Biology subjects

Frankland, P.

Publications and source records attributed to Frankland, P..

10 recordsLinked to original sources

bioRxiv2026

Latent dentate gyrus engrams formed in infancy scaffold adult learning

Infantile amnesia refers to the loss of event-based memories acquired early in life. In mice, however, these memories are not erased; selective optogenetic stimulation of engrams formed in infancy leads to memory recovery in adulthood, indicating that infant-formed engrams can persist in a latent form. We therefore asked whether these latent engrams, although not accessible through natural retrieval, nonetheless influence related adult learning. Using a contextual fear conditioning paradigm, we find that adult learning is facilitated by prior experience in infancy, both for the same and related contexts. Activity-dependent engram tagging revealed that adult learning reactivates infant-acquired dentate gyrus ensembles, and selective inactivation of these ensembles during adulthood abolished this facilitation. These findings indicate that memories formed in infancy persist as latent engrams that scaffold subsequent learning, consistent with a role in establishing schema-like representations.

neuroscience↗

bioRxiv2026

Distinct CA1 inputs support shifts in neural dimensionality and memory resolution

Event-based memories may be encoded with high (e.g., episodic) or low (e.g., gist) mnemonic resolution. While the CA1 region of the hippocampus encodes events at both scales, it is unclear how such dual coding emerges. Consistent with theoretical predictions1,2, here we show that trisynaptic (from CA3) and monosynaptic (from the medial entorhinal cortex) projections to CA1 encode high- and low-resolution event-based memories, respectively. Recruitment of the trisynaptic pathway during contextual fear conditioning promotes feedforward inhibition of CA1 via activation of parvalbumin-positive (PV+) interneurons. This allows sparse encoding of event-based memories in high-dimensional neural states that support high-resolution contextual fear memories, where mice exhibit conditioned fear only in the training context and not similar contexts. Inhibiting this input during training reduces activation of CA1 PV+ interneurons and feedforward inhibition, shifting neural dynamics to low-dimensional states that support low-resolution contextual fear memories where mice freeze in the training context and similar contexts. These experiments identify a circuit-based mechanism that causally links the dimensionality of CA1 neural dynamics to mnemonic resolution.

neuroscience↗

bioRxiv2025

Neurogenesis-dependent transformation of hippocampal memory traces during systems consolidation

Memories for events (i.e., episodic memories) change qualitatively with time. Systems consolidation theories posit that organizational changes accompany qualitative shifts in memory resolution, but differ as to the locus of this reorganization. Whereas some theories favor inter-regional changes in organization (e.g., hippocampus[->]cortex; multiple trace theory), others favor intra-regional reorganization (e.g., within-hippocampus; trace transformation theory). Using an engram tagging and manipulation approach in mice, here we provide evidence that intra-regional changes in organization underlie shifts in memory resolution. We establish that contextual fear memories lose resolution as a function of time, with mice exhibiting conditioned freezing in both the training apparatus (context A) and a second apparatus (context B) at more remote delays (freezingA {equiv} freezingB at remote delay). By tagging either hippocampal (dentate gyrus) or cortical (prelimbic cortex) neuronal ensembles in context A, and then pairing their optogenetic activation with shock (in context C), we monitored the resolution of these artificially-generated memories at recent versus remote post-conditioning delays by testing mice in contexts A and B. Hippocampal engrams for a fear conditioning event were initially high-resolution (recent delay: freezingA >> freezingB) but lost resolution with time (remote delay: freezingA {equiv} freezingB). In contrast, cortical engrams were initially low-resolution and remained low-resolution over time (recent and remote delay: freezingA {equiv} freezingB). Transformation of hippocampal engrams was dependent on adult hippocampal neurogenesis. Eliminating hippocampal neurogenesis arrested hippocampal engrams in a recent-like, high-resolution state where mice continued to exhibit discriminative freezing at remote delays. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/658072v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1aec109org.highwire.dtl.DTLVardef@36e20org.highwire.dtl.DTLVardef@1332e46org.highwire.dtl.DTLVardef@123215d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Assigning Targetable Molecular Pathways to Transdiagnostic Subgroups Across Autism and Related Neurodevelopmental Disorders

