Biology subjects

Zhukovskaya, A.

Publications and source records attributed to Zhukovskaya, A..

5 recordsLinked to original sources

bioRxiv2025

Stress resilience is associated with transcriptional remodeling in the VTA

Individual responses to chronic stress vary, with some individuals remaining resilient while others exhibit susceptibility. The ventral tegmental area (VTA), a region involved in reward learning, and the lateral habenula (LHb), a region involved in aversive learning, have been implicated in the pathophysiology of stress-related mood disorders. Here, we seek to understand the molecular adaptations in these regions at the level of single cells that mediate susceptibility versus resilience. In particular, it remains unclear whether, at the level of gene expression, different cell types within different brain regions mediate stress susceptibility versus resilience, or if these phenotypes are mediated by distinct trajectories within the same cell types. To address this gap, we performed single-nucleus RNA-sequencing of LHb and VTA of mice subjected to chronic social defeat stress. While we found minimal gene expression changes in the LHb after stress, the VTA exhibited widespread, cell type-specific transcriptional remodeling in resilient individuals and few gene expression changes in susceptible individuals. Across VTA cell types, resilience was associated with the coordinated upregulation of genes involved in intercellular signaling and neural communication, with maintenance of receptor-ligand interaction strength in resilience that was not present in susceptibility. Within VTA neurons, gene expression changes were most prominent in glutamatergic and dopaminergic clusters. Multivariate analyses of dopamine and glutamate subclusters showed that resilient neurons diverged more from control than susceptible neurons, but along a similar trajectory, supporting a model in which resilience reflects greater stress-related adaptations in these cell types. Together, these findings highlight the VTA as a key site of molecular plasticity in stress resilience and therefore a potential therapeutic target.

neuroscience↗

bioRxiv2023

Differences in an aversive teaching signal produce brainwide and behavioral substrates of susceptibility

Some individuals are susceptible to the experience of chronic stress and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After, but not before, chronic social defeat stress (CSDS), the LHb is active when susceptible mice are in the proximity of the aggressor strain. During stress itself, LHb activity is higher in susceptible mice during aggressor proximity, and activation of the LHb during stress biases mice towards susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical versus cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.

neuroscience↗

bioRxiv2023

A rapid and bidirectional reporter of neural activity reveals neural correlates of social behaviors in Drosophila

Neural activity is modulated over different timescales encompassing sub-seconds to days reflecting changes in external environment, internal state, and behavior. Using Drosophila as a model, we have developed a rapid and bidirectional reporter that provides a robust cellular readout of recent neural activity. This reporter utilizes nuclear vs cytoplasmic distribution of CREB-regulated transcriptional coactivator, CRTC. Subcellular distribution of GFP-tagged CRTC (CRTC::GFP) bidirectionally changes on the order of minutes and reflects both increases and decreases in neural activity. We establish an automated machine-learning-based routine for efficient quantification of reporter signal. Using this reporter, we demonstrate acute mating- evoked activation of peptidergic neurons. We further investigate the functional role of the master courtship regulator gene, fruitless, and show that fruitless is necessary to ensure activation of male arousal neurons by female cues. Together, our results establish CRTC::GFP as a bidirectional reporter of recent neural activity suitable for examining neural correlates in behavioral contexts.

neuroscience↗

bioRxiv2019

Choice-selective sequences in cortical inputs to the NAc provide a potential substrate for credit assignment

How are actions linked with subsequent outcomes to guide choices? The nucleus accumbens, which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex and midline regions of the thalamus. However, little is known about whether and how representations differ across these input pathways. By comparing these inputs during a reinforcement learning task in mice, we discovered that prelimbic cortical inputs preferentially represent actions and choices, whereas midline thalamic inputs preferentially represent cues. Choice-selective activity in the prelimbic cortical inputs is organized in sequences that persist beyond the outcome. Through computational modeling, we demonstrate that these sequences can support the neural implementation of reinforcement learning algorithms, both in a circuit model based on synaptic plasticity, and one based on neural dynamics. Finally, we test and confirm predictions of our circuit models by direct manipulation of nucleus accumbens input neurons. Thus, we integrate experiment and modeling to suggest neural solutions for credit assignment.

neuroscience↗

bioRxiv2018

Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses

Taste circuits are genetically determined to elicit an innate appetitive or aversive response, ensuring that animals consume nutritious foods and avoid the ingestion of toxins. We have examined the response of the fruit fly Drosophila melanogaster to acetic acid, a tastant that can be a metabolic resource but can also be toxic to the fly. Our data reveal that flies accommodate these conflicting attributes of acetic acid by virtue of a hunger-dependent switch in their behavioral response to this stimulus. Fed flies show taste aversion to acetic acid, likely a response to its potential toxicity, whereas starved flies show a robust appetitive response that may reflect their overriding need for calories. These opposing responses are mediated by two different classes of taste neurons. Acetic acid activates both the sugar and bitter pathways, which have opposing effects on feeding behavior. Hunger shifts the response from aversion to attraction by enhancing the appetitive sugar pathway as well as suppressing the aversive bitter pathway. Thus a single tastant can drive opposing behaviors by activating distinct taste pathways modulated by internal state.

neuroscience↗