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De Paolis ML, Loffredo G, Krashia P, La Barbera L, Nobili A, Cauzzi E, Babicola L, Di Segni M, Coccurello R, Puglisi-Allegra S, Latagliata EC, D'Amelio M. Repetitive prefrontal tDCS activates VTA dopaminergic neurons, resulting in attenuation of Alzheimer's Disease-like deficits in Tg2576 mice. Alzheimers Res Ther 2025; 17:94. [PMID: 40301905 PMCID: PMC12039073 DOI: 10.1186/s13195-025-01736-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 04/07/2025] [Indexed: 05/01/2025]
Abstract
BACKGROUND Emerging evidence implicates early dysfunction of dopaminergic neurons in the Ventral Tegmental Area (VTA) as a key contributor to Alzheimer's Disease (AD) pathophysiology. Specifically, the VTA dopaminergic neurodegeneration and the consequent reduction of dopamine (DA) in mesocorticolimbic targets are associated with the onset of cognitive impairments and neuropsychiatric-like manifestations in AD animal models. Moreover, decreased midbrain volume and functional VTA disconnection are identified as predictors of accelerated progression from Mild Cognitive Impairment to AD-dementia in clinical populations. Given these findings, interventions capable of directly modulating VTA activity and augmenting DA release, despite the ongoing neurodegeneration, may hold therapeutic potential for mitigating DA-related deficits in AD. This study aims at evaluating the therapeutic potential of prefrontal transcranial Direct Current Stimulation (tDCS) in the Tg2576 mouse model of AD, exhibiting early VTA dopaminergic neurodegeneration. METHODS Repeated tDCS was applied to assess its ability to activate VTA DA neurons. We also evaluated tDCS effects on synaptic plasticity, cognitive and non-cognitive behaviours and AD-related pathology. Hippocampal DA release and Nucleus Accumbens (NAc) DA transporter (DAT) expression were measured. With immunohistochemistry we examined microglial density and morphological complexity at different disease stages. Additionally, intracellular amyloid-β (Aβ) levels and plaque burden were evaluated to determine the impact of tDCS on AD pathology. RESULTS Prefrontal tDCS enhanced the activity of VTA dopaminergic neurons, leading to increased hippocampal DA release and higher DAT levels in the NAc. The enhanced DA outflow is associated with restored CA3-CA1 synaptic plasticity and improvements in recognition memory and motivational behaviours. tDCS reduced microglial numbers and morphological complexity in Tg2576 mice at both pre-plaque stage (7-months) and at an advanced stage characterized by plaque accumulation (12-months). Notably, tDCS also decreased Aβ plaque burden, although no changes in intracellular Aβ levels were observed in younger Tg2576 mice. CONCLUSIONS These findings highlight the multifaceted therapeutic potential of prefrontal tDCS in targeting key AD pathophysiological hallmarks, including dopaminergic dysfunction, synaptic impairments, neuroinflammation and plaque deposition. As a non-invasive neuromodulatory approach, prefrontal tDCS emerges as a promising early intervention strategy to complement existing AD treatments, with the potential to improve patient outcomes and quality of life.
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Affiliation(s)
- Maria Luisa De Paolis
- Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
| | - Gilda Loffredo
- Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
| | - Paraskevi Krashia
- Department of Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
- Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso Di Fiorano, 64, 00143, Rome, Italy
| | - Livia La Barbera
- Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
- Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso Di Fiorano, 64, 00143, Rome, Italy
| | - Annalisa Nobili
- Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
- Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso Di Fiorano, 64, 00143, Rome, Italy
| | - Emma Cauzzi
- Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
| | - Lucy Babicola
- Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso Di Fiorano, 64, 00143, Rome, Italy
- Department of Psychology, Sapienza University of Rome, P.Le Aldo Moro, 5, 00185, Rome, Italy
| | - Matteo Di Segni
- Child Psychopathology Unit, IRCCS Eugenio Medea, Via Don Luigi Monza, 20, 23842, Bosisio Parini, Italy
| | - Roberto Coccurello
- Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso Di Fiorano, 64, 00143, Rome, Italy
- National Research Council (CNR), Institute for Complex System (ISC), Via Dei Taurini, 19, 00185, Rome, Italy
| | - Stefano Puglisi-Allegra
- Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Neuromed, Via Atinense, 18, 86077, Pozzilli, Italy
| | - Emanuele Claudio Latagliata
- Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso Di Fiorano, 64, 00143, Rome, Italy.
- Department of Psychology, International Telematic University Uninettuno, Corso Vittorio Emanuele II, 39, 00186, Rome, Italy.
| | - Marcello D'Amelio
- Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy.
- Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Via del Fosso Di Fiorano, 64, 00143, Rome, Italy.
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Sinen O, Gemici Sinen A, Derin N. Central treatment of neuropeptide-S attenuates cognitive dysfunction and hippocampal synaptic plasticity impairment by increasing CaMKII/GluR1 in hemiparkinsonian rats. Neuroscience 2025; 564:194-201. [PMID: 39547334 DOI: 10.1016/j.neuroscience.2024.11.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/04/2024] [Accepted: 11/08/2024] [Indexed: 11/17/2024]
Abstract
Neuropeptide-S (NPS) has been demonstrated to mitigate learning and memory deficits in experimental models of Parkinson's Disease (PD). Despite this, the precise mechanisms through which NPS exerts its influence on cognitive functions remain to be fully unknown. This study aims to elucidate the effects of central administration of NPS on learning and memory deficits associated with an experimental rat hemiparkinsonian model, examining both electrophysiological and molecular parameters. The hemiparkinsonian model was established via stereotactic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle. Central NPS (1 nmol, icv) was administered into the lateral ventricle via a cannula for seven consecutive days following the 6-OHDA lesion. The Morris water maze and object recognition tests were used to evaluate the rat's learning and memory abilities. Long-term potentiation (LTP) recordings were conducted to assess hippocampal synaptic plasticity. Immunohistochemistry was employed to determine the expression levels of phosphorylated CaMKII (pCaMKII), GluR1, and GluR2 in the hippocampus. The 6-OHDA-induced decline in cognitive performance was significantly (p < 0.05) improved in rats that received central NPS. In 6-OHDA-lesioned rats, NPS treatment significantly (p < 0.05) enhanced the amplitude of LTP at the dentate gyrus/perforant path synapses. Furthermore, NPS significantly (p < 0.05) increased the number of pCaMKII and GluR1 immunoreactive cells in the hippocampus, which had been diminished due to 6-OHDA, except for GluR2 levels. These findings provide insight into the mechanisms by which central NPS administration enhances cognitive functions in an experimental model of PD, highlighting its potential therapeutic benefits for addressing cognitive deficits in PD.
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Affiliation(s)
- Osman Sinen
- Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
| | - Ayşegül Gemici Sinen
- Department of Biophysics, Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - Narin Derin
- Department of Biophysics, Akdeniz University, Faculty of Medicine, Antalya, Turkey
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Hagena H, Manahan-Vaughan D. Oppositional and competitive instigation of hippocampal synaptic plasticity by the VTA and locus coeruleus. Proc Natl Acad Sci U S A 2025; 122:e2402356122. [PMID: 39793037 PMCID: PMC11725844 DOI: 10.1073/pnas.2402356122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 10/19/2024] [Indexed: 01/12/2025] Open
Abstract
The novelty, saliency, and valency of ongoing experiences potently influence the firing rate of the ventral tegmental area (VTA) and the locus coeruleus (LC). Associative experience, in turn, is recorded into memory by means of hippocampal synaptic plasticity that is regulated by noradrenaline sourced from the LC, and dopamine, sourced from both the VTA and LC. Two persistent forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD) support the encoding of different kinds of spatial experience. To what extent the VTA and the LC influence the direction of change of synaptic plasticity and therefore the content of stored experience is not clear. Here, we report that test-pulse activation of Schaffer-collateral-CA1 synapses of freely behaving male rats, in conjunction with VTA stimulation, results in LTP (>24 h), whereas concomitant hippocampal afferent and LC stimulation results in LTD (>24 h). Effects are frequency-dependent (1 to 50 Hz) and competitive: high-frequency (25 Hz), but not low-frequency (5 Hz) optogenetic activation of tyrosine hydroxylase-positive (TH+) neurons in the VTA, results in D1/D5R-dependent LTP, whereas 5 Hz (but not 1, or 25 Hz) activation of TH+ neurons in the LC results in hippocampal LTD that is both D1/D5 and β-AR-dependent. These results suggest that the VTA and LC do not work in synergy, but rather function in a competing fashion to drive different forms of information encoding through synaptic plasticity. Our findings indicate that information transmitted by the VTA and LC is likely to play a decisive role in the shaping of hippocampal information storage and the nature of learned experience.
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Affiliation(s)
- Hardy Hagena
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum44780, Germany
| | - Denise Manahan-Vaughan
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum44780, Germany
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Hernández-Frausto M, Galván EJ, López-Rubalcava C. Dopamine D1 receptors activation rescues hippocampal synaptic plasticity and cognitive impairments in the MK-801 neonatal schizophrenia model. Behav Brain Res 2025; 476:115250. [PMID: 39277140 DOI: 10.1016/j.bbr.2024.115250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/27/2024] [Accepted: 09/08/2024] [Indexed: 09/17/2024]
Abstract
Schizophrenia is a disorder with a higher cognitive decline in early adulthood, causing impaired retention of episodic memories. However, the physiological and behavioral functions that underlie cognitive deficits with a potential mechanism to ameliorate and improve cognitive performance are unknown. In this study, we used the MK-801 neurodevelopmental schizophrenia-like model. Rats were divided into two groups: one received MK-801, and the other received saline for five consecutive days (7-11 postnatal days, PND). We evaluated synaptic plasticity late-LTP and spatial memory consolidation in early adolescence and young adulthood using extracellular field recordings in acute hippocampal slices and the Barnes maze task. Next, we examined D1 receptor (D1R) activation as a mechanism to ameliorate cognitive impairments. Our results suggest that MK-801 neonatal treatment induces impairment in late-LTP expression and deficits in spatial memory retrieval in early adolescence that is maintained until young adulthood. Furthermore, we found that activation of dopamine D1R ameliorates the impairments and promotes a robust expression of late-LTP and an improved performance in the Barnes maze task, suggesting a novel and potential therapeutic role in treating cognitive impairments in schizophrenia.
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Affiliation(s)
- Melissa Hernández-Frausto
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, Mexico
| | - Emilio J Galván
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, Mexico
| | - Carolina López-Rubalcava
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, Mexico.
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Selvaraj S, Weerasinghe L. The Role of Nanotechnology in Understanding the Pathophysiology of Traumatic Brain Injury. Cent Nerv Syst Agents Med Chem 2025; 25:20-38. [PMID: 38676493 DOI: 10.2174/0118715249291999240418112531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/19/2024] [Accepted: 03/28/2024] [Indexed: 04/29/2024]
Abstract
Recently, traumatic brain injury (TBI) has been a growing disorder due to frequent brain dysfunction. The Glasgow Coma Scale expresses TBI as classified as having mild, moderate, or severe brain effects, according to the effects on the brain. Brain receptors undergo various modifications in their pathology through chemical synaptic pathways, leading to depression, Alzheimer's, and Parkinson's disease. These brain disorders can be controlled using central receptors such as dopamine, glutamate, and γ-aminobutyric acid, which are clearly explained in this review. Furthermore, there are many complications in TBI's clinical trials and diagnostics, leading to insignificant treatment, causing permanent neuro-damage, physical disability, and even death. Bio-screening and conventional molecular-based therapies are inappropriate due to poor preclinical testing and delayed recovery. Hence, modern nanotechnology utilizing nanopulsed laser therapy and advanced nanoparticle insertion will be suitable for TBI's diagnostics and treatment. In recent days, nanotechnology has an important role in TBI control and provides a higher success rate than conventional therapies. This review highlights the pathophysiology of TBI by comprising the drawbacks of conventional techniques and supports suitable modern alternates for treating TBI.
