finally, PNE reduced the mRNA expression of GluN1-, GluN2B-, and mGluR2-related genes within the PFC of male offspring, whereas it reduced the expression of mRNA coding for GluA2 subunit in female mice. PNE in NMRI mice induced sex-dependent behavioral changes, which parallels clinical findings following maternal cigarette smoke exposure. Alterations detected in PFC mRNA glutamate receptor proteins could contribute to the abnormal behavioral responses observed, but other signaling pathways or brain regions are likely involved in the behavioral susceptibility of PNE individuals.
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Affiliation(s)
- Filip S Polli
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Malthe B Scharff
- Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen 2400, Denmark
| | - Theis H Ipsen
- Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen 2400, Denmark
| | - Susana Aznar
- Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen 2400, Denmark
| | - Kristi A Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Jesper T Andreasen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
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17
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The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties. Neurosci Biobehav Rev 2020; 113:373-407. [PMID: 32298711 DOI: 10.1016/j.neubiorev.2020.04.007] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 02/25/2020] [Accepted: 04/06/2020] [Indexed: 12/31/2022]
Abstract
Rats and mice have been demonstrated to show episodic-like memory, a prototype of episodic memory, as defined by an integrated memory of the experience of an object or event, in a particular place and time. Such memory can be assessed via the use of spontaneous object exploration paradigms, variably designed to measure memory for object, place, temporal order and object-location inter-relationships. We review the methodological properties of these tests, the neurobiology about time and discuss the evidence for the involvement of the medial prefrontal cortex (mPFC), entorhinal cortex (EC) and hippocampus, with respect to their anatomy, neurotransmitter systems and functional circuits. The systematic analysis suggests that a specific circuit between the mPFC, lateral EC and hippocampus encodes the information for event, place and time of occurrence into the complex episodic-like memory, as a top-down regulation from the mPFC onto the hippocampus. This circuit can be distinguished from the neuronal component memory systems for processing the individual information of object, time and place.
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18
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Church JS, Chace-Donahue F, Blum JL, Ratner JR, Zelikoff JT, Schwartzer JJ. Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols. ENVIRONMENTAL HEALTH PERSPECTIVES 2020; 128:47006. [PMID: 32293200 PMCID: PMC7228099 DOI: 10.1289/ehp6067] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
BACKGROUND In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. OBJECTIVE The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. METHODS Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8-10 per group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. RESULTS Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFNγ) in the diencephalon, as well as lower levels of hippocampal IFNγ (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. DISCUSSION These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.
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Affiliation(s)
- Jamie S. Church
- Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, South Hadley, Massachusetts, USA
| | - Fiona Chace-Donahue
- Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, South Hadley, Massachusetts, USA
| | - Jason L. Blum
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Jill R. Ratner
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Judith T. Zelikoff
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Jared J. Schwartzer
- Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, South Hadley, Massachusetts, USA
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Kohlmeier KA, Polli FS. Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function. Front Synaptic Neurosci 2020; 12:3. [PMID: 32116639 PMCID: PMC7019863 DOI: 10.3389/fnsyn.2020.00003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/14/2020] [Indexed: 12/16/2022] Open
Abstract
The brainstem has traditionally been considered an area of the brain with autonomous control of mostly homeostatic functions such as heart rate, respiration, and the sleep and wakefulness state, which would preclude the necessity to exhibit the high degree of synaptic or cellular mechanisms of plasticity typical of regions of the brain responsible for flexible, executive control, such as the medial prefrontal cortex or the hippocampus. The perception that the brainstem does not share the same degree of flexibility to alter synaptic strength and/or wiring within local circuits makes intuitive sense, as it is not easy to understand how "soft wiring" would be an advantage when considering the importance of faithful and consistent performance of the homeostatic, autonomic functions that are controlled by the brainstem. However, many of the molecular and cellular requirements which underlie strengthening of synapses seen in brain regions involved in higher-level processing are present in brainstem nuclei, and recent research suggest that the view of the brainstem as "hard wired," with rigid and static connectivity and with unchanging synaptic strength, is outdated. In fact, information from studies within the last decades, including work conducted in our group, leads us to propose that the brainstem can dynamically alter synaptic proteins, and change synaptic connections in response to prenatal or postnatal stimuli, and this would likely alter functionality and output. This article reviews recent research that has provided information resulting in our revision of the view of the brainstem as static and non-changing by using as example recent information gleaned from a brainstem pontine nucleus, the laterodorsal tegmentum (LDT). The LDT has demonstrated mechanisms underlying synaptic plasticity, and plasticity has been exhibited in the postnatal LDT following exposure to drugs of abuse. Further, exposure of the brain during gestation to drugs of abuse results in alterations in development of signaling pathways in the LDT. As the LDT provides a high degree of innervation of mesoaccumbal and mesocortical circuits involved in salience, as well as thalamocortical circuits involved in control of arousal and orientation, changes in synaptic strength would be expected to alter output, which would significantly impact behavioral state, motivated behavior and directed attention. Further, alterations in developmental trajectory within the LDT following prenatal exposure to drugs of abuse would be expected to impact on later life expression of motivation and arousal.
