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1.  Greater addition of neurons to the olfactory bulb than to the cerebral cortex of eulipotyphlans but not rodents, afrotherians or primates 
The olfactory bulb is an evolutionarily old structure that antedates the appearance of a six-layered mammalian cerebral cortex. As such, the neuronal scaling rules that apply to scaling the mass of the olfactory bulb as a function of its number of neurons might be shared across mammalian groups, as we have found to be the case for the ensemble of non-cortical, non-cerebellar brain structures. Alternatively, the neuronal scaling rules that apply to the olfactory bulb might be distinct in those mammals that rely heavily on olfaction. The group previously referred to as Insectivora includes small mammals, some of which are now placed in Afrotheria, a base group in mammalian radiation, and others in Eulipotyphla, a group derived later, at the base of Laurasiatheria. Here we show that the neuronal scaling rules that apply to building the olfactory bulb differ across eulipotyphlans and other mammals such that eulipotyphlans have more neurons concentrated in an olfactory bulb of similar size than afrotherians, glires and primates. Most strikingly, while the cerebral cortex gains neurons at a faster pace than the olfactory bulb in glires, and afrotherians follow this trend, it is the olfactory bulb that gains neurons at a faster pace than the cerebral cortex in eulipotyphlans, which contradicts the common view that the cerebral cortex is the fastest expanding structure in brain evolution. Our findings emphasize the importance of not using brain structure size as a proxy for numbers of neurons across mammalian orders, and are consistent with the notion that different selective pressures have acted upon the olfactory system of eulipotyphlans, glires and primates, with eulipotyphlans relying more on olfaction for their behavior than glires and primates. Surprisingly, however, the neuronal scaling rules for primates predict that the human olfactory bulb has as many neurons as the larger eulipotyphlan olfactory bulbs, which questions the classification of humans as microsmatic.
PMCID: PMC3990053  PMID: 24782719
olfactory bulb; cortical expansion; mosaic evolution; olfaction
2.  Cellular scaling rules for the brain of Artiodactyla include a highly folded cortex with few neurons 
Quantitative analysis of the cellular composition of rodent, primate, insectivore, and afrotherian 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 a clade-specific manner. Here we analyze the cellular scaling rules that apply to the brain of artiodactyls, a group within the order Cetartiodactyla, believed to be a relatively recent radiation from the common Eutherian ancestor. We find that artiodactyls share non-neuronal scaling rules with all groups analyzed previously. Artiodactyls share with afrotherians and rodents, but not with primates, the neuronal scaling rules that apply to the cerebral cortex and cerebellum. The neuronal scaling rules that apply to the remaining brain areas are, however, distinct in artiodactyls. Importantly, we show that the folding index of the cerebral cortex scales with the number of neurons in the cerebral cortex in distinct fashions across artiodactyls, afrotherians, rodents, and primates, such that the artiodactyl cerebral cortex is more convoluted than primate cortices of similar numbers of neurons. Our findings suggest that the scaling rules found to be shared across modern afrotherians, glires, and artiodactyls applied to the common Eutherian ancestor, such as the relationship between the mass of the cerebral cortex as a whole and its number of neurons. In turn, the distribution of neurons along the surface of the cerebral cortex, which is related to its degree of gyrification, appears to be a clade-specific characteristic. If the neuronal scaling rules for artiodactyls extend to all cetartiodactyls, we predict that the large cerebral cortex of cetaceans will still have fewer neurons than the human cerebral cortex.
PMCID: PMC4228855  PMID: 25429261
evolution; cortical expansion; numbers of neurons; gyrification; brain size
3.  Brain scaling in mammalian evolution as a consequence of concerted and mosaic changes in numbers of neurons and average neuronal cell size 
Enough species have now been subject to systematic quantitative analysis of the relationship between the morphology and cellular composition of their brain that patterns begin to emerge and shed light on the evolutionary path that led to mammalian brain diversity. Based on an analysis of the shared and clade-specific characteristics of 41 modern mammalian species in 6 clades, and in light of the phylogenetic relationships among them, here we propose that ancestral mammal brains were composed and scaled in their cellular composition like modern afrotherian and glire brains: with an addition of neurons that is accompanied by a decrease in neuronal density and very little modification in glial cell density, implying a significant increase in average neuronal cell size in larger brains, and the allocation of approximately 2 neurons in the cerebral cortex and 8 neurons in the cerebellum for every neuron allocated to the rest of brain. We also propose that in some clades the scaling of different brain structures has diverged away from the common ancestral layout through clade-specific (or clade-defining) changes in how average neuronal cell mass relates to numbers of neurons in each structure, and how numbers of neurons are differentially allocated to each structure relative to the number of neurons in the rest of brain. Thus, the evolutionary expansion of mammalian brains has involved both concerted and mosaic patterns of scaling across structures. This is, to our knowledge, the first mechanistic model that explains the generation of brains large and small in mammalian evolution, and it opens up new horizons for seeking the cellular pathways and genes involved in brain evolution.