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Affiliation(s)
- Saranya Selvaraj
- Department of Chemistry, Faculty of Applied sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - Laksiri Weerasinghe
- Department of Chemistry, Faculty of Applied sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
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Park AJ. Novelty triggers time-dependent theta oscillatory dynamics in cortical-hippocampal-midbrain circuitry. Mol Brain 2024; 17:94. [PMID: 39696423 DOI: 10.1186/s13041-024-01167-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 11/26/2024] [Indexed: 12/20/2024] Open
Abstract
Rapid adaptation to novel environments is crucial for survival, and this ability is impaired in many neuropsychiatric disorders. Understanding neural adaptation to novelty exposure therefore has therapeutic implications. Here, I found that novelty induces time-dependent theta (4-12Hz) oscillatory dynamics in brain circuits including the medial prefrontal cortex (mPFC), ventral hippocampus (vHPC), and ventral tegmental area (VTA), but not dorsal hippocampus (dHPC), as mice adapt to a novel environment. Local field potential (LFP) recordings were performed while mice were freely behaving in a novel or a familiar arena for 10 min. Initially, mice exhibited increased exploratory behavior upon exposure to novelty, which gradually decreased to levels observed in mice exposed to the familiar arena. Over the same time course, the mPFC, vHPC, and VTA displayed progressively increasing theta power through novelty exposure. Additionally, theta coherence and theta phase synchrony measures demonstrated that novelty weakened the connectivity between these areas, which then gradually strengthened to the level observed in the familiar group. Conversely, mice exposed to the familiar arena showed steady and consistent behavior as well as theta dynamics in all areas. Treatment with a dopamine D1-receptor (D1R) antagonist in the vHPC disrupted neurophysiological adaptation to novelty specifically in the vHPC-mPFC and vHPC-VTA circuits, without affecting behavior. Thus, novelty induces distinct theta dynamics that are not readily dictated by behavior in the mPFC, vHPC, and VTA circuits, a process mediated by D1Rs in the vHPC. The observed time-dependent circuit dynamics in the key learning and memory circuit would provide new insights for treating neuropsychiatric disorders that often show impaired novelty processing.
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Affiliation(s)
- Alan Jung Park
- Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea.
- The Mortimer B. Zuckerman Mind Brain Behavior Institute at Columbia University, New York, NY, 10032, USA.
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Naseem M, Khan H, Parvez S. TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging. Mol Neurobiol 2024; 61:8307-8319. [PMID: 38485841 DOI: 10.1007/s12035-024-04071-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 02/26/2024] [Indexed: 09/21/2024]
Abstract
In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24 h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.
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Affiliation(s)
- Mehar Naseem
- Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Hiba Khan
- Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Suhel Parvez
- Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India.
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Chae S, Lee HJ, Lee HE, Kim J, Jeong YJ, Lin Y, Kim HY, Leriche G, Ehrlich RS, Lingl SC, Seo MD, Lee YH, Yang J, Kim JI, Hoe HS. The dopamine analogue CA140 alleviates AD pathology, neuroinflammation, and rescues synaptic/cognitive functions by modulating DRD1 signaling or directly binding to Abeta. J Neuroinflammation 2024; 21:200. [PMID: 39129007 PMCID: PMC11317008 DOI: 10.1186/s12974-024-03180-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/17/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. METHODS To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. RESULTS In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. CONCLUSIONS Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.
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Affiliation(s)
- Sehyun Chae
- Neurovascular Unit, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea
| | - Hyun-Ju Lee
- Neurodegenerative Unit, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea
| | - Ha-Eun Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-Gil, Ulsan, 44919, Republic of Korea
| | - Jieun Kim
- Neurodegenerative Unit, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea
| | - Yoo Joo Jeong
- Neurodegenerative Unit, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea
- Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu, 42988, Republic of Korea
| | - Yuxi Lin
- Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Ochang, ChungBuk, 28119, Republic of Korea
| | - Hye Yun Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-Gil, Ulsan, 44919, Republic of Korea
| | - Geoffray Leriche
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093-0358, USA
| | - Rachel S Ehrlich
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093-0358, USA
| | - Sascha Castro Lingl
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093-0358, USA
| | - Min-Duk Seo
- College of Pharmacy and Department of Molecular Science and Technology, Ajou University, Suwon, Gyeonggi, 16499, Republic of Korea
| | - Young-Ho Lee
- Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Ochang, ChungBuk, 28119, Republic of Korea
- Bio-Analytical Science, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
- Department of Systems Biotechnology, Chung-Ang University, Gyeonggi , 17546, Republic of Korea
| | - Jerry Yang
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093-0358, USA.
| | - Jae-Ick Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-Gil, Ulsan, 44919, Republic of Korea.
| | - Hyang-Sook Hoe
- Neurodegenerative Unit, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea.
- Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu, 42988, Republic of Korea.
- Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61 Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea.
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Bin Ibrahim MZ, Wang Z, Sajikumar S. Synapses tagged, memories kept: synaptic tagging and capture hypothesis in brain health and disease. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230237. [PMID: 38853570 PMCID: PMC11343274 DOI: 10.1098/rstb.2023.0237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/29/2024] [Accepted: 02/13/2024] [Indexed: 06/11/2024] Open
Abstract
The synaptic tagging and capture (STC) hypothesis lays the framework on the synapse-specific mechanism of protein synthesis-dependent long-term plasticity upon synaptic induction. Activated synapses will display a transient tag that will capture plasticity-related products (PRPs). These two events, tag setting and PRP synthesis, can be teased apart and have been studied extensively-from their electrophysiological and pharmacological properties to the molecular events involved. Consequently, the hypothesis also permits interactions of synaptic populations that encode different memories within the same neuronal population-hence, it gives rise to the associativity of plasticity. In this review, the recent advances and progress since the experimental debut of the STC hypothesis will be shared. This includes the role of neuromodulation in PRP synthesis and tag integrity, behavioural correlates of the hypothesis and modelling in silico. STC, as a more sensitive assay for synaptic health, can also assess neuronal aberrations. We will also expound how synaptic plasticity and associativity are altered in ageing-related decline and pathological conditions such as juvenile stress, cancer, sleep deprivation and Alzheimer's disease. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Affiliation(s)
- Mohammad Zaki Bin Ibrahim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore117597, Singapore
- Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore119077, Singapore
| | - Zijun Wang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore117597, Singapore
- Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore119077, Singapore
| | - Sreedharan Sajikumar
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore117597, Singapore
- Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore119077, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore117597, Singapore
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Schroyens N, Vercammen L, Özcan B, Salazar VAO, Zaman J, De Bundel D, Beckers T, Luyten L. No evidence that post-training dopamine D2 receptor agonism affects fear generalization in male rats. J Psychopharmacol 2024; 38:672-682. [PMID: 39068641 PMCID: PMC7616352 DOI: 10.1177/02698811241261375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
BACKGROUND The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. AIMS The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice. METHODS In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS- was assessed. RESULTS We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test. CONCLUSION In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats.
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Affiliation(s)
- Natalie Schroyens
- KU Leuven, Centre for the Psychology of Learning and Experimental Psychopathology, Faculty of Psychology and Educational Sciences, Tiensestraat 102 box 3712, 3000Leuven, Belgium
- KU Leuven, Leuven Brain Institute, O&N V Herestraat 49 box 1020, 3000Leuven, Belgium
| | - Laura Vercammen
- KU Leuven, Centre for the Psychology of Learning and Experimental Psychopathology, Faculty of Psychology and Educational Sciences, Tiensestraat 102 box 3712, 3000Leuven, Belgium
- KU Leuven, Leuven Brain Institute, O&N V Herestraat 49 box 1020, 3000Leuven, Belgium
- KU Leuven, Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, Tiensestraat 102 box 3714, 3000Leuven, Belgium
| | - Burcu Özcan
- KU Leuven, Centre for the Psychology of Learning and Experimental Psychopathology, Faculty of Psychology and Educational Sciences, Tiensestraat 102 box 3712, 3000Leuven, Belgium
| | - Victoria Aurora Ossorio Salazar
- KU Leuven, Leuven Brain Institute, O&N V Herestraat 49 box 1020, 3000Leuven, Belgium
- KU Leuven, Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, Tiensestraat 102 box 3714, 3000Leuven, Belgium
| | - Jonas Zaman
- KU Leuven, Health Psychology, Tiensestraat 102 box 3726, 3000Leuven, Belgium
| | - Dimitri De Bundel
- Research Group Experimental Pharmacology, Department of Pharmaceutical Sciences, Center for Neurosciences, Vrije Universiteit Brussel, 1090Brussel, Belgium
| | - Tom Beckers
- KU Leuven, Centre for the Psychology of Learning and Experimental Psychopathology, Faculty of Psychology and Educational Sciences, Tiensestraat 102 box 3712, 3000Leuven, Belgium
- KU Leuven, Leuven Brain Institute, O&N V Herestraat 49 box 1020, 3000Leuven, Belgium
| | - Laura Luyten
- KU Leuven, Centre for the Psychology of Learning and Experimental Psychopathology, Faculty of Psychology and Educational Sciences, Tiensestraat 102 box 3712, 3000Leuven, Belgium
- KU Leuven, Leuven Brain Institute, O&N V Herestraat 49 box 1020, 3000Leuven, Belgium
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11
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Chen X, Liu X, Luan S, Wang X, Zhang Y, Hao Y, Zhang Q, Zhang J, Zhao H. Optogenetic activation of the lateral habenula D1R-ventral tegmental area circuit induces depression-like behavior in mice. Eur Arch Psychiatry Clin Neurosci 2024; 274:867-878. [PMID: 38236282 DOI: 10.1007/s00406-023-01743-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 12/11/2023] [Indexed: 01/19/2024]
Abstract
A number of different receptors are distributed in glutamatergic neurons of the lateral habenula (LHb). These glutamatergic neurons are involved in different neural pathways, which may identify how the LHb regulates various physiological functions. However, the role of dopamine D1 receptor (D1R)-expressing habenular neurons projecting to the ventral tegmental area (VTA) (LHbD1R-VTA) remains not well understood. In the current study, to determine the activity of D1R-expressing neurons in LHb, D1R-Cre mice were used to establish the chronic restraint stress (CRS) depression model. Adeno-associated virus was injected into bilateral LHb in D1R-Cre mice to examine whether optogenetic activation of the LHb D1R-expressing neurons and their projections could induce depression-like behavior. Optical fibers were implanted in the LHb and VTA, respectively. To investigate whether optogenetic inhibition of the LHbD1R-VTA circuit could produce antidepressant-like effects, the adeno-associated virus was injected into the bilateral LHb in the D1R-Cre CRS model, and optical fibers were implanted in the bilateral VTA. The D1R-expressing neuronal activity in the LHb was increased in the CRS depression model. Optogenetic activation of the D1R-expressing neurons in LHb induced behavioral despair and anhedonia, which could also be induced by activation of the LHbD1R-VTA axons. Conversely, optogenetic inhibition of the LHbD1R-VTA circuit improved behavioral despair and anhedonia in the CRS depression model. D1R-expressing glutamatergic neurons in the LHb and their projections to the VTA are involved in the occurrence and regulation of depressive-like behavior.
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Affiliation(s)
- Xiaowei Chen
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Xinmin Street No. 126, Changchun, 130021, People's Republic of China
- Department of Rehabilitation Medicine, First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Xiaofeng Liu
- Neuroscience Research Center, First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Shuxin Luan
- Department of Mental Health, First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Xuxin Wang
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Xinmin Street No. 126, Changchun, 130021, People's Republic of China
| | - Ying Zhang
- Department of Neurology, First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Yulei Hao
- Neuroscience Research Center, First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Qiang Zhang
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Xinmin Street No. 126, Changchun, 130021, People's Republic of China
| | - Jiaming Zhang
- Department of Rehabilitation Medicine, First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Hua Zhao
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Xinmin Street No. 126, Changchun, 130021, People's Republic of China.
- Neuroscience Research Center, First Hospital of Jilin University, Changchun, 130021, People's Republic of China.
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12
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Sayegh FJP, Mouledous L, Macri C, Pi Macedo J, Lejards C, Rampon C, Verret L, Dahan L. Ventral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning. Nat Commun 2024; 15:4100. [PMID: 38773091 PMCID: PMC11109191 DOI: 10.1038/s41467-024-47481-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/28/2024] [Indexed: 05/23/2024] Open
Abstract
In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.
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Affiliation(s)
- Fares J P Sayegh
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France.
| | - Lionel Mouledous
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France
| | - Catherine Macri
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France
| | - Juliana Pi Macedo
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France
| | - Camille Lejards
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France
| | - Claire Rampon
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France
| | - Laure Verret
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France
| | - Lionel Dahan
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France.
