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.
Rodents; Brain size; Evolution; Neurons; Glia; Glires
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.
allometry; brain size; comparative neuroanatomy; glia; neurons; evolution; olfactory bulb
Gorillas and orangutans are primates at least as large as humans, but their brains amount to about one third of the size of the human brain. This discrepancy has been used as evidence that the human brain is about 3 times larger than it should be for a primate species of its body size. In contrast to the view that the human brain is special in its size, we have suggested that it is the great apes that might have evolved bodies that are unusually large, on the basis of our recent finding that the cellular composition of the human brain matches that expected for a primate brain of its size, making the human brain a linearly scaled-up primate brain in its number of cells. To investigate whether the brain of great apes also conforms to the primate cellular scaling rules identified previously, we determine the numbers of neuronal and other cells that compose the orangutan and gorilla cerebella, use these numbers to calculate the size of the brain and of the cerebral cortex expected for these species, and show that these match the sizes described in the literature. Our results suggest that the brains of great apes also scale linearly in their numbers of neurons like other primate brains, including humans. The conformity of great apes and humans to the linear cellular scaling rules that apply to other primates that diverged earlier in primate evolution indicates that prehistoric Homo species as well as other hominins must have had brains that conformed to the same scaling rules, irrespective of their body size. We then used those scaling rules and published estimated brain volumes for various hominin species to predict the numbers of neurons that composed their brains. We predict that Homo heidelbergensis and Homo neanderthalensis had brains with approximately 80 billion neurons, within the range of variation found in modern Homo sapiens. We propose that while the cellular scaling rules that apply to the primate brain have remained stable in hominin evolution (since they apply to simians, great apes and modern humans alike), the Colobinae and Pongidae lineages favored marked increases in body size rather than brain size from the common ancestor with the Homo lineage, while the Homo lineage seems to have favored a large brain instead of a large body, possibly due to the metabolic limitations to having both.
Allometry; Brain size; Great apes; Human; Evolution, human; Neurons, number
The human brain has often been viewed as outstanding among mammalian brains: the most cognitively able, the largest-than-expected from body size, endowed with an overdeveloped cerebral cortex that represents over 80% of brain mass, and purportedly containing 100 billion neurons and 10× more glial cells. Such uniqueness was seemingly necessary to justify the superior cognitive abilities of humans over larger-brained mammals such as elephants and whales. However, our recent studies using a novel method to determine the cellular composition of the brain of humans and other primates as well as of rodents and insectivores show that, since different cellular scaling rules apply to the brains within these orders, brain size can no longer be considered a proxy for the number of neurons in the brain. These studies also showed that the human brain is not exceptional in its cellular composition, as it was found to contain as many neuronal and non-neuronal cells as would be expected of a primate brain of its size. Additionally, the so-called overdeveloped human cerebral cortex holds only 19% of all brain neurons, a fraction that is similar to that found in other mammals. In what regards absolute numbers of neurons, however, the human brain does have two advantages compared to other mammalian brains: compared to rodents, and probably to whales and elephants as well, it is built according to the very economical, space-saving scaling rules that apply to other primates; and, among economically built primate brains, it is the largest, hence containing the most neurons. These findings argue in favor of a view of cognitive abilities that is centered on absolute numbers of neurons, rather than on body size or encephalization, and call for a re-examination of several concepts related to the exceptionality of the human brain.
brain scaling; number of neurons; human; encephalization
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.
Expansion of the cortical gray matter in evolution has been accompanied by an even faster expansion of the subcortical white matter volume and by folding of the gray matter surface, events traditionally considered to occur homogeneously across mammalian species. Here we investigate how white matter expansion and cortical folding scale across species of rodents and primates as the gray matter gains neurons. We find very different scaling rules of white matter expansion across the two orders, favoring volume conservation and smaller propagation times in primates. For a similar number of cortical neurons, primates have a smaller connectivity fraction and less white matter volume than rodents; moreover, as the cortex gains neurons, there is a much faster increase in white matter volume and in its ratio to gray matter volume in rodents than in primates. Order-specific scaling of the white matter can be attributed to different scaling of average fiber caliber and neuronal connectivity in rodents and primates. Finally, cortical folding increases as different functions of the number of cortical neurons in rodents and primates, scaling faster in the latter than in the former. While the neuronal rules that govern gray and white matter scaling are different across rodents and primates, we find that they can be explained by the same unifying model, with order-specific exponents. The different scaling of the white matter has implications for the scaling of propagation time and computational capacity in evolution, and calls for a reappraisal of developmental models of cortical expansion in evolution.
white matter; number of neurons; allometry; brain size; cortical expansion; gyrification
While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species – an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of four different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora), Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble.
