COVID fog demystified.

Acute mild respiratory SARS-CoV-2 infection can lead to a more chronic cognitive syndrome known as "COVID fog." New findings from Fernández-Castañeda et al. reveal how glial dysregulation and consequent neural circuit dysfunction may contribute to cognitive impairments in long COVID.

Fear Extinction Requires Reward.

Learning theorists long hypothesized that appetitive and aversive motivational states influence one another antagonistically. Here, Felsenberg et al. show that the activity of neurons in Drosophila known to be important in appetitive conditioning is necessary for the extinction of aversive conditioning, thereby uncovering biological evidence for this opponent-process.

Forgetting as a form of adaptive engram cell plasticity.

One leading hypothesis suggests that memories are stored in ensembles of neurons (or 'engram cells') and that successful recall involves reactivation of these ensembles. A logical extension of this idea is that forgetting occurs when engram cells cannot be reactivated. Forms of 'natural forgetting' vary considerably in terms of their underlying mechanisms, time course and reversibility. However, we suggest that all forms of forgetting involve circuit remodelling that switches engram cells from an accessible state (where they can be reactivated by natural recall cues) to an inaccessible state (where they cannot). In many cases, forgetting rates are modulated by environmental conditions and we therefore propose that forgetting is a form of neuroplasticity that alters engram cell accessibility in a manner that is sensitive to mismatches between expectations and the environment. Moreover, we hypothesize that disease states associated with forgetting may hijack natural forgetting mechanisms, resulting in reduced engram cell accessibility and memory loss.

Memory Allocation: Mechanisms and Function.

Memories for events are thought to be represented in sparse, distributed neuronal ensembles (or engrams). In this article, we review how neurons are chosen to become part of a particular engram, via a process of neuronal allocation. Experiments in rodents indicate that eligible neurons compete for allocation to a given engram, with more excitable neurons winning this competition. Moreover, fluctuations in neuronal excitability determine how engrams interact, promoting either memory integration (via coallocation to overlapping engrams) or separation (via disallocation to nonoverlapping engrams). In parallel with rodent studies, recent findings in humans verify the importance of this memory integration process for linking memories that occur close in time or share related content. A deeper understanding of allocation promises to provide insights into the logic underlying how knowledge is normally organized in the brain and the disorders in which this process has gone awry.

Neurogenesis-dependent remodeling of hippocampal circuits reduces PTSD-like behaviors in adult mice.

Post-traumatic stress disorder (PTSD) is a hypermnesic condition that develops in a subset of individuals following exposure to severe trauma. PTSD symptoms are debilitating, and include increased anxiety, abnormal threat generalization, and impaired extinction. In developing treatment strategies for PTSD, preclinical studies in rodents have largely focused on interventions that target post-encoding memory processes such as reconsolidation and extinction. Instead, here we focus on forgetting, another post-encoding process that regulates memory expression. Using a double trauma murine model for PTSD, we asked whether promoting neurogenesis-mediated forgetting can weaken trauma memories and associated PTSD-relevant behavioral phenotypes. In the double trauma paradigm, consecutive aversive experiences lead to a constellation of behavioral phenotypes associated with PTSD including increases in anxiety-like behavior, abnormal threat generalization, and deficient extinction. We found that post-training interventions that elevate hippocampal neurogenesis weakened the original trauma memory and decreased these PTSD-relevant phenotypes. These effects were observed using multiple methods to manipulate hippocampal neurogenesis, including interventions restricted to neural progenitor cells that selectively promoted integration of adult-generated granule cells into hippocampal circuits. The same interventions also weakened cocaine place preference memories, suggesting that promoting hippocampal neurogenesis may represent a broadly useful approach in hypermnesic conditions such as PTSD and substance abuse disorders.

Adult neurogenesis acts as a neural regularizer.

New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal circuits, forming new naive synapses. Viewed from this perspective, these new neurons may represent a significant source of "wiring" noise in hippocampal networks. In machine learning, such noise injection is commonly used as a regularization technique. Regularization techniques help prevent overfitting training data and allow models to generalize learning to new, unseen data. Using a computational modeling approach, here we ask whether a neurogenesis-like process similarly acts as a regularizer, facilitating generalization in a category learning task. In a convolutional neural network (CNN) trained on the CIFAR-10 object recognition dataset, we modeled neurogenesis as a replacement/turnover mechanism, where weights for a randomly chosen small subset of hidden layer neurons were reinitialized to new values as the model learned to categorize 10 different classes of objects. We found that neurogenesis enhanced generalization on unseen test data compared to networks with no neurogenesis. Moreover, neurogenic networks either outperformed or performed similarly to networks with conventional noise injection (i.e., dropout, weight decay, and neural noise). These results suggest that neurogenesis can enhance generalization in hippocampal learning through noise injection, expanding on the roles that neurogenesis may have in cognition.