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13
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Pupillo F, Bruckner R. Signed and unsigned effects of prediction error on memory: Is it a matter of choice? Neurosci Biobehav Rev 2023; 153:105371. [PMID: 37633626 DOI: 10.1016/j.neubiorev.2023.105371] [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: 04/27/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 08/28/2023]
Abstract
Adaptive decision-making is governed by at least two types of memory processes. On the one hand, learned predictions through integrating multiple experiences, and on the other hand, one-shot episodic memories. These two processes interact, and predictions - particularly prediction errors - influence how episodic memories are encoded. However, studies using computational models disagree on the exact shape of this relationship, with some findings showing an effect of signed prediction errors and others showing an effect of unsigned prediction errors on episodic memory. We argue that the choice-confirmation bias, which reflects stronger learning from choice-confirming compared to disconfirming outcomes, could explain these seemingly diverging results. Our perspective implies that the influence of prediction errors on episodic encoding critically depends on whether people can freely choose between options (i.e., instrumental learning tasks) or not (Pavlovian learning tasks). The choice-confirmation bias on memory encoding might have evolved to prioritize memory representations that optimize reward-guided decision-making. We conclude by discussing open issues and implications for future studies.
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Affiliation(s)
- Francesco Pupillo
- Department of Psychology, Goethe-Universität Frankfurt, Germany; Tilburg School of Social and Behavioral Sciences, Tilburg University, Netherlands.
| | - Rasmus Bruckner
- Department of Education and Psychology, Freie Universität Berlin, Germany; Max Planck Research Group NeuroCode, Max Planck Institute for Human Development, Berlin, Germany
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14
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Mohammadi M, Eskandari K, Azizbeigi R, Haghparast A. The inhibitory effect of cannabidiol on the rewarding properties of methamphetamine in part mediates by interacting with the hippocampal D1-like dopamine receptors. Prog Neuropsychopharmacol Biol Psychiatry 2023; 126:110778. [PMID: 37100273 DOI: 10.1016/j.pnpbp.2023.110778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/15/2023] [Accepted: 04/21/2023] [Indexed: 04/28/2023]
Abstract
Cannabidiol (CBD) is a potential treatment to decrease the rewarding properties of psychostimulants. However, the exact mechanism and distinct neuroanatomical areas responsible for the CBD's effects remain unclear. Indicatively, the D1-like dopamine receptors (D1R) in the hippocampus (HIP) are essential for expressing and acquiring drug-associated conditioned place preference (CPP). Therefore, given that involving D1Rs in reward-related behaviors and the encouraging results of CBD in attenuating the psychostimulant's rewarding effects, the present study sought to investigate the role of D1Rs of the hippocampal dentate gyrus (DG) in the inhibitory effects of CBD on the acquisition and expression of METH-induced CPP. To this end, over a 5-day conditioning period by METH (1 mg/kg; sc), different groups of rats were given intra-DG SCH23390 (0.25, 1, or 4 μg/0.5 μl, saline) as a D1Rs antagonist before ICV administration of CBD (10 μg/5 μl, DMSO12%). In addition, a different set of animals, after the conditioning period, received a single dose of SCH23390 (0.25, 1, or 4 μg/0.5 μl) before CBD (50 μg/5 μl) administration on the expression day. The results showed that SCH23390 (1 and 4 μg) significantly reduced the suppressive effects of CBD on the acquisition of METH place preference (P < 0.05 and P < 0.001, respectively). Furthermore, the highest dose of SCH23390 (4 μg) in the expression phase remarkably abolished the preventive effects of CBD on the expression of METH-seeking behavior (P < 0.001). In conclusion, the current study revealed that CBD's inhibitory effect on rewarding properties of METH partially acts through D1Rs in the DG area of the HIP.
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Affiliation(s)
- Mahsa Mohammadi
- Department of Physiology, Faculty of Veterinary Science, Islamic Azad University, Sanandaj Branch, Sanandaj, Iran
| | - Kiarash Eskandari
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ronak Azizbeigi
- Department of Physiology, Faculty of Veterinary Science, Islamic Azad University, Sanandaj Branch, Sanandaj, Iran.
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran; Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran.
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15
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Berdasco C, Pinto A, Blake MG, Correa F, Carbajosa NAL, Celi AB, Geoghegan PA, Cangelosi A, Nuñez M, Gironacci MM, Goldstein J. Cognitive Deficits Found in a Pro-inflammatory State are Independent of ERK1/2 Signaling in the Murine Brain Hippocampus Treated with Shiga Toxin 2 from Enterohemorrhagic Escherichia coli. Cell Mol Neurobiol 2023; 43:2203-2217. [PMID: 36227397 PMCID: PMC11412172 DOI: 10.1007/s10571-022-01298-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 10/05/2022] [Indexed: 11/03/2022]
Abstract
Shiga toxin 2 (Stx2) from enterohemorrhagic Escherichia coli (EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS), and acute encephalopathy. The mortality rate in HUS increases significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. The purpose of this work is to elucidate the signaling pathways that may activate the inflammatory processes triggered by Stx2, which produces cognitive alterations at the level of the hippocampus. Results demonstrate that Stx2 produced depression-like behavior, pro-inflammatory cytokine release, and NF-kB activation independent of the ERK1/2 signaling pathway, while co-administration of Stx2 and LPS reduced memory index. On the other hand, LPS activated NF-kB dependent on ERK1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.
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Affiliation(s)
- Clara Berdasco
- Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Laboratorio de Neurofisiopatología, Instituto de Fisiología y Biofísica "Houssay" - CONICET (IFIBIO), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Alipio Pinto
- Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Laboratorio de Neurofisiopatología, Instituto de Fisiología y Biofísica "Houssay" - CONICET (IFIBIO), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mariano G Blake
- Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología y Biofísica "Houssay" - CONICET (IFIBIO), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Fernando Correa
- Laboratorio de Fisiología de la Preñez y el Parto, Facultad de Medicina, Centro de Estudios Farmacológicos y Botánicos - CONICET (CEFyBO), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Nadia A Longo Carbajosa
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química y Fisicoquímica Biológicas - CONICET (IQUIFIB), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ana B Celi
- Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Laboratorio de Neurofisiopatología, Instituto de Fisiología y Biofísica "Houssay" - CONICET (IFIBIO), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Patricia A Geoghegan
- Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos Malbrán" - ANLIS - Centro Nacional de Control de Calidad de Biológicos, Buenos Aires, Argentina
| | - Adriana Cangelosi
- Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos Malbrán" - ANLIS - Centro Nacional de Control de Calidad de Biológicos, Buenos Aires, Argentina
| | - Myriam Nuñez
- Cátedra de Matemáticas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mariela M Gironacci
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química y Fisicoquímica Biológicas - CONICET (IQUIFIB), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jorge Goldstein
- Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
- Laboratorio de Neurofisiopatología, Instituto de Fisiología y Biofísica "Houssay" - CONICET (IFIBIO), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina.
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Mendoza-Torreblanca JG, Cárdenas-Rodríguez N, Carro-Rodríguez J, Contreras-García IJ, Garciadiego-Cázares D, Ortega-Cuellar D, Martínez-López V, Alfaro-Rodríguez A, Evia-Ramírez AN, Ignacio-Mejía I, Vargas-Hernández MA, Bandala C. Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis. Int J Mol Sci 2023; 24:10199. [PMID: 37373348 DOI: 10.3390/ijms241210199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Dopamine (DA) and dopamine agonists (DA-Ag) have shown antiangiogenic potential through the vascular endothelial growth factor (VEGF) pathway. They inhibit VEGF and VEGF receptor 2 (VEGFR 2) functions through the dopamine receptor D2 (D2R), preventing important angiogenesis-related processes such as proliferation, migration, and vascular permeability. However, few studies have demonstrated the antiangiogenic mechanism and efficacy of DA and DA-Ag in diseases such as cancer, endometriosis, and osteoarthritis (OA). Therefore, the objective of this review was to describe the mechanisms of the antiangiogenic action of the DA-D2R/VEGF-VEGFR 2 system and to compile related findings from experimental studies and clinical trials on cancer, endometriosis, and OA. Advanced searches were performed in PubMed, Web of Science, SciFinder, ProQuest, EBSCO, Scopus, Science Direct, Google Scholar, PubChem, NCBI Bookshelf, DrugBank, livertox, and Clinical Trials. Articles explaining the antiangiogenic effect of DA and DA-Ag in research articles, meta-analyses, books, reviews, databases, and clinical trials were considered. DA and DA-Ag have an antiangiogenic effect that could reinforce the treatment of diseases that do not yet have a fully curative treatment, such as cancer, endometriosis, and OA. In addition, DA and DA-Ag could present advantages over other angiogenic inhibitors, such as monoclonal antibodies.
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Affiliation(s)
| | - Noemi Cárdenas-Rodríguez
- Laboratorio de Neurociencias, Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
| | - Jazmín Carro-Rodríguez
- Laboratorio de Medicina Traslacional Aplicada a Neurociencias, Enfermedades Crónicas y Emergentes, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Itzel Jatziri Contreras-García
- Laboratorio de Biología de la Reproducción, Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
| | - David Garciadiego-Cázares
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Daniel Ortega-Cuellar
- Laboratorio Nutrición Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico
| | - Valentín Martínez-López
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Alfonso Alfaro-Rodríguez
- Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Secretaría de Salud, Mexico City 14389, Mexico
| | - Alberto Nayib Evia-Ramírez
- Servicio de Reconstrucción Articular, Cadera y Rodilla, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Iván Ignacio-Mejía
- Laboratorio de Medicina Traslacional, Escuela Militar de Graduados de Sanidad, Mexico City 11200, Mexico
| | | | - Cindy Bandala
- Laboratorio de Medicina Traslacional Aplicada a Neurociencias, Enfermedades Crónicas y Emergentes, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
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Pupillo F, Ortiz-Tudela J, Bruckner R, Shing YL. The effect of prediction error on episodic memory encoding is modulated by the outcome of the predictions. NPJ SCIENCE OF LEARNING 2023; 8:18. [PMID: 37248232 DOI: 10.1038/s41539-023-00166-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 05/05/2023] [Indexed: 05/31/2023]
Abstract
Expectations can lead to prediction errors of varying degrees depending on the extent to which the information encountered in the environment conforms with prior knowledge. While there is strong evidence on the computationally specific effects of such prediction errors on learning, relatively less evidence is available regarding their effects on episodic memory. Here, we had participants work on a task in which they learned context/object-category associations of different strengths based on the outcomes of their predictions. We then used a reinforcement learning model to derive subject-specific trial-to-trial estimates of prediction error at encoding and link it to subsequent recognition memory. Results showed that model-derived prediction errors at encoding influenced subsequent memory as a function of the outcome of participants' predictions (correct vs. incorrect). When participants correctly predicted the object category, stronger prediction errors (as a consequence of weak expectations) led to enhanced memory. In contrast, when participants incorrectly predicted the object category, stronger prediction errors (as a consequence of strong expectations) led to impaired memory. These results highlight the important moderating role of choice outcome that may be related to interactions between the hippocampal and striatal dopaminergic systems.
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Affiliation(s)
- Francesco Pupillo
- Department of Psychology, Goethe University Frankfurt, Frankfurt, Germany.
