Connectomic comparison of mouse and human cortex Loomba, Sahil; Straehle, Jakob; Gangadharan, Vijayan ...
Science (American Association for the Advancement of Science),
07/2022, Letnik:
377, Številka:
6602
Journal Article
Recenzirano
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The human cerebral cortex houses 1000 times more neurons than that of the cerebral cortex of a mouse, but the possible differences in synaptic circuits between these species are still poorly ...understood. We used three-dimensional electron microscopy of mouse, macaque, and human cortical samples to study their cell type composition and synaptic circuit architecture. The 2.5-fold increase in interneurons in humans compared with mice was compensated by a change in axonal connection probabilities and therefore did not yield a commensurate increase in inhibitory-versus-excitatory synaptic input balance on human pyramidal cells. Rather, increased inhibition created an expanded interneuron-to-interneuron network, driven by an expansion of interneuron-targeting interneuron types and an increase in their synaptic selectivity for interneuron innervation. These constitute key neuronal network alterations in the human cortex.
The difference between human and mouse
Over the past few decades, the mouse has become a model organism for brain research. Because of the close evolutionary similarity of ion channels, synaptic receptors, and other key molecular constituents of the brain to that of humans, corresponding similarity has been assumed for cortical neuronal circuits. However, comparative synaptic-resolution connectomic studies are required to determine the degree to which circuit structure has evolved between species. Using three-dimensional electron microscopy, Loomba
et al
. compared mouse and human/macaque cortex synaptic connectivity. Although human cells are much larger compared with mouse neurons and are more numerous, on average, they do not receive more synapses. And, even though there are three times more interneurons in the human cortex than in the mouse, the excitation-to-inhibition ratio is similar between the species. —PRS
Three-dimensional electron microscopy of mouse, macaque, and human brain samples elucidates cell type composition and synaptic circuit architecture.
INTRODUCTION
The analysis of the human brain is a central goal of neuroscience, but for methodological reasons, research has focused on model organisms, the mouse in particular. Because substantial homology was found at the level of ion channels, transcriptional programs, and basic neuronal types, a strong similarity of neuronal circuits across species has also been assumed. However, a rigorous test of the configuration of local neuronal circuitry in mouse versus human—in particular, in the gray matter of the cerebral cortex—is missing.
The about 1000-fold increase in number of neurons is the most obvious evolutionary change of neuronal network properties from mouse to human. Whether the structure of the local cortical circuitry has changed as well is, however, unclear. Recent data from transcriptomic analyses has indicated an increase in the proportion of inhibitory interneurons from mouse to human. But what the effect of such a change is on the circuit configurations found in the human cerebral cortex is not known. This is, however, of particular interest also to the study of neuropsychiatric disorders because in these, the alteration of inhibitory-to-excitatory synaptic balance has been identified as one possible mechanistic underpinning.
RATIONALE
We used recent methodological improvements in connectomics to acquire data from one macaque and two human individuals, using biopsies of the temporal, parietal, and frontal cortex. Human tissue was obtained from neurosurgical interventions related to tumor removal, in which access path tissue was harvested that was not primarily affected by the underlying disease. A key concern in the analysis of human patient tissue has been the relation to epilepsy surgery, when the underlying disease has required often year-long treatment with pharmaceuticals, plausibly altering synaptic connectivity. Therefore, the analysis of nonepileptic surgery tissue seemed of particular importance. We also included data from one macaque individual, who was not known to have any brain-related pathology.
RESULTS
We acquired three-dimensional electron microscopy data from temporal and frontal cortex of human and temporal and parietal cortex of macaque. From these, we obtained connectomic reconstructions and compared these with five connectomes from mouse cortex. On the basis of these data, we were able to determine the effect of the about 2.5-fold expansion of the interneuron pool in macaque and human cortex compared with that of mouse. Contrary to expectation, the inhibitory-to-excitatory synaptic balance on pyramidal neurons in macaque and human cortex was not substantially altered. Rather, the interneuron pool was selectively expanded for bipolar-type interneurons, which prefer the innervation of other interneurons, and which further increased their preference for interneuron innervation from mouse to human. These changes were each multifold, yielding in effect an about 10-fold expanded interneuron-to-interneuron network in the human cortex that is only sparsely present in mouse. The total amount of synaptic input to pyramidal neurons, however, did not change according to the threefold thickening of the cortex; rather, a modest increase from about 12,000 synaptic inputs in mouse to about 15,000 in human was found.