PMCID: PMC4127475  PMID: 25157220
numbers of neurons; brain size; cortical expansion; evolution; cell size
4.  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
5.  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
6.  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
7.  Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth 
eLife  null;3:e03962.
Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1−/− cerebellar phenotype. SDF1α also rescues the Foxc1−/− phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans.
eLife digest
The part of the brain responsible for coordinating and fine-tuning movement, sensory processing and some cognitive functions—the cerebellum—is found tucked away at the back of the brain, where it sits in a hollow in the skull called the posterior fossa. In a relatively common neurological disorder called Dandy-Walker malformation, part of the cerebellum doesn't develop and the posterior fossa is abnormally large.
One contributing factor to Dandy-Walker malformation is the loss of a protein called Foxc1. This protein is a so-called transcription factor, meaning it activates other genes, and so it has various important roles in helping an embryo to develop. In mouse embryos, the gene that produces Foxc1 is not activated in the developing cerebellum itself, but rather in the adjacent mesenchyme, a primitive embryonic tissue that will develop into the membranes that cover the brain and the skull bones that define the posterior fossa. This led Haldipur et al. to propose that the mesenchyme and the cerebellum communicate with each other as they develop.
To investigate this idea, Haldipur et al. carefully analysed how the development of the mouse cerebellum goes awry when Foxc1 is absent. This revealed that Foxc1-deficient mice have lower numbers of a type of cell called radial glial cells in their cerebellum. These are ‘progenitor’ cells that develop into the various types of cell found in the cerebellum, and also act as a scaffold for other neurons to migrate across. Therefore, the loss of radial glial cells in Foxc1-deficient mice substantially disrupts how the cerebellum develops, and how the neurons in the cerebellum work.
One gene activated by the Foxc1 protein encodes another protein called SDF1-alpha. This protein is released from the tissue that will develop into the posterior fossa, and binds to a receptor protein that is present on radial glial cells in the cerebellum. When this binding occurs, the radial glial cells grow and divide, and so the embryo's cerebellum also grows. Haldipur et al. found that mouse embryos specifically missing this receptor develop many of the abnormalities seen in Foxc1-deficient mice and further, when SDF1-alpha was provided back into Foxc1-deficient cerebella, the defects were rescued. This suggests that the cerebellar defects caused by the loss of Foxc1 stem from disrupting the signalling pathways that are triggered by the interaction between SDF1-alpha and its receptor.
These studies highlight that the brain does not develop in isolation. It is strongly dependent on the signals it receives from the embryonic mesenchyme that surrounds it. Identifying these signals and understanding how they can be disrupted by both genetic and non-genetic causes, such as inflammation, may be key to understanding this important class of brain birth defects.
PMCID: PMC4281880  PMID: 25513817
neurodevelopmental disorder; radial glia; cerebellum; Cxcl12; foxc1; mouse
8.  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
9.  Convergence of pontine and proprioceptive streams onto multimodal cerebellar granule cells 
eLife  2013;2:e00400.
Cerebellar granule cells constitute the majority of neurons in the brain and are the primary conveyors of sensory and motor-related mossy fiber information to Purkinje cells. The functional capability of the cerebellum hinges on whether individual granule cells receive mossy fiber inputs from multiple precerebellar nuclei or are instead unimodal; this distinction is unresolved. Using cell-type-specific projection mapping with synaptic resolution, we observed the convergence of separate sensory (upper body proprioceptive) and basilar pontine pathways onto individual granule cells and mapped this convergence across cerebellar cortex. These findings inform the long-standing debate about the multimodality of mammalian granule cells and substantiate their associative capacity predicted in the Marr-Albus theory of cerebellar function. We also provide evidence that the convergent basilar pontine pathways carry corollary discharges from upper body motor cortical areas. Such merging of related corollary and sensory streams is a critical component of circuit models of predictive motor control.
eLife digest
Learning a new motor skill, from riding a bicycle to eating with chopsticks, involves the cerebellum—a structure located at the base of the brain underneath the cerebral hemispheres. Although its name translates as ‘little brain' in Latin, the cerebellum contains more neurons than all other regions of the mammalian brain combined.
