Abstract
The dorsolateral prefrontal cortex (dlPFC) generates the mental representations that are the foundation of abstract thought, and provides top-down regulation of emotion through projections to the medial PFC and cingulate cortices. Physiological recordings from dlPFC Delay cells have shown that the generation of mental representations during working memory relies on NMDAR neurotransmission, with surprisingly little contribution from AMPAR. Systemic administration of low “antidepressant” doses of the NMDAR antagonist, ketamine, erodes these representations and reduces dlPFC Delay cell firing. In contrast to the dlPFC, V1 neuronal firing to visual stimuli depends on AMPAR, with much less contribution from NMDAR. Similarly, neurons in the dlPFC that respond to sensory events (cue cells, response feedback cells) rely on AMPAR, and systemic ketamine increases their firing. Insults to NMDAR transmission, and the impaired ability for dlPFC to generate mental representations, may contribute to cognitive deficits in schizophrenia, e.g., from genetic insults that weaken NMDAR transmission, or from blockade of NMDAR by kynurenic acid. Elevated levels of kynurenic acid in dlPFC may also contribute to cognitive deficits in other disorders with pronounced neuroinflammation (e.g., Alzheimer's disease), or peripheral infections where kynurenine can enter brain (e.g., delirium from sepsis, “brain fog” in COVID19). Much less is known about NMDAR actions in the primate cingulate cortices. However, NMDAR neurotransmission appears to process the affective and visceral responses to pain and other aversive experiences mediated by the cingulate cortices, which may contribute to sustained alterations in mood state. We hypothesize that the very rapid, antidepressant effects of intranasal ketamine may involve the disruption of NMDAR-generated aversive mood states by the anterior and subgenual cingulate cortices, providing a “foot in the door” to allow the subsequent return of top-down regulation by higher PFC areas. Thus, the detrimental vs. therapeutic effects of NMDAR blockade may be circuit dependent.
Highlights
The recent discovery that the NMDA receptor (NMDAR) antagonist, ketamine, can produce rapid, antidepressant actions has stirred interest in the possible mechanisms underlying these therapeutic effects, and why blockade of NMDAR can produce such a swift change in mood
Previous research in rodent classic circuits had found that NMDA-a subunit of the NMDAR (GluN2B) were mostly at extra-synaptic locations [5], or played a role only in immature neurons [6], more recent research has shown that GluN2B play a critical, synaptic role in the primate cortical circuits mediating higher cognition, providing the synaptic events that generate sustained representations of visual space in working memory in the dorsolateral prefrontal cortex (dlPFC) [7, 8]
Recent research has shown that expression of NMDAR with GluN2B subunits encoded by the GRIN2B gene expands across primate cortical evolution [10], and across the cortical hierarchy in humans, with especially high levels in association and limbic cortices such as the anterior cingulate cortex [11]
Summary
The recent discovery that the NMDA receptor (NMDAR) antagonist, ketamine, can produce rapid, antidepressant actions has stirred interest in the possible mechanisms underlying these therapeutic effects, and why blockade of NMDAR can produce such a swift change in mood. The paper will briefly review PFC circuits in primates and their regulation of the cingulate cortices, and discuss the critical role of NMDAR for generating mental representations in dlPFC, the expansion in NMDAR-GluN2B transmission across the cortical hierarchy and across cortical evolution, and the role of NMDAR-GluN2B in the cingulate cortices mediating affective pain responses and depression. It will briefly discuss how stress exposure impairs higher PFC regulation, and will close with an exploration of the idea that ketamine’s rapid antidepressant actions may involve blocking mental representations of aversive mood state in the cingulate cortices
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