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Ang, Mary Jasmin, Sueun Lee, Mai Wada, Poornima D. E. Weerasinghe-Mudiyanselage, Sung-Ho Kim, Taekyun Shin, Tae-Il Jeon, Seung-Soon Im, and Changjong Moon. "SREBP-1c Deficiency Affects Hippocampal Micromorphometry and Hippocampus-Dependent Memory Ability in Mice." International Journal of Molecular Sciences 22, no. 11 (June 5, 2021): 6103. http://dx.doi.org/10.3390/ijms22116103.
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Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration of novel modulatory molecules in the hippocampus and occurrence of schizophrenia-like behaviors in mice. However, the possible underlying mechanisms, related to neuronal plasticity in the hippocampus, are yet to be elucidated. In this study, we investigated the hippocampus-dependent memory function and neuronal architecture of hippocampal neurons in SREBP-1c knockout (KO) mice. During the passive avoidance test, SREBP-1c KO mice showed memory impairment. Based on Golgi staining, the dendritic complexity, length, and branch points were significantly decreased in the apical cornu ammonis (CA) 1, CA3, and dentate gyrus (DG) subregions of the hippocampi of SREBP-1c KO mice, compared with those of wild-type (WT) mice. Additionally, significant decreases in the dendritic diameters were detected in the CA3 and DG subregions, and spine density was also significantly decreased in the apical CA3 subregion of the hippocampi of KO mice, compared with that of WT mice. Alterations in the proportions of stubby and thin-shaped dendritic spines were observed in the apical subcompartments of CA1 and CA3 in the hippocampi of KO mice. Furthermore, the corresponding differential decreases in the levels of SREBP-1 expression in the hippocampal subregions (particularly, a significant decrease in the level in the CA3) were detected by immunofluorescence. This study suggests that the contributions of SREBP-1c to the structural plasticity of the mouse hippocampus may have underlain the behavioral alterations. These findings offer insights into the critical role of SREBP-1c in hippocampal functioning in mice.
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Świetlik, Dariusz, Jacek Białowąs, Janusz Moryś, Ilona Klejbor, and Aida Kusiak. "Computer Modeling of Alzheimer’s Disease—Simulations of Synaptic Plasticity and Memory in the CA3-CA1 Hippocampal Formation Microcircuit." Molecules 24, no. 10 (May 17, 2019): 1909. http://dx.doi.org/10.3390/molecules24101909.
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This paper aims to present computer modeling of synaptic plasticity and memory in the CA3-CA1 hippocampal formation microcircuit. The computer simulations showed a comparison of a pathological model in which Alzheimer’s disease (AD) was simulated by synaptic degradation in the hippocampus and control model (healthy) of CA3-CA1 networks with modification of weights for the memory. There were statistically higher spike values of both CA1 and CA3 pyramidal cells in the control model than in the pathological model (p = 0.0042 for CA1 and p = 0.0033 for CA3). A similar outcome was achieved for frequency (p = 0.0002 for CA1 and p = 0.0001 for CA3). The entropy of pyramidal cells of the healthy CA3 network seemed to be significantly higher than that of AD (p = 0.0304). We need to study a lot of physiological parameters and their combinations of the CA3-CA1 hippocampal formation microcircuit to understand AD. High statistically correlations were obtained between memory, spikes and synaptic deletion in both CA1 and CA3 cells.
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Świetlik, Dariusz, Jacek Białowąs, Janusz Moryś, Ilona Klejbor, and Aida Kusiak. "Effects of Inducing Gamma Oscillations in Hippocampal Subregions DG, CA3, and CA1 on the Potential Alleviation of Alzheimer’s Disease-Related Pathology: Computer Modeling and Simulations." Entropy 21, no. 6 (June 13, 2019): 587. http://dx.doi.org/10.3390/e21060587.
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The aim of this study was to evaluate the possibility of the gamma oscillation function (40–130 Hz) to reduce Alzheimer’s disease related pathology in a computer model of the hippocampal network dentate gyrus, CA3, and CA1 (DG-CA3-CA1) regions. Methods: Computer simulations were made for a pathological model in which Alzheimer’s disease was simulated by synaptic degradation in the hippocampus. Pathology modeling was based on sequentially turning off the connections with entorhinal cortex layer 2 (EC2) and the dentate gyrus on CA3 pyramidal neurons. Gamma induction modeling consisted of simulating the oscillation provided by the septo-hippocampal pathway with band frequencies from 40–130 Hz. Pathological models with and without gamma induction were compared with a control. Results: In the hippocampal regions of DG, CA3, and CA1, and jointly DG-CA3-CA1 and CA3-CA1, gamma induction resulted in a statistically significant improvement in terms of increased numbers of spikes, spikes per burst, and burst duration as compared with the model simulating Alzheimer’s disease (AD). The positive maximal Lyapunov exponent was negative in both the control model and the one with gamma induction as opposed to the pathological model where it was positive within the DG-CA3-CA1 region. Gamma induction resulted in decreased transfer entropy in accordance with the information flow in DG → CA3 and CA3 → CA1. Conclusions: The results of simulation studies show that inducing gamma oscillations in the hippocampus may reduce Alzheimer’s disease related pathology. Pathologically higher transfer entropy values after gamma induction returned to values comparable to the control model.
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Blom, Kim, Huiberdina L. Koek, Maarten H. T. Zwartbol, Rashid Ghaznawi, Hugo J. Kuijf, Theo D. Witkamp, Jeroen Hendrikse, Geert Jan Biessels, and Mirjam I. Geerlings. "Vascular Risk Factors of Hippocampal Subfield Volumes in Persons without Dementia: The Medea 7T Study." Journal of Alzheimer's Disease 77, no. 3 (September 29, 2020): 1223–39. http://dx.doi.org/10.3233/jad-200159.
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Background: Vascular risk factors have been associated with risk of Alzheimer’s disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases. Objective: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia. Methods: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes. Results: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially. Conclusion: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors.
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Zapukhliak, O. S., O. V. Netsyk, and D. S. Isaev. "SYNCHRONIZATION OF EPILEPTIFORM ACTIVITY BETWEEN CA1 AND CA3 HIPPOCAMPAL FIELDS UNDER SYNAPTIC AND NON-SYNAPTIC CONDITIONS IN RAT BRAIN SLICES." Medical Science of Ukraine (MSU) 16, no. 1 (February 28, 2020): 3–7. http://dx.doi.org/10.32345/2664-4738.1.2020.01.
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Relevance. Over-synchronization of neuronal activity results in epileptic-like discharges that can lead to seizures and status epilepticus. Understanding mechanisms of neural net synchronization could provide new insights into the treatment of epileptic disorders.
Objective: to compare the levels of synchronization between CA3 and CA1 hippocampal zones during epileptiform activity induced under synaptic and non-synaptic conditions.
Materials and Methods. Transverse brain slices were obtained from 12-14 days old rats. For induction of epileptiform activity common pro-epileptic agents were used: bicuculline and 4-aminopiridine. Nonsynaptic epileptiform activity was induced by perfusion brain slices with low-Ca2+ and Cd2+-containing artificial cerebrospinal fluid (aCSF). Simultaneous extracellular recordings of field potentials were obtained from the CA3 and CA1 pyramidal cell layer with extracellular glass microelectrodes (2–3 MΩ). Signals were then low-pass filtered (kHz), amplified using a 2-channel differential amplifier M1800, digitized at 10 kHz using analog-to-digital converter. The level of synchronization between CA3 and CA1 was evaluated using cross-correlation analysis.
Results: Perfusion hippocampal slices with bicuculline and 4-aminopyridine induced epileptiform activity with high level of synchronization between CA3 and CA1 hippocampal zones. Removing Ca2+ from extracellular solution as well as adding CdCl2 to the perfusion aCSF induced epileptiform activity that was not synchronized between hippocampal CA3 and CA1 fields.
Conclusions: Synaptic interaction account for high level of CA3-CA1 synchronization induced by pro-epileptic agents bicuculline and 4-aminopiridine. Under non-synaptic conditions, local cellular interactions induce epileptiform activity with no synchronization between CA3 and CA1 hippocampal zones.
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Zapukhliak, Olha, Olga Netsyk, Artur Romanov, Oleksandr Maximyuk, Murat Oz, Gregory L. Holmes, Oleg Krishtal, and Dmytro Isaev. "Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors." PLOS ONE 16, no. 3 (March 12, 2021): e0240074. http://dx.doi.org/10.1371/journal.pone.0240074.
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Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
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Wu, Chiping, Marjan Nassiri Asl, Jesse Gillis, Frances K. Skinner, and Liang Zhang. "An In Vitro Model of Hippocampal Sharp Waves: Regional Initiation and Intracellular Correlates." Journal of Neurophysiology 94, no. 1 (July 2005): 741–53. http://dx.doi.org/10.1152/jn.00086.2005.
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During slow wave sleep and consummatory behaviors, electroencephalographic recordings from the rodent hippocampus reveal large amplitude potentials called sharp waves. The sharp waves originate from the CA3 circuitry and their generation is correlated with coherent discharges of CA3 pyramidal neurons and dependent on activities mediated by AMPA glutamate receptors. To model sharp waves in a relatively large hippocampal circuitry in vitro, we developed thick (1 mm) mouse hippocampal slices by separating the dentate gyrus from the CA2/CA1 areas while keeping the functional dentate gyrus-CA3-CA1 connections. We found that large amplitude (0.3–3 mV) sharp wave-like field potentials occurred spontaneously in the thick slices without extra ionic or pharmacological manipulation and they resemble closely electroencephalographic sharp waves with respect to waveform, regional initiation, pharmacological manipulations, and intracellular correlates. Through measuring tissue O2, K+, and synaptic and single cell activities, we verified that the sharp wave-like potentials are not a consequence of anoxia, nonspecific elevation of extracellular K+ and dissection-related tissue damage. Our data suggest that a subtle but crucial increase in the CA3 glutamatergic activity effectively recruits a population of neurons thus responsible for the generation of the sharp wave-like spontaneous field potentials in isolated hippocampal circuitry.