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Affiliation(s)
- Kristi A. Kohlmeier
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
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20
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Cellular and Molecular Changes in Hippocampal Glutamate Signaling and Alterations in Learning, Attention, and Impulsivity Following Prenatal Nicotine Exposure. Mol Neurobiol 2020; 57:2002-2020. [PMID: 31916029 DOI: 10.1007/s12035-019-01854-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 12/11/2019] [Indexed: 12/18/2022]
Abstract
Over 70 million European pregnant women are smokers during their child-bearing years. Consumption of tobacco-containing products during pregnancy is associated with several negative behavioral outcomes for the offspring, including a higher susceptibility for the development of attention-deficit/hyperactive disorder (ADHD). In efforts to minimize fetal exposure to tobacco smoke, many women around the world switch to nicotine replacement therapies (NRTs) during the gestational period; however, prenatal nicotine exposure (PNE) in any form has been associated with alterations in cognitive processes, including learning, memory, and attention. These processes are controlled by glutamatergic signaling of hippocampal pyramidal neurons within the CA1 region, suggesting actions of nicotine on glutamatergic transmission in this region if present prenatally. Accordingly, we aimed to investigate hippocampal glutamatergic function following PNE treatment in NMRI mice employing molecular, cellular electrophysiology, and pharmacological approaches, as well as to evaluate cognition in the rodent continuous performance task (rCPT), a recently developed mouse task allowing assessment of learning, attention, and impulsivity. PNE induced increases in the expression levels of mRNA coding for different glutamate receptors and subunits within the hippocampus. Functional alterations in AMPA and NMDA receptors on CA1 pyramidal neurons of PNE mice were suggestive of higher GluA2-lacking and lower GluN2A-containing receptors, respectively. Finally, PNE was associated with reduced learning, attention, and enhanced impulsivity in the rCPT. Alterations in glutamatergic functioning in CA1 neurons parallel changes seen in the spontaneously hypertensive rat ADHD model and likely contribute to the lower cognitive performance in the rCPT.
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21
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Liu C, Yin H, Jiang H, Du X, Wang C, Liu Y, Li Y, Yang Z. Extracellular Vesicles Derived from Mesenchymal Stem Cells Recover Fertility of Premature Ovarian Insufficiency Mice and the Effects on their Offspring. Cell Transplant 2020; 29:963689720923575. [PMID: 32363925 PMCID: PMC7586265 DOI: 10.1177/0963689720923575] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/04/2020] [Accepted: 04/09/2020] [Indexed: 12/31/2022] Open
Abstract
It has been reported that extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (HUCMSCs) can promote the proliferative and secretive functions of granulosa cells. In vivo study further demonstrated that EVs derived from HUCMSCs can not only promote the angiogenesis of ovarian tissue but also restore the function of an ovary of chemically induced premature ovarian insufficiency (POI) mice. However, no study investigates the effects of HUCMSCs derived EVs on fertility recovery of POI mice and evaluating their offspring. This study investigates the effects of HUCMSCs derived EVs on fertility recovery and the cognitive function of their offspring. A POI model was established by intraperitoneal injection of cyclophosphamide (CTX) and busulfan (BUS), and randomly divided into EVs-transplantation group (a single injection of 150 µg EVs proteins which suspended in 0.1 ml phosphate buffer saline [PBS] via tail vein), POI group (a single injection of 0.1 ml PBS via tail vein), and normal control group (a single injection of 0.1 ml PBS via tail vein without intraperitoneal injection of CTX and BUS). After EVs treatment, not only the ovarian function of POI mice recovered but also the fertility increased with less time to get pregnant, evaluating by in vitro fertilization and mating test. Cognitive behaviors of the offspring were similar among the three groups through the Y-maze test and novel object recognition task. An anti-apoptotic effect was identified through immunohistochemistry, real-time polymerase chain reaction and western blot. These findings indicate that HUCMSCs derived EVs can improve the fertility of POI mice without adverse effects on the cognitive behavior of their offspring, highlighting the potential value of EVs to be a cell-free therapy for patients suffering from POI.