brain size; brain scaling; mosaic evolution; numbers of neurons; cerebral cortex; cerebellum
Inhibitory interneurons participate in local processing circuits, playing a central role in executive cognitive functions of the prefrontal cortex. Although humans differ from other primates in a number of cognitive domains, it is not currently known whether the interneuron system has changed in the course of primate evolution leading to our species. In this study, we examined the distribution of different interneuron subtypes in the prefrontal cortex of anthropoid primates as revealed by immunohistochemistry against the calcium-binding proteins calbindin, calretinin and parvalbumin. In addition, we tested whether genes involved in the specification, differentiation and migration of interneurons show evidence of positive selection in the evolution of humans. Our findings demonstrate that cellular distributions of interneuron subtypes in human prefrontal cortex are similar to other anthropoid primates and can be explained by general scaling rules. Furthermore, genes underlying interneuron development are highly conserved at the amino acid level in primate evolution. Taken together, these results suggest that the prefrontal cortex in humans retains a similar inhibitory circuitry to that in closely related primates, even though it performs functional operations that are unique to our species. Thus, it is likely that other significant modifications to the connectivity and molecular biology of the prefrontal cortex were overlaid on this conserved interneuron architecture in the course of human evolution.
language; theory of mind; prefrontal cortex; chimpanzee; great ape
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.
Superior colliculus; Visual cortex; Lateral geniculate nucleus; V1; Area MT; Thalamus; Allometry; Brain size; Evolution
The spinal cord can be considered a major sensorimotor interface between the body and the brain. How does the spinal cord scale with body and brain mass, and how are its numbers of neurons related to the number of neurons in the brain across species of different body and brain sizes? Here we determine the cellular composition of the spinal cord in eight primate species and find that its number of neurons varies as a linear function of cord length, and accompanies body mass raised to an exponent close to 1/3. This relationship suggests that the extension, mass and number of neurons that compose the spinal cord are related to body length, rather than to body mass or surface. Moreover, we show that although brain mass increases linearly with cord mass, the number of neurons in the brain increases with the number of neurons in the spinal cord raised to the power of 1.7. This faster addition of neurons to the brain than to the spinal cord is consistent with current views on how larger brains add complexity to the processing of environmental and somatic information.
Allometry; Number of neurons; Evolution; Connectivity
The development of the mammalian neocortex relies heavily on subplate. The proportion of this cell population varies considerably in different mammalian species. Subplate is almost undetectable in marsupials, forms a thin, but distinct layer in mouse and rat, a larger layer in carnivores and big-brained mammals as pig, and a highly developed embryonic structure in human and non-human primates. The evolutionary origin of subplate neurons is the subject of current debate. Some hypothesize that subplate represents the ancestral cortex of sauropsids, while others consider it to be an increasingly complex phylogenetic novelty of the mammalian neocortex. Here we review recent work on expression of several genes that were originally identified in rodent as highly and differentially expressed in subplate. We relate these observations to cellular morphology, birthdating, and hodology in the dorsal cortex/dorsal pallium of several amniote species. Based on this reviewed evidence we argue for a third hypothesis according to which subplate contains both ancestral and newly derived cell populations. We propose that the mammalian subplate originally derived from a phylogenetically ancient structure in the dorsal pallium of stem amniotes, but subsequently expanded with additional cell populations in the synapsid lineage to support an increasingly complex cortical plate development. Further understanding of the detailed molecular taxonomy, somatodendritic morphology, and connectivity of subplate in a comparative context should contribute to the identification of the ancestral and newly evolved populations of subplate neurons.
subplate; cerebral cortex evolution; chick; turtle; Monodelphis domestica; pig; human
The visual system in primates is represented by a remarkably large expanse of the cerebral cortex. While more precise investigative studies that can be performed in non-human primates contribute towards understanding the organization of the human brain, there are several issues of visual cortex organization in monkey species that remain unresolved. In all, more than 20 areas comprise the primate visual cortex, yet there is little agreement as to the exact number, size and visual field representation of all but three. A case in point is the third visual area, V3. It is found relatively early in the visual system hierarchy, yet over the last 40 years its organization and even its very existence have been a matter of debate among prominent neuroscientists. In this review, we discuss a large body of recent work that provides straightforward evidence for the existence of V3. In light of this, we then re-examine results from several seminal reports and provide parsimonious re-interpretations in favour of V3. We conclude with analysis of human and monkey functional magnetic resonance imaging literature to make the case that a complete V3 is an organizational feature of all primate species and may play a greater role in the dorsal stream of visual processing.
cortical organization; human; primate; vision; visual cortex; visual hierarchy
Several theories have been proposed to explain the evolution of species differences in brain size, but no consensus has emerged. One unresolved question is whether brain size differences are a result of neural specializations or of biological constraints affecting the whole brain. Here I show that, among primates, brain size variation is associated with visual specialization. Primates with large brains for their body size have relatively expanded visual brain areas, including the primary visual cortex and lateral geniculate nucleus. Within the visual system, it is, in particular, one functionally specialized pathway upon which selection has acted: evolutionary changes in the number of neurons in parvocellular, but not magnocellular, layers of the lateral geniculate nucleus are correlated with changes in both brain size and ecological variables (diet and social group size). Given the known functions of the parvocellular pathway, these results suggest that the relatively large brains of frugivorous species are products of selection on the ability to perceive and select fruits using specific visual cues such as colour. The separate correlation between group size and visual brain evolution, on the other hand, may indicate the visual basis of social information processing in the primate brain.
