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1
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Fuchsberger T, Stockwell I, Woods M, Brzosko Z, Greger IH, Paulsen O. Dopamine increases protein synthesis in hippocampal neurons enabling dopamine-dependent LTP. eLife 2025; 13:RP100822. [PMID: 40063079 PMCID: PMC11893101 DOI: 10.7554/elife.100822] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025] Open
Abstract
The reward and novelty-related neuromodulator dopamine plays an important role in hippocampal long-term memory, which is thought to involve protein-synthesis-dependent synaptic plasticity. However, the direct effects of dopamine on protein synthesis, and the functional implications of newly synthesised proteins for synaptic plasticity, have not yet been investigated. We have previously reported that timing-dependent synaptic depression (t-LTD) can be converted into potentiation by dopamine application during synaptic stimulation (Brzosko et al., 2015) or postsynaptic burst activation (Fuchsberger et al., 2022). Here, we show that dopamine increases protein synthesis in mouse hippocampal CA1 neurons, enabling dopamine-dependent long-term potentiation (DA-LTP), which is mediated via the Ca2+-sensitive adenylate cyclase (AC) subtypes 1/8, cAMP, and cAMP-dependent protein kinase (PKA). We found that neuronal activity is required for the dopamine-induced increase in protein synthesis. Furthermore, dopamine induced a protein-synthesis-dependent increase in the AMPA receptor subunit GluA1, but not GluA2. We found that DA-LTP is absent in GluA1 knock-out mice and that it requires calcium-permeable AMPA receptors. Taken together, our results suggest that dopamine together with neuronal activity controls synthesis of plasticity-related proteins, including GluA1, which enable DA-LTP via a signalling pathway distinct from that of conventional LTP.
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Affiliation(s)
- Tanja Fuchsberger
- Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of CambridgeCambridgeUnited Kingdom
| | - Imogen Stockwell
- Neurobiology Division, MRC Laboratory of Molecular BiologyCambridgeUnited Kingdom
| | - Matty Woods
- Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of CambridgeCambridgeUnited Kingdom
| | - Zuzanna Brzosko
- Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of CambridgeCambridgeUnited Kingdom
| | - Ingo H Greger
- Neurobiology Division, MRC Laboratory of Molecular BiologyCambridgeUnited Kingdom
| | - Ole Paulsen
- Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of CambridgeCambridgeUnited Kingdom
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2
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Babushkina N, Manahan‐Vaughan D. The Modulation by the Locus Coeruleus of Recent and Remote Memory Retrieval is Activity-Dependent. Hippocampus 2025; 35:e70004. [PMID: 39980081 PMCID: PMC11842585 DOI: 10.1002/hipo.70004] [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: 01/19/2024] [Revised: 12/05/2024] [Accepted: 02/05/2025] [Indexed: 02/22/2025]
Abstract
The hippocampus plays a crucial role in acquiring, storing, and retrieving associative experience. Whereas neuromodulatory control of the hippocampus by the locus coeruleus (LC) enhances memory acquisition and consolidation, less is known about its influence on memory retrieval. The LC fires at tonic (0.5-8 Hz) and phasic frequencies (10-25 Hz), relative to arousal and affective states. Here, we explored to what extent LC stimulation at different frequencies (2-100 Hz) and respective stimulation patterns, before retrieval of recently acquired or remote spatial memory, alter working memory (WM) or reference memory (RM) in male rats. Here, animals learned a spatial memory task in an eight-arm radial maze over a period of 15 days. LC stimulation before recent memory testing did not affect WM. However, LC stimulation at 20 or 100 Hz, but not 5-10 Hz, impaired retrieval of recently consolidated RM. These frequency-dependent impairments were abolished by intracerebral β-adrenergic receptor (β-AR), but not D1/D5 receptor, antagonism. When memory retrieval was assessed 4 weeks after initial consolidation (Day 34), RM was significantly impaired compared to the final day of recent memory testing (on Day 6). RM was not altered by LC stimulation before remote memory retrieval. However, LC stimulation at 2-100 Hz improved WM. Taken together, these data suggest that frequency-dependent NA release from the LC disrupts retrieval of recently acquired RM via activation of β-AR. Strikingly, increasing LC activity in general improves WM of a remotely acquired spatial learning task, assessed 4 weeks after the recent memory testing, suggesting that the increased effort of sustaining WM of a task learned in the past requires higher LC engagement.
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Affiliation(s)
- Natalia Babushkina
- Medical Faculty, Department of NeurophysiologyRuhr University BochumBochumGermany
- International Graduate School of NeuroscienceRuhr University BochumBochumGermany
| | - Denise Manahan‐Vaughan
- Medical Faculty, Department of NeurophysiologyRuhr University BochumBochumGermany
- International Graduate School of NeuroscienceRuhr University BochumBochumGermany
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3
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Yi Y, Kreißl MC, Speck O, Düzel E, Hämmerer D. Decoding Salience: A Functional Magnetic Resonance Imaging Investigation of Reward and Contextual Unexpectedness in Memory Encoding and Retrieval. Hum Brain Mapp 2025; 46:e70124. [PMID: 39764707 PMCID: PMC11705450 DOI: 10.1002/hbm.70124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 12/13/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
The present study investigated the neuromodulatory substrates of salience processing and its impact on memory encoding and behaviour, with a specific focus on two distinct types of salience: reward and contextual unexpectedness. 46 Participants performed a novel task paradigm modulating these two aspects independently and allowing for investigating their distinct and interactive effects on memory encoding while undergoing high-resolution fMRI. By using advanced image processing techniques tailored to examine midbrain and brainstem nuclei with high precision, our study additionally aimed to elucidate differential activation patterns in subcortical nuclei in response to reward-associated and contextually unexpected stimuli, including distinct pathways involving in particular dopaminergic modulation. We observed a differential involvement of the ventral striatum, substantia nigra (SN) and caudate nucleus, as well as a functional specialisation within the subregions of the cingulate cortex for the two salience types. Moreover, distinct subregions within the SN in processing salience could be identified. Dorsal areas preferentially processed salience related to stimulus processing (of both reward and contextual unexpectedness), and ventral areas were involved in salience-related memory encoding (for contextual unexpectedness only). These functional specialisations within SN are in line with different projection patterns of dorsal and ventral SN to brain areas supporting attention and memory, respectively. By disentangling stimulus processing and memory encoding related to two salience types, we hope to further consolidate our understanding of neuromodulatory structures' differential as well as interactive roles in modulating behavioural responses to salient events.
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Affiliation(s)
- Yeo‐Jin Yi
- Institute of Cognitive Neurology and Dementia ResearchOtto‐von‐Guericke UniversityMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
| | - Michael C. Kreißl
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
- Division of Nuclear Medicine, Department of Nuclear MedicineOtto‐von‐Guericke UniversityMagdeburgGermany
| | - Oliver Speck
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
- Biomedical Magnetic Resonance, Faculty of Natural SciencesOtto‐von‐Guericke UniversityMagdeburgGermany
- Center for Behavioral Brain SciencesMagdeburgGermany
- Leibniz Institute for NeurobiologyMagdeburgGermany
| | - Emrah Düzel
- Institute of Cognitive Neurology and Dementia ResearchOtto‐von‐Guericke UniversityMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
- Center for Behavioral Brain SciencesMagdeburgGermany
- Institute of Cognitive NeuroscienceUniversity College LondonUK
| | - Dorothea Hämmerer
- Institute of Cognitive Neurology and Dementia ResearchOtto‐von‐Guericke UniversityMagdeburgGermany
- Center for Behavioral Brain SciencesMagdeburgGermany
- Institute of Cognitive NeuroscienceUniversity College LondonUK
- Department of PsychologyUniversity of InnsbruckInnsbruckAustria
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4
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Phan JMP, Yi J, Foote JHA, Ayabe ARK, Guan K, Garland T, Parfitt KD. Hippocampal long-term potentiation is modulated by exercise-induced alterations in dopaminergic synaptic transmission in mice selectively bred for high voluntary wheel running. Restor Neurol Neurosci 2024:9226028241290400. [PMID: 39973602 DOI: 10.1177/09226028241290400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
BackgroundHigh-Runner (HR) mice, selectively bred for increased voluntary wheel running behavior, exhibit heightened motivation to run. Exercise has been shown to influence hippocampal long-term potentiation (LTP) and memory, and is neuroprotective in several neurodegenerative diseases.ObjectiveThis study aimed to determine the impact of intense running in HR mice with wheel access on hippocampal LTP, compared to HR mice without wheels and non-selected control (C) mice with/without wheels. Additionally, we investigated the involvement of D1/D5 receptors and the dopamine transporter (DAT) in LTP modulation and examined levels of these proteins in HR and C mice.MethodsAdult female HR and C mice were individually housed with/without running wheels for at least two weeks. Hippocampal LTP of extracellular field excitatory postsynaptic potentials (fEPSPs) was measured in area CA1, and SKF-38393 (D1/D5 receptor agonist) and GBR 12909 (DAT inhibitor) were used to probe the role of D1/D5 receptors and DAT in LTP differences. Western blot analyses assessed D1/D5 receptor and DAT expression in the hippocampus, prefrontal cortex, and cerebellum.ResultsHR mice with wheel access showed significantly increased hippocampal LTP compared to those without wheels and to C mice with/without wheels. Treatment with SKF-38393 or GBR 12909 prevented the heightened LTP in HR mice with wheels, aligning it with levels in C mice. Hippocampal D1/D5 receptor levels were lower, and DAT levels were higher in HR mice compared to C mice. No significant changes were observed in other brain regions.ConclusionsThe increased hippocampal LTP seen in HR mice with wheel access may be related to alterations in dopaminergic synaptic transmission that underlie the neurophysiological basis of hyperactivity, motor disorders, and/or motivation.
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Affiliation(s)
| | - Jiwon Yi
- Department of Neuroscience, Pomona College, Claremont, CA, USA
| | | | | | - Kevin Guan
- Department of Neuroscience, Pomona College, Claremont, CA, USA
| | - Theodore Garland
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA, USA
| | - Karen Diane Parfitt
- Program in Molecular Biology, Pomona College, Claremont, CA, USA
- Department of Neuroscience, Pomona College, Claremont, CA, USA
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5
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Jiang J, Foyard E, van Rossum MCW. Reinforcement learning when your life depends on it: A neuro-economic theory of learning. PLoS Comput Biol 2024; 20:e1012554. [PMID: 39466882 PMCID: PMC11542834 DOI: 10.1371/journal.pcbi.1012554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 11/07/2024] [Accepted: 10/14/2024] [Indexed: 10/30/2024] Open
Abstract
Synaptic plasticity enables animals to adapt to their environment, but memory formation can require a substantial amount of metabolic energy, potentially impairing survival. Hence, a neuro-economic dilemma arises whether learning is a profitable investment or not, and the brain must therefore judiciously regulate learning. Indeed, in experiments it was observed that during starvation, Drosophila suppress formation of energy-intensive aversive memories. Here we include energy considerations in a reinforcement learning framework. Simulated flies learned to avoid noxious stimuli through synaptic plasticity in either the energy expensive long-term memory (LTM) pathway, or the decaying anesthesia-resistant memory (ARM) pathway. The objective of the flies is to maximize their lifespan, which is calculated with a hazard function. We find that strategies that switch between the LTM and ARM pathways, based on energy reserve and reward prediction error, prolong lifespan. Our study highlights the significance of energy-regulation of memory pathways and dopaminergic control for adaptive learning and survival. It might also benefit engineering applications of reinforcement learning under resources constraints.
