Prefronto-cortical dopamine D1 receptor sensitivity can critically influence working memory maintenance during delayed response tasks

Abstract

The dopamine (DA) hypothesis of cognitive deficits suggests that too low or too high extracellular DA concentration in the prefrontal cortex (PFC) can severely impair the working memory (WM) maintenance during delay period. Thus, there exists only an optimal range of DA where the sustained-firing activity, the neural correlate of WM maintenance, in the cortex possesses optimal firing frequency as well as robustness against noisy distractions. Empirical evidences demonstrate changes even in the D1 receptor (D1R)-sensitivity to extracellular DA, collectively manifested through D1R density and DA-binding affinity, in the PFC under neuropsychiatric conditions such as ageing and schizophrenia. However, the impact of alterations in the cortical D1R-sensitivity on WM maintenance has yet remained poorly addressed. Using a quantitative neural mass model of the prefronto-mesoprefrontal system, the present study reveals that higher D1R-sensitivity may not only effectuate shrunk optimal DA range but also shift of the range to lower concentrations. Moreover, higher sensitivity may significantly reduce the WM-robustness even within the optimal DA range and exacerbates the decline at abnormal DA levels. These findings project important clinical implications, such as dosage precision and variability of DA-correcting drugs across patients, and failure in acquiring healthy WM maintenance even under drug-controlled normal cortical DA levels.

Dopamine D1 receptor expression in dlPFC inhibitory parvalbumin neurons may contribute to higher visuospatial distractibility in marmosets versus macaques

“…Several microcircuit models of association cortex have already incorporated INEAR-like [73][74][75][76] , and also IOPP-like 24,56,57,59 , inhibition to account for the growing evidence for these structured inhibitory motifs [16][17][18][22][23][24] , thus succeeding early attempts that featured only unstructured 55,[77][78][79][80][81] inhibition. However, despite the long history of simulating D1R effects on dlPFC-mediated cognition 62,[82][83][84][85][86][87][88] , to our knowledge, no study has investigated how D1R modulation of structured inhibition affects higher cognitive functions. In rodents and macaques, D1Rs have been shown to increase inhibition through fast-spiking 41,42 , non-fast spiking 89 , or vasoactive intestinal peptideexpressing (VIP) inhibitory neurons 90 .…”

Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders

“…Stress-induced activation of the HPA axis increases dopamine neurotransmission in the PFC and activation of the downstream signalling cascades that negatively impact mood and cognition [e.g., 316 ; see also 317 – 320 ]. Indeed, it has been shown that emotional stimuli can influence working memory processing, manipulation, and maintenance that depend on the dorsolateral PFC, which is inversely coactive with the ventrolateral PFC [e.g., 321 ] and involve dopaminergic D 1 -receptors signalling.…”

Integrative Brain Dynamics in Childhood Bullying Victimization: Cognitive and Emotional Convergence Associated With Stress Psychopathology

“…The impaired neurocognitive functioning found in bullied children might also emerge from altered cortisol concentrations (e.g., Vaillancourt et al, 2008 , 2011 ; Ouellet-Morin et al, 2011b , 2013 , 2021 ; Östberg et al, 2018b ; Palamarchuk and Vaillancourt, 2021 ), that in turn, affect neurochemical mechanisms (i.e., neurotransmission) of memory, mood, and behavior. Specifically, stress can impact dopamine signaling in the PFC-striatum circuits (e.g., Gamo et al, 2015 ; Reneaux and Gupta, 2018 ), which plays an important part in neuromodulation (i.e., the capacity of a single neuron to regulate wide-ranging populations of other neurons), reward-motivated behavior, reinforcement learning (e.g., Ikemoto, 2007 ), and representational mentalizing (i.e., theory of mind) development (Lackner et al, 2010 ).…”