Mnemonic Information Research Articles

Propagating cortical waves coordinate sensory encoding and memory retrieval in the human brain.

Complex behavior entails a balance between taking in sensory information from the environment and utilizing previously learned internal information. Experiments in behaving mice have demonstrated that the brain continually alternates between outward and inward modes of cognition, switching its mode of operation every few seconds. Further, each state transition is marked by a stereotyped cascade of neuronal spiking that pervades most forebrain structures. Here we analyzed large fMRI datasets to demonstrate that a similar switching mechanism governs the operation of the human brain. We found that human brain activity was punctuated every several seconds by coherent, propagating waves emerging in the exteroceptive sensorimotor regions and terminating in the interoceptive default mode network. As in the mouse, the issuance of such events coincided with fluctuations in pupil size, indicating a tight relationship with arousal fluctuations, and this phenomenon occurred across behavioral states. Strikingly, concurrent measurement of human performance in a visual memory task indicated that each cycle of propagating fMRI waves sequentially promoted the encoding of semantic information and self-directed retrieval of memories. Together, these findings indicate that human cognitive performance is governed by autonomous switching between exteroceptive and interoceptive states. This apparently conserved feature of mammalian brain physiology bears directly on the integration of sensory and mnemonic information during everyday behavior.

Deciphering the Role of the Nucleus Accumbens Shell Area on Spatial Memory Deficits Induced by Neuropathic Pain in Rats

The nucleus accumbens shell (NAcSh) is a major structure associated with distinct aspects of reward and mnemonic information encoding, relying on spatial data to define optimal behavioral strategies. Chronic pain-derived striatal plasticity is considered one underpinning cause of working memory (WM) impairments. However, it is unclear how the NAcSh is involved in these spatial deficits. To address this, we evaluated the impact of unilateral local NAcSh electrical lesions during the execution of a food-reinforced eight-shaped spatial alternation WM task. Behavioral performance was assessed in rats after the onset of the neuropathic pain model—spared nerve injury (SNI). Our findings indicate that the induction of SNI and/or NAcSh lesions did not significantly impact the animals’ performance accuracy or motor activity during the execution of the behavioral task, but altered their response latency patterns. In addition, these manipulations did not induce significant antinociceptive effects. Collectively, these results suggest that the NAcSh may participate in specific aspects of spatial information integration and processing under neuropathic pain conditions.

Mnemonic But Not Contextual Feedback Signals Defy Dedifferentiation in the Aging Early Visual Cortex.

Perception is an intricate interplay between feedforward visual input and internally generated feedback signals that comprise concurrent contextual and time-distant mnemonic (episodic and semantic) information. Yet, an unresolved question is how the composition of feedback signals changes across the lifespan and to what extent feedback signals undergo age-related dedifferentiation, that is, a decline in neural specificity. Previous research on this topic has focused on feedforward perceptual representation and episodic memory reinstatement, suggesting reduced fidelity of neural representations at the item and category levels. In this fMRI study, we combined an occlusion paradigm that filters feedforward input to the visual cortex and multivariate analysis techniques to investigate the information content in cortical feedback, focusing on age-related differences in its composition. We further asked to what extent differentiation in feedback signals (in the occluded region) is correlated to differentiation in feedforward signals. Comparing younger (18-30 years) and older female and male adults (65-75 years), we found that contextual but not mnemonic feedback was prone to age-related dedifferentiation. Semantic feedback signals were even better differentiated in older adults, highlighting the growing importance of generalized knowledge across ages. We also found that differentiation in feedforward signals was correlated with differentiation in episodic but not semantic feedback signals. Our results provide evidence for age-related adjustments in the composition of feedback signals and underscore the importance of examining dedifferentiation in aging for both feedforward and feedback processing.

Temporal encoding in deep reinforcement learning agents

Neuroscientists have observed both cells in the brain that fire at specific points in time, known as “time cells”, and cells whose activity steadily increases or decreases over time, known as “ramping cells”. It is speculated that time and ramping cells support temporal computations in the brain and carry mnemonic information. However, due to the limitations in animal experiments, it is difficult to determine how these cells really contribute to behavior. Here, we show that time cells and ramping cells naturally emerge in the recurrent neural networks of deep reinforcement learning models performing simulated interval timing and working memory tasks, which have learned to estimate expected rewards in the future. We show that these cells do indeed carry information about time and items stored in working memory, but they contribute to behavior in large part by providing a dynamic representation on which policy can be computed. Moreover, the information that they do carry depends on both the task demands and the variables provided to the models. Our results suggest that time cells and ramping cells could contribute to temporal and mnemonic calculations, but the way in which they do so may be complex and unintuitive to human observers.

