The Ins and Outs of Ethanol

Last post for PHYL3004! This post will discuss the favourite drug of many students worldwide- ethanol!

What factors govern absorption of ethanol into the blood stream?

Ethanol is quite water-soluble due to its -OH group. It is also fairly lipid-soluble due to its CH₃CH₂- group. As ethanol is a small, uncharged molecule, it is also able to cross cell membranes and have an effect on the various tissues of our body without requiring any kind of chemical modification.

Ethanol is absorbed into the circulation via passive diffusion. Most (~80%) is absorbed through the small intestine, whereas the remaining 20% is absorbed in the stomach wall. As such, factors governing ethanol absorption are the same as factors governing diffusion in general: concentration gradient, permeability, and surface area. Most ethanol is absorbed in the intestines because the intestines have a much larger surface area than the stomach.

You've probably heard the advice to "never drink on an empty stomach." But why is this? Ethanol is absorbed more slowly after eating. This is because the presence of food in the stomach delays gastric emptying, allowing ethanol to remain in the stomach longer, where it is absorbed at a slower rate. The slower rate of ethanol absorption allows the body more time to metabolise any ethanol that has already been absorbed, which also reduces the peak of blood alcohol concentration.

The distribution of ethanol into various tissues depends on the relative water content of the tissue. Ethanol is both water- and lipid-soluble, as I said earlier, but it is more water-soluble than lipid-soluble. Therefore, it is highly soluble in the blood but has low solubility in fats. Females tend to have a reduced body water compared to males due to increased fat mass and decreased muscle mass (muscle cells have more water than fat cells). Therefore, blood alcohol concentration increases more for females than for males, which is why females are recommended to have fewer drinks than males. Similarly, other populations with reduced muscle mass (e.g. elderly) may also be more susceptible to the effects of alcohol.

What are the determinants of peak blood alcohol concentration?

Blood alcohol concentration is, well, the concentration of alcohol in the blood. It is usually given as a percentage. The legal driving limit in Australia is 0.05%, or 0.05g per 100mL of blood.

I've already hinted at a couple of determinants of peak blood alcohol concentration: stomach fullness and the proportion of fat and muscle. The obvious other determinant of blood alcohol concentration is the number of standard drinks consumed. 1 standard drink is equivalent of 10g of pure alcohol.

Why is the brain susceptible to the effects of ethanol (beginning with the blood-brain barrier)?

Before ethanol gets anywhere near the central nervous system, it already has effects on sensory nerves. Remember how capsaicin stimulates the sensation of heat? Ethanol works through the same pathway, stimulating TRPV1 receptors (i.e. vallinoid receptors, the same receptors stimulated by capsaicin).

Ethanol can cross the blood-brain barrier as it is a small, uncharged molecule. Once in the brain, it causes inhibition by enhancing the activation of inhibitory GABA_A receptors and suppressing the activation of excitatory glutamate receptors. Alcoholics have an adaptive response in which their brain increases its level of excitation. During withdrawal, these compensatory excitatory effects persist long after inhibition by alcohol has ceased, causing withdrawal symptoms.

How is ethanol removed from the body?

Ethanol is not stored- it just hangs around until it gets removed. Most of this removal (~90%) is via metabolism, most of which occurs in the liver. In the liver, alcohol is converted into acetaldehyde by alcohol dehydrogenase (ADH), and acetaldehyde is then converted into acetate via aldehyde dehydrogenase (ALDH). Both of these reactions require NAD+ as a cofactor. As ADH is also expressed in the stomach, a small amount of ethanol is metabolised in the stomach before absorption, reducing the total amount of ethanol absorbed. Interestingly enough, the efficacy of ADH is reduced in alcoholics.

The remaining ~10% of ethanol is excreted unchanged in the urine, breath or sweat. The concentration of ethanol in the blood is the same as in the urine. Urinary clearance is only around 1mL/min, so it's a good thing that we have so many other mechanisms to get rid of alcohol.

Removal of alcohol via the breath is quite unique. While oxygen and carbon dioxide enter the alveoli via the pulmonary circulation, ethanol actually diffuses across the airways from the bronchial circulation. We know this because a graph of breath ethanol concentration shows an exhalation pattern more similar to airway gas exchange than alveolar gas exchange. In alveolar gas exchange, there is an initial plateau (dead space air), a steep increase in concentration (due to transition from dead space air to alveolar air) and a final plateau (alveolar air). In airway gas exchange, like in ethanol, the initial plateau is absent, the steep increase represents the conducting airways, and the plateau phase represents alveolar air that has been modified in the exchange zone. Furthermore, the location of gas exchange appears to depend on the liquid to gas partition ratio, or λ. The blood and water solubility for ethanol (which is exchanged in the airways) is far greater than for oxygen or carbon dioxide (which are absorbed in the alveoli).

