Stable Long-term Memory Research Articles

Using motion-detection cameras to monitor foraging behaviour of individual butterflies.

The activity of many animals follows recurrent patterns and foraging is one of the most important processes in their daily activity. Determining movement in the search for resources and understanding temporal and spatial patterns in foraging has therefore long been central in behavioural ecology. However, identifying and monitoring animal movements is often challenging. In this study we assess the use of camera traps to track a very specific and small-scale interactions focused on the foraging behaviour of Heliconiini butterflies. Data on floral visitation was recorded using marked individuals of three pollen-feeding species of Heliconius (H. erato, H. melpomene and H. sara), and two closely related, non-pollen feeding species (Dryas iulia and Dryadula phaetusa) in a large outdoor insectary. We demonstrate that camera traps efficiently capture individual flower visitation over multiple times and locations and use our experiments to describe some features of their spatial and temporal foraging patterns. Heliconiini butterflies showed higher activity in the morning with strong temporal niche overlap. Differences in foraging activity between males and females was observed with females foraging earlier than males, mirroring published field studies. Some flowers were more explored than others, which may be explained by butterflies foraging simultaneously affecting each other's flower choices. Feeding was grouped in short periods of intense visits to the same flower, which we refer to as feeding bouts. Heliconius also consistently visits the same flower, while non-Heliconius visited a greater number of flowers per day and their feeding bouts were shorter compared with Heliconius. This is consistent with Heliconius having more stable long-term spatial memory and foraging preferences than outgroup genera. More broadly, our study demonstrates that camera traps can provide a powerful tool to gather information about foraging behaviour in small insects such as butterflies. © 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.

Highly stable long-term memory in a mouse model of post-traumatic stress disorder

Highly stable long-term memory in a mouse model of post-traumatic stress disorder

Cofilin overactivation improves hippocampus-dependent short-term memory.

Many living organisms of the animal kingdom have the fundamental ability to form and retrieve memories. Most information is initially stored as short-term memory, which is then converted to a more stable long-term memory through a process called memory consolidation. At the neuronal level, synaptic plasticity is crucial for memory storage. It includes the formation of new spines, as well as the modification of existing spines, thereby tuning and shaping synaptic efficacy. Cofilin critically contributes to memory processes as upon activation, it regulates the shape of dendritic spines by targeting actin filaments. We previously found that prolonged activation of cofilin in hippocampal neurons attenuated the formation of long-term object-location memories. Because the modification of spine shape and structure is also essential for short-term memory formation, we determined whether overactivation of hippocampal cofilin also influences the formation of short-term memories. To this end, mice were either injected with an adeno-associated virus expressing catalytically active cofilin, or an eGFP control, in the hippocampus. We show for the first time that cofilin overactivation improves short-term memory formation in the object-location memory task, without affecting anxiety-like behavior. Surprisingly, we found no effect of cofilin overactivation on AMPA receptor expression levels. Altogether, while cofilin overactivation might negatively impact the formation of long-lasting memories, it may benefit short-term plasticity.

A double dissociation between savings and long-term memory in motor learning.

Memories are easier to relearn than learn from scratch. This advantage, known as savings, has been widely assumed to result from the reemergence of stable long-term memories. In fact, the presence of savings has often been used as a marker for whether a memory has been consolidated. However, recent findings have demonstrated that motor learning rates can be systematically controlled, providing a mechanistic alternative to the reemergence of a stable long-term memory. Moreover, recent work has reported conflicting results about whether implicit contributions to savings in motor learning are present, absent, or inverted, suggesting a limited understanding of the underlying mechanisms. To elucidate these mechanisms, we investigate the relationship between savings and long-term memory by experimentally dissecting the underlying memories based on short-term (60-s) temporal persistence. Components of motor memory that are temporally-persistent at 60 s might go on to contribute to stable, consolidated long-term memory, whereas temporally-volatile components that have already decayed away by 60 s cannot. Surprisingly, we find that temporally-volatile implicit learning leads to savings, whereas temporally-persistent learning does not, but that temporally-persistent learning leads to long-term memory at 24 h, whereas temporally-volatile learning does not. This double dissociation between the mechanisms for savings and long-term memory formation challenges widespread assumptions about the connection between savings and memory consolidation. Moreover, we find that temporally-persistent implicit learning not only fails to contribute to savings, but also that it produces an opposite, anti-savings effect, and that the interplay between this temporally-persistent anti-savings and temporally-volatile savings provides an explanation for several seemingly conflicting recent reports about whether implicit contributions to savings are present, absent, or inverted. Finally, the learning curves we observed for the acquisition of temporally-volatile and temporally-persistent implicit memories demonstrate the coexistence of implicit memories with distinct time courses, challenging the assertion that models of context-based learning and estimation should supplant models of adaptive processes with different learning rates. Together, these findings provide new insight into the mechanisms for savings and long-term memory formation.

