Why didn't the human Cerebrum evolve to have granule cells like the Cerebellum does?

Why didn't the human Cerebrum evolve to have granule cells like the Cerebellum does?

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The Cerebellum is much smaller compared to the Cerebrum yet it contains more than half of the total neurons contained in the brain.

That's mainly due to the granule cells in the Cerebellum which allows it become so densely packed with neurons.

But why is the Cerebrum not like that? Why isn't it as "compressed" as the Cerebellum? Doesn't it make sense for it to be more smaller and compact?

By "cerebrum" I assume you really mean the cerebral neocortex, since the cerebrum includes other subcortical structures that themselves are quite distinct (e.g., the basal ganglia).

Simply, the neocortex and cerebellum have completely different functions. The cerebellum performs a particular class of computations that are very different from the variety of computations performed by the cerebral cortex. They have completely different laminar structures, with neocortex being a ~6-layer structure, the cerebellum has just 2-3. There are a much higher diversity of connections and cell types in neocortex compared to cerebellum.

It seems like an optimal configuration for the cerebellum is a very high cell density. More cells doesn't necessarily mean "better", because the more cells you have the less space you have for connections. There is no unused or empty space in the neocortex: if you packed in some more cells you'd have to lose something else.

Doya, K. (1999). What are the computations of the cerebellum, the basal ganglia and the cerebral cortex?. Neural networks, 12(7-8), 961-974.

Equal ≠ The Same: Sex Differences in the Human Brain

While advances in brain imaging confirm that men and women think in their own way and that their brains are different, the biomedical community mainly uses male animals as testing subjects with the assumption that sex differences in the brain hardly matter. This month’s Cerebrum highlights some of the thinking and research that invalidates that assumption.

E arly in 2013, the Food and Drug Administration (FDA) ordered the makers of the well-known sleep aid Ambien (zolpidem) to cut their recommended dose in half-but only for women. In essence, the FDA was acknowledging that despite extensive testing prior to the drug’s release on the market, millions of women had been overdosing on Ambien for 20 years. On February 9, 2014, CBS’s 60 Minutes highlighted this fact-and sex differences in general-by powerfully asking two questions: Why did this happen, and are men and women treated equally in research and medicine? 1

The answer to the first question is that the biomedical community has long operated on what is increasingly being viewed as a false assumption: that biological sex matters little, if at all, in most areas of medicine. The answer to the second question is no, today’s biomedical research establishment is not treating men and women equally. What are some of the key reasons for the biomedical community’s false assumption, and why is this situation now finally changing? What are some of the seemingly endless controversies about sex differences in the brain generated by “anti-sex difference” investigators? And what lies at the root of the resistance to sex differences research in the human brain?

Studying the Brain in Development

Short of technology that would shrink a remote video camera down to the size of a cellular implant, how can neuroscientists study brain development as an ongoing process in the living animal? The multistage model is useful here, too, as it was in explaining various brain disorders, because it suggests several points at which researchers can alter the process of development in a highly controlled way and learn a great deal by observing the outcome. Currently, three techniques are working especially well for researchers who want to know more about the making of the cerebral cortex, in particular. One technique is based on the knowledge that all the cells destined to become part of the cerebral cortex are first generated near the center of the brain, at the fluid-filled ventricles that have formed from the original three bulges in the neural tube. If a small number of ventricular cells are removed and labeled with various neutral dyes, then reinjected while cell proliferation is still going on, it is possible to follow a particular group of dyed cells as they migrate to their eventual positions in the cortex. So far, this approach has suggested that a cell may already contain the information of its eventual "address" in the cortex when it is generated for example, a cell that is removed when the ventricle is producing layer 3 of the cortex and then injected back into the ventricle during the generation of layer 4 will nonetheless migrate to layer 3. Hence, genetic information may strongly control this aspect of development.

A second technique works at the genetic level by inserting an innocuous retrovirus into ventricular cells. The retrovirus does not affect normal functioning, but its genetic information is incorporated into the living cells' DNA and faithfully replicated in the cells of future generations. The genetic code of the retrovirus can thus be used as a marker, much as dyes were used in the preceding technique. Here, though, the technique allows an investigator to observe successive generations of cells rather than the spatial distribution of cells that are all from one generation.


