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Central Histamine Boosts Perirhinal Cortex Activity and Restores Forgotten Object Memories

Published on Jan 1, 2019in Biological Psychiatry 11.50
· DOI :10.1016/j.biopsych.2018.11.009
Hiroshi Nomura13
Estimated H-index: 13
(UTokyo: University of Tokyo),
Hiroto Mizuta1
Estimated H-index: 1
(Kyoto University)
+ 19 AuthorsYuji Ikegaya44
Estimated H-index: 44
(UTokyo: University of Tokyo)
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Abstract
Abstract Background A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H 3 receptor inverse agonists upregulate histamine release, the inverse agonists may enhance learning and memory. However, whether the inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined. Methods Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H 3 receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. In addition, we conducted a randomized double-blind, placebo-controlled crossover trial in healthy adult participants to investigate whether betahistine treatment promotes memory retrieval in humans. Results The treatment of H 3 receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. The memory recovery was mediated by the disinhibition of histamine release in the perirhinal cortex, which activated the histamine H 2 receptor. Histamine depolarized perirhinal cortex neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neuronal ensembles. A human clinical trial revealed that treatment of H 3 receptor inverse agonists is specifically more effective for items that are more difficult to remember and subjects with poorer performance. Conclusions These results highlight a novel interaction between the central histamine signaling and memory engrams.
  • References (46)
  • Citations (1)
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References46
Newest
Published on Jul 1, 2016in Neuropharmacology 4.37
Bassem Sadek16
Estimated H-index: 16
(United Arab Emirates University),
Ali Saad4
Estimated H-index: 4
(United Arab Emirates University)
+ 3 AuthorsKatarzyna Kieć-Kononowiczc1
Estimated H-index: 1
(Jagiellonian University Medical College)
Abstract It has become clear that histamine H3 receptors (H3Rs) are implicated in modulating epilepsy and memory in laboratory animals. The new non-imidazole H3R antagonist DL77 has excellent selectivity profile and shows high in-vivo potency as well as in-vitro antagonist affinity with ED 50 values of 2.1 ± 0.2 mg/kg and 8.4 ± 1.3 [nM], respectively. In the present study, the anticonvulsant effects of DL77 on maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced s...
Published on Jul 1, 2016in Neuropharmacology 4.37
Robert L. Hudkins21
Estimated H-index: 21
,
John A. Gruner11
Estimated H-index: 11
+ 6 AuthorsMark A. Ator28
Estimated H-index: 28
Abstract CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H 3 receptor (H 3 R) with drug-like properties. High affinity in human (hH 3 R K i = 2.0 ± 0.2 nM) and rat (rH 3 R K i = 3.6 ± 0.7 nM) H 3 R radioligand binding assays was demonstrated. Potent functional antagonism (K b = 0.3 ± 0.1 nM) and inverse agonism (EC 50 = 0.6 ± 0.2 nM) were demonstrated in [ 35 S]guanosine 5 ′ -O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-rel...
Published on Sep 1, 2015in Neuron 14.40
Susumu Tonegawa129
Estimated H-index: 129
(MIT: Massachusetts Institute of Technology),
Xu Liu18
Estimated H-index: 18
(MIT: Massachusetts Institute of Technology)
+ 1 AuthorsRoger L. Redondo7
Estimated H-index: 7
(MIT: Massachusetts Institute of Technology)
The idea that memory is stored in the brain as physical alterations goes back at least as far as Plato, but further conceptualization of this idea had to wait until the 20 th century when two guiding theories were presented: the "engram theory" of Richard Semon and Donald Hebb's "synaptic plasticity theory." While a large number of studies have been conducted since, each supporting some aspect of each of these theories, until recently integrative evidence for the existence of engram cells and ci...
Published on May 29, 2015in Science 41.04
Tomás J. Ryan10
Estimated H-index: 10
(MIT: Massachusetts Institute of Technology),
Dheeraj S. Roy12
Estimated H-index: 12
(Picower Institute for Learning and Memory)
+ 2 AuthorsSusumu Tonegawa129
Estimated H-index: 129
(MIT: Massachusetts Institute of Technology)
When memory researchers induce amnesia, they normally assume that the manipulations prevent the memory engram from effective encoding at consolidation. In accordance with this, Ryan et al. found that after the injection of protein synthesis inhibitors, animals could not retrieve a memory. However, to their surprise, the memory could nevertheless be reactivated by light-induced activation of the neurons tagged during conditioning. Increased synaptic strength that is the result of cellular consoli...
