Ketamine triggers a switch in excitatory neuronal activity across neocortex

Area of Science:

• Neuroscience
• Cellular Biology
• Neuropharmacology

Background:

• The brain can enter a 'dissociated state,' characterized by disconnection from the environment and vivid internal experiences.
• Such states are observed in pathological conditions and under the influence of substances like ketamine (KET).
• The underlying cellular and circuit mechanisms of ketamine-induced dissociation remain largely unknown.

Purpose of the Study:

• To investigate the cellular and circuit mechanisms responsible for ketamine-induced dissociation in the brain.
• To identify the neuronal populations involved in both normal wakefulness and ketamine-altered brain states.

Main Methods:

• Experiments were conducted using mice to observe neuronal activity.
• Ketamine was administered systemically and cortically.
• Neuronal activity, including spontaneous activation and suppression, was monitored across cortical layers and regions.
• The roles of specific interneuron types (parvalbumin and somatostatin) and ion channels (NMDA and HCN) were examined.

Main Results:

• Ketamine (KET) suppressed spontaneously active neurons while activating previously silent neurons.
• This neuronal switch was observed across all cortical layers and regions.
• The effect was mediated by the suppression of parvalbumin and somatostatin interneurons and inhibition of NMDA and HCN channels.
• Two distinct, largely non-overlapping cortical neuronal populations were identified: one for wakefulness and one for the KET-induced state.

Conclusions:

• Ketamine induces a significant shift in cortical neuronal activity by altering the balance between distinct neuronal populations.
• The findings highlight the roles of specific interneurons and ion channels in mediating ketamine's dissociative effects.
• This study provides a foundation for understanding how the brain achieves internal experiences during environmental disconnection.