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Fernández-Pereira C, Agís-Balboa RC. The Insulin-like Growth Factor Family as a Potential Peripheral Biomarker in Psychiatric Disorders: A Systematic Review. Int J Mol Sci 2025; 26:2561. [PMID: 40141202 PMCID: PMC11942524 DOI: 10.3390/ijms26062561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/13/2025] [Accepted: 02/17/2025] [Indexed: 03/28/2025] Open
Abstract
Psychiatric disorders (PDs), including schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BD), autism spectrum disorder (ASD), among other disorders, represent a significant global health burden. Despite advancements in understanding their biological mechanisms, there is still no reliable objective and reliable biomarker; therefore, diagnosis remains largely reliant on subjective clinical assessments. Peripheral biomarkers in plasma or serum are interesting due to their accessibility, low cost, and potential to reflect central nervous system processes. Among these, the insulin-like growth factor (IGF) family, IGF-1, IGF-2, and IGF-binding proteins (IGFBPs), has gained attention for its roles in neuroplasticity, cognition, and neuroprotection, as well as for their capability to cross the blood-brain barrier. This review evaluates the evidence for IGF family alterations in PDs, with special focus on SZ, MDD, and BD, while also addressing other PDs covering almost 40 years of history. In SZ patients, IGF-1 alterations have been linked to metabolic dysregulation, treatment response, and hypothalamic-pituitary-adrenal axis dysfunction. In MDD patients, IGF-1 appears to compensate for impaired neurogenesis, although findings are inconsistent. Emerging studies on IGF-2 and IGFBPs suggest potential roles across PDs. While promising, heterogeneity among studies and methodological limitations highlights the need for further research to validate IGFs as reliable psychiatric biomarkers.
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Affiliation(s)
- Carlos Fernández-Pereira
- Neuro Epigenetics Lab, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain;
- Translational Research in Neurological Diseases (ITEN) Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, SERGAS-USC, 15706 Santiago de Compostela, Spain
- Neurology Service, Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain
| | - Roberto Carlos Agís-Balboa
- Neuro Epigenetics Lab, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain;
- Translational Research in Neurological Diseases (ITEN) Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, SERGAS-USC, 15706 Santiago de Compostela, Spain
- Neurology Service, Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain
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Maheshwari M, Singla A, Rawat A, Banerjee T, Pati S, Shah S, Maiti S, Vaidya VA. Chronic chemogenetic activation of hippocampal progenitors enhances adult neurogenesis and modulates anxiety-like behavior and fear extinction learning. IBRO Neurosci Rep 2024; 16:168-181. [PMID: 39007086 PMCID: PMC11240292 DOI: 10.1016/j.ibneur.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 01/18/2024] [Indexed: 07/16/2024] Open
Abstract
Adult hippocampal neurogenesis is a lifelong process that involves the integration of newborn neurons into the hippocampal network, and plays a role in cognitive function and the modulation of mood-related behavior. Here, we sought to address the impact of chemogenetic activation of adult hippocampal progenitors on distinct stages of progenitor development, including quiescent stem cell activation, progenitor turnover, differentiation and morphological maturation. We find that hM3Dq-DREADD-mediated activation of nestin-positive adult hippocampal progenitors recruits quiescent stem cells, enhances progenitor proliferation, increases doublecortin-positive newborn neuron number, accompanied by an acceleration of differentiation and morphological maturation, associated with increased dendritic complexity. Behavioral analysis indicated anxiolytic behavioral responses in transgenic mice subjected to chemogenetic activation of adult hippocampal progenitors at timepoints when newborn neurons are predicted to integrate into the mature hippocampal network. Furthermore, we noted an enhanced fear memory extinction on a contextual fear memory learning task in transgenic mice subjected to chemogenetic activation of adult hippocampal progenitors. Our findings indicate that hM3Dq-DREAD-mediated chemogenetic activation of adult hippocampal progenitors impacts distinct aspects of hippocampal neurogenesis, associated with the regulation of anxiety-like behavior and fear memory extinction.
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Affiliation(s)
| | | | - Anoop Rawat
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India
| | - Toshali Banerjee
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India
| | - Sthitapranjya Pati
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India
| | - Sneha Shah
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India
| | - Sudipta Maiti
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India
| | - Vidita A. Vaidya
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India
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González-Martínez C, Haarkötter C, Carnero-Montoro E, Lorente JA, Lorente M. Epigenetic changes produced in women victims of intimate partner violence: A systematic review. WOMEN'S HEALTH (LONDON, ENGLAND) 2024; 20:17455057241290335. [PMID: 39568400 PMCID: PMC11580075 DOI: 10.1177/17455057241290335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/19/2024] [Accepted: 09/20/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND Intimate partner violence (IPV) is a prevalent form of violence against women that encompasses physical, sexual, and emotional abuse, as well as controlling behaviors by intimate partners, and predisposes the victims to multiple diseases. OBJECTIVE This systematic review aims to identify epigenetic marks associated with IPV and the resultant stress experienced by victims. DESIGN This study is a systematic review conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. The review includes a comprehensive search and analysis of relevant literature to identify epigenetic changes associated with IPV. DATA SOURCES AND METHODS A systematic search was conducted across four databases: PubMed, Scopus, Web of Science, and ProQuest, using keywords related to IPV and epigenetics. The inclusion criteria were studies published in scientific journals with an experimental approach, focused on female survivors of gender-based violence, and providing information on epigenetic changes. The review included studies published up to June 15, 2024, with no time limits imposed, focusing on female victims of IPV. The inclusion criteria were studies published in scientific journals with an experimental approach, focused on female survivors of gender-based violence, and providing information on epigenetic changes. RESULTS The results revealed that epigenetic changes associated with IPV predominantly affect genes related to the glucocorticoid receptor, insulin-like growth factors, BDNF, and CPLX genes. These observations suggest that IPV is linked to significant epigenetic modifications in both victims and their offspring. CONCLUSION It is concluded that IPV is associated with epigenetic changes both in the woman and in her offspring. These findings underscore the importance of understanding the biological embedding of IPV through epigenetic research to better address the long-term health consequences for women. However, more studies are necessary to validate these results.
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Affiliation(s)
- Coral González-Martínez
- Centre for Genomics and Oncological Research, Pfizer-University of Granada, PTS Granada, Granada, Spain
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
| | - Christian Haarkötter
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
| | - Elena Carnero-Montoro
- Centre for Genomics and Oncological Research, Pfizer-University of Granada, PTS Granada, Granada, Spain
| | - Jose A Lorente
- Centre for Genomics and Oncological Research, Pfizer-University of Granada, PTS Granada, Granada, Spain
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
| | - Miguel Lorente
- LABIGEN, Department of Legal Medicine, School of Medicine, PTS, University of Granada, UGR, Granada, Spain
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Fernández-Pereira C, Penedo MA, Rivera-Baltanás T, Pérez-Márquez T, Alves-Villar M, Fernández-Martínez R, Veiga C, Salgado-Barreira Á, Prieto-González JM, Ortolano S, Olivares JM, Agís-Balboa RC. Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder. Int J Mol Sci 2023; 24:15254. [PMID: 37894932 PMCID: PMC10607273 DOI: 10.3390/ijms242015254] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/13/2023] [Accepted: 10/15/2023] [Indexed: 10/29/2023] Open
Abstract
The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.