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Nwaubani, P., A. Colasanti, M. Cercignani, and A. Warner. "MRI Analysis: Optimization of parameters for diffusion MRI to enhance hippocampal subfield analysis and segmentation (Preliminary Data)." European Psychiatry 65, S1 (June 2022): S638. http://dx.doi.org/10.1192/j.eurpsy.2022.1637.
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Introduction The hippocampus is an important, complex limbic structure anatomically embedded in the medial temporal lobe of each cerebral cortex, which has been implicated in the pathogenesis of neuro-inflammatory disease conditions. Few studies have focused on the characterization of the MRI neuroimaging signatures of highly physio- pathologically relevant subfields of the hippocampus (CA1, CA4-DG, CA2/CA3, SLRM). Objectives Using self-guided manually segmented, Diffusion weighted and NODDI maps created from data obtained from the Human Connectome Project (HCP) we intend to test whether Diffusion MRI-based quantitative imaging parameters (MD, FA, ODI, ISOVF, ICVF), indicative of microstructural characteristics of major hippocampal subfields (CA1, CA2/CA3, CA4-DG and SLRM), correspond to predictions for animal literature and imaging-histology correlations. We will also explore the correlations between these parameters and age. Methods We used images from the Public connectome data (updated April 2018), exploring subjects with the 3T MRI sessions obtainable from the WU-Minn HCP Data section. For the purpose of this study, we selected and downloaded 10 preliminary imaging data (6 females and 4 males) based on age variability in the following ranges (26-30, 31-35 and 36+). We manually segmented, and computed quantitative parameters. Results Converging and consistent literature allude to decreasing volumes with increasing age. Analyzing the volumes from the diffusion maps (pilot data), this was also the case, with volumes computed from CA1 and DG-CA4 sub regions. IQT also allowed for better appreciation of neuroanatomical boundaries and land marks, hence allowing more regions to be easily manually segmented (addition of CA2/CA3). Conclusions Application to Neuroinflammatory imaging data. Disclosure No significant relationships.
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Stojanovic, Tamara, David Velarde Gamez, Gabor Jorrid Schuld, Daniel Bormann, Maureen Cabatic, Pavel Uhrin, Gert Lubec, and Francisco J. Monje. "Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes." Cells 11, no. 2 (January 13, 2022): 261. http://dx.doi.org/10.3390/cells11020261.
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Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212−/−) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3–CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212−/− mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3–CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212−/− mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212−/− mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.
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Daugherty, Ana M., Hillary D. Schwarb, Matthew D. J. McGarry, Curtis L. Johnson, and Neal J. Cohen. "Magnetic Resonance Elastography of Human Hippocampal Subfields: CA3-Dentate Gyrus Viscoelasticity Predicts Relational Memory Accuracy." Journal of Cognitive Neuroscience 32, no. 9 (September 2020): 1704–13. http://dx.doi.org/10.1162/jocn_a_01574.
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The hippocampus is necessary for binding and reconstituting information in relational memory. These essential memory functions are supported by the distinct cytoarchitecture of the hippocampal subfields. Magnetic resonance elastography is an emerging tool that provides sensitive estimates of microstructure vis-à-vis tissue mechanical properties. Here, we report the first in vivo study of human hippocampal subfield viscoelastic stiffness and damping ratio. Stiffness describes resistance of a viscoelastic tissue to a stress and is thought to reflect the relative composition of tissue at the microscale; damping ratio describes relative viscous-to-elastic behavior and is thought to generally reflect microstructural organization. Measures from the subiculum (combined with presubiculum and parasubiculum), cornu ammonis (CA) 1–2, and CA3-dentate gyrus (CA3-DG) were collected in a sample of healthy, cognitively normal men ( n = 20, age = 18–33 years). In line with known cytoarchitecture, the subiculum demonstrated the lowest damping ratio, followed by CA3-DG and then combined CA1–CA2. Moreover, damping ratio of the CA3-DG—potentially reflective of number of cells and their connections—predicted relational memory accuracy and alone replicated most of the variance in performance that was explained by the whole hippocampus. Stiffness did not differentiate the hippocampal subfields and was unrelated to task performance in this sample. Viscoelasticity measured with magnetic resonance elastography appears to be sensitive to microstructural properties relevant to specific memory function, even in healthy younger adults, and is a promising tool for future studies of hippocampal structure in aging and related diseases.
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Kreisman, Norman R., Soheil Soliman, and David Gozal. "Regional Differences in Hypoxic Depolarization and Swelling in Hippocampal Slices." Journal of Neurophysiology 83, no. 2 (February 1, 2000): 1031–38. http://dx.doi.org/10.1152/jn.2000.83.2.1031.
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Pyramidal neurons in the CA1 region of the hippocampus are highly vulnerable to damage from hypoxia-ischemia, whereas neurons in the CA3 region and the dentate gyrus are more resistant. A similar pattern of vulnerability to loss of synaptic and membrane function occurs in the in vitro hippocampal slice preparation, suggesting that intrinsic factors are important in acute neuronal damage. Simultaneous recordings of DC potential and imaging of changes in light transmittance were made in slices from the middle one-third of the hippocampus to characterize the initiation and spread of depolarization and swelling during hypoxia-aglycemia. Hypoxic depolarization (HD) and associated optical changes were initiated simultaneously in the stratum oriens of the CA1 region and thereafter spread to the stratum radiatum of CA1 and later to the upper (inner) blade of the dentate gyrus. A decrease in light transmittance was associated consistently with depolarization in all regions ( n = 22 slices). Investigation of the sequence of activation in intact slices showed that activation of the dentate gyrus arose independently of activation of the CA1 region. This was confirmed by recordings made from minislices in which CA1, CA3, and dentate regions were physically separated. HD and optical changes were never observed in the CA3 region, despite exposure to 40–60 min of combined hypoxia and aglycemia. In contrast, exposure to hypoxia after pretreatment of slices with altered tonicity or ion composition, which triggered episodes of spreading depolarization (SD), provoked depolarization and optical changes simultaneously in both CA1 and CA3 regions. Similarly, pretreatment with agents that cause severe metabolic impairment, such as dinitrophenol (DNP), also rendered the CA3 region vulnerable to subsequent hypoxia. This suggests that the CA3 region in hippocampal slices is normally resistant to HD and only becomes vulnerable after severe impairment of metabolic capacity. The similar order of vulnerability of in vitro and in vivo hippocampus to hypoxia-aglycemia supports the use of the hippocampal slice preparation to investigate early changes potentially contributing to hypoxic-ischemic injury.
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Shcherbak, N. S., G. Yu Yukina, A. G. Gurbo, E. G. Sukhorukova, A. G. Sargsian, V. V. Thomson, and M. M. Galagudza. "Morphofunctional state of microglia and hippocampal neurons in aged rats after anesthesia with chloral hydrate." Regional blood circulation and microcirculation 21, no. 3 (October 12, 2022): 64–71. http://dx.doi.org/10.24884/1682-6655-2022-21-3-64-71.
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Introduction. Successful translating of the fundamental research results into clinical practice is determined by a sufficiently large number of components, including the age of experimental animals and the anesthesia used. Chloral hydrate is often used as an anesthetic in preclinical studies, while its effect on the morphofunctional characteristics of the hippocampus in aged animals remains unexplored, which can lead to significant distortion and incorrect interpretation of the obtain results. Objective – morphofunctional assessment of the neurons and microglia in the layers of CA1, CA2, CA3 and CA4 fields of the hippocampus in aged rats anesthetized with chloral hydrate. Materials and methods. Male Wistar rats at the age of 24 months were anesthetized with chloral hydrate (400 mg/kg). In the early (2 days) period after chloral hydrate anesthesia, the morphofunctional state of neurons and the reaction of microglia were qualitatively and quantitatively assessed by histological, immunohistochemical, and morphometric analysis in the marginal, pyramidal, and molecular layers of fields CA1, CA2, CA3, and CA4 of the hippocampus. Results. 48 hours after 24-month-old Wistar rats were anesthetized with chloral hydrate, changes in the morphofunctional state of the pyramidal layer of the hippocampus were shown to be characterized by a significant decrease in the number of neurons in fields CA1 and CA3 with two nucleoli by 42 and 54 %, respectively, and a decrease in the width of the layer of fields CA1 and CA3 and CA4 by 27, 29 and 21 %, respectively, compared with similar indicators in the control group (P<0.05). In all layers of fields CA1, CA2, CA3 and CA4 of hippocampus, microglia reacted by the transformation of Iba-1-positive microgliocytes body and processes and a significant increase of the Iba-1 protein expression compared to the animals without administration of chloral hydrate (P<0.05). Conclusions. A single chloral hydrate dose administration necessary to anesthetized the aged Wistar rats without model surgery leads to morphofunctional changes in neurons in the most vulnerable fields of the hippocampus with simultaneous activation of microglia in all fields. This circumstance must be taken into account when conducting basic research and preclinical studies.
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Sekino, Yuko, Kunihiko Obata, Manabu Tanifuji, Makoto Mizuno, and Jin Murayama. "Delayed Signal Propagation via CA2 in Rat Hippocampal Slices Revealed by Optical Recording." Journal of Neurophysiology 78, no. 3 (September 1, 1997): 1662–68. http://dx.doi.org/10.1152/jn.1997.78.3.1662.
