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• W3206882840 abstract "The nature of memory has been a source of fascination since at least the ancient Greek philosophers and likely longer. Memory is key to our sense of self as it allows our life histories to shape us into unique personalities. Memory also underpins learning, which allows us to succeed in life and allows animals to adapt to their behaviour to changing environments. Memory has a central position in modern neuroscience as it is the psychological traits that is perhaps most readily quantifiable in animal models. Memory has thus taken on a broader role as the window that allows us to peer into the inner workings of the brain. Our psychological understanding of memory can be connected to the molecular world by combining genetic and pharmacological interventions with behavioural assays measuring memory. Over the last decades, this has allowed neuroscience to identify many of the molecules necessary for memory and to trace their functions to circuits. While the past decade has revealed many details about how memories are formed and maintained, many challenges remain and new tools continue to emerge allowing old conclusions to be revisited. This may thus be a prudent time to take stock of our knowledge and to discuss what remains to be learned. We are happy to present a special issue of the European Journal of Neuroscience on the ‘Proteins and Circuits in Memory’. The special issue was inspired by successful meeting in March 2019 hosted by the ‘Center for Proteins in Memory (PROMEMO)’, a centre of excellence at Aarhus University funded by the Danish National Research Foundation. The meeting focused on connecting molecular mechanism of memory proteins all the way from atomic structures to their roles in circuits including new emerging methods. This special issue has a similar scope and contains six primary research reports and 11 state-of-the-art reviews. Several synaptic proteins lead to memory impairment when knocked-out or inhibited suggesting that they have a role in the molecular mechanisms of memory. Memory proteins identified this way include, but are far from limited to hub proteins such as Arc, neurotransmitter receptors, such as the ionotropic glutamate receptors of the NMDA and AMPA families, kinases such as Ca2+/calmodulin-dependent kinase II and PKMζ. The special issue starts from at the molecular level with reviews and original research reports on some of the most paradigmatic memory proteins as summarized below. Arc is encoded by an immediate early gene whose transcription is activated by synaptic stimulation. In this issue, Zhang and Bramham (2020) review the involvement of Arc in different plasticity mechanisms. As a hub protein, context-dependent Arc interactions with an array of other proteins may explain seeming contradictory results on the role of Arc in different forms of plasticity. The authors propose a model that explains how Arc bidirectionally regulates synaptic strength by controlling AMPA receptor diffusion and the actin cytoskeleton. Activation of the NMDA receptor triggers both LTP/LTD and memory formation. The NMDA receptor has very long cytoplasmic tails, which sets it apart from other ionotropic glutamate receptors. Molecular clues suggest that the tail is intrinsically disordered, which makes it part of a large family of channels that are tuned by such disordered chains (Kjaergaard & Kragelund, 2017). Warnet et al. (2020) review the functions of the C-terminal domains of the NMDA receptor in light of their intrinsically disordered nature covering its involvement in signalling, plasticity and disease. The contribution of hippocampus to spatial learning and memory relies on synaptic and molecular mechanisms. Fraser et al. (2021) present experimental data of AMPA subunit expression, in a ratio of GluA2 to GluA1 as an indicator of plasticity across the hippocampus during a spatial learning task, in a familiar versus a novel training environment, in rats. In the context of time after task and hippocampal subfield, they report differences in this GluA2:GluA1plasticity indicator. The formation of memory depends on the entorhinal cortical (EC)-hippocampal (HPC) network. In this review, Marks and colleagues (Marks et al., 2020) describe recent anatomical findings of neural circuits that are critical for the formation of memory. Furthermore, they look into multiple roles of differential circuits from EC to HPC and their contribution temporal and spatial memory. Finally, they bring new insights into how the neural circuit mechanisms integrate the temporal and spatial aspects of memory encoding in the EC-HPC network. The Ca2+/calmodulin-dependent kinase II (CaMKII) is an archetypical memory protein due to its phosphorylation-dependent bistability, which allows it to act as a