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Central Histamine Boosts Perirhinal Cortex Activity and Restores Forgotten Object Memories

      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 H3 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 H3 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 H3 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 H2 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 H3 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.

      Keywords

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      References

        • Fischer A.
        • Sananbenesi F.
        • Wang X.
        • Dobbin M.
        • Tsai L.
        Recovery of learning and memory is associated with chromatin remodelling.
        Nature. 2007; 447: 178-183
        • Ryan T.J.
        • Roy D.S.
        • Pignatelli M.
        • Arons A.
        • Tonegawa S.
        Engram cells retain memory under retrograde amnesia.
        Science. 2015; 348: 1007-1013
        • Haas H.
        • Panula P.
        The role of histamine and the tuberomamillary nucleus in the nervous system.
        Nat Rev Neurosci. 2003; 4: 121-130
        • Nonaka A.
        • Masuda F.
        • Nomura H.
        • Matsuki N.
        Impairment of fear memory consolidation and expression by antihistamines.
        Brain Res. 2013; 1493: 19-26
        • Masuoka T.
        • Mikami A.
        • Yasuda M.
        • Shinomiya K.
        • Kamei C.
        Effects of histamine H1 receptor antagonists on hippocampal theta rhythm during spatial memory performance in rats.
        Eur J Pharmacol. 2007; 576: 77-82
        • Vuurman E.F.
        • van Veggel L.M.
        • Sanders R.L.
        • Muntjewerff N.D.
        • O’Hanlon J.F.
        Effects of semprex-D and diphenhydramine on learning in young adults with seasonal allergic rhinitis.
        Ann Allergy Asthma Immunol. 1996; 76: 247-252
        • Arrang J.M.
        • Garbarg M.
        • Schwartz J.C.
        Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor.
        Nature. 1983; 302: 832-837
        • Arrang J.M.
        • Garbarg M.
        • Lancelot J.C.
        • Lecomte J.M.
        • Pollard H.
        • Robba M.
        • et al.
        Highly potent and selective ligands for histamine H3-receptors.
        Nature. 1987; 327: 117-123
        • Meguro K.
        • Yanai K.
        • Sakai N.
        • Sakurai E.
        • Maeyama K.
        • Sasaki H.
        • Watanabe T.
        Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice.
        Pharmacol Biochem Behav. 1995; 50: 321-325
        • Miyazaki S.
        • Imaizumi M.
        • Onodera K.
        Ameliorating effects of histidine on scopolamine-induced learning deficits using an elevated plus-maze test in mice.
        Life Sci. 1995; 56: 1563-1570
        • Charlier Y.
        • Brabant C.
        • Serrano M.E.
        • Lamberty Y.
        • Tirelli E.
        The prototypical histamine H3 receptor inverse agonist thioperamide improves multiple aspects of memory processing in an inhibitory avoidance task.
        Behav Brain Res. 2013; 253: 121-127
        • Sadek B.
        • Saad A.
        • Subramanian D.
        • Shafiullah M.
        • Łażewska D.
        • Kieć-Kononowiczc K.
        Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats.
        Neuropharmacology. 2016; 106: 46-55
        • Prast H.
        • Argyriou A.
        • Philippu A.
        Histaminergic neurons facilitate social memory in rats.
        Brain Res. 1996; 734: 316-318
        • Fox G.B.
        • Pan J.B.
        • Radek R.J.
        • Lewis A.M.
        • Bitner R.S.
        • Esbenshade T.A.
        • et al.
        Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization.
        J Pharmacol Exp Ther. 2003; 305: 897-908
        • Pascoli V.
        • Boer-Saccomani C.
        • Hermant J.-F.
        H3 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing retrieval.
        Psychopharmacology (Berl). 2009; 202: 141-152
        • van Ruitenbeek P.
        • Mehta M.A.
        Potential enhancing effects of histamine H1 agonism/H3 antagonism on working memory assessed by performance and bold response in healthy volunteers.
        Br J Pharmacol. 2013; 170: 144-155
        • Egan M.F.
        • Zhao X.
        • Gottwald R.
        • Harper-Mozley L.
        • Zhang Y.
        • Snavely D.
        • et al.
        Randomized crossover study of the histamine H3 inverse agonist MK-0249 for the treatment of cognitive impairment in patients with schizophrenia.
        Schizophr Res. 2013; 146: 224-230
        • Egan M.
        • Yaari R.
        • Liu L.
        • Ryan M.
        • Peng Y.
        • Lines C.
        • Michelson D.
        Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD.
        Curr Alzheimer Res. 2012; 9: 481-490
        • Brown M.W.
        • Aggleton J.P.
        Recognition memory: What are the roles of the perirhinal cortex and hippocampus?.
        Nat Rev Neurosci. 2001; 2: 51-61
        • Pillot C.
        • Heron A.
        • Cochois V.
        • Tardivel-Lacombe J.
        • Ligneau X.
        • Schwartz J.-C.
        • Arrang J.-M.
        A detailed mapping of the histamine H3 receptor and its gene transcripts in rat brain.
        Neuroscience. 2002; 114: 173-193
        • Morisset S.
        • Rouleau A.
        • Ligneau X.
        • Gbahou F.
        • Tardivel-Lacombe J.
        • Stark H.
        • et al.
        High constitutive activity of native H3 receptors regulates histamine neurons in brain.
        Nature. 2000; 408: 860-864
        • Destexhe A.
        • Contreras D.
        Neuronal computations with stochastic network states.
        Science. 2006; 314: 85-90
        • Liu X.
        • Ramirez S.