The human brain develops from the tip of a 3-millimeter-long neural tube. At three to four weeks after conception, the neural groove closes into a tube, and three distinct regions𠅊 hindbrain, midbrain, and forebrain�gin to take form. (more. )

The third technique gives dramatic results by knocking out one generation of cells altogether. For example, exposing a pregnant monkey to x-ray irradiation at a particular point in its pregnancy will interfere with cell division at a discrete stage, so that the cells, say, for layer 3 of the limbic cortex are not generated. Subsequent layers are generated and laid down normally, but with a particular population of cells missing in the middle layer, the connections from one part of the brain to another may falter. Thus, the individual may find it difficult to bring together different types of information or to respond appropriately to a stimulus. Disorders of this kind, which have less to do with overall anatomical structure than with the brain's ability to form and use synaptic connections, may play a role in some psychiatric illnesses for which there is no obvious physical cause.

The cerebral cortex is a fascinating object of study from many perspectives. It comprises by far the largest portion of the human brain�out three-quarters, in the adult𠅊nd is arguably the single anatomical structure that most sets us apart from other animals, even from other hominoids such as the chimpanzee (with whom we share well over 95 percent of our genetic makeup). Yet apparently no single transmitter or type of cell is unique to the human cerebral cortex the molecules found in the cortex can also be found elsewhere, in our muscles, heart, and intestines and in the brains of other animals as well. The molecules, and even the cells, may be the same it is the patterns of connectivity that make a difference. The connections, or synapses, among neurons in the human brain are not only more numerous but also more intricately patterned than anything that has ever been constructed to process information, including the most sophisticated supercomputer.

A structure so complex must be considered in smaller units if it is to be understood at all, and up to now neuroscience has managed to get along quite well with two mutually incompatible systems. One system for subdivision was devised by the German psychiatrist K. Brodmann at the turn of the century. Brodmann distinguished 57 areas of the cortical surface on the basis of their tissue composition, and the reference numbers he assigned are still widely used today. A researcher giving a talk before an international audience of neuroscientists can mention "area 44" and be understood without further explication. The other system subdivides the cortex into areas of specialized function—which do not correspond well to Brodmann's physically discrete areas, unfortunately. Thus, in terms of function, one can refer to Broca's area, which controls the ability to translate thoughts into speech (but not the ability to understand when someone else speaks that function is housed in Wernicke's area, which is nearby, but not adjacent). The area is defined quite clearly in terms of its function, but its physical extent is harder to outline. In Brodmann's scheme, Broca's area occupies some of area 44 and some of area 45, as well as a little of area 4.

Current techniques of magnification and imaging permit the analysis of different tissues at the molecular level and have added another order of information to an already complicated picture. But this new information may ultimately be the bridge between the functional map of the cerebral cortex and the physical map, because it offers finer distinctions within functional areas and reveals the differential distribution of certain molecules along the lines of function. The molecules being considered are often receptor sites and the particular neurotransmitters that go with them and (as we have seen in Chapter 5) it is through the neurotransmitters and their receptor sites that the brain translates its countless functions into chemical terms and back again into function. In this regard, the research team of Pasko Rakic at the Yale University School of Medicine has worked extensively with areas 17 and 18, which roughly correspond to the primary visual cortex—the part of the brain that must receive sensory impulses from the eyes before the visual association cortex (located nearby) can tell us what we see or how we feel about it.

In experimenting with differential development, Rakic and his colleagues have found that neighboring areas can be related in function and yet compete for some of the same resources—namely, territory and energy—so that if chance or environmental circumstances favor it, one area may develop at the expense of another. Clearly, such contests have implications for the shaping of the brain on an evolutionary time scale as well as over the course of an individual's development. Even in the short evolutionary interval from monkeys to humans this kind of reapportionment can be found: for example, the primary visual cortex, which makes up 15 percent of the cerebral cortex in the monkey, accounts for only 3 percent of our own cerebral cortex, while other areas have grown disproportionately larger. Among individuals of the same species, too, and even between the two hemispheres of an individual's brain, there can be variations in the size of a particular area, although nothing like the 3 to 15 percent difference just mentioned. Even when quite subtle, these variations can yield evidence of the intermingled effects on development of genetic information, random mutations, and environmental influences.

Bio-455 Exam 1

A. Folding reduces the metabolic demand of the cortex (and consequently the brain).

B. Folding promotes specialization and evolution of novel functions.

C. Folding allows neurons to have shorter connections to their neighbors.

D. Folding allows a larger neocortex to fit inside a reasonably sized skull.

A. they allow for the maximum number of connections among neurons

B. they ensure that parallel processing occurs

C. they are a necessary feature of feedback loops

D. they ensure that neighboring neurons process similar information

A. The brain is largely homogenous, with nuclei spread relatively evenly throughout. Few if any regions are associated with a specific function.

B. The brain is composed of distinct regions. Though these regions may be associated with a specific function, many functions are distributed across brain areas.

