Biology subjects

Ryan, T. J.

Publications and source records attributed to Ryan, T. J..

10 recordsLinked to original sources

bioRxiv2026

Infantile amnesia results from differential memory retrieval in humans

Infantile amnesia, the inability to recall memories from our earliest years, is the most common form of forgetting in mammals. Whether early memories never form, decay, or persist but become inaccessible remains unknown. Here, we investigated the nature of forgetting during the infantile amnesia period by longitudinally testing toddlers aged 18-24 months across the complete memory cycle from encoding, initial retrieval one day later, and delayed retrieval up to six months later, in a novel naturalistic episodic memory paradigm. Computational modelling revealed that forgetting during the infantile amnesia period was heterogeneous. Toddlers were as likely to retain the full memory as to lose it completely, while nearly a quarter retained only part of the memory. Encoding accuracy predicted which toddlers retained the full memory at the test one day later, but not at the delayed test up to six months on. Instead, a retrieval-specific EEG signature predicted complete, but not partial, memory retrieval, distinguishing which toddlers had retained the full memory before their behavioural response. Finally, leveraging the COVID-19 pandemic as a natural experiment, we found that maternal immune activation during pregnancy, as in rodents, alters vulnerability to infantile forgetting in humans. Together, these findings show that early memories formed during the infantile amnesia period are not simply erased but persist in an increasingly inaccessible form, a transformation whose trajectory can be shaped by both the neural retrieval mechanism and the prenatal environment.

neuroscience↗

bioRxiv2025

Microglial plasticity across development mediates infantile amnesia

Infantile amnesia, the inability to recall episodic memories formed during early childhood, is a hallmark of postnatal brain development. Yet the underlying mechanisms remain poorly understood. This work aimed to gain a better mechanistic understanding of infantile amnesia. Microglia, specialized macrophages of the central nervous system, are known to play an important role in synaptic refinement during postnatal development and have recently been implicated in memory related functions. Here, we identified microglia as key regulators of memory accessibility in infancy. We profiled dynamic changes in microglial morphology across the postnatal window that parallelled the onset of infantile forgetting. We found that pharmacological inhibition of microglial activity during a specific postnatal window prevents infantile amnesia for a contextual fear memory, implicating microglia as active modulators of infant memory persistence. Using activity-dependent tagging of infant encoded engram cells, we demonstrated that microglial inhibition alters engram size and engram reactivation in the amygdala and results in changes in microglia-engram cell interactions. Furthermore, we characterized a relationship between microglial dysfunction and the lack of infantile amnesia in maternal immune activation offspring. Together, these findings reveal a novel role for microglia in regulating infant memory retrieval and suggest that microglial dysfunction may contribute to altered memory trajectories in neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Memory engram synapse 3D molecular architecture visualized by cryoCLEM-guided cryoET

Memory is incorporated into the brain as physicochemical changes to engram cells. These are neuronal populations that form complex neuroanatomical circuits, are modified by experiences to store information, and allow for memory recall. At the molecular level, learning modifies synaptic communication to rewire engram circuits, a mechanism known as synaptic plasticity. However, despite its functional role on memory formation, the 3D molecular architecture of synapses within engram circuits is unknown. Here, we demonstrate the use of engram labelling technology and cryogenic correlated light and electron microscopy (cryoCLEM)-guided cryogenic electron tomography (cryoET) to visualize the in-tissue 3D molecular architecture of engram synapses of a contextual fear memory within the CA1 region of the mouse hippocampus. Engram cells exhibited structural diversity of macromolecular constituents and organelles in both pre- and postsynaptic compartments and within the synaptic cleft, including in clusters of membrane proteins, synaptic vesicle occupancy, and F-actin copy number. This engram to tomogram approach, harnessing in vivo functional neuroscience and structural biology, provides a methodological framework for testing fundamental molecular plasticity mechanisms within engram circuits during memory encoding, storage and recall.

neuroscience↗

bioRxiv2025

Learning-induced plasticity decreases cortical engram cell dendritic excitability during memory recall

The ability to associate stimuli to create a memory is one of the most fundamental functions of the brain. Research from the past decade has revealed that memory is encoded in sparse neuronal networks active during learning called engram cells. Although the cortex is recognized as playing an important role in memory, the biophysical properties of cortical engram cells are largely unknown. To address this, we tagged engram cells in the auditory cortex during tone fear conditioning and compared their dendritic and somatic properties with neighbouring non-engram cells. Using two-photon calcium imaging, we show that tuft dendrites of engram cells had dampened, but synchronous, activity during recall. Ex vivo patch-clamp recordings illustrated that engram cells were preferentially connected with neighbouring engram cells and had decreased excitability due to a transient increase in Ih current. Together, these findings reveal Ih-driven intrinsic plasticity which leads to specific information processing in engram cells.

neuroscience↗

bioRxiv2024

Plasticity of visual looming response reveals a dissociation of innate and learned components