More Stable Memory Retention of Novel Words Learned from Fast Mapping than from Explicit Encoding.

There is a heated debate on a learning paradigm known as "fast mapping" for its early neocortical dependence and retained memory over time for amnesic patients with hippocampal system damage. Whether the fast mapping allows hippocampus independent learning and induces rapid integration is poorly understood. The present study aims to investigate the effect of fast mapping on very long-term retention, which to our knowledge has not been previously explored. We tested memory retention ranging from 10min to 1.5 years, for novel word-object associations learned from fast mapping or explicit encoding procedures. The three-alternative forced choice recognition task was employed to assess memory performance. Besides the slight adjustment of the testing schedule, other settings remained the same in Experiment 2 to replicate and verify the findings of Experiment 1. Results showed that overall memory retrieval performance was higher after explicit encoding as compared to fast mapping. However, retrieval performance after explicit encoding dropped after 1.5 years, but remained stable in the fast mapping condition. Furthermore, matching the semantic category of the known and the novel items during the fast mapping paradigm might affect long-term retention. These results suggest that fast mapping creates more stable long-term memory representations as compared to the explicit encoding strategy.

Comparative Study of the Effect of a DNA Methyltransferase Inhibitor and a Histone Deacetylase Inhibitor on Memory Formation Processes in Anterograde Amnesia.

The participation of DNA methylation and histone acetylation in the mechanisms of anterograde amnesia and memory recovery was studied on grape snails trained in conditioned food aversion. Anterograde amnesia developed 10 days after memory reconsolidation impairment with an NMDA glutamate receptor antagonist and was characterized by long-term memory formation impairment upon repeated training. DNA methyltransferase inhibitor injections to snails 1 h before repeated training, as well as 15 min or 4 h after repeated training, caused rapid formation of memory that persisted for at least 10 days. Injections of histone deacetylase inhibitor before repeated training also induced the formation of a stable long-term memory. However, administration of histone deacetylase inhibitor 15 min after repeated training initiated a temporary memory recovery. Injections of the inhibitor 4 h after repeated training were ineffective. These results indicate that histone-dependent chromatin remodeling and DNA methylation are selectively involved in the mechanisms of anterograde amnesia and memory recovery.

Memory recall: New behavioral protocols for examining distinct forms of context specific recall in animals

This study outlines two novel protocols for examining context specific recall in animals prior to embarking on neurobiological studies. The approach is distinct from and contrasts with studies investigating associative familiarity that depend upon procedural variations of the widely used novel object recognition task. It uses an event arena in which animals are trained across numerous sessions to search for, find and dig up reward from sandwells during sample and choice trials – a prominent spatial event for a rodent. The arena could be laid out as either of two highly distinct contexts with which the animals became fully familiar throughout training. In one protocol, the location of the correct sandwell in each context remained stable across days, whereas in the other, the correct digging location varied in a counterbalanced manner across each successive session. Thus, context-specific recall of the spatial location of successful digging during choice trials was either from a stable long-term memory or could reflect context specific spatial recency of the location where reward had been available that session. Both protocols revealed effective memory recall in choice and probe tests which, at the point of test, were procedurally identical in both cases.

Randomly fluctuating neural connections may implement a consolidation mechanism that explains classic memory laws

How can we reconcile the massive fluctuations in neural connections with a stable long-term memory? Two-photon microscopy studies have revealed that large portions of neural connections (spines, synapses) are unexpectedly active, changing unpredictably over time. This appears to invalidate the main assumption underlying the majority of memory models in cognitive neuroscience, which rely on stable connections that retain information over time. Here, we show that such random fluctuations may in fact implement a type of memory consolidation mechanism with a stable very long-term memory that offers novel explanations for several classic memory ‘laws’, namely Jost’s Law (1897: superiority of spaced learning) and Ribot’s Law (1881: loss of recent memories in retrograde amnesia), for which a common neural basis has been postulated but not established, as well as other general ‘laws’ of learning and forgetting. We show how these phenomena emerge naturally from massively fluctuating neural connections.

