Paul W. Frankland’s research while affiliated with SickKids and other places

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Publications (263)


Neurobiological mechanisms of forgetting across timescales
  • Literature Review

February 2025

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7 Reads

Current Opinion in Neurobiology

Mitchell L. de Snoo

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Paul W. Frankland


Figure 5. Ptchd1-as disruption impacts synaptic plasticity in the adult striatum. a) LTD, 759
An X-linked long non-coding RNA, PTCHD1-AS, regulates autistic behaviors in humans and in mice
  • Preprint
  • File available

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.

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Tagging and Manipulation of Fear Engrams

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.



A sensitive period for the development of episodic-like memory in mice

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.


Fig. 1. Disambiguation of cue associations depends on DG context ensembles. (A) Context-odor paired associate task. Mice (N = 8) were trained concurrently in two spatial contexts. in context 1, digging in peppermint-scented bedding was reinforced, whereas in context 2, digging in carvone-scented bedding was reinforced. (B) Performance improved over training days [shading represents 95% confidence interval (Ci)]. (C) Percent time spent digging and (D) discrimination score in probe test after training (box represents 95% Ci; dashed line represents chance performance). (E) left: AAv-RAM-hM4di was microinjected into the dG. Middle: Removal of doxycycline (dOX) permitted hM4di tagging of dG neuronal ensemble active during pre-exposure to one of the to-be-discriminated contexts. After training, mice (N = 8) were probed in a tagged context after either vehicle (veh) or C21 treatment. Right: hM4di-expressing (red) neurons in dG [blue = 4′,6-diamidino-2-phenylindole (dAPi)]. Scale bar, 500 μm. (F) Performance improved across training (shading represents 95% Ci). (G) Percent time spent digging and (H) discrimination score in probe test after training (box represents 95% Ci; dashed line represents chance performance). *P < 0.05 (group comparison); # P < 0.05 (comparison to zero).
Fig. 2. Activation of dentate gyrus context ensembles reinstates context-specific memory retrieval. (A) AAv-RAM-hM3dq was microinjected into dG. (B) left: Removal of dOX permitted hM3dq tagging of dG neuronal ensemble active during pre-exposure to one of the to-be-discriminated contexts. After training, memory was probed in a novel context or the non-tagged context after either veh or C21 treatment. Right: hM3dq-expressing (red) neurons in the dentate gyrus (blue = dAPi). Scale bar, 500 μm. (C) Performance improved across training (shading represents 95% Ci) (N = 8). (D) Percent time spent digging and (E) discrimination score in probe test in the novel context. (F) Percent time spent digging and (G) discrimination score in probe test in the non-tagged context (box represents 95% Ci; dashed line represents chance performance). *P < 0.05 (group comparison); # P < 0.05 (comparison to zero).
Fig. 3. Experience-dependent plasticity of CA1 contextual representations. (A and B) AAv-RAM-hM3dq was microinjected into dG in thy1-GCaMP6f mice, and a miniature microscope was implanted above CA1. dOX removal permitted hM3dq tagging of dG neuronal ensembles active during context pre-exposure. After training, memory was probed in novel and non-tagged contexts after either veh or C21 treatment. (C) the dotted lines indicate a miniature microscope lens implanted above CA1 (blue = dAPi; green = GCaMP6f + cells). Scale bar, 500 μm. (D) example of CA1 imaging field across sessions. Randomly selected cells are colored by cell identity, and their corresponding denoised fluorescence traces are plotted below. (E) Performance improved across training (shading represents 95% Ci) (N = 6). (F and G) After training, memory was probed in novel (F) and non-tagged (G) contexts. in both contexts, C21 treatment increased digging time in the well which was reinforced in the tagged context during training. (H) CA1 population activity structure across training revealed by dimensionality reduction (trajectories plotted on a reduced set of dimensions using laplacian eigenmaps). (I) For each training day, the average cosine distance was computed between Pvs of trials within the same context (D within ) and between Pvs of trials in different contexts (D between ). Pv distance between contexts increased relative to distance within a context across training (blue = actual). Gray lines indicate distance ratios with randomized context ids (shuffle) (N = 6 mice). (J) latent-space distance between Pvs from different contexts increased with training. For each training day, Pvs were projected to a five-dimensional space using principal components analysis, and the distance between the five-dimensional distributions for each context was calculated (blue = actual). Gray lines and dots indicate chance level distances calculated by randomizing Pv context identity (shuffle) (N = 6 mice). a.u., arbitrary unit; n.s. not significant. *P < 0.05, **P < 0.01, and ***P < 0.001.
Fig. 4. Activation of DG context ensemble does not reinstate long-time scale population activity features of CA1 context-specific neural states. (A and B) For each context and training day, Pvs of average activity were calculated. Blue dots indicate the average similarity between a given day's Pv and the day 10 Pv from the same context. Gray dots signify the similarity between a given day's Pv and the day 10 Pv from the different contexts (n = 217 to 280 cells per session, N = 6 mice). (C and D) dG ensemble activation does not shift the population of active cells to a tagged context-like state in either (C) novel (n = 202 to 278 cells per session, N = 6 mice) or (d) nontagged (n = 162 to 251 cells per session, N = 6 mice) contexts. Pvs of average activity were calculated for all veh and C21 trials, and their correlation to training day 10 Pvs from the tagged (blue) and non-tagged (gray) contexts was calculated. (E and F) For each context and training day, a pairwise normalized correlation matrix (nCM) was computed (see Materials and Methods). dots indicate average similarity between a given day's nCM and the day 10 nCM from the same context (blue) or opposite context (gray) (n = 217 to 280 cells per session, N = 6 mice). (G and H) dG activation does not change the pattern of average pairwise functional connectivity in either (G) novel (n = 202 to 278 cells per session, N = 6 mice) or (h) non-tagged context (n = 162 to 251 cells per session, N = 6 mice). nCMs of average pairwise correlation were calculated for all veh and C21 trials, and their correlation to training day 10 nCMs from the tagged (blue) and non-tagged (gray) contexts was calculated. # P < 0.06, *P < 0.05, **P < 0.01, and ***P < 0.001.
Dentate gyrus ensembles gate context-dependent neural states and memory retrieval

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.


Higher-order interactions between hippocampal CA1 neurons are disrupted in amnestic mice

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.


Comparing behaviours induced by natural memory retrieval and optogenetic reactivation of an engram ensemble in mice

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’.


Citations (67)


... ; 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). ...

Reference:

Memory engram synapse 3D molecular architecture visualized by cryoCLEM-guided cryoET
Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice
  • Citing Article
  • 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. ...

Higher-order interactions between hippocampal CA1 neurons are disrupted in amnestic mice

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] . ...

Comparing behaviours induced by natural memory retrieval and optogenetic reactivation of an engram ensemble in mice

... 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]. ...

Neuronal Excitability in Memory Allocation: Mechanisms and Consequences
  • Citing Chapter
  • 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. ...

Reactivation of encoding ensembles in the prelimbic cortex supports temporal associations

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. ...

Excitability mediates allocation of pre-configured ensembles to a hippocampal engram supporting contextual conditioned threat in mice
  • Citing Article
  • 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). ...

Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus

... 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 . ...

Examining memory linking and generalization using scFLARE2, a temporally precise neuronal activity tagging system

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). ...

Neurogenesis-mediated circuit remodeling reduces engram reinstatement and promotes forgetting

... 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. ...

A shift in the mechanisms controlling hippocampal engram formation during brain maturation
  • Citing Article
  • May 2023

Science