DEFINITIONS OF TERMS Homeostasis tendency to relatively stable equilibrium. Feed-forward inhibition control mechanism whereby the output of one pathway inhibits the activity of another pathway. Negative feedback/feedback inhibition control mechanism whereby activity of a circuit ends up inhibiting the activity of the circuit. For a complete list of defined terms, see the Glossary. Workbook LESSON 4.5 WORKBOOK How do circuits regulate their output? Now that we have discussed an example of a neural circuit, let s take a closer look at how these circuits regulate their output. Circuits do this through the use of different arrangements of excitatory and inhibitory connections. The other sleep clue: time of day Recall that sleepiness is controlled by two factors: time of day and length of time our brains have been awake and active. We ve already discussed the first factor, so let s now explore the second time of day. Before we dive into our discussion of how time of day regulates sleep, let s first remind ourselves how our body regulates the activity of cells, tissues and organs. The activity of all of our bodies cells, tissues, and organs are regulated and integrated with each other. Homeostasis is the name given to the body s overall response to different stimuli. Because a number of different responses are integrated together the overall state is quite stable. For example, take a room whose temperature is regulated by a heater that is controlled by a thermostat. When the room is colder than the temperature the thermostat is set to, the thermostat turns the heater on, and the heater warms the room. Once the room reaches the set temperature, the thermostat turns the heater off. Because the production of heat feeds back to the thermostat and causes it to turn off, this process is called negative feedback or feedback inhibition. Negative feedback control systems are the most common homeostatic control mechanisms in our bodies, so it shouldn t come as a surprise that our nervous system uses negative feedback to control the output of neural circuits. Another type of regulatory process frequently used together with feedback inhibition is feed-forward inhibition. Feed-forward inhibition anticipates changes, improves the speed of the homeostatic responses, and minimizes fluctuations in the level of the variable being regulated. Feed-forward inhibition learns the meaning of cues from the external environment and responds to them. For example with our room analogy, feed forward control might learn that opening a particular door to the outside would make the temperature in the room drop faster than the opening an inside door. So it would learn to make the heater work faster if that door were opened. Not surprisingly, the first time the outside door were opened feed forward control would not know what the result would be, and the first fluctuations in temperature would be much larger than after it learns to anticipate the change. What are the two factors that control sleepiness? What is homeostasis? What are the two types of regulatory processes that our bodies use to control circuit activity? 122
DEFINITIONS OF TERMS Circadian recurring naturally on a twenty-four-hour cycle. Melatonin so-called ' hormone of darkness' released by the pineal gland. When light levels fall, melatonin levels rise. Preoptic nucleus (PON) nucleus in the hypothalamus that signals the pineal gland to release melatonin when light levels fall. Suprachiasmatic nucleus (SCN) nucleus in the hypothalamus that controls that circadian cycles of various body functions For a complete list of defined terms, see the Glossary. Workbook One very well characterized negative feedback loop occurs within our biological clocks which keep track of the time of day and help control our sleep-wake cycles. The signals for sleep the biological clock Our internal biological clock regulates the timing for sleep, keeping us awake during the day and making us sleepy at night. The clock cycles with approximately a 24-hour period, and so it is called circadian (circa diem is the Latin for about the day ). The major brain structure regulating the clock is in the tiny hypothalamus. The hypothalamus has many different brain nuclei that control many aspects of homeostasis. One of these nuclei the suprachiasmatic nucleus (SCN) coordinates the timing of sleep with the light-dark cycle (Figure 23). The SCN consists of two pinhead structures, one on each side of the brain, and acts as a master clock. The SCN nucleus sets the pace for daily cycles of activity, sleep, hormone release, and other bodily functions The SCN is linked to many different brain regions. The SCN receives information about the outside world s light-dark cycle through direct input from the eye via the retina. The SCN then passes on this information to the following brain areas, each of which is also involved in controlling our sleep-wake cycles: The preoptic nucleus (PON) located in the hypothalamus. When it is active the PON stimulates the pineal gland to release melatonin. Melatonin has been called the hormone of darkness because its levels rise at night. It is responsible for causing drowsiness. Thus, when light levels fall, melatonin levels rise and we feel drowsy. Figure 23: The circadian clock in the hypothalamus. The suprachiasmatic nucleus (SCN) receives information about light levels from the retina. When light levels are high, output from the SCN that regulates the timing of sleep is switched off. The sleep neurons in the ventrolateral preoptic nucleus (VLPO) located in the hypothalamus. As we ve already seen, when active the VLPO sleep neurons inhibit arousal neurons, causing us to go to sleep. At times when light levels are high, such as during daylight, the retina signals to the SCN, which then inhibits the pineal gland, preventing it from secreting melatonin. Because the hormone of darkness is not present, we feel awake. How are these regulatory processes similar? How are they different? What is melatonin? How is it involved in our need for sleep? 123
