Memory engram

Subconcussive head impacts are associated with the development of acute and chronic cognitive deficits. We recently reported that high-frequency head impact (HFHI) causes chronic cognitive deficits in mice through synaptic changes. To better understand the mechanisms underlying HFHI-induced memory decline, we used TRAP2/Ai32 transgenic mice to enable visualization and manipulation of memory engrams. We labeled the fear memory engram in male and female mice exposed to an aversive experience and subjected them to sham or HFHI...

While the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted-Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma-related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled...

Memory deficits in Alzheimer's disease (AD) show a strong link with GABAergic interneuron dysfunctions.1 , 2 , 3 , 4 , 5 , 6 , 7 The ensemble dynamics of GABAergic interneurons represent memory encoding and retrieval,8 , 9 , 10 , 11 , 12 but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As the retrosplenial cortex (RSC) is critical for episodic memory13 , 14 , 15 , 16 and is affected by β-amyloid accumulation in early AD,17 , 18 , 19 , 20 , 21 we address this question by performing Ca2+ imaging in RSC parvalbumin (PV)-expressing interneurons during a contextual fear memory task in healthy control mice and the 5XFAD mouse model of AD...

How memories are organized in the brain influences whether they are remembered discretely versus linked with other experiences or whether generalized information is applied to entirely novel situations. Here, we used scFLARE2 (single-chain fast light- and activity-regulated expression 2), a temporally precise tagging system, to manipulate mouse lateral amygdala neurons active during one of two 3 min threat experiences occurring close (3 h) or further apart (27 h) in time. Silencing scFLARE2-tagged neurons showed that two threat experiences occurring at distal times are dis-allocated to orthogonal engram ensembles and remembered discretely, whereas the same two threat experiences occurring in close temporal proximity are linked via co-allocation to overlapping engram ensembles...

The sensory neocortex has been suggested to be a substrate for long-term memory storage, yet which exact single cells could be specific candidates underlying such long-term memory storage remained neither known nor visible for over a century. Here, using a combination of day-by-day two-photon Ca2+ imaging and targeted single-cell loose-patch recording in an auditory associative learning paradigm with composite sounds in male mice, we reveal sparsely distributed neurons in layer 2/3 of auditory cortex emerged step-wise from quiescence into bursting mode, which then invariably expressed holistic information of the learned composite sounds, referred to as holistic bursting (HB) cells...

Freezing is a defensive behavior commonly examined during hippocampal-mediated fear engram reactivation. How these cellular populations engage the brain and modulate freezing across varying environmental demands is unclear. To address this, we optogenetically reactivated a fear engram in the dentate gyrus subregion of the hippocampus across three distinct contexts in male mice. We found that there were differential amounts of light-induced freezing depending on the size of the context in which reactivation occurred: mice demonstrated robust light-induced freezing in the most spatially restricted of the three contexts but not in the largest...

Information derived from experiences is incorporated into the brain as changes to ensembles of cells, termed engram cells, which allow memory storage and recall. The mechanism by which those changes hold specific information is unclear. Here, we test the hypothesis that the specific synaptic wiring between engram cells is the substrate of information storage. First, we monitor how learning modifies the connectivity pattern between engram cells at a monosynaptic connection involving the hippocampal ventral CA1 (vCA1) region and the amygdala...

Stress modulates the activity of various memory systems and can thereby guide behavioral interaction with the environment in an adaptive or maladaptive manner. At the cellular level, a large body of evidence indicates that (nor)adrenaline and glucocorticoid release induced by acute stress-exposure affects synapse function and synaptic plasticity, which are critical substrates for learning and memory. Recent evidence suggests that memories are supported in the brain by sparsely distributed neurons within networks, termed engram cell ensembles...

A longstanding mystery in chronobiology is the location and molecular mechanism of the food-entrainable oscillator (FEO).1 , 2 , 3 The FEO is an enigmatic circadian pacemaker that controls food anticipatory activity (FAA). The FEO is implicated as a circadian oscillator that entrains to feeding time. However, the rhythmic properties of the FEO remain a mystery in part due to technical limitations in distinguishing FAA from locomotor activity controlled by the primary circadian pacemaker in the suprachiasmatic nucleus (SCN)...

Despite recent advancements in identifying engram cells, our understanding of their regulatory and functional mechanisms remains in its infancy. To provide mechanistic insight into engram cell functioning, we introduced a novel local microcircuit labeling technique that enables the labeling of intraregional synaptic connections. Utilizing this approach, we discovered a unique population of somatostatin (SOM) interneurons in the mouse basolateral amygdala (BLA). These neurons are activated during fear memory formation and exhibit a preference for forming synapses with excitatory engram neurons...

