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Salarvandian S, Digaleh H, Khodagholi F, Javadpour P, Asadi S, Zaman AAO, Dargahi L. Harmonic activity of glutamate dehydrogenase and neuroplasticity: The impact on aging, cognitive dysfunction, and neurodegeneration. Behav Brain Res 2025; 480:115399. [PMID: 39675635 DOI: 10.1016/j.bbr.2024.115399] [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: 07/25/2024] [Revised: 11/21/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
In recent years, glutamate has attracted significant attention for its roles in various brain processes. However, one of its key regulators, glutamate dehydrogenase (GDH), remains understudied despite its pivotal role in several biochemical pathways. Dysfunction or dysregulation of GDH has been implicated in aging and various neurological disorders, such as Alzheimer's disease and Parkinson's disease. In this review, the impact of GDH on aging, cognitive impairment, and neurodegenerative conditions, as exemplars of the phenomena that may affected by neuroplasticity, has been reviewed. Despite extensive research on synaptic plasticity, the precise influence of GDH on brain structure and function remains undiscovered. This review of existing literature on GDH and neuroplasticity reveals diverse and occasionally conflicting effects. Future research endeavors should aim to describe the precise mechanisms by which GDH influences neuroplasticity (eg. synaptic plasticity and neurogenesis), particularly in the context of human aging and disease progression. Studies on GDH activity have been limited by factors such as insufficient sample sizes and varying experimental conditions. Researchers should focus on investigating the molecular mechanisms by which GDH modulates neuroplasticity, utilizing various animal strains and species, ages, sexes, GDH isoforms, brain regions, and cell types. Understanding GDH's role in neuroplasticity may offer innovative therapeutic strategies for neurodegenerative and psychiatric diseases, potentially slowing the aging process and promoting brain regeneration.
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Affiliation(s)
- Shakiba Salarvandian
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hadi Digaleh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Neurosurgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Pegah Javadpour
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sareh Asadi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ali Orang Zaman
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Xu M, Liu F, Hu Y, Li H, Wei Y, Zhong S, Pei J, Deng L. Adaptive Synaptic Scaling in Spiking Networks for Continual Learning and Enhanced Robustness. IEEE TRANSACTIONS ON NEURAL NETWORKS AND LEARNING SYSTEMS 2025; 36:5151-5165. [PMID: 38536699 DOI: 10.1109/tnnls.2024.3373599] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Synaptic plasticity plays a critical role in the expression power of brain neural networks. Among diverse plasticity rules, synaptic scaling presents indispensable effects on homeostasis maintenance and synaptic strength regulation. In the current modeling of brain-inspired spiking neural networks (SNN), backpropagation through time is widely adopted because it can achieve high performance using a small number of time steps. Nevertheless, the synaptic scaling mechanism has not yet been well touched. In this work, we propose an experience-dependent adaptive synaptic scaling mechanism (AS-SNN) for spiking neural networks. The learning process has two stages: First, in the forward path, adaptive short-term potentiation or depression is triggered for each synapse according to afferent stimuli intensity accumulated by presynaptic historical neural activities. Second, in the backward path, long-term consolidation is executed through gradient signals regulated by the corresponding scaling factor. This mechanism shapes the pattern selectivity of synapses and the information transfer they mediate. We theoretically prove that the proposed adaptive synaptic scaling function follows a contraction map and finally converges to an expected fixed point, in accordance with state-of-the-art results in three tasks on perturbation resistance, continual learning, and graph learning. Specifically, for the perturbation resistance and continual learning tasks, our approach improves the accuracy on the N-MNIST benchmark over the baseline by 44% and 25%, respectively. An expected firing rate callback and sparse coding can be observed in graph learning. Extensive experiments on ablation study and cost evaluation evidence the effectiveness and efficiency of our nonparametric adaptive scaling method, which demonstrates the great potential of SNN in continual learning and robust learning.
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Xu N, He Y, Wei YN, Bai L, Wang L. Possible antidepressant mechanism of acupuncture: targeting neuroplasticity. Front Neurosci 2025; 19:1512073. [PMID: 40018358 PMCID: PMC11865234 DOI: 10.3389/fnins.2025.1512073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/03/2025] [Indexed: 03/01/2025] Open
Abstract
Major depressive disorder (MDD) is a highly prevalent and severely disabling psychiatric disorder that decreases quality of life and imposes substantial economic burden. Acupuncture has emerged as an effective adjunctive treatment for depression, it regulates neurotransmitters involved in mood regulation and modulates the activity of specific brain regions associated with emotional processing, as evidenced by neuroimaging and biochemical studies. Despite these insights, the precise neuroplastic mechanisms through which acupuncture exerts its antidepressant effects remain not fully elucidated. This review aims to summarize the current knowledge on acupuncture's modulation of neuroplasticity in depression, with a focus on the neuroplasticity-based targets associated with acupuncture's antidepressant effects. We encapsulate two decades of research into the neurobiological mechanisms underpinning the efficacy of acupuncture in treating depression. Additionally, we detail the acupoints and electroacupuncture parameters used in the treatment of depression to better serve clinical application.
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Affiliation(s)
- Ning Xu
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yue He
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yong-Nan Wei
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lu Bai
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Long Wang
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Hagena H, Manahan-Vaughan D. Oppositional and competitive instigation of hippocampal synaptic plasticity by the VTA and locus coeruleus. Proc Natl Acad Sci U S A 2025; 122:e2402356122. [PMID: 39793037 PMCID: PMC11725844 DOI: 10.1073/pnas.2402356122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 10/19/2024] [Indexed: 01/12/2025] Open
Abstract
The novelty, saliency, and valency of ongoing experiences potently influence the firing rate of the ventral tegmental area (VTA) and the locus coeruleus (LC). Associative experience, in turn, is recorded into memory by means of hippocampal synaptic plasticity that is regulated by noradrenaline sourced from the LC, and dopamine, sourced from both the VTA and LC. Two persistent forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD) support the encoding of different kinds of spatial experience. To what extent the VTA and the LC influence the direction of change of synaptic plasticity and therefore the content of stored experience is not clear. Here, we report that test-pulse activation of Schaffer-collateral-CA1 synapses of freely behaving male rats, in conjunction with VTA stimulation, results in LTP (>24 h), whereas concomitant hippocampal afferent and LC stimulation results in LTD (>24 h). Effects are frequency-dependent (1 to 50 Hz) and competitive: high-frequency (25 Hz), but not low-frequency (5 Hz) optogenetic activation of tyrosine hydroxylase-positive (TH+) neurons in the VTA, results in D1/D5R-dependent LTP, whereas 5 Hz (but not 1, or 25 Hz) activation of TH+ neurons in the LC results in hippocampal LTD that is both D1/D5 and β-AR-dependent. These results suggest that the VTA and LC do not work in synergy, but rather function in a competing fashion to drive different forms of information encoding through synaptic plasticity. Our findings indicate that information transmitted by the VTA and LC is likely to play a decisive role in the shaping of hippocampal information storage and the nature of learned experience.
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Affiliation(s)
- Hardy Hagena
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum44780, Germany
| | - Denise Manahan-Vaughan
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum44780, Germany
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Gao Y, Lin F, Cai B, Wu J, Wei C, Grech R, Ji Z. Mapless navigation via Hierarchical Reinforcement Learning with memory-decaying novelty. ROBOTICS AND AUTONOMOUS SYSTEMS 2024; 182:104815. [DOI: 10.1016/j.robot.2024.104815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Martínez-Gallego I, Coatl-Cuaya H, Rodriguez-Moreno A. Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses. eLife 2024; 13:RP98031. [PMID: 39541232 PMCID: PMC11563576 DOI: 10.7554/elife.98031] [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: 11/16/2024] Open
Abstract
The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.
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Affiliation(s)
- Irene Martínez-Gallego
- Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de OlavideSevillaSpain
| | - Heriberto Coatl-Cuaya
- Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de OlavideSevillaSpain
| | - Antonio Rodriguez-Moreno
- Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de OlavideSevillaSpain
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Higa GSV, Viana FJC, Francis-Oliveira J, Cruvinel E, Franchin TS, Marcourakis T, Ulrich H, De Pasquale R. Serotonergic neuromodulation of synaptic plasticity. Neuropharmacology 2024; 257:110036. [PMID: 38876308 DOI: 10.1016/j.neuropharm.2024.110036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/15/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Synaptic plasticity constitutes a fundamental process in the reorganization of neural networks that underlie memory, cognition, emotional responses, and behavioral planning. At the core of this phenomenon lie Hebbian mechanisms, wherein frequent synaptic stimulation induces long-term potentiation (LTP), while less activation leads to long-term depression (LTD). The synaptic reorganization of neuronal networks is regulated by serotonin (5-HT), a neuromodulator capable of modify synaptic plasticity to appropriately respond to mental and behavioral states, such as alertness, attention, concentration, motivation, and mood. Lately, understanding the serotonergic Neuromodulation of synaptic plasticity has become imperative for unraveling its impact on cognitive, emotional, and behavioral functions. Through a comparative analysis across three main forebrain structures-the hippocampus, amygdala, and prefrontal cortex, this review discusses the actions of 5-HT on synaptic plasticity, offering insights into its role as a neuromodulator involved in emotional and cognitive functions. By distinguishing between plastic and metaplastic effects, we provide a comprehensive overview about the mechanisms of 5-HT neuromodulation of synaptic plasticity and associated functions across different brain regions.
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Affiliation(s)
- Guilherme Shigueto Vilar Higa
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil; Departamento de Bioquímica, Instituto de Química (USP), Butantã, São Paulo, SP, 05508-900, Brazil
| | - Felipe José Costa Viana
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - José Francis-Oliveira
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Emily Cruvinel
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Thainá Soares Franchin
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Tania Marcourakis
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química (USP), Butantã, São Paulo, SP, 05508-900, Brazil
| | - Roberto De Pasquale
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil.
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Kramer M, Hoang TH, Yang H, Shchyglo O, Böge J, Neubacher U, Colitti-Klausnitzer J, Manahan-Vaughan D. Intracerebral inoculation of healthy non-transgenic rats with a single aliquot of oligomeric amyloid-β (1-42) profoundly and progressively alters brain function throughout life. Front Aging Neurosci 2024; 16:1397901. [PMID: 39156737 PMCID: PMC11327071 DOI: 10.3389/fnagi.2024.1397901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/09/2024] [Indexed: 08/20/2024] Open
Abstract
One of the puzzling aspects of sporadic Alzheimer's disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Aβ), accompany disease progression, but whether this comprises a trigger or a consequence of AD is still a topic of debate. It is clear however that the cerebral presence of oligomeric Aβ (1-42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Aβ (1-42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Aβ-pathology and learning impairments. Here, we show that a once-off inoculation of the brains of healthy adult rats with oligomeric Aβ (1-42) exerts debilitating effects on the long-term viability of the hippocampus, one of the primary targets of AD. Changes are progressive: months after treatment, synaptic plasticity, neuronal firing and spatial learning are impaired and expression of plasticity-related proteins are changed, in the absence of amyloid plaques. Early changes relate to activation of microglia, whereas later changes are associated with a reconstruction of astroglial morphology. These data suggest that a disruption of Aβ homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD.