C. The brain is largely homogenous, with nuclei spread relatively evenly throughout. Brain functions are served by nuclei in specific areas of the brain.

D. The brain is composed of distinct regions. Few if any of these regions are associated with a specific function, but rather brain functions are widely distributed across many brain areas.

Origins and Formation of The Rhombic Lip

The GC lineage arises at around E8.75 from the URL, an ephemeral structure located atop the 4th ventricle at the intersection of the roof plate and the cerebellar anlage. A two-step process formats the cerebellum and the future GCs: first, arealization of rhombomere 1 of the dorsal neural tube forms the initial cerebellar territory, which includes the URL, and second signaling from the adjacent roof plate assists in cell specification. Innovative techniques have been applied to the analysis of the origins of the primordium𠅏rom the classical chick-quail chimera technique of LeDouarin and colleagues (e.g., Pourquié et al., 1992) to the creative use of transgenic mouse lines. These studies defined rhombomere 1 as the territory that produces the anlage. The application of molecular techniques, whether in situ hybridization (Hallonet and Le Douarin, 1993) or mouse knockouts (McMahon and Bradley, 1990 Millet et al., 1996), further refined the URL to an anterior rhombencephalic region bounded by the isthmic organizer (Otx2+) rostrally and rhombomere 2 (Hoxa2+) caudally. In the arealization of the URL, Gbx2 plays an important role through the antagonism of Otx2 expression (Hashimoto and Hibi, 2012). The isthmic organizer resembles a Spemann–Mangold-like inducer in that its secreted signals can induce cerebellar-like structures when transplanted to ectopic sites and if it is eliminated no cerebellum is produced (e.g., FGF8 Chi et al., 2003). Other molecules documented to play a role in specifying this region as future cerebellum include the Paired-box transcription factor genes Pax2 and Pax5 (Bouchard et al., 2000), and En1 and En2 of the engrailed family (Hanold, 1986 Hanks et al., 1995).

While not contributing to the cells that come to populate the parenchyma of the cerebellum, the roof plate expresses molecules that are key to URL development. Important insights arise from the study of the Dreher mutant mouse (Lmx1adr-J) whose mutated gene was found to be Lmx1a (Millonig et al., 2000). Studies by Chizhikov et al. (2006) led to an appreciation of this extra-cerebellar signaling center. The loss of LMX1A expression from roof plate cells results in both a major loss of GCs (Sekiguchi et al., 1992) and the ablation of the vermis (Millonig et al., 2000 Sillitoe et al., 2014). Lmx1a is also expressed in a subset of rhombic lip progenitors that produce GCs predominantly restricted to the cerebellar posterior vermis. In the absence of Lmx1a, these cells precociously exit the rhombic lip and overmigrate into the anterior vermis. This overmigration is associated with premature regression of the rhombic lip and posterior vermis hypoplasia in Lmx1a null mice (Chizhikov et al., 2010). LMX1A acts downstream to signaling via bone morphogenetic protein receptors (BMPRs) and this pathway is likely involved in the production of the crucial progenitor gene Atoh1 (Atonal homolog 1 a.k.a Math1, Alder et al., 1999 Krizhanovsky and Ben-Arie, 2006). Genetic destruction of the roof plate by using diphtheria toxin driven by the roof plate specific gene Gdf7 resulted in the near-total loss of Atoh1 cells of the URL (Chizhikov et al., 2006). BMPRs assemble into a heterotetramer and phosphorylate members of the SMAD family (Smad1, 5, 8 signaling pathway reviewed in Waite and Eng, 2003). Double knockouts of Bmpr1a Bmpr1b and Smad1 Smad5 result in a dramatic loss of GCPs that is attended by loss of Atoh1 and other critical genes in the GC lineage including Zic1 and Zic2 (Qin et al., 2006 Tong and Kwan, 2013). Interestingly, BMP signaling has also been implicated in the degradation of ATOH1 (Zhao et al., 2008), an effect promoted by Meis1 and Pax6 (Owa et al., 2018).

Atoh1 (Figure 5A) is currently viewed as the definitive marker of the GC lineage, as well as of the other glutamatergic cells that arise from the URL (Akazawa et al., 1995 Ben-Arie et al., 1996). This opened up the molecular analysis of GC development by using transgenesis for gene knockouts and lineage tracing. Of note, evidence was brought to bear on possible upstream genes to Atoh1, for example, Hes1 (Akazawa et al., 1995). This issue is still relatively unexplored although the downstream targets of ATOH1 have been well characterized. Critical genes in the pathway to a glutamatergic phenotype (GCs, glutamatergic projection neurons of the cerebellar nuclei, and UBCs) include Pax6, Tbr1, and Tbr2. Atoh1 deletion results in the elimination of the entire population of GCs in addition to related populations that derive from the full rhombic lip (Ben-Arie et al., 1997 Wang et al., 2005). This dramatic loss places Atoh1 in the headwaters of the GC lineage. The examination of downstream targets of ATOH1 has identified a set of genes that suggest a broad developmental impact of Atoh1 on GC development (Klisch et al., 2011 Machold et al., 2011).