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Affiliation(s)
- Carlos Fernández-Pereira
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain; (C.F.-P.); (M.A.P.)
- Neuro Epigenetics Lab, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain;
- Rare Disease and Pediatric Medicine Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain; (T.P.-M.); (M.A.-V.); (S.O.)
| | - Maria Aránzazu Penedo
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain; (C.F.-P.); (M.A.P.)
| | - Tania Rivera-Baltanás
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain; (C.F.-P.); (M.A.P.)
| | - Tania Pérez-Márquez
- Rare Disease and Pediatric Medicine Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain; (T.P.-M.); (M.A.-V.); (S.O.)
| | - Marta Alves-Villar
- Rare Disease and Pediatric Medicine Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain; (T.P.-M.); (M.A.-V.); (S.O.)
| | - Rafael Fernández-Martínez
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain; (C.F.-P.); (M.A.P.)
| | - César Veiga
- Cardiovascular Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), 36213 Vigo, Spain
| | - Ángel Salgado-Barreira
- Department of Preventive Medicine and Public Health, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública-CIBERESP, 28029 Madrid, Spain
| | - José María Prieto-González
- Neuro Epigenetics Lab, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain;
- Translational Research in Neurological Diseases Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, SERGAS-USC, 15706 Santiago de Compostela, Spain
- Neurology Service, Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain
| | - Saida Ortolano
- Rare Disease and Pediatric Medicine Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain; (T.P.-M.); (M.A.-V.); (S.O.)
| | - José Manuel Olivares
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain; (C.F.-P.); (M.A.P.)
| | - Roberto Carlos Agís-Balboa
- Neuro Epigenetics Lab, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain;
- Translational Research in Neurological Diseases Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, SERGAS-USC, 15706 Santiago de Compostela, Spain
- Neurology Service, Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain
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Zorina II, Avrova NF, Zakharova IO, Shpakov AO. Prospects for the Use of Intranasally Administered Insulin and Insulin-Like Growth Factor-1 in Cerebral Ischemia. BIOCHEMISTRY (MOSCOW) 2023; 88:374-391. [PMID: 37076284 DOI: 10.1134/s0006297923030070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2023]
Abstract
Current approaches to the treatment of stroke have significant limitations, and neuroprotective therapy is ineffective. In view of this, searching for effective neuroprotectors and developing new neuroprotective strategies remain a pressing topic in research of cerebral ischemia. Insulin and insulin-like growth factor-1 (IGF-1) play a key role in the brain functioning by regulating the growth, differentiation, and survival of neurons, neuronal plasticity, food intake, peripheral metabolism, and endocrine functions. Insulin and IGF-1 produce multiple effects in the brain, including neuroprotective action in cerebral ischemia and stroke. Experiments in animals and cell cultures have shown that under hypoxic conditions, insulin and IGF-1 improve energy metabolism in neurons and glial cells, promote blood microcirculation in the brain, restore nerve cell functions and neurotransmission, and produce the anti-inflammatory and antiapoptotic effects on brain cells. The intranasal route of insulin and IGF-1 administration is of particular interest in the clinical practice, since it allows controlled delivery of these hormones directly to the brain, bypassing the blood-brain barrier. Intranasally administered insulin alleviated cognitive impairments in elderly people with neurodegenerative and metabolic disorders; intranasally administered insulin and IGF-1 promoted survival of animals with ischemic stroke. The review discusses the published data and results of our own studies on the mechanisms of neuroprotective action of intranasally administered insulin and IGF-1 in cerebral ischemia, as well as the prospects of using these hormones for normalization of CNS functions and reduction of neurodegenerative changes in this pathology.
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Affiliation(s)
- Inna I Zorina
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, 194223, Russia.
| | - Natalia F Avrova
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, 194223, Russia
| | - Irina O Zakharova
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, 194223, Russia
| | - Alexander O Shpakov
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, 194223, Russia
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Afferni P, Cascino-Milani F, Mattera A, Baldassarre G. A neuro-inspired computational model of life-long learning and catastrophic interference, mimicking hippocampus novelty-based dopamine modulation and lateral inhibitory plasticity. Front Comput Neurosci 2022; 16:954847. [PMID: 36157843 PMCID: PMC9500484 DOI: 10.3389/fncom.2022.954847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
The human brain has a remarkable lifelong learning capability to acquire new experiences while retaining previously acquired information. Several hypotheses have been proposed to explain this capability, but the underlying mechanisms are still unclear. Here, we propose a neuro-inspired firing-rate computational model involving the hippocampus and surrounding areas, that encompasses two key mechanisms possibly underlying this capability. The first is based on signals encoded by the neuromodulator dopamine, which is released by novel stimuli and enhances plasticity only when needed. The second is based on a homeostatic plasticity mechanism that involves the lateral inhibitory connections of the pyramidal neurons of the hippocampus. These mechanisms tend to protect neurons that have already been heavily employed in encoding previous experiences. The model was tested with images from the MNIST machine learning dataset, and with more naturalistic images, for its ability to mitigate catastrophic interference in lifelong learning. The results show that the proposed biologically grounded mechanisms can effectively enhance the learning of new stimuli while protecting previously acquired knowledge. The proposed mechanisms could be investigated in future empirical animal experiments and inspire machine learning models.
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Affiliation(s)
- Pierangelo Afferni
- Department of Engineering, Campus Bio-Medico University, Rome, Italy
- *Correspondence: Pierangelo Afferni
| | - Federico Cascino-Milani
- Department of Genetics and Neurobiology, Julius-Maximilians Universität Würzburg, Würzburg, Germany
| | - Andrea Mattera
- Laboratory of Embodied Natural and Artificial Intelligence, Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
| | - Gianluca Baldassarre
- Laboratory of Embodied Natural and Artificial Intelligence, Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
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7
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Champarini LG, Herrera ML, Comas Mutis RG, Espejo PJ, Molina VA, Calfa GD, Hereñú CB. Effect of intra-BLA overexpression of IGF-1 on the expression of a contextual fear memory trace. Hippocampus 2022; 32:765-775. [PMID: 36000813 DOI: 10.1002/hipo.23465] [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: 11/05/2021] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/08/2022]
Abstract
Growth factors, such as insulin-like growth factor 1 (IGF-1), among others are known for their critical involvement in learning and memory processes. IGF-1 regulates cognitive functions, synapse density, neurotransmission, and adult neurogenesis and induces structural and synaptic plasticity-specific changes. Although IGF-1 has been suggested to participate in different memory processes, its role in memories associated with negative emotional experiences still remains to be elucidated. The principal aim of the present study was to test whether IGF-1 overexpression using adenoviral vectors in basolateral amygdala (BLA) influences both the expression and formation of contextual fear memory, as well as the hippocampal structural plasticity associated with such memory trace. We found that IGF-1 overexpression promotes the formation and expression of a specific contextual fear memory trace, and such effect persisted at least 7 days after recall. Moreover, the overexpression of this growth factor in BLA upregulates the activation of the ERK/MAPK pathway in this brain structure. In addition, intra-BLA IGF-1 overexpression causes dorsal hippocampus (DH) structural plasticity modifications promoting changes in the proportion of mature dendritic spines in the CA1 region, after a weak conditioning protocol. The present findings contribute to the knowledge underlying BLA-DH trace memory of fear and reveal important new insights into the neurobiology and neurochemistry of fear acquisition modulated by IGF-1 overexpression. The understanding of how IGF-1 modulates the formation of a fear contextual trace may pave the way for the development of novel therapeutic strategies focused on fear, anxiety, and trauma-related disorders.
