Biology subjects

Gongwer, M. W.

Publications and source records attributed to Gongwer, M. W..

7 recordsLinked to original sources

bioRxiv2025

Early adversity potentiates prefrontal - amygdala communication through CRH+ glutamatergic neurons

Early life adversity (ELA) has lasting impacts on emotion circuit function1. Exposure to early maltreatment, neglect, or household instability is associated with enduring alterations in threat evaluation and response, hallmarks of mood and anxiety disorders2-4. These alterations often emerge during adolescence and are characterized by excessive avoidance that limits engagement in rewarding experiences5,6. However, the neurodevelopmental mechanisms linking ELA to increased threat responses remain unclear. We identified a stress-sensitive medial prefrontal cortex (mPFC)-basolateral amygdala pathway that co-expresses corticotropin-releasing hormone (CRH) and glutamate. We find that ELA strengthens this pathway and increases threat avoidance behavior during adolescence. Optogenetic inhibition and developmental CRH knockdown in this pathway both rescue ELA-induced elevations in adolescent avoidance, whereas broadly reducing mPFC CRH expression in typically reared mice mimics ELA phenotypes. The same manipulations produced no behavioral effects in adults. Together, our findings indicate that cell type-specific CRH signaling regulates developmental circuit plasticity, biasing emotional circuit function and potentially contributing to psychiatric vulnerability.

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bioRxiv2025

A cell type-specific mechanism driving the rapid antidepressant effects of transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is unknown. We developed a novel mouse model of rTMS with superior clinical face validity and investigated the neural mechanism by which accelerated intermittent theta burst stimulation (aiTBS) - the first rapid-acting rTMS antidepressant protocol - reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns of neural activity in intratelencephalic (IT) and pyramidal tract (PT) projecting neurons in dorsomedial prefrontal cortex (dmPFC). However, only IT neurons exhibited persistently increased activity during both aiTBS and subsequent depression-related behaviors. Similarly, aiTBS reversed stress-related loss of dendritic spines on IT, but not PT neurons, further demonstrating cell type-specific effects of stimulation. Finally, chemogenetic inhibition of dmPFC IT neurons during rTMS blocked the antidepressant-like behavioral effects of aiTBS. Thus, we demonstrate a prefrontal mechanism linking rapid aiTBS-driven therapeutic effects to cell type-specific circuit plasticity.

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bioRxiv2025

Microglia regulate nucleus accumbens synaptic development and circuit function underlying threat avoidance behaviors

While CNS microglia have well-established roles in synapse pruning during neurodevelopment, only a few studies have identified roles for microglia in synapse formation. These studies focused on the cortex and primary sensory circuits during restricted developmental time periods, leaving substantial gaps in our understanding of the early developmental functions of microglia. Here we investigated how the absence of microglia impacts synaptic development in the nucleus accumbens (NAc), a region critical for emotional regulation and motivated behaviors and where dysfunction is implicated in psychiatric disorders that arise early in life. Using a genetically modified mouse that lacks microglia (Csf1r {Delta}FIRE/{Delta}FIRE), we found blunted excitatory synapse formation in the NAc. This effect was most prominent during the second and third postnatal weeks, when we previously found microglia to be overproduced, and was accompanied by an increase in presynaptic release probability and alterations in postsynaptic kinetics. Tissue-level NAc proteomics confirmed that microglial absence impacted numerous proteins involved in synapse structure, trans-synaptic signaling, and pre-synaptic function. However, microglial absence did not perturb levels of astrocyte-derived cues and adhesive proteins that promote synaptogenesis, suggesting that reduced synapse number may be caused by absence of a microglial-derived synaptogenic cue. Although observed electrophysiological synaptic changes were largely normalized by adulthood, we identified lasting effects of microglial absence on threat avoidance behavior, and these behavioral effects were directly associated with alterations of NAc neuronal activity. Together, these results indicate a critical role for microglia in regulating the synaptic landscape of the developing NAc and in establishing functional circuits underlying adult behavioral repertoires.

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bioRxiv2024

A developmental brain-wide screen identifies retrosplenial cortex as a key player in the emergence of persistent memory

Memories formed early in life are short-lived while those formed later persist. Recent work revealed that infant memories are stored in a latent state. But why they fail to be retrieved is poorly understood. Here we investigated brain-wide circuit mechanisms underlying infantile amnesia. We performed a screen that combined contextual fear conditioning, activity-dependent neuronal tagging at different postnatal ages, tissue clearing and light sheet microscopy. We observed striking developmental changes in regional activity patterns between infant, juvenile, and adult mice, including changes in the retrosplenial cortex (RSP) that aligned with the emergence of persistent memory. We then performed a series of targeted investigations of RSP structure and function across development. Chronic chemogenetic reactivation of tagged RSP ensembles during the week after learning enhanced memory in adults and juveniles, but not in infants. However, after 33 days, reactivating infant-tagged RSP ensembles recovered forgotten memories. Changes in the developmental functions of RSP memory ensembles were accompanied by changes in dendritic spine density and the likelihood that those ensembles could be reactivated by contextual cues. These studies show that RSP ensembles store latent infant memories, reveal the time course of RSP functional maturation, and suggest that immature RSP functional networks contribute to infantile amnesia.

