Biology subjects

Maximov, A.

Publications and source records attributed to Maximov, A..

7 recordsLinked to original sources

bioRxiv2025

Artificial hibernation uncovers distinct synaptic engram architecture for memory retention

The memory trace at the neuronal and synaptic levels remains controversial. Stable, larger spines are thought to support memory, but the high turnover of dendritic spines and the drifting of neuronal representations following memory formation suggest alternative possibilities. To elucidate a structural trace underlying memory retention, we utilize a mouse model of artificial hibernation. During hibernation, hippocampal neurons exhibited a substantial reduction in their activity and an extensive elimination of dendritic spines and synapses. Despite these changes, their memory and associated hippocampal neuronal representations are intact after arousal. We find that a subset of spines is maintained during hibernation. These spatially clustered engram-engram synapses are exclusively protected from elimination and characterized by synaptic contacts with multi-synaptic boutons. These findings suggest that synaptic engram architecture, rather than larger spines per se, is resilient to network remodeling and underlies long-term memory retention.

neuroscience↗

bioRxiv2024

Synaptic architecture of a memory engram in the mouse hippocampus

Memory engrams are formed through experience-dependent remodeling of neural circuits, but their detailed architectures have remained unresolved. Using 3D electron microscopy, we performed nanoscale reconstructions of the hippocampal CA3-CA1 pathway following chemogenetic labeling of cellular ensembles with a remote history of correlated excitation during associative learning. Projection neurons involved in memory acquisition expanded their connectomes via multi-synaptic boutons without altering the numbers and spatial arrangements of individual axonal terminals and dendritic spines. This expansion was driven by presynaptic activity elicited by specific negative valence stimuli, regardless of the co-activation state of postsynaptic partners. The rewiring of initial ensembles representing an engram coincided with local, input-specific changes in the shapes and organelle composition of glutamatergic synapses, reflecting their weights and potential for further modifications. Our findings challenge the view that the connectivity among neuronal substrates of memory traces is governed by Hebbian mechanisms, and offer a structural basis for representational drifts.

neuroscience↗

bioRxiv2023

Phosphorylation of pyruvate dehydrogenase marks the inhibition of in vivo neuronal activity

For decades, the expression of immediate early genes (IEGs) such as c-fos has been the most widely used molecular marker representing neuronal activation. However, to date, there is no equivalent surrogate available for the decrease of neuronal activity (i.e., inhibition). Here, we developed an optogenetic-based biochemical screen in which population neural activities can be controlled by light with single action potential precision, followed by unbiased phosphoproteomic profiling. We identified that the phosphorylation of pyruvate dehydrogenase (pPDH) inversely correlated with the intensity of action potential firing in primary neurons. In in vivo mouse models, monoclonal antibody-based pPDH immunostaining detected neuronal inhibition across the brain induced by a wide range of factors including general anesthesia, sensory experiences, and natural behaviors. Thus, as an in vivo marker for neuronal inhibition, pPDH can be used together with IEGs or other cell-type markers to profile and identify bi-directional neural dynamics induced by experiences or behaviors.

neuroscience↗

bioRxiv2022

Nr4a1 regulates inhibitory circuit structure and function in the mouse brain.

Central neurons express unique repertoires of secreted and transmembrane proteins that define their synaptic connectivity. However, how these molecular programs are regulated remains poorly understood. Our study shows that, in inhibitory GABAergic interneurons in the mouse forebrain, transcription of synaptic organizer molecules is controlled by Nr4a1, a nuclear receptor whose expression is transiently induced by sensory experience and required for normal learning. Nr4a1 exserts opposite effects on local axonal wiring of Parvalbumin- and Somatostatin-positive interneurons that innervate different subcellular domains of their postsynaptic partners. Loss of Nr4a1 activity in these interneurons leads to cell-type-specific transcriptional switches in multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal a mechanism by which inducible transcription factors dynamically alter the combinatorial synaptic organizing codes for structural plasticity.

neuroscience↗

bioRxiv2020

Genetically targeted reporter imaging of deep neuronal network in the mammalian brain

Positron Emission Tomography (PET) allows biomolecular tracking, while PET monitoring of brain networks has been hampered by the lack of a suitable reporter. Here, we describe in vivo brain imaging that takes advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP. In mice, peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expressions. This technique is applicable to the visualization of neuronal ensemble activities elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET offers mapping of neuronal projections in non-human primate brains, indicating the availability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET assays of turnover and self-assembly of proteins tagged with ecDHFR mutants. Our findings may facilitate a broad spectrum of PET analyses of a mammalian brain circuit at molecular levels that were not previously applicable for technical reasons.

neuroscience↗

bioRxiv2019

Fear Learning Induces Long-Lasting Changes in Gene Expression and Pathway Specific Presynaptic Growth

The stabilization or consolidation of long-term memories lasting more than a few hours requires new gene expression. While neural activity has been shown to induce expression of a variety of genes within several hours of learning, whether this leads to persistent changes in gene expression that lasts for days or weeks remains unclear. We developed a novel mouse line which expresses Cre recombinase in an inducible manner and used it to examine gene expression in learning-activated neurons of the medial prefrontal cortex (mPFC) one month following contextual fear conditioning. The mPFC is not required for the initial retrieval of contextual memory but becomes necessary after one month, suggesting a slowly developing plasticity. We found a variety of changes in gene expression in learning-activated neural ensembles that were specific to the mPFC. One group of transcriptional changes observed was the coordinated upregulation of presynaptic proteins suggesting a potential learning-induced elaboration of presynaptic terminals. We tested this idea by labeling the projections of mPFC neurons active during initial learning and found an increase in the number of terminals in neurons projecting to the basolateral amygdala at 1 month following training. These results suggest a presynaptic growth mechanism that could account for the enhanced role of the mPFC in fear memory retrieval at long time points after learning.

neuroscience↗

bioRxiv2019

Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription.

The formation of new memories requires transcription. However, the mechanisms that limit signaling of relevant gene programs in space and time for precision of coding and the roles of these programs in specific aspects of information processing remain poorly understood. We found that, during learning, the cellular patterns of expression of early response genes (ERGs) are regulated by class IIa HDACs 4 and 5, transcriptional repressors that transiently enter neuronal nuclei from cytoplasm after sensory input. Mice lacking these repressors in the forebrain have abnormally broad experience-dependent expression of ERGs, altered synaptic architecture and function, elevated anxiety, and severely impaired memory. By acutely manipulating the nuclear activity of class IIa HDACs in behaving animals using a chemical-genetic technique, we further demonstrate that rapid induction of ERG programs is critical for memory acquisition but these programs may become dispensable when a stable memory is formed. These results provide new insights into the molecular basis of memory storage.

neuroscience↗