- TS Social and Behavioral Sciences, Tilburg University, Tilburg, Netherlands.
| | | | - Rasmus Bruckner
- Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany
- Max Planck Research Group NeuroCode, Max Planck Institute for Human Development, Berlin, Germany
| | - Yee Lee Shing
- Department of Psychology, Goethe University Frankfurt, Frankfurt, Germany
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Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway. Mol Psychiatry 2023; 28:1351-1364. [PMID: 36434054 PMCID: PMC10005959 DOI: 10.1038/s41380-022-01877-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022]
Abstract
Spatial learning and memory flexibility are known to require long-term potentiation (LTP) and long-term depression (LTD), respectively, on a cellular basis. We previously showed that cyclin Y (CCNY), a synapse-remodeling cyclin, is a novel actin-binding protein and an inhibitory regulator of functional and structural LTP in vitro. In this study, we report that Ccny knockout (KO) mice exhibit enhanced LTP and weak LTD at Schaffer collateral-CA1 synapses in the hippocampus. In accordance with enhanced LTP, Ccny KO mice showed improved spatial learning and memory. However, although previous studies reported that normal LTD is necessary for memory flexibility, Ccny KO mice intriguingly showed improved memory flexibility, suggesting that weak LTD could exert memory flexibility when combined with enhanced LTP. At the molecular level, CCNY modulated spatial learning and memory flexibility by distinctively affecting the cofilin-actin signaling pathway in the hippocampus. Specifically, CCNY inhibited cofilin activation by original learning, but reversed such inhibition by reversal learning. Furthermore, viral-mediated overexpression of a phosphomimetic cofilin-S3E in hippocampal CA1 regions enhanced LTP, weakened LTD, and improved spatial learning and memory flexibility, thus mirroring the phenotype of Ccny KO mice. In contrast, the overexpression of a non-phosphorylatable cofilin-S3A in hippocampal CA1 regions of Ccny KO mice reversed the synaptic plasticity, spatial learning, and memory flexibility phenotypes observed in Ccny KO mice. Altogether, our findings demonstrate that LTP and LTD cooperatively regulate memory flexibility. Moreover, CCNY suppresses LTP while facilitating LTD in the hippocampus and negatively regulates spatial learning and memory flexibility through the control of cofilin-actin signaling, proposing CCNY as a learning regulator modulating both memorizing and forgetting processes.
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Lorents A, Ruitenberg M, Schomaker J. Novelty-induced memory boosts in humans: The when and how. Heliyon 2023; 9:e14410. [PMID: 36942255 PMCID: PMC10023963 DOI: 10.1016/j.heliyon.2023.e14410] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/10/2023] Open
Abstract
Novel information potentially signals danger or reward and behavioral and psychophysiological studies have suggested that the brain prioritizes its processing. Some effects of novelty even go beyond the stimulus itself. Studies in animals have robustly shown that exposure to novel stimulation can promote memory for information presented before or after this exposure. Research regarding effects of novelty on memory in humans is lagging, but in the last few years, several studies have emerged that suggest that memory-facilitating effects of novelty also exist in humans. Here, we provide a comprehensive overview of these studies. We identified several factors that have been shown to influence whether novelty promotes memory or not, including the timing between the novel experience and the learning events, the involvement with the novel material, and population characteristics (such as clinical diagnosis or age). Finally, we link the behavioral findings to potential neurobiological mechanisms and discuss the relevance of specific findings in light of potential clinical and educational applications that could leverage novelty to improve memory.
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Affiliation(s)
- A. Lorents
- Department of Health Medical and Neuropsychology, Institute of Psychology, Leiden University, the Netherlands
| | - M.F.L. Ruitenberg
- Department of Health Medical and Neuropsychology, Institute of Psychology, Leiden University, the Netherlands
- Leiden Institute for Brain and Cognition, the Netherlands
| | - J. Schomaker
- Department of Health Medical and Neuropsychology, Institute of Psychology, Leiden University, the Netherlands
- Leiden Institute for Brain and Cognition, the Netherlands
- Corresponding author. Department of Health Medical and Neuropsychology, Institute of Psychology, Leiden University, the Netherlands.
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20
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Wang Y, Liu J, Hui Y, Wu Z, Wang L, Wu X, Bai Y, Zhang Q, Li L. Dose and time-dependence of acute intermittent theta-burst stimulation on hippocampus-dependent memory in parkinsonian rats. Front Neurosci 2023; 17:1124819. [PMID: 36866328 PMCID: PMC9972116 DOI: 10.3389/fnins.2023.1124819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/02/2023] [Indexed: 02/16/2023] Open
Abstract
Background The treatment options for cognitive impairments in Parkinson's disease (PD) are limited. Repetitive transcranial magnetic stimulation has been applied in various neurological diseases. However, the effect of intermittent theta-burst stimulation (iTBS) as a more developed repetitive transcranial magnetic stimulation paradigm on cognitive dysfunction in PD remains largely unclear. Objective Our aim was to explore the effect of acute iTBS on hippocampus-dependent memory in PD and the mechanism underlying it. Methods Different blocks of iTBS protocols were applied to unilateral 6-hydroxidopamine-induced parkinsonian rats followed by the behavioral, electrophysiological and immunohistochemical analyses. The object-place recognition and hole-board test were used to assess hippocampus-dependent memory. Results Sham-iTBS and 1 block-iTBS (300 stimuli) didn't alter hippocampus-dependent memory, hippocampal theta rhythm and the density of c-Fos- and parvalbumin-positive neurons in the hippocampus and medial septum. 3 block-iTBS (900 stimuli) alleviated 6-hydroxidopamine-induced memory impairments, and increased the density of hippocampal c-Fos-positive neurons at 80 min post-stimulation but not 30 min compared to sham-iTBS. Interestingly, 3 block-iTBS first decreased and then increased normalized theta power during a period of 2 h following stimulation. Moreover, 3 block-iTBS decreased the density of parvalbumin-positive neurons in the medial septum at 30 min post-stimulation compared to sham-iTBS. Conclusion The results indicate that multiple blocks of iTBS elicit dose and time-dependent effects on hippocampus-dependent memory in PD, which may be attributed to changes in c-Fos expression and the power of theta rhythm in the hippocampus.
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Affiliation(s)
- Yixuan Wang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Jian Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
| | - Yanping Hui
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhongheng Wu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Ling Wang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Xiang Wu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Yihua Bai
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Qiaojun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Libo Li
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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21
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Nalberczak-Skóra M, Beroun A, Skonieczna E, Cały A, Ziółkowska M, Pagano R, Taheri P, Kalita K, Salamian A, Radwanska K. Impaired synaptic transmission in dorsal dentate gyrus increases impulsive alcohol seeking. Neuropsychopharmacology 2023; 48:436-447. [PMID: 36182989 PMCID: PMC9852589 DOI: 10.1038/s41386-022-01464-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 02/02/2023]
Abstract
Both human and animal studies indicate that the dentate gyrus (DG) of the hippocampus is highly exploited by drug and alcohol abuse. Yet, it is poorly understood how DG dysfunction affects addiction-related behaviors. Here, we used an animal model of alcohol use disorder (AUD) in automated IntelliCages and performed local genetic manipulation to investigate how synaptic transmission in the dorsal DG (dDG) affects alcohol-related behaviors. We show that a cue light induces potentiation-like plasticity of dDG synapses in alcohol-naive mice. This process is impaired in mice trained to drink alcohol. Acamprosate (ACA), a drug that reduces alcohol relapse, rescues the impairment of dDG synaptic transmission in alcohol mice. A molecular manipulation that reduces dDG synaptic AMPAR and NMDAR levels increases impulsive alcohol seeking during cue relapse (CR) in alcohol mice but does not affect alcohol reward, motivation or craving. These findings suggest that hindered dDG synaptic transmission specifically underlies impulsive alcohol seeking induced by alcohol cues, a core symptom of AUD.
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Affiliation(s)
- Maria Nalberczak-Skóra
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland ,grid.460447.50000 0001 2161 9572Experimental Psychopathology Lab, Institute of Psychology of Polish Academy of Sciences, Warsaw, Poland
| | - Anna Beroun
- grid.419305.a0000 0001 1943 2944BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Edyta Skonieczna
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Anna Cały
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Magdalena Ziółkowska
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Roberto Pagano
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Pegah Taheri
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Katarzyna Kalita
- grid.419305.a0000 0001 1943 2944BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Ahmad Salamian
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Kasia Radwanska
- Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
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22
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Tsetsenis T, Broussard JI, Dani JA. Dopaminergic regulation of hippocampal plasticity, learning, and memory. Front Behav Neurosci 2023; 16:1092420. [PMID: 36778837 PMCID: PMC9911454 DOI: 10.3389/fnbeh.2022.1092420] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/30/2022] [Indexed: 01/28/2023] Open
Abstract
The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus. Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.
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Affiliation(s)
- Theodoros Tsetsenis
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States,*Correspondence: Theodoros Tsetsenis John I. Broussard John A. Dani
| | - John I. Broussard
- Department of Neurobiology and Anatomy, UT Health Houston McGovern Medical School, Houston, TX, United States,*Correspondence: Theodoros Tsetsenis John I. Broussard John A. Dani
| | - John A. Dani
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States,*Correspondence: Theodoros Tsetsenis John I. Broussard John A. Dani
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23
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Park AJ. Novelty selectively permits learning-associated plasticity in ventral tegmental-hippocampal-prefrontal circuitry. Front Behav Neurosci 2023; 16:1091082. [PMID: 36699657 PMCID: PMC9868659 DOI: 10.3389/fnbeh.2022.1091082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/22/2022] [Indexed: 01/11/2023] Open
Abstract
Modifying established behavior in novel situations is essential, and patients with neuropsychiatric disorders often lack this flexibility. Understanding how novelty affects behavioral flexibility therefore has therapeutic potential. Here, novelty differentially impacts connectivity within the ventral tegmental-hippocampal-medial prefrontal (VTA-HPC-mPFC) circuit, thereby enhancing the ability of mice to overcome established behavioral bias and adapt to new rules. Circuit connectivity was measured by local field potential (LFP) coherence. As mice exposed to novelty learned to overcome previously established spatial bias, the ventral HPC (vHPC) strengthens its coherence with the VTA and mPFC in theta frequency (4-8 Hz). Novelty or learning did not affect circuits involving the dorsal HPC (dHPC). Without novelty, however, mice continued following established spatial bias and connectivity strength remained stable in the VTA-HPC-mPFC circuit. Pharmacologically blocking dopamine D1-receptors (D1Rs) in the vHPC abolished the behavioral and physiological impacts of novelty. Thus, novelty promotes behavioral adaptation by permitting learning-associated plasticity in the vHPC-mPFC and VTA-vHPC circuit, a process mediated by D1Rs in the vHPC.
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Affiliation(s)
- Alan Jung Park
- Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea,Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea,The Mortimer B. Zuckerman Mind Brain Behavior Institute at Columbia University, New York, NY, United States,*Correspondence: Alan Jung Park,
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24
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Hagena H, Stacho M, Laja A, Manahan-Vaughan D. Strain-dependent regulation of hippocampal long-term potentiation by dopamine D1/D5 receptors in mice. Front Behav Neurosci 2022; 16:1023361. [PMID: 36545120 PMCID: PMC9760685 DOI: 10.3389/fnbeh.2022.1023361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/26/2022] [Indexed: 12/12/2022] Open
Abstract
The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is species-dependent: rats express more robust and more prolonged LTP in response to a broader afferent frequency range than mice. The C57Bl/6 mouse is an extremely popular murine strain used in studies of hippocampal synaptic plasticity and spatial learning. Recently it was reported that it expresses impoverished LTP compared to other murine strains. Given the important role of the dopamine D1/D5 receptor (D1/D5R) in the maintenance of LTP and in memory consolidation, we explored to what extent strain-dependent differences in LTP in mice are determined by differences in D1/D5R-control. In CaOlaHsd mice, robust LTP was induced that lasted for over 24 h and which was significantly greater in magnitude than LTP induced in C57Bl/6 mice. Intracerebral treatment with a D1/D5R-antagonist (SCH23390) prevented both the early and late phase of LTP in CaOlaHsd mice, whereas only late-LTP was impaired in C57Bl/6 mice. Treatment with a D1/D5R-agonist (Chloro-PB) facilitated short-term potentiation (STP) into LTP (> 24 h) in both strains, whereby effects became evident earlier in CaOlaHsd compared to C57Bl/6 mice. Immunohistochemical analysis revealed a significantly higher expression of D1-receptors in the stratum lacunosum moleculare of CaOlaHsd compared to C57Bl/6 mice. These findings highlight differences in D1/D5R- dependent regulation of strain-dependent variations in hippocampal LTP in C57Bl/6 and CaOlaHsd mice, that may be mediated, in part, by differences in the expression of D1R in the hippocampus.
