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20.3Control of output to effectors

In animals, information obtained from sensory organs is processed by the central nervous system. In some cases, learning, memory verification, sophisticated predictions and inferences are carried out before output signals for responses such as muscle movement are sent to the effector organs. Most of the output signals sent to the effectors are transmitted by the motor area of the cerebral cortex. However, this is not a completely centrally controlled mechanism in which all the signals are directly sent to the effectors. Effector organs are made to function in a particular set and incorporate automatic controllers to facilitate organized functioning of the set. In many effector organs, this controller is switched on/off to control the overall mechanism. The following section looks at two simple examples of combined control by the automatic controller at the periphery and the central nervous system.

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Dementia and Alzheimer's disease

As of 2009, 13.4% of the Japanese population was under 14 years of age, 64.1% people between 15 and 64, and 22.5% above 65. In 2050, these percentages are expected to change to 8.6%, 51.8%, and 39.6%, respectively (from Latest Demographic Statistics 2007). The issue of an aging population is indeed compelling. Dementia is a condition in which a person shows changes in his/her character (e.g., a person who used to be calm becomes easily angry) and behavior (e.g., a person starts claiming that someone has stolen something from him/her, saying the same thing repeatedly, buying the same thing repeatedly etc.). Such changes are caused by a sudden decrease in the number of neurons. Generally, dementia is roughly categorized by causes into two types: the after damage from stroke or dementia caused by other reasons. The latter type is called Alzheimer’s disease.

Alzheimer’s disease is a condition that was first reported by German neurologist Alois Alzheimer in 1907. He detected characteristic abnormality in the brain image of a woman who suddenly exhibited dementia symptoms in her early 50s. Specifically, silver staining of the brain showed miliary spots on the outside of nerve cells. These deposits are called senile plaques; they consist of the small peptide amyloid β protein (Aβ). Other unique characteristics are twisted filaments in the neurons (neurofibrillary tangles made up mainly of phosphorylated microtubule-associated protein tau). In the early stages of Alzheimer’s disease, there is mild cognitive disorder and atrophy of the brain. Less than 10% of cases of Alzheimer’s disease are familial, while others are sporadic cases associated with long lifespan.

Aβ, the main component of senile plaque, is cleaved from the amyloid precursor protein (APP). The genes responsible for genetic Alzheimer’s disease are presenilin 1 and 2, which code for enzymes involved in the cleavage of APP. Conversely, the most common cause of dementia accompanying longevity around the world is currently a mutant of apolipoprotein E (apoE) seen in the blood serum. ApoE is made up of 299 amino acids and are polymorphic in the 112th and 158th amino acids. Apolipoprotein is called E2 when the 112th and 158th amino acids are both cysteine, E3 when the 112th amino acid is cysteine and the 158th amino acid is arginine, and E4 when both amino acids are arginine. Almost all persons have 1 of these 3 types of apolipoproteins. The human genotype is divided into 6 types: E2/E2, E2/E3, E3/E3, E2/E4, E3/E4, and E4/E4. Among these types, E4/E4 carries the highest risk of Alzheimer's disease, followed by E3/E4. The genetic frequency of E4 among the Japanese population is 0.08. The frequency of E2/E3 is 0.92. Therefore, the frequency of homozygous E4 among the Japanese people is 0.082 = 0.0064, and the frequency of heterozygous E4 among Japanese is 2 × 0.92 × 0.08 = 0.147, which is about 1 out of 7 people.

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20.3.1

Motor control of skeletal muscles

Motor neurons have cellular bodies at the spinal cord and extend nerve fibers to skeletal muscles of the four limbs along with sensory nerves. They trigger muscle contraction by nerve transmission using acetylcholine released from neuromuscular junctions. One motor neuron usually innervates dozens of muscle fibers (muscle cells), meaning that these muscle fibers contract more or less at the same time. The strength of muscle contraction is controlled by the pulse frequency of the excitation sent by motor neurons. Excitation of motor neurons with high pulse frequency continuously releases a large amount of acetylcholine at the neuromuscular junctions, triggering excitation of muscle fibers. By accumulating the contractile force (tetanus) induced by frequency of excitation, muscle fibers can produce strong continuous contractile force. Furthermore, as transmission efficiency differs at neuromuscular junctions according to the muscle fiber (although they are controlled by the same motor neuron), the number of muscle fibers contracting will differ according to the pulse frequency of the excitation sent by the motor neuron. Using this mechanism, regulation of muscle contractile force is finely tuned according to the size of the load or movement.