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Hagena H, Manahan-Vaughan D. Interplay of hippocampal long-term potentiation and long-term depression in enabling memory representations. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230229. [PMID: 38853558 PMCID: PMC11343234 DOI: 10.1098/rstb.2023.0229] [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: 01/08/2024] [Revised: 04/22/2024] [Accepted: 05/07/2024] [Indexed: 06/11/2024] Open
Abstract
Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are Hebbian forms of synaptic plasticity that are widely believed to comprise the physiological correlates of associative learning. They comprise a persistent, input-specific increase or decrease, respectively, in synaptic efficacy that, in rodents, can be followed for days and weeks in vivo. Persistent (>24 h) LTP and LTD exhibit distinct frequency-dependencies and molecular profiles in the hippocampal subfields. Moreover, causal and genetic studies in behaving rodents indicate that both LTP and LTD fulfil specific and complementary roles in the acquisition and retention of spatial memory. LTP is likely to be responsible for the generation of a record of spatial experience, which may serve as an associative schema that can be re-used to expedite or facilitate subsequent learning. In contrast, LTD may enable modification and dynamic updating of this representation, such that detailed spatial content information is included and the schema is rendered unique and distinguishable from other similar representations. Together, LTP and LTD engage in a dynamic interplay that supports the generation of complex associative memories that are resistant to generalization. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Affiliation(s)
- Hardy Hagena
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum44780, Germany
| | - Denise Manahan-Vaughan
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum44780, Germany
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Südkamp N, Shchyglo O, Manahan-Vaughan D. GluN2A or GluN2B subunits of the NMDA receptor contribute to changes in neuronal excitability and impairments in LTP in the hippocampus of aging mice but do not mediate detrimental effects of oligomeric Aβ (1-42). Front Aging Neurosci 2024; 16:1377085. [PMID: 38832073 PMCID: PMC11144909 DOI: 10.3389/fnagi.2024.1377085] [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: 01/26/2024] [Accepted: 04/26/2024] [Indexed: 06/05/2024] Open
Abstract
Studies in rodent models have revealed that oligomeric beta-amyloid protein [Aβ (1-42)] plays an important role in the pathogenesis of Alzheimer's disease. Early elevations in hippocampal neuronal excitability caused by Aβ (1-42) have been proposed to be mediated via enhanced activation of GluN2B-containing N-methyl-D-aspartate receptors (NMDAR). To what extent GluN2A or GluN2B-containing NMDAR contribute to Aβ (1-42)-mediated impairments of hippocampal function in advanced rodent age is unclear. Here, we assessed hippocampal long-term potentiation (LTP) and neuronal responses 4-5 weeks after bilateral intracerebral inoculation of 8-15 month old GluN2A+/- or GluN2B+/- transgenic mice with oligomeric Aβ (1-42), or control peptide. Whole-cell patch-clamp recordings in CA1 pyramidal neurons revealed a more positive resting membrane potential and increased total spike time in GluN2A+/-, but not GluN2B+/--hippocampi following treatment with Aβ (1-42) compared to controls. Action potential 20%-width was increased, and the descending slope was reduced, in Aβ-treated GluN2A+/-, but not GluN2B+/- hippocampi. Sag ratio was increased in Aβ-treated GluN2B+/--mice. Firing frequency was unchanged in wt, GluN2A+/-, and GluN2B+/-hippocampi after Aβ-treatment. Effects were not significantly different from responses detected under the same conditions in wt littermates, however. LTP that lasted for over 2 h in wt hippocampal slices was significantly reduced in GluN2A+/- and was impaired for 15 min in GluN2B+/--hippocampi compared to wt littermates. Furthermore, LTP (>2 h) was significantly impaired in Aβ-treated hippocampi of wt littermates compared to wt treated with control peptide. LTP induced in Aβ-treated GluN2A+/- and GluN2B+/--hippocampi was equivalent to LTP in control peptide-treated transgenic and Aβ-treated wt animals. Taken together, our data indicate that knockdown of GluN2A subunits subtly alters membrane properties of hippocampal neurons and reduces the magnitude of LTP. GluN2B knockdown reduces the early phase of LTP but leaves later phases intact. Aβ (1-42)-treatment slightly exacerbates changes in action potential properties in GluN2A+/--mice. However, the vulnerability of the aging hippocampus to Aβ-mediated impairments of LTP is not mediated by GluN2A or GluN2B-containing NMDAR.
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Hoang TH, Manahan-Vaughan D. Differentiated somatic gene expression is triggered in the dorsal hippocampus and the anterior retrosplenial cortex by hippocampal synaptic plasticity prompted by spatial content learning. Brain Struct Funct 2024; 229:639-655. [PMID: 37690045 PMCID: PMC10978647 DOI: 10.1007/s00429-023-02694-z] [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: 04/05/2023] [Accepted: 08/07/2023] [Indexed: 09/12/2023]
Abstract
Hippocampal afferent inputs, terminating on proximal and distal subfields of the cornus ammonis (CA), enable the functional discrimination of 'what' (item identity) and 'where' (spatial location) elements of a spatial representation. This kind of information is supported by structures such as the retrosplenial cortex (RSC). Spatial content learning promotes the expression of hippocampal synaptic plasticity, particularly long-term depression (LTD). In the CA1 region, this is specifically facilitated by the learning of item-place features of a spatial environment. Gene-tagging, by means of time-locked fluorescence in situ hybridization (FISH) to detect nuclear expression of immediate early genes, can reveal neuronal populations that engage in experience-dependent information encoding. In the current study, using FISH, we examined if learning-facilitated LTD results in subfield-specific information encoding in the hippocampus and RSC. Rats engaged in novel exploration of small items during stimulation of Schaffer collateral-CA1 synapses. This resulted in LTD (> 24 h). FISH, to detect nuclear expression of Homer1a, revealed that the distal-CA1 and proximal-CA3 subcompartments were particularly activated by this event. By contrast, all elements of the proximodistal cornus ammonis-axis showed equal nuclear Homer1a expression following LTD induction solely by means of afferent stimulation. The RSC exhibited stronger nuclear Homer1a expression in response to learning-facilitated LTD, and to novel item-place experience, compared to LTD induced by sole afferent stimulation in CA1. These results show that both the cornus ammonis and RSC engage in differentiated information encoding of item-place learning that is salient enough, in its own right, to drive the expression of hippocampal LTD. These results also reveal a novel role of the RSC in item-place learning.
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Affiliation(s)
- Thu-Huong Hoang
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Universitätsstr. 150, MA 4/150, 44780, Bochum, Germany
| | - Denise Manahan-Vaughan
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Universitätsstr. 150, MA 4/150, 44780, Bochum, Germany.
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Aidil-Carvalho F, Caulino-Rocha A, Ribeiro JA, Cunha-Reis D. Mismatch novelty exploration training shifts VPAC 1 receptor-mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats. J Neurosci Res 2024; 102:e25333. [PMID: 38656542 DOI: 10.1002/jnr.25333] [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: 12/28/2023] [Revised: 03/04/2024] [Accepted: 04/04/2024] [Indexed: 04/26/2024]
Abstract
Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.
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Affiliation(s)
- Fatima Aidil-Carvalho
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ana Caulino-Rocha
- BioISI-Instituto de Biossistemas e Ciências Integrativas, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Departamento de Biologia Vegetal, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Joaquim Alexandre Ribeiro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Diana Cunha-Reis
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- BioISI-Instituto de Biossistemas e Ciências Integrativas, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Departamento de Biologia Vegetal, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
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Nascimento C, Guerreiro-Pinto V, Pawlak S, Caulino-Rocha A, Amat-Garcia L, Cunha-Reis D. Impaired Response to Mismatch Novelty in the Li 2+-Pilocarpine Rat Model of TLE: Correlation with Hippocampal Monoaminergic Inputs. Biomedicines 2024; 12:631. [PMID: 38540244 PMCID: PMC10968540 DOI: 10.3390/biomedicines12030631] [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: 02/08/2024] [Revised: 03/06/2024] [Accepted: 03/08/2024] [Indexed: 11/11/2024] Open
Abstract
Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li2+-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, SRS rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in SRS rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from SRS rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in SRS animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li2+-pilocarpine model of epilepsy 4-8 weeks after the onset of SRSs and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy.
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Affiliation(s)
- Carlos Nascimento
- Unidade de Fisiologia Clínica e Translacional, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| | - Vasco Guerreiro-Pinto
- BioISI—Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
| | - Seweryn Pawlak
- BioISI—Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
| | - Ana Caulino-Rocha
- BioISI—Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
| | - Laia Amat-Garcia
- BioISI—Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
| | - Diana Cunha-Reis
- BioISI—Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
- Departamento de Biologia Vegetal, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
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14
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Savarimuthu A, Ponniah RJ. Receive, Retain and Retrieve: Psychological and Neurobiological Perspectives on Memory Retrieval. Integr Psychol Behav Sci 2024; 58:303-318. [PMID: 36738400 DOI: 10.1007/s12124-023-09752-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2023] [Indexed: 02/05/2023]
Abstract
Memory and learning are interdependent processes that involve encoding, storage, and retrieval. Especially memory retrieval is a fundamental cognitive ability to recall memory traces and update stored memory with new information. For effective memory retrieval and learning, the memory must be stabilized from short-term memory to long-term memory. Hence, it is necessary to understand the process of memory retention and retrieval that enhances the process of learning. Though previous cognitive neuroscience research has focused on memory acquisition and storage, the neurobiological mechanisms underlying memory retrieval and its role in learning are less understood. Therefore, this article offers the viewpoint that memory retrieval is essential for selecting, reactivating, stabilizing, and storing information in long-term memory. In arguing how memories are retrieved, consolidated, transmitted, and strengthened for the long term, the article will examine the psychological and neurobiological aspects of memory and learning with synaptic plasticity, long-term potentiation, genetic transcription, and theta oscillation in the brain.
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Affiliation(s)
- Anisha Savarimuthu
- Department of Humanities and Social Sciences, National Institute of Technology, Tiruchirappalli, India
| | - R Joseph Ponniah
- Department of Humanities and Social Sciences, National Institute of Technology, Tiruchirappalli, India.
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15
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Gutiérrez-Vera B, Reyes-García SE, Escobar ML. Brief environmental enrichment elicits metaplasticity on the insular cortex in vivo and reduces the strength of conditioned taste aversion. Neurobiol Learn Mem 2023; 205:107840. [PMID: 37805119 DOI: 10.1016/j.nlm.2023.107840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 09/20/2023] [Accepted: 10/04/2023] [Indexed: 10/09/2023]
Abstract
Environmental enrichment (EE) is known to improve memory and cognition and modulate the impact of aversive stimuli in animals, promoting the development of resilience to stressful situations. Likewise, it is known that EE can modulate synaptic plasticity as is the case of long-term potentiation (LTP). These findings have been described initially in ex vivo preparations, suggesting that the effects of EE are the result of an early modification of the synaptic excitability and transmission. In this regard, it is known that metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. In addition, we have shown that CTA extinction allows the induction but not the maintenance of IC-LTP of the Bla-IC pathway. Recently, we also showed that prior exposure to environmental enrichment for three weeks reduces the strength of CTA, restoring the brain-derived neurotrophic factor (BDNF) levels in the IC. The present study aimed to analyze the effects of brief exposure to an enriched environment on the strength of aversive memory, as well as on the in vivo IC-LTP. To do so, adult rats were exposed for seven days to an EE, either before CTA training or LTP induction in the Bla-IC pathway. Our results demonstrate that a seven-day exposure to an enriched environment attenuates the aversive response to a strong CTA and allows the induction but not the maintenance of LTP in the insular cortex. These findings provide evidence that metaplastic regulation in a neocortical region takes part in the mechanisms through which brief exposure to enriched environments attenuates an aversive response.
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Affiliation(s)
- Beatriz Gutiérrez-Vera
- División de Investigación y Estudios de Posgrado, Facultad de Psicología, Universidad Nacional Autónoma de México, 04510, Mexico
| | - Salma E Reyes-García
- División de Investigación y Estudios de Posgrado, Facultad de Psicología, Universidad Nacional Autónoma de México, 04510, Mexico
| | - Martha L Escobar
- División de Investigación y Estudios de Posgrado, Facultad de Psicología, Universidad Nacional Autónoma de México, 04510, Mexico.