Published on Jan 14, 2015in The Journal of Neuroscience 6.07
Daisuke Nakayama6
Estimated H-index: 6
(UTokyo: University of Tokyo),
Hirokazu Iwata1
Estimated H-index: 1
(UTokyo: University of Tokyo)
+ 3 AuthorsHiroshi Nomura13
Estimated H-index: 13
(UTokyo: University of Tokyo)
Fear memories typically persist for long time periods, and persistent fear memories contribute to post-traumatic stress disorder. However, little is known about the cellular and synaptic mechanisms that perpetuate long-term memories. Here, we find that mouse hippocampal CA1 neurons exhibit biphasic Arc (also known as Arg3.1) elevations after fear experience and that the late Arc expression regulates the perpetuation of fear memoires. An early Arc increase returned to the baseline after 6 h, foll...
Published on Jan 1, 2015in Current Biology 9.19
Daisuke Nakayama6
Estimated H-index: 6
(UTokyo: University of Tokyo),
Zohal Baraki1
Estimated H-index: 1
(UTokyo: University of Tokyo)
+ 3 AuthorsHiroshi Nomura13
Estimated H-index: 13
(UTokyo: University of Tokyo)
Center for Information and Neural Networks, Suita City,Osaka 565-0871, JapanSummaryThe frontal association cortex (FrA) is implicated in higherbrain function [1]. Aberrant FrA activity is likely to beinvolved in dementia pathology [2–4]. However, the func-tional circuits both within the FrA and with other regionsare unclear. A recent study showed that inactivation of theFrAimpairsmemoryconsolidationofanauditoryfearcondi-tioninginyoungmice[5].Inaddition,dendriticspineremod-eling of FrA neurons is...
Published on Jul 9, 2014in The Journal of Neuroscience 6.07
Ayako Nonaka5
Estimated H-index: 5
(UTokyo: University of Tokyo),
Takeshi Toyoda12
Estimated H-index: 12
(UTokyo: University of Tokyo)
+ 7 AuthorsHiroshi Nomura13
Estimated H-index: 13
(UTokyo: University of Tokyo)
Synaptic plasticity is a cellular mechanism putatively underlying learning and memory. However, it is unclear whether learning induces synaptic modification globally or only in a subset of neurons in associated brain regions. In this study, we genetically identified neurons activated during contextual fear learning and separately recorded synaptic efficacy from recruited and nonrecruited neurons in the mouse basolateral amygdala (BLA). We found that the fear learning induces presynaptic potentia...
Published on May 21, 2014in ChemMedChem 3.02
Yves Auberson23
Estimated H-index: 23
(Novartis),
Thomas J. Troxler9
Estimated H-index: 9
(Novartis)
+ 12 AuthorsMark Perrone3
Estimated H-index: 3
(Novartis)
Ergoline derivative (6aR,9R)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide (1), a CXCR3 antagonist, also inhibits human histamine H3 receptors (H3R) and represents a structurally novel H3R inverse agonist chemotype. It displays favorable pharmacokinetic and in vitro safety profiles, and served as a lead compound in a program to explore ergoline derivatives as potential drug candidates for the treatment of narcolepsy. A...
Published on Apr 1, 2014in Nature Neuroscience 21.13
Mika Mizunuma5
Estimated H-index: 5
,
Hiroaki Norimoto8
Estimated H-index: 8
+ 9 AuthorsTetsuo Nagano82
Estimated H-index: 82
The authors show that sharp-wave events recorded in mouse hippocampal slices are more likely to involve neurons that have been activated during a recent behavioral episode. The excitation/inhibition balance of the synaptic inputs received by these cells during sharp waves is biased toward excitation, suggesting a potential mechanism for their preferential recruitment into these network events.
Published on Mar 1, 2014in Bioorganic & Medicinal Chemistry Letters 2.45
Robert L. Hudkins21
Estimated H-index: 21
,
Kurt A. Josef4
Estimated H-index: 4
+ 5 AuthorsRita Raddatz8
Estimated H-index: 8
Abstract A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1 R ,6 S )-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one ( R , S - 4a ) as a second-generation pyridazin-3-one H 3 R antagonist. Compound R , S - 4a was a potent H 3 R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity i...
Cited By1
Newest
Published on Feb 10, 2019in International Journal of Molecular Sciences 4.18
Takeo Yoshikawa17
Estimated H-index: 17
,
Tadaho Nakamura10
Estimated H-index: 10
,
Kazuhiko Yanai52
Estimated H-index: 52
Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain function...