The cerebrum does not detect and control all loads and contraction length, which are different per motor neuron. The cerebral cortex controls the issue of commands to start movement when required. Other prompt and minute control operations are carried out by the reflective mechanism by the spinal cord (Figure 20-13). The nerves in the motor cortex stimulate motor neurons that send signals via the motor neuron fiber (α fiber) to contract muscle fibers, and at the same time they also send commands to the neuron (γ fiber) that contracts the muscle spindle. Muscle spindles, located inside muscle tissues, are internal sensory receptors that sense changes in muscle length. They are also able to change their own lengths. The brain is unable to discriminate the difference between muscle spindle contraction caused by external force and that caused by internal mechanisms, and thus the muscle reacts in identical ways. Specifically, the stretch receptor in the muscle spindle reacts and sends signals to the spinal cord.

Figure 20-13 Examples of motor control

Output commands from the motor area send commands to specific automatic feedback control circuits rather than directly controlling the contraction of various muscles. This example illustrates that skeletal movements are organized on the whole by sending signals to the spinal reflex paths. The cerebral motor area sends signals to motor neurons that directly contract skeletal muscles (a) as well as muscles in the muscle spindle (A) (b). A reflex contracting the muscle occurs until the contracted muscle spindle relaxes. At the same time, a reflex occurs relaxing the muscle at the antagonistic opposite side, resulting in smooth skeletal movement (B).

Figure 20-14 Experiment investing activities of squirrel before and after damaging SCN

It was found that an animal continuously kept in dark conditions for 24 hours carried out activities at a long cycle of about 25 hours (circadian rhythm). Halfway through the experiment, the suprachiasmatic nucleus (SCN) area (left diagram) of the squirrel was damaged. The circadian rhythm of the animal disappeared completely and its activities became random. Excerpted from Animal Physiology (W. Hill et al.), Sinauer Associates, 2004, Fig. 10.17.

Next, the automatic circuit for the extension reflex of muscles is activated. Within the spinal cord, neurons (Ia fibers) originating from the muscle spindle form excitatory synapses with motor neurons of the muscle, and inhibitory synapses with antagonistic muscles. In other words, one feedback circuit is already formed here. When external force is suddenly applied to the muscle, causing the muscle to unintentionally stretch, the same circuit operates to maintain uniform muscle length. The central nerves of the motor cortex are dedicated to sending commands to this automatic controller from the outside of the circuit; in other words, they only send the expected muscle length information to the muscle spindles. Thus, the cerebrum is not a complex central control system, which monitors the movements of each and every muscle; instead, it leaves the automatic control work to the peripheral feedback circuits as much as possible to raise motor efficiency.

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20.3.2

Control of circadian rhythm

Let’s look at an example that controls behavior in general. Animals are known to have a biological clock. For example, if an animal is kept in a constantly dark environment, the animal will continue its daily activities in a cycle slightly longer than 24 h. This is called circadian rhythm (see Chapters 2 and 22). Normally, the biological clock of animals is reset every day by external brightness stimulus, allowing them to continue activities at a 24-h day/night rhythm. These activities are controlled by a very small area in the brain (Figure 20-14) called suprachiasmatic nucleus (SCN), located near the optic chiasm in animals (see Figure 20-12). SCN is a nucleus where neuron cell bodies concentrate, and is linked directly with the retina via optic nerve fibers. Once SCN receives inputs from the retina, it sends signals to the spinal cord and triggers the secretion of melatonin via the sympathetic nerve system. Melatonin is a hormone which increases in concentration just before waking, thereby enhancing the activities of the sympathetic nerves and the whole body. This SCN automatically divides time and turns melatonin secretion ON/OFF at a more or less 25-h cycle. Here too, animals have an autonomous control loop consisting of hormone secretion and body clock, so visual stimulus is used only to send reset signals to the command neurons of this circuit.