The heterogeneity of autism and related neurodevelopmental conditions has impeded accurate prognoses and treatment discovery. Using translational neuroimaging across 135 mouse models (3,515 mice) and two human MRI datasets (n = 1,234 and n = 1,015), we derived participant subgroups from shared neuroanatomical features. These subgroups did not distinguish autism, ADHD, or OCD diagnoses and only modestly differentiated cognitive and behavioural phenotypes. Instead, they mapped onto four molecular pathways: (1) synaptic function; (2) MAPK and Wnt signalling; (3) chromatin modification and cellular stress responses; and (4) broader chromatin, immune, and second-messenger signalling pathways. This framework bridges preclinical models and idiopathic human neurodevelopmental conditions, linking patients to biologically relevant molecular mechanisms.

neuroscience↗

bioRxiv2024

PTCHD1 interacts with the SNARE-associated protein SNAPIN in vitro via its first exoplasmic loop

BackgroundPatched domain-containing 1 (PTCHD1) is a susceptibility gene for autism spectrum disorder and intellectual disability. Its function in brain development and neurotransmission remains elusive. Studies have sought to characterize PTCHD1 function by elucidating its neural network of interacting proteins. However, given the current paucity of functional information, many PTCHD1 missense variants in clinical databases are classified as variants of uncertain significance (VUSs), severely limiting the healthcare resources available to patients and families. MethodsA yeast two-hybrid assay was used to identify synaptic PTCHD1-interacting proteins. Candidate binding partners were validated by cloning; transient over-expression in HEK293T cells, followed by co-immunoprecipitation and immunoblotting; and immunocytochemistry in differentiated P19 cells. To evaluate the pathogenicity of clinical missense variants, site-directed mutagenesis was employed, followed by transient over-expression and immunocytochemistry in non-neuronal (HEK293T) and neuronal (Neuro-2A cells) systems. ResultsA novel interaction was identified between the first lumenal loop of PTCHD1 and the SNARE-associated protein SNAPIN, which is implicated in synaptic vesicle exocytosis. Clinically associated missense variants within this region did not disrupt SNAPIN binding, indicating that the pathoetiology of these variants is unrelated to this interaction. However, six of the 12 missense variants tested exhibited pronounced retention within the endoplasmic reticulum, and impaired neuronal and non-neuronal trafficking to the plasma membrane. ConclusionsThese data yield insights regarding the role of PTCHD1 in neurodevelopment and neurotransmission, and suggest a neuropathological mechanism for missense variants. These findings provide a platform for diagnostic assay and VUS interpretation, allowing for clinical re-classification of these variants.

molecular biology↗

bioRxiv2023

Neurogenesis-mediated circuit remodeling reduces engram reinstatement and promotes forgetting

Post-training increases in hippocampal neurogenesis are associated with forgetting of hippocampus-dependent memories in adult mice. This form of forgetting might be due to increased numbers of new neurons, remodeling of hippocampal circuitry or some combination of both. Here we tested the hypothesis that neurogenesis-mediated forgetting is caused by remodeling of hippocampal circuits by engineering mice in which adult-generated granule cells hypo- or hyper-integrate into hippocampal circuits. Using gene deletion, opto- and chemogenetic strategies, we find that hypo-integration of newborn neurons prevents post- training exercise-induced forgetting of contextual fear memories. Conversely, inducing hyper- integration of newborn neurons following contextual fear conditioning is sufficient to produce forgetting. Because these interventions did not affect survival of newborn neurons, these findings suggest that neurogenesis-mediated remodeling of hippocampal circuits represents a continuous and active form of interference that alters accessibility of engrams underlying hippocampal memories. Consistent with this, using engram-labeling approaches, we found that exercise-induced forgetting was associated with reduced engram reactivation.

neuroscience↗

bioRxiv2022

Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability

PTCHD1 has been implicated in Autism Spectrum Disorders (ASD) and/or intellectual disability, where copy number variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of PTCHD1 have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization and regulation of the PTCHD1 protein are currently unknown. This paucity of data concerning PTCHD1 prevents the effective evaluation of sequence variants identified during diagnostic screening. Here, we characterize PTCHD1 protein binding partners, extending previously reported interactions with postsynaptic scaffolding protein, SAP102. Six rare missense variants of PTCHD1 were also identified from patients with neurodevelopmental disorders. After modelling these variants on a hypothetical three-dimensional structure of PTCHD1, based on the solved structure of NPC1, PTCHD1 variants harboring these mutations were assessed for protein stability, post-translational processing and protein trafficking. We show here that wild-type PTCHD1 post-translational modification includes complex N-glycosylation and that specific mutant proteins disrupt normal N-link glycosylation processing. However, regardless of their processing, these mutants still localized to PSD95-containing dendritic processes and remained competent for complexing SAP102.