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Sekino, Yuko, Kunihiko Obata, Manabu Tanifuji, Makoto Mizuno, and Jin Murayama. Delayed signal propagation via CA2 in rat hippocampal slices revealed by optical recording. J. Neurophysiol. 78: 1662–1668, 1997. Signal propagation from mossy fibers to CA1 neurons was investigated in rat hippocampal slices by a combination of electrical and optical recordings. The slices were prepared by oblique sectioning of the middle part of the hippocampus to preserve fiber connections. The mossy fibers were stimulated to induce population spikes (PSs) and excitatory postsynaptic potentials in the middle part of the CA1 region. Latencies of maximal PSs in CA1 varied widely among slices; they ranged from 7 to 13.5 ms, with two maxima at 9 and 11.5 ms. The fastest PSs probably are evoked by the Schaffer collaterals that connect the CA3 and CA1 regions in the well-known trisynaptic circuit. However, the slower PSs suggest the existence of additional delayed inputs. To determine the source of the delayed input, slices were stained with a voltage-sensitive dye, RH482, and the optical signals relevant to membrane potential changes were detected by a high-resolution optical imaging system. Optical recording of responses to mossy fiber stimulation indicated two distinct types of signal propagation from CA3 to CA1. In preparations evincing the fast type of propagation, signals spread to CA1 within 7.2 ms after the mossy fiber stimulation. During such propagation, activity flowed directly from CA3 to the stratum radiatum of CA1. Other preparations illustrated slow signal propagation, in which optical signals were generated in CA2 before spreading to CA1. During such slow signal transmission, activity persisted in CA2 and its surrounding area for 3 ms before propagating to the strata radiatum and oriens in CA1. In such cases, CA1 activity was detected within 10.8 ms of mossy fiber stimulation. In some slices, a mixture of the fast and slow propagation patterns was observed, indicating that these two transmission modes can coexist. Our data reveal that CA2 neurons can transmit delayed excitatory signals to CA1 neurons. We therefore conclude that consideration of electrical signal propagation through the hippocampus should include flow through the CA2 region in addition to the traditional dentate gyrus–CA3–CA1 trisynaptic circuit.
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Pang, Cindy Chi-Ching, Clemens Kiecker, John T. O’Brien, Wendy Noble, and Raymond Chuen-Chung Chang. "Ammon’s Horn 2 (CA2) of the Hippocampus: A Long-Known Region with a New Potential Role in Neurodegeneration." Neuroscientist 25, no. 2 (June 5, 2018): 167–80. http://dx.doi.org/10.1177/1073858418778747.
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The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon’s horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigger role than previously thought. Here, we review understanding of hippocampus and CA2 ontogenesis, together with basic and clinical findings about the potential role of this region in neurodegenerative disease. The CA2 has widespread anatomical connectivity, unique signaling molecules, and intrinsic electrophysiological properties. Experimental studies using in vivo models found that the CA2 region has a role in cognition, especially in social memory and object recognition. In models of epilepsy and hypoxia, the CA2 exhibits higher resilience to cell death and hypoxia in comparison with neighboring regions, and while hippocampal atrophy remains poorly understood in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), findings from postmortem PD brain demonstrates clear accumulation of α-synuclein pathology in CA2, and the CA2-CA3 region shows relatively more atrophy compared with other hippocampal subfields. Taken together, there is a growing body of evidence suggesting that the CA2 can be an ideal hallmark with which to differentiate different neurodegenerative stages of PD. Here, we summarize these recent data and provide new perspectives/ideas for future investigations to unravel the contribution of the CA2 to neurodegenerative diseases.
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Suthana, Nanthia A., Markus Donix, David R. Wozny, Adam Bazih, Michael Jones, Robin M. Heidemann, Robert Trampel, et al. "High-resolution 7T fMRI of Human Hippocampal Subfields during Associative Learning." Journal of Cognitive Neuroscience 27, no. 6 (June 2015): 1194–206. http://dx.doi.org/10.1162/jocn_a_00772.
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Examining the function of individual human hippocampal subfields remains challenging because of their small sizes and convoluted structures. Previous human fMRI studies at 3 T have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, CA3, and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study, we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution fMRI scanning at 7 T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.
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Chang, Payne Y., Portia E. Taylor, and Meyer B. Jackson. "Voltage Imaging Reveals the CA1 Region at the CA2 Border as a Focus for Epileptiform Discharges and Long-Term Potentiation in Hippocampal Slices." Journal of Neurophysiology 98, no. 3 (September 2007): 1309–22. http://dx.doi.org/10.1152/jn.00532.2007.
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Voltage-sensitive-dye imaging was used to study the initiation and propagation of epileptiform activity in transverse hippocampal slices. A portion of the slices tested generated epileptiform discharges in response to electrical shocks under normal physiological conditions. The fraction of slices showing epileptiform responses increased from 44 to 86% when bathing [K+] increased from 3.2 to 4 mM. Regardless of stimulation site in the dentate gyrus and hippocampus, discharges generally initiated in the CA3 region. After onset, discharges abruptly appeared in the CA1 region, right at the CA2 border. This spread from the CA3 region to the CA1 region was saltatory, occurring before detectable activity in the intervening CA2 and CA3 regions. Discharges did eventually propagate smoothly through the intervening CA3 region into the CA2 region, but on a slower timescale. The surge in the CA1 region did not spread back into the CA2 region, but spread through the CA1 region toward the subiculum. Tetanic stimulation, theta bursts, and GABAA receptor antagonists failed to alter this characteristic pattern, but did reduce the latency of discharge onset. The part of the CA1 region at the CA2 border, where epileptic responses emerged with relatively short latency, also expressed stronger long-term potentiation (LTP) than the rest of the CA1 region. The CA2 region, where discharges had long latencies and low amplitudes, expressed weaker LTP. Thus the CA1 region at the CA2 border has unique properties, which make this part of the hippocampus an important locus for both epileptiform activity and plasticity.
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Liang, Xia, Li-Ming Hsu, Hanbing Lu, Jessica A. Ash, Peter R. Rapp, and Yihong Yang. "Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via CA1–Frontal Circuit." Cerebral Cortex 30, no. 8 (April 2, 2020): 4297–305. http://dx.doi.org/10.1093/cercor/bhaa008.
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Abstract The CA3 and CA1 principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and CA1 is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via CA1 network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and CA1 fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left CA1 and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by CA1 connectivity with prefrontal cortex. We additionally found that spatial learning and memory were associated with functional connectivity changes lateralized to the left CA3 and CA1 divisions. These results provide novel evidence that network-level dysfunction involving interactions of CA3 with CA1 is an early marker of poor cognitive outcome in aging.
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Segev, Amir, Masaya Yanagi, Daniel Scott, Sarah A. Southcott, Jacob M. Lister, Chunfeng Tan, Wei Li, Shari G. Birnbaum, Saïd Kourrich, and Carol A. Tamminga. "Reduced GluN1 in mouse dentate gyrus is associated with CA3 hyperactivity and psychosis-like behaviors." Molecular Psychiatry 25, no. 11 (July 23, 2018): 2832–43. http://dx.doi.org/10.1038/s41380-018-0124-3.
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Abstract Recent findings from in vivo-imaging and human post-mortem tissue studies in schizophrenic psychosis (SzP), have demonstrated functional and molecular changes in hippocampal subfields that can be associated with hippocampal hyperexcitability. In this study, we used a subfield-specific GluN1 knockout mouse with a disease-like molecular perturbation expressed only in hippocampal dentate gyrus (DG) and assessed its association with hippocampal physiology and psychosis-like behaviors. First, we used whole-cell patch-clamp recordings to measure the physiological changes in hippocampal subfields and cFos immunohistochemistry to examine cellular excitability. DG-GluN1 KO mice show CA3 cellular hyperactivity, detected using two approaches: (1) increased excitatory glutamate transmission at mossy fibers (MF)-CA3 synapses, and (2) an increased number of cFos-activated pyramidal neurons in CA3, an outcome that appears to project downstream to CA1 and basolateral amygdala (BLA). Furthermore, we examined psychosis-like behaviors and pathological memory processing; these show an increase in fear conditioning (FC), a reduction in prepulse inhibition (PPI) in the KO animal, along with a deterioration in memory accuracy with Morris Water Maze (MWM) and reduced social memory (SM). Moreover, with DREADD vectors, we demonstrate a remarkably similar behavioral profile when we induce CA3 hyperactivity. These hippocampal subfield changes could provide the basis for the observed increase in human hippocampal activity in SzP, based on the shared DG-specific GluN1 reduction. With further characterization, these animal model systems may serve as targets to test psychosis mechanisms related to hippocampus and assess potential hippocampus-directed treatments.
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Fujii, Takeshi, Yasushi Kuraishi, Toshikazu Okada, and Masamichi Satoh. "Bifemelane induces translocation of protein kinase C in the CA3, but not the CA1, region of guinea-pig hippocampus." Canadian Journal of Physiology and Pharmacology 68, no. 3 (March 1, 1990): 413–18. http://dx.doi.org/10.1139/y90-058.
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We made use of the [3H]phorbol 12,13-dibutyrate binding assay to investigate the effects of bifemelane on the subcellular distribution of protein kinase C in the CA3 and CA1 regions of guinea-pig hippocampal slices. Bifemelane, a drug that augments the long-term potentiation in the CA3 region, significantly induced the translocation of [3H]phorbol 12,13-dibutyrate binding activity from the cytosol to the membrane in a dose-dependent manner (10−8 to 10−6 M) and with no effects on total binding activity in the CA3 region. Bifemelane, at a concentration of 10−6 M, was without effect on the subcellular distribution of [3H]phorbol 12,13-dibutyrate binding activity in the CA1 region. These observations suggest that bifemelane acts directly on the hippocampus to induce translocation of protein kinase C in the CA3 region. Such an effect may be associated with the bifemelane-induced augmentation of the long-term potentiation in this region of the brain.Key words: bifemelane, protein kinase C, hippocampal slice, translocation, CA3.
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Jordan, Jake T., Yi Tong, and Carolyn L. Pytte. "Transection of the ventral hippocampal commissure impairs spatial reference but not contextual or spatial working memory." Learning & Memory 29, no. 1 (December 15, 2021): 29–37. http://dx.doi.org/10.1101/lm.053483.121.