molecular information storage bit (Lisman, 1994). CaMKII comes in many flavours with four genes that each exists in several splice variants. Here, Sloutsky and Stratton (2020) provide a historical account of the discovery of CaMKII's molecular diversity and discuss functional differences between the variants. Finally, the authors propose a systematic nomenclature for describing CaMKII variants that allow inclusion of forms that remain to be discovered. Once synthesized in response to synaptic stimulation, the kinase PKMζ remains persistently active in the absence of further stimuli, which is key to the maintenance of LTP (Sacktor & Fenton, 2018). Here, Hsieh et al. (2021) use quantitative immunohistochemistry to study the upregulation of PKMζ in synapses encoding active place avoidance. PKMζ levels increase for at least a month and increases with neurons in the CA1, where the Arc promotor was activated. This suggests that PKMζ in the CA3-to-CA1 pathway plays a role in LTP maintenance and information storage. Glycogen synthase kinase 3β (GSK-3β) is dysregulated in neurogenerative and psychiatric disorders. Amici et al. (2020) hypothesized that GSK-3β exerts its effect on plasticity via its substrate phosphatidylinositol 4 kinase IIα (PI4KIIα), which in turn regulates the surface expression of ionotropic glutamate receptors. Using shRNA knockdown and kinase inhibitors, the authors show that GSK-3β phosphorylation of PI4KIIα does not affect AMPA receptors but is needed for NMDA receptor transmission in a subunit-dependent manner. This paper thus provides a mechanistic coupling between GSK-3β and clinical conditions that involve NMDA receptors. These proteins are all integrated into synapses, which are the building blocks of neuronal circuits. The issue continues with a series of articles connecting proteins to the synaptic-tagging-and-capture mechanism, using the synaptic proteins to map the synaptome, new methods for imaging and modifying proteins in synapses before touching on the reverse of memory, the mechanism of forgetting. Memories of trivial everyday activities, like tying your shoelaces, are stored in the hippocampus; however, they are labile and decay rapidly. Here, Okuda et al. (2020) review how memories become consolidated when they are associated with a novel experience, which causes dopamine release in the hippocampus. Okuda et al. suggest that at the cellular level, the synaptic tagging and capture hypothesis can provide a conceptual basis for novel-induced memory consolidation. According to this hypothesis, synapses in a weakly stimulated pathway become selectively ‘tagged’, whereas stronger stimulation of other inputs result in the generation of plasticity-related proteins, which are transported to tagged spines and captured, resulting in long-lasting synaptic strengthening. Okuda et al. review a large number of potential ‘tags’ and conclude that most well-studied candidates (CaMKII comes to mind) are likely modulators of the tag, but not the tag itself. The review discusses various ways in which the molecular mechanisms of synaptic tagging and capture might be elucidated, for instance by taking into account the known role of dopamine. It is well known that the hippocampus plays a key role in memory by storing associations between events as they unfold. Takehara-Nishiuchi (2020) reviews recent insights into what happens next, during memory consolidation. Two key theories, the standard theory of systems consolidation and multiple trace theory, agree about the existence of a hippocampal index code, coding for the neocortical neurons activated by retrieval of a memory. However, the theories differ in other predictions, for instance, the constancy of the hippocampal index code and thereby the role of hippocampus for consolidated memories. Another discrepancy is the role of hippocampal–cortical versus cortical–cortical connections in reinforcement of memory traces. Systematic tagging and imaging of synapses in mice have shown that brain regions have distinct composition of synapses referred to as their synaptome (Zhu et al., 2018). Here, Curran et al. (2020) map the synaptome of the human brain using PSD-95 immunohistochemistry and laser scanning confocal microscopy. The synaptome architecture is conserved between mouse and man, which suggests a conserved hierarchical organization of brain regions. Furthermore, this study demonstrates that it is feasible to make single-synapse molecular atlases of the human brain, where genetic tagging is not possible. Initially, most studies of the mechanisms of memory focused on excitatory synapses, but recently it has become clear that we must also consider the plasticity of inhibitory GABAergic synapses in memory and circuit excitability. Capogna et al. (2020) review the molecular mechanisms of inhibitory synaptic