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Affiliation(s)
- Leandro Gabriel Champarini
- Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Cordoba, Argentina
| | - Macarena Lorena Herrera
- Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Cordoba, Argentina
| | - Ramiro Gabriel Comas Mutis
- Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Cordoba, Argentina
| | - Pablo Javier Espejo
- Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Cordoba, Argentina
| | - Victor Alejandro Molina
- Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Cordoba, Argentina
| | - Gastón Diego Calfa
- Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Cordoba, Argentina
| | - Claudia Beatriz Hereñú
- Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Cordoba, Argentina
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Insulin-like Growth Factor 2 (IGF-2) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) Are Upregulated after Atypical Antipsychotics in Spanish Schizophrenia Patients. Int J Mol Sci 2022; 23:ijms23179591. [PMID: 36076984 PMCID: PMC9455262 DOI: 10.3390/ijms23179591] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/19/2022] [Accepted: 08/19/2022] [Indexed: 11/17/2022] Open
Abstract
Insulin-like growth factor 2 (IGF-2) and IGF binding protein 7 (IGFBP-7) have been related to schizophrenia (SZ) due to their implication in neurodevelopment. The purpose of this study was to assess whether the alterations in IGF-2 and IGFBP-7 in SZ patients are intrinsically related to the psychiatric disorder itself or are a secondary phenomenon due to antipsychotic treatment. In order to test this hypothesis, we measured plasma IGF-2 and IGFBP-7 in drug-naïve first episode (FE) and multiple episodes or chronic (ME) SZ Caucasian patients who have been following treatment for years. A total of 55 SZ patients (FE = 15, ME = 40) and 45 healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS) and the Self-Assessment Anhedonia Scale (SAAS) were employed to check schizophrenic symptomatology and anhedonia, respectively. Plasma IGF-2 and IGFBP-7 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The FE SZ patients had much lower IGF-2, but not IGFBP-7, than controls. Moreover, both IGF-2 and IGFBP-7 significantly increased after atypical antipsychotic treatment (aripiprazole, olanzapine, or risperidone) in these patients. On the other hand, chronic patients showed higher levels of both proteins when compared to controls. Our study suggests that circulatory IGF-2 and IGFBP-7 increase after antipsychotic treatment, regardless of long-term conditions and being lower in drug-naïve FE patients.
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9
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Senko AN, Overall RW, Silhavy J, Mlejnek P, Malínská H, Hüttl M, Marková I, Fabel KS, Lu L, Stuchlik A, Williams RW, Pravenec M, Kempermann G. Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose. PLoS Genet 2022; 18:e1009638. [PMID: 35377872 PMCID: PMC9060359 DOI: 10.1371/journal.pgen.1009638] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 05/02/2022] [Accepted: 03/07/2022] [Indexed: 11/19/2022] Open
Abstract
Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.
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Affiliation(s)
- Anna N. Senko
- German Center for Neurodegenerative Diseases (DZNE) Dresden, Germany
- CRTD–Center for Regenerative Therapies Dresden, Technische Universität Dresden, Germany
| | - Rupert W. Overall
- German Center for Neurodegenerative Diseases (DZNE) Dresden, Germany
- CRTD–Center for Regenerative Therapies Dresden, Technische Universität Dresden, Germany
| | - Jan Silhavy
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Petr Mlejnek
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Hana Malínská
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Martina Hüttl
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Irena Marková
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Klaus S. Fabel
- German Center for Neurodegenerative Diseases (DZNE) Dresden, Germany
- CRTD–Center for Regenerative Therapies Dresden, Technische Universität Dresden, Germany
| | - Lu Lu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Ales Stuchlik
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Robert W. Williams
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Michal Pravenec
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Gerd Kempermann
- German Center for Neurodegenerative Diseases (DZNE) Dresden, Germany
- CRTD–Center for Regenerative Therapies Dresden, Technische Universität Dresden, Germany
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10
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Neurogenic Interventions for Fear Memory via Modulation of the Hippocampal Function and Neural Circuits. Int J Mol Sci 2022; 23:ijms23073582. [PMID: 35408943 PMCID: PMC8998417 DOI: 10.3390/ijms23073582] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 12/15/2022] Open
Abstract
Fear memory helps animals and humans avoid harm from certain stimuli and coordinate adaptive behavior. However, excessive consolidation of fear memory, caused by the dysfunction of cellular mechanisms and neural circuits in the brain, is responsible for post-traumatic stress disorder and anxiety-related disorders. Dysregulation of specific brain regions and neural circuits, particularly the hippocampus, amygdala, and medial prefrontal cortex, have been demonstrated in patients with these disorders. These regions are involved in learning, memory, consolidation, and extinction. These are also the brain regions where new neurons are generated and are crucial for memory formation and integration. Therefore, these three brain regions and neural circuits have contributed greatly to studies on neural plasticity and structural remodeling in patients with psychiatric disorders. In this review, we provide an understanding of fear memory and its underlying cellular mechanisms and describe how neural circuits are involved in fear memory. Additionally, we discuss therapeutic interventions for these disorders based on their proneurogenic efficacy and the neural circuits involved in fear memory.
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Redell JB, Maynard ME, Hood KN, Moore AN, Zhao J, Dash PK. Insulin-Like Growth Factor-2 (IGF-2) Does Not Improve Memory in the Chronic Stage of Traumatic Brain Injury in Rodents. Neurotrauma Rep 2021; 2:453-460. [PMID: 34901941 PMCID: PMC8655797 DOI: 10.1089/neur.2021.0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Persistent cognitive impairment(s) can be a significant consequence of traumatic brain injury (TBI) and can markedly compromise quality of life. Unfortunately, identifying effective treatments to alleviate memory impairments in the chronic stage of TBI has proven elusive. Several studies have demonstrated that insulin-like growth factor-2 (IGF-2) can enhance memory in both normal animals and in experimental models of disease. In this study, we questioned whether IGF-2, when administered before learning, could enhance memory performance in the chronic stage of TBI. Male C57BL/6 mice (n = 7 per group) were injured using an electronic cortical impact injury device. Four months later, mice were tested for their cognitive performance in the fear memory extinction, novel object recognition (NOR), and Morris water maze tasks. Twenty minutes before each day of training, mice received a subcutaneous injection of either 30 μg/kg of IGF-2 or an equal volume of vehicle. Memory testing was carried out 24 h after training in the absence of the drug. Uninjured sham animals treated with IGF-2 (or vehicle) were trained and tested in the fear memory extinction task as a positive control. Our data show that although IGF-2 (30 μg/kg) improved memory extinction in uninjured mice, it was ineffective at improving fear memory extinction in the chronic stage of TBI. Similarly, IGF-2 administration to chronically injured animals did not improve TBI-related deficits in either NOR or spatial memory. Our results indicate that IGF-2, administered in the chronic stage of injury, is ineffective at enhancing memory performance and therefore may not be a beneficial treatment option for lingering cognitive impairments after a TBI.