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Affiliation(s)
- Conghui Liu
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
| | - Huiqun Yin
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
| | - Hong Jiang
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
| | - Xin Du
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
| | - Cunli Wang
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
| | - Yingchun Liu
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
| | - Yu Li
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
| | - Ziling Yang
- Reproductive Medicine Center, 105th Hospital of the People’s Liberation Army, Hefei, China
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Sabzalizadeh M, Afarinesh MR, Mafi F, Mosanejad E, Haghpanah T, Golshan F, Koohkan F, Ezzatabadipour M, Sheibani V. Alcohol and nicotine co-Administration during pregnancy and lactation periods alters sensory discrimination of adult NMRI mice offspring. Physiol Behav 2019; 213:112731. [PMID: 31682889 DOI: 10.1016/j.physbeh.2019.112731] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Revised: 10/09/2019] [Accepted: 10/31/2019] [Indexed: 01/01/2023]
Abstract
The present study investigated the impacts of alcohol, nicotine, and their co-administration during pregnancy and lactation on sensory information processing including visual, tactile, and auditory discrimination in adult NMRI mice offspring. Pregnant mice were injected with saline or 20% alcohol (3 g/kg), or nicotine (1 mg/kg) or their co-administration alcohol+nicotine, intraperitoneally until the end of lactation. The offspring were separated from their mothers after lactation period on postnatal day (PND) 28. The locomotor activity, novel object recognition-dependent on visual system (NOR-VS), novel texture discrimination- dependent on somatosensory system (NTR-SS), and acoustic startle reflex were evaluated in PND90. The results revealed no statistical significance for locomotor activity of alcohol, nicotine, and co-administration alcohol+nicotine groups compared to the saline group in the open field task. The results, however, showed a significant decline in the ability of novel object discrimination in the nicotine and co-administration alcohol + nicotine groups compared to the saline group (P < 0.05) in the NOR-VS task. In the NTR-SS and acoustic startle reflex tasks, texture discrimination and the prepulse inhibition abilities in the offspring administered with nicotine and alcohol alone were reduced when compared to the saline group. Also, co-administration of alcohol+nicotine groups showed a decline in the aforementioned tests compared to the saline group (P <0.05). Administration of alcohol and nicotine during fetal and postpartum development disrupts sensory processing of inputs of visual, tactile, and auditory systems in adult mice.
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Affiliation(s)
- Mansoureh Sabzalizadeh
- Neuroscience Research Center, Institute of Neuropharmachology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Reza Afarinesh
- Neuroscience Research Center, Institute of Neuropharmachology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Fatemeh Mafi
- Neuroscience Research Center, Institute of Neuropharmachology, Kerman University of Medical Sciences, Kerman, Iran
| | - Elahe Mosanejad
- Department of anatomy, School of medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Tahereh Haghpanah
- Department of anatomy, School of medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Golshan
- Neuroscience Research Center, Institute of Neuropharmachology, Kerman University of Medical Sciences, Kerman, Iran
| | - Faezeh Koohkan
- Neuroscience Research Center, Institute of Neuropharmachology, Kerman University of Medical Sciences, Kerman, Iran
| | - Massood Ezzatabadipour
- Department of anatomy, School of medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Vahid Sheibani
- Neuroscience Research Center, Institute of Neuropharmachology, Kerman University of Medical Sciences, Kerman, Iran
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Polli FS, Kohlmeier KA. Alterations in NMDAR-mediated signaling within the laterodorsal tegmental nucleus are associated with prenatal nicotine exposure. Neuropharmacology 2019; 158:107744. [DOI: 10.1016/j.neuropharm.2019.107744] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/23/2019] [Accepted: 08/18/2019] [Indexed: 12/18/2022]
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Polli FS, Kohlmeier KA. Prenatal Nicotine Exposure in Rodents: Why Are There So Many Variations in Behavioral Outcomes? Nicotine Tob Res 2019; 22:1694-1710. [DOI: 10.1093/ntr/ntz196] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 10/05/2019] [Indexed: 01/01/2023]
Abstract
Abstract
Introduction
The World Health Organization (WHO) reported that smoking cessation rates among women have stagnated in the past decade and estimates that hundreds of millions of women will be smokers in the next decade. Social, environmental, and biological conditions render women more susceptible to nicotine addiction, imposing additional challenges to quit smoking during gestation, which is likely why more than 8% of pregnancies in Europe are associated with smoking. In epidemiological investigations, individuals born from gestational exposure to smoking exhibit a higher risk of development of attention-deficit/hyperactive disorder (ADHD) and liability to drug dependence. Among other teratogenic compounds present in tobacco smoke, nicotine actions during neuronal development could contribute to the observed outcomes as nicotine misleads signaling among progenitor cells during brain development. Several experimental approaches have been developed to address the consequences of prenatal nicotine exposure (PNE) to the brain and behavior but, after four decades of studies, inconsistent data have been reported and the lack of consensus in the field has compromised the hypothesis that gestational nicotine exposure participates in cognitive and emotional behavioral deficits.
Aims
In this review, we discuss the most commonly used PNE models with focus on their advantages and disadvantages, their relative validity, and how the different technical approaches could play a role in the disparate outcomes.
Results
We propose methodological considerations, which could improve the translational significance of the PNE models.
Conclusions
Such alterations might be helpful in reconciling experimental findings, as well as leading to development of treatment targets for maladaptive behaviors in those prenatally exposed.
Implications
In this article, we have reviewed the advantages and disadvantages of different variables of the commonly used experimental models of PNE. We discuss how variations in the nicotine administration methods, the timing of nicotine exposure, nicotine doses, and species employed could contribute to the disparate findings in outcomes for PNE offspring, both in behavior and neuronal changes. In addition, recent findings suggest consideration of epigenetic effects extending across generations. Finally, we have suggested improvements in the available PNE models that could contribute to the enhancement of their validity, which could assist in the reconciliation of experimental findings.
