Chemogenetic silencing of neurons in the mouse anterior cingulate area modulates neuronal activity and functional connectivity

Abstract

29The anterior cingulate area (ACA) is an integral part of the prefrontal cortex in mice and has been 30 implicated in several cognitive functions. Previous anatomical and functional imaging studies 31 demonstrated that the ACA is highly interconnected with numerous brain regions acting as a hub region 32 in functional networks. However, the importance of the ACA in regulating functional network activity and 33 connectivity remains to be elucidated. Recently developed neuromodulatory techniques, such as Designer 34Receptors Exclusively Activated by Designer Drugs (DREADDs) allow for precise control of neuronal 35 activity. In this study, we used an inhibitory kappa-opioid receptor DREADDs (KORD) to temporally inhibit 36 neuronal firing in the right ACA of mice and assessed functional network activity and connectivity using 37 non-invasive functional MRI. We demonstrated that KORD-induced inhibition of the right ACA induced 38 blood oxygenation-level dependent (BOLD) signal decreases and increases in connected brain regions 39 throughout of hemispheres. Furthermore, these modulations in neuronal activity were associated with 40 decreased intra-and interhemispheric functional connectivity. These results demonstrate that the 41 combination of the DREADD technology and non-invasive functional imaging methods is a valuable tool 42 for unraveling the underlying mechanisms of network function and dysfunction. 43 44 45 Receptors Exclusively Activated by Designer Drugs (DREADDs), which are engineered receptors for 63 targeted enhancement or silencing of neurons upon binding of an otherwise inert ligand. The combination 64 of chemogenetics and non-invasive neuroimaging methods, such as functional magnetic resonance 65 imaging (fMRI), allows direct evaluation of DREADD-induced changes in neuronal firing on large-scale 66 neuronal activity and FC. As such, Giorgi et al. were able to causally link the chemogenetic activation of 67serotonergic neurons with neuronal activity increases in cortical and subcortical brain areas, measured by 68 relative cerebral blood volume increases [23]. Furthermore, other studies also used blood-oxygenation-69

Chemogenetic Stimulation of Tonic Locus Coeruleus Activity Strengthens the Default Mode Network

“…Using the Frontal, RSC-HIPP, and Association modules ROIs (one-sample t-test, P < 0.0001) and striatum as a reference region due to sparse LC-NE neuron innervation, we examined how NE release from LC modulates fMRI-derived CBV, regional homogeneity (ReHo) (40) and amplitude of low frequency fluctuation (ALFF) (41) changes. We compared a 10 min baseline fMRI data prior to administering CNO against data acquired between 20-30 min post-CNO to account for DREADD-induced activity kinetics reported in fMRI (8,(42)(43)(44)(45) and behavior studies (30,31).…”

“…S4, B and C Using the Frontal, RSC-HIPP, and Association module ROIs (one-sample two-sided t-test, P < 0.0001) and striatum as a reference region due to sparse innervation from LC-NE neurons, we examined how NE release from LC modulates fMRI-derived CBV, regional homogeneity (ReHo) and amplitude of low frequency fluctuation (ALFF) changes. We compared the 10 min, pre-CNO baseline fMRI data against data acquired between 20-30 min post-CNO to account for CNOinduced activity kinetics reported in fMRI (6,(37)(38)(39)(40)(41) and behavior studies (29,30). CNO-evoked LC-NE activation significantly decreased CBV in all DMN modules in LC-NE/hM3Dq (unpaired t test, PFDR-corrected < 0.05) but not in control mice (Fig.…”

“…Several research groups have pioneered chemogenetic fMRI (6,(37)(38)(39)(40)(41) and PET (46) approaches to selectively map the influence of neurotransmitters on brain networks in rodents.…”

Cholinergic Modulation of the Default Mode Like Network in Rats

“…Chemogenetic-fMRI can provide important information about the effects of particular nodes in the brain on whole brain activity and connectivity within specific networks ( Giorgi et al., 2017 ; Peeters et al., 2020 ). In this study, excitatory DREADDs were expressed in the right BFB cholinergic neurons of rats and the effects of DREADDs-induced neural activity alterations were evaluated by means of non-invasive rsfMRI.…”

Combining designer receptors exclusively activated by designer drugs and neuroimaging in experimental models: A powerful approach towards neurotheranostic applications

“…More recently, our group expressed inhibitory KORD in the anterior cingulate area and used BOLD functional MRI to evaluate its effect on neuronal activity and functional connectivity. We observed that inhibition of the anterior cingulate area, which has been identified as a hub region (i.e., a highly interconnected brain region), resulted in large‐scale neuronal activity modulations as well as functional connectivity alterations (Peeters et al, ). Furthermore, other recent studies combined chemogenetics with resting‐state functional MRI in order to evaluate functional connectivity alterations after modulation of the excitation–inhibition balance in the somatosensory cortex (Markicevic et al, ) or to assess the effects of selective stimulation of the locus coeruleus with hM3Dq on a large‐scale functional connectivity (Zerbi et al, ).…”