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Affiliation(s)
- John B Redell
- Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, Texas, USA
| | - Mark E Maynard
- Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, Texas, USA
| | - Kimberly N Hood
- Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, Texas, USA
| | - Anthony N Moore
- Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, Texas, USA
| | - Jing Zhao
- Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, Texas, USA
| | - Pramod K Dash
- Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, Texas, USA
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12
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Cao C, Jia Z, Shao M, Li R, Sun Q, Liu D. Prenatal exposure to polycyclic aromatic hydrocarbons could increase the risk of low birth weight by affecting the DNA methylation states in a Chinese cohort. Reprod Biol 2021; 21:100574. [PMID: 34794034 DOI: 10.1016/j.repbio.2021.100574] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 10/28/2021] [Accepted: 10/30/2021] [Indexed: 11/18/2022]
Abstract
Polycyclic aromatic hydrocarbons (PAHs), as a kind of endocrine disruptors, can enter the fetus body cross the placental barrier from prenatal PAHs exposure to cause adverse birth outcomes. However, it is controversial association between prenatal PAHs exposure and low birth weight (LBW) of their infants. So the present study aimed to estimate the effects of prenatal PAHs exposure during the pregnancy on the risk of LBW in a Chinese cohort through modifying the DNA methylation states. A longitudinal prospective study with 407 pregnant women was established from May to October 2019. The prenatal PAHs exposure during the pregnancy was assessed using the internal dose such as the PAHs metabolites and PAH-DNA adducts in the umbilical cord blood. The methylation levels of genomic DNA and growth-related genes (IGF1 and IGF2) were assessed, while the expressions of these genes were both determined by RT-PCR and Elisa methods. The growth outcomes and relevant Z-scores were recorded at birth. The correlations between the DNA methylation status and concentrations of PAHs, expression levels of growth-related genes and body weight/WAZ were investigated as the measures. According to the PAH-DNA adducts, the subjects were divided into two groups: PAHs-exposed group (PAH-DNA adducts>0, n = 55) and non-exposed group (PAH-DNA adducts = 0, n = 352). Compared with the non-exposed group, it displayed marked decreased birth weight, and increased concentrations of PAHs and DNA methylation levels of the global genomic, IGF1 and IGF2 with their lower expressions in the PAHs-exposed group. These hypermethylation (global genomic, CpG14 and CpG15 of IGF1, and CpG14 of IGF2) were positively correlated with the contents of PAHs in the umbilical cord blood, and negatively correlated with the growth outcomes and their expressions. Totally, prenatal PAHs exposures may contribute to an increased risk of LBW of their infants by modulating the DNA methylation states of genomic DNA and growth-related genes (IGF1 and IGF2) in the umbilical cord blood, which could provide the prenatal prevention of PAHs exposure from possible environmental media except from the occupation and tobacco usage to ensure the health of their infants.
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Affiliation(s)
- Chunxia Cao
- Department of Pediatrics, Zibo Central Hospital, Shandong Province, 255000, China
| | - Zhiyi Jia
- Department of Pediatrics, Zibo Central Hospital, Shandong Province, 255000, China
| | - Mingyu Shao
- Department of Pediatrics, Zibo Central Hospital, Shandong Province, 255000, China
| | - Rongmiao Li
- Department of Thoracic Surgery, Huantai Country People's Hospital, Shandong Province, 255000, China
| | - Qi Sun
- Scientific Education and Communication Cooperation Office, Zibo Central Hospital, Shandong Province, 255000, China
| | - Dong Liu
- Department of Pediatrics, Zibo Central Hospital, Shandong Province, 255000, China.
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13
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Kellum JA, van Till JWO, Mulligan G. Targeting acute kidney injury in COVID-19. Nephrol Dial Transplant 2020; 35:1652-1662. [PMID: 33022712 PMCID: PMC7665651 DOI: 10.1093/ndt/gfaa231] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 08/04/2020] [Indexed: 02/07/2023] Open
Abstract
As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in >21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid-base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia-reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.
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Affiliation(s)
- John A Kellum
- Department of Critical Care Medicine, The Center for Critical Care Nephology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Pardo M, Cheng Y, Sitbon YH, Lowell JA, Grieco SF, Worthen RJ, Desse S, Barreda-Diaz A. Insulin growth factor 2 (IGF2) as an emergent target in psychiatric and neurological disorders. Review. Neurosci Res 2019; 149:1-13. [PMID: 30389571 DOI: 10.1016/j.neures.2018.10.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/05/2018] [Accepted: 10/29/2018] [Indexed: 12/23/2022]
Abstract
Insulin-like growth factor 2 (IGF2) is abundantly expressed in the central nervous system (CNS). Recent evidence highlights the role of IGF2 in the brain, sustained by data showing its alterations as a common feature across a variety of psychiatric and neurological disorders. Previous studies emphasize the potential role of IGF2 in psychiatric and neurological conditions as well as in memory impairments, targeting IGF2 as a pro-cognitive agent. New research on animal models supports that upcoming investigations should explore IGF2's strong promising role as a memory enhancer. The lack of effective treatments for cognitive disturbances as a result of psychiatric diseases lead to further explore IGF2 as a promising target for the development of new pharmacology for the treatment of memory dysfunctions. In this review, we aim at gathering all recent relevant studies and findings on the role of IGF2 in the development of psychiatric diseases that occur with cognitive problems.
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Affiliation(s)
- M Pardo
- University of Miami Miller School of Medicine, Department of Neurology, Miami, FL, USA.
| | - Y Cheng
- University of California Los Angeles, Neurology Department, Los Angeles, CA, USA.
| | - Y H Sitbon
- University of Miami Miller School of Medicine, Department of Molecular and Cellular Pharmacology, Miami, FL, USA.
| | - J A Lowell
- University of Miami, Department of Psychiatry & Behavioral Sciences, Miami, FL, USA.
| | - S F Grieco
- University of California, Department of Anatomy and Neurobiology, Irvine, CA, USA.
| | - R J Worthen
- University of Miami, Department of Psychiatry & Behavioral Sciences, Miami, FL, USA.
| | - S Desse
- University of Miami, Department of Psychiatry & Behavioral Sciences, Miami, FL, USA.
| | - A Barreda-Diaz
- University of Miami Miller School of Medicine, Department of Neurology, Miami, FL, USA.
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15
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Lewitt MS, Boyd GW. The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor-Binding Proteins in the Nervous System. BIOCHEMISTRY INSIGHTS 2019; 12:1178626419842176. [PMID: 31024217 PMCID: PMC6472167 DOI: 10.1177/1178626419842176] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 03/15/2019] [Indexed: 01/23/2023]
Abstract
The insulin-like growth factors (IGF-I and IGF-II) and their receptors are widely expressed in nervous tissue from early embryonic life. They also cross the blood brain barriers by active transport, and their regulation as endocrine factors therefore differs from other tissues. In brain, IGFs have paracrine and autocrine actions that are modulated by IGF-binding proteins and interact with other growth factor signalling pathways. The IGF system has roles in nervous system development and maintenance. There is substantial evidence for a specific role for this system in some neurodegenerative diseases, and neuroprotective actions make this system an attractive target for new therapeutic approaches. In developing new therapies, interaction with IGF-binding proteins and other growth factor signalling pathways should be considered. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.