Most cerebellar neurons are granule cells which, although numerous, are simple neurons with an average of only four excitatory inputs, from axons called mossy fibers. These inputs are diverse in nature, originating from virtually every sensory system and from command centers at multiple levels of the motor hierarchy. However, it is unclear whether individual granule cells receive inputs from only a single sensory source or can instead mix modalities. This distinction has important implications for the functional capabilities of the cerebellum.
Now, Huang et al. have addressed this question by mapping, at extremely high resolution, the projections of two pathways onto individual granule cells—one carrying sensory feedback from the upper body (the proprioceptive stream), and another carrying motor-related information (the pontine stream). Using a combination of genetic and viral techniques to label the pathways, Huang and co-workers identified regions where the two types of fiber terminated in close proximity. They then showed that around 40% of proprioceptive granule cells formed junctions, or synapses, with two (or more) fibers carrying different types of input. These cells were not uniformly distributed throughout the cerebellum but tended to occur in ‘hotspots’.
Lastly, Huang et al. examined the type of information conveyed by the sensory and motor-related input streams whenever they contacted a single granule cell. They confirmed that when the sensory input consisted of feedback from the upper body, the motor input consisted of copies of motor commands related to the same body region. Because it is thought that the cerebellum converts sensory information into representations of the body's movements, directing motor commands to these same circuits may allow the cerebellum to predict the consequences of a planned movement prior to, or without, the actual movement occurring.
The work of Huang et al. provides evidence to support the previously controversial idea that granule cells in the mammalian cerebellum receive both sensory and motor-related inputs. The labeling technique that they used could also be deployed to study the inputs to the cerebellum in greater detail, which should yield new insights into the functioning of this part of the brain.
PMCID: PMC3582988  PMID: 23467508
cerebellum; corollary discharge; proprioception; Mouse
10.  All brains are made of this: a fundamental building block of brain matter with matching neuronal and glial masses 
How does the size of the glial and neuronal cells that compose brain tissue vary across brain structures and species? Our previous studies indicate that average neuronal size is highly variable, while average glial cell size is more constant. Measuring whole cell sizes in vivo, however, is a daunting task. Here we use chi-square minimization of the relationship between measured neuronal and glial cell densities in the cerebral cortex, cerebellum, and rest of brain in 27 mammalian species to model neuronal and glial cell mass, as well as the neuronal mass fraction of the tissue (the fraction of tissue mass composed by neurons). Our model shows that while average neuronal cell mass varies by over 500-fold across brain structures and species, average glial cell mass varies only 1.4-fold. Neuronal mass fraction varies typically between 0.6 and 0.8 in all structures. Remarkably, we show that two fundamental, universal relationships apply across all brain structures and species: (1) the glia/neuron ratio varies with the total neuronal mass in the tissue (which in turn depends on variations in average neuronal cell mass), and (2) the neuronal mass per glial cell, and with it the neuronal mass fraction and neuron/glia mass ratio, varies with average glial cell mass in the tissue. We propose that there is a fundamental building block of brain tissue: the glial mass that accompanies a unit of neuronal mass. We argue that the scaling of this glial mass is a consequence of a universal mechanism whereby numbers of glial cells are added to the neuronal parenchyma during development, irrespective of whether the neurons composing it are large or small, but depending on the average mass of the glial cells being added. We also show how evolutionary variations in neuronal cell mass, glial cell mass and number of neurons suffice to determine the most basic characteristics of brain structures, such as mass, glia/neuron ratio, neuron/glia mass ratio, and cell densities.
PMCID: PMC4228857  PMID: 25429260
allometry; glia/neuron ratio; number of neurons; number of glial cells; cell size; brain size
11.  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
12.  An Adaptive Threshold in Mammalian Neocortical Evolution 
PLoS Biology  2014;12(11):e1002000.
A study of the evolutionary history of cortical folding in mammals, its relationship to physiological and life-history traits and the underlying cortical progenitor behavior during embryogenesis, explains the diversity of folding we see across modern mammals. The diversity of neocortical folding among mammals can be explained by two distinct neurogenic programs, which give rise to mammals with a highly folded neocortex and mammals with slightly folded or unfolded neocortex, each occupying a distinct ecological niche.
