Biology subjects

Zelikowsky, M.

Publications and source records attributed to Zelikowsky, M..

6 recordsLinked to original sources

bioRxiv2026

Extended amygdala orchestrates social motivation in socially isolated mice

Juveniles deprived of social contact for an extended period of time demonstrate a broad range of adverse effects on behavior, including increased social aversion. Employing our recently developed integrative assay to assess social aversion, we discovered that social isolation is sufficient to induce decreases in social motivation and increases in social fear and hesitancy. Unsupervised behavioral analyses revealed that social aversion in isolated mice is largely driven by an inflexible, anxiety-like state marked by heightened social vigilance. Using intersectional, projection-specific neural circuit perturbations and in vivo imaging, we discovered that isolation-induced decreases in social motivation are governed by an underexplored projection from the anterodorsal bed nucleus of the stria terminalis (adBNST) to the nucleus accumbens (NAc). These findings illustrate the complexity with which juvenile isolation serves to negatively impact social behavior and identify a novel circuit through which animals integrate information about social state to orchestrate changes in social motivation.

neuroscience↗

bioRxiv2025

Stress induces distinct social behavior states encoded by the ventral hippocampus

A single, acute traumatic experience can result in a host of negative impacts on behavior, such as increased violence, reduced sociability, and exaggerated fear responses. Despite the large body of research on the neurobiology of stress, we have a poor understanding of how trauma rewires social circuits in the brain. To identify how social circuits are re-organized by stress, we interrogated the role of the ventral hippocampus (VH), a key node for both the orchestration of emotionally-relevant behavior and the integration of sensory information. Using a footshock-based model of traumatic stress, we established that a single exposure to a series of unpredictable, inescapable footshocks was sufficient to negatively alter social behavior, resulting in increased violence and social hesitancy. Critically, we found that stress-induced changes to social behavior engaged neural ensembles in the VH, a critical node in the regulation of emotion states. Using a virally-mediated, activity-dependent cellular tagging approach to label two neural ensembles activated by temporally distinct experiences, we were surprised to find that stress-induced violence and stress-induced social hesitancy recruited largely non-overlapping populations of cells in the VH, in contrast to higher degrees of ensemble overlap in unstressed control mice, suggesting that stress biases the brain towards stronger differentiation of distinct social states. Additionally, we found that activity of VH neurons was required for stress-induced aggression. Finally, we found that stress-induced changes to social behaviors and VH activity profiles could be reversed by the introduction of social buffering post-stress. Collectively, our findings suggest that stress drives the VH to dissociably encode specific behavioral states, rather than a single state of negative valence, consistent with a role for multiple structures and distributed ensembles in the modulation of traumatic stress.

neuroscience↗

bioRxiv2025

Co-release of opposing signaling molecules from cortical neurons controls the escalation and release of aggression

Neuropeptides exert broad effects across the brain to influence behavior. However, the mechanism by which the brain uses neuropeptide signaling to exert top-down control over complex behavioral responses remains poorly understood. Prolonged social isolation induces a distinct internal state that results in sweeping changes to behavior, including increased aggression. Here, we find that isolation-induced aggression activates Tachykinin-2 expressing (Tac2+) neurons in the mouse medial prefrontal cortex (mPFC). Genetic characterization of Tac2+ cells in the mPFC reveals them to be a population of unexplored GABAergic neurons. In-depth behavioral analyses combined with in vivo recordings of neural activity demonstrate that mPFC Tac2+ neurons are tuned to distinct phases of isolation-induced aggression: investigatory behaviors that escalate to attack (aggression escalation) and attack itself (aggression release). Loss-of-function perturbations targeting the release of either Neurokinin B (NkB), the stimulatory peptide encoded by Tac2, or the inhibitory neurotransmitter, GABA, reveal that these signaling molecules exert dissociable control over aggression escalation and release. These findings identify distinct roles for opposing signaling molecules co-released from the same population of cells. This suggests a surprising neurochemical mechanism by which neuropeptidergic populations in the prefrontal cortex exert top-down influence over complex behavior via the co-release of signaling molecules with opposing actions but coordinated impacts on behavior.

neuroscience↗

bioRxiv2024

Inhibitory neurons defined by a synaptogenic molecule impair memory discrimination