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Affiliation(s)
- Moira S Lewitt
- School of Health & Life Sciences, University of the West of Scotland, Paisley, UK
| | - Gary W Boyd
- School of Health & Life Sciences, University of the West of Scotland, Paisley, UK
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16
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17
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Sultan N, Amin LE, Zaher AR, Scheven BA, Grawish ME. Dental pulp stem cells: Novel cell-based and cell-free therapy for peripheral nerve repair. World J Stomatol 2019; 7:1-19. [DOI: 10.5321/wjs.v7.i1.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 11/15/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023] Open
Abstract
The regeneration of peripheral nerves comprises complicated steps involving a set of cellular and molecular events in distal nerve stumps with axonal sprouting and remyelination. Stem cell isolation and expansion for peripheral nerve repair (PNR) can be achieved using a wide diversity of prenatal and adult tissues, such as bone marrow or brain tissues. The ability to obtain stem cells for cell-based therapy (CBT) is limited due to donor site morbidity and the invasive nature of the harvesting process. Dental pulp stem cells (DPSCs) can be relatively and simply isolated from the dental pulps of permanent teeth, extracted for surgical or orthodontic reasons. DPSCs are of neural crest origin with an outstanding ability to differentiate into multiple cell lineages. They have better potential to differentiate into neural and glial cells than other stem cell sources through the expression and secretion of certain markers and a range of neurotropic factors; thus, they should be considered a good choice for PNR using CBT. In addition, these cells have paracrine effects through the secretion of neurotrophic growth factors and extracellular vesicles, which can enhance axonal growth and remyelination by decreasing the number of dying cells and activating local inhabitant stem cell populations, thereby revitalizing dormant or blocked cells, modulating the immune system and regulating inflammatory responses. The use of DPSC-derived secretomes holds great promise for controllable and manageable therapy for peripheral nerve injury. In this review, up-to-date information about the neurotrophic and neurogenic properties of DPSCs and their secretomes is provided.
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Affiliation(s)
- Nessma Sultan
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
| | - Laila E Amin
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed R Zaher
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
| | - Ben A Scheven
- School of Dentistry, Oral Biology, College of Medical and Dental Sciences, University of Birmingham, Birmingham B5 7EG, United Kingdom
| | - Mohammed E Grawish
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
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18
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D'Souza MS. Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits. Front Psychiatry 2019; 10:509. [PMID: 31396113 PMCID: PMC6667748 DOI: 10.3389/fpsyt.2019.00509] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 06/28/2019] [Indexed: 01/10/2023] Open
Abstract
Addiction to psychostimulants like cocaine, methamphetamine, and nicotine poses a continuing medical and social challenge both in the United States and all over the world. Despite a desire to quit drug use, return to drug use after a period of abstinence is a common problem among individuals dependent on psychostimulants. Recovery for psychostimulant drug-dependent individuals is particularly challenging because psychostimulant drugs induce significant changes in brain regions associated with cognitive functions leading to cognitive deficits. These cognitive deficits include impairments in learning/memory, poor decision making, and impaired control of behavioral output. Importantly, these drug-induced cognitive deficits often impact adherence to addiction treatment programs and predispose abstinent addicts to drug use relapse. Additionally, these cognitive deficits impact effective social and professional rehabilitation of abstinent addicts. The goal of this paper is to review neural substrates based on animal studies that could be pharmacologically targeted to reverse psychostimulant-induced cognitive deficits such as impulsivity and impairment in learning and memory. Further, the review will discuss neural substrates that could be used to facilitate extinction learning and thus reduce emotional and behavioral responses to drug-associated cues. Moreover, the review will discuss some non-pharmacological approaches that could be used either alone or in combination with pharmacological compounds to treat the above-mentioned cognitive deficits. Psychostimulant addiction treatment, which includes treatment for cognitive deficits, will help promote abstinence and allow for better rehabilitation and integration of abstinent individuals into society.
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Affiliation(s)
- Manoranjan S D'Souza
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada, OH, United States
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19
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Bryzgalov DV, Kuznetsova IL, Rogaev EI. Enhancement of Declarative Memory: From Genetic Regulation to Non-invasive Stimulation. BIOCHEMISTRY (MOSCOW) 2018; 83:1124-1138. [PMID: 30472951 DOI: 10.1134/s0006297918090146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The problem of memory enhancement is extremely important in intellectual activity areas and therapy of different types of dementia, including Alzheimer's disease (AD). The attempts to solve this problem have come from different research fields. In the first part of our review, we describe the results of targeting certain genes involved in memory-associated molecular pathways. The second part of the review is focused on the deep stimulation of brain structures that can slow down memory loss in AD. The third part describes the results of the use of non-invasive brain stimulation techniques for memory modulation, consolidation, and retrieval in healthy people and animal models. Integration of data from different research fields is essential for the development of efficient strategies for memory enhancement.
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Affiliation(s)
- D V Bryzgalov
- Memory, Oscillations, Brain States (MOBS) Team, Brain Plasticity Unit, CNRS UMR 8249, ESPCI Paris, Paris, France.
| | - I L Kuznetsova
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia
| | - E I Rogaev
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia. .,Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01605, USA.,Lomonosov Moscow State University, Faculty of Biology, Moscow, 119234, Russia.,Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, 119234, Russia
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Abstract
INTRODUCTION Depression and posttraumatic stress disorder (PTSD) are two complex and debilitating psychiatric disorders that result in poor life and destructive behaviors against self and others. Currently, diagnosis is based on subjective rather than objective determinations leading to misdiagnose and ineffective treatments. Advances in novel neurobiological methods have allowed assessment of promising biomarkers to diagnose depression and PTSD, which offers a new means of appropriately treating patients. Areas covered: Biomarkers discovery in blood represents a fundamental tool to predict, diagnose, and monitor treatment efficacy in depression and PTSD. The potential role of altered HPA axis, epigenetics, NPY, BDNF, neurosteroid biosynthesis, the endocannabinoid system, and their function as biomarkers for mood disorders is discussed. Insofar, we propose the identification of a biomarker axis to univocally identify and discriminate disorders with large comorbidity and symptoms overlap, so as to provide a base of support for development of targeted treatments. We also weigh in on the feasibility of a future blood test for early diagnosis. Expert commentary: Potential biomarkers have already been assessed in patients' blood and need to be further validated through multisite large clinical trial stratification. Another challenge is to assess the relation among several interdependent biomarkers to form an axis that identifies a specific disorder and secures the best-individualized treatment. The future of blood-based tests for PTSD and depression is not only on the horizon but, possibly, already around the corner.