Expansion of the neocortex is a hallmark of human evolution. However, determining which adaptive mechanisms facilitated its expansion remains an open question. Here we show, using the gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We find that variation in GI does not evolve linearly across species, but that mammals constitute two principal groups above and below a GI threshold value of 1.5, approximately equal to 109 neurons, which may be characterized by distinct constellations of physiological and life-history traits. By integrating data on neurogenic period, neuroepithelial founder pool size, cell-cycle length, progenitor-type abundances, and cortical neuron number into discrete mathematical models, we identify symmetric proliferative divisions of basal progenitors in the subventricular zone of the developing neocortex as evolutionarily necessary for generating a 14-fold increase in daily prenatal neuron production, traversal of the GI threshold, and thus establishment of two principal groups. We conclude that, despite considerable neuroanatomical differences, changes in the length of the neurogenic period alone, rather than any novel neurogenic progenitor lineage, are sufficient to explain differences in neuron number and neocortical size between species within the same principal group.
Author Summary
What are the key differences in the development and evolution of the cerebral cortex that underlie the differences in its size and degree of folding across mammals? Here, we present phylogenetic evidence that the Jurassic era mammalian ancestor may have been a relatively large-brained species with a folded neocortex. We then show that variation in the degree of cortical folding (gyrencephaly index [GI]) does not evolve linearly across species, as previously assumed, but that mammals fall into two principal groups associated with distinct ecological niches: low-GI mammals (such as mice and tarsiers) and high-GI mammals (such as dolphins and humans), which are found to generate on average 14-fold more brain weight per day of gestation. This greater daily brain weight production in mammals with a highly folded neocortex requires a specific class of progenitor cell-type to adopt a special mode of cell division, which is absent in mammals with slightly folded or unfolded neocortices. Differences among mammals within the same GI group (high or low) are not due to different programming, but rather the result of differences in the length of the neurogenic period. So, the impressively large and folded human neocortex, which is three times the size of the chimpanzee neocortex, can be explained by a modest evolutionary extension of the neurogenic period with respect to its closest primate ancestors.
PMCID: PMC4236020  PMID: 25405475
13.  Cerebellar modules operate at different frequencies 
eLife  2014;3:e02536.
Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions.
eLife digest
The cerebellum, located at the back of the brain underneath the cerebral hemispheres, is best known for its role in the control of movement. Despite its small size, the cerebellum contains more than half of the brain's neurons. These are organized in a repeating pattern in which cells called Purkinje cells receive inputs from two types of fibers: climbing fibers, which ascend into the cerebellum from the brainstem; and parallel fibers, which run perpendicular to the climbing fibers. This gives rise to a characteristic ‘crystalline’ structure.
As a result of this uniform circuitry, it was widely believed was that all Purkinje cells throughout the cerebellum would function the same way. However, the presence of distinct patterns of gene expression in different regions suggests that this is not the case. Molecules called zebrins, for example, are found in some Purkinje cells but not others, and this gives rise to a pattern of zebrin-positive and zebrin-negative stripes. A number of other molecules have similar distributions, suggesting that these differences in molecular machinery could underlie differences in cellular physiology.
Zhou, Lin et al. have now provided one of the first direct demonstrations of such physiological differences by showing that zebrin-positive cells generate action potentials at lower frequencies than zebrin-negative cells. This pattern is seen throughout the cerebellum, and is evident even when the positive and negative cells are neighbors, which indicates that these differences do not simply reflect differences in the locations of the cells or differences in the inputs they receive from parallel fibers. Additional experiments revealed that the distinct firing rates are likely not generated by zebrin itself, but rather by proteins that are expressed alongside zebrin, most notably those that work through an ion channel called TRPC3.
By showing that cells arranged in the same type of circuit can nevertheless have distinct firing rates, the work of Zhou, Lin et al. has revealed an additional level of complexity in the physiology of the cerebellum. In addition to improving our understanding of how the brain controls movement, these findings might also be of interest to researchers studying the increasing number of neurological and psychiatric disorders in which cerebellar dysfunction has been implicated.
