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Thursday, February 15th, 2024

    Time Event
    11:35a
    Hippocampal area CA2 activity supports social investigation following an acute social stress.
    Neuronal activity in the hippocampus is critical for many types of memory acquisition and retrieval and influences an animals response to stress. Moreover, the molecularly distinct principal neurons of hippocampal area CA2 are required for social recognition memory and aggression in mice. To interrogate the effects of stress on CA2-dependent behaviors, we chemogenetically manipulated neuronal activity in vivo during an acute, socially derived stressor and tested whether memory for the defeat was influenced. One day after an acute social defeat (aSD), defeated mice spent significantly less time investigating another mouse when compared to non-defeated control mice. We found that this avoidant phenotype persisted for up to one month following a single defeat encounter. When CA2 pyramidal neuron activity was inhibited with Gi-DREADD receptors during the defeat, subject mice exhibited a significantly higher amount of social avoidance one day later when compared to defeated littermates not expressing DREADDs. Moreover, CA2 inhibition during defeat caused a reduction in submissive defense behaviors in response to aggression. In vitro electrophysiology and tracing experiments revealed a circuit wherein CA2 neurons connect to caudal CA1 projection neurons that, in turn, project to corticolimbic regions including the anterior cingulate cortex. Finally, socially avoidant, defeated mice exhibited significant reductions in cFos expression in caudal hippocampal and limbic brain areas during a social investigation task 24 hours after aSD. Taken together, these results indicate that CA2 neuronal activity is required to support behavioral resilience following an acute social stressor and that submissive defensive behavior during the defeat (vs. fleeing) is a predictor of future resilience to social stress. Furthermore, CA2 preferentially targets a population of caudal CA1 projection neurons that contact cortical brain regions where activity is modulated by an acute social stressor.
    12:46p
    Neural dynamics of shifting attention between perception and working-memory contents
    In everyday tasks, our focus of attention shifts seamlessly between contents in the sensory environment and internal memory representations. Yet, research has mainly considered external and internal attention in isolation. We used magnetoencephalography to compare the neural dynamics of shifting attention to visual contents within vs. between the external and internal domains. Participants performed a combined perception and working-memory task in which two sequential cues guided attention to upcoming (external) or memorised (internal) sensory information. Critically, the second cue could redirect attention to visual content within the same or alternative domain as the first cue. Multivariate decoding unveiled distinct patterns of human brain activity when shifting attention within vs. between domains. Crossing domains did not alter the timing of spatial orienting, as indexed by posterior alpha lateralisation. These findings provide important initial insights into the neural dynamics that govern attentional shifts between perception and working memory.
    2:00p
    Distinct hippocampal mechanisms support concept formation and updating
    Learning systems must constantly decide whether to create new representations or update existing ones. For example, a child learning that a bat is a mammal and not a bird would be best served by creating a new representation, whereas updating may be best when encountering a second similar bat. Characterizing the neural dynamics that underlie these complementary memory operations requires identifying the exact moments when each operation occurs. We address this challenge by interrogating fMRI brain activation with a computational learning model that predicts trial-by-trial when memories are created versus updated. We found distinct neural engagement in anterior hippocampus and ventral striatum for model-predicted memory create and update events during early learning. Notably, the degree of this effect in hippocampus, but not ventral striatum, significantly related to learning outcome. Hippocampus additionally showed distinct patterns of functional coactivation with ventromedial prefrontal cortex and angular gyrus during memory creation and premotor cortex during memory updating. These findings suggest that complementary memory functions, as formalized in computational learning models, underlie the rapid formation of novel conceptual knowledge, with the hippocampus and its interactions with frontoparietal circuits playing a crucial role in successful learning.
    10:51p
    Multi-species community platform for comparative neuroscience in teleost fish
    Studying neural mechanisms in complementary model organisms from different ecological niches in the same animal class can leverage the comparative brain analysis at the cellular level. To advance such a direction, we developed a unified brain atlas platform and specialized tools that allowed us to quantitatively compare neural structures in two teleost larvae, medaka (Oryzias latipes) and zebrafish (Danio rerio). Leveraging this quantitative approach we found that most brain regions are similar but some subpopulations are unique in each species. Specifically, we confirmed the existence of a clear dorsal pallial region in the telencephalon in medaka lacking in zebrafish. Further, our approach allows for extraction of differentially expressed genes in both species, and for quantitative comparison of neural activity at cellular resolution. The web-based and interactive nature of this atlas platform will facilitate the teleost communitys research and its easy extensibility will encourage contributions to its continuous expansion.
    10:51p
    Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells
    Hair cells of the inner ear rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is critical for ribbon-synapse assembly in hair cells. In both mouse and zebrafish models, loss of Nrxn3 results in significantly fewer intact ribbon synapses. In zebrafish we demonstrate that a 60% loss of synapses in nrxn3 mutants dramatically reduces both presynaptic responses in hair cells and postsynaptic responses in afferent neurons. Despite a reduction in synapse function in this model, we find no deficits in the acoustic startle response, a behavior reliant on these synapses. Overall, this work demonstrates that Nrxn3 is a critical and conserved molecule required to assemble ribbon synapses. Understanding how ribbon synapses assemble is a key step towards generating novel therapies to treat forms of age-related and noise-induced hearing loss that occur due to loss of ribbon synapses.

