Children have 1,000 trillion synapses. By the time somebody is 30 years old, though, only 100-500 trillion of their synapses remain. This means that in just 7,000 days, as much as 90% of a person's synapses disappear. Fortunately, though, this decline is not completely disastrous; many studies indicate that 30 year olds are not catatonic. Synapses are specialized neuronal junctions in which neurons, muscles, or glands can communicate with each other. Over time, synapses strengthen, die, and move based on the activities of the individual. Psychoactive drugs affect synapses either directly or indirectly, and can give the patient artificial happiness or emptiness. Synapses are constantly changing to accommodate activities, interact with chemicals, form memories, and encourage development.
Neurons communicate with each other, muscles, and glands via the synapses, which change with age. A synapse is a junction where the presynaptic neuron releases a neurotransmitter, and the postsynaptic cell undergoes transformations in response. As a result, synapses are crucial to thought, perception, mobility, and homeostasis. Humans initially have 1,000 trillion synapses. However, this number declines dramatically in babies as they eliminate excess synapses. This is done by programmed cell death, which makes sure that the growing brain does not get too big. Adolescents undergo further synaptic pruning; very little programmed cell death occurs, however. This makes sure that synapses are made more efficient; more neurotransmitter is available for the synapses, which are necessary. Unnecessary synapses, which impede efficiency, are eliminated. After adolescence, the body remains at a peak for several years. After this peak, though, the body quickly deteriorates in a process called aging. As people continue to get old, the human brain declines in function despite its changes in gene expression. It tries desperately to down-regulate synaptic plasticity genes and synaptic vesicle release. It focuses more on neuronal maintenance by up regulating genes associated with stress, DNA damage, and antioxidant attack. As the synapses become increasingly static and the neurons lose their youth, the effects of senescence take effect and the brain eventually becomes necrotized. This process begins around the age of 25.
To avoid this depressing reality, many people become addicted to drugs which function at the synapse. Agonists, such as nicotine, mimic neurotransmitters to activate receptors. Antagonists, such as atropine, bind to receptors and block their activation. Overexposure to a neurotransmitter results in the disappearance of its receptors. This is a response mechanism to too much neurotransmitter, resulting in drug tolerance. To avoid reality, then, druggies will need to take increasingly high drug doses to try to get their first high. Therefore, overexposure results in decreased synaptic efficacy. There are three primary mechanisms by which these psychoactive drugs take effect. The first is that psychoactive drugs can prevent an action potential from starting, thereby preventing any related synaptic activity. Examples include lidocaine, which binds to voltage-gated sodium channels. The second mechanism is that a drug can alter neurotransmitter synthesis, resulting in no, reduced, or overproduction of a neurotransmitter. A third mechanism is interference with neurotransmitter release. Black Widow Spider toxin increases release of a neurotransmitter, thereby heightening synaptic efficacy momentarily. Botulism and tetanus decrease neurotransmitter release.
When new memories are formed, synaptic changes occur. An extremely basic example of this is shown by Hebb's Rule. According to Hebb's Rule, a synapse that is repeatedly activated in conjunction with the firing of a postsynaptic neuron will be strengthened by structural and chemical changes. For example, many people associate UCLA with bears. The synapses between the UCLA neuron and the bear neuron will therefore strengthen. This strengthening occurs by release of more neurotransmitter, removal of excess synapses, and the presence of more receptors. As people age, though, the genes related to synaptic plasticity are down regulated. As a result, old people have a harder time forming new memories.
In conclusion, the brain is constantly changing. As people approach their third decade on this planet, they are losing hundreds of trillions of synapses. Fortunately, though, this is necessary to remove excess synapses (excess synapses reduce neuronal efficiency). As people get old and lose synapses, their minds also undergo tremendous morphological transformations.
The Neural Tube Dorsal-Ventral Axes and the Role of Shh
Starting at the ventral end, the following structures comprise the spinal cord: floor plate; cell bodies of somatic motor neurons; cell bodies of commisural neurons; roof plate. The floor plate guides axons that grow into it, and the motor neurons send out axons that innervate muscles.
The notochord patterns the neural tube's dorso-ventral axis. An additional notochord transplanted underneath a closing neural tube in the chick embryo induces an additional floorplate with adjacent motor neurons. Removing the notochord from the neural tube results in absence of a floor plate and motor neurons. Thus, the notochord induces at least the most dorsal neural tube structures. Furthermore, both the notochord and floorplate induce adjacent somite tissue into sclerotome, which gives rise to the vertebrae and ribs.
