Remodeling of Sensorimotor Brain Connectivity in Gpr88-Deficient Mice

Abstract

Recent studies have demonstrated that orchestrated gene activity and expression support synchronous activity of brain networks. However, there is a paucity of information on the consequences of single gene function on overall brain functional organization and connectivity and how this translates at the behavioral level. In this study, we combined mouse mutagenesis with functional and structural magnetic resonance imaging (MRI) to determine whether targeted inactivation of a single gene would modify whole-brain connectivity in live animals. The targeted gene encodes GPR88 (G protein-coupled receptor 88), an orphan G protein-coupled receptor enriched in the striatum and previously linked to behavioral traits relevant to neuropsychiatric disorders. Connectivity analysis of Gpr88-deficient mice revealed extensive remodeling of intracortical and cortico-subcortical networks. Most prominent modifications were observed at the level of retrosplenial cortex connectivity, central to the default mode network (DMN) whose alteration is considered a hallmark of many psychiatric conditions. Next, somatosensory and motor cortical networks were most affected. These modifications directly relate to sensorimotor gating deficiency reported in mutant animals and also likely underlie their hyperactivity phenotype. Finally, we identified alterations within hippocampal and dorsal striatum functional connectivity, most relevant to a specific learning deficit that we previously reported in Gpr88 animals. In addition, amygdala connectivity with cortex and striatum was weakened, perhaps underlying the risk-taking behavior of these animals. This is the first evidence demonstrating that GPR88 activity shapes the mouse brain functional and structural connectome. The concordance between connectivity alterations and behavior deficits observed in Gpr88-deficient mice suggests a role for GPR88 in brain communication.

Lack of anticipatory behavior in Gpr88 knockout mice showed by automatized home cage phenotyping

“…This is consistent with the prominent expression of GPR88 in both striatum and cortex . This conclusion also fully accords our recent discovery of specific GPR88 expression in layer 4 of the somatosensory cortex, paralleling delayed sensory processing in Gpr88 −/− mice, as well as our recent fMRI data from Gpr88 −/− mice indicating disrupted functional connectivity predominantly at the level motor and sensory cortices, as well as the striatum in live mutant mice . In further support of our interpretation, the ventral striatum was shown activated in response to ingestive behavior, and dopamine levels in lateral hypothalamic area and the nucleus accumbens are associated with anticipatory and consummatory phases of feeding .…”

Functional imaging evidence for task-induced deactivation and disconnection of a major default mode network hub in the mouse brain

“…Our study developed and validated a fUS protocol, which uses a head-fixed configuration and light medetomidine sedation in awake and behaving mice, to study sensory task-induced changes of FC, while limiting the locomotion-induced effects on activation and connectivity. We report discrete and robust patterns of FC in both in nonsedated and slightly sedated mice and we show that FC strength is highly sensitive to medetomine anesthesia, at doses typical for state-of-the art resting-state fMRI studies (39)(40)(41).…”

“…To overcome the locomotion-induced generalized elevations of FC during whisker stimulation, we investigated the dose-dependent effects of pharmacological sedation, simultaneously on locomotion inhibition and FC, by longitudinal fUS in the same animals. We hypothesized that a very light level of sedation by the α2 adrenergic agonist medetomidine, the most common anesthetics used in current BOLD-based FC studies ( 39 – 41 ), might allow decreasing spontaneous locomotion while preserving near awake levels of FC. Since medetomidine is a vasoconstrictive agent that can affect FC outcome in a dose-dependent fashion ( 42 , 43 ), we tested two different doses of medetomidine inducing either slightly sedated (0.055 mg/kg) or fully anesthetized (0.33 mg/kg) vigilance states ( Table 1 ).…”

GPR88 in D1R-Type and D2R-Type Medium Spiny Neurons Differentially Regulates Affective and Motor Behavior

“…Accordingly, CMV- Gpr88 mice have been shown to have altered transcriptional profiles in these structures where both GPR88 and D1R are expressed (Meirsman et al, 2016b). Most importantly, recent studies using CMV- Gpr88 mice have shown impaired multisensory processing (Ehrlich et al, 2018) and sensorimotor gating (Meirsman et al, 2017) that, coupled with altered sensorimotor and cortico-striatal functional connectivity (Arefin et al, 2017), suggest a role of this receptor in the integration and processing of sensory information. Interestingly, it has also been suggested that modifications of the striato-cortical circuitry may underlie the hyperactivity observed in CMV -Gpr88 mice (Arefin et al, 2017).…”