Ketamine in the Regulation of Behavioral States in Zebrafish

Investigating the Role of Ketamine in the Regulation of Behavioral States in Zebrafish Larvae

Animals adjust to evolving surroundings by integrating prior experiences, a process influenced by temporary disruptions such as emotional occurrences or psychotropic agents. These transient disturbances can produce enduring impacts on neural circuitry and behavior, significantly outlasting the original stimulation. Comprehending the mechanisms of these alterations necessitates a model system that facilitates the observation of both immediate and prolonged effects on global brain activity during behavior.

The larval zebrafish offers a distinct advantage for these experiments. Its optical transparency enables researchers to concurrently see virtually all brain cells while the fish engages in "fictive" activities within a virtual reality environment. A notable trait in zebrafish is futility-induced passivity, a phenomenon wherein the fish shift from active swimming to a passive condition when their swimming becomes ineffective, similar to "giving up."

This behavior originates from an intrinsic reaction termed the optomotor response (OMR), wherein zebrafish move in accordance with visual motion to maintain their location. When swimming ceases to produce forward propulsion, zebrafish initially intensify their exertion but ultimately discontinue swimming entirely. Research has found a noradrenergic-astroglial circuit in the hindbrain that combines futility signals and inhibits swimming via calcium signaling in astrocytes.

Mammals exhibit a comparable behavioral shift when confronted with inescapable stressors, as evidenced by forced swim tests and tail suspension experiments. These passive states, frequently linked to coping mechanisms such as learned helplessness, can be influenced by substances like ketamine, a medication that has fast antidepressant effects in humans. The effects of ketamine on zebrafish behavior have been previously investigated. In adult and larval zebrafish, it has acute anxiolytic effects, while in juveniles, it has been demonstrated to mitigate passivity following inescapable shocks via modulating activity in the habenula and raphe areas of the brain. Nonetheless, the exact mechanisms, especially how it has both immediate and enduring effects on neural and non-neuronal cells, are still unclear.

In animals, the effects of ketamine are varied. In addition to functioning as a dissociative anesthetic, it is recognized for mitigating learned helplessness in rats and serving as a rapid-acting antidepressant in humans. Ketamine engages several molecular targets, primarily the NMDA receptor, and its extensive effects impact different brain areas, such as the prefrontal cortex, serotonergic receptor, dopaminergic systems, and astroglial networks. The role of astrocytes in alterations in behavioral states renders them essential for comprehending the effects of ketamine. Astrocytes are crucial for the integration of brain impulses and the regulation of behavioral responses. Utilizing the optical accessibility of the larval zebrafish brain, researchers want to elucidate how ketamine influences both neuronal and non-neuronal activity during futility-induced inactivity. This research aims to elucidate the intricate relationship between brain circuits and behavioral state transitions, providing enhanced understanding of ketamine's effects and perhaps guiding future therapies for mood disorders.

Zebra Fish Istock:ALesik

Source & Further Reading

Duque, Marc, Alex B. Chen, Eric Hsu, Sujatha Narayan, Altyn Rymbek, Shahinoor Begum, Gesine Saher et al. "Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance." Neuron (2024). DOI: 10.1016/j.neuron.2024.11.011