PMCID: PMC4049173  PMID: 24843004
cerebellum; cerebellar modules; Purkinje cells; zebrin II; TRPC3; mouse
14.  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
15.  The elephant brain in numbers 
What explains the superior cognitive abilities of the human brain compared to other, larger brains? Here we investigate the possibility that the human brain has a larger number of neurons than even larger brains by determining the cellular composition of the brain of the African elephant. We find that the African elephant brain, which is about three times larger than the human brain, contains 257 billion (109) neurons, three times more than the average human brain; however, 97.5% of the neurons in the elephant brain (251 billion) are found in the cerebellum. This makes the elephant an outlier in regard to the number of cerebellar neurons compared to other mammals, which might be related to sensorimotor specializations. In contrast, the elephant cerebral cortex, which has twice the mass of the human cerebral cortex, holds only 5.6 billion neurons, about one third of the number of neurons found in the human cerebral cortex. This finding supports the hypothesis that the larger absolute number of neurons in the human cerebral cortex (but not in the whole brain) is correlated with the superior cognitive abilities of humans compared to elephants and other large-brained mammals.
PMCID: PMC4053853  PMID: 24971054
elephant; cerebral cortex; numbers of neurons; neuronal density; cerebellum; glia/neuron ratio; brain size
16.  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
17.  Hereditary lissencephaly and cerebellar hypoplasia in Churra lambs 
Lissencephaly is a rare developmental brain disorder in veterinary and human medicine associated with defects in neuronal migration leading to a characteristic marked reduction or absence of the convolutional pattern of the cerebral hemispheres. In many human cases the disease has a genetic basis. In sheep, brain malformations, mainly cerebellar hypoplasia and forms of hydrocephalus, are frequently due to in utero viral infections. Although breed-related malformations of the brain have been described in sheep, breed-related lissencephaly has not been previously recorded in a peer reviewed publication.
Here we report neuropathological findings in 42 newborn lambs from a pure Churra breed flock, with clinical signs of weakness, inability to walk, difficulty in sucking and muscular rigidity observed immediately after birth. All the lambs showed near-total agyria with only a rudimentary formation of few sulci and gyri, and a severe cerebellar hypoplasia. On coronal section, the cerebral grey matter was markedly thicker than that of age-matched unaffected lambs and the ventricular system was moderately dilated. Histologically, the normal layers of the cerebral cortex were disorganized and, using an immunohistochemical technique against neurofilaments, three layers were identified instead of the six present in normal brains. The hippocampus was also markedly disorganised and the number and size of lobules were reduced in the cerebellum. Heterotopic neurons were present in different areas of the white matter. The remainder of the brain structures appeared normal. The pathological features reported are consistent with the type LCH-b (lissencephaly with cerebellar hypoplasia group b) defined in human medicine. No involvement of pestivirus or bluetongue virus was detected by immunohistochemistry. An analysis of pedigree data was consistent with a monogenic autosomal recessive pattern inheritance.
The study describes the clinical and pathological findings of lissencephaly with cerebellar hypoplasia in Churra lambs for which an autosomal recessive inheritance was the most likely cause. Histopathological features observed in the cerebral cortex and hippocampus are consistent with a possible failure in neuronal migration during brain development. This report suggests that lissencephaly should be considered in the differential diagnosis of congenital neurological disease in newborn lambs showing weakness, inability to walk and difficulty sucking.
PMCID: PMC3750509  PMID: 23938146
Lissencephaly; Cerebellar hypoplasia; Agyria-pachygyria; Sheep; Autosomal recessive
18.  Phenolic and Tyrosyl Ring Deiodination of Iodothyronines in Rat Brain Homogenates 
Journal of Clinical Investigation  1980;66(3):551-562.
Conversion of thyroxine (T4) to 3,5,3′-triiodothyronine (T3) in rat brain has recently been shown in in vivo studies. This process contributes a substantial fraction of endogenous nuclear T3 in the rat cerebral cortex and cerebellum. Production of T4 metabolites besides T3 in the brain has also been suggested. To determine the nature of these reactions, we studied metabolism of 0.2-1.0 nM [125I]T4 and 0.1-0.3 nM [131I]T3 in whole homogenates and subcellular fractions of rat cerebral cortex and cerebellum. Dithiothreitol (DTT) was required for detectable metabolic reactions: 100 mM DTT was routinely used. Ethanol extracts of incubation mixtures were analyzed by paper chromatography in t-amyl alcohol:hexane:ammonia and in 1-butanol:acetic acid. Rates of production of iodothyronines from T4 and T3 were greater at pH 7.5 than at 6.4 or 8.6 and greater at 37°C than at 22° or 4°C. Lowering the pH, reducing the protein or DTT concentrations, and preheating homogenates to 100°C all increased excess I− production but reduced iodothyronine production.
