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Social Fear Memory Requires Two Stages of Protein Synthesis in Mice

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Social Fear Memory Requires Two Stages of Protein Synthesis in Mice International Journal of Molecular Sciences Communication Social Fear Memory Requires Two Stages of Protein Synthesis in Mice Johannes Kornhuber 1 and Iulia Zoicas 1,2,* 1 Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; [email protected] 2 Department of Behavioural and Molecular Neurobiology, University of Regensburg, 93040 Regensburg, Germany * Correspondence: [email protected]; Tel.: +49-9131-85-46005 Received: 10 June 2020; Accepted: 1 August 2020; Published: 2 August 2020 Abstract: It is well known that long-term consolidation of newly acquired information, including information related to social fear, require de novo protein synthesis. However, the temporal dynamics of protein synthesis during the consolidation of social fear memories is unclear. To address this question, mice received a single systemic injection with the protein synthesis inhibitor, anisomycin, at different time-points before or after social fear conditioning (SFC), and memory was assessed 24 h later. We showed that anisomycin impaired the consolidation of social fear memories in a time-point-dependent manner. Mice that received anisomycin 20 min before, immediately after, 6 h, or 8 h after SFC showed reduced expression of social fear, indicating impaired social fear memory, whereas anisomycin caused no effects when administered 4 h after SFC. These results suggest that consolidation of social fear memories requires two stages of protein synthesis: (1) an initial stage starting during or immediately after SFC, and (2) a second stage starting around 6 h after SFC and lasting for at least 5 h. Keywords: social fear; social anxiety; anisomycin; protein synthesis; social investigation; fear learning; fear acquisition; fear extinction; fear memory; memory consolidation 1. Introduction The capability of animals to form new memories is essential for their survival and for appropriate adaptation to a complex and often-changing environment. Memory can be divided into several sequential phases, including acquisition, consolidation, retention, and retrieval. In simplistic terms, acquisition can be defined as the encoding of new information, consolidation is the stabilization of the new information for storage, retention is the preservation of the information, and retrieval is the later recall of the information [1]. During consolidation, the initial labile memory is stabilized into long-term memory, a process that requires synaptic plasticity. This process relies on different molecular mechanisms, including activation of gene transcription [2] and de-novo protein synthesis [3]. Indeed, blockade of protein synthesis using protein synthesis inhibitors was shown to attenuate the consolidation of different types of memories, including object memories [4], spatial memories [5], social memories [6,7], and cued and contextual fear memories [8–13]. It has also been reported that two distinct stages of protein synthesis are involved in memory consolidation: an initial stage starting during or immediately after training and a second stage starting approximately 3 to 6 h after training [5–10,14,15]. Interestingly, Bourtchouladze et al. [9] have shown that contextual fear memory requires either one or two stages of protein synthesis, depending on the nature of training. As such, weak training was shown to require two stages of protein synthesis, whereas stronger training was shown to require only one stage, suggesting that different training protocols may recruit Int. J. Mol. Sci. 2020, 21, 5537; doi:10.3390/ijms21155537 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5537 2 of 9 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 10 commonmay recruit signaling common pathways signaling in distinctpathways ways in distinct [9]. However, ways [9]. theHowever, requirement the requirement for protein for synthesisprotein in thesynthesis consolidation in the consolidation of social fear of memories social fear is memories less clear. is The less protein clear. The synthesis protein inhibitor synthesis anisomycin inhibitor failedanisomycin to attenuate failed the to consolidation attenuate the of consolidation social fear memories of social whenfear memories administered when before administered training before into the medialtraining prefrontal into the cortex medial [16 prefrontal], ventral hippocampus cortex [16], ventral [17], lateral hippocampus septum [[17],18], andlateral medial septum amygdala [18], and [19 ], althoughmedial theseamygdala brain [19], regions although were these shown brain to region be keys were components shown to ofbe akey neural components circuitry of mediatinga neural thecircuitry formation