The cellular and areal organization of the cerebral cortex impacts how it processes and integrates information. How that organization emerges and how best to characterize it has been debated for over a century. Here we demonstrate and describe in the isocortices of seven primate species a pronounced anterior-to-posterior gradient in the density of neurons and in the number of neurons under a unit area of the cortical surface. Our findings assert that the cellular architecture of the primate isocortex is neither arranged uniformly nor into discrete patches with an arbitrary spatial arrangement. Rather, it exhibits striking systematic variation. We conjecture that these gradients, which establish the basic landscape that richer areal and cellular structure is built upon, result from developmental patterns of cortical neurogenesis which are conserved across species. Moreover, we propose a functional consequence: that the gradient in neurons per unit of cortical area fosters the integration and dimensional reduction of information along its ascent through sensory areas and toward frontal cortex.
cortex; cortical areas; cytoarchitecture; evolutionary development; gradient; neurogenesis; primate evolution
The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal–fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by “non-classical” endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict.
cerebral cortex development; placenta; maternal–fetal unit; evolution; serotonin; eutherians; transcriptome
Neocortex is an important part of the mammalian brain that is quite different from its homologue of the dorsal cortex in the reptilian brain. Whereas dorsal cortex is small, thin, and composed of a single layer of neurons, neocortex is thick and has six layers, while being variable across species in size, number of functional areas, and architectonic differentiation. Early mammals had little neocortex, with perhaps 20 areas of poor structural differentiation. Many extant mammals continue to have small brains with little neocortex, but they often have sensory specializations reflected in the organization of sensory areas in neocortex. In primates, neocortex is variously enlarged and characterized by structural and other specializations, including those of cortical networks devoted to vision and visuomotor processing.In humans, neocortex occupies 80% of the volume of the brain, where as many as 200 areas may exist.
primates; reptiles; dorsal cortex; visual cortex; marsupials; monotremes
When the diminutive skeleton of Homo floresiensis was found on the Indonesian island of Flores, it was interpreted as an island dwarf, conforming to the ‘island rule’ that large animals evolve smaller size on islands, but small animals tend to get larger. However, previous studies of the island rule have not included primates, so the extent to which insular primate populations undergo size change was unknown. We use a comparative database of 39 independently derived island endemic primate species and subspecies to demonstrate that primates do conform to the island rule: small-bodied primates tend to get larger on islands, and large-bodied primates get smaller. Furthermore, larger species undergo a proportionally greater reduction in size on islands.
insular dwarf; comparative method; Homo floresiensis
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.
Comparative neuroanatomy; Glia-to-neuron index; Neuron number
Perception is dependent not only on sensory input but on the state of the brain receiving that input. A classic example is perception of a stable visual world in spite of the saccadic eye movements that shift the image on the retina. The long standing hypothesis is that the brain compensates for the disruption of visual input by using advance knowledge of the impending saccade, an internally generated corollary discharge. A possible neuronal mechanism for this compensation has been previously identified in parietal and frontal cortex of monkeys, but the origin of the necessary corollary discharge remained unknown. Here we consider recent experiments that identified a pathway for a corollary discharge for saccades that extends from the superior colliculus in the midbrain to the frontal eye fields in the cerebral cortex with a relay in the medial dorsal nucleus of the thalamus. We first review the nature of the evidence used to identify a corollary discharge signal in the complexity of the primate brain and show its use for guiding a rapid sequence of eye movements. We then consider two experiments that show this same corollary signal may provide the input to the frontal cortex neurons that alter their activity with saccades in ways that could compensate for the displacements in the visual input produced by saccadic eye movements. The first experiment shows that the corollary discharge signal is spatially and temporally appropriate to produce the alterations in the frontal cortex neurons. The second shows that this signal is necessary for this alteration because inactivation of the corollary reduces the compensation by frontal cortex neurons. The identification of this relatively simple circuit specifies the organization of a corollary discharge in the primate brain for the first time and provides a specific example upon which consideration of the roles of corollary activity in other systems and for other functions can be evaluated.
