Dual enhancement mechanisms for overnight motor memory consolidation

Our brains are constantly processing past events<sup>1</sup>. These offline processes consolidate memories, leading in the case of motor skill memories to an enhancement in performance between training sessions. A similar magnitude of enhancement develops over a night of sleep following an implicit task, in which a sequence of movements is acquired unintentionally, or following an explicit task, in which the same sequence is acquired intentionally<sup>2</sup>. What remains poorly understood, however, is whether these similar offline improvements are supported by similar circuits, or through distinct circuits. We set out to distinguish between these possibilities by applying transcranial magnetic stimulation over the primary motor cortex (M1) or the inferior parietal lobule (IPL) immediately after learning in either the explicit or implicit task. These brain areas have both been implicated in encoding aspects of a motor sequence and subsequently supporting offline improvements over sleep<sup>3,​4,​5</sup>. Here we show that offline improvements following the explicit task are dependent on a circuit that includes M1 but not IPL. In contrast, offline improvements following the implicit task are dependent on a circuit that includes IPL but not M1. Our work establishes the critical contribution made by M1 and IPL circuits to offline memory processing, and reveals that distinct circuits support similar offline improvements

Memory consolidation — Mechanisms and opportunities for enhancement

Abstract Memory consolidation is the process by which relevant information is selected and transferred from a short-term, fragile state, into a stable, longer term domain from which it can be recalled. Effective memory underpins our ability to carry out everyday activities. When memory consolidation fails, such as in Alzheimer’s disease, the consequences can be devastating. Understanding the neurobiology of memory will help develop treatments for patients with memory loss. Here we describe the myriad processes involved in memory consolidation, including cholinergic and dopaminergic neurotransmission predominantly in hippocampal networks. We discuss established therapies as well as potential novel strategies for boosting cognition. Future approaches to enhancement of memory consolidation include not only pharmacological and neurosurgical treatments, but also lifestyle interventions — for example, modifications to sleep, exercise and diet.</jats:p

Delayed intrinsic activation of an NMDA-independent CaM-kinase II in a critical time window is necessary for late consolidation of an associative memory

Calcium/calmodulin-dependent kinases (CaM-kinases) are central to various forms of long-term memory (LTM) in a number of evolutionarily diverse organisms. However, it is still largely unknown what contributions specific CaM-kinases make to different phases of the same specific type of memory, such as acquisition, or early, intermediate, and late consolidation of associative LTM after classical conditioning. Here, we investigated the involvement of CaM-kinase II (CaMKII) in different phases of associative LTM induced by single-trial reward classical conditioning in Lymnaea, a well established invertebrate experimental system for studying molecular mechanisms of learning and memory. First, by using a general CaM-kinase inhibitor, KN-62, we found that CaM-kinase activation was necessary for acquisition and late consolidation, but not early or intermediate consolidation or retrieval of LTM. Then, we used Western blot-based phosphorylation assays and treatment with CaMKIINtide to identify CaMKII as the main CaM-kinase, the intrinsic activation of which, in a critical time window ( approximately 24 h after learning), is central to late consolidation of LTM. Additionally, using MK-801 and CaMKIINtide we found that acquisition was dependent on both NMDA receptor and CaMKII activation. However, unlike acquisition, CaMKII-dependent late memory consolidation does not require the activation of NMDA receptors. Our new findings support the notion that even apparently stable memory traces may undergo further molecular changes and identify NMDA-independent intrinsic activation of CaMKII as a mechanism underlying this "lingering consolidation." This process may facilitate the preservation of LTM in the face of protein turnover or active molecular processes that underlie forgetting

Memory consolidation in the cerebellar cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA(A) agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage

Awake Reactivation of Prior Experiences Consolidates Memories and Biases Cognition.