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25
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Lehr AB, Luboeinski J, Tetzlaff C. Neuromodulator-dependent synaptic tagging and capture retroactively controls neural coding in spiking neural networks. Sci Rep 2022; 12:17772. [PMID: 36273097 PMCID: PMC9588040 DOI: 10.1038/s41598-022-22430-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/14/2022] [Indexed: 01/19/2023] Open
Abstract
Events that are important to an individual's life trigger neuromodulator release in brain areas responsible for cognitive and behavioral function. While it is well known that the presence of neuromodulators such as dopamine and norepinephrine is required for memory consolidation, the impact of neuromodulator concentration is, however, less understood. In a recurrent spiking neural network model featuring neuromodulator-dependent synaptic tagging and capture, we study how synaptic memory consolidation depends on the amount of neuromodulator present in the minutes to hours after learning. We find that the storage of rate-based and spike timing-based information is controlled by the level of neuromodulation. Specifically, we find better recall of temporal information for high levels of neuromodulation, while we find better recall of rate-coded spatial patterns for lower neuromodulation, mediated by the selection of different groups of synapses for consolidation. Hence, our results indicate that in minutes to hours after learning, the level of neuromodulation may alter the process of synaptic consolidation to ultimately control which type of information becomes consolidated in the recurrent neural network.
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Affiliation(s)
- Andrew B. Lehr
- grid.7450.60000 0001 2364 4210Department of Computational Neuroscience, University of Göttingen, Göttingen, Germany ,grid.7450.60000 0001 2364 4210Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany ,grid.7450.60000 0001 2364 4210Department of Computational Synaptic Physiology, University of Göttingen, Göttingen, Germany
| | - Jannik Luboeinski
- grid.7450.60000 0001 2364 4210Department of Computational Neuroscience, University of Göttingen, Göttingen, Germany ,grid.7450.60000 0001 2364 4210Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany ,grid.7450.60000 0001 2364 4210Department of Computational Synaptic Physiology, University of Göttingen, Göttingen, Germany
| | - Christian Tetzlaff
- grid.7450.60000 0001 2364 4210Department of Computational Neuroscience, University of Göttingen, Göttingen, Germany ,grid.7450.60000 0001 2364 4210Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany ,grid.7450.60000 0001 2364 4210Department of Computational Synaptic Physiology, University of Göttingen, Göttingen, Germany
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26
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Chowdhury A, Luchetti A, Fernandes G, Filho DA, Kastellakis G, Tzilivaki A, Ramirez EM, Tran MY, Poirazi P, Silva AJ. A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking. Neuron 2022; 110:3374-3388.e8. [PMID: 36041433 PMCID: PMC10508214 DOI: 10.1016/j.neuron.2022.08.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/07/2022] [Accepted: 07/31/2022] [Indexed: 11/20/2022]
Abstract
Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.
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Affiliation(s)
- Ananya Chowdhury
- Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, and Brain Research Institute, UCLA, Los Angeles, CA 90095
| | - Alessandro Luchetti
- Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, and Brain Research Institute, UCLA, Los Angeles, CA 90095
| | - Giselle Fernandes
- Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, and Brain Research Institute, UCLA, Los Angeles, CA 90095
| | - Daniel Almeida Filho
- Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, and Brain Research Institute, UCLA, Los Angeles, CA 90095
| | - George Kastellakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas (FORTH), Vassilica Vouton, PO Box 1527, GR 711 10 Heraklion, Crete, Greece
| | - Alexandra Tzilivaki
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas (FORTH), Vassilica Vouton, PO Box 1527, GR 711 10 Heraklion, Crete, Greece
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health Charitéplatz 1, 10117 Berlin Germany
- Einstein Center for Neurosciences Berlin Charitéplatz 1, 10117 Berlin Germany
- Neurocure Cluster of Excellence Charitéplatz 1, 10117 Berlin, Germany
| | - Erica M Ramirez
- Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, and Brain Research Institute, UCLA, Los Angeles, CA 90095
| | - Mary Y Tran
- Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, and Brain Research Institute, UCLA, Los Angeles, CA 90095
| | - Panayiota Poirazi
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas (FORTH), Vassilica Vouton, PO Box 1527, GR 711 10 Heraklion, Crete, Greece
| | - Alcino J Silva
- Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, and Brain Research Institute, UCLA, Los Angeles, CA 90095
- Lead contact
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27
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Ogut E, Akcay G, Yildirim FB, Derin N, Aslan M. The influence of syringic acid treatment on total dopamine levels of the hippocampus and on cognitive behavioral skills. Int J Neurosci 2022; 132:901-909. [DOI: https:/doi.org/10.1080/00207454.2020.1849191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/01/2020] [Accepted: 10/21/2020] [Indexed: 07/22/2023]
Affiliation(s)
- Eren Ogut
- Department of Anatomy, School of Medicine, Bahçeşehir University, İstanbul, Turkey
| | - Guven Akcay
- Department of Biophysics, School of Medicine, Akdeniz University, Antalya, Turkey
| | | | - Narin Derin
- Department of Biophysics, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Mutay Aslan
- Department of Biochemistry, School of Medicine, Akdeniz University, Antalya, Turkey
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28
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Ogut E, Akcay G, Yildirim FB, Derin N, Aslan M. The influence of syringic acid treatment on total dopamine levels of the hippocampus and on cognitive behavioral skills. Int J Neurosci 2022; 132:901-909. [PMID: 33175581 DOI: 10.1080/00207454.2020.1849191] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/01/2020] [Accepted: 10/21/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Natural polyphenols have been investigated and are claimed to be mediators of the relationship between dopamine (DA) and memory. Therefore, we aimed to measure and evaluate the effect of syringic acid (SA) on DA expression by behavioral tests related to short-term and recognition memory in Wistar rats. METHODS Rats were randomly assigned to control (0.5 cc corn oil, n = 10), SA (25 mg/kg/day, o.g, n = 10), Deltamethrin (DTM) (1.28 mg/kg/day o.g, n = 10) and DTM (1.28 mg/kg/day o.g, n = 10) + SA (25 mg/kg/day) groups. The Y-maze and Novel Object Recognition (NOR) tests were performed to assess cognitive and behavioral functions in the rats. Dopamine levels in the hippocampus were measured by mass spectrometry. RESULTS Syringic acid significantly increased DA (5.45 ± 1.06 ng/ml, p = 0.0026, p < 0.05) compared with the other groups. SA increased the percent alternation (34.85 ± 0.72%, p < 0.05), time spent in the novel arm (2.88 ± 0.18 min, p < 0.05), and frequency of novel arm entries (44.91 ± 2.28%, p < 0.05), of the rats after the Y-maze test. The SA elevated the discrimination index (70.42 ± 3.59%, p < 0.001), and exploration time (30.44 ± 1.8 sec, p < 0.05) in the NOR test, and increased the short term and recognition memory in behavioral tests. CONCLUSION Our findings support the hypothesis that SA-induced DA levels of the hippocampus may facilitate recognition and short-term memory in Wistar rats through the activation of dopaminergic receptors or pathways during the learning process, and that this can be seen in the cognitive behavior of SA-treated rats.
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Affiliation(s)
- Eren Ogut
- Department of Anatomy, School of Medicine, Bahçeşehir University, İstanbul, Turkey
| | - Guven Akcay
- Department of Biophysics, School of Medicine, Akdeniz University, Antalya, Turkey
| | | | - Narin Derin
- Department of Biophysics, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Mutay Aslan
- Department of Biochemistry, School of Medicine, Akdeniz University, Antalya, Turkey
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29
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Osorio-Gómez D, Guzmán-Ramos K, Bermúdez-Rattoni F. Dopamine activity on the perceptual salience for recognition memory. Front Behav Neurosci 2022; 16:963739. [PMID: 36275849 PMCID: PMC9583835 DOI: 10.3389/fnbeh.2022.963739] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/29/2022] [Indexed: 11/17/2022] Open
Abstract
To survive, animals must recognize relevant stimuli and distinguish them from inconspicuous information. Usually, the properties of the stimuli, such as intensity, duration, frequency, and novelty, among others, determine the salience of the stimulus. However, previously learned experiences also facilitate the perception and processing of information to establish their salience. Here, we propose “perceptual salience” to define how memory mediates the integration of inconspicuous stimuli into a relevant memory trace without apparently altering the recognition of the physical attributes or valence, enabling the detection of stimuli changes in future encounters. The sense of familiarity is essential for successful recognition memory; in general, familiarization allows the transition of labeling a stimulus from the novel (salient) to the familiar (non-salient). The novel object recognition (NOR) and object location recognition (OLRM) memory paradigms represent experimental models of recognition memory that allow us to study the neurobiological mechanisms involved in episodic memory. The catecholaminergic system has been of vital interest due to its role in several aspects of recognition memory. This review will discuss the evidence that indicates changes in dopaminergic activity during exposure to novel objects or places, promoting the consolidation and persistence of memory. We will discuss the relationship between dopaminergic activity and perceptual salience of stimuli enabling learning and consolidation processes necessary for the novel-familiar transition. Finally, we will describe the effect of dopaminergic deregulation observed in some pathologies and its impact on recognition memory.
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Affiliation(s)
- Daniel Osorio-Gómez
- División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Mexico, Mexico
| | - Kioko Guzmán-Ramos
- Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad Lerma, Estado de México, Mexico
| | - Federico Bermúdez-Rattoni
- División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Mexico, Mexico
- *Correspondence: Federico Bermúdez-Rattoni
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Wang JW, Liu J, Wang ZL, Gao F, Yang J, Wang XC, Guo Y, Wang Y, Ma BR, Wang HS, Hu YW, Zhang YM, Hui YP, Zhang L. Activation and blockade of 5-HT 4 receptors in the dorsal hippocampus enhance working and hippocampus-dependent memories in the unilateral 6-hydroxydopamine lesioned rats. Behav Brain Res 2022; 431:113952. [PMID: 35688293 DOI: 10.1016/j.bbr.2022.113952] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 05/28/2022] [Accepted: 06/05/2022] [Indexed: 11/02/2022]
Abstract
Cognitive dysfunction is a common symptom in Parkinson's disease (PD). Serotonin4 (5-HT4) receptors are richly expressed in the dorsal hippocampus (dHIPP) and play an important role in cognitive activities. However, the mechanism underlying the role of dHIPP 5-HT4 receptors in PD-related cognitive dysfunction remains unclear. Here we found that unilateral 6-hydroxydopamine lesions of the medial forebrain bundle increased the protein expression of 5-HT4 receptors in the dHIPP, decreased hippocampal theta rhythm, and impaired working memory and hippocampus-dependent memory in the T-maze and hole-board test, respectively. Both activation and blockade of dHIPP 5-HT4 receptors (agonist BIMU8 and antagonist GR113808) improved working memory and hippocampus-dependent memory in the lesioned rats, but not in sham rats. Activation of dHIPP 5-HT4 receptors increased hippocampal theta rhythm in the lesioned rats. The neurochemical studies showed that injection of BIMU8, GR113808 or GR113808/BIMU8 in the dHIPP increased the levels of dopamine in the medial prefrontal cortex (mPFC), dHIPP and amygdala, and the level of 5-HT in the amygdala in the lesioned rats, but not in sham rats. Injection of GR113808 or GR113808/BIMU8 into the dHIPP also increased the levels of noradrenaline in the mPFC, dHIPP and amygdala only in the lesioned rats. These results suggest that activation or blockade of dHIPP 5-HT4 receptors may improve the cognitive impairments in parkinsonian rats, which may be due to the increase of hippocampal theta rhythm, up-regulated expressions of 5-HT4 receptors in the dHIPP and the changes in the levels of monoamines in the relative brain areas.