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16
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Luo J, Tian G, Zhang DG, Zhang XC, Lu ZN, Zhang ZD, Cai JW, Zhong YN, Xu JL, Gao X, Wang SD. Voltage-Mode Ferroelectric Synapse for Neuromorphic Computing. ACS APPLIED MATERIALS & INTERFACES 2023; 15:48452-48461. [PMID: 37802499 DOI: 10.1021/acsami.3c09506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Ferroelectric materials with a modulable polarization extent hold promise for exploring voltage-driven neuromorphic hardware, in which direct current flow can be minimized. Utilizing a single active layer of an insulating ferroelectric polymer, we developed a voltage-mode ferroelectric synapse that can continuously and reversibly update its states. The device states are straightforwardly manifested in the form of variable output voltage, enabling large-scale direct cascading of multiple ferroelectric synapses to build a deep physical neural network. Such a neural network based on potential superposition rather than current flow is analogous to the biological counterpart driven by action potentials in the brain. A high accuracy of over 97% for the simulation of handwritten digit recognition is achieved using the voltage-mode neural network. The controlled ferroelectric polarization, revealed by piezoresponse force microscopy, turns out to be responsible for the synaptic weight updates in the ferroelectric synapses. The present work demonstrates an alternative strategy for the design and construction of emerging artificial neural networks.
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Affiliation(s)
- Jie Luo
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Guo Tian
- Institute for Advanced Materials and Guangdong Provincial Key Laboratory of Optical Information Materials and Technology, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510006, P. R. China
| | - Ding-Guo Zhang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Xing-Chen Zhang
- Institute for Advanced Materials and Guangdong Provincial Key Laboratory of Optical Information Materials and Technology, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510006, P. R. China
| | - Zhen-Ni Lu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Zhong-Da Zhang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Jia-Wei Cai
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Ya-Nan Zhong
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Jian-Long Xu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Xu Gao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Sui-Dong Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. China
- Macao Institute of Materials Science and Engineering (MIMSE), MUST-SUDA Joint Research Center for Advanced Functional Materials, Macau University of Science and Technology, Taipa, Macao 999078, P. R. China
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17
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Arriagada-Diaz J, Flores-Muñoz C, Gómez-Soto B, Labraña-Allende M, Mattar-Araos M, Prado-Vega L, Hinostroza F, Gajardo I, Guerra-Fernández MJ, Bevilacqua JA, Cárdenas AM, Bitoun M, Ardiles AO, Gonzalez-Jamett AM. A centronuclear myopathy-causing mutation in dynamin-2 disrupts neuronal morphology and excitatory synaptic transmission in a murine model of the disease. Neuropathol Appl Neurobiol 2023; 49:e12918. [PMID: 37317811 DOI: 10.1111/nan.12918] [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: 09/12/2022] [Revised: 04/30/2023] [Accepted: 06/02/2023] [Indexed: 06/16/2023]
Abstract
AIMS Dynamin-2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2-linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a dynamin-2 CNM-causing mutation influences the CNS function. METHODS Heterozygous mice harbouring the p.R465W mutation in the dynamin-2 gene (HTZ), the most common causing autosomal dominant CNM, were used as disease model. We evaluated dendritic arborisation and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests. RESULTS HTZ hippocampal neurons exhibited reduced dendritic arborisation and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the dynamin-2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. CONCLUSION Our findings suggest that the dynamin-2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that this GTPase plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.
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Affiliation(s)
- Jorge Arriagada-Diaz
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Programa de Magister en Ciencias, Mención Neurociencia, Universidad de Valparaíso, Valparaíso, Chile
| | - Carolina Flores-Muñoz
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
| | - Bárbara Gómez-Soto
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Programa de Magister en Ciencias Médicas, Mención Biología Celular y Molecular, Universidad de Valparaíso, Valparaíso, Chile
| | - Marjorie Labraña-Allende
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Programa de Magister en Ciencias Médicas, Mención Biología Celular y Molecular, Universidad de Valparaíso, Valparaíso, Chile
| | - Michelle Mattar-Araos
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
| | - Lorena Prado-Vega
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Programa de Magister en Ciencias, Mención Neurociencia, Universidad de Valparaíso, Valparaíso, Chile
| | - Fernando Hinostroza
- Centro de Investigación de Estudios Avanzados del Maule, CIEAM, Vicerrectoría de Investigación y Postgrado, Universidad Católica del Maule, Talca, Chile
- Centro de Investigación en Neuropsicología y Neurociencias Cognitivas, Facultad de Ciencias de la Salud, Universidad Católica del Maule, Talca, Chile
- Escuela de Química y Farmacia, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca, Chile
| | - Ivana Gajardo
- Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Jorge A Bevilacqua
- Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Ana M Cárdenas
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
| | - Marc Bitoun
- Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, F-75013, France
| | - Alvaro O Ardiles
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Centro de Neurología Traslacional, Facultad de Medicina, Universidad de Valparaíso, Valparaíso, Chile
- Centro Interdisciplinario de Estudios en Salud, Facultad de Medicina, Universidad de Valparaíso, Viña del Mar, Chile
| | - Arlek M Gonzalez-Jamett
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Escuela de Química y Farmacia, Facultad de Farmacia, Universidad de Valparaíso, Valparaíso, Chile
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18
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Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway. Mol Psychiatry 2023; 28:1351-1364. [PMID: 36434054 PMCID: PMC10005959 DOI: 10.1038/s41380-022-01877-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022]
Abstract
Spatial learning and memory flexibility are known to require long-term potentiation (LTP) and long-term depression (LTD), respectively, on a cellular basis. We previously showed that cyclin Y (CCNY), a synapse-remodeling cyclin, is a novel actin-binding protein and an inhibitory regulator of functional and structural LTP in vitro. In this study, we report that Ccny knockout (KO) mice exhibit enhanced LTP and weak LTD at Schaffer collateral-CA1 synapses in the hippocampus. In accordance with enhanced LTP, Ccny KO mice showed improved spatial learning and memory. However, although previous studies reported that normal LTD is necessary for memory flexibility, Ccny KO mice intriguingly showed improved memory flexibility, suggesting that weak LTD could exert memory flexibility when combined with enhanced LTP. At the molecular level, CCNY modulated spatial learning and memory flexibility by distinctively affecting the cofilin-actin signaling pathway in the hippocampus. Specifically, CCNY inhibited cofilin activation by original learning, but reversed such inhibition by reversal learning. Furthermore, viral-mediated overexpression of a phosphomimetic cofilin-S3E in hippocampal CA1 regions enhanced LTP, weakened LTD, and improved spatial learning and memory flexibility, thus mirroring the phenotype of Ccny KO mice. In contrast, the overexpression of a non-phosphorylatable cofilin-S3A in hippocampal CA1 regions of Ccny KO mice reversed the synaptic plasticity, spatial learning, and memory flexibility phenotypes observed in Ccny KO mice. Altogether, our findings demonstrate that LTP and LTD cooperatively regulate memory flexibility. Moreover, CCNY suppresses LTP while facilitating LTD in the hippocampus and negatively regulates spatial learning and memory flexibility through the control of cofilin-actin signaling, proposing CCNY as a learning regulator modulating both memorizing and forgetting processes.
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19
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The times they are a-changin': a proposal on how brain flexibility goes beyond the obvious to include the concepts of "upward" and "downward" to neuroplasticity. Mol Psychiatry 2023; 28:977-992. [PMID: 36575306 PMCID: PMC10005965 DOI: 10.1038/s41380-022-01931-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/07/2022] [Accepted: 12/14/2022] [Indexed: 12/28/2022]
Abstract
Since the brain was found to be somehow flexible, plastic, researchers worldwide have been trying to comprehend its fundamentals to better understand the brain itself, make predictions, disentangle the neurobiology of brain diseases, and finally propose up-to-date treatments. Neuroplasticity is simple as a concept, but extremely complex when it comes to its mechanisms. This review aims to bring to light an aspect about neuroplasticity that is often not given enough attention as it should, the fact that the brain's ability to change would include its ability to disconnect synapses. So, neuronal shrinkage, decrease in spine density or dendritic complexity should be included within the concept of neuroplasticity as part of its mechanisms, not as an impairment of it. To that end, we extensively describe a variety of studies involving topics such as neurodevelopment, aging, stress, memory and homeostatic plasticity to highlight how the weakening and disconnection of synapses organically permeate the brain in so many ways as a good practice of its intrinsic physiology. Therefore, we propose to break down neuroplasticity into two sub-concepts, "upward neuroplasticity" for changes related to synaptic construction and "downward neuroplasticity" for changes related to synaptic deconstruction. With these sub-concepts, neuroplasticity could be better understood from a bigger landscape as a vector in which both directions could be taken for the brain to flexibly adapt to certain demands. Such a paradigm shift would allow a better understanding of the concept of neuroplasticity to avoid any data interpretation bias, once it makes clear that there is no morality with regard to the organic and physiological changes that involve dynamic biological systems as seen in the brain.
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20
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Bielewicz J, Kamieniak M, Szymoniuk M, Litak J, Czyżewski W, Kamieniak P. Diagnosis and Management of Neuropathic Pain in Spine Diseases. J Clin Med 2023; 12:jcm12041380. [PMID: 36835916 PMCID: PMC9961043 DOI: 10.3390/jcm12041380] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/31/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Neuropathic pain is generally defined as a non-physiological pain experience caused by damage to the nervous system. It can occur spontaneously, as a reaction to a given stimulus, or independently of its action, leading to unusual pain sensations usually referred to as firing, burning or throbbing. In the course of spine disorders, pain symptoms commonly occur. According to available epidemiological studies, a neuropathic component of pain is often present in patients with spinal diseases, with a frequency ranging from 36% to 55% of patients. Distinguishing between chronic nociceptive pain and neuropathic pain very often remains a challenge. Consequently, neuropathic pain is often underdiagnosed in patients with spinal diseases. In reference to current guidelines for the treatment of neuropathic pain, gabapentin, serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants constitute first-line therapeutic agents. However, long-term pharmacologic treatment often leads to developing tolerance and resistance to used medications. Therefore, in recent years, a plethora of therapeutic methods for neuropathic pain have been developed and investigated to improve clinical outcomes. In this review, we briefly summarized current knowledge about the pathophysiology and diagnosis of neuropathic pain. Moreover, we described the most effective treatment approaches for neuropathic pain and discussed their relevance in the treatment of spinal pain.