Rapid decay of spatial memory acquired in rats with ventral hippocampus lesions

Several memory consolidation theories have proposed that following a learning situation the hippocampus gradually stabilizes labile recent memories into long-lasting remote memories. Most work in this field has focused on the dorsal hippocampus (DHip), giving little consideration to a possible contribution by the ventral hippocampus (VHip), particularly when spatial paradigms are used. However, in recent years a growing number of studies have suggested the existence of a functional continuum, related to spatial processing and navigation, along the dorsoventral hippocampal axis. For this reason, in the present study we compare the effect of DHip vs. VHip lesions on long-term spatial memory retention. Using a four-arm plus-shaped maze, rats with lesions in the DHip, VHip or sham-lesioned learned to criterion a place discrimination task based on allothetic cues. During two retraining phases (2 days and 24 days after learning) retention of the spatial information learned during the acquisition phase was evaluated. The main findings revealed no deficit 2 days after learning, but 24 days after learning both lesioned groups showed a profound impairment compared to control animals (expt. 1). In contrast, when rats learned a cue-guided navigation task in the acquisition phase, both lesioned groups performed the two retention tests, 2 days and 24 days after learning, at the same level as the control group (expt. 2). These results suggest not only that the DHip is vital, but also that normal VHip activity is critical during the post-learning period in order for a recent spatial memory to become a stable long-term memory.

Hebb repetition learning in adolescents with intellectual disabilities

BackgroundHebb repetition learning is a form of long-term serial order learning that can occur when sequences of items in an immediate serial recall task are repeated. Repetition improves performance because of the gradual integration of serial order information from short-term memory into a more stable long-term memory trace. AimsThe current study assessed whether adolescents with non-specific intellectual disabilities showed Hebb repetition effects, and if their magnitude was equivalent to those of children with typical development, matched for mental age. MethodsTwo immediate serial recall Hebb repetition learning tasks using verbal and visuospatial materials were presented to 47 adolescents with intellectual disabilities (11–15 years) and 47 individually mental age-matched children with typical development (4–10 years). ResultsBoth groups showed Hebb repetition learning effects of similar magnitude, albeit with some reservations. Evidence for Hebb repetition learning was found for both verbal and visuospatial materials; for our measure of Hebb learning the effects were larger for verbal than visuospatial materials. ConclusionsThe findings suggested that adolescents with intellectual disabilities may show implicit long-term serial-order learning broadly commensurate with mental age level. The benefits of using repetition in educational contexts for adolescents with intellectual disabilities are considered.

Consolidation and maintenance of long-term memory involve dual functions of the developmental regulator Apterous in clock neurons and mushroom bodies in the Drosophila brain.

Memory is initially labile but can be consolidated into stable long-term memory (LTM) that is stored in the brain for extended periods. Despite recent progress, the molecular and cellular mechanisms underlying the intriguing neurobiological processes of LTM remain incompletely understood. Using the Drosophila courtship conditioning assay as a memory paradigm, here, we show that the LIM homeodomain (LIM-HD) transcription factor Apterous (Ap), which is known to regulate various developmental events, is required for both the consolidation and maintenance of LTM. Interestingly, Ap is involved in these 2 memory processes through distinct mechanisms in different neuronal subsets in the adult brain. Ap and its cofactor Chip (Chi) are indispensable for LTM maintenance in the Drosophila memory center, the mushroom bodies (MBs). On the other hand, Ap plays a crucial role in memory consolidation in a Chi-independent manner in pigment dispersing factor (Pdf)-containing large ventral–lateral clock neurons (l-LNvs) that modulate behavioral arousal and sleep. Since disrupted neurotransmission and electrical silencing in clock neurons impair memory consolidation, Ap is suggested to contribute to the stabilization of memory by ensuring the excitability of l-LNvs. Indeed, ex vivo imaging revealed that a reduced function of Ap, but not Chi, results in exaggerated Cl− responses to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in l-LNvs, indicating that wild-type (WT) Ap maintains high l-LNv excitability by suppressing the GABA response. Consistently, enhancing the excitability of l-LNvs by knocking down GABAA receptors compensates for the impaired memory consolidation in ap null mutants. Overall, our results revealed unique dual functions of the developmental regulator Ap for LTM consolidation in clock neurons and LTM maintenance in MBs.

