Biology subjects

Iascone, D. M.

Publications and source records attributed to Iascone, D. M..

7 recordsLinked to original sources

bioRxiv2025

From Morphology to Computation: How Synaptic Organization Shapes Place Fields in CA1 Pyramidal Neurons

How spatial organization of synaptic inputs along the dendritic tree of neurons influence their feature selectivity is a central question in neuroscience. Here, we mapped the three-dimensional distribution of all excitatory and inhibitory synapses across the entire dendritic arbor of individual mouse CA1 pyramidal neurons in vivo and built biophysically detailed computational models to probe their functional impact on their ability to emerge as place cells. We found that excitatory, but not inhibitory, synapses are non-uniformly distributed, forming structural clusters preferentially on terminal dendrites. These excitatory synaptic clusters generate high-quality place fields more efficiently than randomized synaptic distributions, requiring fewer active synapses to achieve equivalent somatic output. Crucially, even when firing rates are matched, clustered inputs sustain significantly higher voltage-gated calcium influx and NMDA receptor activation, key substrates for synaptic plasticity. Further analysis reveals that clustering enables domain-specific computational strategies: oblique dendrites rely on cluster location, basal dendrites on cumulative synaptic strength, and the trunk on local input dispersion. Disrupting clustering collapses this compartmentalized processing into uniform summation. Our results establish synaptic clustering as a key mechanism that maximizes computational efficiency and enables sophisticated dendritic processing underlying hippocampal spatial representation.

neuroscience↗

bioRxiv2025

Tanycyte Bmal1 sex-specifically regulates weight gain and hypothalamic neurogenesis in female mice

The hypothalamic radial-glia-like tanycyte population plays important and intertwined roles in feeding and metabolism, reproduction, and seasonality. Although these processes are circadian-regulated and clock genes reportedly show robust cycling along the 3rd ventricle, the role of the clock in tanycytes has not yet been examined. We report here that clock genes cycle with much higher amplitude in ventral tanycytes compared to more dorsal ependymocytes of the 3rd ventricle, and that specific disruption of the tanycyte clock can be achieved by adult Bmal1 deletion using the RaxCreER driver. Adult tanycyte Bmal1 deletion did not affect circadian rhythms of wheel-running and sleep, but did inhibit weight gain on high-fat diet in female mice. Altered tanycyte-derived hypothalamic neurogenesis, which can regulate feeding and weight gain by contributing new neurons to nearby feeding-relevant nuclei, is one mechanism that likely contributes to this phenotype. Fate mapping studies showed that female mice have higher baseline tanycyte-derived neurogenesis than males, with many of the resulting neurons localizing to the feeding-relevant arcuate nucleus. Female but not male mice show reduced tanycyte-derived arcuate neurogenesis after adult tanycyte Bmal1 deletion and an increased percentage of newborn arcuate neurons take on a feeding-suppressing POMC neuropeptidergic fate. Thereby, skewing of feeding and satiety promoting fates link the weight homeostasis and neurogenesis effects. Together, our data establish tanycyte Bmal1 as a sexually dimorphic regulator of weight homeostasis, likely mediated at least in part by a female-specific neurogenesis effect in the feeding circuitry.

neuroscience↗

bioRxiv2024

Neurovascular mitochondrial susceptibility impacts blood-brain barrier function and behavior

Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared to peripheral endothelial cells, although the functional implications of this phenomenon remain unknown. Here we studied BBB mitochondrial function in the context of the 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. As the 22q11.2 deletion includes 6 mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and impact behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived BBB endothelial cells from 22qDS patients, and in BBB endothelial cells from a mouse model of 22qDS. Remarkably, treatment to improve mitochondrial function attenuates mitochondrial deficits and enhances BBB function in both the iPSC and mouse 22qDS models. This treatment also corrected social memory in the mouse model, a deficit previously associated with BBB dysfunction. As BBB integrity correlated with social memory performance, together our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior in 22qDS.

neuroscience↗

bioRxiv2023

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells

Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

cancer biology↗

bioRxiv2022

BigNeuron: A resource to benchmark and predict best-performing algorithms for automated reconstruction of neuronal morphology

BigNeuron is an open community bench-testing platform combining the expertise of neuroscientists and computer scientists toward the goal of setting open standards for accurate and fast automatic neuron reconstruction. The project gathered a diverse set of image volumes across several species representative of the data obtained in most neuroscience laboratories interested in neuron reconstruction. Here we report generated gold standard manual annotations for a selected subset of the available imaging datasets and quantified reconstruction quality for 35 automatic reconstruction algorithms. Together with image quality features, the data were pooled in an interactive web application that allows users and developers to perform principal component analysis, t-distributed stochastic neighbor embedding, correlation and clustering, visualization of imaging and reconstruction data, and benchmarking of automatic reconstruction algorithms in user-defined data subsets. Our results show that image quality metrics explain most of the variance in the data, followed by neuromorphological features related to neuron size. By benchmarking automatic reconstruction algorithms, we observed that diverse algorithms can provide complementary information toward obtaining accurate results and developed a novel algorithm to iteratively combine methods and generate consensus reconstructions. The consensus trees obtained provide estimates of the neuron structure ground truth that typically outperform single algorithms. Finally, to aid users in predicting the most accurate automatic reconstruction results without manual annotations for comparison, we used support vector machine regression to predict reconstruction quality given an image volume and a set of automatic reconstructions.

bioinformatics↗

bioRxiv2018

Whole-neuron synaptic mapping reveals local balance between excitatory and inhibitory synapse organization

The balance between excitatory and inhibitory (E and I) synaptic inputs is thought to be critical for information processing in neural circuits. However, little is known about the principles of spatial organization of E and I synapses across the entire dendritic tree of mammalian neurons. We developed a new, open-source, reconstruction platform for mapping the size and spatial distribution of E and I synapses received by individual, genetically-labeled, layer 2/3 cortical pyramidal neurons (PNs) in vivo. We mapped over 90,000 E and I synapses across twelve L2/3 PNs and uncovered structured organization of E and I synapses across dendritic domains as well as within individual dendritic segments in these cells. Despite significant, domain-specific, variations in the absolute density of E and I synapses, their ratio is strikingly balanced locally across dendritic segments. Computational modeling indicates that this spatially-precise E/I balance dampens dendritic voltage fluctuations and strongly impacts neuronal firing output.

neuroscience↗

bioRxiv2016

Fast Assembling of Neuron Fragments in Serial 3D Sections

AbstractReconstructing neurons from 3D image-stacks of serial sections of thick brain tissue is very time-consuming and often becomes a bottleneck in high-throughput brain mapping projects. We developed NeuronStitcher, a software suite for stitching non-overlapping neuron fragments reconstructed in serial 3D image sections. With its efficient algorithm and user-friendly interface, NeuronStitcher has been used successfully to reconstruct very large and complex human and mouse neurons.

neuroscience↗