The (Un)Conscious Mouse as a Model for Human Brain Functions: Key Principles of Anesthesia and Their Impact on Translational Neuroimaging

Abstract

Awake brain states undergo constant alterations in response to changing contexts of arousal, attention, and behavior (Steriade, 2000;Pfaff, 2005;Olcese et al., 2018;Poulet and Crochet, 2019). The spectrum of EEG patterns during these states ranges from synchronous low-frequency oscillations (<8 Hz) during quiet wakefulness to structured higherfrequency oscillations (∼8-100 Hz) during attentional tasks GABA A Agonists Suppress Neural Activity Across the Central Nervous SystemVolatile ethers and GABA A agonists such as isoflurane and propofol predominantly act on postsynaptic GABA A receptors of excitatory neurons by increasing the preference of those ligand-gated chloride channels for the open state (Bai et al., 1999;Lee and Maguire, 2014). This enhances the inward chloride current and facilitates hyperpolarization and thus

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

“…For example, the most commonly used anesthetic regimens for rodent MRI studies include isoflurane, dexmedetomidine, or a combination of the two. While this drug combination during resting-state fMRI recapitulates awake functional connectivity better than either drug alone ( Paasonen et al, 2018 ), dexmedetomidine is an agonist of the α2-adrenergic inhibitory autoreceptor that dampens LC activity ( Jorm and Stamford, 1993 ; Chiu et al, 1995 ; Zerbi et al, 2019 ; Reimann and Niendorf, 2020 ), making it incompatible for certain fMRI studies. Studies in awake animals are challenging but possible, meaning development of cross-species LC-influenced tasks would be useful for future studies.…”

Cortical silencing results in paradoxical fMRI overconnectivity

“…Second, it should be noted that the light sedation regimen employed in this study is physiologically stable, preserves sensorial responsivity (Orth et al, 2006) and does not induce burst-suppression or cortical hyper-synchronization (Liu et al, 2011), resulting in preserved rsfMRI connectivity topography (Coletta et al, 2020;Whitesell et al, 2020) and state dynamics (Gutierrez-Barragan et al, 2019). These properties make the brain state under which our recordings were carried out not dissimilar from the quiet wakefulness conditions, often bordering into sleep (Tagliazucchi and van Someren, 2017), that characterize most rsfMRI scanning in humans (Reimann and Niendorf, 2020). In keeping with this notion, intracranial recordings under conditions of quiet wakefulness have revealed the presence of significant epochs of delta activity in rodents (Crochet and Petersen, 2006;Vyazovskiy et al, 2011), primates (Lakatos et al, 2008) and humans (Sachdev et al, 2015).…”

“…Although compounded by pathophysiological rearrangements in synaptic activity (Busche and Konnerth, 2016), observations of unexpected increases in functional connectivity in neurological conditions characterized by loss of cortical function such as Alzheimer's disease have been conceptualized as the result of compensatory rerouting of signal propagation along indirect structural paths, a neuroadaptive strategy aimed at maintaining task performance (Hillary and Grafman, 2017;Pusil et al, 2019). Our findings offer an alternative network-level mechanism for these clinical observations, suggesting that rsfMRI overconnectivity may reflect shifts in the balance between the amount of interareal synchronization due to direct axonal communication and low-frequency brainwide synchronization mediated by single centers such as the polymodal thalamus (Gent et al, 2018) or by neuromodulatory nuclei (Safaai et al, 2015;Reimann and Niendorf, 2020), a conceivable scenario in early-stage degenerative or neurological states characterized by loss of neuronal function in higher order cortical areas. MEG and EEG studies in neurodegenerative brain disorders provide indirect support to this hypothesis, as evidence of robust δ hyper-synchronicity in Alzheimer's disease patients has been repeatedly reported, an effect that appears to preferentially involve polymodal cortical areas (Huth et al, 2012;Ranasinghe et al, 2020).…”

“…In keeping with this notion, intracranial recordings under conditions of quiet wakefulness have revealed the presence of significant epochs of delta activity in rodents (Crochet and Petersen, 2006;Vyazovskiy et al, 2011), primates (Lakatos et al, 2008) and humans (Sachdev et al, 2015). Because of the difficulty in controlling restraint-induced stress in highly rousable rodent species (Wang et al, 2017;Reimann and Niendorf, 2020), the state-dependence of our manipulation is an interesting subject for future investigations which can benefit from the implementation of hemodynamic mapping in quite wakefulness, for example using functional ultrasound imaging (Osmanski et al, 2014).…”

Mathematical modeling of neurovascular coupling

“…To study the NVC and its pertaining aspects in vivo, scientists often employ the use of animal studies, and most of our current understanding regarding the inner workings of the brain stem from this practice. Nevertheless, one major issue (besides from translation from animal to human) is the nonvoluntary task conundrum (see [151] and references therein). In contrast to voluntary humans, animals lack interest in participating in experimental studies.…”