Differential Effect of Dopamine D4 Receptor Activation on Low-Frequency Oscillations in the Prefrontal Cortex and Hippocampus May Bias the Bidirectional Prefrontal–Hippocampal Coupling

Abstract

Dopamine D4 receptor (D4R) mechanisms are implicated in psychiatric diseases characterized by cognitive deficits, including schizophrenia, ADHD, and autism. The cellular mechanisms are poorly understood, but impaired neuronal synchronization in cortical networks was proposed to contribute to these deficits. In animal experiments, D4R activation was shown to generate aberrant increased gamma oscillations and to reduce performance on cognitive tasks requiring functional prefrontal cortex (PFC) and hippocampus (HPC) networks. While fast oscillations in the gamma range are important for local synchronization within neuronal ensembles, long-range synchronization between distant structures is achieved by slow rhythms in the delta, theta, alpha ranges. The characteristics of slow oscillations vary between structures during cognitive tasks. HPC activity is dominated by theta rhythm, whereas PFC generates unique oscillations in the 2–4 Hz range. In order to investigate the role of D4R on slow rhythms, cortical activity was recorded in rats under urethane anesthesia in which slow oscillations can be elicited in a controlled manner without behavioral confounds, by electrical stimulation of the brainstem reticular formation. The local field potential segments during stimulations were extracted and subjected to fast Fourier transform to obtain power density spectra. The selective D4R agonist A-412997 (5 and 10 mg/kg) and antagonists L-745870 (5 and 10 mg/kg) were injected systemically and the peak power in the two frequency ranges were compared before and after the injection. We found that D4R compounds significantly changed the activity of both HPC and PFC, but the direction of the effect was opposite in the two structures. D4R agonist enhanced PFC slow rhythm (delta, 2–4 Hz) and suppressed HPC theta, whereas the antagonist had an opposite effect. Analogous changes of the two slow rhythms were also found in the thalamic nucleus reuniens, which has connections to both forebrain structures. Slow oscillations play a key role in interregional cortical coupling; delta and theta oscillations were shown in particular, to entrain neuronal firing and to modulate gamma activity in interconnected forebrain structures with a relative HPC theta dominance over PFC. Thus, the results of this study indicate that D4R activation may introduce an abnormal bias in the bidirectional PFC–HPC coupling which can be reversed by D4R antagonists.

Dysfunctional Hippocampal-Prefrontal Network Underlies a Multidimensional Neuropsychiatric Phenotype following Early-Life Seizure

“…Theta oscillations underlie various cognitive processes and are believed to serve as a temporal organizer for multiple functions, such as sensorimotor integration (Buzsáki and Moser, 2013). However, increases in HPC theta power are also observed in hyperdopaminergic-like states, such as following the administration of ketamine or a dopaminergic agonist (Caixeta et al, 2013;Thörn et al, 2022). Increases in theta power are reported in most studies in patients with schizophrenia (Newson and Thiagarajan, 2019) and have been correlated with poor cognitive performance (Curic et al, 2021).…”

Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure

“…Theta oscillations underlie various cognitive processes and are believed to serve as a temporal organizer for multiple functions, such as sensorimotor integration ( Buzsáki and Moser, 2013 ). However, increases in HPC theta power are also observed in hyperdopaminergic-like states, such as following the administration of ketamine or a dopaminergic agonist ( Caixeta et al, 2013 ; Thörn et al, 2022 ). Increases in theta power are reported in most studies in patients with schizophrenia ( Newson and Thiagarajan, 2018 ) and have been correlated with poor cognitive performance ( Curic et al, 2021 ).…”

Dopamine D1-like receptors modulate synchronized oscillations in the hippocampal–prefrontal–amygdala circuit in contextual fear

“…The thalamic nucleus reuniens (RE) mediates hippocampal-prefrontal coupling via its reciprocal connections with these areas 60 , while the PFC–RE and RE–BLA pathways have been implicated in various learned fear processes 32 , 61 – 63 . Moreover, D1Rs in RE regulate fear extinction memory and dopamine modulates theta oscillations in RE 64 , 65 , suggesting a potential role for RE in D1R modulation of synchrony in this circuit. Nevertheless, this study builds on our understanding of the hippocampal–prefrontal–amygdala circuit mechanisms underlying the neuromodulation of CFC by dopamine.…”