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bioRxiv2023

Developmentally distinct architectures in top-down circuits

The medial prefrontal cortex (mPFC) plays a key role in learning, mood and decision making, including in how individuals respond to threats1-6. mPFC undergoes a uniquely protracted development, with changes in synapse density, cortical thickness, long-range connectivity, and neuronal encoding properties continuing into early adulthood7-21. Models suggest that before adulthood, the slow-developing mPFC cannot adequately regulate activity in faster-developing subcortical centers22,23. They propose that during development, the enhanced influence of subcortical systems underlies distinctive behavioural strategies of juveniles and adolescents and that increasing mPFC control over subcortical structures eventually allows adult behaviours to emerge. Yet it has remained unclear how a progressive strengthening of top-down control can lead to nonlinear changes in behaviour as individuals mature24,25. To address this discrepancy, here we monitored and manipulated activity in the developing brain as animals responded to threats, establishing direct causal links between frontolimbic circuit activity and the behavioural strategies of juvenile, adolescent and adult mice. Rather than a linear strengthening of mPFC synaptic connectivity progressively regulating behaviour, we uncovered multiple developmental switches in the behavioural roles of mPFC circuits targeting the basolateral amygdala (BLA) and nucleus accumbens (NAc). We show these changes are accompanied by axonal pruning coinciding with functional strengthening of synaptic connectivity in the mPFC-BLA and mPFC-NAc pathways, which mature at different rates. Our results reveal how developing mPFC circuits pass through distinct architectures that may make them optimally adapted to the demands of age-specific challenges.

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bioRxiv2022

Mapping whole-brain projections of anatomically defined prefrontal neurons using combined 3D convolution networks

To understand how the brain produces behavior, we must elucidate the relationships between neuronal connectivity and function. The medial prefrontal cortex (mPFC) is critical for complex functions including decision-making and mood. mPFC projection neurons collateralize extensively, but the relationships between mPFC neuronal activity and brain-wide connectivity are poorly understood. We performed whole-brain connectivity mapping and fiber photometry to better understand the mPFC circuits that control threat avoidance. Using tissue clearing and light sheet fluorescence microscopy we mapped the brain-wide axon collaterals of populations of mPFC neurons that project to nucleus accumbens (NAc), ventral tegmental area (VTA), or contralateral mPFC (cmPFC) in mice. We present DeepTraCE, for quantifying bulk-labeled axonal projections in images of cleared tissue, and DeepCOUNT, for quantifying cell bodies. Anatomical maps produced with DeepTraCE aligned with known axonal projection patterns and revealed class-specific topographic projections within regions. During threat avoidance, cmPFC and NAc-projectors encoded conditioned stimuli, but only when action was required to avoid threats. mPFC-VTA neurons encoded learned but not innate avoidance behaviors. Together our results present new and optimized approaches for quantitative whole-brain analysis and indicate that anatomically-defined classes of mPFC neurons have specialized roles in threat avoidance.

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bioRxiv2020

EZcalcium: Open Source Toolbox for Analysis of Calcium Imaging Data

Fluorescence calcium imaging using a range of microscopy approaches, such as 2-photon excitation or head-mounted miniscopes, is one of the preferred methods to record neuronal activity and glial signals in various experimental settings, including acute brain slices, brain organoids, and behaving animals. Because changes in the fluorescence intensity of genetically encoded or chemical calcium indicators correlate with action potential firing in neurons, data analysis is based on inferring such spiking from changes in pixel intensity values across time within different regions of interest. However, the algorithms necessary to extract biologically relevant information from these fluorescent signals are complex and require significant expertise in programming to develop robust analysis pipelines. For decades, the only way to perform these analyses was for individual laboratories to write their own custom code. These routines were typically not well annotated and lacked intuitive graphical user interfaces (GUIs), which made it difficult for scientists in other laboratories to adopt them. Although the panorama is changing with recent tools like CaImAn, Suite2P and others, there is still a barrier for many laboratories to adopt these packages, especially for potential users without sophisticated programming skills. As 2-photon microscopes are becoming increasingly affordable, the bottleneck is no longer the hardware, but the software used to analyze the calcium data in an optimal manner and consistently across different groups. We addressed this unmet need by incorporating recent software solutions for motion correction, segmentation, signal extraction and deconvolution of calcium imaging data into an open-source, easy to use, GUI-based, intuitive and automated data analysis software, which we named EZcalcium.

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