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Plasticity is a neural phenomenon in which experience induces long-lasting changes to neuronal circuits and is at the center of most neurobiological theories of learning and memory. However, too much plasticity is maladaptive and must be balanced with substrate stability. Area CA3 of the hippocampus provides such a balance via hemispheric lateralization, with the left hemisphere dominant in providing plasticity and the right specialized for stability. Left and right CA3 project bilaterally to CA1; however, it is not known whether this downstream merging of lateralized plasticity and stability is functional. We hypothesized that interhemispheric convergence of input from these pathways is essential for integrating spatial memory stored in the left CA3 with navigational working memory facilitated by the right CA3. To test this, we severed interhemispheric connections between the left and right hippocampi in mice and assessed learning and memory. Despite damage to this major hippocampal fiber tract, hippocampus-dependent navigational working memory and short- and long-term memory were both spared. However, tasks that required the integration of information retrieved from memory with ongoing navigational working memory and navigation were impaired. We propose that one function of interhemispheric communication in the mouse hippocampus is to integrate lateralized processing of plastic and stable circuits to facilitate memory-guided spatial navigation.
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Wu, Chiping, Wah Ping Luk, Jesse Gillis, Frances Skinner, and Liang Zhang. "Size Does Matter: Generation of Intrinsic Network Rhythms in Thick Mouse Hippocampal Slices." Journal of Neurophysiology 93, no. 4 (April 2005): 2302–17. http://dx.doi.org/10.1152/jn.00806.2004.
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Rodent hippocampal slices of ≤0.5 mm thickness have been widely used as a convenient in vitro model since the 1970s. However, spontaneous population rhythmic activities do not consistently occur in this preparation due to limited network connectivity. To overcome this limitation, we develop a novel slice preparation of 1 mm thickness from adult mouse hippocampus by separating dentate gyrus from CA3/CA1 areas but preserving dentate–CA3-CA1 connectivity. While superfused in vitro at 32 or 37°C, the thick slice exhibits robust spontaneous network rhythms of 1–4 Hz that originate from the CA3 area. Via assessing tissue O2, K+, pH, synaptic, and single-cell activities of superfused thick slices, we verify that these spontaneous rhythms are not a consequence of hypoxia and nonspecific experimental artifacts. We suggest that the thick slice contains a unitary circuitry sufficient to generate intrinsic hippocampal network rhythms and this preparation is suitable for exploring the fundamental properties and plasticity of a functionally defined hippocampal “lamella” in vitro.
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Lau, JC, J. DeKraker, KW MacDougall, H. Joswig, AG Parrent, JG Burneo, DA Steven, TM Peters, and AR Khan. "P.063 Stereotactic targeting of hippocampal substructures using ultra-high field magnetic resonance imaging: Feasibility study in patients with epilepsy." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, s2 (June 2018): S32—S33. http://dx.doi.org/10.1017/cjn.2018.165.
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Background: The hippocampus can be divided longitudinally into the head, body, and tail; and unfolded medial-to-laterally into the subiculum, cornu ammonis (CA) sectors, and the dentate gyrus. Ultra-high field (≥ 7 Tesla; 7T) magnetic resonance imaging (MRI) enables submillimetric visualization of these hippocampal substructures which could be valuable for surgical targeting. Here, we assess the feasibility of using 7T MRI in conjunction with a novel computational unfolding method for image-based stereotactic targeting of hippocampal substructures. Methods: 53 patients with drug-resistant epilepsy were identified undergoing first-time implantation of the hippocampus. An image processing pipeline was created for computationally transforming post-operative electrode contact locations into our hippocampal coordinate system. Results: Of 178 implanted hippocampal electrodes (88 left; 49.4%), 25 (14.0%) were predominantly in the subiculum, 85 (47.8%) were in CA1, 23 (12.9%) were in CA2, 18 (10.1%) were in CA3/CA4, and 27 (15.2%) were in dentate gyrus. Along the longitudinal axis, hippocampal electrodes were most commonly implanted in the body (92; 51.7%) followed by the head (86; 48.3%). Conclusions: 7T MRI enables high-resolution anatomical imaging on the submillimeter scale in in vivo subjects. Here, we demonstrate the utility of 7T imaging for identifying the relative location of SEEG electrode implantations within hippocampal substructures for the invasive investigation of epilepsy.
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Colom, L. V., and P. Saggau. "Spontaneous interictal-like activity originates in multiple areas of the CA2-CA3 region of hippocampal slices." Journal of Neurophysiology 71, no. 4 (April 1, 1994): 1574–85. http://dx.doi.org/10.1152/jn.1994.71.4.1574.
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1. The sites of origin of spontaneous interictal-like epileptiform activity in hippocampal slices from guinea pig, mouse, and rat were determined. A multisite fast optical recording technique using voltage-sensitive dyes and an array of 100 photodiodes was employed. The use of a low-magnification objective lens allowed the visualization of almost the entire transverse hippocampal slice. Three in vitro models of epilepsy were employed, utilizing different manipulations of the bath perfusion medium to induce epileptiform activity: 1) raising the external potassium (K+) concentration, 2) adding the potassium channel blocker 4-aminopyridine (4-AP), and 3) adding antagonists of gamma-aminobutyric acid-A (GABAA) receptors (bicuculline and picrotoxin, BIC-PTX). 2. Spontaneous epileptiform discharges were detected in each subfield of cornu ammonis (CA) but not in the dentate gyrus (DG) of each studied species. Preliminary experiments confirmed that interictal-like epileptiform activity originated in the CA2-CA3 region. Ictal-like activity was never observed in our experiments. 3. In the guinea pig, when GABAA antagonists were employed, the site of origin of spontaneous epileptiform discharges was consistently located in the CA2-CA3a region. When high K+ or 4-AP was used, this region was the most frequent site of origin. Subsequent epileptiform discharges with similar sites of origin occasionally invaded different areas of the CA2-CA3 region, revealing a variable area of occupance of epileptiform discharges. 4. In the mouse and rat, the site of origin of spontaneous discharges was invariably located in the CA3b-CA3c region independent of the epilepsy model. 5. In both the guinea pig and rat, when the CA2-CA3a region was surgically separated from the CA3b-CA3c region, independent discharges were observed in both regions. Areas that could generate discharges only under certain epileptogenic conditions were found in these species (potential sites of origin). Two independent sites of origin with different propagation patterns and area of occupance were occasionally observed within the CA2-CA3a region. 6. In the guinea pig, such lesions demonstrated that both regions can independently generate epileptiform discharges at different frequencies. When high K+ or 4-AP was employed, epileptiform activity was observed in both regions. Although BIC-PTX only generated discharges in the CA2-CA3a region, a subsequent increase in K+ induced additional discharges in the CA3b-CA3c region, revealing a potential site of origin. 7. In rat hippocampal slices with such lesions, spontaneous epileptiform discharges were observed in both CA2-CA3a and CA3b-CA3c region when 4-AP was employed.(ABSTRACT TRUNCATED AT 400 WORDS)
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Zheng, Yicong, Xiaonan L. Liu, Satoru Nishiyama, Charan Ranganath, and Randall C. O’Reilly. "Correcting the hebbian mistake: Toward a fully error-driven hippocampus." PLOS Computational Biology 18, no. 10 (October 11, 2022): e1010589. http://dx.doi.org/10.1371/journal.pcbi.1010589.
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The hippocampus plays a critical role in the rapid learning of new episodic memories. Many computational models propose that the hippocampus is an autoassociator that relies on Hebbian learning (i.e., “cells that fire together, wire together”). However, Hebbian learning is computationally suboptimal as it does not learn in a way that is driven toward, and limited by, the objective of achieving effective retrieval. Thus, Hebbian learning results in more interference and a lower overall capacity. Our previous computational models have utilized a powerful, biologically plausible form of error-driven learning in hippocampal CA1 and entorhinal cortex (EC) (functioning as a sparse autoencoder) by contrasting local activity states at different phases in the theta cycle. Based on specific neural data and a recent abstract computational model, we propose a new model called Theremin (Total Hippocampal ERror MINimization) that extends error-driven learning to area CA3—the mnemonic heart of the hippocampal system. In the model, CA3 responds to the EC monosynaptic input prior to the EC disynaptic input through dentate gyrus (DG), giving rise to a temporal difference between these two activation states, which drives error-driven learning in the EC→CA3 and CA3↔CA3 projections. In effect, DG serves as a teacher to CA3, correcting its patterns into more pattern-separated ones, thereby reducing interference. Results showed that Theremin, compared with our original Hebbian-based model, has significantly increased capacity and learning speed. The model makes several novel predictions that can be tested in future studies.
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Hamadi, Naserddine, Ömür Gülsüm Deniz, Ahlam Said Abi Issa, Azim Ullah Shamsul Islam, Naheed Amir, Saeed Tariq Minhas, Nather Madjid, Fatima Khelifi-Touhami, Süleyman Kaplan, and Abdu Adem. "Stereological Evidence of Non-Selective Hippocampal Neurodegeneration, IGF-1 Depletion, and Behavioral Deficit following Short Term Bilateral Adrenalectomy in Wistar Rats." Biomolecules 13, no. 1 (December 22, 2022): 22. http://dx.doi.org/10.3390/biom13010022.
