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Josselyn, S. A.

Publications and source records attributed to Josselyn, S. A..

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Delayed maturation of hippocampal trisynaptic circuitry underlies the protracted development of episodic-like memory

The ability to form high-resolution episodic memories emerges relatively late in development, but the circuit mechanisms underlying this transition are unknown. CA1 receives entorhinal input through a direct monosynaptic pathway and an indirect trisynaptic pathway via the dentate gyrus and CA3. In mice, CA3[->]CA1 innervation matured later than MEC[->]CA1 innervation, with pronounced maturation between P20 and P24. Trisynaptic pathway maturation was necessary for high-resolution memory and was shaped by neuronal activity and early-life experience. Mechanistically, trisynaptic activity promoted perineuronal net assembly around downstream parvalbumin-expressing interneurons, facilitating their maturation and subsequent recruitment during learning to constrain CA1 encoding ensembles. Thus, activity-dependent maturation of trisynaptic circuitry provides a unified circuit and cellular account of a sensitive period for the emergence of episodic-like memory.

neuroscience↗

Activity-dependent myelination in prefrontal circuits signals the offset of infantile amnesia

Human and non-human infants can form memories for events, but these memories are not successfully consolidated into remote memory. While the neurobiological basis of this phenomenon-known as infantile amnesia-remains unclear, it is hypothesized that the neural circuits required for successful consolidation are insufficiently mature. Here we find that heightened activity in the prelimbic cortex of developing mice triggers a sequalae of maturational steps that culminates in adult-like memory persistence: Activity-dependent increases in brain-derived neurotrophic factor (BDNF) promote myelination of prelimbic circuits via activation of tyrosine kinase receptor B (TrkB) receptors on oligodendrocyte precursor cells (OPCs). Inhibiting any of these steps within a critical developmental window delays the offset of infantile amnesia, whereas promoting this sequalae results in the precocial emergence of memory persistence. Similar to critical periods in sensory cortices, our results indicate that developmental myelination is required for proper circuit maturation and emergence of adult-like memory function.

neuroscience↗

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

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.

neuroscience↗

A shift in the mechanisms controlling hippocampal engram formation during brain maturation

The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory formation are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 by extracellular perineuronal nets which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision. One-Sentence SummaryEpisodic-like memory precision requires maturation of hippocampal inhibitory interneurons by the extracellular matrix.

neuroscience↗

Evolution of predictive memory in the hippocampus

The brain organizes experiences into memories that can be used to guide future behavior. Hippocampal CA1 population activity may reflect the retrieval of predictive models that contain information about future events, but little is known about how these kinds of memories develop with experience. We trained mice on a series of tone discrimination problems with or without a common statistical structure to observe how memories are formed and updated during learning. Mice that learned structured problems integrated their experiences into a predictive model that contained the solutions to upcoming novel problems. Retrieving the model during learning improved discrimination accuracy and facilitated learning by decreasing the amount of new information that needed to be acquired. Using calcium imaging to track the activity of thousands of CA1 neurons during learning on this task, we observed the emergence of a persistent hippocampal ensemble at the same time that mice formed a predictive model of their environment. This ensemble was reactivated during training and incorporated new neuronal activity patterns from each training problem. Interestingly, the degree to which mice reactivated the ensemble was related to how well their model predicted the content of the current problem, ensuring that the model was only updated with congruent information. In contrast, mice trained on unstructured problems did not form a predictive model or engage a persistent ensemble. These results show how hippocampal activity supports building predictive models by organizing newly learned information according to its congruence with existing memories.

neuroscience↗

Can neurogenesis act as a neural regularizer?

