Functional and Molecular Changes in the Prefrontal Cortex of the Chronic Mild Stress Rat Model of Depression and Modulation by Acute Ketamine

Abstract

Stress is a primary risk factor in the onset of neuropsychiatric disorders, including major depressive disorder (MDD). We have previously used the chronic mild stress (CMS) model of depression in male rats to show that CMS induces morphological, functional, and molecular changes in the hippocampus of vulnerable animals, the majority of which were recovered using acute subanesthetic ketamine in just 24 h. Here, we focused our attention on the medial prefrontal cortex (mPFC), a brain area regulating emotional and cognitive functions, and asked whether vulnerability/resilience to CMS and ketamine antidepressant effects were associated with molecular and functional changes in the mPFC of rats. We found that most alterations induced by CMS in the mPFC were selectively observed in stress-vulnerable animals and were rescued by acute subanesthetic ketamine, while others were found only in resilient animals or were induced by ketamine treatment. Importantly, only a few of these modifications were also previously demonstrated in the hippocampus, while most are specific to mPFC. Overall, our results suggest that acute antidepressant ketamine rescues brain-area-specific glutamatergic changes induced by chronic stress.

Immediate and long-term electrophysiological biomarkers of antidepressant-like behavioral effects after subanesthetic ketamine and medial prefrontal cortex deep brain stimulation treatment

“…Therefore, we hypothesize that the increase in inhibition and decrease in function, in line with the control group, potentially represent ketamine exerting its long-term therapeutic effects by “normalizing” mPFC hyperactivity. Indeed, ketamine increases the inhibitory tone of the mPFC of rats 24 h post-treatment ( Yin et al, 2021 ; Mingardi et al, 2023 ), and reduces the functional connectivity of the human prefrontal cortex for up to two weeks post-treatment ( Chen et al, 2019 ; Siegel et al, 2021 ). Therefore, the modulation of aperiodic parameters and sample entropy after ketamine are perhaps indicative of this sustained cellular and functional normalization.…”

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

“…Preclinical models based on both acute and chronic stress have also shown neuronal dendritic simplification and spine reductions in HPC and PFC, implying that glutamatergic dysfunctions may underlie the architectural abnormalities measured in patients [ 152 , 158 ]. Importantly, functional and morphological alterations induced by chronic stress were selectively observed in vulnerable animals and not resilient ones, confirming that the glutamatergic changes play a role in the maladaptive response to chronic stress [ 159 , 160 , 161 ]. Although the specific mechanisms causing functional impairment and dendritic simplification in corticolimbic areas under chronic stress exposure have not yet been identified, a main hypothesis implicates glutamatergic transmission [ 154 , 156 ].…”