Activity-dependent myelination: A glial mechanism of oscillatory self-organization in large-scale brain networks.

Communication and oscillatory synchrony between distributed neural populations are believed to play a key role in multiple cognitive and neural functions. These interactions are mediated by long-range myelinated axonal fiber bundles, collectively termed as white matter. While traditionally considered to be static after development, white matter properties have been shown to change in an activity-dependent way through learning and behavior-a phenomenon known as white matter plasticity. In the central nervous system, this plasticity stems from oligodendroglia, which form myelin sheaths to regulate the conduction of nerve impulses across the brain, hence critically impacting neural communication. We here shift the focus from neural to glial contribution to brain synchronization and examine the impact of adaptive, activity-dependent changes in conduction velocity on the large-scale phase synchronization of neural oscillators. Using a network model based on primate large-scale white matter neuroanatomy, our computational and mathematical results show that such plasticity endows white matter with self-organizing properties, where conduction delay statistics are autonomously adjusted to ensure efficient neural communication. Our analysis shows that this mechanism stabilizes oscillatory neural activity across a wide range of connectivity gain and frequency bands, making phase-locked states more resilient to damage as reflected by diffuse decreases in connectivity. Critically, our work suggests that adaptive myelination may be a mechanism that enables brain networks with a means of temporal self-organization, resilience, and homeostasis.

The role of the genome in experience-dependent plasticity: Extending the analogy of the genomic action potential.

Our past experiences shape our current and future behavior. These experiences must leave some enduring imprint on our brains, altering neural circuits that mediate behavior and contributing to our individual differences. As a framework for understanding how experiences might produce lasting changes in neural circuits, Clayton [D. F. Clayton, Neurobiol. Learn. Mem. 74, 185-216 (2000)] introduced the concept of the genomic action potential (gAP)-a structured genomic response in the brain to acute experience. Similar to the familiar electrophysiological action potential (eAP), the gAP also provides a means for integrating afferent patterns of activity but on a slower timescale and with longer-lasting effects. We revisit this concept in light of contemporary work on experience-dependent modification of neural circuits. We review the "Immediate Early Gene" (IEG) response, the starting point for understanding the gAP. We discuss evidence for its involvement in the encoding of experience to long-term memory across time and biological levels of organization ranging from individual cells to cell ensembles and whole organisms. We explore distinctions between memory encoding and homeostatic functions and consider the potential for perpetuation of the imprint of experience through epigenetic mechanisms. We describe a specific example of a gAP in humans linked to individual differences in the response to stress. Finally, we identify key objectives and new tools for continuing research in this area.

The role of neuronal excitability, allocation to an engram and memory linking in the behavioral generation of a false memory in mice.

Memory is a constructive, not reproductive, process that is prone to errors. Errors in memory, though, may originate from normally adaptive memory processes. At the extreme of memory distortion is falsely "remembering" an event that did not occur. False memories are well-studied in cognitive psychology, but have received relatively less attention in neuroscience. Here, we took advantage of mechanistic insights into how neurons are allocated or recruited into an engram (memory trace) to generate a false memory in mice using only behavioral manipulations. At the time of an event, neurons compete for allocation to an engram supporting the memory for this event; neurons with higher excitability win this competition (Han et al., 2007). Even after the event, these allocated "engram neurons" remain temporarily (~6 h) more excitable than neighboring neurons. Should a similar event occur in this 6 h period of heightened engram neuron excitability, an overlapping population of neurons will be co-allocated to this second engram, which serves to functionally link the two memories (Rashid et al., 2016). Here, we applied this principle of co-allocation and found that mice develop a false fear memory to a neutral stimulus if exposed to this stimulus shortly (3 h), but not a longer time (24 h), after cued fear conditioning. Similar to co-allocation, the generation of this false memory depended on the post-training excitability of engram neurons such that these neurons remained more excitable during exposure to the neutral stimulus at 3 h but not 24 h. Optogenetically silencing engram neurons 3 h after cued fear conditioning impaired formation of a false fear memory to the neutral stimulus, while optogenetically activating engram neurons 24 h after cued fear conditioning created a false fear memory. These results suggest that some false memories may originate from normally adaptive mnemonic processes such as neuronal excitability-dependent allocation and memory linking.

