Biology subjects

Korotkova, T.

Publications and source records attributed to Korotkova, T..

5 recordsLinked to original sources

bioRxiv2026

Oxytocin receptor Gαi signaling drives valence reassignment to facilitate reversal of social trauma-induced avoidance

Traumatic social experiences often generate social deficits that form the core symptom of psychopathologies like social anxiety disorder (SAD). The failure to overwrite these aversive social associations is a fundamental barrier to recovery from SAD. Using the mouse social fear conditioning (SFC) paradigm, we identify a discrete population of oxytocin receptor (OXTR)-expressing neurons in the caudal lateral septum (LScOXTR) that act as a critical hub for adaptive learning during social fear extinction. Using calcium imaging in mice undergoing extinction training, we show that successful valence reassignment is best predicted by the precise temporal inhibition of LScOXTR neurons during the contact phase of social investigation. This contact-associated suppression of LScOXTR neurons was absent in mice that failed to extinguish fear. Notably, successful extinction was also associated with enhanced oxitocinerg innervation within the LSc. Chemogenetic silencing of LScOXTR neurons prior to extinction impaired extinction, indicating that a specific temporal activity pattern of LScOXTR neurons is necessary for adaptive learning. Pharmacological dissection of downstream OXTR signaling revealed that selective activation of Gi-coupled, but not Gq-coupled, signaling accelerated extinction and promoted social approach. Our findings establish that extinction success is governed by the temporally precise, Gi-mediated silencing of LScOXTR neurons during social contact, revealing a novel mechanism for adaptive social valence processing with direct implications for treatment-resistant SAD.

neuroscience↗

bioRxiv2026

Top-down regulation of ingestive behavior fragmentation

AbstractIn natural environments, animals rarely feed continuously to satiation; instead, feeding occurs in brief bouts separated by pauses. This fragmentation is thought to balance internal drives with external demands, yet its underlying neural mechanisms remain unclear. By combining bidirectional neural activity mapping and behavioral phenotyping, we identify a projection from the dorsal subiculum (dSub) of the hippocampus to the mammillary body (MB) as a key regulator of this fragmentation. Activity along the dSub-MB pathway tracks and gates the duration of individual feeding bouts, independent of homeostatic state. A simple bistable attractor model captures both dSub-MB neural dynamics and associated behaviors across optogenetic and behavioral perturbations. Together, these findings identify a top-down circuit mechanism that implements action selection in a naturalistic setting.

neuroscience↗

bioRxiv2024

Endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses

The selective loss of cerebellar Purkinje cells is a hallmark of various neurodegenerative movement disorders, yet the precise mechanism driving their degeneration remains enigmatic. Here, we show that the endocytic adaptor protein complex 2 (AP-2) is essential for the survival of Purkinje cells. Employing a multidisciplinary approach encompassing mouse genetics, viral tracing, ex vivo calcium imaging, and kinematic analysis, we demonstrate that mice lacking the {micro}-subunit of AP-2 in cerebellar Purkinje cells exhibit early-onset ataxia associated with progressive Purkinje cell degeneration. Importantly, we uncover that synaptic input dysfunctions, characterized by a predominance of parallel fiber (PF) over climbing fiber (CF) synapses, precede Purkinje cell loss. Mechanistically, we find that AP-2 localizes to Purkinje cell dendrites, where it interacts with the PF synapse-enriched protein GRID2IP. The loss of AP-2 results in proteasome-dependent degradation of GRID2IP and accumulation of the glutamate {delta}2 receptor (GLUR{delta}2) in distal Purkinje cell dendrites, leading to an excess of PF synapses while CF synapses are drastically reduced. The overrepresentation of PF synaptic input induces Purkinje cell hyperexcitation, which can be alleviated by enhancing synaptic glutamate clearance using the antibiotic ceftriaxone. Our findings demonstrate the critical role of AP-2 in preventing motor gait dysfunctions by regulating GRID2IP levels in Purkinje cells, thereby preserving the equilibrium of PF and CF synaptic inputs in a cell-autonomous manner.

neuroscience↗

bioRxiv2024

AutoGaitA - Automated Gait Analysis in Python

Individual behaviours require the nervous system to execute specialised motor programs, each characterised by unique patterns of coordinated movements across body parts. Deep learning approaches for body-posture tracking have facilitated the analysis of such motor programs. However, translating the resulting time-stamped coordinate datasets into meaningful kinematic representations of motor programs remains a long-standing challenge. We developed the versatile quantitative framework AutoGaitA (Automated Gait Analysis), a Python toolbox that enables comparisons of motor programs at multiple levels of granularity and across tracking methods, species and behaviours. AutoGaitA allowed us to demonstrate that flies, mice, and humans, despite divergent biomechanics, converge on the age-dependent loss of propulsive strength, and that, in mice, locomotor programs adapt as an integrated function of both age and task difficulty. AutoGaitA represents a truly universal framework for robust analyses of motor programs and changes thereof in health and disease, and across species and behaviours.

animal behavior and cognition↗

bioRxiv2018

Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy

Plasticity related gene 1 encodes a cerebral neuron-specific synaptic transmembrane protein that modulates hippocampal excitatory transmission on glutamatergic neurons. In mice, homozygous Prg1-deficiency results in juvenile epilepsy. Screening a cohort of 18 patients with infantile spasms (West syndrome), we identified one patient with a heterozygous mutation in the highly conserved third extracellular phosphatase domain (p.T299S). The functional relevance of this mutation was verified by in-utero electroporation of a mutant Prg1 construct into neurons of Prg1-knockout embryos, and the subsequent inability of hippocampal neurons to rescue the knockout phenotype on the single cell level. Whole exome sequencing revealed the index patient to additionally harbor a novel heterozygous SCN1A variant (p.N541S) that was inherited from her healthy mother. Only the affected child carried both heterozygous PRG1 and SCN1A mutations. The aggravating effect of Prg1-haploinsufficiency on the epileptic phenotype was verified using the kainate-model of epilepsy. Double heterozygous Prg1-/+|Scn1awt/p.R1648Hmice exhibited higher seizure susceptibility than either wildtype, Prg1-/+, or Scn1awt/p.R1648H littermates. Our study provides evidence that PRG1-mutations have a potential modifying influence on SCN1A-related epilepsy in humans.

neuroscience↗