Figure 4. Formation of the external granular layer. (A) Schematic representation of the embryonic hindbrain (dorsal view, circa E12.5). The view illustrates the departure of GCPs from the URL and the invasion of the EGL (arrowheads). (B) The same process is seen in a sagittal view to show the formation of the EGL. (C) A sketch of extracellular signals and their receptors controlling GCP migration from the URL into the EGL. The URL is represented as a triangle on the left. The location of the isthmic organizer and mesencephalon is on the right side of each box. CXCL12 is released by the leptomeninges (horizontal black line) SLIT2 is released by the URL (triangle) netrin is secreted by the mesencephalic ventral midline. Abbreviations, URL, upper rhombic lip EGL, external granular layer VZ, ventricular zone ChP, choroid plexus Cb, cerebellar anlage.

Figure 5. Figure 5. (A–K) Distribution of eleven transcripts in the embryonic cerebellar primordium. Sagittal sections hybridized in situ with antisense riboprobes specific for genes, cited in the text, that play important roles in the early stages of cerebellar development. Positive territories are labeled black. All images show E13.5 cerebellar primordia, except (G), which shows an E15.5 section. Image credit: Allen Institute. © 2008 Allen Institute for Brain Science. Allen Developing Mouse Brain Atlas. Available online at: Abbreviations: Cb, cerebellar primordium ChP, choroid plexus EGL, external granular layer NTZ, nuclear transitory zone URL, upper rhombic lip VZ, ventricular zone. Scale Bar in (K) = 200 μm and applies to all panels.

With the identification of Atoh1 as key to GC development, it became important to map the timing of the cells that emerge from the Atoh1 lineage by using site-specific recombinase genetic fate mapping (Dymecki and Tomasiewicz, 1998 Zinyk et al., 1998). The earliest cells to emerge from the URL�tween E10.5 and E12.5𠅊re fated to become neurons of the cerebellar nuclei, and give rise to the so-called nuclear transitory zone. They migrate anteriorly over the cerebellar surface as the “rostral rhombic-lip migratory stream” (Wang et al., 2005) or “subpial stream” (Altman and Bayer, 1997 sketched in Figures 4A,B). The GCPs follow the same path from the URL to the EGL. Altman and Bayer’s careful analysis of the rat URL at E10.5 showed two distinct cellular organizations—one tangentially oriented in the exterior lamina of the URL (eURL), and a second with a columnar organization in the interior lamina of the URL (iURL), possibly corresponding to apical radial glial progenitors). We do not know if these laminae are a transitional phase of URL development, but it is clear that they comprise distinct subpopulations based upon the analysis of the Atoh1 null mouse, where the cells of the eURL are absent while the iURL persists in a normal proliferative state (Jensen et al., 2004). Developmental analysis of the Wnt pathway gene Wntless (Wls signaling cascade reviewed in Clevers and Nusse, 2012), which processes Wnt for its extracellular signaling role, confirms this heterogeneity with the identification of a population of Wls+ cells in the iURL that are both Atoh1-independent [i.e., they persist in the Atoh1 knockout and do not express Atoh1 or the corresponding protein (Yeung et al., 2014)]. In the wildtype, an examination of the two URL laminae suggests that the transition from Wls+ to Atoh1+ in the iURL serves as a reservoir for the production of ATOH1+ cells and cells of the glutamatergic lineage generally. Genetic fate-mapping of the Wls+ population would provide insights into this possibility.

The URL as the First Zone of Transit Amplification

The expansion of the GCP population during the formation of the EGL from the URL can be thought of as an example of transit amplification𠅌omparable to the transit amplification of GABAergic interneurons as they migrate from the subventricular zone of the 4th ventricle through the white matter tracts (e.g., Leto and Rossi, 2012). In support of this perspective, Wingate and coworkers have shown GCP transit amplification in teleosts, from which a well-defined EGL is absent (Chaplin et al., 2010). The molecular signals that direct URL progenitor cells to form the EGL include the antagonistic interplay between ATOH1 and LMX1A (Chizhikov et al., 2010). Such a tug-of-war between molecularly distinct compartments—i.e., an interplay between factors that push forward developmental events and those which inhibit that progression—is a common dynamic in CNS development (e.g., Toresson et al., 2000 Yeung et al., 2014 Kullmann et al., 2020). Any quantitative estimate of the initial phase of amplification of the GCP population in the proliferatively-active URL is bound to be uncertain as this population gives rise not only to GCs but also to cerebellar nuclear neurons and UBCs.