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Affiliation(s)
- Joanna Bielewicz
- Department of Neurology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Maciej Kamieniak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Michał Szymoniuk
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
- Correspondence:
| | - Jakub Litak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
- Department of Clinical Immunology, Medical University of Lublin, Chodźki 4A, 20-093 Lublin, Poland
| | - Wojciech Czyżewski
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
- Department of Didactics and Medical Simulation, Medical University of Lublin, Chodźki 4, 20-093 Lublin, Poland
| | - Piotr Kamieniak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
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21
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Neves L, Lobão-Soares B, Araujo APDC, Furtunato AMB, Paiva I, Souza N, Morais AK, Nascimento G, Gavioli E, Tort ABL, Barbosa FF, Belchior H. Theta and gamma oscillations in the rat hippocampus support the discrimination of object displacement in a recognition memory task. Front Behav Neurosci 2022; 16:970083. [PMID: 36620858 PMCID: PMC9811406 DOI: 10.3389/fnbeh.2022.970083] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Episodic memory depends on the recollection of spatial and temporal aspects of past experiences in which the hippocampus plays a critical role. Studies on hippocampal lesions in rodents have shown that dentate gyrus (DG) and CA3 are necessary to detect object displacement in memory tasks. However, the understanding of real-time oscillatory activity underlying memory discrimination of subtle and pronounced displacements remains elusive. Here, we chronically implanted microelectrode arrays in adult male Wistar rats to record network oscillations from DG, CA3, and CA1 of the dorsal hippocampus while animals executed an object recognition task of high and low spatial displacement tests (HD: 108 cm, and LD: 54 cm, respectively). Behavioral analysis showed that the animals discriminate between stationary and displaced objects in the HD but not LD conditions. To investigate the hypothesis that theta and gamma oscillations in different areas of the hippocampus support discrimination processes in a recognition memory task, we compared epochs of object exploration between HD and LD conditions as well as displaced and stationary objects. We observed that object exploration epochs were accompanied by strong rhythmic activity in the theta frequency (6-12 Hz) band in the three hippocampal areas. Comparison between test conditions revealed higher theta band power and higher theta-gamma phase-amplitude coupling in the DG during HD than LD conditions. Similarly, direct comparison between displaced and stationary objects within the HD test showed higher theta band power in CA3 during exploration of displaced objects. Moreover, the discrimination index between displaced and stationary objects directly correlated with CA1 gamma band power in epochs of object exploration. We thus conclude that theta and gamma oscillations in the dorsal hippocampus support the successful discrimination of object displacement in a recognition memory task.
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Affiliation(s)
- Lívia Neves
- Graduate Program in Psychobiology, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Bruno Lobão-Soares
- Graduate Program in Psychobiology, Federal University of Rio Grande do Norte, Natal, RN, Brazil,Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Ana Paula de Castro Araujo
- Graduate Program in Cognitive Neuroscience and Behavior, Federal University of Paraíba, João Pessoa, PB, Brazil,Department of Psychology, Federal University of Paraíba, João Pessoa, PB, Brazil
| | | | - Izabela Paiva
- Brain Institute, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Nicholy Souza
- Graduate Program in Psychobiology, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Anne Kelly Morais
- Graduate Program in Psychobiology, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - George Nascimento
- Department of Biomedical Engineering, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Elaine Gavioli
- Graduate Program in Psychobiology, Federal University of Rio Grande do Norte, Natal, RN, Brazil,Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | | | - Flávio Freitas Barbosa
- Graduate Program in Cognitive Neuroscience and Behavior, Federal University of Paraíba, João Pessoa, PB, Brazil,Department of Psychology, Federal University of Paraíba, João Pessoa, PB, Brazil,*Correspondence: Flávio Freitas Barbosa,
| | - Hindiael Belchior
- Graduate Program in Psychobiology, Federal University of Rio Grande do Norte, Natal, RN, Brazil,Department of Physical Education, Federal University of Rio Grande do Norte, Natal, RN, Brazil,Hindiael Belchior,
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22
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Hagena H, Stacho M, Laja A, Manahan-Vaughan D. Strain-dependent regulation of hippocampal long-term potentiation by dopamine D1/D5 receptors in mice. Front Behav Neurosci 2022; 16:1023361. [PMID: 36545120 PMCID: PMC9760685 DOI: 10.3389/fnbeh.2022.1023361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/26/2022] [Indexed: 12/12/2022] Open
Abstract
The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is species-dependent: rats express more robust and more prolonged LTP in response to a broader afferent frequency range than mice. The C57Bl/6 mouse is an extremely popular murine strain used in studies of hippocampal synaptic plasticity and spatial learning. Recently it was reported that it expresses impoverished LTP compared to other murine strains. Given the important role of the dopamine D1/D5 receptor (D1/D5R) in the maintenance of LTP and in memory consolidation, we explored to what extent strain-dependent differences in LTP in mice are determined by differences in D1/D5R-control. In CaOlaHsd mice, robust LTP was induced that lasted for over 24 h and which was significantly greater in magnitude than LTP induced in C57Bl/6 mice. Intracerebral treatment with a D1/D5R-antagonist (SCH23390) prevented both the early and late phase of LTP in CaOlaHsd mice, whereas only late-LTP was impaired in C57Bl/6 mice. Treatment with a D1/D5R-agonist (Chloro-PB) facilitated short-term potentiation (STP) into LTP (> 24 h) in both strains, whereby effects became evident earlier in CaOlaHsd compared to C57Bl/6 mice. Immunohistochemical analysis revealed a significantly higher expression of D1-receptors in the stratum lacunosum moleculare of CaOlaHsd compared to C57Bl/6 mice. These findings highlight differences in D1/D5R- dependent regulation of strain-dependent variations in hippocampal LTP in C57Bl/6 and CaOlaHsd mice, that may be mediated, in part, by differences in the expression of D1R in the hippocampus.
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23
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Chao OY, Nikolaus S, Yang YM, Huston JP. Neuronal circuitry for recognition memory of object and place in rodent models. Neurosci Biobehav Rev 2022; 141:104855. [PMID: 36089106 PMCID: PMC10542956 DOI: 10.1016/j.neubiorev.2022.104855] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/23/2022] [Accepted: 08/30/2022] [Indexed: 10/14/2022]
Abstract
Rats and mice are used for studying neuronal circuits underlying recognition memory due to their ability to spontaneously remember the occurrence of an object, its place and an association of the object and place in a particular environment. A joint employment of lesions, pharmacological interventions, optogenetics and chemogenetics is constantly expanding our knowledge of the neural basis for recognition memory of object, place, and their association. In this review, we summarize current studies on recognition memory in rodents with a focus on the novel object preference, novel location preference and object-in-place paradigms. The evidence suggests that the medial prefrontal cortex- and hippocampus-connected circuits contribute to recognition memory for object and place. Under certain conditions, the striatum, medial septum, amygdala, locus coeruleus and cerebellum are also involved. We propose that the neuronal circuitry for recognition memory of object and place is hierarchically connected and constructed by different cortical (perirhinal, entorhinal and retrosplenial cortices), thalamic (nucleus reuniens, mediodorsal and anterior thalamic nuclei) and primeval (hypothalamus and interpeduncular nucleus) modules interacting with the medial prefrontal cortex and hippocampus.
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Affiliation(s)
- Owen Y Chao
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA
| | - Susanne Nikolaus
- Department of Nuclear Medicine, University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Yi-Mei Yang
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Joseph P Huston
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University, 40225 Düsseldorf, Germany.
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24
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Dunsmoor JE, Murty VP, Clewett D, Phelps EA, Davachi L. Tag and capture: how salient experiences target and rescue nearby events in memory. Trends Cogn Sci 2022; 26:782-795. [PMID: 35842373 PMCID: PMC9378568 DOI: 10.1016/j.tics.2022.06.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/08/2022] [Accepted: 06/20/2022] [Indexed: 10/17/2022]
Abstract
The long-term fate of a memory is not exclusively determined by the events occurring at the moment of encoding. Research at the cellular, circuit, and behavioral levels is beginning to reveal how neurochemical activations in the moments surrounding an event can retroactively and proactively rescue weak memory for seemingly mundane experiences. We review emerging evidence showing enhancement of weakly formed memories encoded minutes to hours before or after a related motivationally relevant experience. We discuss proposed neurobiological mechanisms for strengthening weak memories formed in temporal proximity to a strong event, and how this knowledge could be leveraged to improve memory for information that is prone to forgetting.
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Affiliation(s)
- Joseph E Dunsmoor
- Department of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas at Austin, Austin, TX, USA; Institute for Neuroscience, University of Texas at Austin, Austin, TX, USA.
| | - Vishnu P Murty
- Department of Psychology, Temple University, Philadelphia, PA, USA
| | - David Clewett
- Department of Psychology, University of California, Los Angeles, CA, USA
| | | | - Lila Davachi
- Nathan Kline Institute, Orangeburg, NY, USA; Department of Psychology, Columbia University, New York, NY, USA.
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25
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Muhia M, YuanXiang P, Sedlacik J, Schwarz JR, Heisler FF, Gromova KV, Thies E, Breiden P, Pechmann Y, Kreutz MR, Kneussel M. Muskelin regulates actin-dependent synaptic changes and intrinsic brain activity relevant to behavioral and cognitive processes. Commun Biol 2022; 5:589. [PMID: 35705737 PMCID: PMC9200775 DOI: 10.1038/s42003-022-03446-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 05/04/2022] [Indexed: 12/02/2022] Open
Abstract
Muskelin (Mkln1) is implicated in neuronal function, regulating plasma membrane receptor trafficking. However, its influence on intrinsic brain activity and corresponding behavioral processes remains unclear. Here we show that murine Mkln1 knockout causes non-habituating locomotor activity, increased exploratory drive, and decreased locomotor response to amphetamine. Muskelin deficiency impairs social novelty detection while promoting the retention of spatial reference memory and fear extinction recall. This is strongly mirrored in either weaker or stronger resting-state functional connectivity between critical circuits mediating locomotor exploration and cognition. We show that Mkln1 deletion alters dendrite branching and spine structure, coinciding with enhanced AMPAR-mediated synaptic transmission but selective impairment in synaptic potentiation maintenance. We identify muskelin at excitatory synapses and highlight its role in regulating dendritic spine actin stability. Our findings point to aberrant spine actin modulation and changes in glutamatergic synaptic function as critical mechanisms that contribute to the neurobehavioral phenotype arising from Mkln1 ablation. A murine muskelin knockout induces increased exploratory drive and alters cognition and functional connectivity. These effects correlate with actin-dependent changes in dendritic branching, spine structure, and AMPAR-mediated synaptic transmission.
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Affiliation(s)
- Mary Muhia
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany. .,Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria.
| | - PingAn YuanXiang
- RG Neuroplasticity Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Jan Sedlacik
- Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Biomedical Engineering Department, Centre for the Developing Brain, School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK
| | - Jürgen R Schwarz
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany
| | - Frank F Heisler
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany
| | - Kira V Gromova
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany
| | - Edda Thies
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany
| | - Petra Breiden
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany
| | - Yvonne Pechmann
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany
| | - Michael R Kreutz
- RG Neuroplasticity Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany.,Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
| | - Matthias Kneussel
- Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany.
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26
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Lifelong changes of neurotransmitter receptor expression and debilitation of hippocampal synaptic plasticity following early postnatal blindness. Sci Rep 2022; 12:9142. [PMID: 35650390 PMCID: PMC9160005 DOI: 10.1038/s41598-022-13127-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 05/06/2022] [Indexed: 11/30/2022] Open
Abstract
In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex and hippocampus occurs. Two fundamental characteristics comprise widespread changes in the relative expression of GABA and glutamate receptors and debilitation of hippocampal synaptic plasticity. Here, we explored whether recovery from adaptive changes in the expression of plasticity-related neurotransmitter receptors and hippocampal synaptic plasticity occurs in the time-period of up to 12 months after onset of sensory loss. We compared receptor expression in CBA/J mice that develop hereditary blindness, with CBA/CaOlaHsd mice that have intact vision and no deficits in other sensory modalities throughout adulthood. GluN1-subunit expression was reduced and the GluN2A:GluN2B ratio was persistently altered in cortex and hippocampus. GABA-receptor expression was decreased and metabotropic glutamate receptor expression was altered. Hippocampal synaptic plasticity was persistently compromised in vivo. But although LTP in blind mice was chronically impaired throughout adulthood, a recovery of the early phase of LTP became apparent when the animals reached 12 months of age. These data show that cortical and hippocampal adaptation to early postnatal blindness progresses into advanced adulthood and is a process that compromises hippocampal function. A partial recovery of hippocampal synaptic plasticity emerges in advanced adulthood, however.