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Affiliation(s)
- Dario Aspesi
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
| | - Graziano Pinna
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
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21
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Olaya JC, Heusner CL, Matsumoto M, Shannon Weickert C, Karl T. Schizophrenia-relevant behaviours of female mice overexpressing neuregulin 1 type III. Behav Brain Res 2018; 353:227-235. [DOI: 10.1016/j.bbr.2018.03.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 03/15/2018] [Accepted: 03/15/2018] [Indexed: 12/20/2022]
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22
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Szekiova E, Slovinska L, Blasko J, Plsikova J, Cizkova D. The neuroprotective effect of rat adipose tissue-derived mesenchymal stem cell-conditioned medium on cortical neurons using an in vitro model of SCI inflammation. Neurol Res 2018; 40:258-267. [PMID: 29384015 DOI: 10.1080/01616412.2018.1432266] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Objectives In this study, a new approach was used with an in vitro model in which neural cells were exposed to conditioned media from the injured spinal cord (SCI-CM) mimicking a local inflammatory microenvironment . Subsequently, the neuroprotective effect of rat adipose tissue-derived msesenchymal stem cell-conditioned media (ATMSC-CM) was investigated through a cell-free based therapy, which was used to treat cortical neurons and astrocytes under inflammation. Methods Primary cell cultures isolated from postnatal day (P6) Wistar rat brain cortex were exposed to SCI-CM derived from the central lesion, rostral and caudal segments of injured spinal cord. After 48 h incubation, the SCI-CM was replaced and primary cultures were cultivated either in DMEM media alone or in ATMSC-CM for 72 h. The impact of ATMSC-CM on the viability of neurons and astrocytes was assessed using a CyQUANT® Direct Cell Proliferation Assay Kit as well as immunocytochemistry analysis. Results Immunocytochemical analysis revealed significant decrease in the number of MAP2 positive neurons exposed to SCI-CM compared to Control. Protection by ATMSC-CM was associated with increased survival of neurons compared to primary culture cultivated in DMEM media alone. The ATMSC-CM effect on astrocytes was more variable and without any significant impact. Conclusion The results demonstrate that SCI-CM mimicking inflammation can reduce cortical neuron survival, and subsequent exposure to ATMSC-CM can stabilize the neuronal population most likely via released neuroprotective and trophic factors. In addition, astrogliosis was not affected by ATMSC-CM.
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Affiliation(s)
- Eva Szekiova
- a Institute of Neurobiology , Slovak Academy of Sciences , Kosice , Slovakia
| | - Lucia Slovinska
- a Institute of Neurobiology , Slovak Academy of Sciences , Kosice , Slovakia
| | - Juraj Blasko
- a Institute of Neurobiology , Slovak Academy of Sciences , Kosice , Slovakia
| | - Jana Plsikova
- b Associated Tissue Bank, Faculty of Medicine , P. J. Safarik Univerzity and L. Pasteur University Hospital , Kosice , Slovakia
| | - Dasa Cizkova
- c Institute of Neuroimmunology , Slovak Academy of Sciences , Bratislava , Slovakia.,d Department of Ananatomy, Histology and Physiology , University of Veterinary Medicine and Pharmacy in Košice , Košice , Slovakia
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Tomas-Roig J, Benito E, Agis-Balboa RC, Piscitelli F, Hoyer-Fender S, Di Marzo V, Havemann-Reinecke U. Chronic exposure to cannabinoids during adolescence causes long-lasting behavioral deficits in adult mice. Addict Biol 2017; 22:1778-1789. [PMID: 27578457 PMCID: PMC5697667 DOI: 10.1111/adb.12446] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 08/07/2016] [Accepted: 08/09/2016] [Indexed: 01/23/2023]
Abstract
Regular use of marijuana during adolescence enhances the risk of long-lasting neurobiological changes in adulthood. The present study was aimed at assessing the effect of long-term administration of the synthetic cannabinoid WIN55212.2 during adolescence in young adult mice. Adolescent mice aged 5 weeks were subjected daily to the pharmacological action of WIN55212.2 for 3 weeks and were then left undisturbed in their home cage for a 5-week period and finally evaluated by behavioral testing. Mice that received the drug during adolescence showed memory impairment in the Morris water maze, as well as a dose-dependent memory impairment in fear conditioning. In addition, the administration of 3 mg/kg WIN55212.2 in adolescence increased adult hippocampal AEA levels and promoted DNA hypermethylation at the intragenic region of the intracellular signaling modulator Rgs7, which was accompanied by a lower rate of mRNA transcription of this gene, suggesting a potential causal relation. Although the concrete mechanisms underlying the behavioral observations remain to be elucidated, we demonstrate that long-term administration of 3 mg/kg of WIN during adolescence leads to increased endocannabinoid levels and altered Rgs7 expression in adulthood and establish a potential link to epigenetic changes.
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Affiliation(s)
- J Tomas-Roig
- Department of Psychiatry and Psychotherapy; University of Göttingen; Germany
- Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB); Germany
| | - E Benito
- Research Group for Epigenetic Mechanisms in Dementia; German Center for Neurodegenerative Diseases (DZNE); Germany
| | - RC Agis-Balboa
- Department of Psychiatry and Psychotherapy; University Medical Center Göttingen; Germany
- Instituto de Investigación Sanitaria Galicia Sur; Spain
| | - F Piscitelli
- Endocannabinoid Research Group; Institute of Biomolecular Chemistry; Italy
| | - S Hoyer-Fender
- Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology; Developmental Biology; Germany
| | - V Di Marzo
- Endocannabinoid Research Group; Institute of Biomolecular Chemistry; Italy
| | - U Havemann-Reinecke
- Department of Psychiatry and Psychotherapy; University of Göttingen; Germany
- Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB); Germany
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Associations between maternal prenatal stress, methylation changes in IGF1 and IGF2, and birth weight. J Dev Orig Health Dis 2017; 9:215-222. [PMID: 29017633 DOI: 10.1017/s2040174417000800] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Maternal stress has been linked to low birth weight in newborns. One potential pathway involves epigenetic changes at candidate genes that may mediate the effects of prenatal maternal stress on birth weight. This relationship has been documented in stress-related genes, such as NR3C1. There is less literature exploring the effect of stress on growth-related genes. IGF1 and IGF2 have been implicated in fetal growth and development, though via different mechanisms as IGF2 is under imprinting control. In this study, we tested for associations between prenatal stress, methylation of IGF1 and IGF2, and birth weight. A total of 24 mother-newborn dyads in the Democratic Republic of Congo were enrolled. Ethnographic interviews were conducted with mothers at delivery to gather culturally relevant war-related and chronic stressors. DNA methylation data were generated from maternal venous, cord blood and placental tissue samples. Multivariate regressions were used to test for associations between stress measures, DNA methylation and birth weight in each of the three tissue types. We found an association between IGF2 methylation in maternal blood and birth weight. Previous literature on the relationship between IGF2 methylation and birth weight has focused on methylation at known differentially methylated regions in cord blood or placental samples. Our findings indicate there may be links between the maternal epigenome and low birth weight that rely on mechanisms outside known imprinting pathways. It thus may be important to consider the effect of maternal exposures and epigenetic profiles on birth weight even in the setting of maternally imprinted genes such as IGF2.
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Delgado-Morales R, Agís-Balboa RC, Esteller M, Berdasco M. Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. Clin Epigenetics 2017; 9:67. [PMID: 28670349 PMCID: PMC5493012 DOI: 10.1186/s13148-017-0365-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 06/11/2017] [Indexed: 12/26/2022] Open
Abstract
Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.