plasticity and the diversity of inhibitory interneurons. A broad picture emerges where inhibitory synapses play a key role in enabling neuronal computation central to the circuits of memory. A wide array of methods have been developed to characterize the proteins key to memory. Mikuni and Uchigashima (2020) review genetic, optogenetic and imaging methods to monitor structural plasticity of dendritic spines. The review focuses on recent developments in genome editing for introducing, e.g., epitope- and fluorescent tags intro synaptic proteins at natural expression levels including SLENDER (Mikuni et al., 2016) and vSLENDER (Nishiyama et al., 2017), which both benefit from the precision of homology-directed repair. As important as it is to form and stabilize memories, some people suffer from intrusive memories that can be deleterious for mental health (e.g., in post-traumatic stress disorder). The question poses itself: Is forgetting a passive process, e.g., simply the absence of remembering, or is it a specific mechanism with its own molecular pathways? Moreno (2020) argues in favour of the latter. Potential mechanisms for forgetting are discussed, including memory extinction, interference, neurogenesis, cell death and synaptic depotentiation. The review focuses on depotentiation and discusses the different molecules involved, most notably AMPA and NMDA receptors, as well as various protein phosphatases and kinases. The review finally points out that it is still unknown whether the mechanism for forgetting is triggered by specific events, or present as a constantly active ‘erasing machinery’, against which synaptic potentiation works. Synaptic connections are combined into circuits spanning different areas of the brains and thus acquire emergent properties. The special issue ends with articles focusing on circuitry and brain anatomy including how it is linked to behavioural effectors such as physical exercise and circadian rhythms. Considerable progress has been made in determining the brain areas involved in the encoding, retrieval and extinction of contextual fear, whereas our knowledge on the neurochemistry remains poor. Here, Stubbendorff and Stevenson (2020) review the current evidence that suggests a role for dopamine as a neurotransmitter regulating processes in contextual fear. Many areas involved in contextual fear express dopamine receptors just as dopamine modulates neural activity and synaptic plasticity in these areas. Catecholamines released from locus coerulus neurons are implicated in the regulation of several neural functions including anxiety, learning, and memory. Noradrenergic and dopaminergic LC neurons terminating in hippocampus play a role for the memory processing in hippocampus. In this review, James et al. (2020) describe the neurophysiological functions of these LC neurons and further discuss the clinical relevance of their degeneration for Alzheimer's disease. Physical exercise improves memory, when it occurs prior to or during encoding. Here, Moore and Loprinzi (2020) review the molecular and circuitry mechanisms by which exercise may improve memory. Exercise affects brain functions at many levels from increasing neurogenesis and myelination to mechanisms that strengthen connections between cells, such a boosting long-term potentiation and the number and size of dendrites. Most of the research on molecular and circuitry mechanisms has been conducted in animals, and the authors end up discussing the pitfalls in extrapolating such studies to humans. Protein synthesis is modulated by a range of molecular signalling cascades; many of these fluctuate in a circadian manner. It is unclear whether hippocampus-dependent memory varies across the day. In this article, Raven et al. (2020) present results suggesting that memory consolidation is similar for day-time and night-time learning, despite the temporal dynamics of the underlying protein synthesis. In conclusion, memory research has developed into diverse field ranging from the molecules to neuronal circuits. Progress will continue to require integration between these different perspectives and levels of understanding. Equally important is the continued development and adoption of new techniques, which entails tight collaboration with adjacent disciplines such as, e.g., engineering and data science. No doubt this will provide new answers to old questions and prompt new questions that were previously out of reach. Has there ever been a more exciting time to work in memory research? The peer review history for this article is available at https://publons.com/publon/10.1111/ejn.15491." @default.
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• W3206882840 title "Introducing the special issue on “Proteins and Circuits in Memory”" @default.
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