Local and long-range GABAergic circuits in hippocampal area CA1 and their link to Alzheimer's disease.

GABAergic inhibitory neurons are the principal source of inhibition in the brain. Traditionally, their role in maintaining the balance of excitation-inhibition has been emphasized. Beyond homeostatic functions, recent circuit mapping and functional manipulation studies have revealed a wide range of specific roles that GABAergic circuits play in dynamically tilting excitation-inhibition coupling across spatio-temporal scales. These span from gating of compartment- and input-specific signaling, gain modulation, shaping input-output functions and synaptic plasticity, to generating signal-to-noise contrast, defining temporal windows for integration and rate codes, as well as organizing neural assemblies, and coordinating inter-regional synchrony. GABAergic circuits are thus instrumental in controlling single-neuron computations and behaviorally-linked network activity. The activity dependent modulation of sensory and mnemonic information processing by GABAergic circuits is pivotal for the formation and maintenance of episodic memories in the hippocampus. Here, we present an overview of the local and long-range GABAergic circuits that modulate the dynamics of excitation-inhibition and disinhibition in the main output area of the hippocampus CA1, which is crucial for episodic memory. Specifically, we link recent findings pertaining to GABAergic neuron molecular markers, electrophysiological properties, and synaptic wiring with their function at the circuit level. Lastly, given that area CA1 is particularly impaired during early stages of Alzheimer's disease, we emphasize how these GABAergic circuits may contribute to and be involved in the pathophysiology.

From basic science to clinical practice: Can cognitive behavioural therapy tasks be augmented with enhanced episodic specificity?

Individuals with depression typically remember their past in a generalised manner, at the cost of retrieving specific event memories. This may impair engagement with cognitive behavioural therapy (CBT) tasks that use concrete episodic information to challenge maladaptive beliefs, potentially limiting their therapeutic benefit. Study 1 demonstrated that an episodic specificity induction increased detail and specificity of autobiographical memory in people with major depression, relative to control conditions (N = 88). We therefore examined whether the induction enhanced the efficacy of CBT tasks that depend on episodic memory – cognitive reappraisal (Study 2, N = 30), evidence gathering (Study 2, N = 30), and planning behavioural experiments (Study 3a, N = 30). Across all three tasks, there were no significant differences in emotion- or belief-change between the specificity and control conditions. Although the induction temporarily enhanced specificity in depressed individuals, it did not significantly augment the efficacy of CBT tasks theorised to benefit from the use of specific mnemonic information.

Age-related differences in transient gamma band activity during working memory maintenance through adolescence

Adolescence is a stage of development characterized by neurodevelopmental specialization of cognitive processes. In particular, working memory continues to improve through adolescence, with increases in response accuracy and decreases in response latency continuing well into the twenties. Human electroencephalogram (EEG) studies indicate that gamma oscillations (35-65Hz) during the working memory delay period support the maintenance of mnemonic information guiding subsequent goal-driven behavior, which decrease in power with development. Importantly, recent electrophysiological studies have shown that gamma events, more so than sustained activity, may underlie working memory maintenance during the delay period. However, developmental differences in gamma events during working memory have not been studied. Here, we used EEG in conjunction with a novel spectral event processing approach to investigate age-related differences in transient gamma band activity during a memory guided saccade (MGS) task in 164 10- to 30-year-olds. Total gamma power was found to significantly decrease through adolescence, replicating prior findings. Results from the spectral event pipeline showed age-related decreases in the mean power of gamma events and trial-by-trial power variability across both the delay period and fixation epochs of the MGS task. In addition, we found that while event number decreased with age during the fixation period, the developmental decrease during the delay period was more dramatic, resulting in an increase in event spiking from fixation to delay in adolescence but not adulthood. While average power of the transient gamma events was found to mediate age-related differences in total gamma power in the fixation and delay periods, the number of gamma events was related to total power in only the delay period, suggesting that the power of gamma events may underlie the sustained gamma activity seen in EEG literature while the number of events may directly support age-related improvements in working memory maintenance. Our findings provide compelling new evidence for mechanistic changes in neural processing characterized by refinements in neural function as behavior becomes optimized in adulthood.

