Biology subjects

Osten, P.

Publications and source records attributed to Osten, P..

15 recordsLinked to original sources

bioRxiv2026

Genetic and stochastic basis of phenotypic discordance in 16p11.2 mouse model deletion

Recurrent copy number variations such as the 16p11.2 deletion (del/+) represent a significant genetic risk for neurodevelopmental disorders, showing incomplete penetrance and variable expressivity. Here we describe a striking discordance in a genetic mouse model of human 16p11.2 deletion. Using electrocorticography experiments, we detected that approximately 50% of the isogenic del/+ mice exhibited increased susceptibility to seizures from low doses of the convulsant drug pentylenetetrazole (PTZ). Some of these mice also displayed spontaneous epileptiform brain activity. Next, we used two-photon microscopy tomography (STPT) with c-Fos-GFP (c-Fos+) as a reporter of neuronal activity to obtain images of the entire mouse brain. We examined del/+ mice that exhibited low or high responses to PTZ. Low responders exhibited minimal c-Fos+ activation. However, they had activating circuits that suggest the presence of compensatory mechanisms that suppress seizures. These circuits include the reticular nucleus of the thalamus, the pretectal region, the pedunculopontine nucleus, and the superior colliculus. In contrast, high-responder mice exhibited high c-Fos+ expression, corresponding to a fast seizure phenotype. Using whole-brain imaging, we analyzed brain volume and detected significant differences in the cortex between low- responder and high-responder del/+ mice. In the group with higher seizure susceptibility, we observed a notable decrease in cortical volume with significant differences in several brain regions compared to low responders. Additionally, some high-responder mice showed null expansion areas compared to low-responder mice. During the longitudinal behavioral analysis, the high-responder group of mice exhibited more severe sleep disturbances and an increase in repetitive grooming. Finally, to identify transcriptional correlates of the low- versus high- response phenotypes in adulthood, we performed bulk RNA-seq on somatosensory cortex punches from adult del/+ mice stratified by seizure response. Seizure-prone del/+ mice exhibited reduced activity-dependent immediate early gene signatures and coordinated changes in regulatory programs, including decreased expression of transcriptional regulators and metabotropic glutamate receptor genes, compared to low responders. Together, these findings define two distinct adult del/+ subgroups with convergent circuit, structural, behavioral, and molecular signatures.

neuroscience↗

bioRxiv2025

Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin

Ketamine has transformed depression treatment by providing therapeutic relief within a single day, unlike monoaminergic antidepressants that require weeks to take effect. Here, we conducted whole-brain screening in mice to compare drug-evoked c-fos expression--acting as a marker of brain activity leading to protein synthesis-dependent forms of plasticity--following treatment with monoaminergic antidepressants, ketamine and psilocybin. Our findings reveal a shared limbic brain circuit comprising subcortical and frontal cortical regions, with a key distinction: c-fos-based activity in the prelimbic and infralimbic frontal cortex--areas strongly implicated in depression--was acutely induced by ketamine and high-dose psilocybin, but emerged only after chronic dosing with the selective serotonin reuptake inhibitor fluoxetine or psilocybin microdosing. These results suggest the existence of a core limbic subcortico-cortical circuit underlying antidepressant efficacy, provide mechanistic insight into the delayed therapeutic effects of monoaminergic antidepressants, and reveal a close similarity in brain activity evoked by monoaminergic antidepressants and psilocybin microdosing.

neuroscience↗

bioRxiv2024

Brain Structural Organization Revealed by Unbiased Cell-Type Distribution Clustering

Cell-type composition across brain regions is a critical structural factor shaping both local and long-range brain circuits. Here, we employed single-cell resolution imaging of the mouse brain, combined with computational analyses, to map the distribution of 30 cell classes and types defined by gene marker expression in Cre recombinase-based genetic mouse models. This approach generated a comprehensive atlas of cell type-specific densities across the male and female brain, revealing (1) surprisingly broad sex differences in cells tagged by developmental cell-type markers, (2) shared cell type composition signatures among functionally related brain structures, and (3) close associations not only between specific cell types but also discrete cell type densities and anatomical regions and subregions. In summary, despite the relatively broad cell type classification enabled by the Cre mouse models, our findings highlight intricate relationships between brain cell type distribution and anatomical organization, associating distinct local cell densities with region-specific brain functions.

neuroscience↗

bioRxiv2023

Sexual coordination in a whole-brain map of prairie-vole pair-bonding

Sexual bonds are central to the social lives of many species, including humans, and monogamous prairie voles have become the predominant model for investigating such attachments. We developed an automated whole-brain mapping pipeline to identify brain circuits underlying pair-bonding behavior. We identified bonding-related c-Fos induction in 68 brain regions clustered in seven major brain-wide neuronal circuits. These circuits include known regulators of bonding, such as the bed nucleus of the stria terminalis, paraventricular hypothalamus, ventral pallidum, and prefrontal cortex. They also include brain regions previously unknown to shape bonding, such as ventromedial hypothalamus, medial preoptic area and the medial amygdala, but that play essential roles in bonding-relevant processes, such as sexual behavior, social reward and territorial aggression. Contrary to some hypotheses, we found that circuits active during mating and bonding were largely sexually monomorphic. Moreover, c-Fos induction across regions was strikingly consistent between members of a pair, with activity best predicted by rates of ejaculation. A novel cluster of regions centered in the amygdala remained coordinated after bonds had formed, suggesting novel substrates for bond maintenance. Our tools and results provide an unprecedented resource for elucidating the networks that translate sexual experience into an enduring bond.