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Affiliation(s)
- Jiamu Jiang
- School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Emilie Foyard
- School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Mark C. W. van Rossum
- School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom
- School of Psychology, University of Nottingham, Nottingham, United Kingdom
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6
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McKenzie S, Sommer AL, Donaldson TN, Pimentel I, Kakani M, Choi IJ, Newman EL, English DF. Event boundaries drive norepinephrine release and distinctive neural representations of space in the rodent hippocampus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.30.605900. [PMID: 39131365 PMCID: PMC11312532 DOI: 10.1101/2024.07.30.605900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Episodic memories are temporally segmented around event boundaries that tend to coincide with moments of environmental change. During these times, the state of the brain should change rapidly, or reset, to ensure that the information encountered before and after an event boundary is encoded in different neuronal populations. Norepinephrine (NE) is thought to facilitate this network reorganization. However, it is unknown whether event boundaries drive NE release in the hippocampus and, if so, how NE release relates to changes in hippocampal firing patterns. The advent of the new GRABNE sensor now allows for the measurement of NE binding with sub-second resolution. Using this tool in mice, we tested whether NE is released into the dorsal hippocampus during event boundaries defined by unexpected transitions between spatial contexts and presentations of novel objections. We found that NE binding dynamics were well explained by the time elapsed after each of these environmental changes, and were not related to conditioned behaviors, exploratory bouts of movement, or reward. Familiarity with a spatial context accelerated the rate in which phasic NE binding decayed to baseline. Knowing when NE is elevated, we tested how hippocampal coding of space differs during these moments. Immediately after context transitions we observed relatively unique patterns of neural spiking which settled into a modal state at a similar rate in which NE returned to baseline. These results are consistent with a model wherein NE release drives hippocampal representations away from a steady-state attractor. We hypothesize that the distinctive neural codes observed after each event boundary may facilitate long-term memory and contribute to the neural basis for the primacy effect.
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Affiliation(s)
- Sam McKenzie
- Department of Neurosciences, University of New Mexico Health Science Center, Albuquerque, NM 87106
| | - Alexandra L. Sommer
- Department of Neurosciences, University of New Mexico Health Science Center, Albuquerque, NM 87106
| | - Tia N. Donaldson
- Department of Neurosciences, University of New Mexico Health Science Center, Albuquerque, NM 87106
| | - Infania Pimentel
- Department of Neurosciences, University of New Mexico Health Science Center, Albuquerque, NM 87106
- Department of Mechanical Engineering, Tufts School of Engineering, Medford MA 02155
| | - Meenakshi Kakani
- Department of Neurosciences, University of New Mexico Health Science Center, Albuquerque, NM 87106
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284
| | - Irene Jungyeon Choi
- Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405
| | - Ehren L. Newman
- Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405
- Program in Neuroscience, Indiana University, Bloomington, IN, 47405
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7
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Velazquez-Delgado C, Perez-Becerra J, Calderon V, Hernandez-Ortiz E, Bermudez-Rattoni F, Carrillo-Reid L. Paradoxical Boosting of Weak and Strong Spatial Memories by Hippocampal Dopamine Uncaging. eNeuro 2024; 11:ENEURO.0469-23.2024. [PMID: 38755011 PMCID: PMC11138129 DOI: 10.1523/eneuro.0469-23.2024] [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: 11/03/2023] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
The ability to remember changes in the surroundings is fundamental for daily life. It has been proposed that novel events producing dopamine release in the hippocampal CA1 region could modulate spatial memory formation. However, the role of hippocampal dopamine increase on weak or strong spatial memories remains unclear. We show that male mice exploring two objects located in a familiar environment for 5 min created a short-term memory (weak) that cannot be retrieved 1 d later, whereas 10 min exploration created a long-term memory (strong) that can be retrieved 1 d later. Remarkably, hippocampal dopamine elevation during the encoding of weak object location memories (OLMs) allowed their retrieval 1 d later but dopamine elevation during the encoding of strong OLMs promoted the preference for a familiar object location over a novel object location after 24 h. Moreover, dopamine uncaging after the encoding of OLMs did not have effect on weak memories whereas on strong memories diminished the exploration of the novel object location. Additionally, hippocampal dopamine elevation during the retrieval of OLMs did not allow the recovery of weak memories and did not affect the retrieval of strong memory traces. Finally, dopamine elevation increased hippocampal theta oscillations, indicating that dopamine promotes the recurrent activation of specific groups of neurons. Our experiments demonstrate that hippocampal dopaminergic modulation during the encoding of OLMs depends on memory strength indicating that hyperdopaminergic levels that enhance weak experiences could compromise the normal storage of strong memories.
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Affiliation(s)
| | - Job Perez-Becerra
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla 76230, México
| | - Vladimir Calderon
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla 76230, México
| | - Eduardo Hernandez-Ortiz
- División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México 04510, México
| | - Federico Bermudez-Rattoni
- División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México 04510, México
| | - Luis Carrillo-Reid
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla 76230, México
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8
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Nagel J, Morgan DP, Gürsoy NÇ, Sander S, Kern S, Feld GB. Memory for rewards guides retrieval. COMMUNICATIONS PSYCHOLOGY 2024; 2:31. [PMID: 39242930 PMCID: PMC11332070 DOI: 10.1038/s44271-024-00074-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 03/11/2024] [Indexed: 09/09/2024]
Abstract
Rewards paid out for successful retrieval motivate the formation of long-term memory. However, it has been argued that the Motivated Learning Task does not measure reward effects on memory strength but decision-making during retrieval. We report three large-scale online experiments in healthy participants (N = 200, N = 205, N = 187) that inform this debate. In experiment 1, we found that explicit stimulus-reward associations formed during encoding influence response strategies at retrieval. In experiment 2, reward affected memory strength and decision-making strategies. In experiment 3, reward affected decision-making strategies only. These data support a theoretical framework that assumes that promised rewards not only increase memory strength, but additionally lead to the formation of stimulus-reward associations that influence decisions at retrieval.
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Affiliation(s)
- Juliane Nagel
- Clinical Psychology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- Addiction Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - David Philip Morgan
- Clinical Psychology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Addiction Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Necati Çağatay Gürsoy
- Clinical Psychology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Addiction Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Samuel Sander
- Clinical Psychology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Addiction Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Simon Kern
- Clinical Psychology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Addiction Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Gordon Benedikt Feld
- Clinical Psychology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- Addiction Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- Department of Psychology, University of Heidelberg, Heidelberg, Germany.
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9
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Wilmot JH, Diniz CRAF, Crestani AP, Puhger KR, Roshgadol J, Tian L, Wiltgen BJ. Phasic locus coeruleus activity enhances trace fear conditioning by increasing dopamine release in the hippocampus. eLife 2024; 12:RP91465. [PMID: 38592773 PMCID: PMC11003744 DOI: 10.7554/elife.91465] [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] [Indexed: 04/10/2024] Open
Abstract
Locus coeruleus (LC) projections to the hippocampus play a critical role in learning and memory. However, the precise timing of LC-hippocampus communication during learning and which LC-derived neurotransmitters are important for memory formation in the hippocampus are currently unknown. Although the LC is typically thought to modulate neural activity via the release of norepinephrine, several recent studies have suggested that it may also release dopamine into the hippocampus and other cortical regions. In some cases, it appears that dopamine release from LC into the hippocampus may be more important for memory than norepinephrine. Here, we extend these data by characterizing the phasic responses of the LC and its projections to the dorsal hippocampus during trace fear conditioning in mice. We find that the LC and its projections to the hippocampus respond to task-relevant stimuli and that amplifying these responses with optogenetic stimulation can enhance long-term memory formation. We also demonstrate that LC activity increases both norepinephrine and dopamine content in the dorsal hippocampus and that the timing of hippocampal dopamine release during trace fear conditioning is similar to the timing of LC activity. Finally, we show that hippocampal dopamine is important for trace fear memory formation, while norepinephrine is not.
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Affiliation(s)
- Jacob H Wilmot
- Department of Psychology, University of California, DavisDavisUnited States
- Center for Neuroscience, University of California, DavisDavisUnited States
| | - Cassiano RAF Diniz
- Center for Neuroscience, University of California, DavisDavisUnited States
| | - Ana P Crestani
- Center for Neuroscience, University of California, DavisDavisUnited States
| | - Kyle R Puhger
- Department of Psychology, University of California, DavisDavisUnited States
- Center for Neuroscience, University of California, DavisDavisUnited States
| | - Jacob Roshgadol
- Center for Neuroscience, University of California, DavisDavisUnited States
- Department of Biomedical Engineering, University of California, DavisDavisUnited States
| | - Lin Tian
- Department of Biochemistry and Molecular Medicine, University of California, DavisDavisUnited States
| | - Brian Joseph Wiltgen
- Department of Psychology, University of California, DavisDavisUnited States
- Center for Neuroscience, University of California, DavisDavisUnited States
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10
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Puhger K, Crestani AP, Diniz CRF, Wiltgen BJ. The hippocampus contributes to retroactive stimulus associations during trace fear conditioning. iScience 2024; 27:109035. [PMID: 38375237 PMCID: PMC10875141 DOI: 10.1016/j.isci.2024.109035] [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: 08/30/2023] [Revised: 12/04/2023] [Accepted: 01/23/2024] [Indexed: 02/21/2024] Open
Abstract
Binding events that occur at different times are essential for memory formation. In trace fear conditioning, animals associate a tone and footshock despite no temporal overlap. The hippocampus is thought to mediate this learning by maintaining a memory of the tone until shock occurrence, however, evidence for sustained hippocampal tone representations is lacking. Here, we demonstrate a retrospective role for the hippocampus in trace fear conditioning. Bulk calcium imaging revealed sustained increases in CA1 activity after footshock that were not observed after tone termination. Optogenetic silencing of CA1 immediately after footshock impaired subsequent memory. Additionally, footshock increased the number of sharp-wave ripples compared to baseline during conditioning. Therefore, post-shock hippocampal activity likely supports learning by reactivating and linking latent tone and shock representations. These findings highlight an underappreciated function of post-trial hippocampal activity in enabling retroactive temporal associations during new learning, as opposed to persistent maintenance of stimulus representations.