CONCLUSION
The principal cells of the cerebral cortex, pyramidal neurons, maintain almost constant inhibitory-to-excitatory input balance and total synaptic input across 100 million years of evolutionary divergence, which is particularly noteworthy with the concomitant 1000-fold expansion of the neuronal network size and the 2.5-fold increase of inhibitory interneurons from mouse to human. Rather, the key network change from mouse to human is an expansion of almost an order of magnitude of an interneuron-to-interneuron network that is virtually absent in mouse but constitutes a substantial part of the human cortical network. Whether this new network is primarily created through the expansion of existing neuronal types, or is related to the creation of new interneuron subtypes, requires further study. The discovery of this network component in human cortex encourages detailed analysis of its function in health and disease.
Connectomic screening across mammalian species: Comparison of five mouse, two macaque, and two human connectomic datasets from the cerebral cortex.
(
A
) Automated reconstructions of all neurons with their cell bodies in the volume shown, using random colors. The analyzed connectomes comprised a total of ~1.6 million synapses. Arrows indicate evolutionary divergence: the last common ancestor between human and mouse, approximately 100 million years ago, and the last common ancestor between human and macaque, about 20 million years ago. (
B
) Illustration of the about 10-fold expansion of the interneuron-to-interneuron network from mouse to human.
Soma location, dendrite morphology, and synaptic innervation may represent key determinants of functional responses of individual neurons, such as sensory-evoked spiking. Here, we reconstruct the 3D ...circuits formed by thalamocortical afferents from the lemniscal pathway and excitatory neurons of an anatomically defined cortical column in rat vibrissal cortex. We objectively classify 9 cortical cell types and estimate the number and distribution of their somata, dendrites, and thalamocortical synapses. Somata and dendrites of most cell types intermingle, while thalamocortical connectivity depends strongly upon the cell type and the 3D soma location of the postsynaptic neuron. Correlating dendrite morphology and thalamocortical connectivity to functional responses revealed that the lemniscal afferents can account for some of the cell type- and location-specific subthreshold and spiking responses after passive whisker touch (e.g., in layer 4, but not for other cell types, e.g., in layer 5). Our data provides a quantitative 3D prediction of the cell type-specific lemniscal synaptic wiring diagram and elucidates structure-function relationships of this physiologically relevant pathway at single-cell resolution.
Introduction:
Computer-assisted navigation (CAN) is a well-established tool in spinal instrumentation surgery. Different techniques – each with specific advantages and disadvantages – are used in the ...cervical spine.
Methods:
A structured summary of different spinal navigation techniques and a review of the literature were done to discuss the advantages and disadvantages of specific navigation tools in the cervical spine.
Results:
In cervical spine surgery, CAN increases the accuracy of pedicle screw placement, reduces screw mispositioning and leads to fewer revision surgeries. Due to the mobility of the cervical spine, preoperative CT followed by region matching or intraoperative CT are recommended.
Conclusions:
CAN increases pedicle screw placement accuracy and should be used in spinal instrumentation for the cervical spine whenever possible.
Although physiological data on microcircuits involving a few inhibitory neurons in the mammalian cerebral cortex are available, data on the quantitative relation between inhibition and excitation in ...cortical circuits involving thousands of neurons are largely missing. Because the distribution of neurons is very inhomogeneous in the cerebral cortex, it is critical to map all neurons in a given volume rather than to rely on sparse sampling methods. Here, we report the comprehensive mapping of interneurons (INs) in cortical columns of rat somatosensory cortex, immunolabeled for neuron-specific nuclear protein and glutamate decarboxylase. We found that a column contains ∼2,200 INs (11.5% of ∼19,000 neurons), almost a factor of 2 less than previously estimated. The density of GABAergic neurons was inhomogeneous between layers, with peaks in the upper third of L2/3 and in L5A. IN density therefore defines a distinct layer 2 in the sensory neocortex. In addition, immunohistochemical markers of IN subtypes were layer-specific. The "hot zones" of inhibition in L2 and L5A match the reported low stimulus-evoked spiking rates of excitatory neurons in these layers, suggesting that these inhibitory hot zones substantially suppress activity in the neocortex.
The cellular organization of the cortex is of fundamental importance for elucidating the structural principles that underlie its functions. It has been suggested that reconstructing the structure and ...synaptic wiring of the elementary functional building block of mammalian cortices, the cortical column, might suffice to reverse engineer and simulate the functions of entire cortices. In the vibrissal area of rodent somatosensory cortex, whisker-related “barrel” columns have been referred to as potential cytoarchitectonic equivalents of functional cortical columns. Here, we investigated the structural stereotypy of cortical barrel columns by measuring the 3D neuronal composition of the entire vibrissal area in rat somatosensory cortex and thalamus. We found that the number of neurons per cortical barrel column and thalamic “barreloid” varied substantially within individual animals, increasing by ∼2.5-fold from dorsal to ventral whiskers. As a result, the ratio between whisker-specific thalamic and cortical neurons was remarkably constant. Thus, we hypothesize that the cellular architecture of sensory cortices reflects the degree of similarity in sensory input and not columnar and/or cortical uniformity principles.
Introduction
The mesial temporal lobe plays a distinct role in epileptogenesis, and tumors in this part of the brain potentially have specific clinical and radiological features. Differentiating ...high-grade from lower-grade tumors or non-neoplastic lesions can be challenging, preventing the decision for early resection that can be critical in high-grade tumors.
Methods
A brain tumor database was analyzed retrospectively to identify patients with temporomesial tumors. We determined clinical features (age, sex, symptoms leading to clinical presentation) as well as neuroradiological (tumor location and the presence of contrast enhancement on initial magnetic resonance imaging (MRI)) and neuropathological findings.
Results
We identified 324 temporal tumors. 39 involved the mesial temporal lobe. 77% of temporomesial tumors occured in males, and 77% presented with seizures, regardless of tumor type or grade. In patients 50 years or older, 90% were male and 80% had glioblastoma (GBM); there was no GBM in patients younger than 50 years. 50% of GBMs lacked contrast enhancement. Male sex was significantly associated with GBM. In both contrast-enhancing and non-enhancing tumors, age of 50 years or older was also significantly associated with GBM.
Conclusion
In middle-aged and older patients with a mesial temporal lobe tumor, GBM is the most likely diagnosis even when there is no MRI contrast enhancement. Prolonged diagnostic workup or surveillance strategies should be avoided and early resection may be justified in these patients.
Cerebral vasospasm is a common complication of aneurysmal SAH and remains a risk factor for delayed cerebral ischemia and poor outcome. The interrater reliability of CTA in combination with CTP has ...not been sufficiently studied. We aimed to investigate the reliability of CTA alone and in combination with CTP in the detection of cerebral vasospasm and the decision to initiate endovascular treatment.
This is a retrospective single-center study including patients treated for aneurysmal SAH. Inclusion criteria were a baseline CTA and follow-up imaging including CTP due to suspected vasospasm. Three neuroradiologists were asked to grade 15 intracranial arterial segments in 71 cases using a tripartite scale (no, mild <50%, or severe >50% vasospasm). Raters further evaluated whether endovascular treatment should be indicated. The ratings were performed in 2 stages with a minimum interval of 6 weeks. The first rating included only CTA images, whereas the second rating additionally encompassed CTP images. All raters were blinded to any clinical information of the patients.
Interrater reliability for per-segment analysis of vessels was highly variable (κ = 0.16-0.61). We observed a tendency toward higher interrater reliability in proximal vessel segments, except for the ICA. CTP did not improve the reliability for the per-segment analysis. When focusing on senior raters, the addition of CTP images resulted in higher interrater reliability for severe vasospasm (κ = 0.28; 95% CI, 0.10-0.46 versus κ = 0.46; 95% CI, 0.26-0.66) and subsequently higher concordance (κ = 0.23; 95% CI, -0.01-0.46 versus κ = 0.73; 95% CI, 0.55-0.91) for the decision of whether endovascular treatment was indicated.
CTA alone offers only low interrater reliability in the graduation of cerebral vasospasm. However, using CTA in combination with CTP might help, especially senior neuroradiologists, to increase the interrater reliability to identify severe vasospasm following aneurysmal SAH and to increase the reliability regarding endovascular treatment decisions.
In diffusely infiltrating gliomas, the maximum extent of tumor resection is an important predictor of overall survival, irrespective of histological or molecular subtype or tumor grade. For ...glioblastoma WHO grade 4 (GBM), it has been shown that resection-related events, such as ventricular opening and ventriculitis, increase the risk for development of communicating hydrocephalus (CH) requiring cerebrospinal fluid (CSF) diversion surgery. Risk factors for the development and the incidence of hydrocephalus following resection of other types of infiltrating gliomas are less well established. In this study, we evaluated the incidence and timing of occurrence of different types of hydrocephalus and potential risk factors for the development of CH following resection of grade 2 and 3 gliomas.
346 patients who underwent tumor resection (WHO grade 2: 42.2%; 3: 57.8%) at our department between 2006 and 2019 were analyzed retrospectively. For each patient, age, sex, WHO grade, histological type, IDH mutation and 1p/19q codeletion status, tumor localization, number of resections, rebleeding, ventriculitis, ventricular opening during resection and postoperative CSF leak were determined. Uni- as well as multivariate analyses were performed to identify associations with CH and independent risk factors.
24 out of 346 (6.9%) patients needed CSF diversion surgery (implantation of a ventriculoperitoneal or ventriculoatrial shunt) following resection. Nineteen patients (5.5%) had CH, on median, 44 days after the last resection (interquartile range: 18-89 days). Two patients had obstructive hydrocephalus (OH), and three patients had other CSF circulation disorders. CH was more frequent in grade 3 compared to grade 2 gliomas (8.5 vs. 1.4%). WHO grade 3 (odds ratio (OR) 7.5,
= 0.00468), rebleeding (OR 5.0,
= 0.00984), ventriculitis (OR 4.1,
= 0.00463) and infratentorial tumor localization (OR 6.6,
= 0.00300) were identified as significant independent risk factors for the development of post-resection CH. Ventricular opening was significantly associated with CH, but it was not an independent risk factor.
Physicians treating brain tumor patients should be aware that postoperative CH requiring CSF shunting occurs not only in GBM but also after resection of lower-grade gliomas, especially in grade 3 tumors. It usually occurs several weeks after resection. Rebleeding and postoperative ventriculitis are independent risk factors.
This is the second article in a series of three studies that investigate the anatomical determinants of thalamocortical (TC) input to excitatory neurons in a cortical column of rat primary ...somatosensory cortex (S1). Here, we report the number and distribution of NeuN-positive neurons within the C2, D2, and D3 TC projection columns in P27 rat somatosensory barrel cortex based on an exhaustive identification of 89 834 somata in a 1.15 mm3 volume of cortex. A single column contained 19 109 ± 444 neurons (17 560 ± 399 when normalized to a standard-size projection column). Neuron density differences along the vertical column axis delineated “cytoarchitectonic” layers. The resulting neuron numbers per layer in the average column were 63 ± 10 (L1), 2039 ± 524 (L2), 3735 ± 905 (L3), 4447 ± 439 (L4), 1737 ± 251 (L5A), 2235 ± 99 (L5B), 3786 ± 168 (L6A), and 1066 ± 170 (L6B). These data were then used to derive the layer-specific action potential (AP) output of a projection column. The estimates confirmed previous reports suggesting that the ensembles of spiny L4 and thick-tufted pyramidal neurons emit the major fraction of APs of a column. The number of APs evoked in a column by a sensory stimulus (principal whisker deflection) was estimated as 4441 within 100 ms post-stimulus.
Introduction
Glioblastoma (GBM) is the most common malignant primary brain tumor. Treatment includes maximally safe surgical resection followed by radiation and/or chemotherapy. However, resection ...can lead to ventricular opening, potentially increasing the risk for development of communicating hydrocephalus (CH). Complications such as rebleeding and infection may also lead to CH and, eventually, the need for cerebrospinal fluid (CSF) diversion surgery. In this study, we evaluated the incidence of different types of hydrocephalus and potential risk factors for the development of CH following glioblastoma resection.
Methods
726 GBM patients who underwent tumor resection at our department between 2006 and 2019 were analyzed retrospectively. Potential risk factors that were determined for each patient were age, sex, tumor location, the number of resection surgeries, ventricular opening during resection, postoperative CSF leak, ventriculitis, and rebleeding. Uni- as well as multivariate analyses were performed to identify associations with CH and independent risk factors.
Results
55 patients (7.6%) needed CSF diversion surgery (implantation of a ventriculoperitoneal or ventriculoatrial shunt) following resection surgery. 47 patients (6.5%) had CH, on median, 24 days after the last resection (interquartile range: 17-52 days). 3 patients had obstructive hydrocephalus (OH) and 5 patients had other CSF circulation disorders. Ventricular opening (odds ratio (OR): 7.9; p=0.000807), ventriculitis (OR 3.3; p=0.000754), and CSF leak (OR 2.3; p=0.028938) were identified as significant independent risk factors for the development of post-resection CH. Having more than one resection surgery was associated with CH as well (OR 2.1; p=0.0128), and frontal tumors were more likely to develop CH (OR 2.4; p=0.00275), while temporal tumors were less likely (OR 0.41; p=0.0158); However, none of those were independent risk factors. Age, sex, or rebleeding were not associated with postoperative CH.
Conclusion
Postoperative CH requiring CSF shunting is not infrequent following GBM resection and is influenced by surgery-related factors. It typically occurs several weeks after resection. If multiple risk factors are present, one should discuss the possibility of postoperative CH with the patient and maybe even consider pre-emptive shunt implantation to avoid interruption of adjuvant tumor therapy. The incidence of CH requiring shunting in GBM patients could rise in the future.
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