The homophilic adhesion molecule Kirrel3 drives synapse formation between dentate granule (DG) neurons and GABA neurons, and Kirrel3 gene variants are associated with neurodevelopmental disorders in humans. However, the circuit function and behavioral relevance of Kirrel3-expressing neurons are unknown. Using intersectional genetics, we identified a population of Kirrel3-expressing GABA neurons that regulate memory discrimination in male and female mice. Using chemogenetics with in vivo electrophysiology and behavioral assays, we discovered that activating Kirrel3-expressing GABA neurons, but not parvalbumin neurons, potently inhibits CA3 neuron activity and impairs contextual memory discrimination during recall, revealing a critical role for these neurons in the retrieval of precise memories. Light and electron microscopy of Kirrel3-expressing GABA neurons suggests that they receive direct excitation from DG neurons and project onto CA3 dendrites. Together, this multi-scale approach demonstrates how cell type-specific expression of adhesion molecules mark subsets of neurons that control key features guiding memory and behavior. SIGNIFICANCE STATEMENTHere, we identified a never-before studied group of inhibitory neurons defined by expression of the gene Kirrel3, which is a synaptic cell adhesion molecule and risk gene for neurodevelopmental disorders. We show that Kirrel3 inhibitory neuron activity exerts exceptionally strong control over CA3 neuron activity and impairs the ability of mice to distinguish between different contexts during memory retrieval. Thus, Kirrel3 inhibitory neurons regulate memory precision in mice, and our study employs a powerful framework linking molecular identity and synaptic specificity to behavioral function in the adult brain.

neuroscience↗

bioRxiv2024

SAUSI: a novel assay for measuring social anxiety and motivation

Social aversion is a key feature of numerous mental health disorders such as Social Anxiety and Autism Spectrum Disorders. Nevertheless, the biobehavioral mechanisms underlying social aversion remain poorly understood. Progress in understanding the etiology of social aversion has been hindered by the lack of comprehensive tools to assess social aversion in model systems. Here, we created a new behavioral task - Selective Access to Unrestricted Social Interaction (SAUSI), which integrates elements of social motivation, hesitancy, decision-making, and free interaction to enable the wholistic assessment of social aversion in mice. Using this novel assay, we found that social isolation-induced social aversion in mice is largely driven by increases in social fear and social motivation. Deep learning analyses revealed a unique behavioral footprint underlying the socially aversive state produced by isolation, demonstrating the compatibility of modern computational approaches with SAUSI. Social aversion was further assessed using traditional assays - including the 3-chamber sociability assay and the resident intruder assay - which were sufficient to reveal fragments of a social aversion phenotype, including changes to either social motivation or social interaction, but which failed to provide a wholistic assessment of social aversion. Critically, these assays were not sufficient to reveal key components of social aversion, including social freezing and social hesitancy behaviors. Lastly, we demonstrated that SAUSI is generalizable, as it can be used to assess social aversion induced by non-social stressors, such as foot shock. Our findings debut a novel task for the behavioral toolbox - one which overcomes limitations of previous assays, allowing for both social choice as well as free interaction, and offers a new approach for assessing social aversion in rodents.

neuroscience↗

bioRxiv2020

The Mouse Action Recognition System (MARS): a software pipeline for automated analysis of social behaviors in mice

The study of naturalistic social behavior requires quantification of animals interactions. This is generally done through manual annotation--a highly time consuming and tedious process. Recent advances in computer vision enable tracking the pose (posture) of freely-behaving animals. However, automatically and accurately classifying complex social behaviors remains technically challenging. We introduce the Mouse Action Recognition System (MARS), an automated pipeline for pose estimation and behavior quantification in pairs of freely interacting mice. We compare MARSs annotations to human annotations and find that MARSs pose estimation and behavior classification achieve human-level performance. We also release the pose and annotation datasets used to train MARS, to serve as community benchmarks and resources. Finally, we introduce the Behavior Ensemble and Neural Trajectory Observatory (BENTO), a graphical user interface for analysis of multimodal neuroscience datasets. Together, MARS and BENTO provide an end-to-end pipeline for behavior data extraction and analysis, in a package that is user-friendly and easily modifiable.

neuroscience↗