From URL to EGL: The Second Stage of Transit Amplification

Once GCPs exit the URL to form the EGL, starting at E13, we estimate that from the time that the EGL covers the cerebellum (񾸕) to the adult population in the GL (~P25), there is a ߣ,000× amplification! As Atoh1+ cells exit the URL, they proliferate and disperse tangentially to cover the entire dorsal surface of the cerebellum as the EGL (Figure 3B). Scant information is available about the molecules that guide GCP migration at this stage. One key factor is chemotactic stromal cell-derived factor 1, encoded by the Cxcl12 gene (Figures 4C, 5D, 6F,G) expressed by the developing leptomeninges and its receptor, CXCR4 (Figures 4C, 5E, 6H,I), expressed by migrating progenitors of the EGL and acting through its downstream effector Shp2 (Hagihara et al., 2009). Fetal cerebellar development in Cxcl12 mutant animals is markedly different from that in wild-type animals, with many proliferating GCs invading the cerebellar anlage (Zou et al., 1998). Mutations in Cxcl12 and Cxcr4 have the same effect on GCP migration, pointing to a monogamous relationship between the corresponding proteins: in the mutant, GCPs depart prematurely from the EGL migrating radially and forming large cell clumps in the cerebellar parenchyma (Ma et al., 1998).

Figure 6. Distribution of nine transcripts in the P4 cerebellum. Sagittal sections hybridized in situ with antisense riboprobes specific for genes cited in the text that play important roles at early stages of cerebellar development. Image credit: Allen Institute. © 2008 Allen Institute for Brain Science. Allen Developing Mouse Brain Atlas. Available online at: Abbreviations: Cb, cerebellum iEGL, inner EGL oEGL, outer EGL. (C,E,J) are magnifications of areas in panels (B,D,I), respectively. Scale bar in panel (A 400 μm) applies to (B,D,F,H,J) scale bar in panel (C 100 μm) applies to (E,G,I,K–O).

During GCP migration into the EGL (Figures 4A,B reviewed in Chຝotal, 2010), the repulsive extracellular signal SLIT-2 is expressed in the URL (Figure 5J) and probably propels migrating ROBO-expressing GCPs (Figures 4C and 5K) out of the URL (Gilthorpe et al., 2002). GCPs also express the chemoattractant netrin receptor deleted in colorectal carcinoma (DCC, Moore et al., 2007). Netrins are a family of laminin-related secreted proteins that direct axon extension and cell migration during neural development. They act as attractants for some cell types and as repellents for others, mediated by distinct receptors (Figure 4C). Among other expression sites, Ntn1, encoding netrin-1, is expressed in the mesencephalic ventral midline (Figure 5G). GCPs express the netrin receptor gene Dcc (Figure 5H), which mediates the attractive response to netrin-1 during EGL formation. Co-expression of the UNC-5C co-receptor converts the response from attractive to repulsive (Figure 4C). GCP migration is confined within the cerebellar anlage by the netrin co-receptor encoded by Unc5c (a.k.a Unc5h3 Figure 5I), which acts cell-autonomously to enact a repulsive response to the netrin-1 ligand (Ackerman et al., 1997 reviewed in Goldowitz et al., 2000), thereby preventing the inappropriate anterior migration of GCPs into the inferior colliculus. Consistent with this, in Pax6 Sey/Sey mice, in which Unc5c is absent, GCPs are not restricted to the cerebellum and migrate ectopically into the inferior colliculus (Engelkamp et al., 1999). Importantly, however, netrin-1 is not expressed at the anterior limit of the cerebellum and it does not repel GC precursors in collagen-gel assays (Alcantara et al., 2000 Gilthorpe et al., 2002). Furthermore, the EGL forms normally in netrin-1 KO mice (Przyborski et al., 1998 Alcantara et al., 2000), possibly suggesting the presence of redundant signals. Another interesting feature of CGPs that migrate to establish the EGL is that they release reelin (D𠆚rcangelo, 2014), which guides neuronal migration in the cerebellum as it does in the developing telencephalic cortical plate. In this respect, we view the cerebellar GC as equivalent to the Cajal-Retzius neuron of the isocortex.