Serotonin Signals Modulate Mushroom Body Output Neurons for Sustaining Water-Reward Long-Term Memory in Drosophila.

Memory consolidation is a time-dependent process through which an unstable learned experience is transformed into a stable long-term memory; however, the circuit and molecular mechanisms underlying this process are poorly understood. The Drosophila mushroom body (MB) is a huge brain neuropil that plays a crucial role in olfactory memory. The MB neurons can be generally classified into three subsets: γ, αβ, and α′β′. Here, we report that water-reward long-term memory (wLTM) consolidation requires activity from α′β′-related mushroom body output neurons (MBONs) in a specific time window. wLTM consolidation requires neurotransmission in MBON-γ3β′1 during the 0–2 h period after training, and neurotransmission in MBON-α′2 is required during the 2–4 h period after training. Moreover, neurotransmission in MBON-α′1α′3 is required during the 0–4 h period after training. Intriguingly, blocking neurotransmission during consolidation or inhibiting serotonin biosynthesis in serotoninergic dorsal paired medial (DPM) neurons also disrupted the wLTM, suggesting that wLTM consolidation requires serotonin signals from DPM neurons. The GFP Reconstitution Across Synaptic Partners (GRASP) data showed the connectivity between DPM neurons and MBON-γ3β′1, MBON-α′2, and MBON-α′1α′3, and RNAi-mediated silencing of serotonin receptors in MBON-γ3β′1, MBON-α′2, or MBON-α′1α′3 disrupted wLTM. Taken together, our results suggest that serotonin released from DPM neurons modulates neuronal activity in MBON-γ3β′1, MBON-α′2, and MBON-α′1α′3 at specific time windows, which is critical for the consolidation of wLTM in Drosophila.

Kinetics and Correlates of the Neutralizing Antibody Response to SARS-CoV-2

A detailed understanding of antibody-based SARS-CoV-2 immunity has critical implications for overcoming the COVID-19 pandemic and informing vaccination strategies. We evaluated SARS-CoV-2 antibody response dynamics in a cohort of 963 individuals over 10 months. Investigating 2,146 samples, we initially detected SARS-CoV-2 antibodies in 94.4% individuals, with 82% and 79% exhibiting serum and IgG neutralization, respectively. Approximately 3% of patients demonstrated exceptional SARS-CoV-2-neutralization, with these ‘elite neutralizers’ also possessing cross-neutralizing IgG to SARS-CoV-1. Multivariate statistical modeling revealed sero-reactivity, age and fever as key factors predicting SARS-CoV-2 neutralizing activity. A loss of anti-spike reactivity in 13% individuals was detected 10 months after infection. Neutralizing activity had half-lives of 14.7 weeks in serum versus 31.4 weeks in purified IgG, indicating a stable long-term memory IgG B-cell repertoire. Our results demonstrate a broad spectrum in the initial SARS-CoV-2-neutralizing antibody response, with sustained antibodies in majority of individuals for 10 months after mild COVID-19.Funding: This work was funded by grants to Florian Kleinfrom the German Center for Infection Research (DZIF), the German Research Foundation (DFG) CRC1279 and CRC1310, European Research Council (ERC) ERC-stG639961 and COVIM: „NaFoUniMedCovid19“ (FKZ: 01KX2021).Ethical Approval: Blood samples were collected from donors who gave their written consent under the protocols 20-1187 and 16-054, approved by the Institutional Review Board (IRB) of the University Hospital Cologne.

Forgetting Rates on the Recency Portion of a Word List Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease.