molecular biology↗

bioRxiv2022

Alcohol dependence modifies brain networks activated during abstinence and reaccess: a c-fos-based analysis in mice

High-level alcohol consumption causes neuroplastic changes in the brain that lead to negative affective and somatic symptoms when alcohol is withdrawn, promoting relapse drinking. We have some understanding of these plastic changes in defined brain circuits and cell types, but unbiased approaches are needed to explore broader patterns of adaptations. Here, we employed whole-brain c-fos mapping and network analysis to assess how brain-wide patterns of neuronal activity are altered during acute alcohol abstinence and reaccess in a well-characterized model of alcohol dependence. Mice underwent four cycles of chronic intermittent ethanol vapor exposure (CIE) with alternating weeks of voluntary alcohol drinking, and a subset of mice underwent forced swim stress (FSS) prior to drinking sessions to further escalate alcohol consumption. After four CIE cycles, brains were collected from mice in each group either 24 hours (abstinence) or immediately following a one-hour period of alcohol reaccess. Brains from CIE mice during acute abstinence displayed widespread neuronal activation relative to those from AIR mice, independent of FSS, and this increase in c-fos was reversed by reaccess drinking. For network analysis, mice were then classified as high or low drinkers (HD or LD). We computed Pearson correlations for all pairs of brain regions and used graph theoretical methods to identify changes in network properties associated with high-drinking behavior. Network modularity, a measure of network segregation into communities, was increased in HD mice after alcohol reaccess relative to abstinence. Within-community strength and diversity measures were computed for each region and condition, and highly coactive regions were identified. One high-diversity region, the cortical amygdala (COA), was further interrogated using a chemogenetic approach. COA silencing in CIE mice reduced voluntary drinking, validating our network analysis and indicating that this region may play an important but underappreciated role in alcohol dependence.

neuroscience↗

bioRxiv2021

Learning to be on time: temporal coordination of neural dynamics by activity-dependent myelination

Activity-dependent myelination is the mechanism by which myelin changes as a function of neural activity, and plays a fundamental role in brain plasticity. Mediated by structural changes in glia, activity-dependent myelination regulates axonal conduction velocity. It remains unclear how neural activity impacts myelination to orchestrate the timing of neural signaling. We developed a model of spiking neurons enhanced with neuron-glia feedback. Inspired by experimental data and use-dependent synaptic plasticity, we introduced a learning rule, called the Activity-Dependent Myelination (ADM) rule, by which conduction velocity scales with firing rates. We found that the ADM rule implements a homeostatic control mechanism that promotes and preserves synchronization. ADM-mediated plasticity was found to optimize synchrony by compensating for variability in axonal lengths by scaling conduction velocity in an axon-specific way. This property was maintained even when the network structure is altered. We further explored how external stimuli interact with the ADM rule to trigger bidirectional and reversible changes in conduction delays. These results highlight the role played by activity-dependent myelination in synchronous neural communication and brain plasticity.

neuroscience↗

bioRxiv2018

Genetic and behavioural requirements for structural brain plasticity

1Human MRI studies show that experience can lead to changes in the volume of task-specific brain regions; however, the behavioural and molecular processes driving these changes remain poorly understood. Here, we used in-vivo mouse MRI and RNA sequencing to investigate the neuroanatomical and transcriptional changes induced by environmental enrichment, exercise, and social interaction. Additionally, we asked whether the volume changes require CREB, a transcription factor critical for memory formation and neuronal plasticity. Enrichment rapidly increased cortical and hippocampal volume, and these effects were not attributable to exercise or social interaction. Instead, they likely arise from learning and sensorimotor experience. Nevertheless, the volume changes were not attenuated in mice with memory impairments caused by loss of CREB, indicating that these effects are driven by processes distinct from this canonical learning and memory pathway. Finally, within brain regions that underwent volume changes, enrichment increased the expression of genes associated with axonogenesis, dendritic spine development, synapse structural plasticity, and neurogenesis, suggesting these processes underlie the volume changes detected with MRI.

neuroscience↗