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Affiliation(s)
- Kyle Puhger
- Department of Psychology, University of California, Davis, 135 Young Hall, 1 Shields Avenue, Davis, CA 95616, USA
- Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, CA 95618, USA
| | - Ana P. Crestani
- Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, CA 95618, USA
| | - Cassiano R.A. F. Diniz
- Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, CA 95618, USA
| | - Brian J. Wiltgen
- Department of Psychology, University of California, Davis, 135 Young Hall, 1 Shields Avenue, Davis, CA 95616, USA
- Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, CA 95618, USA
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11
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Grella SL, Donaldson TN. Contextual memory engrams, and the neuromodulatory influence of the locus coeruleus. Front Mol Neurosci 2024; 17:1342622. [PMID: 38375501 PMCID: PMC10875109 DOI: 10.3389/fnmol.2024.1342622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/19/2024] [Indexed: 02/21/2024] Open
Abstract
Here, we review the basis of contextual memory at a conceptual and cellular level. We begin with an overview of the philosophical foundations of traversing space, followed by theories covering the material bases of contextual representations in the hippocampus (engrams), exploring functional characteristics of the cells and subfields within. Next, we explore various methodological approaches for investigating contextual memory engrams, emphasizing plasticity mechanisms. This leads us to discuss the role of neuromodulatory inputs in governing these dynamic changes. We then outline a recent hypothesis involving noradrenergic and dopaminergic projections from the locus coeruleus (LC) to different subregions of the hippocampus, in sculpting contextual representations, giving a brief description of the neuroanatomical and physiological properties of the LC. Finally, we examine how activity in the LC influences contextual memory processes through synaptic plasticity mechanisms to alter hippocampal engrams. Overall, we find that phasic activation of the LC plays an important role in promoting new learning and altering mnemonic processes at the behavioral and cellular level through the neuromodulatory influence of NE/DA in the hippocampus. These findings may provide insight into mechanisms of hippocampal remapping and memory updating, memory processes that are potentially dysregulated in certain psychiatric and neurodegenerative disorders.
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Affiliation(s)
- Stephanie L. Grella
- MNEME Lab, Department of Psychology, Program in Neuroscience, Loyola University Chicago, Chicago, IL, United States
| | - Tia N. Donaldson
- Systems Neuroscience and Behavior Lab, Department of Psychology, The University of New Mexico, Albuquerque, NM, United States
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12
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Tamatsu Y, Azechi H, Takahashi R, Sawatani F, Ide K, Fujiyama F, Takahashi S. Optogenetic activation of the ventral tegmental area-hippocampal pathway facilitates rapid adaptation to changes in spatial goals. iScience 2023; 26:108536. [PMID: 38089585 PMCID: PMC10711478 DOI: 10.1016/j.isci.2023.108536] [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: 06/09/2023] [Revised: 10/06/2023] [Accepted: 11/20/2023] [Indexed: 04/26/2025] Open
Abstract
Animal adaptation to environmental goals to pursue rewards is modulated by dopamine. However, the role of dopamine in the hippocampus, involved in spatial navigation, remains unclear. Here, we studied dopaminergic inputs from the ventral tegmental area (VTA) to the hippocampus, focusing on spatial goal persistence and adaptation. Mice with VTA dopaminergic lesions struggled to locate and update learned reward locations in a circular maze with dynamic reward locations, emphasizing the importance of VTA dopaminergic neurons in the persistence and adaptation of spatial memory. Further, these deficits were accompanied by motor impairments or motivational loss even when dopamine receptors in the dorsal hippocampus were selectively blocked. Stimulation of VTA dopaminergic axons within the dorsal hippocampus enhanced the mice's ability to adapt to changing reward locations. These findings provide insights into the contribution of dopaminergic inputs within the hippocampus to spatial goal adaptation.
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Affiliation(s)
- Yuta Tamatsu
- Laboratory of Cognitive and Behavioral Neuroscience, Graduate School of Brain Science, Doshisha University, Kyotanabe 610-0394, Japan
| | - Hirotsugu Azechi
- Laboratory of Cognitive and Behavioral Neuroscience, Graduate School of Brain Science, Doshisha University, Kyotanabe 610-0394, Japan
| | - Riku Takahashi
- Laboratory of Cognitive and Behavioral Neuroscience, Graduate School of Brain Science, Doshisha University, Kyotanabe 610-0394, Japan
| | - Fumiya Sawatani
- Laboratory of Cognitive and Behavioral Neuroscience, Graduate School of Brain Science, Doshisha University, Kyotanabe 610-0394, Japan
| | - Kaoru Ide
- Laboratory of Cognitive and Behavioral Neuroscience, Graduate School of Brain Science, Doshisha University, Kyotanabe 610-0394, Japan
| | - Fumino Fujiyama
- Laboratory of Histology and Cytology, Faculty of Medicine, and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Susumu Takahashi
- Laboratory of Cognitive and Behavioral Neuroscience, Graduate School of Brain Science, Doshisha University, Kyotanabe 610-0394, Japan
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13
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Gönner L, Baeuchl C, Glöckner F, Riedel P, Smolka MN, Li SC. Levodopa suppresses grid-like activity and impairs spatial learning in novel environments in healthy young adults. Cereb Cortex 2023; 33:11247-11256. [PMID: 37782941 PMCID: PMC10690865 DOI: 10.1093/cercor/bhad361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/31/2023] [Accepted: 09/01/2023] [Indexed: 10/04/2023] Open
Abstract
Accumulated evidence from animal studies suggests a role for the neuromodulator dopamine in memory processes, particularly under conditions of novelty or reward. Our understanding of how dopaminergic modulation impacts spatial representations and spatial memory in humans remains limited. Recent evidence suggests age-specific regulation effects of dopamine pharmacology on activity in the medial temporal lobe, a key region for spatial memory. To which degree this modulation affects spatially patterned medial temporal representations remains unclear. We reanalyzed recent data from a pharmacological dopamine challenge during functional brain imaging combined with a virtual object-location memory paradigm to assess the effect of Levodopa, a dopamine precursor, on grid-like activity in the entorhinal cortex. We found that Levodopa impaired grid cell-like representations in a sample of young adults (n = 55, age = 26-35 years) in a novel environment, accompanied by reduced spatial memory performance. We observed no such impairment when Levodopa was delivered to participants who had prior experience with the task. These results are consistent with a role of dopamine in modulating the encoding of novel spatial experiences. Our results suggest that dopamine signaling may play a larger role in shaping ongoing spatial representations than previously thought.
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Affiliation(s)
- Lorenz Gönner
- Faculty of Psychology, Chair of Lifespan Developmental Neuroscience, TU Dresden, 01062 Dresden, Germany
- Department of Psychiatry, TU Dresden, 01307 Dresden, Germany
| | - Christian Baeuchl
- Faculty of Psychology, Chair of Lifespan Developmental Neuroscience, TU Dresden, 01062 Dresden, Germany
- Department of Psychiatry, TU Dresden, 01307 Dresden, Germany
| | - Franka Glöckner
- Faculty of Psychology, Chair of Lifespan Developmental Neuroscience, TU Dresden, 01062 Dresden, Germany
| | - Philipp Riedel
- Department of Psychiatry, TU Dresden, 01307 Dresden, Germany
| | | | - Shu-Chen Li
- Faculty of Psychology, Chair of Lifespan Developmental Neuroscience, TU Dresden, 01062 Dresden, Germany
- Centre for Tactile Internet With Human-in-the-Loop, TU Dresden, 01062 Dresden, Germany
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14
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Chen EYH, Wong SMY, Tang EYH, Lei LKS, Suen YN, Hui CLM. Spurious Autobiographical Memory of Psychosis: A Mechanistic Hypothesis for the Resolution, Persistence, and Recurrence of Positive Symptoms in Psychotic Disorders. Brain Sci 2023; 13:1069. [PMID: 37509001 PMCID: PMC10376952 DOI: 10.3390/brainsci13071069] [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: 06/05/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Psychotic disorders are complex disorders with multiple etiologies. While increased dopamine synthesis capacity has been proposed to underlie psychotic episodes, dopamine-independent processes are also involved (less responsive to dopamine receptor-blocking medications). The underlying mechanism(s) of the reduction in antipsychotic responsiveness over time, especially after repeated relapses, remain unclear. Despite the consistent evidence of dopamine overactivity and hippocampal volume loss in schizophrenia, few accounts have been provided based on the interactive effect of dopamine on hippocampal synapse plasticity mediating autobiographical memory processes. The present hypothesis builds upon previous works showing the potential effects of dopamine overactivity on hippocampal-mediated neuroplasticity underlying autobiographical memory, alongside known patterns of autobiographical memory dysfunction in psychosis. We propose that spurious autobiographical memory of psychosis (SAMP) produced during active psychosis may be a key mechanism mediating relapses and treatment non-responsiveness. In a hyperdopaminergic state, SAMP is expected to be generated at an increased rate during active psychosis. Similar to other memories, it will undergo assimilation, accommodation, and extinction processes. However, if SAMP fails to integrate with existing memory, a discontinuity in autobiographical memory may result. Inadequate exposure to normalizing experiences and hyposalience due to overmedication or negative symptoms may also impede the resolution of SAMP. Residual SAMP is hypothesized to increase the propensity for relapse and treatment non-responsiveness. Based on recent findings on the role of dopamine in facilitating hippocampal synapse plasticity and autobiographical memory formation, the SAMP hypothesis is consistent with clinical observations of DUP effects, including the repetition of contents in psychotic relapses as well as the emergence of treatment non-responsiveness after repeated relapses. Clinical implications of the hypothesis highlight the importance of minimizing active psychosis, integrating psychosis memory, avoiding over-medication, and fostering normalizing experiences.
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Affiliation(s)
- Eric Y H Chen
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China
| | - Stephanie M Y Wong
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Eric Y H Tang
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lauren K S Lei
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yi-Nam Suen
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Christy L M Hui
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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15
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Duszkiewicz AJ, Rossato JI, Moreno A, Takeuchi T, Yamasaki M, Genzel L, Spooner P, Canals S, Morris RGM. Execution of new trajectories toward a stable goal without a functional hippocampus. Hippocampus 2023; 33:769-786. [PMID: 36798045 PMCID: PMC10946713 DOI: 10.1002/hipo.23497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 02/18/2023]
Abstract
The hippocampus is a critical component of a mammalian spatial navigation system, with the firing sequences of hippocampal place cells during sleep or immobility constituting a "replay" of an animal's past trajectories. A novel spatial navigation task recently revealed that such "replay" sequences of place fields can also prospectively map onto imminent new paths to a goal that occupies a stable location during each session. It was hypothesized that such "prospective replay" sequences may play a causal role in goal-directed navigation. In the present study, we query this putative causal role in finding only minimal effects of muscimol-induced inactivation of the dorsal and intermediate hippocampus on the same spatial navigation task. The concentration of muscimol used demonstrably inhibited hippocampal cell firing in vivo and caused a severe deficit in a hippocampal-dependent "episodic-like" spatial memory task in a watermaze. These findings call into question whether "prospective replay" of an imminent and direct path is actually necessary for its execution in certain navigational tasks.