Inhibition is a prevalent mode of activity in the neocortex around awake hippocampal ripples in mice.

Coordinated peri-ripple activity in the hippocampal-neocortical network is essential for mnemonic information processing in the brain. Hippocampal ripples likely serve different functions in sleep and awake states. Thus, the corresponding neocortical activity patterns may differ in important ways. We addressed this possibility by conducting voltage and glutamate wide-field imaging of the neocortex with concurrent hippocampal electrophysiology in awake mice. Contrary to our previously published sleep results, deactivation and activation were dominant in post-ripple neocortical voltage and glutamate activity, respectively, especially in the agranular retrosplenial cortex (aRSC). Additionally, the spiking activity of aRSC neurons, estimated by two-photon calcium imaging, revealed the existence of two subpopulations of excitatory neurons with opposite peri-ripple modulation patterns: one increases and the other decreases firing rate. These differences in peri-ripple spatiotemporal patterns of neocortical activity in sleep versus awake states might underlie the reported differences in the function of sleep versus awake ripples.

Concurrent contextual and time-distant mnemonic information co-exist as feedback in the human visual cortex

Efficient processing of the visual environment necessitates the integration of incoming sensory evidence with concurrent contextual inputs and mnemonic content from our past experiences. To examine how this integration takes place in the brain, we isolated different types of feedback signals from the neural patterns of non-stimulated areas of the early visual cortex in humans (i.e., V1 and V2). Using multivariate pattern analysis, we showed that both contextual and time-distant information, coexist in V1 and V2 as feedback signals. In addition, we found that the extent to which mnemonic information is reinstated in V1 and V2 depends on whether the information is retrieved episodically or semantically. Critically, this reinstatement was independent on the retrieval route in the object-selective cortex. These results demonstrate that our early visual processing contains not just direct and indirect information from the visual surrounding, but also memory-based predictions.

Adult-born dentate granule cells promote hippocampal population sparsity

The dentate gyrus (DG) gates neocortical information flow to the hippocampus. Intriguingly, the DG also produces adult-born dentate granule cells (abDGCs) throughout the lifespan, but their contribution to downstream firing dynamics remains unclear. Here, we show that abDGCs promote sparser hippocampal population spiking during mnemonic processing of novel stimuli. By combining triple-(DG-CA3-CA1) ensemble recordings and optogenetic interventions in behaving mice, we show that abDGCs constitute a subset of high-firing-rate neurons with enhanced activity responses to novelty and strong modulation by theta oscillations. Selectively activating abDGCs in their 4–7-week post-birth period increases sparsity of hippocampal population patterns, whereas suppressing abDGCs reduces this sparsity, increases principal cell firing rates and impairs novel object recognition with reduced dimensionality of the network firing structure, without affecting single-neuron spatial representations. We propose that adult-born granule cells transiently support sparser hippocampal population activity structure for higher-dimensional responses relevant to effective mnemonic information processing.

Does ROC asymmetry reverse when detecting new stimuli? Reinvestigating whether the retrievability of mnemonic information is task-dependent

Recently, it has been suggested that the mnemonic information that underlies recognition decisions changes when participants are asked to indicate whether a test stimulus is new rather than old (Brainerd et al., 2021, Journal of Experimental Psychology: Learning Memory, and Cognition, advance online publication). However, some observations that have been interpreted as evidence for this assertion need not be due to mnemonic changes, but may instead be the result of conservative response strategies if the possibility of asymmetric receiver operating characteristics (ROCs) is taken into account. Conversely, recent findings in support of asymmetric ROCs rely on the assumption that the mnemonic information accessed by the decision-maker does not depend on whether an old or a new item is considered to be the target Kellen et al. (2021, Psychological Review 128[6], 1022–1050). Here, we aim to clarify whether there is such a difference in accessibility of mnemonic information by applying signal detection theory. To this end, we used two versions of a simultaneous detection and identification task in which we presented participants with two test stimuli at a time. In one version, the old item was the target; in the other, the new item was the target. This allowed us to assess differences in mnemonic information retrieved in the two tasks while taking possible ROC asymmetry into account. Results clearly indicate that there is indeed a difference in the accessibility of mnemonic information as postulated by (Brainerd et al., 2021, Journal of Experimental Psychology: Learning Memory, and Cognition, advance online publication).