In cerebral cortical homogenates from normal rats, products of T4 degradation were as follows (percent added T4±SEM in nine experiments): T3, 1.9±0.5%; 3,3′,5′-triiodothyronine (rT3), 34.0±2.4%; 3,3′-diiodothyronine (3,3′-T2), 5.8±1.6%; 3′-iodothyronine (3′-T1), ≤2.5%; and excess I−, 4.7±1.2%. In the same experiments, products of T3 degradation were 3,3′-T2, 63.3±5.5%, and 3′-T1, 12.6±1.4%. Cerebral cortical homogenates from hyperthyroid rats and normals were similar in regard to T4 to T3 deiodination. In contrast, in cerebral cortical homogenates from hypothyroid rats, phenolic ring deiodination rates were increased and tyrosyl ring deiodination rates were decreased compared with normals.
T4 to T3 conversion rates in cerebellar homogenates were greater than rates in cerebral cortical homogenates from the same normal rats and less than rates in cerebellar homogenates from hypothyroid rats. T4 and T3 tyrosyl ring deiodination rates were greatly diminished in cerebellar homogenates compared with cerebral cortical homogenates in normal and hypothyroid rats. High-speed (1,000-160,000 g) pellets from cerebral cortical homogenates were enriched in phenolic and tyrosyl ring deiodinating activities relative to cytosol. Fractional conversion of T4 to T3 was inhibited by T4, iopanoic acid, and rT3, but not by T3. Tyrosyl ring deiodination reactions were inhibited by T3, T4, and iopanoic acid, but not by rT3.
These studies demonstrate separate phenolic and tyrosyl ring iodothyronine deiodinase enzymes in rat brain. The brain phenolic ring deiodinase serves in vivo as a T4 5′-deiodinase and closely resembles anterior pituitary T4 5′-deiodinase in physiological and biochemical characteristics. The physiological significance of the tyrosyl ring iodothyronine deiodinase enzyme is unclear; it shares several properties with rat hepatic T4 5-deiodinase.
PMCID: PMC371684  PMID: 7400328
19.  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
20.  A voxel-based morphometry study of grey matter loss in fragile X-associated tremor/ataxia syndrome 
Brain  2011;134(3):863-878.
Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disorder that primarily affects older male premutation carriers of the fragile X mental retardation gene. Although its core symptoms are mainly characterized by motor problems such as intention tremor and gait ataxia, cognitive decline and psychiatric problems are also commonly observed. Past radiological and histological approaches have focused on prominent neurodegenerative changes in specific brain structures including the cerebellum and limbic areas. However, quantitative investigations of the regional structural abnormalities have not been performed over the whole brain. In this study, we adopted the voxel-based morphometry method together with regions of interest analysis for the cerebellum to examine the pattern of regional grey matter change in the male premutation carriers with and without fragile X-associated tremor/ataxia syndrome. In a comparison with healthy controls, we found striking grey matter loss of the patients with fragile X-associated tremor/ataxia syndrome in multiple regions over the cortical and subcortical structures. In the cerebellum, the anterior lobe and the superior posterior lobe were profoundly reduced in both vermis and hemispheres. In the cerebral cortex, clusters of highly significant grey matter reduction were found in the extended areas in the medial surface of the brain, including the dorsomedial prefrontal cortex, anterior cingulate cortex and precuneus. The other prominent grey matter loss was found in the lateral prefrontal cortex, orbitofrontal cortex, amygdala and insula. Although the voxel-wise comparison between the asymptomatic premutation group and healthy controls did not reach significant difference, a regions of interest analysis revealed significant grey matter reduction in anterior subregions of the cerebellar vermis and hemisphere in the asymptomatic premutation group. Correlation analyses using behavioural scales of the premutation groups showed significant associations between grey matter loss in the left amygdala and increased levels of obsessive–compulsiveness and depression, and between decreased grey matter in the left inferior frontal cortex and anterior cingulate cortex and poor working memory performance. Furthermore, regression analyses revealed a significant negative effect of CGG repeat size on grey matter density in the dorsomedial frontal regions. A significant negative correlation with the clinical scale for the severity of fragile X-associated tremor/ataxia syndrome was found in a part of the vermis. These observations reveal the anatomical patterns of the neurodegenerative process that underlie the motor, cognitive and psychiatric problems of fragile X-associated tremor/ataxia syndrome, together with incipient structural abnormalities that may occur before the clinical onset of this disease.