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Affiliation(s)
- Adrian J. Duszkiewicz
- Centre for Discovery Brain Sciences, Edinburgh NeuroscienceUniversity of EdinburghEdinburghUK
- Department of PsychologyUniversity of StirlingStirlingScotlandUK
| | - Janine I. Rossato
- Centre for Discovery Brain Sciences, Edinburgh NeuroscienceUniversity of EdinburghEdinburghUK
- Department of PhysiologyUniversidade Federal do Rio Grande do NorteRio Grande do NorteBrazil
| | - Andrea Moreno
- Centre for Discovery Brain Sciences, Edinburgh NeuroscienceUniversity of EdinburghEdinburghUK
- Instituto de Neurociencias, CSIC‐UMHSan Juan de AlicanteSpain
- Department of Biomedicine, Danish Research Institute of Translational Neuroscience (DANDRITE)Aarhus UniversityAarhus CDenmark
| | - Tomonori Takeuchi
- Centre for Discovery Brain Sciences, Edinburgh NeuroscienceUniversity of EdinburghEdinburghUK
- Department of Biomedicine, Danish Research Institute of Translational Neuroscience (DANDRITE)Aarhus UniversityAarhus CDenmark
| | - Miwako Yamasaki
- Department of Anatomy, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Lisa Genzel
- Centre for Discovery Brain Sciences, Edinburgh NeuroscienceUniversity of EdinburghEdinburghUK
- Donders Institute for Brain, Cognition, and BehaviourRadboud University and RadboudumcNijmegenThe Netherlands
| | - Patrick Spooner
- Centre for Discovery Brain Sciences, Edinburgh NeuroscienceUniversity of EdinburghEdinburghUK
| | - Santiago Canals
- Instituto de Neurociencias, CSIC‐UMHSan Juan de AlicanteSpain
| | - Richard G. M. Morris
- Centre for Discovery Brain Sciences, Edinburgh NeuroscienceUniversity of EdinburghEdinburghUK
- Instituto de Neurociencias, CSIC‐UMHSan Juan de AlicanteSpain
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16
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Noroozian M, Kormi-Nouri R, Nyberg L, Persson J. Hippocampal and motor regions contribute to memory benefits after enacted encoding: cross-sectional and longitudinal evidence. Cereb Cortex 2023; 33:3080-3097. [PMID: 35802485 DOI: 10.1093/cercor/bhac262] [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: 10/19/2021] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
The neurobiological underpinnings of action-related episodic memory and how enactment contributes to efficient memory encoding are not well understood. We examine whether individual differences in level (n = 338) and 5-year change (n = 248) in the ability to benefit from motor involvement during memory encoding are related to gray matter (GM) volume, white matter (WM) integrity, and dopamine-regulating genes in a population-based cohort (age range = 25-80 years). A latent profile analysis identified 2 groups with similar performance on verbal encoding but with marked differences in the ability to benefit from motor involvement during memory encoding. Impaired ability to benefit from enactment was paired with smaller HC, parahippocampal, and putamen volume along with lower WM microstructure in the fornix. Individuals with reduced ability to benefit from encoding enactment over 5 years were characterized by reduced HC and motor cortex GM volume along with reduced WM microstructure in several WM tracts. Moreover, the proportion of catechol-O-methyltransferase-Val-carriers differed significantly between classes identified from the latent-profile analysis. These results provide converging evidence that individuals with low or declining ability to benefit from motor involvement during memory encoding are characterized by low and reduced GM volume in regions critical for memory and motor functions along with altered WM microstructure.
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Affiliation(s)
- Maryam Noroozian
- Department of Psychiatry, School of Medicine, South Kargar Str., Tehran 13185/1741, Iran
| | - Reza Kormi-Nouri
- School of Law, Psychology and Social Work, Örebro University, Fakultetsgatan 1, Örebro 702 81, Sweden
| | - Lars Nyberg
- Department of Radiation Sciences, Radiology, Umeå University, Universitetstorget 4, Umeå 901 87, Sweden
- Department of Integrative Medical Biology, Umeå University, Universitetstorget 4, Umeå 901 87, Sweden
- Umeå Center for Functional Brain Imaging, Umeå University, Universitetstorget 4, Umeå 901 87, Sweden
| | - Jonas Persson
- School of Law, Psychology and Social Work, Center for Lifespan Developmental Research (LEADER), Örebro University, Fakultetsgatan 1, Örebro 702 81, Sweden
- Aging Research Center (ARC), Stockholm University and Karolinska Institute, Tomtebodavägen 18A, Solna 171 65, Sweden
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17
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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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18
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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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19
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Dede AJO, Mishra A, Marzban N, Reichert R, Anderson PM, Cohen MX. Intra- and inter-regional dynamics in cortical-striatal-tegmental networks. J Neurophysiol 2022; 128:1-18. [PMID: 35642803 DOI: 10.1152/jn.00104.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
It is increasingly recognized that networks of brain areas work together to accomplish computational goals. However, functional connectivity networks are not often compared between different behavioral states and across different frequencies of electrical oscillatory signals. In addition, connectivity is always defined as the strength of signal relatedness between two atlas-based anatomical locations. Here, we performed an exploratory analysis using data collectected from high density arrays in the prefrontal cortex (PFC), striatum (STR), and ventral tegmental area (VTA) of male rats. These areas have all been implicated in a wide range of different tasks and computations including various types of memory as well as reward valuation, habit formation and execution, and skill learning. Novel intra-regional clustering analyses identified patterns of spatially restricted, temporally coherent, and frequency specific signals that were reproducible across days and were modulated by behavioral states. Multiple clusters were identified within each anatomical region, indicating a mesoscopic scale of organization. Generalized eigendecomposition (GED) was used to dimension-reduce each cluster to a single component time series. Dense inter-cluster connectivity was modulated by behavioral state, with connectivity becoming reduced when the animals were exposed to a novel object, compared to a baseline condition. Behavior-modulated connectivity changes were seen across the spectrum, with delta, theta, and gamma all being modulated. These results demonstrate the brain's ability to reorganize functionally at both the intra- and inter-regional levels during different behavioral states.
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Affiliation(s)
- Adam J O Dede
- Department of Psychology, grid.11835.3eUniversity of Sheffield, Sheffield, United Kingdom.,Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Clinical Outcomes Research and Integration (Unicorn), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Ashutosh Mishra
- Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, Netherlands.,Donders Centre for Medical Neuroscience, Nijmegen, The Netherlands
| | - Nader Marzban
- Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, Netherlands.,Donders Centre for Medical Neuroscience, Nijmegen, The Netherlands
| | - Robert Reichert
- Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, Netherlands.,Donders Centre for Medical Neuroscience, Nijmegen, The Netherlands
| | - Paul M Anderson
- Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, Netherlands.,Donders Centre for Medical Neuroscience, Nijmegen, The Netherlands
| | - Michael X Cohen
- Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, Netherlands.,Donders Centre for Medical Neuroscience, Nijmegen, The Netherlands
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20
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Berners-Lee A, Feng T, Silva D, Wu X, Ambrose ER, Pfeiffer BE, Foster DJ. Hippocampal replays appear after a single experience and incorporate greater detail with more experience. Neuron 2022; 110:1829-1842.e5. [PMID: 35381188 DOI: 10.1016/j.neuron.2022.03.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 11/01/2021] [Accepted: 03/08/2022] [Indexed: 01/20/2023]
Abstract
The hippocampus is implicated in memory formation, and neurons in the hippocampus take part in replay sequences that have been proposed to reflect memory of explored space. By recording from large ensembles of hippocampal neurons as rats explored various tracks, we show that sustained replay appears after a single experience. Further, we found that with repeated experience in a novel environment, replay slows down, taking more time to traverse the same trajectory. This effect was dependent on experience, not passage of time, and was environment specific. By investigating the slow-gamma (25-50 Hz) hover-and-jump dynamics within replays, we show that replay slows by adding more hover locations, increasing the resolution of the behavioral trajectory. We provide evidence that inhibition and cortical engagement both increase as replay slows. Thus, replays can reflect single experiences and evolve with re-exposure, in a manner consistent with the encoding of greater detail into replay memories with experience.
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Affiliation(s)
- Alice Berners-Lee
- Helen Wills Neuroscience Institute and Department of Psychology, University of California Berkeley, CA 94720, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ting Feng
- Philips Research North America, Cambridge, MA 02141, USA
| | | | - Xiaojing Wu
- New York University Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA
| | | | - Brad E Pfeiffer
- Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - David J Foster
- Helen Wills Neuroscience Institute and Department of Psychology, University of California Berkeley, CA 94720, USA.
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21
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González-Granillo AE, Gnecco D, Díaz A, Garcés-Ramírez L, de la Cruz F, Juarez I, Morales-Medina JC, Flores G. Curcumin induces cortico-hippocampal neuronal reshaping and memory improvements in aged mice. J Chem Neuroanat 2022; 121:102091. [PMID: 35334275 DOI: 10.1016/j.jchemneu.2022.102091] [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: 12/01/2021] [Revised: 03/11/2022] [Accepted: 03/11/2022] [Indexed: 11/28/2022]
Abstract
Aging induces cognitive decline, reduces of synaptic plasticity and increases oxidative reactive species (ROS) in the central nervous system. Traditional medicine has long benefitted from naturally occurring molecules such as curcumin (diferuloymethane). Curcumin is extracted from the plant Curcuma longa and is known for its synaptic and antioxidant-related benefits. In this study, we tested the hypothesis that chronic curcumin treatment reduces cognitive and cellular effects of aging. Curcumin-treated mice showed improved learning and memory using the Morris Water Maze and novel object recognition task. In addition, using the Golgi-Cox stain, curcumin treatment increased spine density in all evaluated regions and increased dendritic arborization in the prefrontal cortex (PFC) layer 3 and CA3 subregion of the hippocampus. Moreover, chronic curcumin exposure increased synaptophysin and actin expression and reduced glial fibrillary acidic protein expression, a marker of astrocytes, in the hippocampus (CA1 and CA3 subregions), while simultaneously reducing the ROS-related molecule, metallothionein 3 expression in the PFC and hippocampus. Collectively, these novel findings suggest that curcumin reduces cognitive, neuronal and astrocytic signs of aging in mice.
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Affiliation(s)
- Aldo Efrain González-Granillo
- Lab. Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 14 Sur 6301, San Manuel, 72570 Puebla, Mexico; Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Dino Gnecco
- Centro de Química, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Alfonso Díaz
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Linda Garcés-Ramírez
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Fidel de la Cruz
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Ismael Juarez
- Laboratorio de Fisiología, Facultad de Estomatología, Benemérita Universidad Autónoma de Puebla, Puebla 72410, Mexico
| | - Julio César Morales-Medina
- Centro de Investigación en Reproducción Animal, CINVESTAV, Universidad Autónoma de Tlaxcala, AP 62, CP 90000 Tlaxcala, Mexico
| | - Gonzalo Flores
- Lab. Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 14 Sur 6301, San Manuel, 72570 Puebla, Mexico.
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22
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Weerasinghe-Mudiyanselage PDE, Ang MJ, Kang S, Kim JS, Moon C. Structural Plasticity of the Hippocampus in Neurodegenerative Diseases. Int J Mol Sci 2022; 23:3349. [PMID: 35328770 PMCID: PMC8955928 DOI: 10.3390/ijms23063349] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 12/10/2022] Open
Abstract
Neuroplasticity is the capacity of neural networks in the brain to alter through development and rearrangement. It can be classified as structural and functional plasticity. The hippocampus is more susceptible to neuroplasticity as compared to other brain regions. Structural modifications in the hippocampus underpin several neurodegenerative diseases that exhibit cognitive and emotional dysregulation. This article reviews the findings of several preclinical and clinical studies about the role of structural plasticity in the hippocampus in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In this study, literature was surveyed using Google Scholar, PubMed, Web of Science, and Scopus, to review the mechanisms that underlie the alterations in the structural plasticity of the hippocampus in neurodegenerative diseases. This review summarizes the role of structural plasticity in the hippocampus for the etiopathogenesis of neurodegenerative diseases and identifies the current focus and gaps in knowledge about hippocampal dysfunctions. Ultimately, this information will be useful to propel future mechanistic and therapeutic research in neurodegenerative diseases.