Neural basis of distractor resistance during visual working memory maintenance

Visual working memory representations must be protected from the intervening irrelevant visual input. While it is well known that interference resistance is most challenging when distractors match the prioritised mnemonic information, its neural mechanisms remain poorly understood. Here, we identify two top-down attentional control processes that have opposing effects on distractor resistance. We reveal an early selection negativity in the EEG responses to matching as compared to non-matching distractors, the magnitude of which is negatively associated with behavioural distractor resistance. Additionally, matching distractors lead to reduced post-stimulus alpha power as well as increased fMRI responses in the object-selective visual cortical areas and the inferior frontal gyrus. However, the congruency effect found on the post-stimulus periodic alpha power and the inferior frontal gyrus fMRI responses show a positive association with distractor resistance. These findings suggest that distractor interference is enhanced by proactive memory content-guided selection processes and diminished by reactive allocation of top-down attentional resources to protect memorandum representations within visual cortical areas retaining the most selective mnemonic code.

The importance of urgency in decision making based on dynamic information.

A standard view in the literature is that decisions are the result of a process that accumulates evidence in favor of each alternative until such accumulation reaches a threshold and a decision is made. However, this view has been recently questioned by an alternative proposal that suggests that, instead of accumulated, evidence is combined with an urgency signal. Both theories have been mathematically formalized and supported by a variety of decision-making tasks with constant information. However, recently, tasks with changing information have shown to be more effective to study the dynamics of decision making. Recent research using one of such tasks, the tokens task, has shown that decisions are better described by an urgency mechanism than by an accumulation one. However, the results of that study could depend on a task where all fundamental information was noiseless and always present, favoring a mechanism of non-integration, such as the urgency one. Here, we wanted to address whether the same conclusions were also supported by an experimental paradigm in which sensory evidence was removed shortly after it was provided, making working memory necessary to properly perform the task. Here, we show that, under such condition, participants’ behavior could be explained by an urgency-gating mechanism that low-pass filters the mnemonic information and combines it with an urgency signal that grows with time but not by an accumulation process that integrates the same mnemonic information. Thus, our study supports the idea that, under certain situations with dynamic sensory information, decisions are better explained by an urgency-gating mechanism than by an accumulation one.

Moment-by-moment tracking of naturalistic learning and its underlying hippocampo-cortical interactions

Humans form lasting memories of stimuli that were only encountered once. This naturally occurs when listening to a story, however it remains unclear how and when memories are stored and retrieved during story-listening. Here, we first confirm in behavioral experiments that participants can learn about the structure of a story after a single exposure and are able to recall upcoming words when the story is presented again. We then track mnemonic information in high frequency activity (70–200 Hz) as patients undergoing electrocorticographic recordings listen twice to the same story. We demonstrate predictive recall of upcoming information through neural responses in auditory processing regions. This neural measure correlates with behavioral measures of event segmentation and learning. Event boundaries are linked to information flow from cortex to hippocampus. When listening for a second time, information flow from hippocampus to cortex precedes moments of predictive recall. These results provide insight on a fine-grained temporal scale into how episodic memory encoding and retrieval work under naturalistic conditions.

Neurogenesis-dependent transformation of hippocampal engrams

In humans and other mammals, memories of events are encoded by neuronal ensembles (or engrams) in the hippocampus. The mnemonic information stored in these engrams can then be used to guide future behavior, including prediction- and decision-making in dynamic environments. While some hippocampal engrams may be persistently stored, others are modified over time, suggesting that the represented memories may also be transformed. How might hippocampal engrams be modified through time? Adult hippocampal neurogenesis represents one process that continuously rewires hippocampal circuitry, presumably including stored hippocampal engrams. At intermediate stages, we propose that neurogenesis-mediated rewiring of hippocampal engram circuitry induces forgetting of specific stimulus attributes, and this less precise engram allows for generalization. At more advanced stages, we propose that neurogenesis-mediated rewiring of hippocampal engram circuitry leads to silencing of hippocampal engrams, rendering them no longer accessible by natural retrieval cues.

Hypothalamic Glutamate/GABA Cotransmission Modulates Hippocampal Circuits and Supports Long-Term Potentiation.

