Prefrontal dopamine D1 receptor manipulation influences anxiety behavior and induces neuroinflammation within the hippocampus

Abstract

Background Prefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is increased in patients with bipolar disorder in plasma samples, imaging studies and postmortem tissue and is an indicator for an inflammatory state. We could previously show that lentiviral overexpression of D1R in the medial prefrontal cortex (mPFC) of male adult rats and its termination induces bipolar disorder-like behavior. The purpose of this study was to investigate anxiety and the role of the immune system, specifically IL-6 positive neurons in this animal model. Due to its high density of inflammatory mediator receptors and therewith sensibility to immune activation, the hippocampus was investigated. Methods Expression of the gene for D1R in glutamatergic neurons within the mPFC of male, adult rats was manipulated through an inducible lentiviral vector. Animals over-expressing the gene (mania-like state), after termination of the expression (depressive-like) and their respective control groups were investigated. Anxiety behavior was studied in the elevated plus maze and marble burying test. Furthermore, IL-6-positive cells were counted within several subregions of the hippocampus. Results D1R manipulation in the mPFC had only mild effects on anxiety behavior in the elevated plus maze. However, subjects after termination buried more marbles compared to D1R over-expressing animals and their respective control animals indicating elevated anxiety behavior. In addition, animals in the depressive-like state showed higher numbers of IL-6 positive cells reflecting an elevated pro-inflammatory state in the hippocampus, in the CA3 and dentate gyrus. Consistently, inflammatory state in the whole hippocampus and anxiety behavior correlated positively, indicating a connection between anxiety and inflammatory state of the hippocampus. Conclusions Behavioral and neurobiological findings support the association of manipulation of the D1R in the mPFC on anxiety and inflammation in the hippocampus. In addition, by confirming changes in the inflammatory state, the proposed animal model for bipolar disorder has been further validated.

Risky decision-making following prefrontal D1 receptor manipulation

“…D1R-manipulated animals in contrast did not increase the number of earned pellets. Previous studies reported depressive-like behavior of D1R “OFF” subjects indicated via increased anxiety, learned helplessness, reduced sucrose preference, and decreased locomotor activity [ 2 , 4 ]. The reduced amount of earned pellets in the D1R “OFF” animals could result from improved learning of dsRed subjects, which was not observable in D1R rats.…”

“…Viral overexpression of the dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) of adult rats was associated with increased drug seeking and taking, impulsivity, hedonic, and sexual behavior [ 2 , 3 ]. Interestingly, when terminating the overexpression, animals show anhedonia, hypoactivity, increased anxiety, and helplessness indicating a switch from mania- to depressive-like behavior [ 2 , 4 ]. In healthy controls, too much or too little D1R stimulation in the PFC has a negative effect on cognitive processes [ 5 ].…”

Unraveling the mystery of white matter in depression: A translational perspective on recent advances

“…Preclinical studies in rats and mice allow for a disentanglement of neuronal implications on a molecular level using animal models of psychiatric disorders such as addiction (Mundorf et al., 2020 ), bipolar disorder (Beyer et al., 2021 ), schizophrenia (Juckel et al., 2021 ; Mundorf, Kubitza, et al., 2021 ; Wegrzyn et al., 2021 ), as well as stress‐induced impairments (Bölükbas et al., 2020 ; Mundorf et al., 2019 ; Mundorf, Koch, et al., 2021 ). Preclinical studies conducted mostly on rats and mice as well as clinical studies investigating humans both play an important role in furthering the understanding of the pathogenesis of MDD.…”

Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice

“…The microglia-mediated neuroinflammatory response in the brain, especially in the hippocampus and medial prefrontal cortex, has been demonstrated to be an important pathogenesis for psychological disorders including anxiety [ 4 , 5 ]. For instance, the toll-like receptor 2/4 (TLR2/4) has been reported to mediate stress-induced microglial activation in the prefrontal cortex, which subsequently induces the development of anxiety-like behaviors in animals [ 6 ].…”