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Affiliation(s)
- Poornima D. E. Weerasinghe-Mudiyanselage
- Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea; (P.D.E.W.-M.); (M.J.A.); (S.K.); (J.-S.K.)
| | - Mary Jasmin Ang
- Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea; (P.D.E.W.-M.); (M.J.A.); (S.K.); (J.-S.K.)
- College of Veterinary Medicine, University of the Philippines Los Baños, Los Baños 4031, Philippines
| | - Sohi Kang
- Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea; (P.D.E.W.-M.); (M.J.A.); (S.K.); (J.-S.K.)
| | - Joong-Sun Kim
- Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea; (P.D.E.W.-M.); (M.J.A.); (S.K.); (J.-S.K.)
| | - Changjong Moon
- Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea; (P.D.E.W.-M.); (M.J.A.); (S.K.); (J.-S.K.)
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Dai ZH, Xu X, Chen WQ, Nie LN, Liu Y, Sui N, Liang J. The role of hippocampus in memory reactivation: an implication for a therapeutic target against opioid use disorder. CURRENT ADDICTION REPORTS 2022; 9:67-79. [PMID: 35223369 PMCID: PMC8857535 DOI: 10.1007/s40429-022-00407-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2022] [Indexed: 12/29/2022]
Abstract
Purpose of the review The abuse of opioids induces many terrible problems in human health and social stability. For opioid-dependent individuals, withdrawal memory can be reactivated by context, which is then associated with extremely unpleasant physical and emotional feelings during opioid withdrawal. The reactivation of withdrawal memory is considered one of the most important reasons for opioid relapse, and it also allows for memory modulation based on the reconsolidation phenomenon. However, studies exploring withdrawal memory modulation during the reconsolidation window are lacking. By summarizing the previous findings about the reactivation of negative emotional memories, we are going to suggest potential neural regions and systems for modulating opioid withdrawal memory. Recent findings Here, we first present the role of memory reactivation in its modification, discuss how the hippocampus participates in memory reactivation, and discuss the importance of noradrenergic signaling in the hippocampus for memory reactivation. Then, we review the engagement of other limbic regions receiving noradrenergic signaling in memory reactivation. We suggest that noradrenergic signaling targeting hippocampus neurons might play a potential role in strengthening the disruptive effect of withdrawal memory extinction by facilitating the degree of memory reactivation. Summary This review will contribute to a better understanding of the mechanisms underlying reactivation-dependent memory malleability and will provide new therapeutic avenues for treating opioid use disorders.
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Affiliation(s)
- Zhong-hua Dai
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Xing Xu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Wei-qi Chen
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
| | - Li-na Nie
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Ying Liu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Nan Sui
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Jing Liang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
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Survival of the salient: Aversive learning rescues otherwise forgettable memories via neural reactivation and post-encoding hippocampal connectivity. Neurobiol Learn Mem 2022; 187:107572. [PMID: 34871800 PMCID: PMC8755594 DOI: 10.1016/j.nlm.2021.107572] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 10/17/2021] [Accepted: 11/26/2021] [Indexed: 01/03/2023]
Abstract
The effects of aversive events on memory are complex and go beyond the simple enhancement of threatening information. Negative experiences can also rescue related but otherwise forgettable details encoded close in time. Here, we used functional magnetic resonance imaging (fMRI) in healthy young adults to examine the brain mechanisms that support this retrograde memory effect. In a two-phase incidental encoding paradigm, participants viewed different pictures of tools and animals before and during Pavlovian fear conditioning. During Phase 1, these images were intermixed with neutral scenes, which provided a unique 'context tag' for this specific phase of encoding. A few minutes later, during Phase 2, new pictures from one category were paired with a mild shock (threat-conditioned stimulus; CS+), while pictures from the other category were not shocked. FMRI analyses revealed that, across-participants, individuals who showed aversive learning-related retroactive memory benefits for Phase 1 CS+ items were also more likely to exhibit three brain effects: first, greater spontaneous reinstatement of the Phase 1 context when participants viewed conceptually-related CS+ items in Phase 2; second, greater successful encoding-related VTA/SN and LC activation for Phase 2 CS+ items; and third, learning-dependent increases in post-encoding hippocampal functional coupling with CS+ category-selective cortex. These biases in hippocampal-cortical connectivity also mediated the relationship between VTA/SN aversive encoding effects and across-participant variability in the retroactive memory benefit. Collectively, our findings suggest that both online and offline brain mechanisms may enable threatening events to preserve memories that acquire new significance in the future.
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25
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Lima KR, da Rosa ACDS, Picua SS, E Silva SS, Soares NM, Mello-Carpes PB. Novelty promotes recognition memory persistence by D1 dopamine receptor and protein kinase A signalling in rat hippocampus. Eur J Neurosci 2021; 55:78-90. [PMID: 34904283 DOI: 10.1111/ejn.15568] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 11/18/2021] [Accepted: 12/05/2021] [Indexed: 11/28/2022]
Abstract
Strategies for improving memory are increasingly studied, and exposure to a novel experience can be an efficient neuromodulator. Novelty effects on memory depend on D1-family dopamine receptors (D1Rs) activation. Here, we evaluated the novelty effect on memory persistence of Wistar rats and investigated the contribution of D1Rs and their signalling pathways by protein kinase A (PKA) and C (PKC). Animals with infusion cannulae inserted into the CA1 hippocampus area were trained on the novel object recognition (NOR) task, which involved exploring two different objects. After training, some rats received intrahippocampal infusions of vehicle or D1Rs agonist; others explored a novel environment for 5 min and were infused with a variety of drugs targeting D1Rs and their signalling pathways. We demonstrated that pharmacological stimulation of D1Rs or novelty exposure promoted NOR memory persistence for 14 days and that the novelty effect depended on D1Rs activation. To determine if the D1 and D5 receptor subtypes were necessary for the impact of novelty exposure on memory, we blocked or stimulated PKA or PKC-protein kinases activated mainly by D1 and D5, respectively. Only PKA inhibition impaired the effect of novelty on memory persistence. After novelty and D1Rs blocking, PKA but not PKC stimulation maintained the memory persistence effect. Thus, we concluded that novelty promoted memory persistence by a mechanism-dependent on activating hippocampal D1Rs and PKA pathway.
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Affiliation(s)
- Karine Ramires Lima
- Physiology Research Group, Stress, Memory and Behavior Lab, Federal University of Pampa, Uruguaiana, Brazil
| | | | - Steffanie Severo Picua
- Physiology Research Group, Stress, Memory and Behavior Lab, Federal University of Pampa, Uruguaiana, Brazil
| | - Shara Souza E Silva
- Physiology Research Group, Stress, Memory and Behavior Lab, Federal University of Pampa, Uruguaiana, Brazil
| | - Náthaly Marks Soares
- Physiology Research Group, Stress, Memory and Behavior Lab, Federal University of Pampa, Uruguaiana, Brazil
| | - Pâmela Billig Mello-Carpes
- Physiology Research Group, Stress, Memory and Behavior Lab, Federal University of Pampa, Uruguaiana, Brazil
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26
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Vadakkan KI. Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens. World J Psychiatry 2021; 11:681-695. [PMID: 34733636 PMCID: PMC8546768 DOI: 10.5498/wjp.v11.i10.681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/27/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
It is necessary to find a mechanism that generates first-person inner sensation of pleasure to understand what causes addiction and associated behaviour by drugs of abuse. The actual mechanism is expected to explain several disparate findings in nucleus accumbens (NAc), a brain region associated with pleasure, in an interconnected manner. Previously, it was possible to derive a mechanism for natural learning and explain: (1) Generation of inner sensation of memory using changes generated by learning; and (2) Long-term potentiation as an experimental delayed scaled-up change by the same mechanism that occur during natural learning. By extending these findings and by using disparate third person observations in NAc from several studies, present work provides a framework of a mechanism that generates internal sensation of pleasure that can provide interconnected explanations for: (1) Ability to induce robust long-term depression (LTD) in NAc from naïve animals; (2) Impaired ability to induce LTD in “addicted” state; (3) Attenuation of postsynaptic potentials by cocaine; and (4) Reduced firing of medium spiny neurons in response to cocaine or dopamine. Findings made by this work are testable.
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27
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Castillo Díaz F, Caffino L, Fumagalli F. Bidirectional role of dopamine in learning and memory-active forgetting. Neurosci Biobehav Rev 2021; 131:953-963. [PMID: 34655655 DOI: 10.1016/j.neubiorev.2021.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/05/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Dopaminergic neurons projecting from the Substantia Nigra to the Striatum play a critical role in motor functions while dopaminergic neurons originating in the Ventral Tegmental Area (VTA) and projecting to the Nucleus Accumbens, Hippocampus and other cortical structures regulate rewarding learning. While VTA mainly consists of dopaminergic neurons, excitatory (glutamate) and inhibitory (GABA) VTA-neurons have also been described: these neurons may also modulate and contribute to shape the final dopaminergic response, which is critical for memory formation. However, given the large amount of information that is handled daily by our brain, it is essential that irrelevant information be deleted. Recently, apart from the well-established role of dopamine (DA) in learning, it has been shown that DA plays a critical role in the intrinsic active forgetting mechanisms that control storage information, contributing to the deletion of a consolidated memory. These new insights may be instrumental to identify therapies for those disorders that involve memory alterations.
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Affiliation(s)
- Fernando Castillo Díaz
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
| | - Lucia Caffino
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
| | - Fabio Fumagalli
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
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28
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Abstract
An organism's survival can depend on its ability to recall and navigate to spatial locations associated with rewards, such as food or a home. Accumulating research has revealed that computations of reward and its prediction occur on multiple levels across a complex set of interacting brain regions, including those that support memory and navigation. However, how the brain coordinates the encoding, recall and use of reward information to guide navigation remains incompletely understood. In this Review, we propose that the brain's classical navigation centres - the hippocampus and the entorhinal cortex - are ideally suited to coordinate this larger network by representing both physical and mental space as a series of states. These states may be linked to reward via neuromodulatory inputs to the hippocampus-entorhinal cortex system. Hippocampal outputs can then broadcast sequences of states to the rest of the brain to store reward associations or to facilitate decision-making, potentially engaging additional value signals downstream. This proposal is supported by recent advances in both experimental and theoretical neuroscience. By discussing the neural systems traditionally tied to navigation and reward at their intersection, we aim to offer an integrated framework for understanding navigation to reward as a fundamental feature of many cognitive processes.