Clonal Expansion in the EGL

Long before the bulk of clonal expansion, DNA synthesis is detected in the prospective EGL. It is not clear whether GCPs divide after completing their migration or combine migration and proliferation simultaneously, similar to basal progenitors of the cerebral cortex. Prenatal migration of GCPs over the cerebellar primordium (E13�.5) and subsequent EGL maintenance (E18–P20) both require contacts with the basement membrane, involving both the basal endfeet of radial glial progenitors and fibroblasts of the pia mater. In 1985 Hausmann and Sievers (1985) identified in the E14 rat (roughly corresponding to E12.5 in the mouse) an EGL cell type oriented tangentially to the cerebellar surface and characterized by persistent contact with the basal lamina via an external process with a lamellipodial tip and a cytoskeleton characteristic of migratory cells. They proposed that the basal lamina guides the tangentially migrating GCPs and that persistent contacts with the basal lamina mediate stimuli that maintain GCPs in a proliferative state. The bulk of proliferation starts shortly before birth and continues for about 15 days, peaking around P6 (Figure 3B). Clonal expansion requires a mitogenic signal released by neighboring PCs (Smeyne et al., 1995). The nature of this signal is well established—PCs release the morphogen and mitogen sonic hedgehog (SHH) that promotes a massive GCP proliferation (Dahmane and Ruiz-I-Altaba, 1999 Wallace, 1999 Wechsler-Reya and Scott, 1999) accordingly, Shh deletion abolishes GCP expansion (Lewis et al., 2004). GCPs are competent to respond to SHH because they express the receptor Patched-1, located near the base of the cell cilium, and the G-protein-coupled transmembrane co-receptor smoothened (SMO signaling pathway reviewed in Ruiz i Altaba et al., 2002 reviewed in Di Pietro et al., 2017 Lospinoso Severini et al., 2020). SMO activates an inhibitory G protein that in turn activates GLI transcription factors and promotes cell cycle progression. However, the SHH signaling intermediates that regulate GCP proliferation are only just starting to be defined.

Brainy mammals

By 360 million years ago, our ancestors had colonised the land, eventually giving rise to the first mammals about 200 million years ago. These creatures already had a small neocortex – extra layers of neural tissue on the surface of the brain responsible for the complexity and flexibility of mammalian behaviour. How and when did this crucial region evolve? That remains a mystery. Living amphibians and reptiles do not have a direct equivalent, and since their brains do not fill their entire skull cavity, fossils tell us little about the brains of our amphibian and reptilian ancestors.

What is clear is that the brain size of mammals increased relative to their bodies as they struggled to contend with the dinosaurs. By this point, the brain filled the skull, leaving impressions that provide tell-tale signs of the changes leading to this neural expansion.

Timothy Rowe at the University of Texas at Austin recently used CT scans to look at the brain cavities of fossils of two early mammal-like animals, Morganucodon and Hadrocodium, both tiny, shrew-like creatures that fed on insects. This kind of study has only recently become feasible. “You could hold these fossils in your hands and know that they have answers about the evolution of the brain, but there was no way to get inside them non-destructively,” he says. “It’s only now that we can get inside their heads.”

Rowe’s scans revealed that the first big increases in size were in the olfactory bulb, suggesting mammals came to rely heavily on their noses to sniff out food. There were also big increases in the regions of the neocortex that map tactile sensations – probably the ruffling of hair in particular – which suggests the sense of touch was vital too (Science, vol 332, p 955). The findings fit in beautifully with the widely held idea that early mammals were nocturnal, hiding during the day and scurrying around in the undergrowth at night when there were fewer hungry dinosaurs running around.

After the dinosaurs were wiped out, about 65 million years ago, some of the mammals that survived took to the trees – the ancestors of the primates. Good eyesight helped them chase insects around trees, which led to an expansion of the visual part of the neocortex. The biggest mental challenge, however, may have been keeping track of their social lives.

If modern primates are anything to go by, their ancestors likely lived in groups. Mastering the social niceties of group living requires a lot of brain power. Robin Dunbar at the University of Oxford thinks this might explain the enormous expansion of the frontal regions of the primate neocortex, particularly in the apes. “You need more computing power to handle those relationships,” he says. Dunbar has shown there is a strong relationship between the size of primate groups, the frequency of their interactions with one another and the size of the frontal neocortex in various species.

Besides increasing in size, these frontal regions also became better connected, both within themselves, and to other parts of the brain that deal with sensory input and motor control. Such changes can even be seen in the individual neurons within these regions, which have evolved more input and output points.