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Affiliation(s)
- Filip Souza Polli
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristi Anne Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Hawkey A, Junaid S, Yao L, Spiera Z, White H, Cauley M, Levin ED. Gestational exposure to nicotine and/or benzo[a]pyrene causes long-lasting neurobehavioral consequences. Birth Defects Res 2019; 111:1248-1258. [PMID: 31368242 DOI: 10.1002/bdr2.1568] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 07/02/2019] [Accepted: 07/18/2019] [Indexed: 12/14/2022]
Abstract
Tobacco smoke is a complex mixture that includes thousands of compounds. Previously, we have found that gestational exposure to the complex mixture of tobacco smoke extract caused long-term neurobehavioral impairments. In this study, we examined the interaction of two of the most biologically active, nicotine and benzo[a]pyrene (BaP). Developmental effects were determined in Sprague-Dawley rats prenatally exposed to low doses of BaP and nicotine (0.03 mg/kg/day of BaP and 2 mg/kg/day of nicotine) via maternal osmotic minipumps throughout gestation. Behavioral function was assessed in the offspring via a battery of tests through adolescence into adulthood. There were sex-selective effects in four of the behavioral tests. In the elevated plus maze, there was a significant interaction of BaP and sex, where BaP-treated males showed a trend for increased activity. In the novelty suppressed feeding test, there were significant sex selective effects in males such that the normal sex difference in the behavior in this test was eliminated. Male offspring with prenatal exposure to either nicotine or BaP showed significant reductions in fear response. In the Figure-8 locomotor activity test, BAP-exposed male offspring were significantly hyperactive. This also eliminated the sex difference typically seen in this test. This effect persisted into adulthood. In the attention task, males exposed to nicotine during gestation showed a significant percent hit impairment. BaP reversed this effect. No significant effects were seen with percent correct rejection. These data show that both nicotine and BaP cause persisting sex-selective behavioral effects that persist into adulthood.
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Affiliation(s)
- Andrew Hawkey
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Shaqif Junaid
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Leah Yao
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Zachary Spiera
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Hannah White
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Marty Cauley
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Edward D Levin
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
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Alkam T, Nabeshima T. Molecular mechanisms for nicotine intoxication. Neurochem Int 2019; 125:117-126. [PMID: 30779928 DOI: 10.1016/j.neuint.2019.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 01/28/2019] [Accepted: 02/12/2019] [Indexed: 01/25/2023]
Abstract
Nicotine, one of the more than 4700 ingredients in tobacco smoke, is a neurotoxin and once used as pesticides in agriculture. Although its use in agriculture is prohibited in many countries, nicotine intoxication is still a problem among the workers in tobacco farms, and young children as well as adults due to the accidental or suicidal ingestions of nicotine products. Understanding the mechanism of nicotine intoxication is important not only for the prevention and treatment but also for the appropriate regulatory approaches. Here, we review pharmacokinetics of nicotine and the molecular mechanisms for acute and chronic intoxication from nicotine that might be relevant to the central and the peripheral nervous system. We include green tobacco sickness, acute intoxication from popular nicotine products, circadian rhythm changes, chronic intoxication from nicotine through prenatal nicotine exposure, newborn behaviors, and sudden infant death syndrome.
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Affiliation(s)
- Tursun Alkam
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan; Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.
| | - Toshitaka Nabeshima
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan; Advanced Diagnostic System Research Laboratory, Graduate School of Health Sciences, Fujita Health University, Toyoake, Japan.
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McCarthy DM, Morgan TJ, Lowe SE, Williamson MJ, Spencer TJ, Biederman J, Bhide PG. Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants. PLoS Biol 2018; 16:e2006497. [PMID: 30325916 PMCID: PMC6191076 DOI: 10.1371/journal.pbio.2006497] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 09/13/2018] [Indexed: 12/27/2022] Open
Abstract
Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.