After experiences are encoded into memory, post-encoding reactivation mechanisms have been proposed to mediate long-term memory stabilization and transformation. Spontaneous reactivation of hippocampal representations, together with hippocampal-cortical interactions, are leading candidate mechanisms for promoting systems-level memory strengthening and reorganization. While the replay of spatial representations has been extensively studied in rodents, here we review recent fMRI work that provides evidence for spontaneous reactivation of nonspatial, episodic event representations in the human hippocampus and cortex, as well as for experience-dependent alterations in systems-level hippocampal connectivity. We focus on reactivation during awake post-encoding periods, relationships between reactivation and subsequent behavior, how reactivation is modulated by factors that influence consolidation, and the implications of persistent reactivation for biasing ongoing perception and cognition

Post-learning Arousal Enhances Veridical Memory And Reduces False Memory In The Deese-Roediger-McDermott Paradigm

The Deese-Roediger-McDermott (DRM) paradigm examines false memory by introducing words associated with a non-presented ‘critical lure’ as memoranda, which typically causes the lures to be remembered as frequently as studied words. Our prior work has shown enhanced veridical memory and reduced misinformation effects when arousal is induced after learning (i.e., during memory consolidation). These effects have not been examined in the DRM task, or with signal detection analysis, which can elucidate the mechanisms underlying memory alterations. Thus, 130 subjects studied and then immediately recalled six DRM lists, one after another, and then watched a 3-min arousing (n = 61) or neutral (n = 69) video. Recognition tested 70 min later showed that arousal induced after learning led to better delayed discrimination of studied words from (a) critical lures, and (b) other non-presented ‘weak associates.’ Furthermore, arousal reduced liberal response bias (i.e., the tendency toward accepting dubious information) for studied words relative to all foils, including critical lures and ‘weak associates.’ Thus, arousal induced after learning effectively increased the distinction between signal and noise by enhancing access to verbatim information and reducing endorsement of dubious information. These findings provide important insights into the cognitive mechanisms by which arousal modulates early memory consolidation processes

Memory consolidation is linked to spindle-mediated information processing during sleep

How are brief encounters transformed into lasting memories? Previous research has established the role of non-rapid eye movement (NREM) sleep, along with its electrophysiological signatures of slow oscillations (SOs) and spindles, for memory consolidation [1–4]. In related work, experimental manipulations have demonstrated that NREM sleep provides a window of opportunity to selectively strengthen particular memory traces via the delivery of auditory cues [5–10], a procedure known as targeted memory reactivation (TMR). It has remained unclear, however, whether TMR triggers the brain's endogenous consolidation mechanisms (linked to SOs and/or spindles) and whether those mechanisms in turn mediate effective processing of mnemonic information. We devised a novel paradigm in which associative memories (adjective-object and adjective-scene pairs) were selectively cued during a post-learning nap, successfully stabilizing next-day retention relative to non-cued memories. First, we found that, compared to novel control adjectives, memory cues evoked an increase in fast spindles. Critically, during the time window of cue-induced spindle activity, the memory category linked to the verbal cue (object or scene) could be reliably decoded, with the fidelity of this decoding predicting the behavioral consolidation benefits of TMR. These results provide correlative evidence for an information processing role of sleep spindles in service of memory consolidation. Sleep spindles play a crucial role in memory consolidation, but the underlying mechanisms are not well understood. Using an auditory memory-cueing technique and EEG analysis in humans, Cairney et al. show that sleep spindles mediate the informational content of reactivated memory traces in service of offline mnemonic processing

Optimal stimulation protocol in a bistable synaptic consolidation model

Consolidation of synaptic changes in response to neural activity is thought to be fundamental for memory maintenance over a timescale of hours. In experiments, synaptic consolidation can be induced by repeatedly stimulating presynaptic neurons. However, the effectiveness of such protocols depends crucially on the repetition frequency of the stimulations and the mechanisms that cause this complex dependence are unknown. Here we propose a simple mathematical model that allows us to systematically study the interaction between the stimulation protocol and synaptic consolidation. We show the existence of optimal stimulation protocols for our model and, similarly to LTP experiments, the repetition frequency of the stimulation plays a crucial role in achieving consolidation. Our results show that the complex dependence of LTP on the stimulation frequency emerges naturally from a model which satisfies only minimal bistability requirements.Comment: 23 pages, 6 figure

