Biology subjects

Nagaeva, E.

Publications and source records attributed to Nagaeva, E..

7 recordsLinked to original sources

bioRxiv2026

A roadmap for enriching rare cell populations from human post-mortem brain, demonstrated by 100% microglial purity.

Understanding brain disease requires studying the specific cell types that drive each condition: microglia in Alzheimers, dopaminergic neurons in Parkinsons, motor neurons in ALS, and many others. For most of these rare populations, protocols to isolate them from human post-mortem brain at the required purity have never been developed. The shared hurdles are reliable nuclear markers, compatible fluorescent dyes, antibody host-species cross-reactivity, and achieving pure rather than merely enriched populations. Here we present a generalisable roadmap for developing fluorescence-activated nuclear sorting (FANS) protocols for rare cell populations in human brain. We demonstrate it on microglia, reaching 100% purity in cortex and 98% in cerebellum, with the cortex sort simultaneously yielding astrocytes at 93% purity. The roadmap tackles each hurdle including an on-bench antibody labelling step that expands fluorescence channels without cross-reactivity problem and an affordable single-nucleus RNA-seq validation workflow, giving labs a pathway for enriching any rare cell type reliably.

neuroscience↗

bioRxiv2026

Decades of Parkinson's disease neuropathology yield a sparse and underpowered map of neuronal vulnerability: a systematic review and meta-analysis

Selective vulnerability is widely assumed in Parkinson's disease (PD), but whether dopaminergic neurons of the substantia nigra are uniquely vulnerable has not been established. Explanations of neuronal degeneration in Parkinson's disease often centre on the distinctive properties of substantia nigra dopaminergic neurons. Whether these properties are necessary for substantial neuronal loss remains unclear. We preregistered a systematic review of 166 post-mortem case-control studies published between 1963 and 2025 and synthesised neuronal counts and densities from 152 studies using a multilevel meta-analysis. After six decades, only 18% of countable brain atlas labels had been examined, and most populations were represented by a single study. Substantial loss beyond dopaminergic and classically pigmented populations shows that neither dopaminergic identity nor neuromelanin is necessary for marked degeneration, challenging key tenets of selective vulnerability in PD. Comparisons across other anatomical and physiological features remain limited by sparse sampling and uncertainty. We identify less-studied populations with substantial estimated loss and estimate the additional sampling needed to improve precision under specified assumptions. These findings direct replication and comparative counting towards uncertainties that limit explanations of neuronal loss across affected and potentially spared populations.

neuroscience↗

bioRxiv2025

JNK regulates GABAAR expression at the cell surface via the receptor clustering protein GIT1 (ArfGAP1)

GABAA-type receptors (GABAARs) mediate fast and tonic inhibition and are essential for maintaining excitatory/inhibitory balance in neural circuits. Disrupted GABAergic signaling leads to maladaptive changes associated with neuropsychiatric disorders, yet the mechanisms that regulate GABAAR surface availability remain incompletely understood. We previously identified that the stress-activated kinase JNK1 drives anxiety-like behaviours in mice suggesting a potential link between stress signalling and GABAergic regulation. Here, we show that genetic deletion or inhibition of JNK1 increases surface expression of {beta}3-containing GABAARs at extrasynaptic sites and at excitatory synapses where they may participate in shunting inhibition. We identify the signalling scaffold GIT1 as a direct JNK1 substrate, phosphorylated at S371, and find that GIT1 accumulates in dendritic spines in Jnk1-/- neurons or following JNK inhibition, whereas the phosphomimetic GIT1-S371D is excluded. Moreover, GIT1 is required for JNK-dependent regulation of {beta}3-GABAAR trafficking. Accordingly, neurons from Jnk1-/- mice exhibit increased spontaneous inhibitory postsynaptic potentials and enhanced tonic inhibition. These results reveal a JNK1-GIT1 signalling axis that suppresses GABAAR stability and inhibitory tone, providing a mechanism by which the stress-activated JNK pathway modulates synaptic and extrasynaptic inhibition.