All of which equipped the later primates with an extraordinary ability to integrate and process the information reaching their bodies, and then control their actions based on this kind of deliberative reasoning. Besides increasing their overall intelligence, this eventually leads to some kind of abstract thought&colon the more the brain processes incoming information, the more it starts to identify and search for overarching patterns that are a step away from the concrete, physical objects in front of the eyes.

Which brings us neatly to an ape that lived about 14 million years ago in Africa. It was a very smart ape but the brains of most of its descendants – orang-utans, gorillas and chimpanzees – do not appear to have changed greatly compared with the branch of its family that led to us. What made us different?

It used to be thought that moving out of the forests and taking to walking on two legs lead to the expansion of our brains. Fossil discoveries, however, show that millions of years after early hominids became bipedal, they still had small brains.

We can only speculate about why their brains began to grow bigger around 2.5 million years ago, but it is possible that serendipity played a part. In other primates, the “bite” muscle exerts a strong force across the whole of the skull, constraining its growth. In our forebears, this muscle was weakened by a single mutation, perhaps opening the way for the skull to expand. This mutation occurred around the same time as the first hominids with weaker jaws and bigger skulls and brains appeared (Nature, vol 428, p 415).

Once we got smart enough to innovate and adopt smarter lifestyles, a positive feedback effect may have kicked in, leading to further brain expansion. “If you want a big brain, you’ve got to feed it,” points out Todd Preuss of Emory University in Atlanta, Georgia.

He thinks the development of tools to kill and butcher animals around 2 million years ago would have been essential for the expansion of the human brain, since meat is such a rich source of nutrients. A richer diet, in turn, would have opened the door to further brain growth.

Primatologist Richard Wrangham at Harvard University thinks that fire played a similar role by allowing us to get more nutrients from our food. Eating cooked food led to the shrinking of our guts, he suggests. Since gut tissue is expensive to grow and maintain, this loss would have freed up precious resources, again favouring further brain growth.

Mathematical models by Luke Rendell and colleagues at the University of St Andrews in the UK not only back the idea that cultural and genetic evolution can feed off each other, they suggest this can produce extremely strong selection pressures that lead to “runaway” evolution of certain traits. This type of feedback might have played a big role in our language skills. Once early humans started speaking, there would be strong selection for mutations that improved this ability, such as the famous FOXP2 gene, which enables the basal ganglia and the cerebellum to lay down the complex motor memories necessary for complex speech.

“Cultural and genetic evolution can feed off each other, leading to ‘runaway’ evolution”

The overall picture is one of a virtuous cycle involving our diet, culture, technology, social relationships and genes. It led to the modern human brain coming into existence in Africa by about 200,000 years ago.

Evolution never stops, though. According to one recent study, the visual cortex has grown larger in people who migrated from Africa to northern latitudes, perhaps to help make up for the dimmer light up there (Biology Letters, DOI&colon 10.1098/rsbl.2011.0570).

How we study the brain

The brain is difficult to study because it is housed inside the thick bone of the skull. What&rsquos more, it is difficult to access the brain without hurting or killing the owner of the brain. As a result, many of the earliest studies of the brain (and indeed this is still true today) focused on unfortunate people who happened to have damage to some particular area of their brain. For instance, in the 1880s a surgeon named Paul Broca conducted an autopsy on a former patient who had lost his powers of speech. Examining his patient&rsquos brain, Broca identified a damaged area&mdashnow called the &ldquoBroca&rsquos Area&rdquo&mdashon the left side of the brain (see Figure 1.4.9) (AAAS, 1880). Over the years a number of researchers have been able to gain insights into the function of specific regions of the brain from these types of patients.

Figure 1.4.9: Broca's Area [Image: Charlyzon,, CC BY-SA 3.0,]

An alternative to examining the brains or behaviors of humans with brain damage or surgical lesions can be found in the instance of animals. Some researchers examine the brains of other animals such as rats, dogs and monkeys. Although animals brains differ from human brains in both size and structure there are many similarities as well. The use of animals for study can yield important insights into human brain function.

In modern times, however, we do not have to exclusively rely on the study of people with brain lesions. Advances in technology have led to ever more sophisticated imaging techniques. Just as X-ray technology allows us to peer inside the body, neuroimaging techniques allow us glimpses of the working brain (Raichle,1994). Each type of imaging uses a different technique and each has its own advantages and disadvantages.