Various visual information processes are carried out in the retina, but most of its signals are transmitted to the primary visual cortex via structures called the optic nerve and lateral geniculate body (Figure 20-12). Some routes do not pass through this lateral geniculate body, including those projecting to the cerebral cortex via the superior colliculus (Figure 20-9) (related to unconscious visual functions) and visions that are projected to regions other than the cerebral cortex (such as pupillary reflex and circadian rhythm). All of the images that we are aware of as vision, however, are signals that arrive at the primary visual area via the lateral geniculate body.

The cerebral cortex consists of layered structures that are very much alike but have different roles. There are the primary sensory areas that process the simplest functions projected from sensory cells and higher sensory centers performing more complex activities such as extraction of features, determination of stimulus type, and referencing. These areas are located in layers adjacent to each other and stimulus information is exchanged regularly, eventually allowing higher information processing to be carried out. The ability of the brain to carry out various information processes in the same region, functioning as “hardware,” can sometimes be likened to the computer, which also performs varied activities using different programs running on one CPU. However, one major difference between the human brain and computer is that the brain is able to carry out parallel processing, as well as fuzzy processing that is incorrect at times.

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Schizophrenia

Schizophrenia, which is said to affect 1% of the world population, is characterized by breakdown of thought processes and behavioral disorders. Symptoms are characterized as positive or negative. For example, positive symptoms include delusion, hallucination, rambling, and inappropriate emotions, whereas negative symptoms include blunted affect, poverty of speech, curbing of interests, and memory problems. As a disease that has gained prominence in the 21st century, it is one of the heaviest burdens on societies. Given the high prevalence amongst identical twins, schizophrenia is suspected to be genetic; however, the specific genes involved have yet to be identified. In 1990, a case of schizophrenia caused by mutual translocation was reported, and the gene DISC1 was identified in the cut portion. Patients who have mutual translocation were found to have different and diverse conditions even within the same family, with symptoms ranging from schizophrenia, bipolar disorders and major depression. Autistic symptoms were also reported. The difficulty in determining the symptoms of schizophrenia is one of the reasons attributed to the poor progress in research on the disease. The following, however, introduces the results of a new analytical approach for schizophrenia research that applies molecular genetics. Presently, there are reports suggesting that schizophrenia can be caused by the deletion of genes such as ERBB4, SLC1A3, and RAPGEF4; duplication of CIT gene, and by SNP at the intron of the dysbindin gene. However, it is unknown how these genes are expressed in the brain, and why symptoms appear when they mutate. In recent years, schizophrenia caused by the copy number variations (CNV, see Selection 5 of Chapter 24) has been drawing attention. An increase/decrease in DNA fragments from 1 kbp to several Mbps is reported to not only cause simple gene deletions, but also to produce fusion proteins due to deletion of the regulatory region, changes in imprinting, and changes in genetic expression due to duplication. A recent study investigated whether new regions associated with CNV were deleted in schizophrenic patients by examining 10,000 parents and children. The results indicated that the deletion of 1q21.1 (long arm of chromosome 1 at position 21.1, hereafter the same), 15q11.2, and 15q13.3 (hemizygote) also poses the risk of schizophrenia. In addition, several cases of schizophrenia associated with the deletion of 12p11.23 and 16p12.1-12.2 have also been reported. As another example, 1 of 4 patients with velo-cardio-facial syndrome (VCFS) may demonstrate psychiatric symptoms resembling schizophrenia, autism, and attention-deficit hyperactivity disorder (ADHD). The deletion of 15q13.3 has been reported to cause mental retardation and autism, resulting in a wide range of psychiatric diseases.

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