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Affiliation(s)
- Jia-Wei Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Jian Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Zhao-Long Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Feng Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Jie Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Xiao-Chen Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Yuan Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Yong Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Bo-Rui Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Hui-Sheng Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Yi-Wei Hu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Yu-Ming Zhang
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Yan-Ping Hui
- Department of Rehabilitation Medicine, The Second Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Li Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
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31
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Lattin CR, Kelly TR, Kelly MW, Johnson KM. Constitutive gene expression differs in three brain regions important for cognition in neophobic and non-neophobic house sparrows (Passer domesticus). PLoS One 2022; 17:e0267180. [PMID: 35536842 PMCID: PMC9089922 DOI: 10.1371/journal.pone.0267180] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 04/04/2022] [Indexed: 12/13/2022] Open
Abstract
Neophobia (aversion to new objects, food, and environments) is a personality trait that affects the ability of wildlife to adapt to new challenges and opportunities. Despite the ubiquity and importance of this trait, the molecular mechanisms underlying repeatable individual differences in neophobia in wild animals are poorly understood. We evaluated wild-caught house sparrows (Passer domesticus) for neophobia in the lab using novel object tests. We then selected a subset of neophobic and non-neophobic individuals (n = 3 of each, all females) and extracted RNA from four brain regions involved in learning, memory, threat perception, and executive function: striatum, caudal dorsomedial hippocampus, medial ventral arcopallium, and caudolateral nidopallium (NCL). Our analysis of differentially expressed genes (DEGs) used 11,889 gene regions annotated in the house sparrow reference genome for which we had an average of 25.7 million mapped reads/sample. PERMANOVA identified significant effects of brain region, phenotype (neophobic vs. non-neophobic), and a brain region by phenotype interaction. Comparing neophobic and non-neophobic birds revealed constitutive differences in DEGs in three of the four brain regions examined: hippocampus (12% of the transcriptome significantly differentially expressed), striatum (4%) and NCL (3%). DEGs included important known neuroendocrine mediators of learning, memory, executive function, and anxiety behavior, including serotonin receptor 5A, dopamine receptors 1, 2 and 5 (downregulated in neophobic birds), and estrogen receptor beta (upregulated in neophobic birds). These results suggest that some of the behavioral differences between phenotypes may be due to underlying gene expression differences in the brain. The large number of DEGs in neophobic and non-neophobic birds also implies that there are major differences in neural function between the two phenotypes that could affect a wide variety of behavioral traits beyond neophobia.
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Affiliation(s)
- Christine R. Lattin
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, United States of America
- * E-mail:
| | - Tosha R. Kelly
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, United States of America
| | - Morgan W. Kelly
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, United States of America
| | - Kevin M. Johnson
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, United States of America
- Center for Coastal Marine Sciences, California Polytechnic State University, San Luis Obispo, CA, United States of America
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32
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Guzmán-Ramos K, Osorio-Gómez D, Bermúdez-Rattoni F. Cognitive impairment in alzheimer’s and metabolic diseases: A catecholaminergic hypothesis. Neuroscience 2022; 497:308-323. [DOI: 10.1016/j.neuroscience.2022.05.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/19/2022] [Accepted: 05/24/2022] [Indexed: 12/16/2022]
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Caragea VM, Manahan-Vaughan D. Bidirectional Regulation of Hippocampal Synaptic Plasticity and Modulation of Cumulative Spatial Memory by Dopamine D2-Like Receptors. Front Behav Neurosci 2022; 15:803574. [PMID: 35095441 PMCID: PMC8789653 DOI: 10.3389/fnbeh.2021.803574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/20/2021] [Indexed: 01/11/2023] Open
Abstract
Dopamine is a key factor in the enablement of cognition and hippocampal information processing. Its action in the hippocampus is mediated by D1/D5 and D2-like (D2, D3, D4) receptors. While D1/D5-receptors are well recognized as strong modulators of hippocampal synaptic plasticity and information storage, much less is known about the role of D2-like receptors (D2R) in these processes. Here, we explored to what extent D2R contribute to synaptic plasticity and cumulative spatial memory derived from semantic and episodic-like information storage. In freely behaving adult rats, we also assessed to what extent short and long-term forms of synaptic plasticity are influenced by pharmacological activation or blockade of D2R. Antagonism of D2R by means of intracerebral treatment with remoxipride, completely prevented the expression of both short-term (<1 h) and long-term potentiation (>4 h), as well as the expression of short-term depression (STD, <1 h) in the hippocampal CA1 region. Scrutiny of involvement of D2R in spatial learning revealed that D2R-antagonism prevented retention of a semantic spatial memory task, and also significantly impaired retention of recent spatiotemporal aspects of an episodic-like memory task. Taken together, these findings indicate that D2R are required for bidirectional synaptic plasticity in the hippocampal CA1 region. Furthermore, they are critically involved in enabling cumulative and episodic-like forms of spatial learning.
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Affiliation(s)
- Violeta-Maria Caragea
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Denise Manahan-Vaughan
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
- *Correspondence: Denise Manahan-Vaughan
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34
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Gonzalez MC, Radiske A, Conde-Ocazionez S, Rossato JI, Bevilaqua LR, Cammarota M. Reactivation-dependent amnesia for object recognition memory is contingent on hippocampal theta-gamma coupling during recall. Learn Mem 2022; 29:1-6. [PMID: 34911798 PMCID: PMC8686592 DOI: 10.1101/lm.053482.121] [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: 08/06/2021] [Accepted: 10/25/2021] [Indexed: 01/03/2023]
Abstract
Hippocampal dopamine D1/D5 receptor-dependent destabilization is necessary for object recognition memory (ORM) updating through reconsolidation. Dopamine also regulates hippocampal theta and gamma oscillations, which are involved in novelty and memory processing. We found that, in adult male rats, ORM recall in the presence of a novel object, but not in the presence of a familiar one, triggers hippocampal theta-gamma coupling. Hippocampal theta-gamma coupling (hPAC) does not happen when ORM destabilization is prevented by blocking D1/D5 receptors, but artificial hPAC generation during recall in the presence of a familiar object enables the amnesic effect of reconsolidation inhibitors. Therefore, hPAC controls ORM destabilization, and its modulation could increase reconsolidation-based psychotherapy efficacy.
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Affiliation(s)
- Maria Carolina Gonzalez
- Memory Research Laboratory, Brain Institute, Federal University of Rio Grande do Norte, Natal 59076-550, Brazil,Edmond and Lily Safra International Institute of Neuroscience, Natal 59280-000, Brazil
| | - Andressa Radiske
- Memory Research Laboratory, Brain Institute, Federal University of Rio Grande do Norte, Natal 59076-550, Brazil
| | | | - Janine I. Rossato
- Memory Research Laboratory, Brain Institute, Federal University of Rio Grande do Norte, Natal 59076-550, Brazil,Department of Physiology, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil
| | - Lia R.M. Bevilaqua
- Memory Research Laboratory, Brain Institute, Federal University of Rio Grande do Norte, Natal 59076-550, Brazil
| | - Martín Cammarota
- Memory Research Laboratory, Brain Institute, Federal University of Rio Grande do Norte, Natal 59076-550, Brazil
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35
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ÖZKAN A, BÜLBÜL M, DERİN N, SİNEN O, AKÇAY G, PARLAK H, AYDIN ASLAN M, AĞAR A. Neuropeptide-S affects cognitive impairment and depression-like behavior on MPTP induced experimental mouse model of Parkinson’s disease. Turk J Med Sci 2021; 51:3126-3135. [PMID: 34289654 PMCID: PMC10734830 DOI: 10.3906/sag-2105-74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 12/13/2021] [Accepted: 07/21/2021] [Indexed: 11/03/2022] Open
Abstract
Background/aim The present study proposes to investigate the effect of neuropeptide–S (NPS) on cognitive functions and depression-like behavior of MPTP-induced experimental model of Parkinson’s disease (PD). Materials and methods Three-month-old C57BL/6 mice were randomly divided into three groups as; Control, Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and MPTP + NPS 0.1 nmol (received intraperitoneal injection of MPTP and intracerebroventricular injection of NPS, 0.1 nmol for seven days). The radial arm maze and pole tests were carried out, and the levels of tyrosine hydroxylase (TH) were determined using western blotting. A mass spectrometer was used to measure the levels of dopamine, glutamic acid, and glutamine. Results The T-turn and time to descend enhanced in MPTP group, while these parameters were decreased by NPS treatment. In the MPTP group, the number of working memory errors (WME) and reference memory errors (RME) increased, whereas NPS administration decreased both parameters. Sucrose preference decreased in the MPTP group while increasing in the NPS group. MPTP injection significantly reduced dopamine, glutamic acid, and glutamine levels. NPS treatment restored the MPTP-induced reduction in glutamine and glutamic acid levels. Conclusion NPS may be involved in the future treatment of cognitive impairments and depression-like behaviors in PD.
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Affiliation(s)
- Ayşe ÖZKAN
- Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
| | - Mehmet BÜLBÜL
- Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
| | - Narin DERİN
- Department of Biophysics, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
| | - Osman SİNEN
- Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
| | - Güven AKÇAY
- Department of Biophysics, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
| | - Hande PARLAK
- Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
| | - Mutay AYDIN ASLAN
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
| | - Aysel AĞAR
- Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya,
Turkey
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36
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Di Filippo M, Mancini A, Bellingacci L, Gaetani L, Mazzocchetti P, Zelante T, La Barbera L, De Luca A, Tantucci M, Tozzi A, Durante V, Sciaccaluga M, Megaro A, Chiasserini D, Salvadori N, Lisetti V, Portaccio E, Costa C, Sarchielli P, Amato MP, Parnetti L, Viscomi MT, Romani L, Calabresi P. Interleukin-17 affects synaptic plasticity and cognition in an experimental model of multiple sclerosis. Cell Rep 2021; 37:110094. [PMID: 34879272 DOI: 10.1016/j.celrep.2021.110094] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/06/2021] [Accepted: 11/12/2021] [Indexed: 12/20/2022] Open
Abstract
Cognitive impairment (CI) is a disabling concomitant of multiple sclerosis (MS) with a complex and controversial pathogenesis. The cytokine interleukin-17A (IL-17A) is involved in the immune pathogenesis of MS, but its possible effects on synaptic function and cognition are still largely unexplored. In this study, we show that the IL-17A receptor (IL-17RA) is highly expressed by hippocampal neurons in the CA1 area and that exposure to IL-17A dose-dependently disrupts hippocampal long-term potentiation (LTP) through the activation of its receptor and p38 mitogen-activated protein kinase (MAPK). During experimental autoimmune encephalomyelitis (EAE), IL-17A overexpression is paralleled by hippocampal LTP dysfunction. An in vivo behavioral analysis shows that visuo-spatial learning abilities are preserved when EAE is induced in mice lacking IL-17A. Overall, this study suggests a key role for the IL-17 axis in the neuro-immune cross-talk occurring in the hippocampal CA1 area and its potential involvement in synaptic dysfunction and MS-related CI.
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MESH Headings
- Animals
- Behavior, Animal
- CA1 Region, Hippocampal/metabolism
- CA1 Region, Hippocampal/pathology
- CA1 Region, Hippocampal/physiopathology
- Cognition
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/physiopathology
- Encephalomyelitis, Autoimmune, Experimental/psychology
- Interleukin-17/genetics
- Interleukin-17/metabolism
- Long-Term Potentiation
- Male
- Mice, Biozzi
- Mice, Inbred C57BL
- Mice, Knockout
- Neuronal Plasticity
- Receptors, Interleukin-17/genetics
- Receptors, Interleukin-17/metabolism
- Signal Transduction
- Spatial Learning
- Synapses/metabolism
- Synapses/pathology
- p38 Mitogen-Activated Protein Kinases
- Mice
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Affiliation(s)
- Massimiliano Di Filippo
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
| | - Andrea Mancini
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Laura Bellingacci
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Lorenzo Gaetani
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Petra Mazzocchetti
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Teresa Zelante
- Section of Pathology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Livia La Barbera
- Unit of Molecular Neurosciences, Department of Medicine, University Campus-Biomedico, Rome, Italy
| | - Antonella De Luca
- Section of Pathology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Michela Tantucci
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessandro Tozzi
- Section of Physiology and Biochemistry, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Valentina Durante
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Miriam Sciaccaluga
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alfredo Megaro
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Davide Chiasserini
- Section of Physiology and Biochemistry, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Nicola Salvadori
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Viviana Lisetti
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Emilio Portaccio
- Department of NEUROFARBA, University of Florence, Florence, Italy
| | - Cinzia Costa
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Paola Sarchielli
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Maria Pia Amato
- Department of NEUROFARBA, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
| | - Lucilla Parnetti
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Maria Teresa Viscomi
- Section of Histology and Embryology, Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luigina Romani
- Section of Pathology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Paolo Calabresi
- Neurology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy; Section of Neurology, Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
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Parmar S, Tadavarty R, Sastry BR. G-protein coupled receptors and synaptic plasticity in sleep deprivation. World J Psychiatry 2021; 11:954-980. [PMID: 34888167 PMCID: PMC8613756 DOI: 10.5498/wjp.v11.i11.954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/05/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Insufficient sleep has been correlated to many physiological and psychoneurological disorders. Over the years, our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes. In addition, during sleep, electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system (CNS). Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour. Memory consolidation and learning that take place during sleep cycles, can be affected by changes in synaptic plasticity during sleep disturbances. G-protein coupled receptors (GPCRs), with their versatile structural and functional attributes, can regulate synaptic plasticity in CNS and hence, may be potentially affected in sleep deprived conditions. In this review, we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.