Workbook However, when light levels fall, the retina no longer signals to the SCN, and the SCN can no longer inhibit the pineal gland, which is now able to secrete melatonin (Figure 24). Because the hormone of darkness is present, we feel drowsy. A. During light B. During darkness Inhibits Figure 24: The SCN also controls the flip-flop switch. Light activates the SCN which inhibits the VLPO and prevents the pineal gland from secreting the hormone melatonin. However, in darkness, the SCN is not activated and therefore no longer inhibits either the VLPO or the pineal gland, which can now secrete melatonin. Together, the activity of the VLPO and the hormone melatonin promote sleepiness. SCN activity is regulated by genes that are called clock genes. The clock genes synthesize clock proteins. The clock proteins slowly enter the cell nucleus and stop the clock genes from synthesizing more clock proteins (Figure 25). But over a period of about 24 hours, these clock proteins break down and so the clock genes become active again and are able to synthesize more clock proteins. They slowly enter the nucleus etc. etc. This control of clock gene expression is a good example of feedback inhibition at the level of the individual cells in the SCN. Figure 25: Feedback inhibition controls the production of clock proteins. Clock genes express clock proteins which then affect behavior and other activities. When levels of clock proteins are high, they enter the nucleus and suppress the genes responsible for their production. Over time the levels of clock proteins fall, which removes the inhibition on the clock genes, so they can again synthesize more clock proteins. Inhibits The circadian clock in humans actually cycles at just over 24 hours, so the cellular clock must match the light-dark cycle. The cue for matching the cellular clock to the circadian clock is light. Neurons in the eye that are sensitive to light (photoreceptors) transmit signals to the SCN, which sets the clock genes so they match the environmental cues. If the clock genes fail to reset properly, the neurons in the SCN become out of sync with the environment and can produce various problems such as jet lag, seasonal affective disorder, and Monday morning blues. How does the SCN connect with the flip-flop switch? What is the biological clock? Where is it located? How does it control our need for sleep? 124
Workbook Biological clock disorders Jet Lag Travelers who cross multiple time zones rapidly (such as by plane) often suffer from jet lag (Figure 26). Jet lag has many unwelcome effects, including disrupting sleep, causing loss of concentration, poor motor control, slowed reflexes, nausea, and irritability. Jet lag happens because our circadian clock can t immediately adjust to the changes in the light cues that result from crossing time zones quickly. So, the clock is out of step with the cues in the new time zone. This conflict between external and internal clocks affects more than just the sleep-wake cycle. All the rhythms are out of sync, and they take a number of days to re-match (also known as re-entrain to) the new time zone. Eastward travel generally causes more severe jet lag than westward travel, because traveling east requires that we shorten our day and adjust to time cues occurring earlier than our clock is used to. Seasonal affective disorder (SAD) Seasonal affective disorder (SAD) is a form of depression that occurs at a certain time of year, when the hours of daylight decrease i.e. winter (Figure 27). The change of seasons in the fall brings on both a loss of daylight savings time (fall back one hour) and a shortening of the daytime. During this season of short days and long nights, too little bright light reaching the biological clock in the SCN causes some individuals to develop symptoms similar to jet lag but more severe. These symptoms include decreased appetite, loss of concentration and focus, lack of energy, feelings of depression and despair, and excessive sleepiness. Treatment with light boxes that artificially increase the length of daylight are very effective. Figure 26: Jet lag is the bane of frequent travelers because our circadian clocks can t automatically readjust to changes in light-dark cycles that happen rapidly with modern day travel. Figure 27: Seasonal affective disorder (SAD) is caused by lack of sunlight to reset our biological clocks. It can be helped by light therapy to stimulate summer, or at least brighter light conditions. How does jet lag happen? How does jet lag affect our sleep-wake cycles? How does SAD happen? How does SAD affect our sleep-wake cycles? 125
Workbook Monday morning blues By staying up later and sleeping in more than usual on the weekends, we provide our biological clocks with cues that push it toward a later nighttime phase. If we keep a late sleep schedule on both weekend nights, our internal clock can become two hours or more behind our usual weekday schedule. This delay in our clocks (not to mention facing another work week) makes it very difficult to wake up on Monday morning a condition called the Monday morning blues (Figure 28). To cure the Monday morning blues, it is recommended we stay on our weekday sleep schedules on the weekends. (We know it s hard, but it s what recommended in order to not throw off your biological clock.) Figure 29: People who work the night shift often encounter behavioral problems like jet lag and SAD. Shift work Figure 28: Monday morning blues. The circadian clock is not set exactly at 24 hours, so if we go to bed and sleep late on the weekends, our internal clock becomes behind schedule, making Monday mornings particularly miserable. Humans are normally active during daylight hours and sleep at night. This pattern is called diurnal activity. For humans and other diurnally active animals, light signals the time to awake, and sleep occurs during the dark. People who work the night shift may experience mental and physical difficulties similar to jet lag and SAD because their internal clocks and external daylight and darkness signals, are no longer synchronized (Figure 29). How do the Monday morning blues happen? How do they affect our sleep-wake cycles? How does shift work affect our sleep-wake cycles? 126
STUDENT RESPONSES What are the benefits of using feedback and feed-forward inhibition to control circuit activity? Remember to identify your sources How do our biological clocks use feedback and feed-forward inhibition to control our sleep-wake cycles? Workbook 127