neuroscience↗

bioRxiv2023

High-throughput confocal airy beam oblique light-sheet tomography of brain-wide imaging at single-cell resolution

Brain research is an area of research characterized by its cutting-edge nature, with brain mapping constituting a crucial aspect of this field. As sequencing tools have played a crucial role in gene sequencing, brain mapping largely depends on automated, high-throughput and high-resolution imaging techniques. Over the years, the demand for high-throughput imaging has scaled exponentially with the rapid development of microscopic brain mapping. In this paper, we introduce the novel concept of confocal Airy beam into oblique light-sheet tomography named CAB-OLST. We demonstrate that this technique enables the high throughput of brain-wide imaging of long-distance axon projection for the entire mouse brain at a resolution of 0.26 m x 0.26 m x 1.06 m in 58 hours. This technique represents an innovative contribution to the field of brain research by setting a new standard for high-throughput imaging techniques.

neuroscience↗

bioRxiv2023

Building functional circuits in multispecies brains.

The genome is the ultimate architect of the brain. Its evolutionary variations build the neural circuits that endow each species with its innate senses and behaviors. A central question for neuroscience and translational medicine is whether neural circuits from two species can be made to function in an intact brain. Here, we establish genetic tools and use blastocyst complementation to selectively build and test interspecies neural circuits in rat-mouse brains. Despite [~]10-20 million years of evolution and prominent differences in brain size and cellular composition, rat pluripotent stem cells injected into mouse blastocysts widely populate and persist in the mouse brain. Unexpectedly, the mouse niche reprograms the birthdates of cortical and hippocampal rat neurons, where they also form synaptically active rat-mouse circuits. By genetically disabling host olfactory circuitry, we show that rat neurons restore synaptic information flow from the nose to the cortex. Rat neurons can also rescue a primal olfactory behavior (food-seeking), though less than mouse controls. By enabling a mouse to sense the world with rat neurons, we highlight the power of interspecies neural blastocyst complementation to uncover mechanisms of neural circuit development and evolution, and to inform efforts to rescue neural circuits affected by injury or disease.

developmental biology↗

bioRxiv2022

A circuit from the locus coeruleus to the anterior cingulate cortex modulates offspring interactions in mice

Social sensitivity to other individuals in distress is crucial for survival. The anterior cingulate cortex (ACC) is a structure involved in making behavioral choices and is influenced by observed pain or distress. Nevertheless, our understanding of the neural circuitry underlying this sensitivity is incomplete. Here, we reveal unexpected sex-dependent activation of ACC when parental mice respond to distressed pups by returning them to the nest ( pup retrieval). We observe sex differences in the interactions between excitatory and inhibitory ACC neurons during parental care, and inactivation of ACC excitatory neurons increased pup neglect. Locus coeruleus (LC) releases noradrenaline in ACC during pup retrieval, and inactivation of the LC-ACC pathway disrupts parental care. We conclude that ACC maintains sex-dependent sensitivity to pup distress under LC modulation. We propose that ACCs involvement in parenting presents an opportunity to identify neural circuits that support sensitivity to the emotional distress of others.

neuroscience↗

bioRxiv2021

The cellular architecture of microvessels, pericytes and neuronal cell types in organizing regional brain energy homeostasis in mice

Cerebrovasculature and its mural cells must meet dynamic energy demands of different neuronal cell types across the brain, but their spatial relationship is largely unknown. Here, we apply brain-wide mapping methods to create a comprehensive cellular-resolution resource comprising the distribution of and quantitative relationship between cerebrovasculature, pericytes, and glutamatergic and GABAergic neurons, including neuronal nitric oxide synthase-positive (nNOS+) neurons and their subtypes, as well as simulation-ready vascular tracing data in mice. We discover strikingly high densities of vasculature and pericytes with high blood perfusion in primary motor-sensory cortices compared to association cortices that show significant positive and negative correlation with parvalbumin+ and nNOS+ neurons, respectively. Thalamo-striatal areas linked to primary motor-sensory cortices also contain high densities of vasculature and pericytes compared to association areas. Collectively, our results unveil a finely tuned spatial relationship between cerebrovascular network and neuronal cell composition in meeting regional energy needs of the brain.

neuroscience↗

bioRxiv2020

Super-resolution light-sheet fluorescence microscopy by SOFI.