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Affiliation(s)
- Shweta Parmar
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
| | - Ramakrishna Tadavarty
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
| | - Bhagavatula R Sastry
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
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Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function. Mol Psychiatry 2021; 26:6427-6450. [PMID: 33879865 PMCID: PMC8526653 DOI: 10.1038/s41380-021-01099-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 03/20/2021] [Accepted: 04/01/2021] [Indexed: 02/02/2023]
Abstract
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2α in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2α phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.
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39
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Di Cicco G, Marzano E, Iacovelli L, Celli R, van Luijtelaar G, Nicoletti F, Ngomba RT, Wall MJ. Group I metabotropic glutamate receptor-mediated long term depression is disrupted in the hippocampus of WAG/Rij rats modelling absence epilepsy. Neuropharmacology 2021; 196:108686. [PMID: 34197893 DOI: 10.1016/j.neuropharm.2021.108686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 11/19/2022]
Abstract
Absence epilepsy is frequently associated with cognitive dysfunction, although the underlying mechanisms are not well understood. Here we report that some forms of hippocampal synaptic plasticity are abnormal in symptomatic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Metabotropic Glu 1/5 receptor-mediated long term depression (LTD) at Schaffer collateral CA1 synapses is significantly reduced in symptomatic, 5-6 months old WAG/Rij rats compared to age-matched non epileptic control rats. There were no significant changes in mGlu1/5-dependent LTD in pre-symptomatic, 4-6 weeks old WAG/Rij rats compared to age matched controls. The changes in LTD found in symptomatic WAG/Rij forms are not indicative of general deficits in all forms of synaptic plasticity as long term potentiation (LTP) was unchanged. Immunoblot analysis of hippocampal tissue showed a significant reduction in mGlu5 receptor expression, a trend to an increase in pan Homer protein levels and a decrease in GluA1 receptor expression in the hippocampus of symptomatic WAG/Rij rats vs non-epileptic control rats. There were no changes in mGlu1α receptor or GluA2 protein levels. These findings suggest that abnormalities in hippocampal mGlu5 receptor-dependent synaptic plasticity are associated with the pathological phenotype of WAG/Rij rats. This lays the groundwork for the study of mGlu5 receptors as a candidate drug target for the treatment of cognitive dysfunction linked to absence epilepsy.
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Affiliation(s)
- Gabriele Di Cicco
- Departments of Physiology and Pharmacology, University Sapienza of Rome, Italy
| | - Emanuela Marzano
- Departments of Physiology and Pharmacology, University Sapienza of Rome, Italy
| | - Luisa Iacovelli
- Departments of Physiology and Pharmacology, University Sapienza of Rome, Italy
| | | | | | - Ferdinando Nicoletti
- Departments of Physiology and Pharmacology, University Sapienza of Rome, Italy; IRCCS Neuromed, Pozzilli, Italy
| | - Richard T Ngomba
- University of Lincoln, School of Pharmacy Lincoln, United Kingdom; and, Coventry, UK.
| | - Mark J Wall
- School of Life Sciences, University of Warwick, Coventry, UK.
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40
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Schmalz JT, Kumar G. A computational model of dopaminergic modulation of hippocampal Schaffer collateral-CA1 long-term plasticity. J Comput Neurosci 2021; 50:51-90. [PMID: 34431067 DOI: 10.1007/s10827-021-00793-6] [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: 02/19/2021] [Revised: 05/14/2021] [Accepted: 05/28/2021] [Indexed: 10/20/2022]
Abstract
Dopamine plays a critical role in modulating the long-term synaptic plasticity of the hippocampal Schaffer collateral-CA1 pyramidal neuron synapses (SC-CA1), a widely accepted cellular model of learning and memory. Limited results from hippocampal slice experiments over the last four decades have shown that the timing of the activation of dopamine D1/D5 receptors relative to a high/low-frequency stimulation (HFS/LFS) in SC-CA1 synapses regulates the modulation of HFS/LFS-induced long-term potentiation/depression (LTP/LTD) in these synapses. However, the existing literature lacks a complete picture of how various concentrations of D1/D5 agonists and the relative timing between the activation of D1/D5 receptors and LTP/LTD induction by HFS/LFS, affect the spatiotemporal modulation of SC-CA1 synaptic dynamics. In this paper, we have developed a computational model, a first of its kind, to make quantitative predictions of the temporal dose-dependent modulation of the HFS/LFS induced LTP/LTD in SC-CA1 synapses by various D1/D5 agonists. Our model combines the biochemical effects with the electrical effects at the electrophysiological level. We have estimated the model parameters from the published electrophysiological data, available from diverse hippocampal CA1 slice experiments, in a Bayesian framework. Our modeling results demonstrate the capability of our model in making quantitative predictions of the available experimental results under diverse HFS/LFS protocols. The predictions from our model show a strong nonlinear dependency of the modulated LTP/LTD by D1/D5 agonists on the relative timing between the activated D1/D5 receptors and the HFS/LFS protocol and the applied concentration of D1/D5 agonists.
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Bin Ibrahim MZ, Benoy A, Sajikumar S. Long-term plasticity in the hippocampus: maintaining within and 'tagging' between synapses. FEBS J 2021; 289:2176-2201. [PMID: 34109726 DOI: 10.1111/febs.16065] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/15/2021] [Accepted: 06/01/2021] [Indexed: 12/11/2022]
Abstract
Synapses between neurons are malleable biochemical structures, strengthening and diminishing over time dependent on the type of information they receive. This phenomenon known as synaptic plasticity underlies learning and memory, and its different forms, long-term potentiation (LTP) and long-term depression (LTD), perform varied cognitive roles in reinforcement, relearning and associating memories. Moreover, both LTP and LTD can exist in an early transient form (early-LTP/LTD) or a late persistent form (late-LTP/LTD), which are triggered by different induction protocols, and also differ in their dependence on protein synthesis and the involvement of key molecular players. Beyond homosynaptic modifications, synapses can also interact with one another. This is encapsulated in the synaptic tagging and capture hypothesis (STC), where synapses expressing early-LTP/LTD present a 'tag' that can capture the protein synthesis products generated during a temporally proximal late-LTP/LTD induction. This 'tagging' phenomenon forms the framework of synaptic interactions in various conditions and accounts for the cellular basis of the time-dependent associativity of short-lasting and long-lasting memories. All these synaptic modifications take place under controlled neuronal conditions, regulated by subcellular elements such as epigenetic regulation, proteasomal degradation and neuromodulatory signals. Here, we review current understanding of the different forms of synaptic plasticity and its regulatory mechanisms in the hippocampus, a brain region critical for memory formation. We also discuss expression of plasticity in hippocampal CA2 area, a long-overlooked narrow hippocampal subfield and the behavioural correlate of STC. Lastly, we put forth perspectives for an integrated view of memory representation in synapses.
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Affiliation(s)
- Mohammad Zaki Bin Ibrahim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore
| | - Amrita Benoy
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore
| | - Sreedharan Sajikumar
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore.,Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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42
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Naseem M, Vishnoi S, Kaushik M, Parvez S. Behavioural tagging: Effect of novelty exploration on plasticity related molecular signatures. Exp Brain Res 2021; 239:2359-2374. [PMID: 34097099 DOI: 10.1007/s00221-021-06099-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 03/28/2021] [Indexed: 11/25/2022]
Abstract
Learning and memory are one of those frontier areas of neurobiology which attract us to investigate the intricacy of this process. Here, we aimed to investigate the general mechanism of "Behavioural Tagging and Capture" in long term memory (LTM) formation and to find the key factors playing role in consolidation of LTM. In this study, we've shown that not only plasticity related proteins (PRPs) but neurotransmitters and immediate early genes (IEGs) also play an important role in memory formation process. It's very well evident that memory traces can last longer if close in time novelty is introduced around memory encoding. Here our results point out that this novelty exploration acts as a modulator in memory consolidation by providing PRPs such as brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), enhancing neurotransmitters (Dopamine), IEGs (cFos) and some enzymes such as acetylcholinesterase (AChE), monoamine oxidase (MAO), sodium-potassium ATPase (Na+K+-ATPase). Therefore, by using a Novel Object Recognition task (NOR) in combination with novel task exposure, we evaluated the role of molecular markers in memory consolidation employing a behavioural tagging model. The purpose of the current study was first to evaluate the effect of novelty exposure around a single trail of NOR task in a critical time window on memory consolidation in rats after 24 h and second to determine the expression of BDNF, CREB, c-fos, AChE, MAO, Na+K+-ATPase as potential markers in the medial prefrontal cortex (mPFC) during memory formation. In the present study, to identify and validate the role of these molecular signatures in memory consolidation, infusion of the protein synthesis inhibitor Anisomycin (Ani) was done around the training session that causes a deficit in the formation of LTM when tested 24 h after weak encoding. Altogether, here we are providing the first comprehensive set of evidences indicating that BDNF, CREB, dopamine, some enzymes and c-fos role in modulating LTM by employing behavioural tagging model.
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Affiliation(s)
- Mehar Naseem
- Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Shruti Vishnoi
- Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Medha Kaushik
- Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Suhel Parvez
- Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India.
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Oliveira da Cruz JF, Busquets-Garcia A, Zhao Z, Varilh M, Lavanco G, Bellocchio L, Robin L, Cannich A, Julio-Kalajzić F, Lesté-Lasserre T, Maître M, Drago F, Marsicano G, Soria-Gómez E. Specific Hippocampal Interneurons Shape Consolidation of Recognition Memory. Cell Rep 2021; 32:108046. [PMID: 32814049 PMCID: PMC7443618 DOI: 10.1016/j.celrep.2020.108046] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 06/15/2020] [Accepted: 07/27/2020] [Indexed: 12/27/2022] Open
Abstract
A complex array of inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically affects memory processes is not well understood. We find that a small subclass of type 1 cannabinoid receptor (CB1R)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D1 receptor (D1R) signaling to GABAergic transmission. Mice lacking CB1Rs in D1-positive cells (D1-CB1-KO) display impairment in long-term, but not short-term, novel object recognition memory (NOR). Re-expression of CB1Rs in hippocampal D1R-positive cells rescues this NOR deficit. Learning induces an enhancement of in vivo hippocampal long-term potentiation (LTP), which is absent in mutant mice. CB1R-mediated NOR and the associated LTP facilitation involve local control of GABAergic inhibition in a D1-dependent manner. This study reveals that hippocampal CB1R-/D1R-expressing interneurons control NOR memory, identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral outcomes.
CB1Rs are present in hippocampal D1R-positive interneurons CB1R/D1R-positive interneurons control the late phase of recognition memory CB1R/D1R-positive interneurons control learning-induced facilitation of LTP
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Affiliation(s)
- Jose F Oliveira da Cruz
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France; New York University, Center for Neural Science, New York, NY 10003, USA
| | - Arnau Busquets-Garcia
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France; Integrative Pharmacology and System Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
| | - Zhe Zhao
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France
| | - Marjorie Varilh
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France
| | - Gianluca Lavanco
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France; Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95124, Italy
| | - Luigi Bellocchio
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France
| | - Laurie Robin
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France
| | - Astrid Cannich
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France
| | - Francisca Julio-Kalajzić
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France
| | - Thierry Lesté-Lasserre
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France
| | - Marlène Maître
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France
| | - Filippo Drago
- Integrative Pharmacology and System Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
| | - Giovanni Marsicano
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France.
| | - Edgar Soria-Gómez
- INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France; Ikerbasque-Basque Foundation for Science, Bilbao 48013, Spain; Department of Neuroscience, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU) Leioa 48940, Spain; Achucarro Basque Center for Neuroscience, Leioa 48940, Spain.
