Ketamine Corrects Stress-Induced Cognitive Dysfunction through JAK2/STAT3 Signaling in the Orbitofrontal Cortex

Area of Science:

• Neuroscience
• Psychiatry
• Pharmacology

Background:

• Cognitive flexibility deficits are common in depression.
• Ketamine shows rapid antidepressant effects, but its impact on cognitive symptoms is unclear.
• Chronic intermittent cold (CIC) stress in rats models depression-related cognitive dysfunction, specifically impairing orbitofrontal cortex (OFC)-mediated reversal learning.

Purpose of the Study:

• To investigate if ketamine improves stress-induced reversal learning deficits.
• To determine the role of JAK2/STAT3 signaling in ketamine's effects on cognitive flexibility.
• To explore ketamine's impact on neural plasticity in the OFC via JAK2/STAT3.

Main Methods:

• Rats were subjected to CIC stress to induce cognitive deficits.
• Ketamine (10 mg/kg) was administered, and reversal learning was assessed.
• JAK2 phosphorylation, local field potentials, and Arc protein expression in the OFC were measured.
• JAK2 inhibition (AG490) was used to probe the signaling pathway.

Main Results:

• Ketamine administration rescued CIC stress-induced reversal learning deficits.
• CIC stress reduced JAK2 phosphorylation in the OFC; ketamine restored it.
• JAK2 inhibition blocked ketamine's beneficial effects on reversal learning and OFC neural plasticity.
• Ketamine increased neural plasticity-related protein Arc expression in the OFC, an effect blocked by JAK2 inhibition.

Conclusions:

• Ketamine ameliorates stress-induced cognitive deficits in reversal learning.
• The JAK2/STAT3 signaling pathway is a key mechanism mediating ketamine's cognitive benefits.
• Ketamine promotes neural plasticity in the OFC through JAK2/STAT3 activation.
• Targeting the JAK2/STAT3 pathway may offer novel therapeutic strategies for stress-related cognitive dysfunction.