Here we describe a new method, named LS-SOFI, that combines light-sheet fluorescence microscopy and super-resolution optical fluctuation imaging to achieve fast nanoscale-resolution imaging over large fields of view in native 3D tissues. We demonstrate the use of LS-SOFI in super-resolution analysis of neuronal structures and synaptic proteins, including cortical axons, dendritic spines, pre- and postsynaptic cytoskeletal proteins and postsynaptic AMPA receptors, in thick mouse brain sections. We also introduce an algorithm to determine the number of active fluorophore emitters detected, allowing the localization of individual molecules in LS-SOFI images. We conclude that LS-SOFI is a versatile method for fast super-resolution imaging from any tissue of the body using both commercial and custom LSFM instruments.

neuroscience↗

bioRxiv2020

Genetic dissection of glutamatergic neuron subpopulations and developmental trajectories in the cerebral cortex

Diverse types of glutamatergic pyramidal neurons (PyNs) mediate the myriad processing streams and output channels of the cerebral cortex, yet all derive from neural progenitors of the embryonic dorsal telencephalon. Here, we establish genetic strategies and tools for dissecting and fate mapping PyN subpopulations based on their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target the temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable combinatorial targeting of major progenitor types and projection classes. Intersectional converter lines confer viral access to specific subsets defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of PyN subpopulations that assemble cortical processing networks and output channels.

neuroscience↗

bioRxiv2019

Social isolation uncovers a brain-wide circuit underlying context-dependent territory-covering micturition behavior

The controlled and volitional release of urine, or micturition, serves a fundamental physiological function and, in many species, is critical for social communication. In mice, the decision to release urine is modulated by external and internal factors such as environmental stimuli and social history and is transmitted to the spinal cord via the pontine micturition center (PMC). The neural pathways by which social experience and sensory stimuli interact to control PMC activity and regulate micturition are unclear. Here we establish a behavioral paradigm in which mice, depending on their strain, social experience, and immediate sensory context, display either high or low territory-covering micturition (TCM). We demonstrate that social context is represented by coordinated global activity changes in the urination network upstream of the PMC, whereas sensory context is represented by the activation of discrete nodes in the network. Furthermore, we show that the lateral hypothalamic area (LHA), which is directly upstream of PMC, is a key node that can switch micturition behavior between high and low TCM modes.

neuroscience↗

bioRxiv2018

A brain network basis of Fragile X syndrome behavioral penetrance determined by X chromosome inactivation in female mice

Non-random (skewed) X chromosome inactivation (XCI) in the female brain can ameliorate X-linked phenotypes, though clinical studies typically consider 80-90% skewing favoring the healthy allele as necessary for this effect1-10. Here we quantify for the first time whole-brain XCI at single-cell resolution and discover a preferential inactivation of paternal to maternal X at [~]60:40 ratio, which surprisingly impacts disease penetrance. In Fragile-X-syndrome mouse model, Fmr1-KO allele transmitted maternally in [~]60% brain cells causes phenotypes, but paternal transmission in [~]40% cells is unexpectedly tolerated. In the affected maternal Fmr1-KO(m)/+ mice, local XCI variability within distinct brain networks further determines sensory versus social manifestations, revealing a stochastic source of X-linked phenotypic diversity. Taken together, our data show that a modest [~]60% bias favoring the healthy allele is sufficient to ameliorate X-linked phenotypic penetrance, suggesting that conclusions of many clinical XCI studies using the 80-90% threshold should be re-evaluated. Furthermore, the paternal origin of the XCI bias points to a novel evolutionary mechanism acting to counter the higher rate of de novo mutations in male germiline11-16. Finally, the brain capacity to tolerate a major genetic lesion in [~]40% cells is also relevant for interpreting other neurodevelopmental genetic conditions, such as brain somatic mosaicism.

neuroscience↗

bioRxiv2018

Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus

The thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain-stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF forms the densest subcortical projection to the striatum. This projection arises from transcriptionally- and physiologically-distinct classes of PF neurons that are also reciprocally connected with functionally-distinct cortical regions, differentially innervate striatum neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and motor circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum.

neuroscience↗

bioRxiv2018

Radial glial lineage progression and differential intermediate progenitor amplification underlie striatal compartments and circuit organization

The circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of and relationships between these organizations are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPSs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPMs) with expanded capacity. Remarkably, direct and indirect pathway SPNs arise within both aIPS and bIPM pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry organization.

neuroscience↗

bioRxiv2017

A High Resolution Whole Brain Imaging Using Oblique Light Sheet Tomography

Present light sheet fluorescence microscopes lack the wherewithal to image the whole brain (large tissues) with uniform illumination/detection parameters and high enough resolution to provide an understanding of the various aspects of neuroanatomy. To overcome this, we developed an oblique version of the light sheet microscope (Oblique Light Sheet Tomography, OLST) that includes a high magnification objective and serial sectioning, for volumetric imaging of the whole mouse brain at high spatial resolution at constant illumination/detection. We developed a novel gelatin based re-embedding procedure that makes the cleared brain rigid so that it can sectioned using our integrated microtome. Here, we characterize OLST and show that it can be used to observe dendritic morphology, spines and follow axons over a few mm in the mouse brain.

neuroscience↗