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. Patients with bipolar disorder show alternations in the dopamingergic and immune system. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is increased in plasma samples, imaging studies and post mortem tissue. Manipulation of the D1R in the medial prefrontal cortex (mPFC) e.g. results in BD-like behavior. The purpose of the study is the investigation of the influence of D1R over-expression and its termination on the immune system and anxiety behavior in rats.Methods – Expression of the gene for D1R in glutamatergic neurons within the mPFC of male, adult rats was manipulated through an inducible (Tet.On) lentiviral vector. Anxiety behavior was studied in the elevated plus maze and marble burying test in ‘ON’ (D1R over-expression) and ‘OFF’ (termination of D1R over-expression) states. IL-6-positive cells were counted to identify the inflammatory state within several subregions of the hippocampus.Results - D1R ‘OFF’ subjects buried more marbles compared to D1R ‘ON’ and their respective control animals indicating an increased anxiety behavior. D1R ‘OFF’ animals reflected an elevated pro-inflammatory state in the hippocampus, in the CA3 and dentate gyrus especially. 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 molecular findings support the association of D1R’s impact on anxiety and inflammation. In addition, by confirming an involvement of IL-6, the new animal model for bipolar disorder has been further validated.

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.…”