Biology subjects

Garaschuk, O.

Publications and source records attributed to Garaschuk, O..

9 recordsLinked to original sources

bioRxiv2025

Glomerulus-specific inhomogeneity of the basal activity map in the olfactory bulb supports olfactory-driven behavior

Glomeruli are signal-processing units of the olfactory bulb (OB), playing a key role in many OB computations, including contrast enhancement, gain control, and odorant-selective habituation. In awake mice, we uncover an extremely stable inhomogeneous map of basal glomerulus-specific activity as a background against which olfactory signal processing is performed. This activity is strongly driven by (i) centrifugal cholinergic projections, (ii) endogenous, and (iii) airflow-evoked spiking of olfactory sensory neurons and, to a small extent, (iv) by the odor environment. Importantly, early olfactory impairment in a mouse model of Alzheimers disease is parallelled by the loss of glomerular map inhomogeneity and diminished cholinergic innervation. These results reveal an important layer in the signal-processing network of the OB, likely acting by increasing the variance in and dynamic range of the system via glomerulus-specific functional inhomogeneity. TeaserA new layer in the signal-processing network of the olfactory bulb supports olfactory-driven behavior.

neuroscience↗

bioRxiv2025

Early postnatal CA3 hyperexcitability drives hippocampal development and epileptogenesis in SCN2A developmental and epileptic encephalopathy

Developmental and epileptic encephalopathies caused by pathogenic variants in SCN2A (SCN2A-DEE), encoding the voltage-gated sodium channel Nav1.2, present with early-life seizures, developmental delay, and increased mortality. Using a novel Scn2a p.A263V gain-of-function (GOF) mouse model, we demonstrate gene-dose and background-dependent phenotypes ranging from self-limited neonatal seizures to chronic epilepsy with high mortality. In vivo electrophysiology revealed hippocampal seizures as early as postnatal day 2.5, with CA3-driven gamma oscillations preceding seizure onset. CA3 and CA1 pyramidal neurons exhibited transient hyperexcitability during early postnatal development, resolving by P24-30. Single-cell RNA sequencing uncovered gene dose-dependent accelerated maturation of hippocampal networks, peaking at P7, alongside widespread transcriptional changes in excitatory and inhibitory neurons. In adulthood, persistent hippocampal network alterations emerged, marked by reduced mid-gamma oscillations and theta-gamma coupling. Our findings establish hippocampal CA3 hyperexcitability as an early driver of epileptogenesis in SCN2A-DEE and highlight it as a potential therapeutic target to mitigate disease progression.

neuroscience↗

bioRxiv2025

Global metabolic reprogramming and sex-specific impact of caloric restriction in a mouse model of Alzheimer's disease

BackgroundAlzheimers disease (AD), disproportionally affecting women, is generally regarded as a disease of the brain. Yet, cumulative evidence increasingly supports a more systemic, full-body view on this incurable disorder, with the liver and kidneys playing an important role in amyloid clearance. The latter is likely potentiated by caloric restriction (CR), but its impact on the metabolism of key amyloid-handling tissues is poorly understood. MethodsWe examined the sex-specific effects of amyloidosis and CR on oxidative and metabolic processes in APPPS1 mice, expressing mutant amyloidogenic proteins under the neuronal Thy-1 promoter. Wild-type (WT) and APPPS1 mice were either fed ad libitum (AL) or received 70% of their individual AL intake (CR regimen). ResultsCompared to age-matched WT controls, the brain, liver, and kidney of 9-month-old AL APPPS1 mice exhibited higher levels of oxidative stress markers along with altered activity of antioxidant enzymes, including higher superoxide dismutase and lower catalase activity. These differences were sex- and tissue-specific, with kidneys showing the largest AD-induced differences between sexes. As for key glycolytic enzymes, APPPS1 mice possessed higher activity of pyruvate kinase than WT mice in all organs and higher hexokinase and phosphofructokinase activities in the brain, with stronger effects observed in males. CR intensified oxidative stress in the liver and the female brain but reduced it in the female kidney. Moreover, it potentiated glycolysis predominantly in females and modulated glutathione-dependent enzymes in a sex-dependent manner. ConclusionsNeuron-driven amyloidosis induces strong and significant metabolic changes in the entire body, encompassing ubiquitous oxidative damage, enhancement of glycolysis, and antioxidant defense. The lower activity of glycolytic enzymes in the female brain and decreased antioxidant defense in the female liver and kidney provide yet another facet to the complex picture of female vulnerability in AD. Females seemed to profit more from CR, but the general CR effect was not very strong.

neuroscience↗

bioRxiv2024

Impairment of brain function in a mouse model of Alzheimer's disease during the pre-depositing phase: the role of alpha7 nicotinic acetylcholine receptors

Alzheimers disease (AD) is an age-dependent incurable neurodegenerative disorder accompanied by neuroinflammation, amyloid accumulation and memory impairment. It begins decades before the first clinical symptoms appear, and identifying early biomarkers is key for developing disease-modifying therapies. We show now in a mouse model of AD that before any amyloid deposition the brains of 1.5-month-old mice contain increased levels of pro-inflammatory cytokines IL-1{beta} and IL-6, decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain and brain mitochondria and increased amounts of 7 nAChR-bound A{beta}1-42, along with impaired episodic memory and increased risk of apoptosis. Both acute (1-week-long) and chronic (4-month-long) treatments with 7-selective agonist PNU282987, starting at 1.5 months of age, were well tolerated. The acute treatment did not affect the levels of soluble A{beta}1-42 but consistently upregulated the 7 nAChR expression, decreased the level of 7- A{beta}1-42 complexes and improved episodic memory of 1.5-month-old mice. The chronic treatment, covering the disease development phase, strongly upregulated the expression of all abundant brain nAChRs, reduced both free and 7-coupled A{beta}1-42 within the brain, had anti-inflammatory and antiapoptotic effects, and potently upregulated cognition, thus identifying 7 nAChRs as both early biomarker and potent therapeutic target for fighting this devastating disease.

