Prophylactic (R,S)-Ketamine and (2S,6S)-Hydroxynorketamine Decrease Fear Expression by Differentially Modulating Fear...

Area of Science:

• Neuroscience
• Pharmacology
• Behavioral Science

Background:

• Previous research indicated that (R,S)-ketamine and (2S,6S)-hydroxynorketamine (HNK) attenuate learned fear.
• The precise neural mechanisms underlying these fear-attenuating effects, whether convergent or divergent, remained undetermined.

Purpose of the Study:

• To investigate the neural activity patterns associated with fear attenuation by (R,S)-ketamine and (2S,6S)-HNK.
• To identify specific brain regions and network changes involved in the therapeutic effects of these compounds.

Main Methods:

• Male mice were administered (R,S)-ketamine or (2S,6S)-HNK one week before a contextual fear conditioning paradigm.
• Following re-exposure to the context, brain activity was assessed using c-fos immunoreactivity and a wide-scale imaging pipeline to map neural networks.

Main Results:

• Both (R,S)-ketamine and (2S,6S)-HNK successfully attenuated learned fear.
• Distinct and overlapping alterations in neural activity were observed in various brain regions, including the hippocampus (dorsal CA3, ventral CA3, CA1), prefrontal cortex (infralimbic, prelimbic), insular cortex, retrosplenial cortex, piriform cortex, nucleus reuniens, periaqueductal gray, and the paraventricular nucleus of the thalamus (PVT).
• (R,S)-ketamine modulated connectivity between cortical and subcortical regions, while (2S,6S)-HNK enhanced connectivity within these regions.

Conclusions:

• Novel fear network nodes, including the nucleus reuniens, piriform cortex, insular cortex, periaqueductal gray, and retrosplenial cortex, were identified.
• These newly identified nodes represent potential targets for neuromodulatory strategies and pharmaceutical interventions for fear-induced disorders.
• The findings support optimizing drug engagement and dosing for existing medications through a deeper understanding of their neural targets.