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Affiliation(s)
- Raúl Delgado-Morales
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain.,Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands
| | - Roberto Carlos Agís-Balboa
- Psychiatric Diseases Research Group, Galicia Sur Health Research Institute, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, CIBERSAM, Vigo, Spain
| | - Manel Esteller
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain.,Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - María Berdasco
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain
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26
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Teixeira FG, Panchalingam KM, Assunção-Silva R, Serra SC, Mendes-Pinheiro B, Patrício P, Jung S, Anjo SI, Manadas B, Pinto L, Sousa N, Behie LA, Salgado AJ. Modulation of the Mesenchymal Stem Cell Secretome Using Computer-Controlled Bioreactors: Impact on Neuronal Cell Proliferation, Survival and Differentiation. Sci Rep 2016; 6:27791. [PMID: 27301770 PMCID: PMC4908397 DOI: 10.1038/srep27791] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 05/19/2016] [Indexed: 01/09/2023] Open
Abstract
In recent years it has been shown that the therapeutic benefits of human mesenchymal stem/stromal cells (hMSCs) in the Central Nervous System (CNS) are mainly attributed to their secretome. The implementation of computer-controlled suspension bioreactors has shown to be a viable route for the expansion of these cells to large numbers. As hMSCs actively respond to their culture environment, there is the hypothesis that one can modulate its secretome through their use. Herein, we present data indicating that the use of computer-controlled suspension bioreactors enhanced the neuroregulatory profile of hMSCs secretome. Indeed, higher levels of in vitro neuronal differentiation and NOTCH1 expression in human neural progenitor cells (hNPCs) were observed when these cells were incubated with the secretome of dynamically cultured hMSCs. A similar trend was also observed in the hippocampal dentate gyrus (DG) of rat brains where, upon injection, an enhanced neuronal and astrocytic survival and differentiation, was observed. Proteomic analysis also revealed that the dynamic culturing of hMSCs increased the secretion of several neuroregulatory molecules and miRNAs present in hMSCs secretome. In summary, the appropriate use of dynamic culture conditions can represent an important asset for the development of future neuro-regenerative strategies involving the use of hMSCs secretome.
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Affiliation(s)
- Fábio G Teixeira
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
| | - Krishna M Panchalingam
- Pharmaceutical Production Research Facility (PPRF), Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada
| | - Rita Assunção-Silva
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
| | - Sofia C Serra
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
| | - Bárbara Mendes-Pinheiro
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
| | - Patrícia Patrício
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
| | - Sunghoon Jung
- Pharmaceutical Production Research Facility (PPRF), Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada
| | - Sandra I Anjo
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.,Faculty of Sciences and Technology, University of Coimbra, Portugal
| | - Bruno Manadas
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.,Biocant - Biotechnology Innovation Center, Cantanhede, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
| | - Leo A Behie
- Pharmaceutical Production Research Facility (PPRF), Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Lab, Braga/Guimarães, Portugal
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27
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Nieto-Estévez V, Oueslati-Morales CO, Li L, Pickel J, Morales AV, Vicario-Abejón C. Brain Insulin-Like Growth Factor-I Directs the Transition from Stem Cells to Mature Neurons During Postnatal/Adult Hippocampal Neurogenesis. Stem Cells 2016; 34:2194-209. [DOI: 10.1002/stem.2397] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 03/23/2016] [Accepted: 04/11/2016] [Indexed: 01/29/2023]
Affiliation(s)
- Vanesa Nieto-Estévez
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC)
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Carlos O. Oueslati-Morales
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC)
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
| | - Lingling Li
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC)
| | - James Pickel
- Transgenic Core, National Institute of Mental Health, National Institutes of Health; Bethesda Maryland USA
| | - Aixa V. Morales
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC)
| | - Carlos Vicario-Abejón
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC)
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Madrid Spain
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28
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Benedetti F, Poletti S, Hoogenboezem TA, Locatelli C, Ambrée O, de Wit H, Wijkhuijs AJM, Mazza E, Bulgarelli C, Vai B, Colombo C, Smeraldi E, Arolt V, Drexhage HA. Stem Cell Factor (SCF) is a putative biomarker of antidepressant response. J Neuroimmune Pharmacol 2016; 11:248-58. [DOI: 10.1007/s11481-016-9672-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 04/14/2016] [Indexed: 02/06/2023]
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29
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Terauchi A, Johnson-Venkatesh EM, Bullock B, Lehtinen MK, Umemori H. Retrograde fibroblast growth factor 22 (FGF22) signaling regulates insulin-like growth factor 2 (IGF2) expression for activity-dependent synapse stabilization in the mammalian brain. eLife 2016; 5. [PMID: 27083047 PMCID: PMC4868541 DOI: 10.7554/elife.12151] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 04/14/2016] [Indexed: 02/06/2023] Open
Abstract
Communication between pre- and postsynaptic cells promotes the initial organization of synaptic specializations, but subsequent synaptic stabilization requires transcriptional regulation. Here we show that fibroblast growth factor 22 (FGF22), a target-derived presynaptic organizer in the mouse hippocampus, induces the expression of insulin-like growth factor 2 (IGF2) for the stabilization of presynaptic terminals. FGF22 is released from CA3 pyramidal neurons and organizes the differentiation of excitatory nerve terminals formed onto them. Local application of FGF22 on the axons of dentate granule cells (DGCs), which are presynaptic to CA3 pyramidal neurons, induces IGF2 in the DGCs. IGF2, in turn, localizes to DGC presynaptic terminals and stabilizes them in an activity-dependent manner. IGF2 application rescues presynaptic defects of Fgf22(-/-) cultures. IGF2 is dispensable for the initial presynaptic differentiation, but is required for the following presynaptic stabilization both in vitro and in vivo. These results reveal a novel feedback signal that is critical for the activity-dependent stabilization of presynaptic terminals in the mammalian hippocampus.
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Affiliation(s)
- Akiko Terauchi
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
| | - Erin M Johnson-Venkatesh
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
| | - Brenna Bullock
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
| | - Maria K Lehtinen
- Department of Pathology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
| | - Hisashi Umemori
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
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30
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Nieto-Estévez V, Defterali Ç, Vicario-Abejón C. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain. Front Neurosci 2016; 10:52. [PMID: 26941597 PMCID: PMC4763060 DOI: 10.3389/fnins.2016.00052] [Citation(s) in RCA: 192] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/05/2016] [Indexed: 12/28/2022] Open
Abstract
The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits.
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Affiliation(s)
- Vanesa Nieto-Estévez
- Consejo Superior de Investigaciones Científicas (CSIC), Instituto CajalMadrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)Madrid, Spain
| | - Çağla Defterali
- Consejo Superior de Investigaciones Científicas (CSIC), Instituto CajalMadrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)Madrid, Spain
| | - Carlos Vicario-Abejón
- Consejo Superior de Investigaciones Científicas (CSIC), Instituto CajalMadrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)Madrid, Spain
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31
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Tu KY, Wu MK, Chen YW, Lin PY, Wang HY, Wu CK, Tseng PT. Significantly Higher Peripheral Insulin-Like Growth Factor-1 Levels in Patients With Major Depressive Disorder or Bipolar Disorder Than in Healthy Controls: A Meta-Analysis and Review Under Guideline of PRISMA. Medicine (Baltimore) 2016; 95:e2411. [PMID: 26825882 PMCID: PMC5291552 DOI: 10.1097/md.0000000000002411] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
An increasing amount of research has focused on insulin-like growth factor-1 (IGF-1) because of multiple neurotrophic effects, including neurogenesis, remyelination, and synaptogenesis. In addition, IGF-1 can mediate an antidepressant effect in patients with major affective disorder, and its levels in the cerebrospinal fluid have been found to vary with antidepressant treatment. Furthermore, it has been proven to crossover the blood-brain barrier, with a reciprocal feedback loop being the central effect. However, recent studies have reported inconclusive findings about the role of IGF-1 in major affective disorder. The aim of the current study was to conduct a thorough meta-analysis of changes in peripheral IGF-1 levels in patients with major depressive disorder (MDD) or bipolar disorder (BD). We conducted a thorough literature search and compared peripheral IGF-1 levels in patients with MDD or BD and in healthy controls, and investigated clinical variables through meta-regression. Electronic research was conducted through platform of PubMed. We used inclusion criteria as clinical trials discussing comparisons of peripheral IGF-1 protein levels in patients with MDD or BD and those in healthy controls. We analyzed the cases from 9 studies with the random-effect model. The main finding was that peripheral IGF-1 levels in the patients were significantly higher than in the healthy controls (P < 0.001), with a significant inverse association with duration of illness (P = 0.03). In meta-analysis comparing peripheral IGF-1 levels in patients with BD or MDD before and after treatment, there was no significant change in peripheral IGF-1 levels after treatment (P = 0.092). The small numbers of studies and lack of correlation data with growth hormone in current studies are the main limitations of this meta-analysis. Our results indicated that peripheral IGF-1 levels may not be an indicator of disease severity, but may be a disease trait marker or an indicator of cognition. However, further investigations on the correlation between cognitive function and peripheral IGF-1 levels are needed to explore the role of IGF-1 in the pathophysiology of MDD and BD.