neuroscience↗

bioRxiv2024

Morphotype-specific calcium signaling in human microglia

Key functions of Ca2+ signaling in rodent microglia include monitoring the brain state or the surrounding neuronal activity and sensing the danger or damage in their vicinity. Microglial Ca2+ dyshomeostasis is a disease hallmark in many mouse models of neurological disorders but the Ca2+ signal properties of human microglia remain unknown. Using a newly developed toolbox, we analyzed in situ Ca2+ signaling of decades-old human cortical microglia. The data revealed marked compartmentalization of Ca2+ signals, with signal properties differing across the compartments and resident morphotypes. The basal Ca2+ levels were low in ramified and high in ameboid microglia. The fraction of cells with ongoing Ca2+ signaling, the fraction and the amplitude of process Ca2+ signals and the duration of somatic Ca2+ signals decreased when moving from ramified via hypertrophic to ameboid microglia. In contrast, the size of active compartments, the fraction and amplitude of somatic Ca2+ signals and the duration of process Ca2+ signals increased along this pathway.

immunology↗

bioRxiv2022

Microglial colonisation of the developing brain is facilitated by clonal expansion of highly proliferative progenitors and follows an allometric scaling

Microglia are the resident immune cells of the brain and arise from yolk sac-derived macrophages during early embryogenesis. On entering the brain, microglia undergo in situ proliferation and eventually colonise the entire brain by the second and third postnatal weeks in mice. However, the intricate dynamics of their developmental expansion remain unclear. Here, we examine and characterise the proliferative dynamics of microglia during embryonic and postnatal development. Using complementary fate-mapping techniques, we demonstrate that the developmental colonisation of the brain by microglia is facilitated by clonal expansion of highly proliferative microglial progenitors that occupy spatial niches throughout the brain. We also find that the distribution of microglia switches from a clustered to a random pattern between embryonic and late postnatal development. Moreover, the developmental increase in microglia follows the proportional growth of the brain in an allometric manner with the density of microglia eventually stabilising when the mosaic distribution has been established. Overall, our findings offer insight into how the competition for space acts as a driving force for microglial colonisation by clonal expansion during development.

neuroscience↗

bioRxiv2021

Patterned endogenous activity controls migration, morphogenesis and survival of adult-born neurons in the mouse olfactory bulb

The development and survival of adult-born neurons is believed to be driven by sensory signaling. By genetically manipulating excitability of adult-born cells (via cell-specific overexpression of either Kv1.2 or Kir2.1 K+ channels), longitudinal in vivo monitoring of their Ca2+ signaling and transcriptome analyses, we show that endogenous but not sensory-driven activity governs migration, morphogenesis, survival, and functional integration of adult-born juxtaglomerular neurons in the mouse olfactory bulb. The proper development of these cells required fluctuations of cytosolic Ca2+ levels, phosphorylation of CREB, and pCREB-mediated gene expression. Attenuating Ca2+ fluctuations via K+ channel overexpression strongly downregulated genes involved in neuronal migration, differentiation, and morphogenesis and upregulated apoptosis-related genes, thus locking adult-born cells in the vulnerable and immature state. Together, the data reveal signaling pathways connecting the endogenous intermittent neuronal activity/Ca2+ fluctuations as well as proper Kv1.2/Kir2.1 K+ channel function to migration, maturation, and survival of adult-born neurons.

neuroscience↗

bioRxiv2021

Stable behavioral state-specific large scale activity patterns in the developing cortex of neonates

Endogenous neuronal activity is a hallmark of the developing brain. In rodents, a handful of such activities were described in different cortical areas but the unifying macroscopic perspective is still lacking. Here we combined large-scale in vivo Ca2+ imaging of the dorsal cortex in non-anesthetized neonatal mice with advanced mathematical analyses to reveal unique behavioral state-specific maps of endogenous activity. These maps were remarkably stable over time within and across experiments and used patches of correlated activity with little hemispheric symmetry as well as stationary and propagating waves as building blocks. Importantly, the maps recorded during motion and rest were almost inverse, with sensory-motor areas active during motion and posterior-lateral areas active at rest. The retrosplenial cortex engaged in both resting- and motion-related activities, building functional long-range connections with respective cortical areas. The data obtained bind different region-specific activity patterns described so far into a single consistent picture and set the stage for future inactivation studies, probing the exact function of this complex activity pattern for cortical wiring in neonates.

neuroscience↗

bioRxiv2020

Enhanced ongoing endogenous activity predicts elimination of adult-born neurons in the mouse olfactory bulb

Adult-born cells, arriving daily into the rodent olfactory bulb, either integrate into the neural circuitry or get eliminated. Whether these two populations differ in their morphological or functional properties remains, however, unclear. Using longitudinal in vivo two-photon imaging, we monitored dendritic morphogenesis, odor-evoked responsiveness, endogenous Ca2+ signaling, and survival/death of adult-born juxtaglomerular neurons (abJGNs). We found that maturation of abJGNs is accompanied by a significant reduction in dendritic complexity, with surviving and subsequently eliminated cells showing similar degrees of dendritic remodeling. Surprisingly, 63% of eliminated abJGNs acquired odor-responsiveness before death, with amplitudes and time courses of odor-evoked responses similar to those recorded in surviving cells. We observed, however, a significant long-lasting enhancement of endogenous Ca2+ signaling in subsequently eliminated abJGNs, visible already 6 days before death. These findings identify ongoing endogenous Ca2+ signaling as a key predictor of abJGNs fate.

neuroscience↗