Long Days Enhance Recognition Memory and Increase Insulin-like Growth Factor 2 in the Hippocampus

Light improves cognitive function in humans; however, the neurobiological mechanisms underlying positive effects of light remain unclear. One obstacle is that most rodent models have employed lighting conditions that cause cognitive deficits rather than improvements. Here we have developed a mouse model where light improves cognitive function, which provides insight into mechanisms underlying positive effects of light. To increase light exposure without eliminating daily rhythms, we exposed mice to either a standard photoperiod or a long day photoperiod. Long days enhanced long-term recognition memory, and this effect was abolished by loss of the photopigment melanopsin. Further, long days markedly altered hippocampal clock function and elevated transcription of Insulin-like Growth Factor2 (Igf2). Up-regulation of Igf2 occurred in tandem with suppression of its transcriptional repressor Wilm’s tumor1. Consistent with molecular de-repression of Igf2, IGF2 expression was increased in the hippocampus before and after memory training. Lastly, long days occluded IGF2-induced improvements in recognition memory. Collectively, these results suggest that light changes hippocampal clock function to alter memory, highlighting novel mechanisms that may contribute to the positive effects of light. Furthermore, this study provides insight into how the circadian clock can regulate hippocampus-dependent learning by controlling molecular processes required for memory consolidation

DNA methylation and transcriptional control in memory formation, persistence and suppression

Memory formation is a complex process regulated by various molecular mechanisms, including unique transcriptional signatures and epigenetic factors. In addition, the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. While the role of epigenetic modifications, such as DNA methylation, in cognition has been established, there are still significant gaps in our understanding of the specific functions of individual DNA methyltransferases (Dnmts) and how their downstream effectors orchestrate memory. Moreover, the molecular mechanisms underlying memory persistence and memory suppression remain largely unexplored. I investigated the role of specific Dnmts in long-term memory formation, highlighting their unique functions and downstream effects. Additionally, I explored how DNA methylation contributes to the transfer of information from the hippocampus to the cortex for long-term storage and the stabilisation of cortical engrams to drive memory persistence. First, I examined the involvement of Dnmt3a1, the predominant Dnmt3a isoform in the adult brain, in hippocampus-dependent long-term memory formation. I identified an activity-regulated Dnmt3a1-dependent gene expression program and found a downstream effector gene (Neuropilin-1) with a previously undescribed function in memory formation. Intriguingly, I found that despite a common requirement for memory formation, Dnmt3a1 and Dnmt3a2 regulate this process via distinct mechanisms - Nrp1 overexpression rescued Dnmt3a1, but not Dnmt3a2, knockdown-driven impairments in memory formation. Next, I investigated the molecular mechanisms underlying memory persistence and systems consolidation, the gradual transfer of information from the hippocampus to the cortex. By modulating DNA methylation processes in the dorsal hippocampus, a short-lasting memory could be converted into a long-lasting one. The applied manipulation resulted in improved reactivation of cortical engrams and increased fear generalisation, mimicking the characteristics of remote memory. These findings provide compelling evidence for the facilitatory role of DNA methylation in memory information transfer to the cortex for long-term storage. Furthermore, I examined the temporal expression patterns of immediate early genes (IEGs), specifically neuronal PAS domain protein 4 (Npas4), and its potential role in memory suppression. My investigation revealed that highly salient stimuli induced a biphasic expression of Npas4 in the hippocampus, with the later phase dependent on NMDA receptor activity. Notably, this later phase of Npas4 expression restricted memory consolidation, suggesting a role in balancing the formation of highly salient memories and preventing the development of maladaptive behaviours. These findings highlighted the intricate regulatory network by which experience salience modulates IEG expression and thereby fine-tunes memory consolidation. Overall, this study uncovered the unique functions of distinct Dnmts in memory formation and persistence and shed light on the associated mechanisms that are responsible to facilitate the transfer of information required for long-term storage. This comprehensive understanding of the molecular processes underlying memory formation contributes to our broader knowledge of memory consolidation and may have implications for therapeutic interventions targeting memory-related disorders