    Summary StatementHearing and balance depend on specialized ribbon synapses that transmit sensory stimuli between hair cells and afferent neurons. We identify Nrxn3 as a key molecular player in ribbon-synapse assembly in hair cells.
    11:17p
    Neural Circuit Revision in Retinal Remodeling, A Pathoconnectomics Approach
    The Aii glycinergic amacrine cell (Aii) plays a central role in bridging rod pathways with cone pathways, enabling an increased dynamic range of vision from scotopic to photopic ranges. The Aii integrates scotopic signals via chemical synapses from rod bipolar cells (RodBCs) onto the arboreal processes of Aii ACs, injecting signals into ON-cone bipolar cells (CBbs) via gap junctions with Aiis on the arboreal processes and the waist of the Aii ACs. The CBbs then carry this information to ON and OFF ganglion cell classes. In addition, the Aii is involved in the surround inhibition of OFF cone bipolar cells (CBas) through glycinergic chemical synapses from Aii ACs onto CBas. We have previously shown changes in RodBC connectivity as a consequence of rod photoreceptor degeneration in a pathoconnectome of early retinal degeneration: RPC1. Here, we evaluated the impact of rod photoreceptor degeneration on the connectivity of the Aii to determine the impacts of photoreceptor degeneration on the downstream network of the neural retina and its suitability for integrating therapeutic interventions as rod photoreceptors are lost. Previously, we reported that in early retinal degeneration, prior to photoreceptor cell loss, Rod BCs make pathological gap junctions with Aiis. Here, we further characterize this altered connectivity and additional shifts in both the excitatory drive and gap junctional coupling of Aiis in retinal degeneration, along with discussion of the broader impact of altered connectivity networks. New findings reported here demonstrate that Aiis make additional gap junctions with CBas increasing the number of BC classes that make pathological gap junctional connectivity with Aiis in degenerating retina. In this study, we also report that the Aii, a tertiary retinal neuron alters their synaptic contacts early in photoreceptor degeneration, indicating that rewiring occurs in more distant members of the retinal network earlier in degeneration than was previously predicted. This rewiring impacts retinal processing, presumably acuity, and ultimately its ability to support therapeutics designed to restore image-forming vision. Finally, these Aii alterations may be the cellular network level finding that explains one of the first clinical complaints from human patients with retinal degenerative disease, an inability to adapt back and forth from photopic to scotopic conditions.
    11:17p
    Adeno-associated viruses for efficient gene expression in the axolotl nervous system
    Axolotls are models for studying nervous system evolution, development, and regeneration. Tools to visualize and manipulate cells of the axolotl nervous system with high efficiency, spatial and temporal precision are therefore greatly required. Recombinant adeno-associated viruses (AAVs) are frequently used for in vivo gene transfer of the nervous system but virus-mediated gene delivery to the axolotl nervous system has not yet been described. Here, we demonstrate the use of AAVs for efficient gene transfer within the axolotl brain and the retina. We show that serotypes AAV8, AAV9, AAVRG and AAVPHP.eB are suitable viral vectors to infect both excitatory and inhibitory neuronal populations of the axolotl brain. We further use AAV9 to trace retrograde and anterograde projections between the retina and the brain and identify a cell population projecting from the brain to the retina. Together, our work establishes AAVs as a powerful tool to interrogate neuronal organization in the axolotl.
    11:17p
    Fraudulent studies are undermining the reliability of systematic reviews - a study of the prevalence of problematic images in preclinical studies of depression
    Systematic reviews are considered by many to constitute the highest level of scientific evidence. A caveat is that the methods used in a systematic review - combining information from multiple studies - are predicated on all of the reports being truthful. Currently, we do not know how frequent fraudulent studies are in systematic reviews, or how they affect the resulting evidence base. For a systematic review of preclinical studies of depression, we found that potentially fraudulent studies were not only common but also that they biased the findings of the review. In a sample of 1,035 studies, we found that 19 % of peer-reviewed reports displayed data in the form of problematic images. In a majority of the cases, images had been altered or recycled in a way that makes us suspect foul play. Making things worse, these studies reported larger effect sizes, on average, than did studies where we did not identify problems. Counter to commonly held beliefs, reports with problematic images were not cited less or published in lower-impact journals, nor were their authors isolated to any specific geographic area. The sheer prevalence of problematic studies, and the fact that we could not find a simple pattern for identifying them, undermines the validity of systematic reviews within our research field. We suspect that this is symptomatic of a broader problem that needs immediate addressing.

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