Finding the engram.

Many attempts have been made to localize the physical trace of a memory, or engram, in the brain. However, until recently, engrams have remained largely elusive. In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram. Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times. We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram.

Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories.

Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression.SIGNIFICANCE STATEMENT New neurons are generated in the hippocampus throughout life. As they integrate into the hippocampus, they remodel neural circuitry, potentially making information stored in those circuits harder to access. Consistent with this, increasing hippocampal neurogenesis after learning induces forgetting of the learnt information. The current study in mice asks whether these forgetting effects depend on the age of the memory. We found that post-training increases in hippocampal neurogenesis only impacted recently acquired, and not remotely acquired, hippocampal memories. These experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting, and suggest remote memories are less sensitive to changes in hippocampal neurogenesis levels because they no longer depend critically on the hippocampus for their expression.

Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients.

Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents.SIGNIFICANCE STATEMENT Pediatric medulloblastoma survivors develop cognitive dysfunction following cranial radiotherapy treatment. We report that radiotherapy treatment impairs the ability to form new autobiographical memories, but spares preoperatively acquired autobiographical memories. Reductions in hippocampal volume and cortical volume in regions of the recollection network appear to contribute to this pattern of preserved preoperative, but impaired postoperative, memory. These findings have significant implications for understanding disrupted mnemonic processing in the medial temporal lobe memory system and in the broader recollection network, which are inadvertently affected by standard treatment methods for medulloblastoma tumors in children.

Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity.

The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near -65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼ 15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor-based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure-function relationships of the light-gated pore.

Heroes of the Engram.

In 1904, Richard Semon introduced the term "engram" to describe the neural substrate responsible for (or at least important in) storing and recalling memories (i.e., a memory trace). The recent introduction of a vast array of powerful new tools to probe and manipulate memory function at the cell and neuronal circuit level has spurred an explosion of interest in studying the engram. However, the present "engram renaissance" was not borne in isolation but rather builds on a long tradition of memory research. We believe it is important to acknowledge the debts our current generation of scientists owes to those scientists who have offered key ideas, persevered through failed experiments and made important discoveries before us. Examining the past can also offer a fresh perspective on the present state and future promise of the field. Given the large amount of empirical advances made in recent years, it seems particularly timely to look back and review the scientists who introduced the seminal terminology, concepts, methodological approaches, and initial data pertaining to engrams. Rather than simply list their many accomplishments, here we color in some details of the lives and milestone contributions of our seven personal heroes of the engram (Richard Semon, Karl Lashley, Donald Hebb, Wilder Penfield, Brenda Milner, James McConnell, and Richard Thompson). In reviewing their historic role, we also illustrate how their work remains relevant to today's studies.

Functional Connectivity of Multiple Brain Regions Required for the Consolidation of Social Recognition Memory.

Social recognition memory is an essential and basic component of social behavior that is used to discriminate familiar and novel animals/humans. Previous studies have shown the importance of several brain regions for social recognition memories; however, the mechanisms underlying the consolidation of social recognition memory at the molecular and anatomic levels remain unknown. Here, we show a brain network necessary for the generation of social recognition memory in mice. A mouse genetic study showed that cAMP-responsive element-binding protein (CREB)-mediated transcription is required for the formation of social recognition memory. Importantly, significant inductions of the CREB target immediate-early genes c-fos and Arc were observed in the hippocampus (CA1 and CA3 regions), medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and amygdala (basolateral region) when social recognition memory was generated. Pharmacological experiments using a microinfusion of the protein synthesis inhibitor anisomycin showed that protein synthesis in these brain regions is required for the consolidation of social recognition memory. These findings suggested that social recognition memory is consolidated through the activation of CREB-mediated gene expression in the hippocampus/mPFC/ACC/amygdala. Network analyses suggested that these four brain regions show functional connectivity with other brain regions and, more importantly, that the hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas the ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. We have found that a brain network composed of the hippocampus/mPFC/ACC/amygdala is required for the consolidation of social recognition memory.SIGNIFICANCE STATEMENT Here, we identify brain networks composed of multiple brain regions for the consolidation of social recognition memory. We found that social recognition memory is consolidated through CREB-meditated gene expression in the hippocampus, medial prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Importantly, network analyses based on c-fos expression suggest that functional connectivity of these four brain regions with other brain regions is increased with time spent in social investigation toward the generation of brain networks to consolidate social recognition memory. Furthermore, our findings suggest that hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions.