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The development of animal models to study cell death in the brain is a delicate task. One of the models, that was discovered in the late eighties, is the induction of neurodegeneration through glucocorticoid withdrawal by adrenalectomy in albino rats. Such a model is one of the few noninvasive models for studying neurodegeneration. In the present study, using stereological technique and ultrastructural examination, we aimed to investigate the impact of short-term adrenalectomy (2 weeks) on different hippocampal neuronal populations in Wistar rats. In addition, the underlying mechanism(s) of degeneration in these neurons were investigated by measuring the levels of insulin-like growth factor-1 (IGF-1) and β-nerve growth factor (β-NGF). Moreover, we examined whether the biochemical and histological changes in the hippocampus, after short-term adrenalectomy, have an impact on the cognitive behavior of Wistar rats. Stereological counting in the hippocampus revealed significant neuronal deaths in the dentate gyrus and CA4/CA3, but not in the CA2 and CA1 areas, 7 and 14 days post adrenalectomy. The ultrastructural examinations revealed degenerated and degenerating neurons in the dentate, as well as CA4, and CA3 areas, over the course of 3, 7 and 14 days. The levels of IGF-1 were significantly decreased in the hippocampus of ADX rats 24 h post adrenalectomy, and lasted over the course of two weeks. However, β-NGF was not affected in rats. Using a passive avoidance task, we found a cognitive deficit in the ADX compared to the SHAM operated rats over time (3, 7, and 14 days). In conclusion, both granule and pyramidal cells were degenerated in the hippocampus following short-term adrenalectomy. The early depletion of IGF-1 might play a role in hippocampal neuronal degeneration. Consequently, the loss of the hippocampal neurons after adrenalectomy leads to cognitive deficits.
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van der Veldt, Suzanne, Guillaume Etter, Coralie-Anne Mosser, Frédéric Manseau, and Sylvain Williams. "Conjunctive spatial and self-motion codes are topographically organized in the GABAergic cells of the lateral septum." PLOS Biology 19, no. 8 (August 30, 2021): e3001383. http://dx.doi.org/10.1371/journal.pbio.3001383.
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The hippocampal spatial code’s relevance for downstream neuronal populations—particularly its major subcortical output the lateral septum (LS)—is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animal’s location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior–posterior and dorsal–ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using transsynaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network.
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Buss, Eric W., Nicola J. Corbett, Joshua G. Roberts, Natividad Ybarra, Timothy F. Musial, Dina Simkin, Elizabeth Molina-Campos, et al. "Cognitive aging is associated with redistribution of synaptic weights in the hippocampus." Proceedings of the National Academy of Sciences 118, no. 8 (February 16, 2021): e1921481118. http://dx.doi.org/10.1073/pnas.1921481118.
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Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others’ lifespans outlast their “mindspans.”
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D'Antuono, Margherita, Ruba Benini, Giuseppe Biagini, Giovanna D'Arcangelo, Michaela Barbarosie, Virginia Tancredi, and Massimo Avoli. "Limbic Network Interactions Leading to Hyperexcitability in a Model of Temporal Lobe Epilepsy." Journal of Neurophysiology 87, no. 1 (January 1, 2002): 634–39. http://dx.doi.org/10.1152/jn.00351.2001.
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In mouse brain slices that contain reciprocally connected hippocampus and entorhinal cortex (EC) networks, CA3 outputs control the EC propensity to generate experimentally induced ictal-like discharges resembling electrographic seizures. Neuronal damage in limbic areas, such as CA3 and dentate hilus, occurs in patients with temporal lobe epilepsy and in animal models (e.g., pilocarpine- or kainate-treated rodents) mimicking this epileptic disorder. Hence, hippocampal damage in epileptic mice may lead to decreased CA3 output function that in turn would allow EC networks to generate ictal-like events. Here we tested this hypothesis and found that CA3-driven interictal discharges induced by 4-aminopyridine (4AP, 50 μM) in hippocampus-EC slices from mice injected with pilocarpine 13–22 days earlier have a lower frequency than in age-matched control slices. Moreover, EC-driven ictal-like discharges in pilocarpine-treated slices occur throughout the experiment (≤6 h) and spread to the CA1/subicular area via the temporoammonic path; in contrast, they disappear in control slices within 2 h of 4AP application and propagate via the trisynaptic hippocampal circuit. Thus, different network interactions within the hippocampus-EC loop characterize control and pilocarpine-treated slices maintained in vitro. We propose that these functional changes, which are presumably caused by seizure-induced cell damage, lead to seizures in vivo. This process is facilitated by a decreased control of EC excitability by hippocampal outputs and possibly sustained by the reverberant activity between EC and CA1/subiculum networks that are excited via the temporoammonic path.
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Ros, Jacqueline, Luc Pellerin, Fulvio Magara, Julien Dauguet, Françoise Schenk, and Pierre J. Magistretti. "Metabolic Activation Pattern of Distinct Hippocampal Subregions during Spatial Learning and Memory Retrieval." Journal of Cerebral Blood Flow & Metabolism 26, no. 4 (August 31, 2005): 468–77. http://dx.doi.org/10.1038/sj.jcbfm.9600208.
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Activation dynamics of hippocampal subregions during spatial learning and their interplay with neocortical regions is an important dimension in the understanding of hippocampal function. Using the (14C)-2-deoxyglucose autoradiographic method, we have characterized the metabolic changes occurring in hippocampal subregions in mice while learning an eight-arm radial maze task. Autoradiogram densitometry revealed a heterogeneous and evolving pattern of enhanced metabolic activity throughout the hippocampus during the training period and on recall. In the early stages of training, activity was enhanced in the CA1 area from the intermediate portion to the posterior end as well as in the CA3 area within the intermediate portion of the hippocampus. At later stages, CA1 and CA3 activations spread over the entire longitudinal axis, while dentate gyrus (DG) activation occurred from the anterior to the intermediate zone. Activation of the retrosplenial cortex but not the amygdala was also observed during the learning process. On recall, only DG activation was observed in the same anterior part of the hippocampus. These results suggest the existence of a functional segmentation of the hippocampus, each subregion being dynamically but also differentially recruited along the acquisition, consolidation, and retrieval process in parallel with some neocortical sites.
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Wicks, Robert T., Mark R. Witcher, Daniel E. Couture, Adrian W. Laxton, Gautam Popli, Christopher T. Whitlow, Dustin Fetterhoff, et al. "Hippocampal CA1 and CA3 neural recording in the human brain: validation of depth electrode placement through high-resolution imaging and electrophysiology." Neurosurgical Focus 49, no. 1 (July 2020): E5. http://dx.doi.org/10.3171/2020.4.focus20164.
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OBJECTIVEIntracranial human brain recordings typically utilize recording systems that do not distinguish individual neuron action potentials. In such cases, individual neurons are not identified by location within functional circuits. In this paper, verified localization of singly recorded hippocampal neurons within the CA3 and CA1 cell fields is demonstrated.METHODSMacro-micro depth electrodes were implanted in 23 human patients undergoing invasive monitoring for identification of epileptic seizure foci. Individual neurons were isolated and identified via extracellular action potential waveforms recorded via macro-micro depth electrodes localized within the hippocampus. A morphometric survey was performed using 3T MRI scans of hippocampi from the 23 implanted patients, as well as 46 normal (i.e., nonepileptic) patients and 26 patients with a history of epilepsy but no history of depth electrode placement, which provided average dimensions of the hippocampus along typical implantation tracks. Localization within CA3 and CA1 cell fields was tentatively assigned on the basis of recording electrode site, stereotactic positioning of the depth electrode in comparison with the morphometric survey, and postsurgical MRI. Cells were selected as candidate CA3 and CA1 principal neurons on the basis of waveform and firing rate characteristics and confirmed within the CA3-to-CA1 neural projection pathways via measures of functional connectivity.RESULTSCross-correlation analysis confirmed that nearly 80% of putative CA3-to-CA1 cell pairs exhibited positive correlations compatible with feed-forward connection between the cells, while only 2.6% exhibited feedback (inverse) connectivity. Even though synchronous and long-latency correlations were excluded, feed-forward correlation between CA3-CA1 pairs was identified in 1071 (26%) of 4070 total pairs, which favorably compares to reports of 20%–25% feed-forward CA3-CA1 correlation noted in published animal studies.CONCLUSIONSThis study demonstrates the ability to record neurons in vivo from specified regions and subfields of the human brain. As brain-machine interface and neural prosthetic research continues to expand, it is necessary to be able to identify recording and stimulation sites within neural circuits of interest.
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Kubota, Don, Laura Lee Colgin, Malcolm Casale, Fernando A. Brucher, and Gary Lynch. "Endogenous Waves in Hippocampal Slices." Journal of Neurophysiology 89, no. 1 (January 1, 2003): 81–89. http://dx.doi.org/10.1152/jn.00542.2002.
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Sharp waves (SPWs) are thought to play a major role in intrinsic hippocampal operations during states in which subcortical and cortical inputs to hippocampus are reduced. This study describes evidence that such activity occurs spontaneously in appropriately prepared rat hippocampal slices. Irregular waves, with an average frequency of approximately 4 Hz, were recorded from field CA3 in slices prepared from the temporal region of hippocampus. The waves persisted for hours and were not accompanied by aberrant discharges. Multi-electrode analyses established that they were locally generated within each of the subfields of CA3 and yet were coherent between subfields. The sharp waves were reversibly blocked by either cholinergic or serotonergic stimulation. Various lines of evidence indicate that they are propagated by the CA3 associational system.
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Hsiao, Yi-Tse, Chenguang Zheng, and Laura Lee Colgin. "Slow gamma rhythms in CA3 are entrained by slow gamma activity in the dentate gyrus." Journal of Neurophysiology 116, no. 6 (December 1, 2016): 2594–603. http://dx.doi.org/10.1152/jn.00499.2016.
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In hippocampal area CA1, slow (∼25–55 Hz) and fast (∼60–100 Hz) gamma rhythms are coupled with different CA1 afferents. CA1 slow gamma is coupled to inputs from CA3, and CA1 fast gamma is coupled to inputs from the medial entorhinal cortex (Colgin LL, Denninger T, Fyhn M, Hafting T, Bonnevie T, Jensen O, Moser MB, Moser EI. Nature 462: 353–357, 2009). CA3 gives rise to highly divergent associational projections, and it is possible that reverberating activity in these connections generates slow gamma rhythms in the hippocampus. However, hippocampal gamma is maximal upstream of CA3, in the dentate gyrus (DG) region (Bragin A, Jando G, Nadasdy Z, Hetke J, Wise K, Buzsaki G. J Neurosci 15: 47–60, 1995). Thus it is possible that slow gamma in CA3 is driven by inputs from DG, yet few studies have examined slow and fast gamma rhythms in DG recordings. Here we investigated slow and fast gamma rhythms in paired recordings from DG and CA3 in freely moving rats to determine whether slow and fast gamma rhythms in CA3 are entrained by DG. We found that slow gamma rhythms, as opposed to fast gamma rhythms, were particularly prominent in DG. We investigated directional causal influences between DG and CA3 by Granger causality analysis and found that DG slow gamma influences CA3 slow gamma. Moreover, DG place cell spikes were strongly phase-locked to CA3 slow gamma rhythms, suggesting that DG excitatory projections to CA3 may underlie this directional influence. These results indicate that slow gamma rhythms do not originate in CA3 but rather slow gamma activity upstream in DG entrains slow gamma rhythms in CA3.
