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The anterior cingulate area (ACC) is an integral part of the prefrontal cortex in mice and supports cognitive functions, including attentional processes, motion planning and execution as well as remote memory, fear and pain. Previous anatomical and functional imaging studies demonstrated that the ACC is interconnected with numerous brain regions, such as motor and sensory cortices, amygdala and limbic areas, suggesting it serves as a hub in functional networks. However, the exact role of the ACC in regulating functional network activity and connectivity remains to be elucidated. Recently developed neuromodulatory techniques, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allow for precise control of neuronal activity. In this study, we used an inhibitory kappa-opioid receptor DREADD (KORD) to temporally inhibit neuronal firing in the right ACC of mice and assessed functional network activity and connectivity using non-invasive functional magnetic resonance imaging (MRI). We demonstrated that KORD-induced inhibition of the right ACC induced blood oxygenation-level dependent (BOLD) signal decreases and increases in connected brain regions of both hemispheres. More specifically, altered neuronal activity could be observed in functional brain networks including connections with sensory cortex, thalamus, basolateral amygdala and ventral pallidum, areas involved in attention processes, working memory, fear behavior and reward respectively. Furthermore, these modulations in neuronal activity were associated with decreased intra- and interhemispheric functional connectivity. Our results consolidate the hub role of the mouse ACC in functional networks and further demonstrate that the combination of the DREADD technology and non-invasive functional imaging methods is a valuable tool for unraveling mechanisms of network function and dysfunction by reversible inactivation of selected targets. •ACC differentially controls neuronal activity in specific functional brain networks.•ACC inhibition disrupts functional integrity in specific functional brain networks.•KOR-DREADDs - fMRI is a valuable tool for studying brain network functioning.

One of the main challenges in brain research is to link all aspects of brain function: on a cellular, systemic, and functional level. Multimodal neuroimaging methodology provides a continuously evolving platform. Being able to combine calcium imaging, optogenetics, electrophysiology, chemogenetics and functional magnetic resonance imaging (fMRI) as part of the numerous efforts on brain functional mapping, we have a unique opportunity to better understand brain function. This review will focus on the developments in application of these tools within fMRI studies and highlight the challenges and choices neurosciences face when designing multimodal experiments.

Background Imbalanced synaptic transmission appears to be an early driver in Alzheimer’s disease (AD) leading to brain network alterations. Early detection of altered synaptic transmission and insight into mechanisms causing early synaptic alterations would be valuable treatment strategies. This study aimed to investigate how whole-brain networks are influenced at pre- and early-plague stages of AD and if these manifestations are associated with concomitant cellular and synaptic deficits.  Methods To this end, we used an established AD rat model (TgF344-AD) and employed resting state functional MRI and quasi-periodic pattern (QPP) analysis, a method to detect recurrent spatiotemporal motifs of brain activity, in parallel with state-of-the-art immunohistochemistry in selected brain regions. Results At the pre-plaque stage, QPPs in TgF344-AD rats showed decreased activity of the basal forebrain (BFB) and the default mode-like network. Histological analyses revealed increased astrocyte abundance restricted to the BFB, in the absence of amyloid plaques, tauopathy, and alterations in a number of cholinergic, gaba-ergic, and glutamatergic synapses. During the early-plaque stage, when mild amyloid-beta (Aβ) accumulation was observed in the cortex and hippocampus, QPPs in the TgF344-AD rats normalized suggesting the activation of compensatory mechanisms during this early disease progression period. Interestingly, astrogliosis observed in the BFB at the pre-plaque stage was absent at the early-plaque stage. Moreover, altered excitatory/inhibitory balance was observed in cortical regions belonging to the default mode-like network. In wild-type rats, at both time points, peak activity in the BFB preceded peak activity in other brain regions—indicating its modulatory role during QPPs. However, this pattern was eliminated in TgF344-AD suggesting that alterations in BFB-directed neuromodulation have a pronounced impact in network function in AD. Conclusions This study demonstrates the value of rsfMRI and advanced network analysis methods to detect early alterations in BFB function in AD, which could aid early diagnosis and intervention in AD. Restoring the global synaptic transmission, possibly by modulating astrogliosis in the BFB, might be a promising therapeutic strategy to restore brain network function and delay the onset of symptoms in AD.

Neurons are embedded in an extracellular matrix (ECM), which functions both as a scaffold and as a regulator of neuronal function. The ECM is in turn dynamically altered through the action of serine proteases, which break down its constituents. This pathway has been implicated in the regulation of synaptic plasticity and of neuronal intrinsic excitability. In this study, we determined the short-term effects of interfering with proteolytic processes in the ECM, with a newly developed serine protease inhibitor. We monitored the spontaneous electrophysiological activity of in vitro primary rat cortical cultures, using microelectrode arrays. While pharmacological inhibition at a low dosage had no significant effect, at elevated concentrations it altered significantly network synchronization and functional connectivity but left unaltered single-cell electrical properties. These results suggest that serine protease inhibition affects synaptic properties, likely through its actions on the ECM.