PMCID: PMC3044831  PMID: 21354978
fragile X-associated tremor/ataxia syndrome; movement disorder; voxel based morphometry; cerebellum; atrophy
21.  Genome-Wide Divergence of DNA Methylation Marks in Cerebral and Cerebellar Cortices 
PLoS ONE  2010;5(6):e11357.
Emerging evidence suggests that DNA methylation plays an expansive role in the central nervous system (CNS). Large-scale whole genome DNA methylation profiling of the normal human brain offers tremendous potential in understanding the role of DNA methylation in brain development and function.
Methodology/Significant Findings
Using methylation-sensitive SNP chip analysis (MSNP), we performed whole genome DNA methylation profiling of the prefrontal, occipital, and temporal regions of cerebral cortex, as well as cerebellum. These data provide an unbiased representation of CpG sites comprising 377,509 CpG dinucleotides within both the genic and intergenic euchromatic region of the genome. Our large-scale genome DNA methylation profiling reveals that the prefrontal, occipital, and temporal regions of the cerebral cortex compared to cerebellum have markedly different DNA methylation signatures, with the cerebral cortex being hypermethylated and cerebellum being hypomethylated. Such differences were observed in distinct genomic regions, including genes involved in CNS function. The MSNP data were validated for a subset of these genes, by performing bisulfite cloning and sequencing and confirming that prefrontal, occipital, and temporal cortices are significantly more methylated as compared to the cerebellum.
These findings are consistent with known developmental differences in nucleosome repeat lengths in cerebral and cerebellar cortices, with cerebrum exhibiting shorter repeat lengths than cerebellum. Our observed differences in DNA methylation profiles in these regions underscores the potential role of DNA methylation in chromatin structure and organization in CNS, reflecting functional specialization within cortical regions.
PMCID: PMC2893206  PMID: 20596539
22.  Interaction of plasticity and circuit organization during the acquisition of cerebellum-dependent motor learning 
eLife  2013;2:e01574.
Motor learning occurs through interactions between the cerebellar circuit and cellular plasticity at different sites. Previous work has established plasticity in brain slices and suggested plausible sites of behavioral learning. We now reveal what actually happens in the cerebellum during short-term learning. We monitor the expression of plasticity in the simple-spike firing of cerebellar Purkinje cells during trial-over-trial learning in smooth pursuit eye movements of monkeys. Our findings imply that: 1) a single complex-spike response driven by one instruction for learning causes short-term plasticity in a Purkinje cell’s mossy fiber/parallel-fiber input pathways; 2) complex-spike responses and simple-spike firing rate are correlated across the Purkinje cell population; and 3) simple-spike firing rate at the time of an instruction for learning modulates the probability of a complex-spike response, possibly through a disynaptic feedback pathway to the inferior olive. These mechanisms may participate in long-term motor learning.
eLife digest
Practice makes perfect in many areas of life, such as playing sport or even just drinking coffee from a cup without spilling any. Our brains can learn and improve these motor skills through trial, error and learning, with such “motor learning” depending on the cerebellum, a part of the brain that helps to coordinate all kinds of movements.
Motor learning is a product of the organization of the cerebellar circuit, which is well understood, and the “plasticity” in the synapses that determine how cerebellar neurons interact with each other. The cerebellum contains cells called Purkinje cells that receive distinctive inputs from two pathways: a pathway involving inputs from many parallel fibers, which convey signals related to sensory events or motor commands; and a pathway involving input from a single climbing-fiber, which conveys signals from a part of the brain called the inferior olive nucleus.
Research on slices of brain has revealed many sites and forms of cerebellar plasticity that could participate in motor learning. In one form of plasticity, the strength of the synapses between the parallel fibers and the Purkinje cell can be changed when a signal sent along the climbing fiber arrives the Purkinje cell.
Yang and Lisberger have now taken the next step by studying the cerebellum of a monkey as it performs a motor learning task. Remarkably these experiments show that the climbing fiber inputs cause plasticity of Purkinje cell activity, just as happens in the experiments on brain slices. Further, some learning in the cerebellum restricts further learning, so that the cerebellum puts boundaries on its own learning. Overall the results make clear how learning is a property of groups of neurons working together in a circuit, rather than simply of changes in the strength of specific synapses.