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA, and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs). Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting INs and GCs receive primarily synaptic inhibition. Although SuM excitation alone is insufficient to excite GCs, it enhances the GC spiking precision and reduces the latencies in response to excitatory drives. Furthermore, SuM excitation enhances the GC spiking in response to the cortical input, thereby promoting induction of long-term potentiation at cortical-GC synapses. Collectively, these findings provide physiological significance of the cotransmission of glutamate/GABA by SuM neurons in the DG network.SIGNIFICANCE STATEMENT The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval, whereas subcortical input engages in modulation of communication between the cortex and hippocampus. The supramammillary nucleus (SuM) neurons of the hypothalamus innervate the dentate gyrus (DG) by coreleasing glutamate and GABA onto granule cells (GCs) and interneurons and support memories. However, how the SuM input regulates the activity of various DG cell types and thereby contributes to synaptic plasticity remains unexplored. Combining optogenetic and electrophysiological approaches, we demonstrate that the SuM input differentially regulates DG cell dynamics and consequently enhances GC excitability as well as synaptic plasticity at cortical input-GC synapses. Our findings highlight a significant role of glutamate/GABA cotransmission in regulating the input-output dynamics of DG circuits.

Content-specific vulnerability of recent episodic memories in Alzheimer's disease

Endel Tulving's episodic memory framework emphasizes the multifaceted re-experiencing of personal events. Indeed, decades of research focused on the experiential nature of episodic memories, usually treating recent episodic memory as a coherent experiential quality. However, recent insights into the functional architecture of the medial temporal lobe show that different types of mnemonic information are segregated into distinct neural pathways in brain circuits empirically associated with episodic memory. Moreover, recent memories do not fade as a whole under conditions of progressive neurodegeneration in these brain circuits, notably in Alzheimer's disease. Instead, certain memory content seem particularly vulnerable from the moment of their encoding while other content can remain memorable consistently across individuals and contexts. We propose that these observations are related to the content-specific functional architecture of the medial temporal lobe and consequently to a content-specific impairment of memory at different stages of the neurodegeneration. To develop Endel Tulving's inspirational legacy further and to advance our understanding of how memory function is affected by neurodegenerative conditions such as Alzheimer's disease, we postulate that it is compelling to focus on the representational content of recent episodic memories.

Dynamics of coherent activity between cortical areas defines a two-stage process of top-down attention.

Analysing a visual scene requires the brain to briefly keep in memory potentially relevant items of that scene and then direct attention to their locations for detailed processing. To reveal the neuronal basis of the underlying working memory and top-down attention processes, we trained macaques to match two patterns presented with a delay between them. As the above processes are likely to require communication between brain regions, and the parietal cortex is known to be involved in spatial attention, we simultaneously recorded neuronal activities from the interconnected parietal and middle temporal areas. We found that mnemonic information about features of the first pattern was retained in coherent oscillating activity between the two areas in high-frequency bands, followed by coherent activity in lower frequency bands mediating top-down attention on the relevant spatial location. Oscillations maintaining featural information also modulated activity of the cells of the parietal cortex that mediate attention. This could potentially enable transfer of information to organize top-down signals necessary for selective attention. Our results provide evidence in support of a two-stage model of visual attention where the first stage involves creating a saliency map representing a visual scene and at the second stage attentional feedback is provided to cortical areas involved in detailed analysis of the attended parts of a scene.

Integrating new memories into the hippocampal network activity space.

By investigating the topology of neuronal coactivity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low activity cells join coactivity motifs across behavioural events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.

Associations Between Delay Discounting and Connectivity of the Valuation-control System in Healthy Young Adults

The process of valuation assists in determining if an object or course of action is rewarding. Delay discounting is the observed decay of a rewards’ subjective value over time. Encoding the subjective value of rewards across a spectrum has been attributed to brain regions belonging to the valuation and executive control systems. The valuation system (VS) encodes reward value over short and long delays, influencing reinforcement learning and reward representation. The executive control system (ECS) becomes more active as choice difficulty increases, integrating contextual and mnemonic information with salience signals in the modulation of decision-making. Here, we aimed to identify resting-state functional connectivity-based patterns of the VS and ECS correlated with value-setting and delay discounting (outside-scanner paradigm) in a large (n = 992) cohort of healthy young adults from the Human Connectome Project (HCP). Results suggest the VS may be involved in value-setting of small, immediate rewards while the ECS may be involved in value-setting and delay discounting for large and small rewards over a range of delays. We observed magnitude sensitive connections involving the posterior cingulate cortex, time-sensitive connections with the ventromedial and lateral prefrontal cortex while connections involving the posterior parietal cortex appeared both magnitude- and time-sensitive. The ventromedial prefrontal cortex and posterior parietal cortex could act as “comparator” regions, weighing the value of small rewards against large rewards across various delay duration to aid in decision-making.