February 2025
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7 Reads
Current Opinion in Neurobiology
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February 2025
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7 Reads
Current Opinion in Neurobiology
January 2025
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13 Reads
Cell Reports
December 2024
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45 Reads
There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.
December 2024
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45 Reads
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2 Citations
The American Journal of Human Genetics
November 2024
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8 Reads
The ability to manipulate neurons involved in memory formation and retrieval is a key factor to understanding neuronal circuits involved in cognition. In this chapter, we provide methods to tag and/or allocate neurons to a fear conditioning engram in the hippocampus and manipulate these neurons using optogenetic and chemogenetic approaches. For tagging, we describe IEG-based methods (TRAP2 mice or the viral RAM system) to express transgenes, such as designer receptors exclusively activated by designer drugs (DREADDs) or channelrhodopsin in fear engram cells. For allocation, the excitability of neurons in the CA1 region may be transiently and reversibly heightened using opsins, and heightened excitability increases the chance of the neurons being integrated into the fear conditioning engram. Allocated/tagged neurons then can be subsequently activated or silenced during the memory test using optogenetic or chemogenetic transgenes leading to heightened or decreased freezing, respectively.
November 2024
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64 Reads
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5 Citations
Cell
November 2024
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60 Reads
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2 Citations
Episodic-like memory is a later-developing cognitive function supported by the hippocampus. In mice, the formation of extracellular perineuronal nets in subfield CA1 of the dorsal hippocampus controls the emergence of episodic-like memory during the fourth postnatal week (Ramsaran et al., 2023). Whether the timing of episodic like memory onset is hard-wired, or flexibly set by early life experiences during a critical or sensitive period for hippocampal maturation, is unknown. Here, we show that the trajectories for episodic-like memory development vary for mice given different sets of experiences spanning the second and third postnatal weeks. Specifically, episodic like memory precision developed later in mice that experienced early-life adversity, while it developed earlier in mice that experienced early-life enrichment. Moreover, we demonstrate that early-life experiences set the timing of episodic-like memory development by modulating the pace of perineuronal net formation in dorsal CA1. These results indicate that the hippocampus undergoes a sensitive period during which early-life experiences determine the timing for episodic-like memory development.
August 2024
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30 Reads
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1 Citation
Science Advances
Memories of events are linked to the contexts in which they were encoded. This contextual linking ensures enhanced access to those memories that are most relevant to the context at hand, including specific associations that were previously learned in that context. This principle, referred to as encoding specificity, predicts that context-specific neural states should bias retrieval of particular associations over others, potentially allowing for the disambiguation of retrieval cues that may have multiple associations or meanings. Using a context-odor paired associate learning paradigm in mice, here, we show that chemogenetic manipulation of dentate gyrus ensembles corresponding to specific contexts reinstates context-specific neural states in downstream CA1 and biases retrieval toward context-specific associations.
July 2024
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51 Reads
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5 Citations
Nature Neuroscience
Across systems, higher-order interactions between components govern emergent dynamics. Here we tested whether contextual threat memory retrieval in mice relies on higher-order interactions between dorsal CA1 hippocampal neurons requiring learning-induced dendritic spine plasticity. We compared population-level Ca2⁺ transients as wild-type mice (with intact learning-induced spine plasticity and memory) and amnestic mice (TgCRND8 mice with high levels of amyloid-β and deficits in learning-induced spine plasticity and memory) were tested for memory. Using machine-learning classifiers with different capacities to use input data with complex interactions, our findings indicate complex neuronal interactions in the memory representation of wild-type, but not amnestic, mice. Moreover, a peptide that partially restored learning-induced spine plasticity also restored the statistical complexity of the memory representation and memory behavior in Tg mice. These findings provide a previously missing bridge between levels of analysis in memory research, linking receptors, spines, higher-order neuronal dynamics and behavior.