New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal circuits, forming new naive synapses. Viewed from this perspective, these new neurons may represent a significant source of wiring noise in hippocampal networks. In machine learning, such noise injection is commonly used as a regularization technique. Regularization techniques help prevent overfitting training data, and allow models to generalize learning to new, unseen data. Using a computational modeling approach, here we ask whether a neurogenesis-like process similarly acts as a regularizer, facilitating generalization in a category learning task. In a convolutional neural network (CNN) trained on the CIFAR-10 object recognition dataset, we modeled neurogenesis as a replacement/turnover mechanism, where weights for a randomly chosen small subset of neurons in a chosen hidden layer were re-initialized to new values as the model learned to categorize 10 different classes of objects. We found that neurogenesis enhanced generalization on unseen test data compared to networks with no neurogenesis. Moreover, neurogenic networks either outperformed or performed similarly to networks with conventional noise injection (i.e., dropout, weight decay, and neural noise). These results suggest that neurogenesis can enhance generalization in hippocampal learning through noise-injection, expanding on the roles that neurogenesis may have in cognition. Author SummaryIn deep neural networks, various forms of noise injection are used as regularization techniques to prevent overfitting and promote generalization on unseen test data. Here, we were interested in whether adult neurogenesis- the lifelong production of new neurons in the hippocampus- might similarly function as a regularizer in the brain. We explored this question computationally, assessing whether implementing a neurogenesis-like process in a hidden layer within a convolutional neural network trained in a category learning task would prevent overfitting and promote generalization. We found that neurogenesis regularization was as least as effective as, or more effective than, conventional regularizers (i.e., dropout, weight decay and neural noise) in improving model performance. These results suggest that optimal levels of hippocampal neurogenesis may improve memory-guided decision making by preventing overfitting, thereby promoting the formation of more generalized memories that can be applied in a broader range of circumstances. We outline how these predictions may be evaluated behaviorally in rodents with altered hippocampal neurogenesis.

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Automated curation of CNMF-E-extracted ROI spatial footprints and calcium traces using open-source AutoML tools

In vivo 1-photon calcium imaging is an increasingly prevalent method in behavioural neuroscience. Numerous analysis pipelines have been developed to improve the reliability and scalability of pre-processing and ROI extraction for these large calcium imaging datasets. Despite these advancements in pre-processing methods, manual curation of the extracted spatial footprints and calcium traces of neurons remains important for quality control. Here, we propose an additional semi-automated curation step for sorting spatial footprints and calcium traces from putative neurons extracted using the popular CNMF-E algorithm. We used the automated machine learning tools TPOT and AutoSklearn to generate classifiers to curate the extracted ROIs trained on a subset of human-labeled data. AutoSklearn produced the best performing classifier, achieving an F1 score > 92% on the ground truth test dataset. This automated approach is a useful strategy for filtering ROIs with relatively few labeled data points, and can be easily added to pre-existing pipelines currently using CNMF-E for ROI extraction.

neuroscience↗

A compact head-mounted endoscope for in vivo calcium imaging in freely-behaving mice

Miniaturized fluorescence microscopes for imaging calcium transients are a promising tool for investigating the relationship between behaviour and population-level neuronal activity in rodents. However, commercially available miniature microscopes may be costly, and, because they are closed-source, may not be easily modified based on particular experimental requirements. Here, we describe how to build and use a low-cost compact head-mounted endoscope (CHEndoscope) system for in vivo calcium imaging. The CHEndoscope uses an implanted gradient index (GRIN) lens along with the genetically encoded calcium indicator GCaMP6 to image calcium transients from hundreds of neurons simultaneously in awake behaving mice. This system is affordable, open-source, and flexible, permitting modification depending on the particular experiment. This Unit describes in detail the assembly, surgical implantation, data collection, and processing of calcium signals using the CHEndoscope system. The aim of this open framework model is to provide an accessible set of miniaturized calcium imaging tools for the neuroscience research community.\n\nSignificance StatementThe ability to image calcium transients in awake, behaving rodents using miniature microscopes opens exciting and novel avenues for gaining insights into how information is encoded in neural circuits. The development of this tool has already had a significant impact on neuroscience research. The cost of commercial systems, however, may be prohibitive for many laboratories. Here, we describe an affordable, open-source compact head-mounted endoscope (CHEndoscope) system for performing in vivo calcium imaging in freely-behaving mice. CHEndoscopes may be manufactured by individual laboratories at relatively minor cost. Our hope is that greater availability of affordable, open-source tools (such as the one presented here) will accelerate the pace of discoveries in systems neuroscience.

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