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Affiliation(s)
- Deirdre M. McCarthy
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, United States of America
| | - Thomas J. Morgan
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, United States of America
| | - Sarah E. Lowe
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, United States of America
| | - Matthew J. Williamson
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, United States of America
| | - Thomas J. Spencer
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Pradeep G. Bhide
- Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, United States of America
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Bassey RB, Gondré-Lewis MC. Combined early life stressors: Prenatal nicotine and maternal deprivation interact to influence affective and drug seeking behavioral phenotypes in rats. Behav Brain Res 2018; 359:814-822. [PMID: 30055209 DOI: 10.1016/j.bbr.2018.07.022] [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: 04/30/2018] [Revised: 07/18/2018] [Accepted: 07/24/2018] [Indexed: 12/21/2022]
Abstract
Early life stress (ELS) increases the risk for later cognitive and emotional dysfunction, and has been implicated in the etiology of multiple psychiatric disorders. We hypothesize that combined insults during gestation and infancy, critical periods of neural development, could exacerbate neuropsychiatric outcomes in later life. Thus, we investigated the effects of maternal deprivation (MD) stress alone or combined with prenatal nicotine exposure (PNE) on negative affective states, ethanol drinking, and development of mesolimbic loci that regulate depression and drug dependence. On the elevated plus maze (EPM), MD rats exhibited ∼50% increase in risk-taking behavior/decreased anxiety when compared to control, but the combined MD + PNE did not affect this specific behavior. In the open field test, however, both MD and MD + PNE groups showed 2-fold greater locomotor activity. Furthermore, whereas MD showed greater latency to fall at 40 RPM on the rotarod compared to control, the MD + PNE animals' latency to fall was significantly greater at all RPMs tested, with an approximate 15% enhancement in motor coordination overall compared to control and MD. Analyses of depressive symptomatology with the forced swim test (FST) yielded 2- and 3-fold higher immobility times in MD and MD + PNE respectively. When tested in an operant drinking paradigm to quantify the effect of treatment on 10%v/v ethanol drinking, the MD and MD + PNE groups showed heightened ethanol consumption by ∼3- and 2-fold respectively. However, the experience of PNE reduced ethanol consumption in adults relative to MD alone. To test the stressors' impact on neurons in the amygdala and ventral tegmental area (VTA), mesolimbic anatomical regions associated with mood and reward, unbiased stereological measurements were performed and revealed ∼15% increase in number and density of neurons in the amygdala for both MD and MD + PNE, and ∼13% reduction in dopaminergic-like neurons in the VTA compared to control. We report here that multiple early stressors including prenatal nicotine and MD can modulate the neuroanatomy of the amygdala and VTA. These early life stressors can interact to influence the development of depressive-like and addictive behaviors.
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Affiliation(s)
- Rosemary B Bassey
- Department of Anatomy, Howard University, College of Medicine, Washington D.C. 20059, USA; Department of Psychiatry and Behavioral Sciences, Howard University, College of Medicine, Washington D.C. 20059, USA
| | - Marjorie C Gondré-Lewis
- Department of Anatomy, Howard University, College of Medicine, Washington D.C. 20059, USA; Department of Psychiatry and Behavioral Sciences, Howard University, College of Medicine, Washington D.C. 20059, USA.
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Chao OY, Yunger R, Yang YM. Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: Implications for an animal model of psychiatric comorbidity in autism. Behav Brain Res 2018; 347:140-147. [DOI: 10.1016/j.bbr.2018.03.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/09/2018] [Accepted: 03/09/2018] [Indexed: 10/17/2022]
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30
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Ipsen TH, Polli FS, Kohlmeier KA. Calcium rises induced by AMPA and nicotine receptors in the ventral tegmental area show differences in mouse brain slices prenatally exposed to nicotine. Dev Neurobiol 2018; 78:828-848. [PMID: 29923678 DOI: 10.1002/dneu.22607] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/24/2018] [Accepted: 05/24/2018] [Indexed: 12/13/2022]
Abstract
Nicotine exposure during gestation is associated with a higher risk of adverse behavioral outcomes including a heightened liability for dependency to drugs of abuse, which can exhibit drug-specificity influenced by gender. This enhanced liability suggests that nicotine use during pregnancy alters neural development in circuits involved in motivation and reward-based learning. The ventral tegmental area (VTA) is critical in motivated behaviors and we hypothesized that gestational exposure to nicotine alters the development of excitatory circuits in this nucleus. Accordingly, in VTA brain slices from male and female mice exposed to nicotine during the prenatal period (PNE) and controls, we compared cellular rises in calcium induced by AMPA receptor and nicotinic acetylcholine receptor (nAChR) stimulation by use of the ratiometric calcium binding dye, Fura-2AM. We found that AMPA induced smaller amplitude calcium rises in the PNE VTA, which was an effect only detected in males. Further, while the amplitude did not vary between treatment and control in females, a greater number of cells responded with rises in calcium in the PNE. Conversely, the proportions of cells responding with calcium rises induced by nAChR stimulation did not change in either gender according to treatment. However, larger rises in calcium in PNE females were detected. When taken together our data show that excitatory signaling in the VTA is altered in a gender-specific manner by PNE and suggest that alterations in signaling could play a role in drug-specific differences in maladaptive, motivated behaviors exhibited by males and females born to mothers exposed to nicotine during pregnancy. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 2018.