In airway exchange of ethanol, ethanol first moves into the airway surface liquid that lines the airways and humidifies inspired gas. Ethanol then moves down the airways during inspiration (as this means that it is moving down its concentration gradient). Movement of ethanol down the airways causes saturation of alveolar air with ethanol, so there is no concentration gradient in the alveoli. Therefore, there is no alveolar exchange of ethanol.

And I think that's it! Good luck in exams!

Obesity and the Respiratory System

Last week of PHYL3004 content! That went by quickly...

In this post, we will be talking about the effect of body fat on obesity. In particular, we will be talking about subcutaneous fat. (Visceral or intra-abdominal fat presents its own problems, as mentioned here.) Body fat distribution varies a bit between males and females- males tend to have more belly fat ("apple shape"), whereas women tend to have more fat around the hips ("pear shape"). Since fat adds mechanical load to the respiratory system, opposing the contraction of respiratory muscles, it is important to know how and why obesity impacts the respiratory system.

Before continuing further, it might help to brush up on mechanics of breathing and lung volumes if you don't remember from previous semesters.

Effect of obesity on lung volumes

In obesity, TLC (total lung capacity) decreases. Most of this decrease occurs in FRC (functional residual capacity), particularly in ERV (expiratory reserve volume).

Mechanism(s) for reduced respiratory system compliance and respiratory muscle function

In obesity, lung and chest compliance decrease for several reasons. Fat directly decreases compliance, and increased pulmonary blood flow, which is associated with high BMI, also decreases compliance. As such, lung function changes in obesity are similar to those in restrictive lung diseases, where compliance is reduced. FVC (forced vital capacity) and FEV1 (forced expiratory volume in 1 second) both decrease in both obesity and restrictive disease. However, in obesity, the FEV1/FVC ratio usually remains unchanged, whereas this ratio may increase in restrictive disease (as FVC may decrease to a greater extent than FEV1).

Respiratory muscles, such as the diaphragm, can be negatively impacted by obesity. A large abdominal mass will push the diaphragm upwards, stretching it in the process. If the diaphragm is stretched beyond its optimum length, force will decrease (I've discussed why here).

Interrelationship between obesity, lung volume, airway resistance and airway hyperresponsiveness

Obesity tends to decrease lung volume (as discussed earlier) and thus decrease the total radius of the airways. Since resistance is inversely proportional to airway radius, a decrease in radius causes an increase in airway resistance, which in turn increases difficulty in breathing, particularly during exercise. As such, tidal volume may fall in extremely obese individuals (though it generally remains unchanged).

Low lung volumes have many more negative effects. Breathing at low lung volumes causes alveoli to collapse. This is known as "atelectasis." According to the LaPlace equation (pressure = (2*tension)/(radius)), reducing the alveolar radius increases pressure and tendency to collapse.

Yet another negative impact of low lung volumes is that when lung volume is low, the amount of load placed on airway smooth muscle is also low. As decreased afterload increases shortening (see here), muscle force is more likely to become greater than the opposing load, resulting in narrowing. (If muscle force was smaller than opposing load, bronchodilation woudl result instead.) This phenomenon is also referred to as "airway hyperresponsiveness," and can be quantified using PC20 (see here). Weight loss has been shown to improve PC20.

Changes in upper airway function in obese subjects and the association with obstructive sleep apnoea

The pharynx is more prone to collapse in patients with high BMI. The pharynx, which is quite floppy compared to the nasal cavity (which is surrounded by bone) and the trachea (which is surrounded by cartilage), is supported by the genioglossus muscle (tongue) and other pharyngeal muscles. These muscles provide dilatory pressure that keeps the pharynx open, opposing negative luminal pressures and positive tissue pressures. In obesity, the tissue pressure increases, making it more likely that the pharynx will collapse. The luminal pressure that causes pharyngeal collapse is known as the Pcrit, or critical closing pressure. A lower Pcrit is better.