Infantile amnesia is possibly the most ubiquitous form of memory loss in mammals. We investigated how memories are stored in the brain throughout development by integrating engram labeling technology with mouse models of infantile amnesia. Here, we found a phenomenon in which male offspring in maternal immune activation models of autism spectrum disorder do not experience infantile amnesia. Maternal immune activation altered engram ensemble size and dendritic spine plasticity. We rescued the same apparently forgotten infantile memories in neurotypical mice by optogenetically reactivating dentate gyrus engram cells labeled during complex experiences in infancy...

The amygdala is a brain region primarily associated with emotional response. The use of genetic markers and single-cell transcriptomics can provide insights into behavior-associated cell state changes. Here we present a detailed cell-type taxonomy of the adult mouse amygdala during fear learning and memory consolidation. We perform single-cell RNA sequencing on naïve and fear-conditioned mice, identify 130 neuronal cell types and validate their spatial distributions. A subset of all neuronal types is transcriptionally responsive to fear learning and memory retrieval...

The organization of fear memory involves the participation of multiple brain regions. However, it is largely unknown how fear memory is formed, which circuit pathways are used for "printing" memory engrams across brain regions, and the role of identified brain circuits in memory retrieval. With advanced genetic methods, we combinatorially blocked presynaptic output and manipulated N-methyl-D-aspartate receptor (NMDAR) in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) before and after cued fear conditioning...

The hippocampus (HPC), traditionally known for its role in learning and memory, has emerged as a controller of food intake. While prior studies primarily associated the HPC with food intake inhibition, recent research suggests a critical role in appetitive processes. We hypothesized that orexigenic HPC neurons differentially respond to fats and/or sugars, potent natural reinforcers that contribute to obesity development. Results uncover previously-unrecognized, spatially-distinct neuronal ensembles within the dorsal HPC (dHPC) that are responsive to separate nutrient signals originating from the gut...

Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement, allowing the organism to re-adapt to ever-changing situations. Based on the behavioral hypothesis that extinction is new learning and forms an extinction memory, this new memory is more readily forgettable than the original fear memory. The brain's cellular and synaptic traces underpinning this inherently fragile yet reinforceable extinction memory remain unclear. Intriguing questions are about the whereabouts of the engram neurons that emerged during extinction learning and how they constitute a dynamically evolving functional construct that works in concert to store and express the extinction memory...

The recent emergence of reprogramming technologies to convert brain cell types or epigenetically alter neurons and neural progenitors in vivo and in situ hold significant promises in brain repair and neuronal aging reversal. However, given the significant epigenetic and transcriptomic changes to components of the existing neuronal cells and network, we question if these reprogramming technology might inadvertently alter or erase memory engrams, conceivably resulting in changes in narrative identity or personality...

Fear memory formation and recall are highly regulated processes, with the central amygdala (CeA) contributing to fear memory-related behaviors. We recently reported that a remote fear memory engram is resident in the anterior basolateral amygdala (aBLA). However, the extent to which downstream neurons in the CeA participate in this engram is unknown. We tested the hypothesis that CeA neurons activated during fear memory formation are reactivated during remote memory retrieval such that a CeA engram participates in remote fear memory recall and its associated behavior...

Information derived from experiences is incorporated into the brain as changes to ensembles of cells, termed engram cells, that allow memory storage and recall. The mechanism by which those changes hold specific information is unclear. Here we test the hypothesis that the specific synaptic wiring between engram cells is the substrate of information storage. First, we monitor how learning modifies the connectivity pattern between engram cells at a monosynaptic connection involving the hippocampal vCA1 region and the amygdala...

Self-organizing memristive nanowire connectomes have been exploited for physical (in materia) implementation of brain-inspired computing paradigms. Despite having been shown that the emergent behavior relies on weight plasticity at single junction/synapse level and on wiring plasticity involving topological changes, a shift to multiterminal paradigms is needed to unveil dynamics at the network level. Here, we report on tomographical evidence of memory engrams (or memory traces) in nanowire connectomes, i.e...

BACKGROUND: Learning is a long-term memory process, influenced by working memory control processes, including recognition of semantic properties of items by which subjects generate a semantic structure of engrams. OBJECTIVES: The aim of the study is to investigate the verbal learning strategies of individuals with Parkinson's disease (PD). METHOD: Thirty individuals with idiopathic PD and healthy control (HC) subjects were tested with a multi-trial word list learning, under two conditions: without cue and then with an explicit cue suggesting the categories in the list, respectively...