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Sun, Wei, Xuanyin Zhao, Yiwen Wan, Yang Yang, Xiaoliang Li, Xiao Chen, Yazi Mei, and Lei An. "Prenatal cyanuric acid exposure induced spatial learning impairments associated with alteration of acetylcholine-mediated neural information flow at the hippocampal CA3-CA1 synapses of male rats." Human & Experimental Toxicology 42 (March 8, 2023): 096032712311634. http://dx.doi.org/10.1177/09603271231163477.
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Cyanuric acid (CA) is reported to induce nephrotoxicity but its toxic effect is not fully known. Prenatal CA exposure causes neurodevelopmental deficits and abnormal behavior in spatial learning ability. Dysfunction of the acetyl-cholinergic system in neural information processing is correlated with spatial learning impairment and was found in the previous reports of CA structural analogue melamine. To further investigate the neurotoxic effects and the potential mechanism, the acetylcholine (ACh) level was detected in the rats which were exposed to CA during the whole of gestation. Local field potentials (LFPs) were recorded when rats infused with ACh or cholinergic receptor agonist into hippocampal CA3 or CA1 region were trained in the Y-maze task. We found the expression of ACh in the hippocampus was significantly reduced in dose-dependent manners. Intra-hippocampal infusion of ACh into the CA1 but not the CA3 region could effectively mitigate learning deficits induced by CA exposure. However, activation of cholinergic receptors did not rescue the learning impairments. In the LFP recording, we found that the hippocampal ACh infusions could enhance the values of phase synchronization between CA3 and CA1 regions in theta and alpha oscillations. Meanwhile, the reduction in the coupling directional index and the strength of CA3 driving CA1 in the CA-treated groups was also reversed by the ACh infusions. Our findings are consistent with the hypothesis and provide the first evidence that prenatal CA exposure induced spatial learning defect is attributed to the weakened ACh-mediated neuronal coupling and NIF in the CA3-CA1 pathway.
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Stokes, Jared, Colin Kyle, and Arne D. Ekstrom. "Complementary Roles of Human Hippocampal Subfields in Differentiation and Integration of Spatial Context." Journal of Cognitive Neuroscience 27, no. 3 (March 2015): 546–59. http://dx.doi.org/10.1162/jocn_a_00736.
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The unique circuitry of the hippocampus is thought to support the encoding and retrieval of context-rich episodic memories. Given the neuroanatomical differences between the hippocampal subfields, determining their functional roles during representation of contextual features in humans is an important yet unaddressed research goal. Prior studies suggest that, during the acquisition of information from the environment, the dentate gyrus (DG) and CA3 subfields rapidly differentiate competing contextual representations, whereas CA1, situated downstream from CA3/DG, is believed to process input from both CA3 and neocortical areas via the temporoammonic pathway. To further explore the functionality of these roles, we used high-resolution fMRI to investigate multivariate response patterns within CA3/DG and CA1 during the processing of spatial context. While undergoing functional imaging, participants viewed videos of virtual environments and were asked to discriminate between similar yet geometrically distinct cities. We manipulated a single contextual feature by systematically morphing the city configurations from one common geometric shape to another, resulting in four cities—two distinctively shaped cities and two intermediate “morphed” cities. Pattern similarity within CA3/DG scaled with geometric changes to the environment. In contrast, CA1 pattern similarity, as well as interregional pattern similarity between CA1 and parahippocampal cortex, increased for the regularly shaped configurations compared with the morphs. These results highlight different roles for subfields CA3/DG and CA1 in memory and advance our understanding of how subcomponents of the human hippocampal circuit represent contextual features of memories.
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Tole, S., C. Christian, and E. A. Grove. "Early specification and autonomous development of cortical fields in the mouse hippocampus." Development 124, no. 24 (December 15, 1997): 4959–70. http://dx.doi.org/10.1242/dev.124.24.4959.
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Studies of the specification of distinct areas in the developing cerebral cortex have until now focused mainly on neocortex. We demonstrate that the hippocampus, an archicortical structure, offers an elegant, alternative system in which to explore cortical area specification. Individual hippocampal areas, called CA fields, display striking molecular differences in maturity. We use these distinct patterns of gene expression as markers of CA field identity, and show that the two major hippocampal fields, CA1 and CA3, are specified early in hippocampal development, during the period of neurogenesis. Two field-specific markers display consistent patterns of expression from the embryo to the adult. Presumptive CA1 and CA3 fields (Pca1, Pca3) can therefore be identified between embryonic days 14.5 and 15.5 in the mouse, a week before the fields are morphologically distinct. No other individual cortical areas have been detected by gene expression as early in development. Indeed, other features that distinguish between the CA fields appear after birth, indicating that mature CA field identity is acquired over at least 3 weeks. To determine if Pca1 and Pca3 are already specified to acquire mature CA field identities, the embryonic fields were isolated from further potential specification cues by maintaining them in slice culture. CA field development proceeds in slices of the entire embryonic hippocampus. More strikingly, slices restricted to Pca1 or Pca3 alone also develop appropriate mature features of CA1 or CA3. Pca1 and Pca3 are therefore able to develop complex characteristics of mature CA field identity autonomously, that is, without contact or innervation from other fields or other parts of the brain. Because Pca1 and Pca3 can be identified before major afferents grow into the hippocampus, innervation may also be unnecessary for the initial division of the hippocampus into separate fields. Providing a clue to the source of the true specifying signals, the earliest field markers appear first at the poles of the hippocampus, then progress inwards. General hippocampal development does not follow this pronounced pattern. We suggest that the sources of signals that specify hippocampal field identity lie close to the hippocampal poles, and that the signals operate first on cells at the poles, then move inwards.
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Tallent, Melanie K., and George R. Siggins. "Somatostatin Acts in CA1 and CA3 to Reduce Hippocampal Epileptiform Activity." Journal of Neurophysiology 81, no. 4 (April 1, 1999): 1626–35. http://dx.doi.org/10.1152/jn.1999.81.4.1626.
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Somatostatin acts in CA1 and CA3 to reduce hippocampal epileptiform activity. Although the peptide somatostatin (SST) has been speculated to function in temporal lobe epilepsy, its exact role is unclear, as in vivo studies have suggested both pro- and anticonvulsant properties. We have shown previously that SST has multiple inhibitory cellular actions in the CA1 region of the hippocampus, suggesting that in this region SST should have antiepileptic actions. To directly assess the effect of SST on epileptiform activity, we studied two in vitro models of epilepsy in the rat hippocampal slice preparation using extracellular and intracellular recording techniques. In one, GABA-mediated neurotransmission was inhibited by superfusion of the GABAA receptor antagonist bicuculline. In the second, we superfused Mg2+-free artificial cerebrospinal fluid to remove the Mg2+ block of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor. We show here that SST markedly reduces the intensity of evoked epileptiform afterdischarges and the frequency of spontaneous bursts in both CA1 and CA3. SST appears to act additively in the two regions to suppress the transmission of epileptiform events through the hippocampus. We further examined SST’s actions in CA3 and found that SST dramatically reduced the frequency of paroxysmal depolarizing shifts (PDSs) recorded intracellularly in current clamp, as well as increasing the threshold for evoking “giant” excitatory postsynaptic currents (EPSCs), large polysynaptically mediated EPSCs that are the voltage-clamp correlate of PDSs. We also examined the actions of SST on pharmacologically isolated EPSCs generated at both mossy fiber (MF) and associational/commissural (A/C) synapses. SST appears to act specifically to reduce recurrent excitation between CA3 neurons because it depresses A/C- but not MF-evoked EPSCs. SST also increased paired-pulse facilitation of A/C EPSCs, suggesting a presynaptic site of action. Reciprocal activation of CA3 neurons through A/C fibers is critical for generation of epileptiform activity in hippocampus. Thus SST reduces feedforward excitation in rat hippocampus, acting to “brake” hyperexcitation. This is a function unique from that described for other hippocampal neuropeptides, which affect more standard neurotransmission. Our results suggest that SST receptors could be a unique, selective clinical target for treatment of limbic seizures.
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Eom, Kisang. "Partial EC outputs by degraded cues are amplified in hippocampal CA3 circuits for retrieving stored patterns." PLOS ONE 18, no. 4 (April 19, 2023): e0281458. http://dx.doi.org/10.1371/journal.pone.0281458.
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Hippocampus is known to be important for episodic memories. Measuring of hippocampal neural ensembles is therefore important for observing hippocampal cognitive processes such as pattern completion. Previous studies on pattern completion had a limitation because the activities of CA3 were not simultaneously observed with the activities of the entorhinal cortex that project to the CA3. In addition, in previous research and modelling, distinct concepts such as pattern completion and pattern convergence have not been considered separately. Here, I used a molecular analysis technique that enables comparison of neural ensembles that evoked two successive events and evaluated neural ensembles in the hippocampal CA3 region and entorhinal cortex. By comparing neural ensembles in hippocampus and entorhinal cortex, I could obtain evidence that suggests pattern completion occurring in the CA3 region was induced by the partial input from EC. Use of the molecular-based ensemble measurement allows measuring two or more brain regions simultaneously, which can lead to insights into the cognitive functions of neural circuits.
