Spatial signatures of anesthesia-induced burst-suppression differ between primates and rodents.

During deep anesthesia, the electroencephalographic (EEG) signal of the brain alternates between bursts of activity and periods of relative silence (suppressions). The origin of burst-suppression and its distribution across the brain remain matters of debate. In this work, we used functional magnetic resonance imaging (fMRI) to map the brain areas involved in anesthesia-induced burst-suppression across four mammalian species: humans, long-tailed macaques, common marmosets, and rats. At first, we determined the fMRI signatures of burst-suppression in human EEG-fMRI data. Applying this method to animal fMRI datasets, we found distinct burst-suppression signatures in all species. The burst-suppression maps revealed a marked inter-species difference: in rats, the entire neocortex engaged in burst-suppression, while in primates most sensory areas were excluded-predominantly the primary visual cortex. We anticipate that the identified species-specific fMRI signatures and whole-brain maps will guide future targeted studies investigating the cellular and molecular mechanisms of burst-suppression in unconscious states.

The development of anesthesia was a significant advance in medicine. It allows individuals to undergo surgery without feeling pain or remembering the experience. But scientists still do not know how anesthesia works. During anesthesia, scientists have measured brain activity using electroencephalograms (EEG) and found that the brain appears to turn on and off. Comatose patients also have similar switches between bursts of electrical activity and periods of silence. This burst-suppression pattern may be related to unconsciousness. But scientists still have many questions about how anesthesia causes burst-suppression. One challenge is that while an EEG can tell scientists when the brain turns on and off, it does not show exactly where this occurs. Another imaging method called functional Magnetic Resonance Imaging (fMRI) may fill this gap by allowing scientists to map where the brain activity occurs. Sirmpilatze et al. have created detailed maps of burst-suppression in humans, primates, and rats under anesthesia by analyzing brain scans using fMRI. In rats, the entire outer layer or cortex of the brain underwent a synchronized pattern of burst-suppression. In humans and primates, areas of the brain like those responsible for eyesight did not follow the rest of the cortex in switching on and off. The experiments reveal crucial differences in how rats and humans and other primates respond to anesthesia. The fMRI mapping technique Sirmpilatze et al. created may help scientists learn more about these differences and why some parts of human brains do not undergo burst-suppression. This may help scientists learn more about unconsciousness and help improve anesthesia or the care of comatose patients.

A collaborative resource platform for non-human primate neuroimaging.

Neuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field .

Increased Callosal Connectivity in Reeler Mice Revealed by Brain-Wide Input Mapping of VIP Neurons in Barrel Cortex.

The neocortex is composed of layers. Whether layers constitute an essential framework for the formation of functional circuits is not well understood. We investigated the brain-wide input connectivity of vasoactive intestinal polypeptide (VIP) expressing neurons in the reeler mouse. This mutant is characterized by a migration deficit of cortical neurons so that no layers are formed. Still, neurons retain their properties and reeler mice show little cognitive impairment. We focused on VIP neurons because they are known to receive strong long-range inputs and have a typical laminar bias toward upper layers. In reeler, these neurons are more dispersed across the cortex. We mapped the brain-wide inputs of VIP neurons in barrel cortex of wild-type and reeler mice with rabies virus tracing. Innervation by subcortical inputs was not altered in reeler, in contrast to the cortical circuitry. Numbers of long-range ipsilateral cortical inputs were reduced in reeler, while contralateral inputs were strongly increased. Reeler mice had more callosal projection neurons. Hence, the corpus callosum was larger in reeler as shown by structural imaging. We argue that, in the absence of cortical layers, circuits with subcortical structures are maintained but cortical neurons establish a different network that largely preserves cognitive functions.

Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination.

Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2+ OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin+ progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin+ stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.

Temporal stability of fMRI in medetomidine-anesthetized rats.

Medetomidine has become a popular choice for anesthetizing rats during long-lasting sessions of blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI). Despite this, it has not yet been thoroughly established how commonly reported fMRI readouts evolve over several hours of medetomidine anesthesia and how they are affected by the precise timing, dose, and route of administration. We used four different protocols of medetomidine administration to anesthetize rats for up to six hours and repeatedly evaluated somatosensory stimulus-evoked BOLD responses and resting state functional connectivity. We found that the temporal evolution of fMRI readouts strongly depended on the method of administration. Intravenous administration of a medetomidine bolus (0.05 mg/kg), combined with a subsequent continuous infusion (0.1 mg/kg/h), led to temporally stable measures of stimulus-evoked activity and functional connectivity throughout the anesthesia. Deviating from the above protocol-by omitting the bolus, lowering the medetomidine dose, or using the subcutaneous route-compromised the stability of these measures in the initial two-hour period. We conclude that both an appropriate protocol of medetomidine administration and a suitable timing of fMRI experiments are crucial for obtaining consistent results. These factors should be considered for the design and interpretation of future rat fMRI studies.