Amnestic mild cognitive impairment has a greater risk of progressing to Alzheimer's disease (AD). Consistent with AD patients' distinctive deficit in consolidating new memory traces, in a recent study we demonstrated that the forgetting rate on the recency portion of a word list differentiates AD from other forms of dementia. In line with this finding, the aim of this study was to investigate whether increased recency forgetting could be a reliable index for predicting amnestic mild cognitive impairment (MCI) patients' conversion to AD. For this purpose, we compared accuracy in immediate and delayed recall from different portions of a word list in a group of patients with amnestic MCI who converted (C-MCI) or did not convert (S-MCI) to AD during a three-year follow-up period and in a group of normal controls. The results of the present study show that the forgetting from the recency portion of the list (operationalized as a ratio between immediate and delayed recall) was significantly larger in C-MCI than in S-MCI patients. Consistently, the hierarchical logistic regression analyses demonstrated that the recency ratio is a strong predictor of group membership. Similar to what occurs in full-blown AD patients, the results of our study suggest that the increased forgetting rate from the recency portion of the list in C-MCI patients is due to severely reduced efficiency in converting transitory short-term memory representations into stable long-term memory traces. This is consistent with prominent involvement of neuropathological changes in the cortical areas of the medial-temporal lobes and suggests that the recency ratio is a cognitive marker able to identify MCI patients who have a greater likelihood of progressing to AD.

Noradrenergic stabilization of heterosynaptic LTP requires activation of Epac in the hippocampus.

Beta-adrenergic receptor (β-AR) activation by norepinephrine (NE) enhances memory and stabilizes long-term potentiation (LTP), a form of synaptic plasticity believed to underlie some forms of hippocampal memory. LTP can occur at multiple synaptic pathways as a result of strong stimulation to one pathway preceding milder stimulation of an adjacent, independent pathway. Synaptic tagging allows LTP to be transferred, or captured, at heterosynaptic pathways. Previous research has shown that β-AR activation promotes heterosynaptic LTP by engaging various signaling cascades. In particular, cyclic adenosine monophosphate (cAMP) activates cAMP-dependent protein kinase A (PKA) and guanine nucleotide exchange protein activated by cAMP (Epac), to enhance LTP. Epac activation can occlude subsequent induction of stable homosynaptic LTP after β-AR activation, but it is unclear whether Epac activation is required for heterosynaptic LTP following pairing of the natural transmitter, NE, with one 100 Hz train of stimulation (“NE-LTP”). Using electrophysiologic recordings of CA1 field excitatory postsynaptic potentials during stimulation of two independent synaptic pathways in murine hippocampal slices, we show that distinct inhibitors of Epac blocked stabilization of homo- and heterosynaptic NE-LTP. PKA inhibition also attenuated heterosynaptic transfer of NE-LTP, but only when a PKA inhibitor was applied during tetanization of a second, heterosynaptic pathway that was not treated with NE. Our data suggest that NE, paired with 100 Hz, activates Epac to stabilize homo- and heterosynaptic LTP. Epac may regulate the production of plasticity-related proteins and subsequent synaptic capture of NE-LTP at a heterosynaptic pathway. Epac activation under these conditions may enable behavioral experiences that engage noradrenergic inputs to hippocampal circuits to be transformed into stable long-term memories.

Forgetting Rate on the Recency Portion of a Word List Differentiates Mild to Moderate Alzheimer's Disease from Other Forms of Dementia.

Patients with Alzheimer's disease (AD) demonstrate a disproportionately larger forgetting rate in episodic memory tasks. Previous studies documented that, in comparison with healthy controls, the increased forgetting manifested by AD patients in word list recall tasks is confined to the recency portion of the list with normal forgetting rates on the primacy and mid-list portions. In this study we compared the primacy, mid-list, and recency ratios, obtained by dividing the immediate and delayed recall of words in position 1-4, 5-11, and 12-15 of a 15-word list, in different groups of demented patients, i.e., AD, frontal variant of frontotemporal dementia (fvFTD), Lewy body disease (LBD), subcortical ischemic vascular dementia (SIVD), and a group of normal controls (NC). The aim was to investigate whether the above reported forgetting pattern would differentiate AD performance from that of other dementia groups. Results of the statistical analysis showed that only the recency ratio differentiated AD from patients in the other dementia groups. Consistently, hierarchical logistic regression analyses demonstrated that the recency ratio discriminated between AD patients and individuals affected by other forms of dementia. In particular, the discrimination power was high in differentiating AD from fvFTD patients but was less accurate in differentiating AD from LBD and SIVD patients. We assume that the increased forgetting in AD patients is due to a deficit in memory consolidation mechanisms (specific to AD) that prevent the terminal items in a list from being transferred from a temporary short-term memory store to a stable long-term memory store.