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27
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Singh SP, William M, Malavia M, Chu XP. Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders. MEMBRANES 2022; 12:membranes12050499. [PMID: 35629827 PMCID: PMC9143857 DOI: 10.3390/membranes12050499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/26/2022] [Accepted: 05/03/2022] [Indexed: 02/01/2023]
Abstract
The broad distribution of voltage-gated potassium channels (VGKCs) in the human body makes them a critical component for the study of physiological and pathological function. Within the KCNQ family of VGKCs, these aqueous conduits serve an array of critical roles in homeostasis, especially in neural tissue. Moreover, the greater emphasis on genomic identification in the past century has led to a growth in literature on the role of the ion channels in pathological disease as well. Despite this, there is a need to consolidate the updated findings regarding both the pharmacotherapeutic and pathological roles of KCNQ channels, especially regarding neural plasticity and motor disorders which have the largest body of literature on this channel. Specifically, KCNQ channels serve a remarkable role in modulating the synaptic efficiency required to create appropriate plasticity in the brain. This role can serve as a foundation for clinical approaches to chronic pain. Additionally, KCNQ channels in motor disorders have been utilized as a direction for contemporary pharmacotherapeutic developments due to the muscarinic properties of this channel. The aim of this study is to provide a contemporary review of the behavior of these channels in neural plasticity and motor disorders. Upon review, the behavior of these channels is largely dependent on the physiological role that KCNQ modulatory factors (i.e., pharmacotherapeutic options) serve in pathological diseases.
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28
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Babushkina N, Manahan-Vaughan D. Frequency-dependency of the involvement of dopamine D1/D5 and beta-adrenergic receptors in hippocampal LTD triggered by locus coeruleus stimulation. Hippocampus 2022; 32:449-465. [PMID: 35478421 DOI: 10.1002/hipo.23419] [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: 10/20/2021] [Revised: 04/01/2022] [Accepted: 04/07/2022] [Indexed: 11/06/2022]
Abstract
Patterned stimulation of the locus coeruleus (LC, 100 Hz), in conjunction with test-pulse stimulation of hippocampal afferents, results in input-specific long-term depression (LTD) of synaptic plasticity in the hippocampus. Effects are long-lasting and have been described in Schaffer-collateral-CA1 and perforant path-dentate gyrus synapses in behaving rats. To what extent LC-mediated hippocampal LTD (LC-LTD) is frequency-dependent is unclear. Here, we report that LC-LTD can be triggered by LC stimulation with 2 and 5 Hz akin to tonic activity, 10 Hz equivalent to phasic activity, and 100 Hz akin to high-phasic activity in the dentate gyrus (DG) of freely behaving rats. LC-LTD at both 2 and 100 Hz can be significantly prevented by an NMDA receptor antagonist. The LC releases both noradrenaline (NA) and dopamine (DA) from its hippocampal terminals and may also trigger hippocampal DA release by activating the ventral tegmental area (VTA). Unclear is whether both neurotransmitters contribute equally to hippocampal LTD triggered by LC stimulation (LC-LTD). Both DA D1/D5 receptors (D1/D5R) and beta-adrenergic receptors (β-AR) are critically required for hippocampal LTD that is induced by patterned stimulation of hippocampal afferents, or is facilitated by spatial learning. We, therefore, explored to what extent these receptor subtypes mediate frequency-dependent hippocampal LC-LTD. LC-LTD elicited by 2, 5, and 10 Hz stimulation was unaffected by antagonism of β-AR with propranolol, whereas LC-LTD induced by these frequencies was prevented by D1/D5R-antagonism using SCH23390. By contrast, LC-LTD evoked at 100 Hz was prevented by β-AR-antagonism and only mildly affected by D1/D5R-antagonism. Taken together, these findings support that LC-LTD can be triggered by LC activity at a wide range of frequencies. Furthermore, the contribution of D1/D5R and β-AR to hippocampal LTD that is triggered by LC activity is frequency-dependent and suggests that D1/D5R may be involved in LC-mediated hippocampal tonus.
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Affiliation(s)
- Natalia Babushkina
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany.,International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Denise Manahan-Vaughan
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany.,International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
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29
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Stacho M, Manahan-Vaughan D. The Intriguing Contribution of Hippocampal Long-Term Depression to Spatial Learning and Long-Term Memory. Front Behav Neurosci 2022; 16:806356. [PMID: 35548697 PMCID: PMC9084281 DOI: 10.3389/fnbeh.2022.806356] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 03/10/2022] [Indexed: 01/03/2023] Open
Abstract
Long-term potentiation (LTP) and long-term depression (LTD) comprise the principal cellular mechanisms that fulfill established criteria for the physiological correlates of learning and memory. Traditionally LTP, that increases synaptic weights, has been ascribed a prominent role in learning and memory whereas LTD, that decreases them, has often been relegated to the category of "counterpart to LTP" that serves to prevent saturation of synapses. In contradiction of these assumptions, studies over the last several years have provided functional evidence for distinct roles of LTD in specific aspects of hippocampus-dependent associative learning and information encoding. Furthermore, evidence of the experience-dependent "pruning" of excitatory synapses, the majority of which are located on dendritic spines, by means of LTD has been provided. In addition, reports exist of the temporal and physical restriction of LTP in dendritic compartments by means of LTD. Here, we discuss the role of LTD and LTP in experience-dependent information encoding based on empirical evidence derived from conjoint behavioral and electrophysiological studies conducted in behaving rodents. We pinpoint the close interrelation between structural modifications of dendritic spines and the occurrence of LTP and LTD. We report on findings that support that whereas LTP serves to acquire the general scheme of a spatial representation, LTD enables retention of content details. We argue that LTD contributes to learning by engaging in a functional interplay with LTP, rather than serving as its simple counterpart, or negator. We propose that similar spatial experiences that share elements of neuronal representations can be modified by means of LTD to enable pattern separation. Therewith, LTD plays a crucial role in the disambiguation of similar spatial representations and the prevention of generalization.
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30
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Wert-Carvajal C, Reneaux M, Tchumatchenko T, Clopath C. Dopamine and serotonin interplay for valence-based spatial learning. Cell Rep 2022; 39:110645. [PMID: 35417691 DOI: 10.1016/j.celrep.2022.110645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 10/31/2021] [Accepted: 03/17/2022] [Indexed: 11/17/2022] Open
Abstract
Dopamine (DA) and serotonin (5-HT) are important neuromodulators of synaptic plasticity that have been linked to learning from positive or negative outcomes or valence-based learning. In the hippocampus, both affect long-term plasticity but play different roles in encoding uncertainty or predicted reward. DA has been related to positive valence, from reward consumption or avoidance behavior, and 5-HT to aversive encoding. We propose DA produces overall LTP while 5-HT elicits LTD. Here, we compare two reward-modulated spike timing-dependent plasticity (R-STDP) rules to describe the action of these neuromodulators. We examined their role in cognitive performance and flexibility for computational models of the Morris water maze task and reversal learning. Our results show that the interplay of DA and 5-HT improves learning performance and can explain experimental evidence. This study reinforces the importance of neuromodulation in determining the direction of plasticity.
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Affiliation(s)
- Carlos Wert-Carvajal
- Bioengineering Department, Imperial College London, London SW7 2AZ, UK; Theory of Neural Dynamics Group, Max Planck Institute for Brain Research, 60438 Frankfurt, Germany; Institute of Experimental Epileptology and Cognition Research, Life and Brain Center, University of Bonn Medical Center, 53127 Bonn, Germany
| | - Melissa Reneaux
- Bioengineering Department, Imperial College London, London SW7 2AZ, UK
| | - Tatjana Tchumatchenko
- Theory of Neural Dynamics Group, Max Planck Institute for Brain Research, 60438 Frankfurt, Germany; Institute of Experimental Epileptology and Cognition Research, Life and Brain Center, University of Bonn Medical Center, 53127 Bonn, Germany; Institute of Physiological Chemistry, University of Mainz Medical Center, 55131 Mainz, Germany.
| | - Claudia Clopath
- Bioengineering Department, Imperial College London, London SW7 2AZ, UK.
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31
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Correa J, Tintorelli R, Budriesi P, Viola H. Persistence of spatial memory induced by spaced training involves a behavioral-tagging process. Neuroscience 2022; 497:215-227. [PMID: 35276307 DOI: 10.1016/j.neuroscience.2022.02.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/04/2022] [Accepted: 02/26/2022] [Indexed: 11/27/2022]
Abstract
Spaced training, which involves long inter-trial intervals, has positive effects on memories. One of the main attributes of long-term memories (LTM) is persistence. Here, to identify the process that promotes LTM persistence by spaced learning, we used the spatial object recognition (SOR) task. The protocol consisted of a first strong training session that induced LTM formation (tested 1 day after training), but not LTM persistence (tested 7 or 14 days after training); and a second weak training session that promoted memory persistence when applied 1 day, but not 7 days, after the first training. We propose that the promotion of memory persistence is based on the Behavioral Tagging (BT) mechanism operating when the memory trace is retrieved. BT involves the setting of a tag induced by learning which gives rise to input selectivity, and the use of plasticity-related proteins (PRPs) to establish the mnemonic trace. We postulate that retraining will mainly retag the sites initially activated by the original learning, where the PRPs needed for memory expression and/or induced by retrieval would be used to maintain a persistent mnemonic trace. Our results suggest that the mechanism of memory expression, but not those of memory reinforcement or reconsolidation, is necessary to promote memory persistence after retraining. The molecular mechanisms involve ERKs1/2 activity to set the SOR learning tag, and the availability of GluA2-containing AMPA receptor. In conclusion, both the synthesis of PRPs and the setting of a learning tag are key processes triggered by retraining that allow SOR memory persistence.
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Affiliation(s)
- J Correa
- Facultad de Medicina. Universidad de Buenos Aires. Buenos Aires, Argentina; Laboratorio de Memoria, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), Facultad de Medicina, UBA-CONICET, Buenos Aires, Argentina
| | - R Tintorelli
- Facultad de Medicina. Universidad de Buenos Aires. Buenos Aires, Argentina; Laboratorio de Memoria, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), Facultad de Medicina, UBA-CONICET, Buenos Aires, Argentina
| | - P Budriesi
- Facultad de Medicina. Universidad de Buenos Aires. Buenos Aires, Argentina; Laboratorio de Memoria, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), Facultad de Medicina, UBA-CONICET, Buenos Aires, Argentina
| | - H Viola
- Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado" (FBMC), Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina; Laboratorio de Memoria, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), Facultad de Medicina, UBA-CONICET, Buenos Aires, Argentina; Instituto Tecnológico de Buenos Aires (ITBA), Buenos Aires, Argentina.
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32
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Keith RE, Ogoe RH, Dumas TC. Behind the scenes: Are latent memories supported by calcium independent plasticity? Hippocampus 2022; 32:73-88. [PMID: 33905147 PMCID: PMC8548406 DOI: 10.1002/hipo.23332] [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: 11/11/2020] [Revised: 04/08/2021] [Accepted: 04/11/2021] [Indexed: 02/03/2023]
Abstract
N-methyl-D-aspartate receptors (NMDARs) can be considered to be the de facto "plasticity" receptors in the brain due to their central role in the activity-dependent modification of neuronal morphology and synaptic transmission. Since the 1980s, research on NMDARs has focused on the second messenger properties of calcium and the downstream signaling pathways that mediate alterations in neural form and function. Recently, NMDARs were shown to drive activity-dependent synaptic plasticity without calcium influx. How this "nonionotropic" plasticity occurs in vitro is becoming clearer, but research on its involvement in behavior and cognition is in its infancy. There is a partial overlap in the downstream signaling molecules that are involved in ionotropic and nonionotropic NMDAR-dependent plasticity. Given this, and prior studies of the cognitive impacts of ionotropic NMDAR plasticity, a preliminary model explaining how NMDAR nonionotropic plasticity affects learning and memory can be established. We hypothesize that nonionotropic NMDAR plasticity takes part in latent memory encoding in immature rodents through nonassociative depression of synaptic efficacy, and possibly shrinking of dendritic spines. Further, the late postnatal alteration in NMDAR composition in the hippocampus appears to reduce nonionotropic signaling and remove a restriction on memory retrieval. This framework substantially alters the canonical model of NMDAR involvement in spatial cognition and hippocampal maturation and provides novel and exciting inroads for future studies.