By shedding light on what happens in the cerebellum during short-term motor learning, the work of Yang and Lisberger will benefit efforts to understand how the cerebellum is involved in motor learning on all time scales.
PMCID: PMC3871706  PMID: 24381248
non-human primate; smooth pursuit eye movements; climbing fiber; cerebellar learning; trial-over-trial learning; floccular complex; Other
23.  Unique Features of the Human Brainstem and Cerebellum 
The cerebral cortex is greatly expanded in the human brain. There is a parallel expansion of the cerebellum, which is interconnected with the cerebral cortex. We have asked if there are accompanying changes in the organization of pre-cerebellar brainstem structures. We have examined the cytoarchitectonic and neurochemical organization of the human medulla and pons. We studied human cases from the Witelson Normal Brain Collection, analyzing Nissl sections and sections processed for immunohistochemistry for multiple markers including the calcium-binding proteins calbindin, calretinin, and parvalbumin, non-phosphorylated neurofilament protein, and the synthetic enzyme for nitric oxide, nitric oxide synthase. We have also compared the neurochemical organization of the human brainstem to that of several other species including the chimpanzee, macaque and squirrel monkey, cat, and rodent, again using Nissl staining and immunohistochemistry. We found that there are major differences in the human brainstem, ranging from relatively subtle differences in the neurochemical organization of structures found in each of the species studied to the emergence of altogether new structures in the human brainstem. Two aspects of human cortical organization, individual differences and left–right asymmetry, are also seen in the brainstem (principal nucleus of the inferior olive) and the cerebellum (the dentate nucleus). We suggest that uniquely human motor and cognitive abilities derive from changes at all levels of the central nervous system, including the cerebellum and brainstem, and not just the cerebral cortex.
PMCID: PMC3985031  PMID: 24778611
medulla; dentate nucleus; vestibular nuclei; nonphosphorylated neurofilament protein; cerebellar cortex; saccadic eye movements; inferior olive; calcium-binding proteins
24.  A volumetric comparison of the insular cortex and its subregions in primates 
Journal of human evolution  2013;64(4):263-279.
The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body’s homeostatic state. We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent = 1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent = 1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee.
PMCID: PMC3756831  PMID: 23466178
Allometry; Brain; Evolution; Frontoinsular cortex; Hominoids
25.  Auditory cortex of bats and primates: managing species-specific calls for social communication 
Individuals of many animal species communicate with each other using sounds or “calls” that are made up of basic acoustic patterns and their combinations. We are interested in questions about the processing of communication calls and their representation within the mammalian auditory cortex. Our studies compare in particular two species for which a large body of data has accumulated: the mustached bat and the rhesus monkey. We conclude that the brains of both species share a number of functional and organizational principles, which differ only in the extent to which and how they are implemented. For instance, neurons in both species use “combination-sensitivity” (nonlinear spectral and temporal integration of stimulus components) as a basic mechanism to enable exquisite sensitivity to and selectivity for particular call types. Whereas combination-sensitivity is already found abundantly at the primary auditory cortical and also at subcortical levels in bats, it becomes prevalent only at the level of the lateral belt in the secondary auditory cortex of monkeys. A parallel-hierarchical framework for processing complex sounds up to the level of the auditory cortex in bats and an organization into parallel-hierarchical, cortico-cortical auditory processing streams in monkeys is another common principle. Response specialization of neurons seems to be more pronounced in bats than in monkeys, whereas a functional specialization into “what” and “where” streams in the cerebral cortex is more pronounced in monkeys than in bats. These differences, in part, are due to the increased number and larger size of auditory areas in the parietal and frontal cortex in primates. Accordingly, the computational prowess of neural networks and the functional hierarchy resulting in specializations is established early and accelerated across brain regions in bats. The principles proposed here for the neural “management” of species-specific calls in bats and primates can be tested by studying the details of call processing in additional species. Also, computational modeling in conjunction with coordinated studies in bats and monkeys can help to clarify the fundamental question of perceptual invariance (or “constancy”) in call recognition, which has obvious relevance for understanding speech perception and its disorders in humans.
PMCID: PMC4276140  PMID: 17485400
Language; Speech; Neural coding; Bats; Primates; Review

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