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29
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Alireza Halabian, Mehranfard N, Ghasemi M, Radahmadi M, Alaei H. Chronic Standard Scheduled-Diet Improves Memory Performance and Is Associated with Positive Correlation between Plasma Ghrelin and Hippocampal Dopamine Level in Rats. NEUROCHEM J+ 2021. [DOI: 10.1134/s1819712421020069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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30
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Yoo J, Min S, Lee SK, Han S. Neural correlates of episodic memory modulated by temporally delayed rewards. PLoS One 2021; 16:e0249290. [PMID: 33826665 PMCID: PMC8026031 DOI: 10.1371/journal.pone.0249290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 03/16/2021] [Indexed: 11/18/2022] Open
Abstract
When a stimulus is associated with an external reward, its chance of being consolidated into long-term memory is boosted via dopaminergic facilitation of long-term potentiation in the hippocampus. Given that higher temporal distance (TD) has been found to discount the subjective value of a reward, we hypothesized that memory performance associated with a more immediate reward will result in better memory performance. We tested this hypothesis by measuring both behavioral memory performance and brain activation using functional magnetic resonance imaging (fMRI) during memory encoding and retrieval tasks. Contrary to our hypothesis, both behavioral and fMRI results suggest that the TD of rewards might enhance the chance of the associated stimulus being remembered. The fMRI data demonstrate that the lateral prefrontal cortex, which shows encoding-related activation proportional to the TD, is reactivated when searching for regions that show activation proportional to the TD during retrieval. This is not surprising given that this region is not only activated to discriminate between future vs. immediate rewards, it is also a part of the retrieval-success network. These results provide support for the conclusion that the encoding-retrieval overlap provoked as the rewards are more delayed may lead to better memory performance of the items associated with the rewards.
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Affiliation(s)
- Jungsun Yoo
- Department of Psychology, Yonsei University, Seoul, Republic of Korea
| | - Seokyoung Min
- Department of Psychology, Yonsei University, Seoul, Republic of Korea
| | - Seung-Koo Lee
- Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Integrated Neurocognitive Functional Imaging Center, Yonsei University, Seoul, Republic of Korea
| | - Sanghoon Han
- Department of Psychology, Yonsei University, Seoul, Republic of Korea
- * E-mail:
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31
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Speranza L, di Porzio U, Viggiano D, de Donato A, Volpicelli F. Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells 2021; 10:735. [PMID: 33810328 PMCID: PMC8066851 DOI: 10.3390/cells10040735] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/20/2021] [Accepted: 03/23/2021] [Indexed: 01/11/2023] Open
Abstract
Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places this molecule at the interface between the motor and the cognitive systems. Specifically, we will be focusing on PD, vascular dementia, and schizophrenia.
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Affiliation(s)
- Luisa Speranza
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA;
| | - Umberto di Porzio
- Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, 80131 Naples, Italy
| | - Davide Viggiano
- Department of Translational Medical Sciences, Genetic Research Institute “Gaetano Salvatore”, University of Campania “L. Vanvitelli”, IT and Biogem S.c.a.r.l., 83031 Ariano Irpino, Italy; (D.V.); (A.d.D.)
| | - Antonio de Donato
- Department of Translational Medical Sciences, Genetic Research Institute “Gaetano Salvatore”, University of Campania “L. Vanvitelli”, IT and Biogem S.c.a.r.l., 83031 Ariano Irpino, Italy; (D.V.); (A.d.D.)
| | - Floriana Volpicelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy;
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32
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One single physical exercise session improves memory persistence by hippocampal activation of D1 dopamine receptors and PKA signaling in rats. Brain Res 2021; 1762:147439. [PMID: 33753064 DOI: 10.1016/j.brainres.2021.147439] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 03/11/2021] [Accepted: 03/13/2021] [Indexed: 01/01/2023]
Abstract
Previously, we demonstrated that one single physical exercise session could positively modulate recognition memory persistence by D1/D5 activation. Here, we aim to investigate whether the effect of physical exercise on memory occurs due to the activation of both receptors, D1 and D5, or only one of them. Adult male Wistar rats were habituated on a treadmill one week before experiments. After learning session in the object recognition task, some animals received intrahippocampal infusions of the vehicle or a D1/D5 agonist (SKF 38393, 12.5 μg/μL/side), whereas others performed a single session of physical exercise on a treadmill (30 min at an intensity of 60-70% of indirect VO2 max.). Immediately after physical exercise, some animals received intrahippocampal infusions of vehicle or D1/D5 antagonist (SCH 23390, 1 μg/μL/side). Signaling pathways of D1 and D5 receptors in the hippocampus were evaluated by pharmacological activation or inactivation of protein kinases A (PKA) and C (PKC), respectively. According to previous findings, D1/D5 agonist and a single physical exercise session after learning promoted memory persistence, and D1/D5 block impaired physical exercise effect. Importantly, here we demonstrated for the first time that PKA inhibition, but not PKC, impairs the effect of acute physical exercise on memory persistence. Besides, PKA stimulation can promote its effects on memory. Therefore, we provide evidence that corroborates the idea that D1-like dopaminergic receptors, by activation of the PKA pathway, are involved in the effects of acute physical exercise on memory.
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33
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Espadas I, Ortiz O, García-Sanz P, Sanz-Magro A, Alberquilla S, Solis O, Delgado-García JM, Gruart A, Moratalla R. Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse. Cereb Cortex 2021; 31:2187-2204. [PMID: 33264389 PMCID: PMC7945019 DOI: 10.1093/cercor/bhaa354] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/04/2020] [Accepted: 10/23/2020] [Indexed: 12/24/2022] Open
Abstract
Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2-/-) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.
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Affiliation(s)
- Isabel Espadas
- Neurobiologia Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid 28002, Spain
- CIBERNED, ISCIII, Madrid 28002, Spain
| | - Oscar Ortiz
- Neurobiologia Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid 28002, Spain
- CIBERNED, ISCIII, Madrid 28002, Spain
| | - Patricia García-Sanz
- Neurobiologia Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid 28002, Spain
- CIBERNED, ISCIII, Madrid 28002, Spain
| | - Adrián Sanz-Magro
- Neurobiologia Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid 28002, Spain
- CIBERNED, ISCIII, Madrid 28002, Spain
| | - Samuel Alberquilla
- Neurobiologia Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid 28002, Spain
- CIBERNED, ISCIII, Madrid 28002, Spain
| | - Oscar Solis
- Neurobiologia Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid 28002, Spain
- CIBERNED, ISCIII, Madrid 28002, Spain
| | | | - Agnès Gruart
- División de Neurociencias, Univ. Pablo de Olavide, Sevilla 41013, Spain
| | - Rosario Moratalla
- Neurobiologia Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid 28002, Spain
- CIBERNED, ISCIII, Madrid 28002, Spain
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Tessereau C, O’Dea R, Coombes S, Bast T. Reinforcement learning approaches to hippocampus-dependent flexible spatial navigation. Brain Neurosci Adv 2021; 5:2398212820975634. [PMID: 33954259 PMCID: PMC8042550 DOI: 10.1177/2398212820975634] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/21/2020] [Indexed: 11/17/2022] Open
Abstract
Humans and non-human animals show great flexibility in spatial navigation, including the ability to return to specific locations based on as few as one single experience. To study spatial navigation in the laboratory, watermaze tasks, in which rats have to find a hidden platform in a pool of cloudy water surrounded by spatial cues, have long been used. Analogous tasks have been developed for human participants using virtual environments. Spatial learning in the watermaze is facilitated by the hippocampus. In particular, rapid, one-trial, allocentric place learning, as measured in the delayed-matching-to-place variant of the watermaze task, which requires rodents to learn repeatedly new locations in a familiar environment, is hippocampal dependent. In this article, we review some computational principles, embedded within a reinforcement learning framework, that utilise hippocampal spatial representations for navigation in watermaze tasks. We consider which key elements underlie their efficacy, and discuss their limitations in accounting for hippocampus-dependent navigation, both in terms of behavioural performance (i.e. how well do they reproduce behavioural measures of rapid place learning) and neurobiological realism (i.e. how well do they map to neurobiological substrates involved in rapid place learning). We discuss how an actor-critic architecture, enabling simultaneous assessment of the value of the current location and of the optimal direction to follow, can reproduce one-trial place learning performance as shown on watermaze and virtual delayed-matching-to-place tasks by rats and humans, respectively, if complemented with map-like place representations. The contribution of actor-critic mechanisms to delayed-matching-to-place performance is consistent with neurobiological findings implicating the striatum and hippocampo-striatal interaction in delayed-matching-to-place performance, given that the striatum has been associated with actor-critic mechanisms. Moreover, we illustrate that hierarchical computations embedded within an actor-critic architecture may help to account for aspects of flexible spatial navigation. The hierarchical reinforcement learning approach separates trajectory control via a temporal-difference error from goal selection via a goal prediction error and may account for flexible, trial-specific, navigation to familiar goal locations, as required in some arm-maze place memory tasks, although it does not capture one-trial learning of new goal locations, as observed in open field, including watermaze and virtual, delayed-matching-to-place tasks. Future models of one-shot learning of new goal locations, as observed on delayed-matching-to-place tasks, should incorporate hippocampal plasticity mechanisms that integrate new goal information with allocentric place representation, as such mechanisms are supported by substantial empirical evidence.
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Affiliation(s)
- Charline Tessereau
- School of Mathematical Sciences, University of Nottingham, Nottingham, UK
- School of Psychology, University of Nottingham, Nottingham, UK
- Neuroscience@Nottingham
| | - Reuben O’Dea
- School of Mathematical Sciences, University of Nottingham, Nottingham, UK
- Neuroscience@Nottingham
| | - Stephen Coombes
- School of Mathematical Sciences, University of Nottingham, Nottingham, UK
- Neuroscience@Nottingham
| | - Tobias Bast
- School of Psychology, University of Nottingham, Nottingham, UK
- Neuroscience@Nottingham
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35
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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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36
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Sharp ME, Duncan K, Foerde K, Shohamy D. Dopamine is associated with prioritization of reward-associated memories in Parkinson's disease. Brain 2020; 143:2519-2531. [PMID: 32844197 DOI: 10.1093/brain/awaa182] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/08/2020] [Accepted: 04/16/2020] [Indexed: 01/23/2023] Open
Abstract
Patients with Parkinson's disease have reduced reward sensitivity related to dopaminergic neuron loss, which is associated with impairments in reinforcement learning. Increasingly, however, dopamine-dependent reward signals are recognized to play an important role beyond reinforcement learning. In particular, it has been shown that reward signals mediated by dopamine help guide the prioritization of events for long-term memory consolidation. Meanwhile, studies of memory in patients with Parkinson's disease have focused on overall memory capacity rather than what is versus what isn't remembered, leaving open questions about the effect of dopamine replacement on the prioritization of memories by reward and the time-dependence of this effect. The current study sought to fill this gap by testing the effect of reward and dopamine on memory in patients with Parkinson's disease. We tested the effect of dopamine modulation and reward on two forms of long-term memory: episodic memory for neutral objects and memory for stimulus-value associations. We measured both forms of memory in a single task, adapting a standard task of reinforcement learning with incidental episodic encoding events of trial-unique objects. Objects were presented on each trial at the time of feedback, which was either rewarding or not. Memory for the trial-unique images and for the stimulus-value associations, and the influence of reward on both, was tested immediately after learning and 2 days later. We measured performance in Parkinson's disease patients tested either ON or OFF their dopaminergic medications and in healthy older control subjects. We found that dopamine was associated with a selective enhancement of memory for reward-associated images, but that it did not influence overall memory capacity. Contrary to predictions, this effect did not differ between the immediate and delayed memory tests. We also found that while dopamine had an effect on reward-modulated episodic memory, there was no effect of dopamine on memory for stimulus-value associations. Our results suggest that impaired prioritization of cognitive resource allocation may contribute to the early cognitive deficits of Parkinson's disease.