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Affiliation(s)
- Kun-Yu Tu
- From the Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Taiwan (K-YT, H-YW, C-KW, P-TT); Department of Neurology, E-Da Hospital, Kaohsiung, Taiwan (Y-WC); Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan (M-KW, P-YL); and Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (P-YL)
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32
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Iwamoto T, Ouchi Y. Emerging evidence of insulin-like growth factor 2 as a memory enhancer: a unique animal model of cognitive dysfunction with impaired adult neurogenesis. Rev Neurosci 2015; 25:559-74. [PMID: 24778346 DOI: 10.1515/revneuro-2014-0010] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 03/28/2014] [Indexed: 12/29/2022]
Abstract
In the current aging society, cognitive dysfunction is one of the most serious issues that should be urgently resolved. It also affects a wide range of age groups harboring neurological and psychiatric disorders, such as Alzheimer's disease and schizophrenia. Although the molecular mechanism of memory impairment still remains to be determined, neuronal loss and dysfunction has been revealed to mainly attribute to its pathology. The discovery of neural stem cells in the adult brain that are proliferating and able to generate functional neurons has given rise to the idea that neuronal loss could be rescued by manipulating endogenous neural progenitor and stem cells. To this end, we must characterize them in detail and their developmental programming must be better understood. A growing body of evidence has indicated that insulin-like peptides are involved in learning and memory and maintenance of neural progenitor and stem cells, and clinical trials of insulin as a memory enhancer have begun. In contrast to the expectation of insulin and IGF1, the roles of IGF2 in cognitive ability have been poorly understood. However, recent evidence demonstrated in rodents suggests that IGF2 may play a pivotal role in adult neurogenesis and cognitive function. Here, we would like to review the rapidly growing world of IGF2 in cognitive neuroscience and introduce the evidence that its deficit is indeed involved in the impairment of the hippocampal neurogenesis and cognitive dysfunction in the model mouse of 22q11.2 deletion syndrome, which deletes Dgcr8, a critical gene for microRNA processing.
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Abstract
New neurons continue to be generated in the dentate gyrus throughout life, providing this region of the hippocampus with exceptional structural plasticity, but the function of this ongoing neurogenesis is unknown. Inhibition of adult neurogenesis produces some behavioral impairments that suggest a role for new neurons in learning and memory; however, other behavioral changes appear inconsistent with this function. A review of studies investigating the function of the hippocampus going back several decades reveals many ideas that seem to converge on a critical role for the hippocampus in stress response and emotion. These potential hippocampal functions provide new avenues for investigating the behavioral functions of adult neurogenesis. And, conversely, studies in animals lacking adult neurogenesis, which are likely to have more limited and more specific impairments than are seen with lesions, may provide valuable new insights into the function of the hippocampus. A complete understanding of the function of the hippocampus must explain its role in emotion and the relationship between its emotional and memory functions.
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Affiliation(s)
- Heather A Cameron
- Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892;
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34
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Martin-Montañez E, Pavia J, Santin LJ, Boraldi F, Estivill-Torrus G, Aguirre JA, Garcia-Fernandez M. Involvement of IGF-II receptors in the antioxidant and neuroprotective effects of IGF-II on adult cortical neuronal cultures. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1842:1041-1051. [PMID: 24667322 DOI: 10.1016/j.bbadis.2014.03.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 03/14/2014] [Accepted: 03/17/2014] [Indexed: 01/26/2023]
Abstract
Insulin-like growth factor-II (IGF-II) is a naturally occurring peptide that exerts known pleiotropic effects ranging from metabolic modulation to cellular development, growth and survival. IGF-II triggers its actions by binding to and activating IGF (IGF-I and IGF-II) receptors. In this study, we assessed the neuroprotective effect of IGF-II on corticosterone-induced oxidative damage in adult cortical neuronal cultures and the role of IGF-II receptors in this effect. We provide evidence that treatment with IGF-II alleviates the glucocorticoid-induced toxicity to neuronal cultures, and this neuroprotective effect occurred due to a decrease in reactive oxygen species (ROS) production and a return of the antioxidant status to normal levels. IGF-II acts via not only the regulation of synthesis and/or activity of antioxidant enzymes, especially manganese superoxide dismutase, but also the restoration of mitochondrial cytochrome c oxidase activity and mitochondrial membrane potential. Although the antioxidant effect of IGF-I receptor activation has been widely reported, the involvement of the IGF-II receptor in these processes has not been clearly defined. The present report is the first evidence describing the involvement of IGF-II receptors in redox homeostasis. IGF-II may therefore contribute to the mechanisms of neuroprotection by acting as an antioxidant, reducing the neurodegeneration induced by oxidative insults. These results open the field to new pharmacological approaches to the treatment of diseases involving imbalanced redox homeostasis. In this study, we demonstrated that the antioxidant effect of IGF-II is at least partially mediated by IGF-II receptors.
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Affiliation(s)
- Elisa Martin-Montañez
- Department of Pharmacology and Paediatrics, Malaga University, Biomedical Research Institute of Malaga (IBIMA), E-29071 Malaga, Spain
| | - José Pavia
- Department of Pharmacology and Paediatrics, Malaga University, Biomedical Research Institute of Malaga (IBIMA), E-29071 Malaga, Spain; Clinical Neurosciences Unit, Research Laboratory and Microscopy Unit, Biomedical Research Institute of Malaga (IBIMA), Regional University Hospital of Malaga, E-29010 Málaga, Spain
| | - Luis J Santin
- Department of Psychobiology, Malaga University, Biomedical Research Institute of Malaga (IBIMA), E-29071 Malaga, Spain
| | - Federica Boraldi
- Department of Life Sciences, University of Modena e Reggio Emilia, I-41010 Modena, Italy
| | - Guillermo Estivill-Torrus
- Clinical Neurosciences Unit, Research Laboratory and Microscopy Unit, Biomedical Research Institute of Malaga (IBIMA), Regional University Hospital of Malaga, E-29010 Málaga, Spain
| | - José A Aguirre
- Department of Human Physiology, Malaga University, Biomedical Research Institute of Malaga (IBIMA), E-29071 Malaga, Spain
| | - Maria Garcia-Fernandez
- Department of Human Physiology, Malaga University, Biomedical Research Institute of Malaga (IBIMA), E-29071 Malaga, Spain.
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