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Affiliation(s)
- Theis H Ipsen
- Faculty of Health Sciences, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 2100, Denmark
| | - Filip S Polli
- Faculty of Health Sciences, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 2100, Denmark
| | - Kristi A Kohlmeier
- Faculty of Health Sciences, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 2100, Denmark
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Morris M, Shaw A, Lambert M, Perry HH, Lowenstein E, Valenzuela D, Velazquez-Ulloa NA. Developmental nicotine exposure affects larval brain size and the adult dopaminergic system of Drosophila melanogaster. BMC DEVELOPMENTAL BIOLOGY 2018; 18:13. [PMID: 29898654 PMCID: PMC6001141 DOI: 10.1186/s12861-018-0172-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 05/21/2018] [Indexed: 01/15/2023]
Abstract
BACKGROUND Pregnant women may be exposed to nicotine if they smoke or use tobacco products, nicotine replacement therapy, or via e-cigarettes. Prenatal nicotine exposure has been shown to have deleterious effects on the nervous system in mammals including changes in brain size and in the dopaminergic system. The genetic and molecular mechanisms for these changes are not well understood. A Drosophila melanogaster model for these effects of nicotine exposure could contribute to faster identification of genes and molecular pathways underlying these effects. The purpose of this study was to determine if developmental nicotine exposure affects the nervous system of Drosophila melanogaster, focusing on changes to brain size and the dopaminergic system at two developmental stages. RESULTS We reared flies on control or nicotine food from egg to 3rd instar larvae or from egg to adult and determined effectiveness of the nicotine treatment. We used immunohistochemistry to visualize the whole brain and dopaminergic neurons, using tyrosine hydroxylase as the marker. We measured brain area, tyrosine hydroxylase fluorescence, and counted the number of dopaminergic neurons in brain clusters. We detected an increase in larval brain hemisphere area, a decrease in tyrosine hydroxylase fluorescence in adult central brains, and a decrease in the number of neurons in the PPM3 adult dopaminergic cluster. We tested involvement of Dα7, one of the nicotinic acetylcholine receptor subunits, and found it was involved in eclosion, as previously described, but not involved in brain size. CONCLUSIONS We conclude that developmental nicotine exposure in Drosophila melanogaster affects brain size and the dopaminergic system. Prenatal nicotine exposure in mammals has also been shown to have effects on brain size and in the dopaminergic system. This study further establishes Drosophila melanogaster as model organism to study the effects of developmental nicotine exposure. The genetic and molecular tools available for Drosophila research will allow elucidation of the mechanisms underlying the effects of nicotine exposure during development.
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Affiliation(s)
- Melanie Morris
- School of Medicine, University of Washington, Seattle, USA
| | - Ariel Shaw
- Biochemistry, Cell and Molecular Biology Program, Lewis & Clark College, Portland, USA
| | | | | | - Eve Lowenstein
- Biology Department, Lewis & Clark College, Portland, USA
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Zhang L, Spencer TJ, Biederman J, Bhide PG. Attention and working memory deficits in a perinatal nicotine exposure mouse model. PLoS One 2018; 13:e0198064. [PMID: 29795664 PMCID: PMC5967717 DOI: 10.1371/journal.pone.0198064] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/14/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cigarette smoking by pregnant women is associated with a significant increase in the risk for cognitive disorders in their children. Preclinical models confirm this risk by showing that exposure of the developing brain to nicotine produces adverse behavioral outcomes. Here we describe behavioral phenotypes resulting from perinatal nicotine exposure in a mouse model, and discuss our findings in the context of findings from previously published studies using preclinical models of developmental nicotine exposure. METHODOLOGY/PRINCIPAL FINDINGS Female C57Bl/6 mice received drinking water containing nicotine (100μg/ml) + saccharin (2%) starting 3 weeks prior to breeding and continuing throughout pregnancy, and until 3 weeks postpartum. Over the same period, female mice in two control groups received drinking water containing saccharin (2%) or plain drinking water. Offspring from each group were weaned at 3-weeks of age and subjected to behavioral analyses at 3 months of age. We examined spontaneous locomotor activity, anxiety-like behavior, spatial working memory, object based attention, recognition memory and impulsive-like behavior. We found significant deficits in attention and working memory only in male mice, and no significant changes in the other behavioral phenotypes in male or female mice. Exposure to saccharin alone did not produce significant changes in either sex. CONCLUSION/SIGNIFICANCE The perinatal nicotine exposure produced significant deficits in attention and working memory in a sex-dependent manner in that the male but not female offspring displayed these behaviors. These behavioral phenotypes are associated with attention deficit hyperactivity disorder (ADHD) and have been reported in other studies that used pre- or perinatal nicotine exposure. Therefore, we suggest that preclinical models of developmental nicotine exposure could be useful tools for modeling ADHD and related disorders.
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Affiliation(s)
- Lin Zhang
- Center for Brain Repair, Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
| | - Thomas J. Spencer
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Pradeep G. Bhide
- Center for Brain Repair, Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
- * E-mail:
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Toriumi K, Tanaka J, Mamiya T, Alkam T, Kim HC, Nitta A, Nabeshima T. Shati/Nat8l knockout mice show behavioral deficits ameliorated by atomoxetine and methylphenidate. Behav Brain Res 2018; 339:207-214. [DOI: 10.1016/j.bbr.2017.11.040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 11/10/2017] [Accepted: 11/30/2017] [Indexed: 11/16/2022]
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Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene. Neurobiol Learn Mem 2017; 146:12-20. [PMID: 29107702 DOI: 10.1016/j.nlm.2017.10.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/26/2017] [Accepted: 10/27/2017] [Indexed: 01/15/2023]
Abstract
The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.