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Affiliation(s)
- Madeleine E Sharp
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Katherine Duncan
- Department of Psychology, University of Toronto, Toronto, Canada
| | - Karin Foerde
- New York State Psychiatric Institute and Department of Psychiatry, Columbia University, New York, NY, USA
| | - Daphna Shohamy
- Department of Psychology, Columbia University, New York, NY, USA.,Zuckerman Mind, Brain, Behavior Institute, Columbia University, New York, NY, USA.,Kavli Institute for Brain Science, Columbia University, New York, NY, USA
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37
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Chen N, Tsai TC, Hsu KS. Exposure to Novelty Promotes Long-Term Contextual Fear Memory Formation in Juvenile Mice: Evidence for a Behavioral Tagging. Mol Neurobiol 2020; 57:3956-3968. [DOI: 10.1007/s12035-020-02005-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 06/26/2020] [Indexed: 11/29/2022]
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38
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Chen PS, Jamil A, Liu LC, Wei SY, Tseng HH, Nitsche MA, Kuo MF. Nonlinear Effects of Dopamine D1 Receptor Activation on Visuomotor Coordination Task Performance. Cereb Cortex 2020; 30:5346-5355. [DOI: 10.1093/cercor/bhaa116] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 04/17/2020] [Accepted: 04/17/2020] [Indexed: 02/06/2023] Open
Abstract
Abstract
Dopamine plays an important role in the modulation of neuroplasticity, which serves as the physiological basis of cognition. The physiological effects of dopamine depend on receptor subtypes, and the D1 receptor is critically involved in learning and memory formation. Evidence from both animal and human studies shows a dose-dependent impact of D1 activity on performance. However, the direct association between physiology and behavior in humans remains unclear. In this study, four groups of healthy participants were recruited, and each group received placebo or medication inducing a low, medium, or high amount of D1 activation via the combination of levodopa and a D2 antagonist. After medication, fMRI was conducted during a visuomotor learning task. The behavioral results revealed an inverted U-shaped effect of D1 activation on task performance, where medium-dose D1 activation led to superior learning effects, as compared to placebo as well as low- and high-dose groups. A respective dose-dependent D1 modulation was also observed for cortical activity revealed by fMRI. Further analysis demonstrated a positive correlation between task performance and cortical activation at the left primary motor cortex. Our results indicate a nonlinear curve of D1 modulation on motor learning in humans and the respective physiological correlates in corresponding brain areas.
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Affiliation(s)
- Po See Chen
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Asif Jamil
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund 44139, Germany
| | - Lin-Cho Liu
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund 44139, Germany
| | - Shyh-Yuh Wei
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Huai-Hsuan Tseng
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Michael A Nitsche
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund 44139, Germany
- Department of Neurology, University Medical Hospital Bergmannsheil, Ruhr University Bochum, Bochum 44789, Germany
| | - Min-Fang Kuo
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund 44139, Germany
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39
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Papalini S, Beckers T, Vervliet B. Dopamine: from prediction error to psychotherapy. Transl Psychiatry 2020; 10:164. [PMID: 32451377 PMCID: PMC7248121 DOI: 10.1038/s41398-020-0814-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 04/14/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023] Open
Abstract
Dopamine, one of the main neurotransmitters in the mammalian brain, has been implicated in the coding of prediction errors that govern reward learning as well as fear extinction learning. Psychotherapy too can be viewed as a form of error-based learning, because it challenges erroneous beliefs and behavioral patterns in order to induce long-term changes in emotions, cognitions, and behaviors. Exposure therapy, for example, relies in part on fear extinction principles to violate erroneous expectancies of danger and induce novel safety learning that inhibits and therefore reduces fear in the long term. As most forms of psychotherapy, however, exposure therapy suffers from non-response, dropout, and relapse. This narrative review focuses on the role of midbrain and prefrontal dopamine in novel safety learning and investigates possible pathways through which dopamine-based interventions could be used as an adjunct to improve both the response and the long-term effects of the therapy. Convincing evidence exists for an involvement of the midbrain dopamine system in the acquisition of new, safe memories. Additionally, prefrontal dopamine is emerging as a key ingredient for the consolidation of fear extinction. We propose that applying a dopamine prediction error perspective to psychotherapy can inspire both pharmacological and non-pharmacological studies aimed at discovering innovative ways to enhance the acquisition of safety memories. Additionally, we call for further empirical investigations on dopamine-oriented drugs that might be able to maximize consolidation of successful fear extinction and its long-term retention after therapy, and we propose to also include investigations on non-pharmacological interventions with putative prefrontal dopaminergic effects, like working memory training.
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Affiliation(s)
- Silvia Papalini
- Laboratory of Biological Psychology (LBP), Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium. .,Leuven Brain Institute, KU Leuven, Leuven, Belgium.
| | - Tom Beckers
- grid.5596.f0000 0001 0668 7884Leuven Brain Institute, KU Leuven, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Centre for the Psychology of Learning and Experimental Psychopathology (CLEP), Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium
| | - Bram Vervliet
- grid.5596.f0000 0001 0668 7884Laboratory of Biological Psychology (LBP), Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Leuven Brain Institute, KU Leuven, Leuven, Belgium
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40
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Aberg KC, Kramer EE, Schwartz S. Interplay between midbrain and dorsal anterior cingulate regions arbitrates lingering reward effects on memory encoding. Nat Commun 2020; 11:1829. [PMID: 32286275 PMCID: PMC7156375 DOI: 10.1038/s41467-020-15542-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 03/12/2020] [Indexed: 12/17/2022] Open
Abstract
Rewarding events enhance memory encoding via dopaminergic influences on hippocampal plasticity. Phasic dopamine release depends on immediate reward magnitude, but presumably also on tonic dopamine levels, which may vary as a function of the average accumulation of reward over time. Using model-based fMRI in combination with a novel associative memory task, we show that immediate reward magnitude exerts a monotonically increasing influence on the nucleus accumbens, ventral tegmental area (VTA), and hippocampal activity during encoding, and enhances memory. By contrast, average reward levels modulate feedback-related responses in the VTA and hippocampus in a non-linear (inverted U-shape) fashion, with similar effects on memory performance. Additionally, the dorsal anterior cingulate cortex (dACC) monotonically tracks average reward levels, while VTA-dACC functional connectivity is non-linearly modulated (inverted U-shape) by average reward. We propose that the dACC computes the net behavioral impact of average reward and relays this information to memory circuitry via the VTA.
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Affiliation(s)
| | - Emily Elizabeth Kramer
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Sophie Schwartz
- Department of Neuroscience, University of Geneva, Geneva, Switzerland.,Swiss Center for Affective Sciences, University of Geneva, Geneva, Switzerland.,Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland
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41
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Dopamine Receptor Dop1R2 Stabilizes Appetitive Olfactory Memory through the Raf/MAPK Pathway in Drosophila. J Neurosci 2020; 40:2935-2942. [PMID: 32102921 DOI: 10.1523/jneurosci.1572-19.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 02/03/2020] [Accepted: 02/06/2020] [Indexed: 11/21/2022] Open
Abstract
In Drosophila, dopamine signaling to the mushroom body intrinsic neurons, Kenyon cells (KCs), is critical to stabilize olfactory memory. Little is known about the downstream intracellular molecular signaling underlying memory stabilization. Here we address this question in the context of sugar-rewarded olfactory long-term memory (LTM). We show that associative training increases the phosphorylation of MAPK in KCs, via Dop1R2 signaling. Consistently, the attenuation of Dop1R2, Raf, or MAPK expression in KCs selectively impairs LTM, but not short-term memory. Moreover, we show that the LTM deficit caused by the knockdown of Dop1R2 can be rescued by expressing active Raf in KCs. Thus, the Dop1R2/Raf/MAPK pathway is a pivotal downstream effector of dopamine signaling for stabilizing appetitive olfactory memory.SIGNIFICANCE STATEMENT Dopaminergic input to the Kenyon cells (KCs) is pivotal to stabilize memory in Drosophila This process is mediated by dopamine receptors like Dop1R2. Nevertheless, little is known for its underlying molecular mechanism. Here we show that the Raf/MAPK pathway is specifically engaged in appetitive long-term memory in KCs. With combined biochemical and behavioral experiments, we reveal that activation of the Raf/MAPK pathway is regulated through Dop1R2, shedding light on how dopamine modulates intracellular signaling for memory stabilization.
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42
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Neuromodulators and Long-Term Synaptic Plasticity in Learning and Memory: A Steered-Glutamatergic Perspective. Brain Sci 2019; 9:brainsci9110300. [PMID: 31683595 PMCID: PMC6896105 DOI: 10.3390/brainsci9110300] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/24/2019] [Accepted: 10/29/2019] [Indexed: 12/19/2022] Open
Abstract
The molecular pathways underlying the induction and maintenance of long-term synaptic plasticity have been extensively investigated revealing various mechanisms by which neurons control their synaptic strength. The dynamic nature of neuronal connections combined with plasticity-mediated long-lasting structural and functional alterations provide valuable insights into neuronal encoding processes as molecular substrates of not only learning and memory but potentially other sensory, motor and behavioural functions that reflect previous experience. However, one key element receiving little attention in the study of synaptic plasticity is the role of neuromodulators, which are known to orchestrate neuronal activity on brain-wide, network and synaptic scales. We aim to review current evidence on the mechanisms by which certain modulators, namely dopamine, acetylcholine, noradrenaline and serotonin, control synaptic plasticity induction through corresponding metabotropic receptors in a pathway-specific manner. Lastly, we propose that neuromodulators control plasticity outcomes through steering glutamatergic transmission, thereby gating its induction and maintenance.
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43
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Tian J, Guo L, Sui S, Driskill C, Phensy A, Wang Q, Gauba E, Zigman JM, Swerdlow RH, Kroener S, Du H. Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer's disease. Sci Transl Med 2019; 11:eaav6278. [PMID: 31413143 PMCID: PMC6776822 DOI: 10.1126/scitranslmed.aav6278] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 06/24/2019] [Indexed: 12/12/2022]
Abstract
Hippocampal lesions are a defining pathology of Alzheimer's disease (AD). However, the molecular mechanisms that underlie hippocampal synaptic injury in AD have not been fully elucidated. Current therapeutic efforts for AD treatment are not effective in correcting hippocampal synaptic deficits. Growth hormone secretagogue receptor 1α (GHSR1α) is critical for hippocampal synaptic physiology. Here, we report that GHSR1α interaction with β-amyloid (Aβ) suppresses GHSR1α activation, leading to compromised GHSR1α regulation of dopamine receptor D1 (DRD1) in the hippocampus from patients with AD. The simultaneous application of the selective GHSR1α agonist MK0677 with the selective DRD1 agonist SKF81297 rescued Ghsr1α function from Aβ inhibition, mitigating hippocampal synaptic injury and improving spatial memory in an AD mouse model. Our data reveal a mechanism of hippocampal vulnerability in AD and suggest that a combined activation of GHSR1α and DRD1 may be a promising approach for treating AD.
