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Single-molecule fluorescence resonance energy transfer (smFRET) is applied in live cells and reveals the conformational changes of individual SNARE proteins upon entering a SNARE complex. We combined single-molecule fluorescence resonance energy transfer (smFRET) with single-particle tracking in live cells to detect the in vivo conformation of individual proteins. We site-specifically labeled recombinant SNARE proteins with a FRET donor and acceptor before microinjecting them into cultured cells. Individual proteins rapidly incorporated into folded complexes at the cell membrane, demonstrating the potential of this method to reveal dynamic interactions within cells.

Significance Episodic memory refers to the ability to recall specifics of past events in our lives. An essential aspect of events is timing when things occur during an episode. A number of recent studies have shown that the hippocampus, a structure known to be essential to form episodic memories, possesses neurons that explicitly mark moments in time. We add a previously unidentified finding to this work by showing that individual primate hippocampal neurons not only track time, but do so only when specific contextual information (e.g., object identity/location) is cued. These time context-sensitive neurons represent a novel way in which the brain unites disparate streams that comprise an episode and will aid in our understanding of how we store and retrieve episodic memories. We examined timing-related signals in primate hippocampal cells as animals performed an object-place (OP) associative learning task. We found hippocampal cells with firing rates that incrementally increased or decreased across the memory delay interval of the task, which we refer to as incremental timing cells (ITCs). Three distinct categories of ITCs were identified. Agnostic ITCs did not distinguish between different trial types. The remaining two categories of cells signaled time and trial context together: One category of cells tracked time depending on the behavioral action required for a correct response (i.e., early vs. late release), whereas the other category of cells tracked time only for those trials cued with a specific OP combination. The context-sensitive ITCs were observed more often during sessions where behavioral learning was observed and exhibited reduced incremental firing on incorrect trials. Thus, single primate hippocampal cells signal information about trial timing, which can be linked with trial type/context in a learning-dependent manner.

High-frequency oscillatory events, termed ripples, represent synchrony of neural activity in the brain. Recent evidence suggests that medial temporal lobe (MTL) ripples support memory retrieval. However, it is unclear if ripples signal the reinstatement of episodic memories. Analyzing electrophysiological MTL recordings from 245 neurosurgical participants performing episodic recall tasks, we find that the rate of hippocampal ripples rises just prior to the free recall of recently formed memories. This prerecall ripple effect (PRE) is stronger in the CA1 and CA3/dentate gyrus (CA3/DG) subfields of the hippocampus than the neighboring MTL regions entorhinal and parahippocampal cortex. PRE is also stronger prior to the retrieval of temporally and semantically clustered, as compared with unclustered, recalls, indicating the involvement of ripples in contextual reinstatement, which is a hallmark of episodic memory.

The CA3 and dentate gyrus (DG) regions of the hippocampus are considered key for disambiguating sensory inputs from similar experiences in memory, a process termed pattern separation. The neural mechanisms underlying pattern separation, however, have been difficult to compare across species: rodents offer robust recording methods with less human-centric tasks, while humans provide complex behavior with less recording potential. To overcome these limitations, we trained monkeys to perform a visual pattern separation task similar to those used in humans while recording activity from single CA3/DG neurons. We find that, when animals discriminate recently seen novel images from similar (lure) images, behavior indicative of pattern separation, CA3/DG neurons respond to lure images more like novel than repeat images. Using a population of these neurons, we are able to classify novel, lure, and repeat images from each other using this pattern of firing rates. Notably, one subpopulation of these neurons is more responsible for distinguishing lures and repeats—the key discrimination indicative of pattern separation.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery. While the contribution of sharp wave ripples in memory consolidation and decision-making is established in rodent models, our understanding of their role in human memory is incomplete. Here, the authors discuss common methodological challenges in detecting, analyzing, and reporting sharp wave ripples, then they suggest practical solutions to distinguish them from other high-frequency events

The ability to retrieve a single episode encountered just once is a hallmark of human intelligence and episodic memory[1]. Yet, decoding a specific memory from neuronal activity in the human brain remains a formidable challenge. Here, we develop a transformer neural network model[2, 3] trained on neuronal spikes from intracranial microelectrodes recorded during a single viewing of an audiovisual episode. Combining spikes throughout the brain via cross-channel attention[4], capable of discovering neural patterns spread across brain regions and timescales, individual participant models predict memory retrieval of specific concepts such as persons or places. Brain regions differentially contribute to memory decoding before and after sleep. Models trained using only medial temporal lobe (MTL) spikes significantly decode concepts before but not after sleep, while models trained using only frontal cortex (FC) spikes decode concepts after but not before sleep. These findings suggest a system-wide distribution of information across neural populations that transforms over wake/sleep cycles[5]. Such decoding of internally generated memories suggests a path towards brain-computer interfaces to treat episodic memory disorders through enhancement or muting of specific memories.