June 2024
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37 Reads
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2 Citations
Memories are thought to be stored within sparse collections of neurons known as engram ensembles. Neurons active during a training episode are allocated to an engram ensemble (‘engram neurons’). Memory retrieval is initiated by external sensory or internal cues present at the time of training reactivating engram neurons. Interestingly, optogenetic reactivation of engram ensemble neurons alone in the absence of external sensory cues is sufficient to induce behaviour consistent with memory retrieval in mice. However, there may exist differences between the behaviours induced by natural retrieval cues or artificial engram reactivation. Here, we compared two defensive behaviours (freezing and the syllable structure of ultrasonic vocalizations, USVs) induced by sensory cues present at training (natural memory retrieval) and optogenetic engram ensemble reactivation (artificial memory retrieval) in a threat conditioning paradigm in the same mice. During natural memory recall, we observed a strong positive correlation between freezing levels and distinct USV syllable features (characterized by an unsupervised algorithm, MUPET (Mouse Ultrasonic Profile ExTraction)). Moreover, we observed strikingly similar behavioural profiles in terms of freezing and USV characteristics between natural memory recall and artificial memory recall in the absence of sensory retrieval cues. Although our analysis focused on two behavioural measures of threat memory (freezing and USV characteristics), these results underscore the similarities between threat memory recall triggered naturally and through optogenetic reactivation of engram ensembles. This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
... ; https://doi.org/10.1101/2025.01.09.632151 doi: bioRxiv preprint and gain a deeper understanding of plasticity mechanisms that mediate different stages of memory encoding. More broadly, defining the synaptic and structural plasticity mechanisms behind engram formation and function is key to understanding how the brain computes information to adapt to changing environments 95 and could also provide insight into the molecular changes to engram synapses associated with development, aging, stress, trauma, and models of neuropsychiatric and neurodegenerative disorders [96][97][98][99][100][101][102][103][104][105][106] . (208395/Z/17/Z). ...
November 2024
Cell
... In the hippocampus, the CA1 and CA3 regions strongly contribute to memory encoding and consolidation. 24,25 During SWS in particular, CA3 pyramidal neurons are spontaneously activated in synchronous bursts that trigger massive activation of CA1 pyramidal cells, promoting the strength of connections between clusters and ultimately completing the consolidation of memories. Moreover, hippocampal levels of the memory-associated transcription factors CREB and cAMP are elevated during REM sleep. ...
July 2024
Nature Neuroscience
... This could resolve specific changes at engram synapses relating to different phases of memory encoding, such as recall, consolidation and storage, and relating to different brain regions 5,21,80,89 . Moreover, the combination of our workflow with both natural or artificial optogenetic memory recalls could enable the comparison of engram synapses between active and inactive memory circuits [90][91][92][93] . ...
June 2024
... A host of experimental evidence supports the hypothesis that synaptic plasticity is 9 essential for memory storage. However, some recent results indicate that also 10 non-synaptic plasticity such as the regulation of neuronal membrane properties 11 contributes to the creation of memory engrams [4][5][6][7][8]. In fact, there has been some 12 scepticism about the role of synaptic plasticity in memory formation [6,9,10]. ...
September 2020
... Mice underwent a single fear conditioning training session similar to other reports [37][38][39]. The session consisted of seven pairings of tones and foot shocks. ...
March 2024
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
... Since relative excitability has been shown to be a major determinant of neuronal allocation to a coding ensemble in the DG 88 , as well as in the CA1 region and amygdala 89,90 , cells that are most affected by adversity in the epigenetically and transcriptionally heterogenous population of MIA vDGCs may have increased excitability. However, expression of FOS and other IEGs was comparable in MIA and CON FOS+ cells (e.g., were not DEGs) suggesting no apparent difference in neuronal activity between the MIA and CON FOS+ DGC populations. ...
March 2024
Neuron
... 97 This gene is part of a complex on chromosome Xp22.11, which also encompasses DDX53, placing this locus among the most prevalent and impactful genetic factors for ASD (see the related paper 98 in this issue of The American Journal of Human Genetics) and other neurodevelopmental disorders. In fact, a recent XWAS focusing on Alzheimer disease 81 also detected a variant (rs12006935, chrX:22857207) located within the locus on PTCHD1-AS (chrX:22835975-22875494). ...
December 2023
... Recent technological advancements, including FLiCRE technology (but see also references for Cal-Light and FLARE [26][27][28][29], have paved the way for differentiating between and tagging cell populations with higher temporal resolution. This was unachievable with drug-and IEG-based engram tagging, considering that both the timing of drug delivery and that of IEG-derived protein production occur at a larger time scale than the acquisition window and that the expression of IEGs changes across brain regions, tasks, and moments 8,30,31 . ...
December 2023
Cell Reports
... Running wheels were placed in the home cage 1-2 d after training. Mice voluntarily ran on the wheels as described previously [14,17,34]. Running wheels remained in the cage until the day before testing began (~28 d). ...
October 2023
... encode extracellular matrix (ECM) proteins that are components of perineuronal nets (PNNs) [112,113]. Ramsaran et al. [114]. reported that Hapln1 mediates the functional maturation of hippocampal parvalbumin interneurons through assembly of PNNs; this mechanism mediates the development of memory precision during early childhood. ...
May 2023
Science