There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to controlled cortical impact (CCI) injury, sham surgery, or skin incision (naïve). CCI-injured (n = 18) and sham-operated rats (n = 6) underwent positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18F]PBR111 and diffusion tensor imaging (DTI) in the subacute phase (≤3 weeks post-injury) to quantify inflammation and microstructural alterations. CCI-injured, sham-operated, and naïve rats (n = 8) underwent behavioral testing in the chronic phase (5.5–10 months post-injury): open field and sucrose preference tests, two one-week video-electroencephalogram (vEEG) monitoring periods, pentylenetetrazole (PTZ) seizure susceptibility tests, and a Morris water maze (MWM) test. In vivo imaging revealed pronounced neuroinflammation, decreased fractional anisotropy, and increased diffusivity in perilesional cortex and ipsilesional hippocampus of CCI-injured rats. Behavioral analysis revealed disinhibition, anhedonia, increased seizure susceptibility, and impaired learning in CCI-injured rats. Subacute TSPO expression and changes in DTI metrics significantly correlated with several chronic deficits (Pearson's |r| = 0.50–0.90). Certain specific PET and DTI parameters had good sensitivity and specificity (area under the receiver operator characteristic [ROC] curve = 0.85–1.00) to distinguish between TBI animals with and without particular behavioral deficits. Depending on the investigated behavioral deficit, PET or DTI data alone, or the combination, could very well predict the variability in functional outcome data (adjusted R2 = 0.54–1.00). Taken together, both TSPO PET and DTI seem promising prognostic biomarkers to predict different chronic TBI sequelae.

The default mode network is a large-scale brain network that is active during rest and internally focused states and deactivates as well as desynchronizes during externally oriented (top-down) attention demanding cognitive tasks. However, it is not sufficiently understood if salient stimuli, able to trigger bottom-up attentional processes, could also result in similar reduction of activity and functional connectivity in the DMN. In this study, we investigated whether bottom-up sensory processing could influence the default mode-like network (DMLN) in rats. DMLN activity was examined using block-design visual functional magnetic resonance imaging (fMRI) while its synchronization was investigated by comparing functional connectivity during a resting versus a continuously stimulated brain state by unpredicted light flashes. We demonstrated that the BOLD response in DMLN regions was decreased during visual stimulus blocks and increased during blanks. Furthermore, decreased inter-network functional connectivity between the DMLN and visual networks as well as decreased intra-network functional connectivity within the DMLN was observed during the continuous visual stimulation. These results suggest that triggering of bottom-up attention mechanisms in sedated rats can lead to a cascade similar to top-down orienting of attention in humans and is able to deactivate and desynchronize the DMLN. •Bottom-up sensory processing can influence the default mode-like network in rats.•Block design visual stimulation induces negative bold responses in nodes of the DMLN.•Continuous visual stimulation reduces intra- and inter-DMLN functional connectivity.

The septohippocampal pathway plays an important role in learning and memory. It projects from the medial septum-vertical limb of the diagonal band of Broca (MSDB) to the hippocampus and provides the latter with its main cholinergic innervation. To assess the importance of cholinergic selectivity and timing of MSDB stimulation in modulating learning and memory, we directly compared the effects of several MSDB stimulation strategies in healthy rats. We evaluated the effects of DREADD-mediated selective cholinergic neuronal MSDB stimulation and nonselective neuronal MSDB stimulation on spatial learning and memory in the appetitive radial arm maze and on resting-state brain networks using resting-state functional MRI. DREADDs were activated with the novel DREADD agonist J60. Selective cholinergic MSDB stimulation during – but not after – radial arm maze training improved spatial learning compared with J60-treated sham rats and had no effect on working memory or reversal learning. J60-treated sham rats had a worse working memory than saline-treated sham rats during the reversal phase of the radial arm maze task, suggesting an adverse effect of chronic use of J60. Nonselective MSDB stimulation during training resulted in a loss of appetite and exclusion from the radial arm maze training. Acute selective cholinergic and nonselective MSDB stimulation induced decreased functional connectivity (FC) in the default mode-like network. In addition, acute nonselective MSDB stimulation resulted in increased intrahippocampal FC, while selective cholinergic MSDB stimulation led to globally increased FC with the nucleus accumbens. While the combined effect of radial arm maze learning and the necessary chronic food restriction with or without chronic MSDB stimulation had no observable effect on resting-state networks, chronic food restriction alone globally increased FC in the brain.

The anterior cingulate area (ACA) is an integral part of the prefrontal cortex in mice and has been implicated in several cognitive functions. Previous anatomical and functional imaging studies demonstrated that the ACA is highly interconnected with numerous brain regions acting as a hub region in functional networks. However, the importance of the ACA in regulating functional network activity and connectivity remains to be elucidated. Recently developed neuromodulatory techniques, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allow for precise control of neuronal activity. In this study, we used an inhibitory kappa-opioid receptor DREADDs (KORD) to temporally inhibit neuronal firing in the right ACA of mice and assessed functional network activity and connectivity using non-invasive functional MRI. We demonstrated that KORD-induced inhibition of the right ACA induced blood oxygenation-level dependent (BOLD) signal decreases and increases in connected brain regions throughout of hemispheres. Furthermore, these modulations in neuronal activity were associated with decreased intra- and interhemispheric functional connectivity. These results demonstrate that the combination of the DREADD technology and non-invasive functional imaging methods is a valuable tool for unraveling the underlying mechanisms of network function and dysfunction.