Figure 1.4.10: Above: A PET scan - Below: An fMRI scan [Image: Erik1980,, CC BY-SA 3.0,

Positron Emission Tomography (PET) records metabolic activity in the brain by detecting the amount of radioactive substances, which are injected into a person&rsquos bloodstream, the brain is consuming. This technique allows us to see how much an individual uses a particular part of the brain while at rest, or not performing a task. Another technique, known as Functional Magnetic Resonance Imaging (fMRI) relies on blood flow. This method measures changes in the levels of naturally occurring oxygen in the blood. As a brain region becomes active, it requires more oxygen. This technique measures brain activity based on this increase oxygen level. This means fMRI does not require a foreign substance to be injected into the body. Both PET and fMRI scans have poor temporal resolution , meaning that they cannot tell us exactly when brain activity occurred. This is because it takes several seconds for blood to arrive at a portion of the brain working on a task.

One imaging technique that has better temporal resolution is Electroencephalography (EEG), which measures electrical brain activity instead of blood flow. Electrodes are place on the scalp of participants and they are nearly instantaneous in picking up electrical activity. Because this activity could be coming from any portion of the brain, however, EEG is known to have poor spatial resolution, meaning that it is not accurate with regards to specific location.

Another technique, known as Diffuse Optical Imaging (DOI) can offer high temporal and spatial resolution. DOI works by shining infrared light into the brain. It might seem strange that light can pass through the head and brain. Light properties change as they pass through oxygenated blood and through active neurons. As a result, researchers can make inferences regarding where and when brain activity is happening.

Neuronal Migration Disorders

Neuronal migration and positioning are critical processes during CNS development and circuitry formation, and defects in neuronal migration can lead to devastating brain diseases (Manto et al., 2013). It is well known that malfunctioning of the migratory process causes neuronal migration disorders (NMDs). NMDs are a heterogeneous group of birth defects with the same etiopathological mechanisms caused by the abnormal migration of neurons in the developing brain. This can result in neurological disorders with clinical manifestations including schizophrenia, autism, ataxia and epilepsy (Gleeson and Walsh, 2000 Nadarajah et al., 2003 Deutsch et al., 2010 Guerrini and Parrini, 2010 Demkow and Ploski, 2015 Marzban et al., 2015 Qin et al., 2017). The role of the Reelin pathway in neuronal migration has been extensively studied and in humans homozygous mutations in the RELN gene are associated with ataxia, cognitive abnormalities and cerebellar hypoplasia. In this context it has been also shown that the abnormal migration of cortical neurons is associated with reduced number of cortical gyri (lissencephaly). These results suggest an important role for Reelin in neuronal migration during the development. It should be noted that decreased levels of RELN expression have severe negative effects on the development of the human brain and may result in psychiatric diseases. For instance, patients who suffered from schizophrenia had reduced levels of RELN expression in the inhibitory neurons of their cortical areas. Additionally, decreased expression of Reelin has been observed in patients with other mental diseases, such as autistic-like disorders, bipolar disorder and major depressive disorder. Together these results suggest that Reelin has an important role in neuronal migration and synapse formation and deficits in Reelin expression may contribute to the pathophysiology of these disorders (Fatemi, 2005).

Psychology Chapter 4: PRACTICE QUESTIONS

Spinal reflexes are automatic responses that occur without conscious effort. In fact, spinal reflexes do not even require the brain to occur.

Motor nerves carry commands from the central nervous system to skeletal muscles and glands.

Sensory nerves carry information from sense organs to the spinal cord and the brain.

Individuals with multiple sclerosis, loss of myelin causes erratic nerve signals, leading to loss of sensation, weakness or paralysis, lack of coordination, or vision problems.

Recall that 11 of 12 of the cranial nerves are found in the brain stem.
The other 1 the olfactory is separate for smell.

Dopamine in the brain is involved in the control of voluntary movement, learning, memory, pleasure and rewards, and response to novelty.

Acetylcholine affects neurons involved in muscle action, arousal, vigilance, memory and emotion.

General conclusion

We have underlined multiple facets of cerebellar functions. Despite its highly homogeneous and cristalline anatomical structure, we still lack a consensus on the operational mode of the cerebellum, one of the top mysteries for CNS disorders. However, no doubt that progress has been made in the theories of cerebellar functions. The universal cerebellar transform embedded within the dysmetria of thought theory is an example of the effort to unify the operational mode of the cerebellum [126].

Its dense connectivity with cerebral cortex, thalamic nuclei, brainstem nuclei and spinal cord, as well as its critically high number of neurons put the cerebellum in a unique position for a participation in cognitive, affective and sensorimotor operations. This special session has highlighted this aspect by taking fear behaviour, motor control, timing contributions and tremor as 4 examples of productive fields of research.

Watch the video: Πώς αντιλαμβάνεται ο εγκέφαλος το όμορφο (February 2023).