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Alkam T, Mamiya T, Kimura N, Yoshida A, Kihara D, Tsunoda Y, Aoyama Y, Hiramatsu M, Kim HC, Nabeshima T. Prenatal nicotine exposure decreases the release of dopamine in the medial frontal cortex and induces atomoxetine-responsive neurobehavioral deficits in mice. Psychopharmacology (Berl) 2017; 234:1853-1869. [PMID: 28332006 DOI: 10.1007/s00213-017-4591-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 03/05/2017] [Indexed: 02/06/2023]
Abstract
Increased risk of attention-deficit/hyperactivity disorder (AD/HD) is partly associated with the early developmental exposure to nicotine in tobacco smoke. Emerging reports link tobacco smoke exposure or prenatal nicotine exposure (PNE) with AD/HD-like behaviors in rodent models. We have previously reported that PNE induces cognitive behavioral deficits in offspring and decreases the contents of dopamine (DA) and its turnover in the prefrontal cortex (PFC) of offspring It is well known that the dysfunction of DAergic system in the brain is one of the core factors in the pathophysiology of AD/HD. Therefore, we examined whether the effects of PNE on the DAergic system underlie the AD/HD-related behavioral changes in mouse offspring. PNE reduced the release of DA in the medial PFC (mPFC) in mouse offspring. PNE reduced the number of tyrosine hydroxylase (TH)-positive varicosities in the mPFC and in the core as well as the shell of nucleus accumbens, but not in the striatum. PNE also induced behavioral deficits in cliff avoidance, object-based attention, and sensorimotor gating in offspring. These behavioral deficits were attenuated by acute treatment with atomoxetine (3 mg/kg, s.c.) or partially attenuated by acute treatment with MPH (1 mg/kg, s.c.). Taken together, our findings support the notion that PNE induces neurobehavioral abnormalities in mouse offspring by disrupting the DAergic system and improve our understanding about the incidence of AD/HD in children whose mothers were exposed to nicotine during their pregnancy.
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Affiliation(s)
- Tursun Alkam
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
- Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA
| | - Takayoshi Mamiya
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Nami Kimura
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Aya Yoshida
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Daisuke Kihara
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Yuki Tsunoda
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Yuki Aoyama
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Masayuki Hiramatsu
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Hyoung-Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, South Korea
| | - Toshitaka Nabeshima
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan.
- Advanced Diagnostic System Research Laboratory, Graduate School of Health Sciences, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
- Aino University, Ibaraki, Japan.
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Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism. Int J Genomics 2017; 2017:7526592. [PMID: 28567415 PMCID: PMC5439185 DOI: 10.1155/2017/7526592] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 04/02/2017] [Indexed: 01/07/2023] Open
Abstract
The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD) hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates), persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment.
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37
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Zhu J, Fan F, McCarthy DM, Zhang L, Cannon EN, Spencer TJ, Biederman J, Bhide PG. A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD‐associated cognitive phenotypes. Int J Dev Neurosci 2017; 58:26-34. [DOI: 10.1016/j.ijdevneu.2017.01.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 01/21/2017] [Accepted: 01/27/2017] [Indexed: 12/13/2022] Open
Affiliation(s)
- Jinmin Zhu
- Center for Brain Repair and The Department of Biomedical SciencesFlorida State University College of MedicineTallahasseeFL32306United States
| | - Fangfang Fan
- Center for Brain Repair and The Department of Biomedical SciencesFlorida State University College of MedicineTallahasseeFL32306United States
| | - Deirdre M. McCarthy
- Center for Brain Repair and The Department of Biomedical SciencesFlorida State University College of MedicineTallahasseeFL32306United States
| | - Lin Zhang
- Center for Brain Repair and The Department of Biomedical SciencesFlorida State University College of MedicineTallahasseeFL32306United States
| | - Elisa N. Cannon
- Center for Brain Repair and The Department of Biomedical SciencesFlorida State University College of MedicineTallahasseeFL32306United States
| | - Thomas J. Spencer
- Pediatric Psychopharmacology, Department of PsychiatryMassachusetts General Hospital, Harvard Medical SchoolBostonMA02114United States
| | - Joseph Biederman
- Pediatric Psychopharmacology, Department of PsychiatryMassachusetts General Hospital, Harvard Medical SchoolBostonMA02114United States
| | - Pradeep G. Bhide
- Center for Brain Repair and The Department of Biomedical SciencesFlorida State University College of MedicineTallahasseeFL32306United States
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38
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Tashiro T, Murakami Y, Mouri A, Imamura Y, Nabeshima T, Yamamoto Y, Saito K. Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions. Behav Brain Res 2017; 317:279-285. [DOI: 10.1016/j.bbr.2016.09.050] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 09/20/2016] [Accepted: 09/22/2016] [Indexed: 01/05/2023]
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39
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Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1. Sci Rep 2016; 6:29920. [PMID: 27436416 PMCID: PMC4951771 DOI: 10.1038/srep29920] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/27/2016] [Indexed: 01/05/2023] Open
Abstract
Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites’ levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.