Contextual fear conditioning in zebrafish.

Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects of learning and memory in adult fish. Here, we describe the development of a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by an established amnestic agent (MK-801), lasts at least 14 d, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory.

Memory Transformation Enhances Reinforcement Learning in Dynamic Environments.

Over the course of systems consolidation, there is a switch from a reliance on detailed episodic memories to generalized schematic memories. This switch is sometimes referred to as "memory transformation." Here we demonstrate a previously unappreciated benefit of memory transformation, namely, its ability to enhance reinforcement learning in a dynamic environment. We developed a neural network that is trained to find rewards in a foraging task where reward locations are continuously changing. The network can use memories for specific locations (episodic memories) and statistical patterns of locations (schematic memories) to guide its search. We find that switching from an episodic to a schematic strategy over time leads to enhanced performance due to the tendency for the reward location to be highly correlated with itself in the short-term, but regress to a stable distribution in the long-term. We also show that the statistics of the environment determine the optimal utilization of both types of memory. Our work recasts the theoretical question of why memory transformation occurs, shifting the focus from the avoidance of memory interference toward the enhancement of reinforcement learning across multiple timescales. SIGNIFICANCE STATEMENT: As time passes, memories transform from a highly detailed state to a more gist-like state, in a process called "memory transformation." Theories of memory transformation speak to its advantages in terms of reducing memory interference, increasing memory robustness, and building models of the environment. However, the role of memory transformation from the perspective of an agent that continuously acts and receives reward in its environment is not well explored. In this work, we demonstrate a view of memory transformation that defines it as a way of optimizing behavior across multiple timescales.

Running promotes spatial bias independently of adult neurogenesis.

Different memory systems offer distinct advantages to navigational behavior. The hippocampus forms complex associations between environmental stimuli, enabling flexible navigation through space. In contrast, the dorsal striatum associates discrete cues and favorable behavioral responses, enabling habit-like, automated navigation. While these two systems often complement one another, there are instances where striatal-dependent responses (e.g. approach a cue) conflict with hippocampal representations of spatial goals. In conflict situations, preference for spatial vs. response strategies varies across individuals and depends on previous experience, plasticity and the integrity of these two memory systems. Here, we investigated the role of adult hippocampal neurogenesis and exercise on mouse search strategies in a water maze task that can be solved with either a hippocampal-dependent place strategy or a striatal-dependent cue-response strategy. We predicted that inhibiting adult neurogenesis would impair hippocampal function and shift behavior towards striatal-dependent cue responses. However, blocking neurogenesis in a transgenic nestin-TK mouse did not affect strategy choice. We then investigated whether a pro-neurogenic stimulus, running, would bias mice towards hippocampal-dependent spatial strategies. While running indeed promoted spatial strategies, it did so even when neurogenesis was inhibited in nestin-TK mice. These findings indicate that exercise-induced increases in neurogenesis are not always required for enhanced cognitive function. Furthermore, our data identify exercise as a potentially useful strategy for promoting flexible, cognitive forms of memory in habit-related disorders that are characterized by excessive responding to discrete cues.

Age-dependent changes in spatial memory retention and flexibility in mice.

In humans, memories for events happening early in life are forgotten more rapidly than those for events later in life. This form of accelerated forgetting in infancy is also observed in non-human species, and has been most extensively characterized in rats. Here we expand the characterization of infantile forgetting to mice, a species where a broader range of genetic tools can be used to understand the neurobiological mechanisms underlying this form of forgetting. Using a hidden platform version of the water maze task, we first assessed retention in mice that ranged in age from 15 to 150days-old at the beginning of training. All groups exhibited spatial memory when tested one day after training. However, only mice that were 20days or older at the time of training could remember one month later. Second, forgetting in younger cohorts of mice was not due to weaker encoding, since when younger mice were over-trained, such that their performance exceeded that of adult mice, they still exhibited forgetting. Third, in young mice, presentation of a reminder one month following training led to memory recovery, indicating that forgetting was due to a retrieval, rather than storage, deficit. Fourth, younger mice exhibited superior reversal learning compared to older mice, raising the possibility that a by-product of infantile forgetting might be greater flexibility.