BrainMaps.org is an interactive high-resolution digital brain atlas and virtual microscope that is based on over 20 million megapixels of scanned images of serial sections of both primate and non-primate brains and that is integrated with a high-speed database for querying and retrieving data about brain structure and function over the internet. Complete brain datasets for various species, including Homo sapiens, Macaca mulatta, Chlorocebus aethiops, Felis catus, Mus musculus, Rattus norvegicus, and Tyto alba, are accessible online. The methods and tools we describe are useful for both research and teaching, and can be replicated by labs seeking to increase accessibility and sharing of neuroanatomical data. These tools offer the possibility of visualizing and exploring completely digitized sections of brains at a sub-neuronal level, and can facilitate large-scale connectional tracing, histochemical and stereological analyses.
brain mapping; brain atlas; virtual microscopy; image pyramid
Life-history theory posits a fundamental trade-off between number and size of offspring that structures the variability in parental investment across and within species. We investigate this ‘quantity–quality’ trade-off across primates and present evidence that a similar trade-off is also found across natural-fertility human societies. Restating the classic Smith–Fretwell model in terms of allometric scaling of resource supply and offspring investment predicts an inverse scaling relation between birth rate and offspring size and a −¼ power scaling between birth rate and body size. We show that these theoretically predicted relationships, in particular the inverse scaling between number and size of offspring, tend to hold across increasingly finer scales of analyses (i.e. from mammals to primates to apes to humans). The advantage of this approach is that the quantity–quality trade-off in humans is placed into a general framework of parental investment that follows directly from first principles of energetic allocation.
quantity–quality trade-off; Smith–Fretwell model; number and size of offspring; natural-fertility human societies; primate life histories; quarter-power scaling
Despite decades of evidence for functional plasticity in the adult brain, the role of structural plasticity in its manifestation remains unclear. To examine the extent of neuronal remodeling that occurs in the brain on a day-to-day basis, we used a multiphoton-based microscopy system for chronic in vivo imaging and reconstruction of entire neurons in the superficial layers of the rodent cerebral cortex. Here we show the first unambiguous evidence (to our knowledge) of dendrite growth and remodeling in adult neurons. Over a period of months, neurons could be seen extending and retracting existing branches, and in rare cases adding new branch tips. Neurons exhibiting dynamic arbor rearrangements were GABA-positive non-pyramidal interneurons, while pyramidal cells remained stable. These results are consistent with the idea that dendritic structural remodeling is a substrate for adult plasticity and they suggest that circuit rearrangement in the adult cortex is restricted by cell type–specific rules.
Chronic in vivo imaging of fluorescent-labeled neurons in adult mice reveals extension and retraction of dendrites in GABAergic non-pyramidal interneurons of the cerebral cortex.
The non-human primate is an important translational species for understanding the normal function and disease processes of the human brain. Unbiased stereology, the method accepted as state-of-the-art for quantification of biological objects in tissue sections2, generates reliable structural data for biological features in the mammalian brain3. The key components of the approach are unbiased (systematic-random) sampling of anatomically defined structures (reference spaces), combined with quantification of cell numbers and size, fiber and capillary lengths, surface areas, regional volumes and spatial distributions of biological objects within the reference space4. Among the advantages of these stereological approaches over previous methods is the avoidance of all known sources of systematic (non-random) error arising from faulty assumptions and non-verifiable models. This study documents a biological application of computerized stereology to estimate the total neuronal population in the frontal cortex of the vervet monkey brain (Chlorocebus aethiops sabeus), with assistance from two commercially available stereology programs, BioQuant Life Sciences and Stereologer (Figure 1). In addition to contrast and comparison of results from both the BioQuant and Stereologer systems, this study provides a detailed protocol for the Stereologer system.
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.
Testicular orphan nuclear receptor 4; cerebellar atrophy; locomotor
Accumulating evidence indicates that structural synaptic plasticity in limbic areas plays a vital role not only in normal brain functions, such as cognition and mood, but also in the development of neurological and mental disorders. We have learned from studies investigating neuronal remodeling that estrogens have an exceptional synaptogenic potential that seems to be specific to limbic areas of the adult female brain. On the other hand, structural synaptic plasticity in the adult male brain and the synaptogenic effect of androgens received relatively little attention. During the last five years, the Leranth laboratory provided conclusive evidence that the hippocampus and prefrontal cortex of adult male rodents and non-human primates retain considerable structural synaptic plasticity similar to the female, and that androgens are capable of inducing spine synapse growth in both the hippocampus and prefrontal cortex similar to estrogens. Our recent work also demonstrates that androgen-induced remodeling of spine synapses in the prefrontal cortex of adult male rats is dependent, at least to some extent, on functional androgen receptors, while being entirely independent of the androgen receptor in the hippocampus. Based on these findings and on their many beneficial effects, we believe that androgens hold a great and undeservingly neglected therapeutic potential that could be employed to reverse synaptic pathology in various neurocognitive and neuropsychiatric disorders.
Androgen; androgen receptor; testicular feminization mutant; hippocampus; prefrontal cortex; spine synapse; electron microscopic stereology