Pharyngeal muscles are mainly driven by reflexes. These muscles respond to negative luminal pressures (i.e. pressures that pull the lumen in), rising carbon dioxide and falling oxygen levels. Their activity is reduced during sleep, which is why obstructive sleep apnoea can be a problem in some patients, particularly in obese patients. Patients with obstructive sleep apnoea may be helped with CPAP machines, which maintain high airway pressure. Unfortunately, they are also uncomfortable to use.

The decreased lung volumes in obesity can also impact the pharynx. When lung volume decreases, tracheal tension, which is the tension of the trachea pulling on the pharynx, also decreases. As such, the compliance and tendency to collapse of the pharynx also increase.

Only one more lecture to go for this unit!

Circadian Rhythms: Adaptations to Pregnancy and Disruption by Obesity

I've already spoken about circadian rhythms here, but time to go into more detail I guess...

Control of circadian rhythms

The main "clock" involved in circadian rhythms is in the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. This SCN clock is entrained by "zeitgebers," which I'm pretty sure is German for "timers" or literally "time-givers." These zeitgebers are mainly environmental cues, such as light, food and temperature. Zeitgebers induce changes in molecular clock genes, such as Bmal1 and Clock.

Just like all other genes, Bmal1 and Clock are transcribed in the nucleus and translated in the cytoplasm. In the cytoplasm, they dimerise and then return to the nucleus, where they induce transcription of Per and Cry genes. After translation in the cytoplasm, Per and Cry also dimerise, and return to the nucleus where they downregulate Bmal1 and Clock. As such, Bmal1/Clock genes tend to peak when Per/Cry is at a minimum, and vice versa. Bmal1/Clock heterodimers can also activate accessory clock genes, such as Rev-erbα and Rorα. Rev-erbα can inhibit Bmal1, whereas Rorα can stimulate Bmal1 and Clock. All of these clock genes have further effects on clock-controlled genes that are found all over the body.

Clock genes are important in metabolic homeostasis. If Clock is deleted, hyperphagia and metabolic syndrome results. Deletion of Bmal1 results in altered carbohydrate metabolism and, as mentioned here, extreme weight loss. Deletion of Cry1 and Cry2 can result in an inflammatory phenotype. Food intake can also affect clock gene expression: for example, Bmal1, Clock and Per2 have all been shown to decrease with a high-fat diet.

Maternal adaptations to pregnancy

There are many changes that occur during pregnancy, mostly due to the endocrine placenta. In the first phase of pregnancy, a lot of anabolism occurs in order to store nutrients for later use. In the second phase, a lot of catabolism occurs in order to supply the fetus with nutrients. Since we know that clock genes are important in metabolism, the next step is to see whether or not circadian rhythms are important in the metabolic changes during pregnancy. Most experiments have been done in rats, using cosinor analysis (kind of like a linear regression but with the cosine function rather than a straight line). The attributes that experimenters look for are the mesor (average over the cycle) and amplitude (distance from the mesor to the base or peak of the curve).

Studies in rats have shown that body temperature circadian rhythm appears to be somewhat disrupted during pregnancy (though our lecturer didn't really explain how...) and decreases over the course of pregnancy. On the other hand, circadian rhythms of glucocorticoids are maintained, but absolute levels are increased (as mentioned here, glucocorticoids are important for fetal organ maturation). Gene expression in maternal livers and adipose tissue are also altered: in early pregnancy, maternal liver Bmal1 and Per1 increase in both mesor and amplitude. At the same time, adipose Bmal1, Per1, Per2 and Rev-erbα decrease in mesor, and Bmal1 and Rev-erbα also decrease in amplitude.

Since shift workers have been found to have an increased risk of preterm birth, low birthweight and spontaneous abortion, rat studies have also looked at how disruptions to the circadian rhythm can affect pregnancy. Sure enough, corticosterone, glucose, insulin, leptin, free fatty acids, triglycerides and cholesterol have all been found to be disrupted by disrupting the circadian rhythms of rats. The maternal liver has been found to have disrupted Bmal1 and Per1 expression, while the fetal liver has been shown to have disrupted Per2 and Rev-erbα expression. The offspring were also found to have an increase in weight gain and possible insulin resistance.

Obesity

Roughly 50% of women in the USA enter pregnancy either overweight or obese, which is a real problem as obesity is associated with gestational diabetes, preeclampsia (hypertension and proteinuria), miscarriage and abnormal birth weight. Studies in rats have shown that inducing obesity with a poor diet can alter clock gene expression, which in turn can alter metabolism. Altering metabolism may in turn affect fetal growth, as detailed here. In rats fed a poor diet, the mesor and amplitude of clock genes decreased. There was also a phase advance (left shift in the graph) in hepatic clock gene expression.

