Pathology and Anticatalytic Treatment of Exacerbated COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated inflammasome diseases. Moreover, its pathophysiology involves the angiotensin-converting enzyme 2 (ACE2) receptor, Toll-like receptor 4 (TLR4) pathway, neuropilin‑1 pathway, inflammasome activation pathway, sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization pathway, cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, spike protein/inflammasome-genetic pathway, and immunological memory engram pathway. Therefore, it is necessary to prescribe anticatalytic treatments to alleviate the SARS-CoV-2 inflammasome, immunologic engram, and spike protein levels.

Synaptic and mitochondrial plasticity associated with fear memory revealed by deep learning-based 3D reconstruction

Reconstruction of serial section electron microscopy (ssEM) data greatly facilitates neuroscience research, but such reconstruction is computationally expensive. Informative data about physiological functions can in theory be obtained from ssEM datasets by extracting distinct cellular structures without large-scale reconstruction, but an efficient method is needed to accomplish this. Here, we developed a Region-CNN (R-CNN) based deep learning method to identify, segment, and reconstruct synapses and mitochondria from ssEM data. We applied this method to explore the changes in synaptic and mitochondrial configuration in the auditory cortex of mice subjected to auditory fear conditioning. Upon reconstructing over 135,000 mitochondria and 160,000 synapses, we found that fear conditioning significantly increases the number while decreasing the size of mitochondria, and also noted that it promoted the formation of multi-contact synapses comprising a single axonal bouton and multiple postsynaptic sites from different dendrites. Combinatorial modeling indicated that such multi-dendritic synapses increased information storage capacity of new synapses by over 50%, representing a synaptic memory engram. Our method achieved high accuracy and speed in synapse and mitochondrion extraction, and its application revealed structural and functional insights about cellular engrams associated with fear conditioning.

The Mechanisms and Boundary Conditions of Drug Memory Reconsolidation

Drug addiction can be seen as a disorder of maladaptive learning characterized by relapse. Therefore, disrupting drug-related memories could be an approach to improving therapies for addiction. Pioneering studies over the last two decades have revealed that consolidated memories are not static, but can be reconsolidated after retrieval, thereby providing candidate pathways for the treatment of addiction. The limbic–corticostriatal system is known to play a vital role in encoding the drug memory engram. Specific structures within this system contribute differently to the process of memory reconsolidation, making it a potential target for preventing relapse. In addition, as molecular processes are also active during memory reconsolidation, amnestic agents can be used to attenuate drug memory. In this review, we focus primarily on the brain structures involved in storing the drug memory engram, as well as the molecular processes involved in drug memory reconsolidation. Notably, we describe reports regarding boundary conditions constraining the therapeutic potential of memory reconsolidation. Furthermore, we discuss the principles that could be employed to modify stored memories. Finally, we emphasize the challenge of reconsolidation-based strategies, but end with an optimistic view on the development of reconsolidation theory for drug relapse prevention.

Roles and Transcriptional Responses of Inhibitory Neurons in Learning and Memory

Increasing evidence supports a model whereby memories are encoded by sparse ensembles of neurons called engrams, activated during memory encoding and reactivated upon recall. An engram consists of a network of cells that undergo long-lasting modifications of their transcriptional programs and connectivity. Ground-breaking advancements in this field have been made possible by the creative exploitation of the characteristic transcriptional responses of neurons to activity, allowing both engram labeling and manipulation. Nevertheless, numerous aspects of engram cell-type composition and function remain to be addressed. As recent transcriptomic studies have revealed, memory encoding induces persistent transcriptional and functional changes in a plethora of neuronal subtypes and non-neuronal cells, including glutamatergic excitatory neurons, GABAergic inhibitory neurons, and glia cells. Dissecting the contribution of these different cellular classes to memory engram formation and activity is quite a challenging yet essential endeavor. In this review, we focus on the role played by the GABAergic inhibitory component of the engram through two complementary lenses. On one hand, we report on available physiological evidence addressing the involvement of inhibitory neurons to different stages of memory formation, consolidation, storage and recall. On the other, we capitalize on a growing number of transcriptomic studies that profile the transcriptional response of inhibitory neurons to activity, revealing important clues on their potential involvement in learning and memory processes. The picture that emerges suggests that inhibitory neurons are an essential component of the engram, likely involved in engram allocation, in tuning engram excitation and in storing the memory trace.

Restoring persistent accessibility to memories after sleep deprivation-induced amnesia

It is well established that sleep deprivation after learning impairs hippocampal memory processes and causes amnesia. It is unknown, however, whether it leads to the actual loss of information or merely suppresses the retrievability of this information stored under suboptimal conditions. Here, we reveal that hippocampal memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training using optogenetic memory engram activation or treatment with the clinically-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, when optogenetic memory engram activation and roflumilast treatment were combined two days following training and subsequent sleep deprivation, it resulted in a more persistent memory trace that allowed for natural (i.e., manipulation free) retrieval several days later. Our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss, but instead leads to the suboptimal storage of information that is difficult to retrieve. We also provide proof of principle that these suboptimally stored memories can be made accessible again far beyond the learning episode and that the clinically-approved PDE4 inhibitor roflumilast may be used to successfully retrieve information thought to be lost.

Basal forebrain cholinergic neurons are part of the threat memory engram

Although the engagement of cholinergic signaling in threat memory is well established (Knox, 2016a), our finding that specific cholinergic neurons are requisite partners in a threat memory engram is likely to surprise many. Neurons of the basal forebrain nucleus basalis and substantia innonimata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA), whose activation are required for both the acquisition and retrieval of cued threat memory and innate threat response behavior. The retrieval of threat memory by the presentation of the conditioning tone alone elicits acetylcholine (ACh) release in the BLA and the BLA-projecting cholinergic neurons manifest immediate early gene responses and display increased intrinsic excitability for 2-5 hours following the cue-elicited memory response to the conditioned stimulus. Silencing cue-associated engram-enrolled cholinergic neurons prevents the expression of the defensive response and the subset of cholinergic neurons activated by cue is distinct from those engaged by innate threat. Taken together we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli via the BLA, demonstrating exquisite, functionally refined organization of specific types of memory within the cholinergic basal forebrain.

The Quest for the Hippocampal Memory Engram: From Theories to Experimental Evidence

More than a century after Richard Semon's theoretical proposal of the memory engram, technological advancements have finally enabled experimental access to engram cells and their functional contents. In this review, we summarize theories and their experimental support regarding hippocampal memory engram formation and function. Specifically, we discuss recent advances in the engram field which help to reconcile two main theories for how the hippocampus supports memory formation: The Memory Indexing and Cognitive Map theories. We also highlight the latest evidence for engram allocation mechanisms through which memories can be linked or separately encoded. Finally, we identify unanswered questions for future investigations, through which a more comprehensive understanding of memory formation and retrieval may be achieved.