(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice

Social isolation significantly impacts mental health, leading to cognitive dysfunction and depression. Reduced social interaction during childhood particularly contributes to adult social cognition impairments. Rodent models demonstrate that prolonged social isolation (>2 weeks) causes behavioral abnormalities, including reduced sociability. Maintaining social cognitive function involves the insula and prefrontal cortices, but the precise neural regions involved in recovery from social cognitive dysfunction, especially in response to therapeutic interventions, remain unclear. Ketamine, a racemic mixture of (S)- and (R)-ketamine, exhibits rapid antidepressant effects and improves negative emotional behaviors. Its potential to improve cognitive dysfunction in rodent models and patients with depression is also recognized. The rapid antidepressant effects are attributed to neuroplastic changes in the prefrontal cortex, BDNF-TrkB signaling activation, and suppression of neural bursts under stress. However, the efficacy of each ketamine enantiomer is controversial, and understanding the underlying neural mechanisms is crucial for developing effective therapies. Studies have revealed differences in the biochemical properties of the enantiomers; for example, (S)-ketamine has stronger N-methyl-D-aspartate (NMDA) receptor inhibition properties than (R)-ketamine. (R)-ketamine shows synergistic effects in the frontal cortex, while (S)-ketamine induces dopamine release, highlighting pharmacological differences. The behavioral and neurophysiological effects of these enantiomers, however, remain largely unknown. This study aims to compare the effects of ketamine enantiomers on behavioral and social cognitive dysfunction, brain-wide neural activation, and neuronal activity during social interaction.

Existing literature highlights the detrimental effects of social isolation on mental health, particularly social cognition and the development of depression. Animal models of social isolation consistently demonstrate behavioral abnormalities and reduced sociability. The insula and prefrontal cortex are known to be involved in social cognitive function, but the neural mechanisms underlying recovery from social cognitive deficits, especially in response to therapeutic interventions, require further elucidation. Ketamine's rapid antidepressant effects and potential cognitive benefits have been established, with mechanisms involving neuroplasticity, BDNF-TrkB signaling, and the modulation of neural activity. However, the specific roles of (S)- and (R)-ketamine and their underlying neural mechanisms remain an area of active investigation. Previous studies have reported differences in the pharmacological properties of the ketamine enantiomers, with (S)-ketamine showing stronger NMDA receptor antagonism and (R)-ketamine exhibiting distinct effects on frontal cortex activity and dopamine release. This study aims to address these knowledge gaps by investigating the differential effects of (S)- and (R)-ketamine on socially isolated mice.

The study used socially isolated and group-reared mice. Brain-wide immediate early gene (IEG) mapping using the FAST system was performed to assess neuronal responses to ketamine treatment. Linear support vector machine (SVM) classification was used to identify key brain regions responsive to (R)-ketamine. Chemogenetic manipulations (using DREADDs hM4Di and hM3Dq) were employed to inhibit and activate the anterior insular cortex (aIC), respectively, to investigate its role in ketamine's effects. Fiber photometry was used to measure aIC neuronal activity during social interaction in the three-chamber test. A social memory test was conducted to assess social cognition. Whole-cell voltage clamp recordings of aIC pyramidal neurons were performed to investigate the mechanism of (R)-ketamine's action. Pharmacological studies using TrkB inhibitors were conducted to assess the role of BDNF-TrkB signaling. Statistical analyses included ANOVA, t-tests, and Spearman's correlation.

Social isolation-reared mice exhibited increased immobility time in the forced swim test (FST), indicating a depression-like phenotype. (R)-ketamine, but not (S)-ketamine, significantly reduced immobility time in both group-reared and socially isolated mice. Brain-wide IEG mapping and SVM classification revealed unique aIC activation in (R)-ketamine-treated socially isolated mice. Chemogenetic inhibition of the aIC blocked (R)-ketamine's effect on immobility time in the FST, while chemogenetic activation of the aIC mimicked (R)-ketamine's effects. Fiber photometry demonstrated that social isolation attenuated aIC neuronal activation during social contact, an effect reversed by (R)-ketamine. (R)-ketamine improved social memory in socially isolated mice, an effect again blocked by aIC inactivation. Whole-cell voltage clamp recordings showed no direct effects of (R)-ketamine on aIC pyramidal neuron currents, suggesting indirect action. Pharmacological inhibition of TrkB did not affect (R)-ketamine's ability to restore aIC function, indicating that BDNF-TrkB signaling is not the primary mechanism.

The findings demonstrate that aIC activation mediates the effects of (R)-ketamine in reversing social isolation-induced cognitive deficits. (R)-ketamine's unique activation of the aIC, a region involved in social cognition and stress responses, contributes to its therapeutic effects. The aIC's connections with other brain regions, particularly the ventral striatum, may play a role in modulating responses to social stimuli. (R)-ketamine's effects are likely not limited to the aIC but also involve other regions of the salience network, which is implicated in processing external stimuli and is dysfunctional in major depressive disorder. The study highlights the importance of considering the neural circuitry of these regions for a comprehensive understanding of (R)-ketamine's mechanisms of action. The results also suggest that (R)-ketamine's effects on social cognition may be distinct from its effects on mood, reflecting complex interactions beyond conventional models of mood and cognition. The implications for the treatment of social cognitive deficits in various mental disorders are substantial.

This study demonstrates that (R)-ketamine restores social cognitive deficits in socially isolated mice by activating the anterior insular cortex (aIC). The findings highlight the aIC's crucial role in mediating the therapeutic effects of (R)-ketamine and suggest its potential as a novel therapeutic target for social cognitive deficits associated with various mental health disorders. Future research should investigate the downstream targets and pathways involved in aIC-mediated improvements in social cognition and explore the translational potential of (R)-ketamine for treating social cognitive impairments in humans.

The study primarily focuses on the effects of ketamine in mice, limiting the direct generalizability to humans. While chemogenetic manipulations provide valuable insights into the role of the aIC, they may not perfectly replicate the complex effects of ketamine in vivo. Further studies are needed to explore potential interactions of (R)-ketamine with other brain regions and neuronal pathways to obtain a more comprehensive understanding of its mechanism of action. The limited sample size in some experimental groups might slightly affect the statistical power of certain findings.