Vertebrate Sonic hedgehog protein (Shh, homolog of Drosophila Hedgehog) is localized to the notochord and floorplate of the spinal cord. Perhaps Shh is the notochord signal that patterns the neural tube in dorso-ventral axis, and that patterns the somites. Addition of cells producing Shh has a similar effect to adding an additional notochord: an ectopic floorplate and motor neurons. The floorplate differentiates where the level of ectopic Shh is highest and the motor neurons where the level is lower. This indicates that a gradient of Shh released from the notochord patterns the neural tube.
The key role of Sonic hedgehog was revealed by the phenotype of Sonic hedgehog knockout mice. Shh-/- mice die early and are extremely defective. The defects observed are consistent with a role of Shh in inductions:
|Floorplate||Shh form the notochord induces the floorplate. Shh-/- fetuses have severe ventral midline defects, i. e., the ventral midline seems to degenerate. This results in a fusion of the eye and nose primordia in the ventral midline (cyclopia). This defect is consistent with the known role of Shh in inducing the formation of the floorplate and other ventral cell types in the neural tube.|
|Sclerotomes||Shh from the notochord and floor induces sclerotomes. Another defect is the virtual absence of the vertebrae and the ribs. Again, this is consistent with the role of Shh in giving a more ventral identity (sclerotome) to a portion of each somite. We will discuss this aspect of Shh signaling in a future lecture.|
What experiments demonstrate how the anterior-posterior axes are patterned in the neural tube?
Hox genes and head gap genes
The posterior neural tube gives rise to the spinal cord. The anterior neural tube gives rise to the brain. The neural tube begins subdividing into a complex series of bulges (later forming the brain) before it has even completely formed at the posterior. First, three primary vesicles are formed. Starting at the anterior: the forebrain (prosencephalon), the midbrain (mesencephalon) and the hindbrain (rhombencephalon). The prosencephalon then becomes subdivided into the telencephalon at the anterior and the diencephalon at the posterior. The telencephalon will give rise to the cerebral hemispheres. The diencephalon evaginates to form the optic cup (which will form much of the eye), and also will give rise to the thalamic and hypothalamic regions of the brain.
The rhombencephalon is the only part of the brain that appears to be segmented into separate bulges, referred to as rhombomeres. Each rhombomere is a morphologically distinct compartment. A compartment is a region of cell lineage restriction. Once boundaries between individual compartments form, cells are confined to their respective compartments and cannot cross from one side of a boundary to another. This implies that the cells within each compartment have differential affinities for each other, but not for cells from neighboring compartments. This is similar to the segments of the Drosophila embryo. Different types of appendages arise from different Drosophila segments. Similarly, distinct cranial nerves arise from different rhombomeres.
The strongest evidence that rhombomeres represent metameric units analogous to the segments of the Drosophila embryo is that their identities are controlled by Hox genes. Anterior boundaries of expression of individual Hox genes mark boundaries between rhombomeres. Knockouts of certain Hox genes in mice (for example Hoxa-1 and Hoxa-3) result in abnormal development of the anteriormost rhombomere in which the gene is normally expressed. As with Drosophila segments, loss of Hox genes leads to transformations to a more anterior identity. Hox genes thus appear to play similar roles in rhombomere identity, vertebral identity and Drosophila segment identity.
Hox genes are not expressed in the midbrain and forebrain. These regions are probably also divided up into subunits by the spatially localized expression of various other transcription factors. There are at least 25 homeobox-containing genes that are expressed in regionally restricted patterns in the forebrain. Many of the genes expressed in these overlapping patterns (Emx, Otx, Dlx) are homologous to genes (ems, otd, Dll) expressed in segmental patterns in the embryonic fly head. The few mutations observed so far have been instructive. For example, Drosophila otd (and its murine homolog Otx) mutants lack the anterior portion of the brain.
A key feature of cells located at the boundaries of compartments is that they often serve as signaling centers. We saw this when we considered the segment polarity genes of Drosophila. We saw that the cells on either side of the compartment boundary expressed either Hedgehog or Wingless proteins.
These proteins then diffused away from their sources and influenced the development of neighboring cells in the compartments. Similarly, boundaries of lineage restriction in the developing midbrain and forebrain act as signaling centers. For example, a signaling center forms at the boundary between the midbrain and hindbrain.