Forgetting Rate on the Recency Portion of a Word List Differentiates Mild to Moderate Alzheimer's Disease from Other Forms of Dementi.

Patients with Alzheimer's disease (AD) demonstrate a disproportionately larger forgetting rate in episodic memory tasks. Previous studies documented that, in comparison with healthy controls, the increased forgetting manifested by AD patients in word list recall tasks is confined to the recency portion of the list with normal forgetting rates on the primacy and mid-list portions. In this study we compared the primacy, mid-list, and recency ratios, obtained by dividing the immediate and delayed recall of words in position 1-4, 5-11, and 12-15 of a 15-word list, in different groups of demented patients, i.e., AD, frontal variant of frontotemporal dementia (fvFTD), Lewy body disease (LBD), subcortical ischemic vascular dementia (SIVD), and a group of normal controls (NC). The aim was to investigate whether the above reported forgetting pattern would differentiate AD performance from that of other dementia groups. Results of the statistical analysis showed that only the recency ratio differentiated AD from patients in the other dementia groups. Consistently, hierarchical logistic regression analyses demonstrated that the recency ratio discriminated between AD patients and individuals affected by other forms of dementia. In particular, the discrimination power was high in differentiating AD from fvFTD patients but was less accurate in differentiating AD from LBD and SIVD patients. We assume that the increased forgetting in AD patients is due to a deficit in memory consolidation mechanisms (specific to AD) that prevent the terminal items in a list from being transferred from a temporary short-term memory store to a stable long-term memory store.

Prefrontal Cortex Represents Long-Term Memory of Object Values for Months

As a central hub for cognitive control, prefrontal cortex (PFC) is thought to utilize memories. However, unlike working or short-term memory, the neuronal representation of long-term memory in PFC has not been systematically investigated. Using single-unit recordings in macaques, we show that PFC neurons rapidlyupdate and maintain responses to objects based on short-term reward history. Interestingly, after repeated object-reward association, PFC neurons continue to show value-biased responses to objects even in the absence of reward. This value-biased response is retained for several months after training and is resistant to extinction and to interference fromnew object-reward learning for many complex objects (>90). Accordingly, the monkeys remember thevalues of the learned objects for several months in separate testing. These findings reveal that in addition to flexible short-term and low-capacity memories, primate PFC represents stable long-term and high-capacity memories, which could prioritize valuable objects far into the future.

Long-term memory requires sequential protein synthesis in three subsets of mushroom body output neurons in Drosophila

Creating long-term memory (LTM) requires new protein synthesis to stabilize learning-induced synaptic changes in the brain. In the fruit fly, Drosophila melanogaster, aversive olfactory learning forms several phases of labile memory to associate an odor with coincident punishment in the mushroom body (MB). It remains unclear how the brain consolidates early labile memory into LTM. Here, we survey 183 Gal4 lines containing almost all 21 distinct types of MB output neurons (MBONs) and show that sequential synthesis of learning-induced proteins occurs at three types of MBONs. Downregulation of oo18 RNA-binding proteins (ORBs) in any of these MBONs impaired LTM. And, neurotransmission outputs from these MBONs are all required during LTM retrieval. Together, these results suggest an LTM consolidation model in which transient neural activities of early labile memory in the MB are consolidated into stable LTM at a few postsynaptic MBONs through sequential ORB-regulated local protein synthesis.

The dynamic connectome

When trying to gain intuitions about the computations implemented in neural circuits, we often use comparisons with electronic circuits. However, one fundamental difference to hard-wired electronic circuits is that the structure of neural circuits undergoes constant remodeling. Here, we discuss recent findings highlighting the dynamic nature of neural circuits and the underlying mechanisms. The dynamics of neural circuits follows rules that explain steady state statistics of synaptic properties observed at a single time point. Interestingly, these rules allow the prediction of future network states and extend the insights gained from serial sectioning electron microscopy of brain samples, which inherently provides information from only a single time point. We argue how the connectome’s dynamic nature can be reconciled with stable functioning and long-term memory storage and how it may even benefit learning.