neuroscience↗

bioRxiv2024

Effects of serotonin agonists LSD and 25CN-NBOH on conditioned place preference and on synaptic plasticity of VTA dopamine neurons in mice

The current research on psychedelic compounds such as lysergic amide diethylamide (LSD) is leaning heavily on the notion that psychedelics are not addictive. While much of the literature supports this argument, some of the common use patterns and the descriptions of the subjective effects of these compounds in humans, together with rather lacking and mixed data from non-human animal studies leave room for questions of potentially rewarding or reinforcing stimulus effects. Initiated by a surprising finding in a control study, we investigated these potential rewarding effects of LSD and a selective 5-HT2A agonist 25CN-NBOH using both unbiased and biased designs of conditioned place preference as well as ex vivo patch-clamp electrophysiology measurements of glutamatergic synaptic plasticity on midbrain ventral tegmental area (VTA) dopamine neurons in C57Bl6/J mice. Our results showed no reliable formation of place preference with either compound, agreeing with previous claims of psychedelics having at most weak reinforcing effects. However, we did observe single doses of the drugs, especially LSD, inducing synaptic plasticity in the medially located VTA dopamine neurons, implicating a role for the midbrain dopamine system in the effects of psychedelic drugs. Graphical abstractTreatment with mixed serotonin receptor agonist, psychedelics lysergic acid diethylamide (LSD) or selective serotonin 2A receptor agonist 25CN-NBOH did not cause reliable induction of conditioned place preference in C57Bl/6J mice. However, we did observe single doses of the drugs, especially LSD, inducing synaptic plasticity in the medially located VTA dopamine neurons. These findings challenge some of the previous rodent data but are in general in line with the claims of psychedelics having at most weak reinforcing effects. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/628157v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@57a87org.highwire.dtl.DTLVardef@1af3827org.highwire.dtl.DTLVardef@8fb256org.highwire.dtl.DTLVardef@5504b_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Motor learning is regulated by GDNF levels in postnatal cerebellar Purkinje cells

Purkinje cells, the sole output neurons of the cerebellar cortex, are crucial for cerebellum-dependent motor learning. Previously we demonstrated that a ubiquitous 2-3-fold increase of endogenous glial cell line-derived neurotrophic factor (GDNF) improves motor learning. However, GDNF impacts many organ systems and cell types throughout the body leaving the underlying mechanism elusive. Here, we utilize an innovative conditional GDNF Hypermorphic mouse model to show that a 2-fold increase in endogenous GDNF specifically in postnatal Purkinje cells (PCs) is sufficient to enhance motor learning in adult animals. We demonstrate that improved motor learning is associated with increased glutamatergic input to PCs and elevated spontaneous firing rate of these cells, opposite to cerebellar ataxia where reduction in motor function and learning associates with decreased spontaneous activity of PCs. Notably, the GDNF expression levels variation range studied in our mouse models cerebellum falls within the normal range of variation observed in healthy human cerebellums. Our findings uncover a molecular pathway and a specific cell type that regulate motor learning, potentially explaining some individual differences in human motor skill acquisition.

neuroscience↗

bioRxiv2023

Somatostatin-expressing neurons in the ventral tegmental area innervate specific forebrain regions and are involved in the stress response

Expanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Recently, we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighbouring dopaminergic neurons (Nagaeva et al., 2020). Here, we report that VTA Sst neurons especially from the anterolateral part also project far outside the VTA and innervate several forebrain regions that are mainly involved in the regulation of emotional behaviour. Deletion of these VTA Sst neurons affected several behaviours and drug responses, such as home cage activity, sensitization of locomotor activity to morphine, fear conditioning responses, and reactions to inescapable stress of forced swimming, often in a sex-dependent manner. Together, these data demonstrate that VTA Sst neurons have selective projection targets, which are distinct from the main targets of VTA dopamine neurons and involved in the regulation of a variety of behaviours mostly associated with the stress response. This, makes Sst neurons a meaningful addition to the remote VTA circuit and stress-related neuronal network.

neuroscience↗

bioRxiv2020

Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area

The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.

neuroscience↗