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40
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Aoyama Y, Toriumi K, Mouri A, Hattori T, Ueda E, Shimato A, Sakakibara N, Soh Y, Mamiya T, Nagai T, Kim HC, Hiramatsu M, Nabeshima T, Yamada K. Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex. Neuropsychopharmacology 2016; 41:578-89. [PMID: 26105135 PMCID: PMC5130133 DOI: 10.1038/npp.2015.186] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 05/22/2015] [Accepted: 06/13/2015] [Indexed: 12/20/2022]
Abstract
Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.
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Affiliation(s)
- Yuki Aoyama
- Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya, Japan,Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Kazuya Toriumi
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Akihiro Mouri
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan,Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Tomoya Hattori
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Eriko Ueda
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Akane Shimato
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Nami Sakakibara
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Yuka Soh
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Takayoshi Mamiya
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan,Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Taku Nagai
- Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Hyoung-Chun Kim
- Department of Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, South Korea
| | - Masayuki Hiramatsu
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan,Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Toshitaka Nabeshima
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan,Nabeshima Laboratory, Faculty of Pharmacy, Meijo University, Nagoya, Japan,Nabeshima Laboratory, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan, Tel: +81 52 839 2756, Fax: +81 52 839 2756, E-mail:
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya, Japan,Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan,Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan, Tel: +81 52 744 2674, Fax: +81 52 744 2979, E-mail:
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41
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Smith D, Aherrera A, Lopez A, Neptune E, Winickoff JP, Klein JD, Chen G, Lazarus P, Collaco JM, McGrath-Morrow SA. Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life. PLoS One 2015; 10:e0137953. [PMID: 26372012 PMCID: PMC4570802 DOI: 10.1371/journal.pone.0137953] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 08/25/2015] [Indexed: 01/28/2023] Open
Abstract
Nicotine exposure has been associated with an increased likelihood of developing attention deficit hyperactivity disorder (ADHD) in offspring of mothers who smoked during pregnancy. The goal of this study was to determine if exposure to E-cigarette nicotine vapors during late prenatal and early postnatal life altered behavior in adult mice.
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Affiliation(s)
- Dani Smith
- Neurogenetics and Behavior Center, Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Angela Aherrera
- Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Armando Lopez
- Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins Medical Institutes, Baltimore, Maryland, United States of America
| | - Enid Neptune
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins Medical Institutes, Baltimore, Maryland, United States of America
| | - Jonathan P. Winickoff
- Julius B. Richmond Center of Excellence, American Academy of Pediatrics, Elk Grove Village, Illinois, United States of America
- Division of General Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Jonathan D. Klein
- Julius B. Richmond Center of Excellence, American Academy of Pediatrics, Elk Grove Village, Illinois, United States of America
| | - Gang Chen
- Department of Pharmacology, Washington State University, Pullman, Washington, United States of America
| | - Philip Lazarus
- Department of Pharmacology, Washington State University, Pullman, Washington, United States of America
| | - Joseph M. Collaco
- Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Julius B. Richmond Center of Excellence, American Academy of Pediatrics, Elk Grove Village, Illinois, United States of America
| | - Sharon A. McGrath-Morrow
- Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Julius B. Richmond Center of Excellence, American Academy of Pediatrics, Elk Grove Village, Illinois, United States of America
- * E-mail:
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42
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Ueda S, Niwa M, Hioki H, Sohn J, Kaneko T, Sawa A, Sakurai T. Sequence of Molecular Events during the Maturation of the Developing Mouse Prefrontal Cortex. MOLECULAR NEUROPSYCHIATRY 2015; 1:94-104. [PMID: 26457295 DOI: 10.1159/000430095] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recent progress in psychiatric research has accumulated many mouse models relevant to developmental neuropsychiatric disorders using numerous genetic and environmental manipulations. Since the prefrontal cortex (PFC) is essential for cognitive functions whose impairments are central symptoms associated with the disorders in humans, it has become crucial to clarify altered developmental processes of PFC circuits in these mice. To that end, we aimed to understand a sequence of molecular events during normal mouse PFC development. Expression profiles for representative genes covering diverse biological processes showed that while there were little changes in genes for neuroreceptors and synaptic molecules during postnatal period, there were dramatic increases in expression of myelin-related genes and parvalbumin gene, peaking at postnatal day (P) 21 and P35, respectively. The timing of the peaks is different from one observed in the striatum. Furthermore, evaluation of the circuitry maturation by measuring extracellular glutamate in PFC revealed that sensitivity to an NMDA antagonist became adult-like pattern at P56, suggesting that some of maturation processes continue till P56. The trajectory of molecular events in the PFC maturation described here should help us to characterize how the processes are affected in model mice, an important first step for translational research.
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Affiliation(s)
- Shuhei Ueda
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
| | - Minae Niwa
- Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Hiroyuki Hioki
- Department of Morphological Brain Science, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
| | - Jaerin Sohn
- Department of Morphological Brain Science, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
| | - Takeshi Kaneko
- Department of Morphological Brain Science, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
| | - Akira Sawa
- Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Takeshi Sakurai
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
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