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Affiliation(s)
- Rachel E. Keith
- Interdisciplinary Program in Neuroscience, College of Science, George Mason University, Fairfax, Virginia
| | - Richard H. Ogoe
- Department of Psychology, College of Humanities and Social Sciences, George Mason University, Fairfax, Virginia
| | - Theodore C. Dumas
- Interdisciplinary Program in Neuroscience, College of Science, George Mason University, Fairfax, Virginia,Department of Psychology, College of Humanities and Social Sciences, George Mason University, Fairfax, Virginia
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33
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Caragea VM, Manahan-Vaughan D. Bidirectional Regulation of Hippocampal Synaptic Plasticity and Modulation of Cumulative Spatial Memory by Dopamine D2-Like Receptors. Front Behav Neurosci 2022; 15:803574. [PMID: 35095441 PMCID: PMC8789653 DOI: 10.3389/fnbeh.2021.803574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/20/2021] [Indexed: 01/11/2023] Open
Abstract
Dopamine is a key factor in the enablement of cognition and hippocampal information processing. Its action in the hippocampus is mediated by D1/D5 and D2-like (D2, D3, D4) receptors. While D1/D5-receptors are well recognized as strong modulators of hippocampal synaptic plasticity and information storage, much less is known about the role of D2-like receptors (D2R) in these processes. Here, we explored to what extent D2R contribute to synaptic plasticity and cumulative spatial memory derived from semantic and episodic-like information storage. In freely behaving adult rats, we also assessed to what extent short and long-term forms of synaptic plasticity are influenced by pharmacological activation or blockade of D2R. Antagonism of D2R by means of intracerebral treatment with remoxipride, completely prevented the expression of both short-term (<1 h) and long-term potentiation (>4 h), as well as the expression of short-term depression (STD, <1 h) in the hippocampal CA1 region. Scrutiny of involvement of D2R in spatial learning revealed that D2R-antagonism prevented retention of a semantic spatial memory task, and also significantly impaired retention of recent spatiotemporal aspects of an episodic-like memory task. Taken together, these findings indicate that D2R are required for bidirectional synaptic plasticity in the hippocampal CA1 region. Furthermore, they are critically involved in enabling cumulative and episodic-like forms of spatial learning.
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Affiliation(s)
- Violeta-Maria Caragea
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Denise Manahan-Vaughan
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
- *Correspondence: Denise Manahan-Vaughan
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34
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Sethumadhavan N, Strauch C, Hoang TH, Manahan-Vaughan D. The Perirhinal Cortex Engages in Area and Layer-Specific Encoding of Item Dimensions. Front Behav Neurosci 2022; 15:744669. [PMID: 35058755 PMCID: PMC8763964 DOI: 10.3389/fnbeh.2021.744669] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
The perirhinal cortex (PRC), subdivided into areas 35 and 36, belongs to the parahippocampal regions that provide polysensory input to the hippocampus. Efferent and afferent connections along its rostro-caudal axis, and of areas 35 and 36, are extremely diverse. Correspondingly functional tasks in which the PRC participates are manifold. The PRC engages, for example, in sensory information processing, object recognition, and attentional processes. It was previously reported that layer II of the caudal area 35 may be critically involved in the encoding of large-scale objects. In the present study we aimed to disambiguate the roles of the different PRC layers, along with areas 35 and 36, and the rostro-caudal compartments of the PRC, in processing information about objects of different dimensions. Here, we compared effects on information encoding triggered by learning about subtle and discretely visible (microscale) object information and overt, highly visible landmark (macroscale) information. To this end, nuclear expression of the immediate early gene Arc was evaluated using fluorescence in situ hybridization. Increased nuclear Arc expression occurred in layers III and V-VI of the middle and caudal parts of area 35 in response to both novel microscale and macroscale object exposure. By contrast, a significant increase in Arc expression occurred in area 36 only in response to microscale objects. These results indicate that area 36 is specifically involved in the encoding of small and less prominently visible items. In contrast, area 35 engages globally (layer III to VI) in the encoding of object information independent of item dimensions.
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Affiliation(s)
- Nithya Sethumadhavan
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Christina Strauch
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany
| | - Thu-Huong Hoang
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Denise Manahan-Vaughan
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany
- *Correspondence: Denise Manahan-Vaughan
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Méndez-Couz M, González-Pardo H, Arias JL, Conejo NM. Hippocampal neuropeptide Y 2 receptor blockade improves spatial memory retrieval and modulates limbic brain metabolism. Neurobiol Learn Mem 2021; 187:107561. [PMID: 34838984 DOI: 10.1016/j.nlm.2021.107561] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 10/19/2022]
Abstract
INTRODUCTION The neuropeptide Y (NPY) is broadly distributed in the central nervous system (CNS), and it has been related to neuroprotective functions. NPY seems to be an important component to counteract brain damage and cognitive impairment mediated by drugs of abuse and neurodegenerative diseases, and both NPY and its Y2 receptor (Y2R) are highly expressed in the hippocampus, critical for learning and memory. We have recently demonstrated its influence on cognitive functions; however, the specific mechanism and involved brain regions where NPY modulates spatial memory by acting on Y2R remain unclear. METHODS Here, we examined the involvement of the hippocampal NPY Y2R in spatial memory and associated changes in brain metabolism by bilateral administration of the selective antagonist BIIE0246 into the rat dorsal hippocampus. To further evaluate the relationship between memory functions and neuronal activity, we analysed the regional expression of the mitochondrial enzyme cytochrome c oxidase (CCO) as an index of oxidative metabolic capacity in limbic and non-limbic brain regions. RESULTS The acute blockade of NPY Y2R significantly improved spatial memory recall in rats trained in the Morris water maze that matched metabolic activity changes in spatial memory processing regions. Specifically, CCO activity changes were found in the dentate gyrus of the dorsal hippocampus and CA1 subfield of the ventral hippocampus, the infralimbic region of the PFC and the mammillary bodies. CONCLUSIONS These findings suggest that the NPY hippocampal system, through its Y2R receptor, influences spatial memory recall (retrieval) and exerts control over patterns of brain activation that are relevant for associative learning, probably mediated by Y2R modulation of long-term potentiation and long-term depression.
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Affiliation(s)
- Marta Méndez-Couz
- Laboratory of Neuroscience, Department of Psychology, Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Pl. Feijoo s/n, 33003 Oviedo, Spain; Dept. Neurophysiology. Medical Faculty, Ruhr-University Bochum. Universitätsstraße, 150. Building MA 01/551, 44780 Bochum, Germany.
| | - Héctor González-Pardo
- Laboratory of Neuroscience, Department of Psychology, Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Pl. Feijoo s/n, 33003 Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain
| | - Jorge L Arias
- Laboratory of Neuroscience, Department of Psychology, Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Pl. Feijoo s/n, 33003 Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain
| | - Nélida M Conejo
- Laboratory of Neuroscience, Department of Psychology, Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Pl. Feijoo s/n, 33003 Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain
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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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Fernandes G, Mishra PK, Nawaz MS, Donlin-Asp PG, Rahman MM, Hazra A, Kedia S, Kayenaat A, Songara D, Wyllie DJA, Schuman EM, Kind PC, Chattarji S. Correction of amygdalar dysfunction in a rat model of fragile X syndrome. Cell Rep 2021; 37:109805. [PMID: 34644573 DOI: 10.1016/j.celrep.2021.109805] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/19/2021] [Accepted: 09/16/2021] [Indexed: 10/20/2022] Open
Abstract
Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of in vitro and in vivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology.
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Affiliation(s)
- Giselle Fernandes
- National Centre for Biological Sciences, TIFR, Bangalore 560065, India
| | - Pradeep K Mishra
- National Centre for Biological Sciences, TIFR, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India
| | - Mohammad Sarfaraz Nawaz
- National Centre for Biological Sciences, TIFR, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India
| | | | - Mohammed Mostafizur Rahman
- Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA, USA
| | - Anupam Hazra
- National Centre for Biological Sciences, TIFR, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India
| | - Sonal Kedia
- Department of Biology, Brandeis University, Waltham, MA, USA
| | - Aiman Kayenaat
- National Centre for Biological Sciences, TIFR, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; University of Transdisciplinary Health Sciences and Technology, Bangalore 560064, India
| | - Dheeraj Songara
- National Centre for Biological Sciences, TIFR, Bangalore 560065, India
| | - David J A Wyllie
- Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Simons Initiative for the Developing Brain and Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK
| | - Erin M Schuman
- Max Planck Institute for Brain Research, Frankfurt, Germany
| | - Peter C Kind
- Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Simons Initiative for the Developing Brain and Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK
| | - Sumantra Chattarji
- National Centre for Biological Sciences, TIFR, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Simons Initiative for the Developing Brain and Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.
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Kim SM, Zhang S, Park J, Sung HJ, Tran TDT, Chung C, Han IO. REM Sleep Deprivation Impairs Learning and Memory by Decreasing Brain O-GlcNAc Cycling in Mouse. Neurotherapeutics 2021; 18:2504-2517. [PMID: 34312767 PMCID: PMC8804064 DOI: 10.1007/s13311-021-01094-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2021] [Indexed: 12/17/2022] Open
Abstract
Rapid eye movement (REM) sleep is implicated learning and memory (L/M) functions and hippocampal long-term potentiation (LTP). Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory in mouse is linked to a reduction in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD, O-GlcNAcylation, and O-GlcNAc transferase (OGT) were downregulated while O-GlcNAcase was upregulated compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), which were significantly inhibited in brains of the REMSD group. Intriguingly, REMSD-induced defects in L/M functions and FC-induced PKA/CREB activation were restored upon increasing O-GlcNAc cycling with glucosamine (GlcN) or Thiamet G. Furthermore, Thiamet G restored the REMSD-induced decrease in dendritic spine density. Suppression of O-GlcNAcylation by the glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitor, 6-diazo-5-oxo-L-norleucine (DON), or OGT inhibitor, OSMI-1, impaired memory function, and inhibited FC-induced PKA/CREB activation. DON additionally reduced the amplitude of baseline field excitatory postsynaptic potential (fEPSP) and magnitude of long-term potentiation (LTP) in normal mouse hippocampal slices. To our knowledge, this is the first study to provide comprehensive evidence of dynamic O-GlcNAcylation changes during the L/M process in mice and defects in this pathway in the brain of REM sleep-deprived mice. Our collective results highlight HBP/O-GlcNAc cycling as a novel molecular link between sleep and cognitive function.
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Affiliation(s)
- Sang-Min Kim
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, Korea
| | - Seungjae Zhang
- Department of Biological Sciences, Konkuk University, Seoul, Korea
| | - Jiwon Park
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, Korea
| | - Hyun Jae Sung
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, Korea
| | - Thuy-Duong Thi Tran
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, Korea
| | - ChiHye Chung
- Department of Biological Sciences, Konkuk University, Seoul, Korea
| | - Inn-Oc Han
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, Korea.
