Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory

Abstract

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline-and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.basolateral amygdala | norepinephrine | memory accuracy | hippocampus | systems consolidation E motionally arousing experiences are well-retained in memory (1, 2). Beyond their increased strength, emotionally enhanced memories are also often characterized by increased vividness and the subjective feeling of remembering (3, 4). Both animal and human research indicate that noradrenergic activation of the basolateral amygdala (BLA) enhances memory of emotionally arousing experiences by regulating neural plasticity and information storage processes in other brain regions (5-12). A majority of studies investigating the effects of noradrenergic activation of the BLA in memory have focused on episodic (declarative) or contextual tasks that involve functioning of the hippocampus (13-17). The BLA sends extensive projections to the hippocampus (18) and has a major impact on hippocampal functioning (19-21).There is extensive evidence that the memory enhancement induced by BLA activation by norepinephrine (NE) administration or emotional arousal during or shortly after learning involves hippocampal activation (20,(22)(23)(24). This activa...

Dose-dependent atrophy of the amygdala after radiotherapy

“…The hippocampus and amygdala both contribute to memory systems, with the hippocampus involved in the consolidation of long-term, episodic, or declarative memory (such as conscious fact-recall) and the amygdala more involved in emotional memory and memories with emotional context 22,43 . The amygdala and hippocampus also have neural connections thought to allow them to work in concert for the development and preservation of emotional and remote memory 22,43,44 . Physiologically, the basolateral complex of the amygdala has substantial projections to the memory structures of the medial temporal lobe, with afferents to the hippocampus 45,46 , while the hippocampus has reciprocal projections (mainly originating in the subicular region) that send sensory information to the amygdala 45,47 .…”

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“…Since we aimed at replicating previous rat studies in our lab (e.g. Roozendaal et al, 2006;Barsegyan et al, 2014;Atucha et al, 2017;Chen et al, 2018), in which only male rats were used, we restricted our studies to male mice only. Training and testing was performed during the light phase of the cycle, between 10:00 and 15:00 h. All experimental procedures were in compliance with European Union Directive 2010/63/EU and approved by the Institutional Animal Care and Use Committee of Radboud University, Nijmegen, The Netherlands.…”

Evolutionary conserved role of neural cell adhesion molecule-1 in memory

“…In addition, the promoter region of the human NCAM1 was previously shown to contain a high proportion of CpG sites and to lack active TATA or CCAAT as transcriptional regulatory elements 21 , suggesting that methylation could be an important mechanism for the regulation of this gene's expression. Generally, DNA methylation seems to be centrally involved in memory coding [22][23][24][25][26][27] , formation as well as maintenance 15,16,[23][24][25][26][27] .…”