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Ciufolini, Simone, Matthew Kempton, Charlotte Gayer-Anderson, Heather Taylor, Tiago Reis Marques, Helen Fisher, Marta Di Forti, et al. "S186. THE EFFECTS OF CHILDHOOD TRAUMA ON HIPPOCAMPAL VOLUME IN FIRST EPISODE PSYCHOSIS: DOES CORTISOL PLAY A ROLE?" Schizophrenia Bulletin 46, Supplement_1 (April 2020): S109. http://dx.doi.org/10.1093/schbul/sbaa031.252.
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Abstract Background Childhood trauma is one of the most important risk factors in psychosis. Mounting evidence is associating early trauma exposure with alterations in stress sensitive areas, like the hippocampus, and abnormal concentrations of the main stress hormone, cortisol. As hippocampus is a pivotal brain region in the hypothalamus–pituitary–adrenal (HPA) axis regulation of cortisol, better understanding the relationship between childhood trauma, hippocampus structure and cortisol concentration would help clarify how childhood trauma exposure can increase the risk of developing psychosis later on in life. Methods Brain structure was evaluated with a 3T MRI scan in 86 first episode psychosis patients (FEP) (49 of which positive for severe childhood trauma) (mean age: 27.8 SD ± 9.1 years). Hippocampal volume and the segmentation of the hippocampal subfields was obtained using FreeSurfer 6. Salivary cortisol samples were collected to measure cortisol levels at awakening (CAR). Initially two separate linear regression models were ran: 1) to predict hippocampal volume changes with childhood trauma as the independent variable and 2) to predict hippocampal volume changes with CAR as independent variable. Finally, we introduced CAR as moderator in the linear model 1 to explore whether it changed the relationship between childhood abuse and hippocampal volume. Results Individuals with psychosis and severe childhood abuse presented smaller volume of the right hippocampal head (β = -108.9, p = 0.027), particularly in subfields CA1, CA3, CA4 and in the right GC-ML-DG head (all significant at p < 0.05 with βs between – 110 and -90) (linear model 1). CAR did not predict changes in hippocampal volumes (linear model 2). However, when CAR was introduced the relationship between childhood abuse and hippocampal volume (linear model 1) it showed a moderator role. Indeed low levels of CAR were associated with an even further reduction in hippocampal volume in the right hippocampal head and particularly in subfields CA1, CA3 and CA4 (all significant at p < 0.05 and βs between – 150 and -180). Discussion These results suggest that exposure to childhood trauma has a long-term effect on the adult brain particularly in hippocampal areas related to the encoding and retrieval of memories. Importantly, low levels of CAR are associated with even smaller hippocampal head in patients who childhood trauma This is particularly important, because an abnormal hippocampal structure could alter the hippocampal feedback on the HPA axis leading to dysfunctional (lower) cortisol production, which in turn would amplify the impact on brain stress sensitive regions of further stress exposure.
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Lin, Xiaoxiao, Michelle Amalraj, Crisylle Blanton, Brenda Avila, Todd C. Holmes, Douglas A. Nitz, and Xiangmin Xu. "Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway." PLOS Biology 19, no. 12 (December 20, 2021): e3001127. http://dx.doi.org/10.1371/journal.pbio.3001127.
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The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.
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Rutecki, Paul A., Robert G. Grossman, Dawna Armstrong, and Susan Irish-Loewen. "Electrophysiological connections between the hippocampus and entorhinal cortex in patients with complex partial seizures." Journal of Neurosurgery 70, no. 5 (May 1989): 667–75. http://dx.doi.org/10.3171/jns.1989.70.5.0667.
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✓ The electrophysiological properties of the neural pathways between the hippocampus and the entorhinal cortex were studied intraoperatively in 31 patients undergoing anterior temporal lobectomy for medically intractable complex partial seizures. The hippocampus, removed en bloc, was studied histologically and the pathology was correlated with the electrophysiological findings. In 29 of the patients, entorhinal stimulation evoked a characteristic positive-negative potential in the hippocampus. The entorhinal-evoked hippocampal response closely resembled, or was identical to, the spontaneously occurring hippocampal interictal spike discharge. In patients with Ammon's horn sclerosis in whom there was a major loss of neurons in the hippocampal subfields CA1, CA3, and CA4, the evoked responses were of simple morphology and long latency(mean 21.9 msec to the peak of the first potential). In patients with a ganglioglioma in whom the hippocampus was histologically normal, the evoked responses were of greater complexity and shorter latency (mean 11.8 msec). Stimulation at a single entorhinal site evoked similar waveforms at different hippocampal recording sites. Conversely, stimulation at different entorhinal sites evoked similar responses at a single hippocampal recording site. Stimulation of the hippocampus evoked a potential in the entorhinal cortex and, in some instances, in the amygdala, insula, and lateral temporal cortex. These connections may produce a positive feedback loop that favors seizure generation.
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Li, Guomin, Xuezhu Zhang, Haiyan Cheng, Xuemei Shang, Hui Xie, Xin Zhang, Jianchun Yu, and Jingxian Han. "Acupuncture Improves Cognitive Deficits and Increases Neuron Density of the Hippocampus in Middle-Aged Samp8 Mice." Acupuncture in Medicine 30, no. 4 (December 2012): 339–45. http://dx.doi.org/10.1136/acupmed-2012-010180.
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Objectives To examine whether acupuncture could improve cognitive deficits and reduce the loss of neurons in mice models of ageing. Methods Male 7.5-month-old senescence-accelerated mouse prone 8 (SAMP8) and age-matched senescence-resistant inbred strains 1 (SAMR1) were divided into four groups (n=15 per group): SAMP8 acupuncture group (Pa), SAMP8 non-acupuncture point control group (Pn), SAMP8 control group (Pc) and SAMR1 normal control group (Rc). The behaviours were examined by the Morris water maze test and the neuron density in the hippocampus was estimated by the optical fractionator technique. Results The Morris water maze test demonstrated that the cognitive deficits of SAMP8 mice were improved by acupuncture treatment. Neuronal loss was found in hippocampal regions CA1 (−24%), CA3 (−18%) and DG (−28%) of Pc compared with Rc. The neuron number in hippocampal CA3 and DG of the Pa group was significantly increased by therapeutic acupuncture compared with the Pc group. Conclusions Acupuncture improved the cognitive impairment of middle-aged SAMP8 mice which could be attributed to the reduced neuron loss in hippocampal regions CA3 and DG. These results suggest that reducing neuron loss in the hippocampus by acupuncture is a potential therapeutic approach for the treatment of Alzheimer's disease and cognitive impairment diseases.
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Tønder, Niels, Flemming F. Johansen, Jens Zimmer, and Nils H. Diemer. "The Susceptibility of CA1 Pyramidal Cells to Cerebral Ischemia is Maintained after Neonatal, Lesion-Induced Reorganization of the Hippocampal Circuitry." Journal of Cerebral Blood Flow & Metabolism 14, no. 3 (May 1994): 391–96. http://dx.doi.org/10.1038/jcbfm.1994.50.
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Acute lesions of hippocampal pathways have been shown previously to ameliorate CA1 pyramidal cell loss after subsequent transient cerebral ischemia. In this study, we examined the effect of chronic neonatal lesion with reorganization of hippocampal circuitry on adult postischemic neuron loss in the hippocampus. Newborn rats were subjected to unilateral knife-cut lesions at various positions along the trisynaptic entorhino-dentatohippocampal pathway. Seven months later, the rats were subjected to transient cerebral ischemia using the four-vessel occlusion technique. At the time of killing 4 days later, a Nissl stain was used to demonstrate neuronal degeneration, while connective reorganization resulting from the neonatal lesions was monitored by Timm staining. In one group of rats, neonatal lesions had caused severe depletion of entorhinal projections to the septodorsal fascia dentata and hippocampus (CA1 and CA3), without any direct damage to the dorsal hippocampus itself. Another group had extensive damage of the dorsal CA3, with removal of the Schaffer collaterals from these levels to CA1, and variable damage to the entorhinal afferents. In both groups, the extent and pattern of ischemia-induced degeneration of CA1 pyramidal cells were the same on the lesioned and nonlesioned sides of the brain, demonstrating that neonatal lesions and the subsequent connective reorganization did not have a sparing effect. Seen in relationship to previous observations in adult rats of the neuroprotective actions of acute, preischemic lesions of the trisynaptic hippocampal pathway, it is concluded that CA1 pyramidal cell loss requires the presence of intact excitatory afferents rather than an intact hippocampal circuitry.
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Bickler, Philip E., Xinhua Zhan, and Christian S. Fahlman. "Isoflurane Preconditions Hippocampal Neurons against Oxygen–Glucose Deprivation." Anesthesiology 103, no. 3 (September 1, 2005): 532–39. http://dx.doi.org/10.1097/00000542-200509000-00016.
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Background Isoflurane preconditions neurons to improve tolerance of subsequent ischemia in both intact animal models and in in vitro preparations. The mechanisms for this protection remain largely undefined. Because isoflurane increases intracellular Ca2+ concentrations and Ca2+ is involved in many processes related to preconditioning, the authors hypothesized that isoflurane preconditions neurons via Ca2+-dependent processes involving the Ca2+- binding protein calmodulin and the mitogen-activated protein kinase-ERK pathway. Methods The authors used a preconditioning model in which organotypic cultures of rat hippocampus were exposed to 0.5-1.5% isoflurane for a 2-h period 24 h before an ischemia-like injury of oxygen-glucose deprivation. Survival of CA1, CA3, and dentate neurons was assessed 48 later, along with interval measurements of intracellular Ca2+ concentration (fura-2 fluorescence microscopy in CA1 neurons), mitogen-activated protein kinase p42/44, and the survival associated proteins Akt and GSK-3beta (in situ immunostaining and Western blots). Results Preconditioning with 0.5-1.5% isoflurane decreased neuron death in CA1 and CA3 regions of hippocampal slice cultures after oxygen-glucose deprivation. The preconditioning period was associated with an increase in basal intracellular Ca2+ concentration of 7-15%, which involved Ca2+ release from inositol triphosphate-sensitive stores in the endoplasmic reticulum, and transient phosphorylation of mitogen-activated protein kinase p42/44 and the survival-associated proteins Akt and GSK-3beta. Preconditioning protection was eliminated by the mitogen-activated extracellular kinase inhibitor U0126, which prevented phosphorylation of p44 during preconditioning, and by calmidazolium, which antagonizes the effects of Ca2+-bound calmodulin. Conclusions Isoflurane, at clinical concentrations, preconditions neurons in hippocampal slice cultures by mechanisms that apparently involve release of Ca2+ from the endoplasmic reticulum, transient increases in intracellular Ca2+ concentration, the Ca2+ binding protein calmodulin, and phosphorylation of the mitogen-activated protein kinase p42/44.