        • Pang P.T.
        • Puryear C.B.
        • Govindarajan A.
        • Deisseroth K.
        • Tonegawa S.
        Optogenetic stimulation of a hippocampal engram activates fear memory recall.
        Nature. 2012; 484: 381-385
        • Reijmers L.G.
        • Perkins B.L.
        • Matsuo N.
        • Mayford M.
        Localization of a stable neural correlate of associative memory.
        Science. 2007; 317: 1230-1233
        • Nonaka A.
        • Toyoda T.
        • Miura Y.
        • Hitora-Imamura N.
        • Naka M.
        • Eguchi M.
        • et al.
        Synaptic plasticity associated with a memory engram in the basolateral amygdala.
        J Neurosci. 2014; 34: 9305-9309
        • Eguchi M.
        • Yamaguchi S.
        In vivo and in vitro visualization of gene expression dynamics over extensive areas of the brain.
        NeuroImage. 2009; 44: 1274-1283
        • Tonegawa S.
        • Liu X.
        • Ramirez S.
        • Redondo R.
        Memory engram cells have come of age.
        Neuron. 2015; 87: 918-931
        • Mizunuma M.
        • Norimoto H.
        • Tao K.
        • Egawa T.
        • Hanaoka K.
        • Sakaguchi T.
        • et al.
        Unbalanced excitability underlies offline reactivation of behaviorally activated neurons.
        Nat Neurosci. 2014; 17: 503-505
        • Armbruster B.N.
        • Li X.
        • Pausch M.H.
        • Herlitze S.
        • Roth B.L.
        Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.
        Proc Natl Acad Sci U S A. 2007; 104: 5163-5168
        • Lein E.S.
        • Hawrylycz M.J.
        • Ao N.
        • Ayres M.
        • Bensinger A.
        • Bernard A.
        • et al.
        Genome-wide atlas of gene expression in the adult mouse brain.
        Nature. 2007; 445: 168-176
        • Haas H.L.
        • Konnerth A.
        Histamine and noradrenaline decrease calcium-activated potassium conductance in hippocampal pyramidal cells.
        Nature. 1983; 302: 432-434
        • Nomura H.
        • Nonaka A.
        • Imamura N.
        • Hashikawa K.
        • Matsuki N.
        Memory coding in plastic neuronal subpopulations within the amygdala.
        NeuroImage. 2012; 60: 153-161
        • Tayler K.K.
        • Tanaka K.Z.
        • Reijmers L.G.
        • Wiltgen B.J.
        Reactivation of neural ensembles during the retrieval of recent and remote memory.
        Curr Biol. 2013; 23: 99-106
        • Nakayama D.
        • Baraki Z.
        • Onoue K.
        • Ikegaya Y.
        • Matsuki N.
        • Nomura H.
        Frontal association cortex is engaged in stimulus integration during associative learning.
        Current Biol. 2015; 25: 117-123
        • Nakayama D.
        • Iwata H.
        • Teshirogi C.
        • Ikegaya Y.
        • Matsuki N.
        • Nomura H.
        Long-delayed expression of the immediate early gene Arc/Arg3.1 refines neuronal circuits to perpetuate fear memory.
        J Neurosci. 2015; 35: 819-830
        • Benzi R.
        • Sutera A.
        • Vulpiani A.
        The mechanism of stochastic resonance.
        J Phys A Math Gen. 1981; 14: L453-L457
        • McDonnell M.D.
        • Ward L.M.
        The benefits of noise in neural systems: Bridging theory and experiment.
        Nat Rev Neurosci. 2011; 12: 415-426
        • Woloszyn L.
        • Sheinberg D.L.
        Effects of long-term visual experience on responses of distinct classes of single units in inferior temporal cortex.
        Neuron. 2012; 74: 193-205
        • Thome A.
        • Erickson C.A.
        • Lipa P.
        • Barnes C.A.
        Differential effects of experience on tuning properties of macaque MTL neurons in a passive viewing task.
        Hippocampus. 2012; 22: 2000-2011
        • Burke S.N.
        • Maurer A.P.
        • Hartzell A.L.
        • Nematollahi S.
        • Uprety A.
        • Wallace J.L.
        • Barnes C.A.
        Representation of three-dimensional objects by the rat perirhinal cortex.
        Hippocampus. 2012; 22: 2032-2044
        • Cho W.
        • Maruff P.
        • Connell J.
        • Gargano C.
        • Calder N.
        • Doran S.
        • et al.
        Additive effects of a cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans.
        Psychopharmacology (Berl). 2011; 218: 513-524
        • Jeck-Thole S.
        • Wagner W.
        Betahistine: A retrospective synopsis of safety data.
        Drug Saf. 2006; 29: 1049-1059
        • Gbahou F.
        • Davenas E.
        • Morisset S.
        • Arrang J.-M.
        Effects of betahistine at histamine H3 receptors: Mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo.
        J Pharmacol Exp Ther. 2010; 334: 945-954
        • Hudkins R.L.
        • Gruner J.A.
        • Raddatz R.
        • Mathiasen J.R.
        • Aimone L.D.
        • Marino M.J.
        • et al.
        3-(1'-Cyclobutylspiro[4H-1,3-benzodioxine-2,4'-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazin-6-one (CEP-32215), a new wake-promoting histamine H3 antagonist/inverse agonist.
        Neuropharmacology. 2016; 106: 37-45
        • Auberson Y.P.
        • Troxler T.
        • Zhang X.
        • Yang C.R.
        • Fendt M.
        • Feuerbach D.
        • et al.
        Ergoline-derived inverse agonists of the human H3 receptor for the treatment of narcolepsy.
        ChemMedChem. 2014; 9: 1683-1696
        • Hudkins R.L.
        • Josef K.A.
        • Becknell N.C.
        • Aimone L.D.
        • Lyons J.A.
        • Mathiasen J.R.
        • et al.
        Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R, S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity.
        Bioorg Med Chem Lett. 2014; 24: 1303-1306

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