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44
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Reset of hippocampal-prefrontal circuitry facilitates learning. Nature 2021; 591:615-619. [PMID: 33627872 PMCID: PMC7990705 DOI: 10.1038/s41586-021-03272-1] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 01/20/2021] [Indexed: 01/31/2023]
Abstract
The ability to rapidly adapt to novel situations is essential for survival, and this flexibility is impaired in many neuropsychiatric disorders1. Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Exposure to novelty recruits the hippocampus and medial prefrontal cortex (mPFC)2 and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity. Here we show that novelty resets the neural circuits that link the ventral hippocampus (vHPC) and the mPFC, facilitating the ability to overcome an established strategy. Exposing mice to novelty disrupted a previously encoded strategy by reorganizing vHPC activity to local theta (4-12 Hz) oscillations and weakening existing vHPC-mPFC connectivity. As mice subsequently adapted to a new task, vHPC neurons developed new task-associated activity, vHPC-mPFC connectivity was strengthened, and mPFC neurons updated to encode the new rules. Without novelty, however, mice adhered to their established strategy. Blocking dopamine D1 receptors (D1Rs) or inhibiting novelty-tagged cells that express D1Rs in the vHPC prevented these behavioural and physiological effects of novelty. Furthermore, activation of D1Rs mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC-mPFC circuitry, thereby enabling subsequent learning-associated circuit plasticity.
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Kramar CP, Castillo-Díaz F, Gigante ED, Medina JH, Barbano MF. The late consolidation of an aversive memory is promoted by VTA dopamine release in the dorsal hippocampus. Eur J Neurosci 2021; 53:841-851. [PMID: 33617053 DOI: 10.1111/ejn.15076] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/10/2020] [Accepted: 11/24/2020] [Indexed: 11/30/2022]
Abstract
The hippocampus has been implicated in the processing and storage of aversive memories but the precise mechanisms by which these memories persist in time remain elusive. We have demonstrated that dopaminergic neurotransmission in the dorsal hippocampus regulates the long-term storage of both appetitive and aversive memories at a critical time point known as "late consolidation" (12 hr after the learning experience). This modulation appears to have opposite effects depending on the valence of the stimuli, with hippocampal dopamine release peaking immediately and 13-17 hr after a rewarding experience. Here, we determined the release pattern of hippocampal dopamine following an aversive experience, in order to better understand this opposite modulation process. We observed significant increases in dopamine levels at several times (6-8, 11-12, and 15 hr) after subjecting rats to a conditioned place aversion (CPA) task with the aversive agent lithium chloride (LiCl). Early pharmacological blockade of hippocampal DA receptors impaired CPA memory consolidation. In addition and consistent with previous findings showing that late post-training infusions of dopaminergic agents into the hippocampus modulate the long-term storage of aversive memories, we found that the photostimulation of dopaminergic VTA fibers in the dorsal hippocampus 11-12 hr after CPA training was enough to transform a short-lasting long-term memory into a long-lasting one. The fact that the persistence of an aversive memory can still be affected several hours after the learning experience opens new avenues to develop behavioral and pharmacological strategies for the treatment of a variety of mental disorders.
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Affiliation(s)
- Cecilia P Kramar
- Instituto de Biología Celular y Neurociencias (CONICET-UBA), Facultad de Medicina, UBA, Buenos Aires, Argentina
| | - Fernando Castillo-Díaz
- Instituto de Biología Celular y Neurociencias (CONICET-UBA), Facultad de Medicina, UBA, Buenos Aires, Argentina
| | - Eduardo D Gigante
- National Institute on Drug Abuse (NIDA/NIH), Neuronal Networks Section, Baltimore, MD, USA
| | - Jorge H Medina
- Instituto de Biología Celular y Neurociencias (CONICET-UBA), Facultad de Medicina, UBA, Buenos Aires, Argentina
| | - M Flavia Barbano
- Instituto de Biología Celular y Neurociencias (CONICET-UBA), Facultad de Medicina, UBA, Buenos Aires, Argentina.,National Institute on Drug Abuse (NIDA/NIH), Neuronal Networks Section, Baltimore, MD, USA
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Zhuang Y, Xu P, Mao C, Wang L, Krumm B, Zhou XE, Huang S, Liu H, Cheng X, Huang XP, Shen DD, Xu T, Liu YF, Wang Y, Guo J, Jiang Y, Jiang H, Melcher K, Roth BL, Zhang Y, Zhang C, Xu HE. Structural insights into the human D1 and D2 dopamine receptor signaling complexes. Cell 2021; 184:931-942.e18. [PMID: 33571431 PMCID: PMC8215686 DOI: 10.1016/j.cell.2021.01.027] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/02/2020] [Accepted: 01/15/2021] [Indexed: 12/26/2022]
Abstract
The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-Gs and D2R-Gi signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.
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MESH Headings
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology
- Amino Acid Sequence
- Conserved Sequence
- Cryoelectron Microscopy
- Cyclic AMP/metabolism
- GTP-Binding Proteins/metabolism
- HEK293 Cells
- Humans
- Ligands
- Models, Molecular
- Mutant Proteins/chemistry
- Mutant Proteins/metabolism
- Receptors, Adrenergic, beta-2/metabolism
- Receptors, Dopamine D1/chemistry
- Receptors, Dopamine D1/metabolism
- Receptors, Dopamine D1/ultrastructure
- Receptors, Dopamine D2/chemistry
- Receptors, Dopamine D2/metabolism
- Receptors, Dopamine D2/ultrastructure
- Signal Transduction
- Structural Homology, Protein
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Affiliation(s)
- Youwen Zhuang
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Peiyu Xu
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Chunyou Mao
- Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Laboratory for Systems and Precison Medicine, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Lei Wang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Brian Krumm
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA
| | - X Edward Zhou
- Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Sijie Huang
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Heng Liu
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Xi Cheng
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xi-Ping Huang
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA
| | - Dan-Dan Shen
- Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Laboratory for Systems and Precison Medicine, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Tinghai Xu
- Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Yong-Feng Liu
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA
| | - Yue Wang
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jia Guo
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yi Jiang
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hualiang Jiang
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Karsten Melcher
- Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Bryan L Roth
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
| | - Yan Zhang
- Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Laboratory for Systems and Precison Medicine, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou 310058, China.
| | - Cheng Zhang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - H Eric Xu
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
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Walther T, Diekmann N, Vijayabaskaran S, Donoso JR, Manahan-Vaughan D, Wiskott L, Cheng S. Context-dependent extinction learning emerging from raw sensory inputs: a reinforcement learning approach. Sci Rep 2021; 11:2713. [PMID: 33526840 PMCID: PMC7851139 DOI: 10.1038/s41598-021-81157-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 12/08/2020] [Indexed: 11/09/2022] Open
Abstract
The context-dependence of extinction learning has been well studied and requires the hippocampus. However, the underlying neural mechanisms are still poorly understood. Using memory-driven reinforcement learning and deep neural networks, we developed a model that learns to navigate autonomously in biologically realistic virtual reality environments based on raw camera inputs alone. Neither is context represented explicitly in our model, nor is context change signaled. We find that memory-intact agents learn distinct context representations, and develop ABA renewal, whereas memory-impaired agents do not. These findings reproduce the behavior of control and hippocampal animals, respectively. We therefore propose that the role of the hippocampus in the context-dependence of extinction learning might stem from its function in episodic-like memory and not in context-representation per se. We conclude that context-dependence can emerge from raw visual inputs.
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Affiliation(s)
- Thomas Walther
- Institute for Neural Computation, Ruhr University Bochum, Bochum, Germany
| | - Nicolas Diekmann
- Institute for Neural Computation, Ruhr University Bochum, Bochum, Germany
| | | | - José R Donoso
- Institute for Neural Computation, Ruhr University Bochum, Bochum, Germany
| | | | - Laurenz Wiskott
- Institute for Neural Computation, Ruhr University Bochum, Bochum, Germany
| | - Sen Cheng
- Institute for Neural Computation, Ruhr University Bochum, Bochum, Germany.
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48
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Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system. Pharmacol Ther 2021; 223:107808. [PMID: 33476640 DOI: 10.1016/j.pharmthera.2021.107808] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 01/05/2021] [Indexed: 12/15/2022]
Abstract
G protein-gated inwardly rectifying potassium channels (Kir3/GirK) are important for maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Coupled to numerous G protein-coupled receptors (GPCRs), they mediate the effects of many neurotransmitters, neuromodulators and hormones contributing to the general homeostasis and particular synaptic plasticity processes, learning, memory and pain signaling. A growing number of behavioral and genetic studies suggest a critical role for the appropriate functioning of the central nervous system, as well as their involvement in many neurologic and psychiatric conditions, such as neurodegenerative diseases, mood disorders, attention deficit hyperactivity disorder, schizophrenia, epilepsy, alcoholism and drug addiction. Hence, GirK channels emerge as a very promising tool to be targeted in the current scenario where these conditions already are or will become a global public health problem. This review examines recent findings on the physiology, function, dysfunction, and pharmacology of GirK channels in the central nervous system and highlights the relevance of GirK channels as a worthful potential target to improve therapies for related diseases.
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49
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Yoo DY, Jung HY, Kim W, Hahn KR, Kwon HJ, Nam SM, Chung JY, Yoon YS, Kim DW, Hwang IK. Entacapone promotes hippocampal neurogenesis in mice. Neural Regen Res 2021; 16:1005-1110. [PMID: 33269743 PMCID: PMC8224137 DOI: 10.4103/1673-5374.300447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Entacapone, a catechol-O-methyltransferase inhibitor, can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease. However, few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice. To investigate the effects of entacapone, a modulator of dopamine, on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus, 60 mice (7 weeks old) were randomly divided into a vehicle-treated group and the groups treated with 10, 50, or 200 mg/kg entacapone. The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition. Immunohistochemical staining results revealed that after entacapone treatment, the numbers of Ki67-positive proliferating cells, doublecortin-positive immature neurons, and phosphorylated cAMP response element-binding protein (pCREB)-positive cells were significantly increased. Western blot analysis results revealed that treatment with tyrosine kinase receptor B (TrkB) receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor (BDNF). Entacapone treatment antagonized the effects of TrkB receptor antagonist. These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway. This study was approved by the Institutional Animal Care and Use Committee of Seoul National University (approval No. SNU-130730-1) on February 24, 2014.
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Affiliation(s)
- Dae Young Yoo
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea; Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Hyo Young Jung
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea
| | - Woosuk Kim
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul; Department of Biomedical Sciences, and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, South Korea
| | - Kyu Ri Hahn
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea
| | - Hyun Jung Kwon
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, South Korea
| | - Sung Min Nam
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, Seoul, South Korea
| | - Jin Young Chung
- Department of Veterinary Internal Medicine and Geriatrics, College of Veterinary Medicine, Kangwon National University, Chuncheon, South Korea
| | - Yeo Sung Yoon
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea
| | - Dae Won Kim
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, South Korea
| | - In Koo Hwang
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea
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Vaseghi S, Nasehi M, Zarrindast MR. How do stupendous cannabinoids modulate memory processing via affecting neurotransmitter systems? Neurosci Biobehav Rev 2020; 120:173-221. [PMID: 33171142 DOI: 10.1016/j.neubiorev.2020.10.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/17/2020] [Accepted: 10/26/2020] [Indexed: 12/27/2022]
Abstract
In the present study, we wanted to review the role of cannabinoids in learning and memory in animal models, with respect to their interaction effects with six principal neurotransmitters involved in learning and memory including dopamine, glutamate, GABA (γ-aminobutyric acid), serotonin, acetylcholine, and noradrenaline. Cannabinoids induce a wide-range of unpredictable effects on cognitive functions, while their mechanisms are not fully understood. Cannabinoids in different brain regions and in interaction with different neurotransmitters, show diverse responses. Previous findings have shown that cannabinoids agonists and antagonists induce various unpredictable effects such as similar effect, paradoxical effect, or dualistic effect. It should not be forgotten that brain neurotransmitter systems can also play unpredictable roles in mediating cognitive functions. Thus, we aimed to review and discuss the effect of cannabinoids in interaction with neurotransmitters on learning and memory. In addition, we mentioned to the type of interactions between cannabinoids and neurotransmitter systems. We suggested that investigating the type of interactions is a critical neuropharmacological issue that should be considered in future studies.
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Affiliation(s)
- Salar Vaseghi
- Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
| | - Mohammad Nasehi
- Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mohammad-Reza Zarrindast
- Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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