Animals rely on innate and learned behaviour to respond to their environment, but how the brain balances hardwired responses with adaptive flexibility remains unclear. Here, we demonstrate that innate looming stimulus responses in mice can be attenuated via repeated unreinforced presentation. This attenuation is long-lasting and generalising, but is rapidly recovered when the stimulus is paired with an electric foot-shock. Fiber photometry recordings reveal attenuation of responses to visual looming stimuli in the SC and PAG, which do not recover following recovery of behavioural responses. Analysis of c-Fos expression uncovered a ventral CA1 (vCA1) ensemble that is active during both innate and learned looming fear responses. We report that this vCA1 engram is not necessary for innate defensive behaviour but is necessary for learned fear responses. These findings reveal a novel role of the hippocampus in adapting to looming stimuli, and provide a platform for understanding the interaction of memory and instinct.

neuroscience↗

bioRxiv2023

Engram cell connectivity as a mechanism for information storage and memory function

Information derived from experiences is incorporated into the brain as changes to ensembles of cells, termed engram cells, that allow memory storage and recall. The mechanism by which those changes hold specific information is unclear. Here we test the hypothesis that the specific synaptic wiring between engram cells is the substrate of information storage. First, we monitor how learning modifies the connectivity pattern between engram cells at a monosynaptic connection involving the hippocampal vCA1 region and the amygdala. Then, we assess the functional significance of these connectivity changes by artificially activating or inhibiting its presynaptic and postsynaptic components respectively. Finally, we identify a synaptic plasticity mechanism mediated by PSD-95, which impacts the connectivity pattern among engram cells and contributes to the long-term stability of the memory. These findings impact our theory of learning and memory by helping us explain the translation of specific information into engram cells and how these connections shape brain function.

neuroscience↗

bioRxiv2023

Natural Forgetting is Modulated by Experience

Memories are stored as ensembles of engram neurons and their successful recall involves the reactivation of these cellular networks. However, significant gaps remain in connecting these cell ensembles with the process of forgetting. Here, we utilized a mouse model of object memory and investigated the conditions in which a memory could be preserved, retrieved, or forgotten. Direct modulation of engram activity via optogenetic stimulation or inhibition either facilitated or prevented the recall of an object memory. In addition, through behavioral and pharmacological interventions, we successfully prevented or accelerated forgetting of an object memory. Finally, we showed that these results can be explained by a computational model in which engrams that are subjectively less relevant for adaptive behavior are more likely to be forgotten. Together, these findings suggest that forgetting may be an adaptive form of engram plasticity which allows engrams to switch from an accessible state to an inaccessible state.

neuroscience↗

bioRxiv2022

Immune activation state modulates retrieval of infant engrams

Infantile amnesia is possibly the most ubiquitous form of memory loss in mammals. Despite its widespread relevance, little is known about the biological conditions for infantile amnesia to occur and its effect on the engram cells that encode a memory. We investigated how memories are stored in the brain throughout development by integrating engram labeling technology with mouse models of infantile amnesia. Here, we discovered a phenomenon in which male offspring in maternal immune activation models of autism spectrum disorder do not experience infantile amnesia. We rescued the same apparently forgotten infantile memories in mice by optogenetically reactivating dentate gyrus engram cells labeled during complex infant development experiences. Further, we were able to permanently reinstate lost infantile memories by artificially updating the memory engram, demonstrating that infantile amnesia is a reversible process. Our findings suggest that immune activation during development modulates innate, and reversible, forgetting switches that determine whether infantile amnesia will occur.

neuroscience↗

bioRxiv2021

Mammals adjust diel activity across gradients of urbanization

Time is a fundamental component of ecological processes. How animal behavior changes over time has been explored through well-known ecological theories like niche partitioning and predator-prey dynamics. Yet, changes in animal behavior within the shorter 24-hour light-dark cycle have largely gone unstudied. Understanding if an animal can adjust their temporal activity to mitigate or adapt to environmental change has become a recent topic of discussion and is important for effective wildlife management and conservation. While spatial habitat is a fundamental consideration in wildlife management and conservation, temporal habitat is often ignored. We formulated a temporal resource selection model to quantify the diel behavior of eight mammal species across ten U.S. cities. We found high variability in diel activity patterns within and among species and species-specific correlations between diel activity and human population density, impervious land cover, available greenspace, vegetation cover, and mean daily temperature. We also found that some species may modulate temporal behaviors to manage both natural and anthropogenic risks. Our results highlight the complexity with which temporal activity patterns interact with local environmental characteristics, and suggest that urban mammals may use time along the 24-hour cycle to reduce risk, adapt, and therefore persist in human-dominated ecosystems.

ecology↗

bioRxiv2018

Synaptic combinatorial molecular mechanisms generate repertoires of innate and learned behavior

Although molecular mechanisms underpinning specific behaviors have been described, whether there are mechanisms that orchestrate a behavioral repertoire is unknown. To test if the postsynaptic proteome of excitatory synapses could impart such a mechanism we conducted the largest genetic study of mammalian synapses yet undertaken. A repertoire of sixteen innate and learned behaviors was assessed from 290,850 measures in 55 lines of mutant mice carrying targeted mutations in the principal classes of postsynaptic proteins. Each innate and learned behavior used a different combination of proteins. These combinations were comprised of proteins that amplified or attenuated the magnitude of each behavioral response. All behaviors required proteins found in PSD95 supercomplexes. We show the vertebrate increase in proteome complexity drove an expansion in behavioral repertoires and generated susceptibility to a wide range of diseases. Our results reveal a molecular mechanism that generates a versatile and complex behavioral repertoire that is central to human behavioral disorders.

neuroscience↗