mediating of social the fear formation memories of social in a modelfear memories of conditioned in a model defeat of conditioned in Syrian hamstersdefeat in Syrian [16–18 ]. However,hamsters when [16–18]. administered However, intowhen the administered basolateral amygdalainto the basolateral before training, amygdala anisomycin before training, caused a reductionanisomycin in the caused expression a reduction of social in fearthe expression [19], suggesting of social that fear de-novo [19], suggesting protein synthesis that de-novo is required protein for thesynthesis consolidation is required of social for the fear consolidation memories in of a brainsocial region-specificfear memories in manner. a brain region-specific manner. InIn this this study, study, we we aimed aimed to to investigate investigate the the temporal temporal dynamicsdynamics of protein protein synthesis synthesis during during the the consolidationconsolidation of of social social fear fear memories. memories. For For thisthis purpose,purpose, wewe administered anisomycin anisomycin systemically systemically (intraperitoneal;(intraperitoneal; i.p.) i.p.) at di atfferent different time-points time-points before before or after or social after fear social conditioning fear conditioning (SFC). Anisomycin (SFC). administrationAnisomycin (i.p.)administration was shown (i.p.) to inhibitwas shown protein to synthesisinhibit protein in the synthesis brain for in up the to 6brain h [20 for]. During up to 6 SFC, h [20]. During SFC, mice receive mild electric foot shocks while investigating an unknown conspecific mice receive mild electric foot shocks while investigating an unknown conspecific [21,22]. This training [21,22]. This training results in long-term social fear, which is expressed as reduced investigation of results in long-term social fear, which is expressed as reduced investigation of both known and unknown both known and unknown conspecifics [21]. The expression of SFC-induced social fear relies on the conspecifics [21]. The expression of SFC-induced social fear relies on the dorsal hippocampus, central dorsal hippocampus, central amygdala, and dorsolateral septum [23,24], although other brain amygdala, and dorsolateral septum [23,24], although other brain regions might also be involved. As only regions might also be involved. As only a short training session is needed to induce robust and a short training session is needed to induce robust and long-lasting social fear memory, this paradigm long-lasting social fear memory, this paradigm is ideal for examining the molecular mechanisms is idealcontributing for examining to the different the molecular memory mechanisms stages. contributing to the different memory stages. 2. Results 2. Results Anisomycin Impairs the Consolidation of Social Fear Memory in a Time-Point-Dependent Manner 2.1. Anisomycin Impairs the Consolidation of Social Fear Memory in a Time-Point-Dependent Manner In order to investigate the temporal dynamics of protein synthesis during the consolidation of In order to investigate the temporal dynamics of protein synthesis during the consolidation of + socialsocial fear fear memories, memories, we studiedwe studied conditioned conditioned mice mice (SFC (SFCmice)+ mice) and and unconditioned unconditioned control control mice mice (SFC − mice)(SFC that− mice) received that received a single a i.p.single injection i.p. injection either either with with anisomycin anisomycin or vehicleor vehicle (0.9% (0.9% saline) saline) either either 20 min20 before, min before, immediately immediately after, after, 4 h, 64 h,h, or6 h, 8 hor after 8 h after training training in the in SFCthe SFC paradigm paradigm (day (day 1; Figures 1; Figures1–3 ). + SFC1–3).mice SFC received+ mice received mild electric mild footelectric shocks foot each shocks time each they time investigated they investigated an unknown an conspecific,unknown whereasconspecific, SFC− micewhereas investigated SFC− mice an investigated unknown an conspecific unknown without conspecific receiving without foot receiving shocks. foot Twenty-four shocks. + hoursTwenty-four after SFC, hours during after social SFC, fear during extinction, social wefear assessed extinction, the we time assessed that the the SFC timeand that SFC the− SFCmice+ and spent investigatingSFC− mice spent six unknown investigating conspecifics six unknown (i.e., social conspecifics investigation) (i.e., social as a investigation) read-out of social as a fearread-out memory of (Figuresocial1). fear memory (Figure 1). FigureFigure 1. Schematic1. Schematic representation representation of of the the social social fearfear conditioningconditioning (SFC) paradigm. During During SFC SFC on on dayday 1, mice1, mice were were placed placed in in the the conditioning conditioning chamber chamber and,and, after
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