This project researched the possibility of photosynthetic life on Mars. Cyanobacteria were used as potential analogs and were subjected to various Martian-simulated conditions. Synechocystis sp. PCC 6803 was exposed to low pressure, ultraviolet radiation and Martian-simulated atmospheric composition, and proved resistant to the combination of these stresses. However, this organism could neither grow within Martian Regolith Simulant, owing to the lack of soluble nitrogen, nor could it grow in cold temperatures. As a result, later research focused on psychrotolerant cyanobacteria capable of utilizing atmospheric nitrogen. These Antarctic nitrogen-fixing strains were able to grow in Martian Regolith Simulant at temperatures as low as 4 °C. In addition, they proved resistant to salinity, ultraviolet radiation and freeze/thaw conditions. These results suggest that Antarctic nitrogen-fixing cyanobacteria are good analogs for potential Martian life and should be considered in future exploratory missions for life on the red planet.

Recent human electrophysiology work has uncovered the presence of high frequency oscillatory events, termed ripples, during awake behavior. This work focuses on ripples in the medial temporal lobe (MTL) during memory retrieval. Few studies, however, investigate ripples during item encoding. Many studies have found neural activity during encoding that predicts later recall, termed subsequent memory effects (SMEs), but it is unclear if encoding ripples also predict subsequent recall. Detecting ripples in 124 neurosurgical participants performing an episodic memory task, we do not find ripple SMEs in any MTL region, even as these regions exhibit robust high frequency activity (HFA) SMEs. Instead, hippocampal ripples increase during encoding of items leading to recall of temporally or semantically associated items, a phenomenon known as clustering. This subsequent clustering effect (SCE) arises specifically when hippocampal ripples occur during both encoding and retrieval, suggesting that ripples mediate the encoding and future reinstatement of episodic memories. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://memory.psych.upenn.edu/Publications

An integral feature of human memory is the ability to recall past events. What distinguishes such episodic memory from associative and semantic memories is the joint encoding and retrieval of \"what,\" \"where,\" and \"when\" (WWW) of events. Here, we investigated whether the WWW components of episodes are retrieved with equal fidelity. Using a novel task where human participants were probed on the WWW components of a recently-viewed synthetic movie, we found fundamental differences in mnemonic accuracy between these components. The memory of \"when\" had the lowest accuracy and was most severely influenced by primacy and recency. Further, the memory of \"when\" and \"where\" were most susceptible to interference due to changes in memory load. These findings suggest that episodes are not stored and retrieved as a coherent whole. Rather, memory components preserve a degree of independence, suggesting that remembering coherent episodes is an active reconstruction process.

Abstract The role of the hippocampus in recognition memory has long been a source of debate. Tasks used to study recognition that typically require an explicit probe, where the participant must make a response to prove they remember, yield mixed results on hippocampal involvement. Here, we tasked monkeys to freely view naturalistic videos, and only tested their memory via looking times for two separate novel v. repeat video conditions on each trial. Notably, a large proportion of hippocampal neurons differentiated these videos via changes in firing rates time-locked to the duration of their presentation on screen, and not during the delay period between them as would be expected for working memory. Single neurons often contributed to both retrieval conditions, and did so across many trials with trial-unique video content, suggesting they detect familiarity. The majority of neurons contributing to the classifier showed an enhancement in firing rate on repeat compared to novel videos, a pattern which has not previously been shown in hippocampus. These results suggest the hippocampus contributes to recognition memory via familiarity during free-viewing. Significance Statement Recognition memory enables distinction of new from previously encountered stimuli. In the majority of recognition memory work, humans or animals are tasked to explicitly identify whether a stimulus is old or new. In some of these studies—but for unknown reasons not others—there is evidence of hippocampal involvement. Here, when we present trial-unique, naturalistic videos to monkeys, firing rates from many single hippocampal neurons surprisingly differentiate new from repeated videos. The ability of these hippocampal neurons to detect recently-viewed stimuli, despite the videos’ unfamiliar content, suggests they contribute to memory. These results are consistent with hippocampal involvement in the familiarity aspect of recognition memory during free-viewing. Competing Interest Statement The authors have declared no competing interest. Footnotes * After many rounds of review, I am uploading the current version of the manuscript. The data and figures are largely unchanged, but the interpretation of the results has been modified.