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Affiliation(s)
- Jing Tian
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Lan Guo
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Shaomei Sui
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
- Department of Neurology, Qianfoshan Hospital, Shandong First Medical University, Jinan, Shandong 250014, China
| | - Christopher Driskill
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Aarron Phensy
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Qi Wang
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
- Department of Neurology, Qianfoshan Hospital, Shandong First Medical University, Jinan, Shandong 250014, China
| | - Esha Gauba
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Jeffrey M Zigman
- Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Russell H Swerdlow
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Sven Kroener
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Heng Du
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA.
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44
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Cognitive and anxiety-like impairments accompanied by serotonergic ultrastructural and immunohistochemical alterations in early stages of parkinsonism. Brain Res Bull 2019; 146:213-223. [DOI: 10.1016/j.brainresbull.2019.01.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/04/2019] [Accepted: 01/07/2019] [Indexed: 12/21/2022]
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45
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McQuown S, Xia S, Baumgärtel K, Barido R, Anderson G, Dyck B, Scott R, Peters M. Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus. Front Mol Neurosci 2019; 12:21. [PMID: 30792627 PMCID: PMC6374598 DOI: 10.3389/fnmol.2019.00021] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 01/21/2019] [Indexed: 12/28/2022] Open
Abstract
Augmentation of cyclic nucleotide signaling through inhibition of phosphodiesterase (PDE) activity has long been understood to enhance memory. Efforts in this domain have focused predominantly on PDE4, a cAMP-specific phosphodiesterase implicated in consolidation. But less is known about the function of other PDEs expressed in neuroanatomical regions critical to memory. The PDE1 isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/Calmodulin (CaM) dependent manner. Here, we show that knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall. Our data clearly demonstrate a role for the PDE1B isoforms as negative regulators of memory, and they implicate PDE1 in an early phase of consolidation, but not retrieval. Inhibition of PDE1B is a promising therapeutic mechanism for treating memory impairment.
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Affiliation(s)
- Susan McQuown
- Dart NeuroScience, LLC, San Diego, CA, United States
| | - Shouzhen Xia
- Dart NeuroScience, LLC, San Diego, CA, United States
| | | | | | - Gary Anderson
- Dart NeuroScience, LLC, San Diego, CA, United States
| | - Brian Dyck
- Dart NeuroScience, LLC, San Diego, CA, United States
| | | | - Marco Peters
- Dart NeuroScience, LLC, San Diego, CA, United States
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46
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Dopamine in the hippocampal dentate gyrus modulates spatial learning via D1-like receptors. Brain Res Bull 2019; 144:101-107. [DOI: 10.1016/j.brainresbull.2018.11.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 11/08/2018] [Accepted: 11/19/2018] [Indexed: 10/27/2022]
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47
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Stubbendorff C, Hale E, Cassaday HJ, Bast T, Stevenson CW. Dopamine D1-like receptors in the dorsomedial prefrontal cortex regulate contextual fear conditioning. Psychopharmacology (Berl) 2019; 236:1771-1782. [PMID: 30656366 PMCID: PMC6602997 DOI: 10.1007/s00213-018-5162-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 12/21/2018] [Indexed: 11/29/2022]
Abstract
RATIONALE Dopamine D1 receptor (D1R) signalling is involved in contextual fear conditioning. The D1R antagonist SCH23390 impairs the acquisition of contextual fear when administered systemically or infused locally into the dorsal hippocampus or basolateral amygdala. OBJECTIVES We determined if state dependency may account for the impairment in contextual fear conditioning caused by systemic SCH23390 administration. We also examined if the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens (NAc), and ventral hippocampus (VH) are involved in mediating the effect of systemic SCH23390 treatment on contextual fear conditioning. METHODS In experiment 1, SCH23390 (0.1 mg/kg) or vehicle was given before contextual fear conditioning and/or retrieval. In experiment 2, SCH23390 (2.5 μg/0.5 uL) or vehicle was infused locally into dmPFC, NAc, or VH before contextual fear conditioning, and retrieval was tested drug-free. Freezing was quantified as a measure of contextual fear. RESULTS In experiment 1, SCH23390 given before conditioning or before both conditioning and retrieval decreased freezing at retrieval, whereas SCH23390 given only before retrieval had no effect. In experiment 2, SCH23390 infused into dmPFC before conditioning decreased freezing at retrieval, while infusion of SCH23390 into NAc or VH had no effect. CONCLUSIONS The results of experiment 1 confirm those of previous studies indicating that D1Rs are required for the acquisition but not retrieval of contextual fear and rule out state dependency as an explanation for these findings. Moreover, the results of experiment 2 provide evidence that dmPFC is also part of the neural circuitry through which D1R signalling regulates contextual fear conditioning.
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Affiliation(s)
- Christine Stubbendorff
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK.
| | - Ed Hale
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD UK
| | - Helen J. Cassaday
- School of Psychology@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK ,School of Neuroscience@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK
| | - Tobias Bast
- School of Psychology@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK ,School of Neuroscience@Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD UK
| | - Carl W. Stevenson
- School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD UK
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48
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Braun EK, Wimmer GE, Shohamy D. Retroactive and graded prioritization of memory by reward. Nat Commun 2018; 9:4886. [PMID: 30459310 PMCID: PMC6244210 DOI: 10.1038/s41467-018-07280-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 10/24/2018] [Indexed: 11/08/2022] Open
Abstract
Many decisions are based on an internal model of the world. Yet, how such a model is constructed from experience and represented in memory remains unknown. We test the hypothesis that reward shapes memory for sequences of events by retroactively prioritizing memory for objects as a function of their distance from reward. Human participants encountered neutral objects while exploring a series of mazes for reward. Across six data sets, we find that reward systematically modulates memory for neutral objects, retroactively prioritizing memory for objects closest to the reward. This effect of reward on memory emerges only after a 24-hour delay and is stronger for mazes followed by a longer rest interval, suggesting a role for post-reward replay and overnight consolidation, as predicted by neurobiological data in animals. These findings demonstrate that reward retroactively prioritizes memory along a sequential gradient, consistent with the role of memory in supporting adaptive decision-making.
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Affiliation(s)
- Erin Kendall Braun
- Department of Psychology, Columbia University, 406 Schermerhorn Hall, 1190 Amsterdam Ave MC 5501, New York, NY, 10027, USA.
| | - G Elliott Wimmer
- Max Planck University College London Centre for Computational Psychiatry and Ageing Research and Wellcome Centre for Human Neuroimaging, University College London, London, WC1B 5EH, UK
| | - Daphna Shohamy
- Department of Psychology, Columbia University, 406 Schermerhorn Hall, 1190 Amsterdam Ave MC 5501, New York, NY, 10027, USA
- Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, 3327 Broadway, New York, NY, 10027, USA
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49
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Buckley MG, Bast T. A new human delayed-matching-to-place test in a virtual environment reverse-translated from the rodent watermaze paradigm: Characterization of performance measures and sex differences. Hippocampus 2018; 28:796-812. [PMID: 30451330 DOI: 10.1002/hipo.22992] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 03/14/2018] [Accepted: 05/27/2018] [Indexed: 11/09/2022]
Abstract
Watermaze tests of place learning and memory in rodents and corresponding reverse-translated human paradigms in real or virtual environments are key tools to study hippocampal function. In common variants, the animal or human participant has to find a hidden goal that remains in the same place over many trials, allowing for incremental learning of the place with reference to distal cues surrounding the circular, featureless maze. Although the hippocampus is involved in incremental place learning, rodent studies have shown that the delayed-matching-to-place (DMP) watermaze test is a more sensitive assay of hippocampal function. On the DMP test, the goal location changes every four trials, requiring the rapid updating of place memory. Here, we developed a virtual DMP test reverse-translated from the rat watermaze DMP paradigm. In two replications, participants showed 1-trial place learning, evidenced by marked latency and path length savings between Trials 1 and 2 to the same goal location, and by search preference for the vicinity of the goal when Trial 2 was run as probe trial (during which the goal was removed). The performance was remarkably similar to rats' performance on the watermaze DMP test. In both replications, male participants showed greater savings and search preferences compared to female participants. Male participants also showed better mental rotation performance, although mental rotation scores did not consistently correlate with DMP performance measures, pointing to distinct neurocognitive mechanisms. The remarkable similarity between rodent and human DMP performance suggests similar underlying neuro-psychological mechanisms, including hippocampus dependence. The new virtual DMP test may, therefore, provide a sensitive tool to probe human hippocampal function.
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Affiliation(s)
| | - Tobias Bast
- School of Psychology and Neuroscience@Nottingham, University of Nottingham, Nottingham, United Kingdom
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Duszkiewicz AJ, McNamara CG, Takeuchi T, Genzel L. Novelty and Dopaminergic Modulation of Memory Persistence: A Tale of Two Systems. Trends Neurosci 2018; 42:102-114. [PMID: 30455050 PMCID: PMC6352318 DOI: 10.1016/j.tins.2018.10.002] [Citation(s) in RCA: 190] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 09/26/2018] [Accepted: 10/01/2018] [Indexed: 11/10/2022]
Abstract
Adaptation to the ever-changing world is critical for survival, and our brains are particularly tuned to remember events that differ from previous experiences. Novel experiences induce dopamine release in the hippocampus, a process which promotes memory persistence. While axons from the ventral tegmental area (VTA) were generally thought to be the exclusive source of hippocampal dopamine, recent studies have demonstrated that noradrenergic neurons in the locus coeruleus (LC) corelease noradrenaline and dopamine in the hippocampus and that their dopamine release boosts memory retention as well. In this opinion article, we propose that the projections originating from the VTA and the LC belong to two distinct systems that enhance memory of novel events. Novel experiences that share some commonality with past ones (‘common novelty’) activate the VTA and promote semantic memory formation via systems memory consolidation. By contrast, experiences that bear only a minimal relationship to past experiences (‘distinct novelty’) activate the LC to trigger strong initial memory consolidation in the hippocampus, resulting in vivid and long-lasting episodic memories. Novelty induces dopamine release in the hippocampus, triggering memory consolidation to boost memory persistence. Two dopaminergic systems (the ventral tegmental area- and locus coeruleus-hippocampus systems) can stabilise memory through novelty-induced dopamine release in the hippocampus. Novel experiences can be viewed as a spectrum, from experiences that, while clearly novel, share some commonality with past experiences (‘common novelty’), to more fundamentally distinct experiences that bear minimal relationships to past experiences (‘distinct novelty’). We propose that events characterised by ‘common novelty’ boost memory retention via activation of the ventral tegmental area-hippocampus system, resulting in initial consolidation followed by systems consolidation to create neocortical, semantic, long-term memories. We further propose that events characterised by ‘distinct novelty’ lead to the boost of detailed hippocampal, episodic, long-term memory via activation of the locus coeruleus-hippocampus system through strong upregulation of the synaptic tagging and capture mechanism.
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Affiliation(s)
- Adrian J Duszkiewicz
- Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Colin G McNamara
- MRC Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford, UK
| | - Tomonori Takeuchi
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic-EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark.
| | - Lisa Genzel
- Donders Institute for Brain, Cognition, and Behaviour, Radboud University and Radboudumc, Nijmegen, The Netherlands.
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