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Subramaniyan M, Manivannan S, Chelur V, Tsetsenis T, Jiang E, Dani JA. Fear conditioning potentiates the hippocampal CA1 commissural pathway in vivo and increases awake phase sleep. Hippocampus 2021; 31:1154-1175. [PMID: 34418215 PMCID: PMC9290090 DOI: 10.1002/hipo.23381] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/10/2021] [Accepted: 07/24/2021] [Indexed: 11/24/2022]
Abstract
The hippocampus is essential for spatial learning and memory. To assess learning we used contextual fear conditioning (cFC), where animals learn to associate a place with aversive events like foot‐shocks. Candidate memory mechanisms for cFC are long‐term potentiation (LTP) and long‐term depression (LTD), but there is little direct evidence of them operating in the hippocampus in vivo following cFC. Also, little is known about the behavioral state changes induced by cFC. To address these issues, we recorded local field potentials in freely behaving mice by stimulating in the left dorsal CA1 region and recording in the right dorsal CA1 region. Synaptic strength in the commissural pathway was monitored by measuring field excitatory postsynaptic potentials (fEPSPs) before and after cFC. After cFC, the commissural pathway's synaptic strength was potentiated. Although recordings occurred during the wake phase of the light/dark cycle, the mice slept more in the post‐conditioning period than in the pre‐conditioning period. Relative to awake periods, in non‐rapid eye movement (NREM) sleep the fEPSPs were larger in both pre‐ and post‐conditioning periods. We also found a significant negative correlation between the animal's speed and fEPSP size. Therefore, to avoid confounds in the fEFSP potentiation estimates, we controlled for speed‐related and sleep‐related fEPSP changes and still found that cFC induced long‐term potentiation, but no significant long‐term depression. Synaptic strength changes were not found in the control group that simply explored the fear‐conditioning chamber, indicating that exploration of the novel place did not produce the measurable effects caused by cFC. These results show that following cFC, the CA1 commissural pathway is potentiated, likely contributing to the functional integration of the left and right hippocampi in fear memory consolidation. In addition, the cFC paradigm produces significant changes in an animal's behavioral state, which are observable as proximal changes in sleep patterns.
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Affiliation(s)
- Manivannan Subramaniyan
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sumithrra Manivannan
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Vikas Chelur
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Theodoros Tsetsenis
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Evan Jiang
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - John A Dani
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Perez DM. Current Developments on the Role of α 1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism. Front Cell Dev Biol 2021; 9:652152. [PMID: 34113612 PMCID: PMC8185284 DOI: 10.3389/fcell.2021.652152] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/29/2021] [Indexed: 12/13/2022] Open
Abstract
The α1-adrenergic receptors (ARs) are G-protein coupled receptors that bind the endogenous catecholamines, norepinephrine, and epinephrine. They play a key role in the regulation of the sympathetic nervous system along with β and α2-AR family members. While all of the adrenergic receptors bind with similar affinity to the catecholamines, they can regulate different physiologies and pathophysiologies in the body because they couple to different G-proteins and signal transduction pathways, commonly in opposition to one another. While α1-AR subtypes (α1A, α1B, α1C) have long been known to be primary regulators of vascular smooth muscle contraction, blood pressure, and cardiac hypertrophy, their role in neurotransmission, improving cognition, protecting the heart during ischemia and failure, and regulating whole body and organ metabolism are not well known and are more recent developments. These advancements have been made possible through the development of transgenic and knockout mouse models and more selective ligands to advance their research. Here, we will review the recent literature to provide new insights into these physiological functions and possible use as a therapeutic target.
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Affiliation(s)
- Dianne M Perez
- The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH, United States
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41
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Collitti-Klausnitzer J, Hagena H, Dubovyk V, Manahan-Vaughan D. Preferential frequency-dependent induction of synaptic depression by the lateral perforant path and of synaptic potentiation by the medial perforant path inputs to the dentate gyrus. Hippocampus 2021; 31:957-981. [PMID: 34002905 DOI: 10.1002/hipo.23338] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 04/28/2021] [Accepted: 05/02/2021] [Indexed: 12/19/2022]
Abstract
The encoding of spatial representations is enabled by synaptic plasticity. The entorhinal cortex sends information to the hippocampus via the lateral (LPP) and medial perforant (MPP) paths that transfer egocentric item-related and allocentric spatial information, respectively. To what extent LPP and MPP information-relay results in different homosynaptic synaptic plasticity responses is unclear. We examined the frequency dependency (at 1, 5, 10, 50, 100, 200 Hz) of long-term potentiation (LTP) and long-term depression (LTD) at MPP and LPP synapses in the dentate gyrus (DG) of freely behaving adult rats. We report that whereas the MPP-DG synapses exhibit a predisposition toward the expression of LTP, LPP-DG synapses prefer to express synaptic depression. The divergence of synaptic plasticity responses is most prominent at afferent frequencies of 5, 100, Hz and 200 Hz. Priming with 10 or 50 Hz significantly modified the subsequent plasticity response in a frequency-dependent manner, but failed to change the preferred direction of change in synaptic strength of MPP and LPP synapses. Evaluation of the expression of GluN1, GluN2A, or GluN2B subunits of the NMDA receptor revealed equivalent expression in the outer and middle thirds of the molecular layer where LPP and MPP inputs convene, respectively, thus excluding NMDA receptors as a substrate for the frequency-dependent differences in bidirectional plasticity. These findings demonstrate that the LPP and MPP inputs to the DG enable differentiated and distinct forms of synaptic plasticity in response to the same afferent frequencies. Effects are extremely robust and resilient to metaplastic priming. These properties may support the functional differentiation of allocentric and item information provided to the DG by the MPP and LPP, respectively, that has been proposed by others. We propose that allocentric spatial information, conveyed by the MPP is encoded through hippocampal LTP in a designated synaptic network. This network is refined and optimized to include egocentric contextual information through LTD triggered by LPP inputs.
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Affiliation(s)
| | - Hardy Hagena
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Germany
| | - Valentyna Dubovyk
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Germany
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Robledo-Menendez A, Vella M, Grandes P, Soria-Gomez E. Cannabinoid control of hippocampal functions: the where matters. FEBS J 2021; 289:2162-2175. [PMID: 33977665 DOI: 10.1111/febs.15907] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/23/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022]
Abstract
In the brain, hippocampal circuits are crucial for cognitive performance (e.g., memory) and deeply affected in pathological conditions (e.g., epilepsy, Alzheimer). Specialized molecular mechanisms regulate different cell types underlying hippocampal circuitries functions. Among them, cannabinoid receptors exhibit various roles depending on the cell type (e.g., neuron, glial cell) or subcellular organelle (e.g., mitochondria). Determining the site of action and precise mechanisms triggered by cannabinoid receptor activation at a local cellular and subcellular level helps us understand hippocampal pathophysiological states. In doing so, past and current research have advanced our knowledge of cannabinoid functions and proposed novel routes for potential therapeutics. By outlining these data in this work, we aim to showcase current findings and highlight the pathophysiological impact of the cannabinoid receptor type 1 (CB1) localization/activation in hippocampal circuits.
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Affiliation(s)
- Almudena Robledo-Menendez
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Maria Vella
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Pedro Grandes
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Edgar Soria-Gomez
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
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Hoang TH, Böge J, Manahan-Vaughan D. Hippocampal subfield-specific Homer1a expression is triggered by learning-facilitated long-term potentiation and long-term depression at medial perforant path synapses. Hippocampus 2021; 31:897-915. [PMID: 33964041 DOI: 10.1002/hipo.23333] [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: 10/05/2020] [Revised: 03/22/2021] [Accepted: 04/11/2021] [Indexed: 12/23/2022]
Abstract
Learning about general aspects, or content details, of space results in differentiated neuronal information encoding within the proximodistal axis of the hippocampus. These processes are tightly linked to long-term potentiation (LTP) and long-term depression (LTD). Here, we explored the precise sites of encoding of synaptic plasticity in the hippocampus that are mediated by information throughput from the perforant path. We assessed nuclear Homer1a-expression that was triggered by electrophysiological induction of short and long forms of hippocampal synaptic plasticity, and compared it to Homer1a-expression that was triggered by LTP and LTD enabled by different forms of spatial learning. Plasticity responses were induced by patterned stimulation of the perforant path and were recorded in the dentate gyrus (DG) of freely behaving rats. We used fluorescence in situ hybridization to detect experience-dependent nuclear encoding of Homer1a in proximodistal hippocampal subfields. Induction of neither STP nor STD resulted in immediate early gene (IEG) encoding. Electrophysiological induction of robust LTP, or LTD, resulted in highly significant and widespread induction of nuclear Homer1a in all hippocampal subfields. LTP that was facilitated by novel spatial exploration triggered similar widespread Homer1a-expression. The coupling of synaptic depression with the exploration of a novel configuration of landmarks resulted in localized IEG expression in the proximal CA3 region and the lower (infrapyramidal) blade of the DG. Our findings support that synaptic plasticity induction via perforant path inputs promotes widespread hippocampal information encoding. Furthermore, novel spatial exploration promotes the selection of a hippocampal neuronal network by means of LTP that is distributed in an experience-dependent manner across all hippocampus subfields. This network may be modified during spatial content learning by LTD in specific hippocampal subfields. Thus, long-term plasticity-inducing events result in IEG expression that supports establishment and/or restructuring of neuronal networks that are necessary for long-term information storage.
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Affiliation(s)
- Thu-Huong Hoang
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany.,International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Juliane Böge
- Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany
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Méndez-Couz M, Krenzek B, Manahan-Vaughan D. Genetic Depletion of BDNF Impairs Extinction Learning of a Spatial Appetitive Task in the Presence or Absence of the Acquisition Context. Front Behav Neurosci 2021; 15:658686. [PMID: 33994970 PMCID: PMC8119774 DOI: 10.3389/fnbeh.2021.658686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Brain derived neurotropic factor (BDNF) supports neuronal survival, growth, and differentiation and is involved in forms of hippocampus-dependent and independent learning, as well as hippocampus-dependent learning. Extinction learning comprises active inhibition of no-longer relevant learned information, in conjunction with a decreased response of a previously learned behavior. It is highly dependent on context, and evidence exists that it requires hippocampal activation. The participation of BDNF in memory processing is experience-dependent. For example, BDNF has been associated with synaptic plasticity needed for spatial learning, and it is involved in acquisition and extinction learning of fear conditioning. However, little is known about its role in spatial appetitive extinction learning. In this study, we evaluated to what extent BDNF contributes to spatial appetitive extinction learning in the presence (ABA) or absence (AAA) of exposure to the acquisition context. Daily training, of BDNF+/--mice or their wildtype (WT) littermates, to reach acquisition criterion in a T-maze, resulted in a similar performance outcome. However, extinction learning was delayed in the AAA, and impaired in the ABA-paradigm compared to performance in WT littermates. Trial-by-trial learning analysis indicated differences in the integration of the context into extinction learning by BDNF+/--mice compared to WT littermates. Taken together, these results support an important role for BDNF in processes that relate to information updating and retrieval that in turn are crucial for effective extinction learning.
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Affiliation(s)
- Marta Méndez-Couz
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
| | - Beate Krenzek
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
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Lopes da Cunha P, Tintorelli R, Correa J, Budriesi P, Viola H. Behavioral tagging as a mechanism for aversive-memory formation under acute stress. Eur J Neurosci 2021; 55:2651-2665. [PMID: 33914357 DOI: 10.1111/ejn.15249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 04/01/2021] [Accepted: 04/15/2021] [Indexed: 02/03/2023]
Abstract
The behavioral tagging (BT) hypothesis postulates that a weak learning experience, which only induces short-term memory, may benefit from another event that provides plasticity-related proteins (PRPs) to establish a long-lasting memory. According to BT, the weak experience sets a transient learning tag at specific activated sites, and its temporal and spatial convergence with the PRPs allows the long-term memory (LTM) formation. In this work, rats were subjected to a weak inhibitory avoidance (IAw) training and we observed that acute stress (elevated platform, EP) experienced 1 hr before IAw promoted IA-LTM formation. This effect was dependent on glucocorticoid-receptor activity as well as protein synthesis in the dorsal hippocampus. However, the same stress has negative effects on IA-LTM formation when training is strong, probably by competing for necessary PRPs. Furthermore, our experiments showed that EP immediately after training did not impair the setting of the learning tag and even facilitated IA-LTM formation. These findings reveal different impacts of a given acute stressful experience on the formation of an aversive memory that could be explained by BT processes.