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Dai, Yaling, Yuhao Zhang, Minguang Yang, Huawei Lin, Yulu Liu, Wenshan Xu, Yanyi Ding, Jing Tao, and Weilin Liu. "Electroacupuncture Increases the Hippocampal Synaptic Transmission Efficiency and Long-Term Plasticity to Improve Vascular Cognitive Impairment." Mediators of Inflammation 2022 (June 23, 2022): 1–15. http://dx.doi.org/10.1155/2022/5985143.
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Studies have shown that electroacupuncture (EA) can effectively improve vascular cognitive impairment (VCI), but its mechanisms have not been clearly elucidated. This study is aimed at investigating the mechanisms underlying the effects of EA treatment on hippocampal synaptic transmission efficiency and plasticity in rats with VCI. Methods. Sprague–Dawley rats were subjected to VCI with bilateral common carotid occlusion (2VO). EA stimulation was applied to Baihui (GV20) and Shenting (GV24) acupoints for 30 min once a day, five times a week, for four weeks. Our study also included nonacupoint groups to confirm the specificity of EA therapy. The Morris water maze (MWM) was used to assess cognitive function. Electrophysiological techniques were used to detect the field characteristics of the hippocampal CA3–CA1 circuit in each group of rats, including input-output (I/O), paired-pulse facilitation ratios (PPR), field excitatory postsynaptic potential (fEPSP), and excitatory postsynaptic current (EPSC). The expression of synapse- and calcium-mediated signal transduction associated proteins was detected through western blotting. Results. The MWM behavioural results showed that EA significantly improved cognitive function in VCI model rats. EA increased the I/O curve of VCI model rats from 20 to 90 μA. No significant differences were observed in hippocampal PPR. The fEPSP of the hippocampal CA3–CA1 circuit was significantly increased after EA treatment compared with that after nonacupuncture treatment. We found that EA led to an increase in the EPSC amplitude and frequency, especially in the decay and rise times. In addition, the protein expression and phosphorylation levels of N-methyl-D-aspartate receptor 2B, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor 1, and Ca2+-calmodulin-dependent protein kinase II increased to varying degrees in the hippocampus of VCI model rats. Conclusion. EA at GV20 and GV24 acupoints increased the basic synaptic transmission efficiency and synaptic plasticity of the hippocampal CA3–CA1 circuit, thereby improving learning and memory ability in rats with VCI.
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SAMURA, TOSHIKAZU, and MOTONOBU HATTORI. "HIPPOCAMPAL MEMORY MODIFICATION INDUCED BY PATTERN COMPLETION AND SPIKE-TIMING DEPENDENT SYNAPTIC PLASTICITY." International Journal of Neural Systems 15, no. 01n02 (February 2005): 13–22. http://dx.doi.org/10.1142/s0129065705000025.
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One of the roles of the hippocampus is viewed as modifying episodic memory so that it can contribute to form semantic memory. In this paper, we show that pattern completion ability of the hippocampal CA3 and symmetric spike timing-dependent synaptic plasticity (STDP) induce memory modification so that the hippocampal CA3 can memorize invariable parts of repetitive episodes as essential elements and forget variable parts of them as unnecessary ones.
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Suwabe, Kazuya, Kyeongho Byun, Kazuki Hyodo, Zachariah M. Reagh, Jared M. Roberts, Akira Matsushita, Kousaku Saotome, et al. "Rapid stimulation of human dentate gyrus function with acute mild exercise." Proceedings of the National Academy of Sciences 115, no. 41 (September 24, 2018): 10487–92. http://dx.doi.org/10.1073/pnas.1805668115.
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Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%V˙O2peak) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3−neocortical functional connectivity.
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Seress, László, Hajnalka Ábrahám, Zsolt Horváth, Tamás Dóczi, József Janszky, Joyce Klemm, Richard Byrne, and Roy A. E. Bakay. "Survival of mossy cells of the hippocampal dentate gyrus in humans with mesial temporal lobe epilepsy." Journal of Neurosurgery 111, no. 6 (December 2009): 1237–47. http://dx.doi.org/10.3171/2008.11.jns08779.
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Object Hippocampal sclerosis can be identified in most patients with mesial temporal lobe epilepsy (TLE). Surgical removal of the sclerotic hippocampus is widely performed to treat patients with drug-resistant mesial TLE. In general, both epilepsy-prone and epilepsy-resistant neurons are believed to be in the hippocampal formation. The hilar mossy cells of the hippocampal dentate gyrus are usually considered one of the most vulnerable types of neurons. The aim of this study was to clarify the fate of mossy cells in the hippocampus in epileptic humans. Methods Of the 19 patients included in this study, 15 underwent temporal lobe resection because of drug-resistant TLE. Four patients were used as controls because they harbored tumors that had not invaded the hippocampus and they had experienced no seizures. Histological evaluation of resected hippocampal tissues was performed using immunohistochemistry. Results Mossy cells were identified in the control as well as the epileptic hippocampi by using cocaine- and amphetamine-regulated transcript peptide immunohistochemistry. In most cases the number of mossy cells was reduced and thorny excrescences were smaller in the epileptic hippocampi than in controls; however, there was a significant loss of pyramidal cells and a partial loss of granule cells in the same epileptic hippocampi in which mossy cell loss was apparent. The loss of mossy cells could be correlated with the extent of hippocampal sclerosis, patient age at seizure onset, duration of epilepsy, and frequency of seizures. Conclusions In many cases large numbers of mossy cells were present in the hilus of the dentate gyrus when most pyramidal neurons of the CA1 and CA3 areas of the Ammon's horn were lost, suggesting that mossy cells may not be more vulnerable to epileptic seizures than the hippocampal pyramidal neurons.
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Zilli, Jessica, Anne Schänzer, Kathrin Büttner, Monika Kressin, and Martin J. Schmidt. "Quantitative and qualitative evaluation of the hippocampal cytoarchitecture in adult cats with regard to the pathological diagnosis of hippocampal sclerosis." PLOS ONE 17, no. 5 (May 13, 2022): e0268010. http://dx.doi.org/10.1371/journal.pone.0268010.
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Cats are known to be affected by hippocampal sclerosis, potentially causing antiseizure drug(s) resistance. In order to lay the foundation for a standardized, systematic classification and diagnosis of this pathology in cats, this prospective study aimed at evaluating normal reference values of cellular densities and the cytoarchitecture of the feline hippocampus. Three transverse sections (head, body and tail) of each left hippocampus were obtained from 17 non-epileptic cats of different brachycephalic and mesocephalic breeds and age classes (range: 3–17 years). Histological (hematoxylin and eosin, Nissl) and immunohistochemical (NeuN, GFAP) staining was performed to investigate neuron and astroglial cell populations, as well as the layer thickness of the pyramidal cell layer and granule cell layer. Significant differences in neuronal density (in CA2-CA4 and the granule cell layer) and layer thickness (in CA1-CA3 and the granule cell layer) were evidenced throughout the longitudinal hippocampal axis (p<0.05); on the other hand, the astrocyte density did not differ. Moreover, reference ranges were defined for these parameters in the pyramidal cell layer and in the granule cell layer. The findings did not differ according to breed or age. In veterinary medicine these parameters have not been evaluated in cats so far. As surgical treatment may become a therapeutic option for cats with temporal lobe epilepsy, estimating normal values of the hippocampal cytoarchitecture will help in the standardized histopathological examination of resected hippocampal specimens to reach a diagnosis of hippocampal sclerosis.
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Radenovic, Lidija, Vesna Selakovic, A. Bajic, and P. R. Andjus. "Use of confocal microscopy in the study of ischemia-induced hippocampal neuronal damage." Archives of Biological Sciences 60, no. 4 (2008): 561–65. http://dx.doi.org/10.2298/abs0804561r.
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The present study was undertaken to reveal by means of confocal laser microscopy the cytoarchitecture of hippocampal CA3 neurons in Mongolian gerbils before and after cerebral ischemia of different duration. The common carotid arteries of gerbils were occluded for 5, 10, or 15 min. On the 4th, 14th and 28th day after reperfusion, neuronal damage was examined by laser scanning confocal microscopy in the CA3 region of hippocampus (30 ?m slices). Slices were stained with fluorescent Nissl staining and fluorescent membrane tracer DiI. Increased duration of cerebral ischemia resulted in a progressive loss of hippocampal CA3 neurons. Four days after the ischemic insult, neuronal damage in the hippocampal CA3 region was mild but visible. On the 28th day after reperfusion, neuronal damage in the observed brain structure was most severe. These results demonstrate the temporal profile of neuronal damage after an ischemic insult as observed using confocal microscopy.
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Wagatsuma, Akiko, Teruhiro Okuyama, Chen Sun, Lillian M. Smith, Kuniya Abe, and Susumu Tonegawa. "Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context." Proceedings of the National Academy of Sciences 115, no. 2 (December 26, 2017): E310—E316. http://dx.doi.org/10.1073/pnas.1714082115.
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The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the single-trial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus.