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1.  Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution 
PLoS ONE  2011;6(3):e17514.
It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution.
PMCID: PMC3046985  PMID: 21390261
2.  Cellular Scaling Rules for the Brains of an Extended Number of Primate Species 
Brain, Behavior and Evolution  2010;76(1):32-44.
What are the rules relating the size of the brain and its structures to the number of cells that compose them and their average sizes? We have shown previously that the cerebral cortex, cerebellum and the remaining brain structures increase in size as a linear function of their numbers of neurons and non-neuronal cells across 6 species of primates. Here we describe that the cellular composition of the same brain structures of 5 other primate species, as well as humans, conform to the scaling rules identified previously, and that the updated power functions for the extended sample are similar to those determined earlier. Accounting for phylogenetic relatedness in the combined dataset does not affect the scaling slopes that apply to the cerebral cortex and cerebellum, but alters the slope for the remaining brain structures to a value that is similar to that observed in rodents, which raises the possibility that the neuronal scaling rules for these structures are shared among rodents and primates. The conformity of the new set of primate species to the previous rules strongly suggests that the cellular scaling rules we have identified apply to primates in general, including humans, and not only to particular subgroups of primate species. In contrast, the allometric rules relating body and brain size are highly sensitive to the particular species sampled, suggesting that brain size is neither determined by body size nor together with it, but is rather only loosely correlated with body size.
PMCID: PMC2980814  PMID: 20926854
Allometry; Brain size; Evolution; Glia, number; Neurons, number; Primates
3.  Updated Neuronal Scaling Rules for the Brains of Glires (Rodents/Lagomorphs) 
Brain, Behavior and Evolution  2011;78(4):302-314.
Brain size scales as different functions of its number of neurons across mammalian orders such as rodents, primates, and insectivores. In rodents, we have previously shown that, across a sample of 6 species, from mouse to capybara, the cerebral cortex, cerebellum and the remaining brain structures increase in size faster than they gain neurons, with an accompanying decrease in neuronal density in these structures [Herculano-Houzel et al.: Proc Natl Acad Sci USA 2006;103:12138–12143]. Important remaining questions are whether such neuronal scaling rules within an order apply equally to all pertaining species, and whether they extend to closely related taxa. Here, we examine whether 4 other species of Rodentia, as well as the closely related rabbit (Lagomorpha), conform to the scaling rules identified previously for rodents. We report the updated neuronal scaling rules obtained for the average values of each species in a way that is directly comparable to the scaling rules that apply to primates [Gabi et al.: Brain Behav Evol 2010;76:32–44], and examine whether the scaling relationships are affected when phylogenetic relatedness in the dataset is accounted for. We have found that the brains of the spiny rat, squirrel, prairie dog and rabbit conform to the neuronal scaling rules that apply to the previous sample of rodents. The conformity to the previous rules of the new set of species, which includes the rabbit, suggests that the cellular scaling rules we have identified apply to rodents in general, and probably to Glires as a whole (rodents/lagomorphs), with one notable exception: the naked mole-rat brain is apparently an outlier, with only about half of the neurons expected from its brain size in its cerebral cortex and cerebellum.
PMCID: PMC3237106  PMID: 21985803
Rodents; Brain size; Evolution; Neurons; Glia; Glires
4.  Distinct and Overlapping Functional Zones in the Cerebellum Defined by Resting State Functional Connectivity 
Cerebral Cortex (New York, NY)  2009;20(4):953-965.
The cerebellum processes information from functionally diverse regions of the cerebral cortex. Cerebellar input and output nuclei have connections with prefrontal, parietal, and sensory cortex as well as motor and premotor cortex. However, the topography of the connections between the cerebellar and cerebral cortices remains largely unmapped, as it is relatively unamenable to anatomical methods. We used resting-state functional magnetic resonance imaging to define subregions within the cerebellar cortex based on their functional connectivity with the cerebral cortex. We mapped resting-state functional connectivity voxel-wise across the cerebellar cortex, for cerebral–cortical masks covering prefrontal, motor, somatosensory, posterior parietal, visual, and auditory cortices. We found that the cerebellum can be divided into at least 2 zones: 1) a primary sensorimotor zone (Lobules V, VI, and VIII), which contains overlapping functional connectivity maps for domain-specific motor, somatosensory, visual, and auditory cortices; and 2) a supramodal zone (Lobules VIIa, Crus I, and II), which contains overlapping functional connectivity maps for prefrontal and posterior-parietal cortex. The cortical connectivity of the supramodal zone was driven by regions of frontal and parietal cortex which are not directly involved in sensory or motor processing, including dorsolateral prefrontal cortex and the frontal pole, and the inferior parietal lobule.
PMCID: PMC2837094  PMID: 19684249
cerebellum; fMRI; functional connectivity; networks; resting-state
5.  Cellular scaling rules for the brain of afrotherians 
Quantitative analysis of the cellular composition of rodent, primate and eulipotyphlan brains has shown that non-neuronal scaling rules are similar across these mammalian orders that diverged about 95 million years ago, and therefore appear to be conserved in evolution, while neuronal scaling rules appear to be free to vary in evolution in a clade-specific manner. Here we analyze the cellular scaling rules that apply to the brain of afrotherians, believed to be the first clade to radiate from the common eutherian ancestor. We find that afrotherians share non-neuronal scaling rules with rodents, primates and eulipotyphlans, as well as the coordinated scaling of numbers of neurons in the cerebral cortex and cerebellum. Afrotherians share with rodents and eulipotyphlans, but not with primates, the scaling of number of neurons in the cortex and in the cerebellum as a function of the number of neurons in the rest of the brain. Afrotheria also share with rodents and eulipotyphlans the neuronal scaling rules that apply to the cerebral cortex. Afrotherians share with rodents, but not with eulipotyphlans nor primates, the neuronal scaling rules that apply to the cerebellum. Importantly, the scaling of the folding index of the cerebral cortex with the number of neurons in the cerebral cortex is not shared by either afrotherians, rodents, or primates. The sharing of some neuronal scaling rules between afrotherians and rodents, and of some additional features with eulipotyphlans and primates, raise the interesting possibility that these shared characteristics applied to the common eutherian ancestor. In turn, the clade-specific characteristics that relate to the distribution of neurons along the surface of the cerebral cortex and to its degree of gyrification suggest that these characteristics compose an evolutionarily plastic suite of features that may have defined and distinguished mammalian groups in evolution.
PMCID: PMC3925844  PMID: 24596544
evolution; glia-neuron ratio; numbers of neurons; cortical expansion; gyrification
6.  Faster scaling of visual neurons in cortical areas relative to subcortical structures in non-human primate brains 
Brain structure & function  2012;218(3):805-816.
Cortical expansion, both in absolute terms and in relation to subcortical structures, is considered a major trend in mammalian brain evolution with important functional implications, given that cortical computations should add complexity and flexibility to information processing. Here, we investigate the numbers of neurons that compose 4 structures in the visual pathway across 11 non-human primate species to determine the scaling relationships that apply to these structures and among them. We find that primary visual cortex, area V1, as well as the superior colliculus (SC) and lateral geniculate nucleus scale in mass faster than they gain neurons. Areas V1 and MT gain neurons proportionately to the entire cerebral cortex, and represent fairly constant proportions of all cortical neurons (36 and 3 %, respectively), while V1 gains neurons much faster than both subcortical structures examined. Larger primate brains therefore have increased ratios of cortical to subcortical neurons involved in processing visual information, as observed in the auditory pathway, but have a constant proportion of cortical neurons dedicated to the primary visual representation, and a fairly constant ratio of about 45 times more neurons in primary visual than in primary auditory cortical areas.
PMCID: PMC3727908  PMID: 22684638
Superior colliculus; Visual cortex; Lateral geniculate nucleus; V1; Area MT; Thalamus; Allometry; Brain size; Evolution
7.  Cellular Scaling Rules of Insectivore Brains 
Insectivores represent extremes in mammalian body size and brain size, retaining various “primitive” morphological characteristics, and some species of Insectivora are thought to share similarities with small-bodied ancestral eutherians. This raises the possibility that insectivore brains differ from other taxa, including rodents and primates, in cellular scaling properties. Here we examine the cellular scaling rules for insectivore brains and demonstrate that insectivore scaling rules overlap somewhat with those for rodents and primates such that the insectivore cortex shares scaling rules with rodents (increasing faster in size than in numbers of neurons), but the insectivore cerebellum shares scaling rules with primates (increasing isometrically). Brain structures pooled as “remaining areas” appear to scale similarly across all three mammalian orders with respect to numbers of neurons, and the numbers of non-neurons appear to scale similarly across all brain structures for all three orders. Therefore, common scaling rules exist, to different extents, between insectivore, rodent, and primate brain regions, and it is hypothesized that insectivores represent the common aspects of each order. The olfactory bulbs of insectivores, however, offer a noteworthy exception in that neuronal density increases linearly with increasing structure mass. This implies that the average neuronal cell size decreases with increasing olfactory bulb mass in order to accommodate greater neuronal density, and represents the first documentation of a brain structure gaining neurons at a greater rate than mass. This might allow insectivore brains to concentrate more neurons within the olfactory bulbs without a prohibitively large and metabolically costly increase in structure mass.
PMCID: PMC2713736  PMID: 19636383
allometry; brain size; comparative neuroanatomy; glia; neurons; evolution; olfactory bulb
8.  Abnormal Cerebellar Cytoarchitecture and Impaired Inhibitory Signaling in Adult Mice Lacking Testicular Orphan Nuclear Receptor 4 
Brain research  2007;1168:72-82.
Since Testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4−/−) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4−/− brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4−/− cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4−/− cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4−/− cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4−/− mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4−/− brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development.
PMCID: PMC2084075  PMID: 17706948
Testicular orphan nuclear receptor 4; cerebellar atrophy; locomotor
9.  Evaluation of Morphological Plasticity in the Cerebella of Basketball Players with MRI 
Journal of Korean Medical Science  2006;21(2):342-346.
Cerebellum is a key structure involved in motor learning and coordination. In animal models, motor skill learning increased the volume of molecular layer and the number of synapses on Purkinje cells in the cerebellar cortex. The aim of this study is to investigate whether the analogous change of cerebellar volume occurs in human population who learn specialized motor skills and practice them intensively for a long time. Magnetic resonance image (MRI)-based cerebellar volumetry was performed in basketball players and matched controls with V-works image software. Total brain volume, absolute and relative cerebellar volumes were compared between two groups. There was no significant group difference in the total brain volume, the absolute and the relative cerebellar volume. Thus we could not detect structural change in the cerebellum of this athlete group in the macroscopic level.
PMCID: PMC2734016  PMID: 16614526
Basketball; Cerebellum; Magnetic Resonance Imaging; Motor Skills; Neuronal Plasticity
10.  Motor thalamus integration of cortical, cerebellar and basal ganglia information: implications for normal and parkinsonian conditions 
Motor thalamus (Mthal) is implicated in the control of movement because it is strategically located between motor areas of the cerebral cortex and motor-related subcortical structures, such as the cerebellum and basal ganglia (BG). The role of BG and cerebellum in motor control has been extensively studied but how Mthal processes inputs from these two networks is unclear. Specifically, there is considerable debate about the role of BG inputs on Mthal activity. This review summarizes anatomical and physiological knowledge of the Mthal and its afferents and reviews current theories of Mthal function by discussing the impact of cortical, BG and cerebellar inputs on Mthal activity. One view is that Mthal activity in BG and cerebellar-receiving territories is primarily “driven” by glutamatergic inputs from the cortex or cerebellum, respectively, whereas BG inputs are modulatory and do not strongly determine Mthal activity. This theory is steeped in the assumption that the Mthal processes information in the same way as sensory thalamus, through interactions of modulatory inputs with a single driver input. Another view, from BG models, is that BG exert primary control on the BG-receiving Mthal so it effectively relays information from BG to cortex. We propose a new “super-integrator” theory where each Mthal territory processes multiple driver or driver-like inputs (cortex and BG, cortex and cerebellum), which are the result of considerable integrative processing. Thus, BG and cerebellar Mthal territories assimilate motivational and proprioceptive motor information previously integrated in cortico-BG and cortico-cerebellar networks, respectively, to develop sophisticated motor signals that are transmitted in parallel pathways to cortical areas for optimal generation of motor programmes. Finally, we briefly review the pathophysiological changes that occur in the BG in parkinsonism and generate testable hypotheses about how these may affect processing of inputs in the Mthal.
PMCID: PMC3822295  PMID: 24273509
motor thalamus; basal ganglia; motor cortex; cerebellum; Parkinson’s disease; LTS burst
11.  Brain acetylcholinesterase activity is markedly reduced in dominantly-inherited olivopontocerebellar atrophy. 
The activity was measured of the acetylcholine catabolising enzyme acetylcholinesterase (AChE) in brain after necropsy of seven patients from one established pedigree with dominantly-inherited olivopontocerebellar atrophy (OPCA), a cerebellar ataxia disorder in which neuropathological changes are assumed to be primarily restricted to cerebellum, lower brain stem and spinal cord. Mean AChE activity was significantly reduced in cerebral (-51% to 65%) and cerebellar (-47%) cortex with a less severe change (-37%) in the hippocampus. The magnitude of the enzyme reduction in cerebral cortex was equal to or greater than that reported in brain of demented Alzheimer's and Parkinson's disease patients having loss of AChE-containing nucleus basalis cholinergic neurons. It is concluded that the data provide additional biochemical evidence suggesting a cerebral cortical cholinergic denervation in OPCA.
PMCID: PMC1032971  PMID: 3164041
12.  Resting state cortico-cerebellar functional connectivity networks: a comparison of anatomical and self-organizing map approaches 
The cerebellum plays a role in a wide variety of complex behaviors. In order to better understand the role of the cerebellum in human behavior, it is important to know how this structure interacts with cortical and other subcortical regions of the brain. To date, several studies have investigated the cerebellum using resting-state functional connectivity magnetic resonance imaging (fcMRI; Krienen and Buckner, 2009; O'Reilly et al., 2010; Buckner et al., 2011). However, none of this work has taken an anatomically-driven lobular approach. Furthermore, though detailed maps of cerebral cortex and cerebellum networks have been proposed using different network solutions based on the cerebral cortex (Buckner et al., 2011), it remains unknown whether or not an anatomical lobular breakdown best encompasses the networks of the cerebellum. Here, we used fcMRI to create an anatomically-driven connectivity atlas of the cerebellar lobules. Timecourses were extracted from the lobules of the right hemisphere and vermis. We found distinct networks for the individual lobules with a clear division into “motor” and “non-motor” regions. We also used a self-organizing map (SOM) algorithm to parcellate the cerebellum. This allowed us to investigate redundancy and independence of the anatomically identified cerebellar networks. We found that while anatomical boundaries in the anterior cerebellum provide functional subdivisions of a larger motor grouping defined using our SOM algorithm, in the posterior cerebellum, the lobules were made up of sub-regions associated with distinct functional networks. Together, our results indicate that the lobular boundaries of the human cerebellum are not necessarily indicative of functional boundaries, though anatomical divisions can be useful. Additionally, driving the analyses from the cerebellum is key to determining the complete picture of functional connectivity within the structure.
PMCID: PMC3415673  PMID: 22907994
cerebellum; resting state functional connectivity; self-organizing map
13.  In and out of the loop: external and internal modulation of the olivo-cerebellar loop 
Cerebellar anatomy is known for its crystal like structure, where neurons and connections are precisely and repeatedly organized with minor variations across the Cerebellar Cortex. The olivo-cerebellar loop, denoting the connections between the Cerebellar cortex, Inferior Olive and Cerebellar Nuclei (CN), is also modularly organized to form what is known as the cerebellar module. In contrast to the relatively organized and static anatomy, the cerebellum is innervated by a wide variety of neuromodulator carrying axons that are heterogeneously distributed along the olivo-cerebellar loop, providing heterogeneity to the static structure. In this manuscript we review modulatory processes in the olivo-cerebellar loop. We start by discussing the relationship between neuromodulators and the animal behavioral states. This is followed with an overview of the cerebellar neuromodulatory signals and a short discussion of why and when the cerebellar activity should be modulated. We then devote a section for three types of neurons where we briefly review its properties and propose possible neuromodulation scenarios.
PMCID: PMC3630299  PMID: 23626524
cerebellum; neuromodulation; olivo-cerebellar loop; aminergic modulation; inferior olive; cerebellar nuclei; cerebellar cortex
14.  DNA microarray analysis of functionally discrete human brain regions reveals divergent transcriptional profiles 
Neurobiology of disease  2003;14(2):240-250.
Transcriptional profiles within discrete human brain regions are likely to reflect structural and functional specialization. Using DNA microarray technology, this study investigates differences in transcriptional profiles of highly divergent brain regions (the cerebellar cortex and the cerebral cortex) as well as differences between two closely related brain structures (the anterior cingulate cortex and the dorsolateral prefrontal cortex). Replication of this study across three independent laboratories, to address false-positive and false-negative results using microarray technology, is also discussed. We find greater than a thousand transcripts to be differentially expressed between cerebellum and cerebral cortex and very few transcripts to be differentially expressed between the two neocortical regions. We further characterized transcripts that were found to be specifically expressed within brain regions being compared and found that ontological classes representing signal transduction machinery, neurogenesis, synaptic transmission, and transcription factors were most highly represented.
PMCID: PMC3098567  PMID: 14572446
Microarray; Cerebellum; Prefrontal cortex; Cingulate cortex; Depression; Schizophrenia; Psychiatric disorder
15.  Constancy and trade-offs in the neuroanatomical and metabolic design of the cerebral cortex 
Mammalian brains span about four orders of magnitude in cortical volume and have to operate in different environments that require diverse behavioral skills. Despite these geometric and behavioral diversities, the examination of cerebral cortex across species reveals that it contains a substantial number of conserved characteristics that are associated with neuroanatomy and metabolism, i.e., with neuronal connectivity and function. Some of these cortical constants or invariants have been known for a long time but not sufficiently appreciated, and others were only recently discovered. The focus of this review is to present the cortical invariants and discuss their role in the efficient information processing. Global conservation in neuroanatomy and metabolism, as well as their correlated regional and developmental variability suggest that these two parallel systems are mutually coupled. It is argued that energetic constraint on cortical organization can be strong if cerebral blood supplied is either below or above a certain level, and it is rather soft otherwise. Moreover, because maximization or minimization of parameters associated with cortical connectivity, function and cost often leads to conflicts in design, it is argued that the architecture of the cerebral cortex is a result of structural and functional compromises.
PMCID: PMC3920482  PMID: 24574975
cerebral cortex; conservation; connectivity; metabolism; capillary; constraints; allometry; evolutionary design
16.  Cortico-Cerebellar Coherence and Causal Connectivity During Slow-Wave Activity 
Neuroscience  2009;166(2):698-711.
Cerebral cortical slow-wave activity (SWA) is prominent during sleep and also during ketamine-induced anesthesia. SWA in EEG recordings is closely linked to prominent fluctuations between up- and down-states in the membrane potential of pyramidal neurons. However, little is known about how the cerebellum is linked into SWA and whether slow oscillations influence sensory cerebellar responses. To examine these issues, we simultaneously recorded EEG from the cerebral cortex (SI, MI, and SMA), local field potentials at the input stage of cerebellar processing in the cerebellar granule cell layer (GCL) and inferior olive (IO), and single unit activity at the output stage of the cerebellum in the deep cerebellar nuclei (DCN). We found that in ketamine-anesthetized rats, SWA was synchronized between all recorded cortical areas and was phase locked with local field potentials of the GCL, IO, and single unit activity in the DCN. We found that cortical up-states are linked to activation of GCL neurons but to inhibition of cerebellar output from the DCN, with the latter an effect likely mediated by Purkinje cells. A partial coherence analysis showed further that a large portion of SWA shared between GCL and DCN was transmitted from the cortex, since the coherence shared between GCL and DCN was diminished when the effect of cortical activity was subtracted. To determine the causal flow of information between structures, a directed transfer function was calculated between the simultaneous activities of SI, MI, SMA, GCL and DCN. This analysis showed that the primary direction of information flow was from cortex to the cerebellum, and that SI had a stronger influence than other cortical areas on DCN activity. The strong functional connectivity with SI in particular is in agreement with previous findings of a strong cortical component in cerebellar sensory responses.
PMCID: PMC2823967  PMID: 20036719
Rat; Deep Cerebellar Nuclei; Cerebral Cortex; Single Unit Activity; Local Field Potential; Directed Transfer Function
17.  Age associated changes in gene expression in human brain and isolated neurons 
Neurobiology of aging  2012;34(4):1199-1209.
Previous studies have suggested that there are genes whose expression levels are associated with chronological age. However, which genes show consistent age association across studies, and which are specific to a given organism or tissue remains unresolved. Here, we re-assessed this question using two independently ascertained series of human brain samples from two anatomical regions, the frontal lobe of the cerebral cortex and cerebellum. Using microarrays to estimate gene expression, we found sixty associations between expression and chronological age that were statistically significant and were replicated in both series in at least one tissue. There were a greater number of significant associations in the frontal cortex compared to the cerebellum. We then repeated the analysis in a subset of samples using laser capture microdissection to isolate purkinje neurons from the cerebellum. We were able to replicate five gene associations from either frontal cortex or cerebellum in the Purkinje cell dataset, suggesting that there is a subset of genes have robust changes withs aging. Of these, the most consistent and strongest association was with expression of RHBDL3, a rhomboid protease family member. We confirmed several hits using an independent technique (qRT-PCR) and in an independent published sample series that used a different array platform. We also interrogated larger patterns of age related gene expression using weighted gene correlation network analysis (WGCNA). We found several modules that showed significant associations with chronological age and, of these, several that showed negative associations were enriched for genes encoding components of mitochondria. Overall, our results show that there is a distinct and reproducible gene signature for aging in the human brain.
PMCID: PMC3545059  PMID: 23177596
18.  The scalable mammalian brain: emergent distributions of glia and neurons 
Biological Cybernetics  2008;98(5):439-445.
In this paper, we demonstrate that two characteristic properties of mammalian brains emerge when scaling-up modular, cortical structures. Firstly, the glia-to-neuron ratio is not constant across brains of different sizes: large mammalian brains have more glia per neuron than smaller brains. Our analyses suggest that if one assumes that glia number is proportional to wiring, a particular quantitative relationship emerges between brain size and glia-to-neuron ratio that fits the empirical data. Secondly, many authors have reported that the number of neurons underlying one mm2 of mammalian cortex is remarkably constant, across both areas and species. Here, we will show that such a constancy emerges when enlarging modular, cortical brain structures. Our analyses thus corroborate recent studies on the mammalian brain as a scalable architecture, providing a possible mechanism to explain some of the principles, constancies and rules that hold across brains of different size.
PMCID: PMC2798959  PMID: 18414892
Comparative neuroanatomy; Glia-to-neuron index; Neuron number
19.  LINCing lamin B2 to neuronal migration: growing evidence for cell-specific roles of B-type lamins 
Nucleus (Austin, Tex.)  2010;1(5):407-411.
Nuclear lamins are major components of the nuclear lamina, and play essential roles in supporting the nucleus and organizing nuclear structures. While a large number of clinically important mutations have been mapped to the LMNA gene in humans, very few mutations have been associated with the B-type lamins. We have shown that lamin B2–deficiency in mice results in severe brain abnormalities. While the early stages of forebrain development in lamin B2–deficient mice appear to be normal, cortical neurons fail to migrate and organize into proper layers within the cerebral cortex. The morphogenesis of the hippocampus and cerebellum is also severely impaired. These phenotypes are reminiscent of lissencephaly, a human brain developmental disorder characterized by an abnormal neuronal migration. Most mutations in lissencephaly patients affect cytoplasmic regulators of nuclear translocation, which is a crucial step in neuronal migration. The phenotypes of lamin B2–deficient mice suggest that lamin B2 may also play a key role in nuclear translocation. Potential mechanisms for lamin B2 involvement, which include mechanical and non-mechanical roles, and participation in LINC complexes in the nuclear envelope, are discussed along with evidence that lamins B1 and B2 play distinct, cell-specific functions.
PMCID: PMC3027074  PMID: 21278813
nuclear envelope; nuclear lamina; lamin B2; LINC complex; nesprin; SUN; lissencephaly; neuronal migration; cortical neurons; nuclear translocation
20.  LINCing lamin B2 to neuronal migration 
Nucleus  2010;1(5):407-411.
Nuclear lamins are major components of the nuclear lamina, and play essential roles in supporting the nucleus and organizing nuclear structures. While a large number of clinically important mutations have been mapped to the LMNA gene in humans, very few mutations have been associated with the B-type lamins. We have shown that lamin B2-deficiency in mice results in severe brain abnormalities. While the early stages of forebrain development in lamin B2-deficient mice appear to be normal, cortical neurons fail to migrate and organize into proper layers within the cerebral cortex. The morphogenesis of the hippocampus and cerebellum is also severely impaired. These phenotypes are reminiscent of lissencephaly, a human brain developmental disorder characterized by an abnormal neuronal migration. Most mutations in lissencephaly patients affect cytoplasmic regulators of nuclear translocation, which is a crucial step in neuronal migration. The phenotypes of lamin B2-deficient mice suggest that lamin B2 may also play a key role in nuclear translocation. Potential mechanisms for lamin B2 involvement, which include mechanical and non-mechanical roles and participation in LINC complexes in the nuclear envelope, are discussed along with evidence that lamins B1 and B2 play distinct, cell-specific functions.
PMCID: PMC3027074  PMID: 21278813
nuclear envelope; nuclear lamina; lamin B2; LINC complex; nesprin; SUN; lissencephaly; neuronal migration; cortical neurons; nuclear translocation
21.  Theoretical Limitations on Functional Imaging Resolution in Auditory Cortex 
Brain research  2010;1319:175-189.
Functional imaging can reveal detailed organizational structure in cerebral cortical areas, but neuronal response features and local neural interconnectivity can influence the resulting images, possibly limiting the inferences that can be drawn about neural function. Discerning the fundamental principles of organizational structure in the auditory cortex of multiple species has been somewhat challenging historically both with functional imaging and with electrophysiology. A possible limitation affecting any methodology using pooled neuronal measures may be the relative distribution of response selectivity throughout the population of auditory cortex neurons. One neuronal response type inherited from the cochlea, for example, exhibits a receptive field that increases in size (i.e., decreases in selectivity) at higher stimulus intensities. Even though these neurons appear to represent a minority of auditory cortex neurons, they are likely to contribute disproportionately to the activity detected in functional images, especially if intense sounds are used for stimulation. To evaluate the potential influence of neuronal subpopulations upon functional images of primary auditory cortex, a model array representing cortical neurons was probed with virtual imaging experiments under various assumptions about the local circuit organization. As expected, different neuronal subpopulations were activated preferentially under different stimulus conditions. In fact, stimulus protocols that can preferentially excite selective neurons, resulting in a relatively sparse activation map, have the potential to improve the effective resolution of functional auditory cortical images. These experimental results also make predictions about auditory cortex organization that can be tested with refined functional imaging experiments.
PMCID: PMC2832293  PMID: 20079343
virtual imaging; computational mode; self-organizing feature map; SOFM; topographic map; topography
22.  GPR56-regulated granule cell adhesion is essential for rostral cerebellar development 
Mutations in GPR56, an orphan G-protein coupled receptor (GPCR), cause bilateral frontoparietal polymicrogyria (BFPP), a disorder characterized by mental retardation, seizures, motor developmental delay, and ataxia. BFPP patients have structural abnormalities of the cerebral cortex, cerebellum and pons. To shed light on the function of GPR56 and the anatomical and behavioral defects underlying BFPP, we analyzed the cerebellum of mice lacking this GPCR. Gpr56 −/− mice display a severe malformation of the rostral cerebellum that develops perinatally. Defects involve fusion of adjacent lobules, disrupted layering of neurons and glia, and fragmentation of the pial basement membrane. At the age of defect onset, GPR56 expression is restricted specifically to developing granule cells in the rostral cerebellum, suggesting that GPR56 regulates properties of these cells. Indeed, granule cells from the rostral region of perinatal Gpr56 −/− cerebella show loss of adhesion to extracellular matrix molecules of the pial basement membrane. RNAi-mediated knockdown of GPR56 recapitulates the loss of adhesion seen in knockouts and re-expression of GPR56 rescues the adhesion defect in knockout granule cells. Loss of GPR56 does not affect cell proliferation, migration or neurite outgrowth. These studies establish a novel role for GPR56 in the adhesion of developing neurons to basal lamina molecules, and suggest that this adhesion is critical for maintenance of the pia and proper cerebellar morphogenesis.
PMCID: PMC2744696  PMID: 19515912
anterior cerebellum; BFPP; basement membrane; cerebellar patterning; neuronal migration; pia; basal lamina
23.  Familial motor neurone disease with dementia: phenotypic variation and cerebellar pathology 
Objectives:To characterise the neuropathological phenotypes of two affected individuals from a family with an unusual clinical phenotype resembling motor neurone disease and dementia.
Methods:Histological sections of cerebral cortex, basal ganglia, brain stem, cerebellum, and spinal cord were stained with haematoxylin-eosin, luxol fast blue, silver stains, anti-tau, anti-ubiquitin, anti-α-synuclein, and anti-neurofilament.
Results:Numerous ubiquitin positive, tau and α-synuclein negative intraneuronal inclusions were present in the cerebral cortex (particularly within the dentate gyrus), cerebellar cortex, brain stem, and spinal cord. The cerebellar ubiquitinated inclusions were located in the proximal dendrite of the Purkinje cells. Loss of Purkinje cells and occasional silver and neurofilament positive axonal swellings (torpedoes) were also seen within the cerebellar cortex. The main difference between the two cases was the severity of the spinal cord involvement: no significant pathology was present within one, but obvious motor neurone disease within the other.
Conclusions:The clinical and neuropathological findings in this family are best described as an example of familial motor neurone disease with dementia. Intraneuronal ubiquitin inclusions together with agyrophilic, neurofilament positive torpedoes were present within the cerebellar cortex, both previously unrecognised findings in this group of diseases.
PMCID: PMC1738228  PMID: 14617708
24.  Isolation and characterization of postsynaptic densities from various brain regions: enrichment of different types of postsynaptic densities 
The Journal of Cell Biology  1980;86(3):831-845.
Postsynaptic densities (PSDs) have been isolated from cerebral cortex, midbrain, cerebellum, and brain stem by the Triton X-100 method previously used in the isolation of cerebral PSDs (Cohen et al., 1977, J. Cell Biol. 74:181). These PSDs have been compared in protein composition, protein phosphorylation, and morphology. Thin-section electron microscopy revealed that cerebral cortex and midbrain PSDs were identical, being approximately 57 nm thick and composed of apparent aggregates 20-30 nm in diameter. Isolated cerebellar PSDs appeared thinner (33 nm) than cerebral cortex PSDs and lacked the apparent 20- to 30-nm aggregates, but had a latticelike structure. In unidirectional and rotary-shadowed replicas, the cerebrum and midbrain PSDs were circular in shape with a large central perforation or hole in the center of them. Cerebellum PSDs did not have a large perforation, but did have numerous smaller perforations in a lattice like structure. Filaments (6-9 nm) were observed connecting possible 20- to 30-nm aggregates in cerebrum PSDs and were also observed radiating from one side of the PSD. Both cerebral cortex and midbrain PSDs exhibited identical protein patterns on SDS gel electrophoresis. In comparison, cerebellar PSDs (a) lacked the major 51,000 Mr protein, (b) contained two times less calmodulin, and (c) contained a unique protein at 73,000 Mr. Calcium plus calmodulin stimulated the phosphorylation of the 51,000 and 62,000 Mr bands in both cerebral cortex and midbrain PSDs. In cerebellar PSDs, only the 58,000 and 62,000 Mr bands were phosphorylated. In the PSDs from all brain regions, cAMP stimulated the phosphorylation of Protein Ia (73,000 Mr), Protein Ib (68.000 Mr), and a 60,000 Mr protein, although cerebrum and midbrain PSDs contained very much higher levels of phosphorylated protein than did the cerebellum. On the basis of the morphological criteria, it is possible that PSDs isolated from cerebrum and midbrain were derived from the Gray type I, or asymmetric, synapses, whereas cerebellum PSDs were derived from the Gray type II, or symmetric, synapses. Since there is some evidence that the type I synapses are involved in excitatory mechanisms while the type II are involved in inhibitory mechanisms, the role of the PSD and of some of its proteins in these synaptic responses is discussed.
PMCID: PMC2110694  PMID: 7410481
25.  Selective Neurodegeneration, Without Neurofibrillary Tangles, in a Mouse Model of Niemann-Pick C Disease 
The BALB/c mouse model of Niemann-Pick type C (NPC) disease exhibits neuropathological similarities to the human condition. There is an age-related cerebral atrophy, demyelination of the corpus callosum, and degeneration of cerebellar Purkinje cells in the NPC mouse. In human NPC, many cortical and subcortical neurons contain neurofibrillary tangles, which are thought by some investigators to play an important role in the neurodegenerative process. The purpose of the present study was to determine whether neurodegeneration occurs in the NPC mouse, in brain regions other than the cerebellum and whether the degeneration is related to the presence of neurofibrillary tangles. Using light microscopic methods with immunohistochemistry, electron microscopy, and cell counting methods, 11-week-old NPC+/+ and NPC−/− animals were examined. In the NPC−/− mice, there were 96% fewer Purkinje cells, 28% fewer neurons in the prefrontal cortex, 20% fewer neurons in the thalamus, and 63% fewer glial cells in the corpus callosum. On the other hand, previous studies indicate normal numbers of neurons and glial cells in these same neuroanatomical regions in young NPC−/− mice. There were normal numbers of cholinergic neurons in sections assessed in the striatum and basal forebrain in the 11-week-old animals and no evidence of neurofibrillary tangles within cells. The present data indicate that both neurons and glial cells die in the NPC mouse but that all cells are not equally vulnerable. There was no evidence for neurofibrillary tangles in the NPC mouse, and therefore the degenerative process in the mouse is unrelated to the neurofibrillary tangle.
PMCID: PMC3408615  PMID: 11298365
Purkinje cells; corpus callosum; prefrontal cortex; glial cells; thalamus; cholinergic neurons; stereology

Results 1-25 (557254)