The cells at this boundary not only act as a barrier of cell lineage restriction, but also secrete extrinsic signals, such as FGF8 and Wnt1 (a homolog of Wingless). These molecules are thought to form gradients that pattern adjacent regions. Roles for FGF8 and Wnt1 are demonstrated by the fact that tissue-specific loss of these genes in neural tissue leads to loss of the midbrain. Other signaling centers have been found in the forebrain, but their functions are less well understood.
What are the effects of mutations in Shh in neural tissues?
Injecting Sonic hedgehog protein (Shh) → extra floor plate. Sonic hedgehog is expressed in notochord and floorplate. Shh is a homolog of Drosophila hedgehog. High levels of Shh → floorplate. Low levels of Shh → motor neurons.
What is a compartment? How does this compare to Drosophila segments?
As the primitive streak regresses posteriorly, cells furthest from the node are no longer under the influence of FGF. Once outside the influence of FGF, paraxial mesoderm cells begin to compartmentalize into somites. Cells within an individual somite compact by increasing cadherin expression. These changes in cell adhesion cause the newly forming somite to separate from the rest of the paraxial mesoderm.
The region separating a newly formed epithelial somite from neighboring unsegmented paraxial mesoderm is a boundary. Boundaries arise in vertebrate brain rhombomere compartments and Drosophila embryo segments. Compartments are kept separate due to differences in cell adhesion. The same is true for cells in somites and in the unsegmented paraxial mesoderm.
The advantage of dividing the paraxial mesoderm into separate somites, each of which is an individual compartment, is that this allows the formation of repetitive structures such as vertebrae to use a common genetic pathway in each somite. The Notch pathway is critical for formation of a boundary between the newly formed somite and unsegmented mesoderm, and between rhombomeres.
How does Notch/Delta signaling affect cell fate decisions in the nervous system?
The most apical (facing the lumen of the neural tube) zone is the ventricular zone; this is where neuronal progenitors undergo cell division. This can be seen as the region where 3H-thymidine is incorporated. Once cells are postmitotic (undergone their last division) they migrate away from the ventricular zone to differentiate. The identity of the newly born neuronal or glial cell is specified before it starts to migrate.
Asymmetric cell division may be involved in the formation of neuroblasts (cells committed to terminal differentiation) from neural progenitor cells in the ventricular zone. In Drosophila, asymmetric cell divisions lead to the segregation of cytoplasmic determinants that affect the Notch pathway. There is some evidence that similar mechanisms operate in parts of the vertebrate nervous system.
In order to generate a functional nervous system, the correct numbers of neurons must be generated, and they must differentiate into the correct cell types. How is the number of neurons regulated? Due to lateral inhibition, only one cell in each proneural cluster becomes a neuroblast. Similarly, in vertebrates, lateral inhibition controls the rate at which neuroblasts are specified from the cells in the ventricular zone.
Lateral inhibition is mediated by the Notch signal transduction system. Notch and Delta are transmembrane proteins. Notch is a receptor that interacts with specific ligands including Delta. Therefore, the Notch-Delta interaction requires direct cell-cell contact. Initially, all cells in the proneural cluster express low levels of Notch and Delta. Activating the Notch receptor inhibits expresion of proneural genes, and Notch-Delta interaction downregulates Delta expression. Through an unknown mechanism, one cell in each proneural cluster gains a slight advantage over the others by expressing slightly more Delta.
In a likely schochastic (random) process, one cells expresses slightly more Delta than its neighbors. This cell thus engages more Notch receptors on neighboring cells, downregulating their expression of proneural genes and Delta whilst retaining their Notch expression. Thus, these neighboring cells lose the ability to differentiate as neurons (due to decreased proneural gene expression) and also the ability to inhibit proneural expression in other cells (due to decreased expression of Delta). As a result the single cell that expressed slightly more Delta is the only cell in which proneural gene expression is maintained.
The importance of Notch-Delta signaling can be seen from analysis of mutants in this pathway. A clear example is provided by the sensory receptor cells of the inner ear. These cells are called hair cells for the characteristic cilia on their apical surfaces. These cilia are deflected by mechanical forces created by sound waves, and the signal is transmitted along axons to the brain. Hair cells are surrounded by various types of support cells.
The pattern of hair cells in the inner ear is highly invariant, and this regular pattern is required for proper sound reception. In Delta-/- mutants, lateral inhibition is defective, and all cells, including the support cells, develop as hair cells. Thus, lateral inhibition normally regulates the number of hair cells that develop, ensuring that there is a correct balance between hair cells and supporting cells.
Part of this was originally published as "You Can Think Even Though Your Brain is 70% Water" on 17 February 2006.