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Affiliation(s)
- Pamela Lopes da Cunha
- Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Biología Celular y Neurociencias "Dr Eduardo De Robertis" (IBCN), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ramiro Tintorelli
- Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Biología Celular y Neurociencias "Dr Eduardo De Robertis" (IBCN), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Julieta Correa
- Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Biología Celular y Neurociencias "Dr Eduardo De Robertis" (IBCN), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Pablo Budriesi
- Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Biología Celular y Neurociencias "Dr Eduardo De Robertis" (IBCN), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Haydee Viola
- Instituto de Biología Celular y Neurociencias "Dr Eduardo De Robertis" (IBCN), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.,Departamento de Fisiología, Biología Molecular y Celular "Dr. Hector Maldonado" (FBMC), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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Santa-Marinha L, Castanho I, Silva RR, Bravo FV, Miranda AM, Meira T, Morais-Ribeiro R, Marques F, Xu Y, Point du Jour K, Wenk M, Chan RB, Di Paolo G, Pinto V, Oliveira TG. Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning. Cell Rep 2021; 30:4197-4208.e6. [PMID: 32209478 DOI: 10.1016/j.celrep.2020.02.102] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/29/2020] [Accepted: 02/27/2020] [Indexed: 01/01/2023] Open
Abstract
Phosphatidic acid (PA) is a signaling lipid involved in the modulation of synaptic structure and functioning. Based on previous work showing a decreasing PA gradient along the longitudinal axis of the rodent hippocampus, we asked whether the dorsal hippocampus (DH) and the ventral hippocampus (VH) are differentially affected by PA modulation. Here, we show that phospholipase D1 (PLD1) is a major hippocampal PA source, compared to PLD2, and that PLD1 ablation affects predominantly the lipidome of the DH. Moreover, Pld1 knockout (KO) mice show specific deficits in novel object recognition and social interaction and disruption in the DH-VH dendritic arborization differentiation in CA1/CA3 pyramidal neurons. Also, Pld1 KO animals present reduced long-term depression (LTD) induction and reduced GluN2A and SNAP-25 protein levels in the DH. Overall, we observe that PLD1-derived PA reduction leads to differential lipid signatures along the longitudinal hippocampal axis, predominantly affecting DH organization and functioning.
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Affiliation(s)
- Luísa Santa-Marinha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Isabel Castanho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rita Ribeiro Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Francisca Vaz Bravo
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - André Miguel Miranda
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Torcato Meira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rafaela Morais-Ribeiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Fernanda Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Yimeng Xu
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Kimberly Point du Jour
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
| | - Markus Wenk
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
| | - Robin Barry Chan
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
| | - Gilbert Di Paolo
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
| | - Vítor Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Tiago Gil Oliveira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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PSD-95 in CA1 Area Regulates Spatial Choice Depending on Age. J Neurosci 2021; 41:2329-2343. [PMID: 33472821 DOI: 10.1523/jneurosci.1996-20.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 10/06/2020] [Accepted: 12/21/2020] [Indexed: 11/21/2022] Open
Abstract
Cognitive processes that require spatial information rely on synaptic plasticity in the dorsal CA1 area (dCA1) of the hippocampus. Since the function of the hippocampus is impaired in aged individuals, it remains unknown how aged animals make spatial choices. Here, we used IntelliCage to study behavioral processes that support spatial choices of aged female mice living in a group. As a proxy of training-induced synaptic plasticity, we analyzed the morphology of dendritic spines and the expression of a synaptic scaffold protein, PSD-95. We observed that spatial choice training in young adult mice induced correlated shrinkage of dendritic spines and downregulation of PSD-95 in dCA1. Moreover, long-term depletion of PSD-95 by shRNA in dCA1 limited correct choices to a reward corner, while reward preference was intact. In contrast, old mice used behavioral strategies characterized by an increased tendency for perseverative visits and social interactions. This strategy resulted in a robust preference for the reward corner during the spatial choice task. Moreover, training decreased the correlation between PSD-95 expression and the size of dendritic spines. Furthermore, PSD-95 depletion did not impair place choice or reward preference in old mice. Thus, our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices, old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment.SIGNIFICANCE STATEMENT It remains poorly understood how aging affects behavioral and molecular processes that support cognitive functions. It is, however, essential to understand these processes to develop therapeutic interventions that support successful cognitive aging. Our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices (i.e., choices that require spatial information), old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment. Second, the contribution of PSD-95-dependent synaptic functions in spatial choice changes with age.
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Südkamp N, Shchyglo O, Manahan-Vaughan D. Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice. Front Aging Neurosci 2021; 13:591735. [PMID: 33796018 PMCID: PMC8007872 DOI: 10.3389/fnagi.2021.591735] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 02/18/2021] [Indexed: 01/02/2023] Open
Abstract
Beta-amyloid protein [Aβ(1-42)] plays an important role in the disease progress and pathophysiology of Alzheimer's disease (AD). Membrane properties and neuronal excitability are altered in the hippocampus of transgenic AD mouse models that overexpress amyloid precursor protein. Although gap junction hemichannels have been implicated in the early pathogenesis of AD, to what extent Pannexin channels contribute to Aβ(1-42)-mediated brain changes is not yet known. In this study we, therefore, investigated the involvement of Pannexin1 (Panx1) channels in Aβ-mediated changes of neuronal membrane properties and long-term potentiation (LTP) in an animal model of AD. We conducted whole-cell patch-clamp recordings in CA1 pyramidal neurons 1 week after intracerebroventricular treatments of adult wildtype (wt) and Panx1 knockout (Panx1-ko) mice with either oligomeric Aβ(1-42), or control peptide. Panx1-ko hippocampi treated with control peptide exhibited increased neuronal excitability compared to wt. In addition, action potential (AP) firing frequency was higher in control Panx1-ko slices compared to wt. Aβ-treatment reduced AP firing frequency in both cohorts. But in Aβ-treated wt mice, spike frequency adaptation was significantly enhanced, when compared to control wt and to Aβ-treated Panx1-ko mice. Assessment of hippocampal LTP revealed deficits in Aβ-treated wt compared to control wt. By contrast, Panx1-ko exhibited LTP that was equivalent to LTP in control ko hippocampi. Taken together, our data show that in the absence of Pannexin1, hippocampi are more resistant to the debilitating effects of oligomeric Aβ. Both Aβ-mediated impairments in spike frequency adaptation and in LTP that occur in wt animals, are ameliorated in Panx1-ko mice. These results suggest that Panx1 contributes to early changes in hippocampal neuronal and synaptic function that are triggered by oligomeric Aβ.
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Affiliation(s)
- Nicolina Südkamp
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany.,International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Olena Shchyglo
- Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
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Upreti C, Woodruff CM, Zhang XL, Yim MJ, Zhou ZY, Pagano AM, Rehanian DS, Yin D, Kandel ER, Stanton PK, Nicholls RE. Loss of retinoid X receptor gamma subunit impairs group 1 mGluR mediated electrophysiological responses and group 1 mGluR dependent behaviors. Sci Rep 2021; 11:5552. [PMID: 33692389 PMCID: PMC7946894 DOI: 10.1038/s41598-021-84943-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 02/17/2021] [Indexed: 11/09/2022] Open
Abstract
Retinoid X receptors are members of the nuclear receptor family that regulate gene expression in response to retinoic acid and related ligands. Group 1 metabotropic glutamate receptors are G-protein coupled transmembrane receptors that activate intracellular signaling cascades in response to the neurotransmitter, glutamate. These two classes of molecules have been studied independently and found to play important roles in regulating neuronal physiology with potential clinical implications for disorders such as depression, schizophrenia, Parkinson's and Alzheimer's disease. Here we show that mice lacking the retinoid X receptor subunit, RXRγ, exhibit impairments in group 1 mGluR-mediated electrophysiological responses at hippocampal Schaffer collateral-CA1 pyramidal cell synapses, including impaired group 1 mGluR-dependent long-term synaptic depression (LTD), reduced group 1 mGluR-induced calcium release, and loss of group 1 mGluR-activated voltage-sensitive currents. These animals also exhibit impairments in a subset of group 1 mGluR-dependent behaviors, including motor performance, spatial object recognition, and prepulse inhibition. Together, these observations demonstrate convergence between the RXRγ and group 1 mGluR signaling pathways that may function to coordinate their regulation of neuronal activity. They also identify RXRγ as a potential target for the treatment of disorders in which group 1 mGluR signaling has been implicated.
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Affiliation(s)
- Chirag Upreti
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA
| | - Caitlin M Woodruff
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Xiao-Lei Zhang
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA
| | - Michael J Yim
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Zhen-Yu Zhou
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.,Department of Neurology, New York Medical College, Valhalla, NY, 10595, USA
| | - Andrew M Pagano
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Dina S Rehanian
- Department of Pathology and Cell Biology, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA.,Taub Institute for Research on Alzheimer's Disease and Aging Brain, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA
| | - Deqi Yin
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Howard Hughes Medical Institute, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Eric R Kandel
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Howard Hughes Medical Institute, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Kavli Institute for Brain Science, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Patric K Stanton
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.,Department of Neurology, New York Medical College, Valhalla, NY, 10595, USA
| | - Russell E Nicholls
- Department of Pathology and Cell Biology, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA. .,Taub Institute for Research on Alzheimer's Disease and Aging Brain, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA.
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50
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Schomaker J, Wittmann BC. Effects of active exploration on novelty-related declarative memory enhancement. Neurobiol Learn Mem 2021; 179:107403. [PMID: 33592311 DOI: 10.1016/j.nlm.2021.107403] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 12/24/2020] [Accepted: 02/04/2021] [Indexed: 11/17/2022]
Abstract
Exploration of novel environments has reliably been shown to enhance learning in rodents. More recently, these effects have been replicated in humans using virtual reality: Memory is enhanced after exploration of novel compared to familiar virtual environments. However, exploration of a novel versus familiar environment differs in another aspect. Navigating familiar territory can rely more on habits, while navigating new territory requires active decision-making. This difference in choices could contribute to the positive effects of novelty exploration on memory. In this study, we aimed to investigate this possibility. Participants familiarized with a virtual environment (day 1) and were exposed to this environment again (day 2 or 3) and to a novel environment (day 2 or 3). Participants either actively explored the environments or were passively exposed to the exploration behavior of another participant in virtual reality. After exposure to the environment, participants performed a word-learning task and filled out questionnaires regarding virtual presence and the novelty seeking personality trait. Mixed models suggested that memory performance was higher after participants actively explored versus were passively exposed to a novel environment, while these effects were reversed for a familiar environment. Bayesian statistics provided further weak evidence that memory performance was influenced by the interaction between novelty and exposure type. Taken together, our findings suggest that active exploration may contribute to novelty-induced memory benefits, but future studies need to confirm this finding.
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Affiliation(s)
- J Schomaker
- Department of Psychology, Health and Medical Neuropsychology, Leiden University, the Netherlands.
| | - B C Wittmann
- Department of Psychology, Biological Psychology, Justus Liebig University, Giessen, Germany
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