Effects of the gut microbiome on control of organ and tissue function

Last four lectures for PHYL3004! These last few topics are a bit all over the place, but I guess that just adds to the fun I guess...?

So why are researchers looking at the gut microbiome? The gut microbiome has become of interest due to the actions of Toxoplasma gondii. Toxoplasma gondii is a single-celled gut parasite in cats. Rodents can become infected with T. gondii by contact with cat faecal matter. Once infected, rats lose their normal fear of cats and may even become sexually aroused by cat urine. This makes them more likely to spend time around cats, resulting in them becoming cat food and completing the life cycle of T. gondii.

The gut microbiome

As I've already written about here, we have a helluva lot of bacteria living on and in us. Usually, initial colonisation occurs at birth during vaginal delivery, as well as during breast feeding. In fact, babies delivered via a C-section have been found to have a higher risk of obesity and diabetes, and it has been suggested that the gut microbiome may have been a factor. The three main types of gut bacteria are Prevotella, Bifidobacteria and Bacteroidetes, and each has a preference for a different kind of food. Prevotella prefer carbohydrates, Bifidobacteria prefer dietary fibre, and Bacteroidetes prefer fats. Changes in diet can therefore change the relative proportions of these different bacterial species.

Effects of gut bacteria on eating behaviour

Competition for nutrients provides a selective advantage to bacteria that can influence their host to consume more of the food that they like. For example, if Bacteroidetes can influence us to eat more fat, that will help Bacteroidetes survive in the long term. Indeed, gut bacteria may manipulate our reward pathways, produce toxins that alter mood, alter our taste receptors and/or hijack vagal transmission in order to manipulate our eating behaviour. Many bacteria also manufacture peptides with very similar structures to hormones that regulate appetite, such as leptin and neuropeptide Y. They can also secrete short-chain fatty acids (SCFAs), which can activate enteric nerves.

Interestingly enough, obesity is associated with reduced bacterial species numbers and decreased genetic diversity of gut bacteria. Bacterial transfer experiments in mice have also shown that mice who are given fecal transplants from obese humans are more likely to gain weight than mice who are given fecal transplants from lean humans, even if food consumption doesn't change. One possible explanation is that certain bacteria can produce SCFAs from fibre, creating an increased amount of digestible fat and an increase in adiposity.

Thankfully, we can probably use this to our advantage. Mice who are fed probiotics ("good bacteria") are less likely to gain weight, regardless of whether they eat a high- or low-fat diet. Probiotic treatment may also improve glucose control in mice fed a high-fat diet. Probiotics appear to increase faecal secretion of SCFAs, such as butyrate. Butyrate also increases release of GLP-1, an incretin released from epithelial cells which can increase insulin release.

Effects of gut bacteria on other behaviours

As I mentioned earlier, the whole reason why we're looking at the effects of the microbiome is because it appears to have impacts on rats and their fear (or lack of) of cats. Some other studies involving germ free (GF) mice, which are specially raised to have no gut bacteria, have shown that these mice have a greater release of ACTH and corticosterone compared to controls. The stress response of GF mice is normalised once given a faecal transplant. Experiments with BALB/c mice (which are naturally more timid) and Swiss mice (which are naturally less timid) have also shown a link between gut bacteria and timid/anxious behaviour, as measured with a "step down test." In the "step down test," mice are put on a little step, and are timed to see how long it takes for the rat to step down and start exploring its surroundings.

Several possible explanations for the effects of gut bacteria on behaviour have been proposed. Gut bacteria can produce neurotransmitters such as serotonin, as well as neurotransmitter precursors such as tryptophan. They can also produce SCFAs which, as I've said before, have neuro-active properties. They may also be able to activate the vagus nerve directly, and in fact vagotomy can eliminate some of the behaviour-related changes induced by probiotics (which I'll mention in a bit). Gut bacteria can also modulate the immune system, and all of those cytokines may have effects on the CNS.

Just like with satiety and weight gain, probiotics can play a role in behaviour. Probiotic treatment with Lactobacillus rhamnosus has been found to decrease corticosterone levels and anxiety and depression-like behaviour in mice. There were also region-dependent alterations in GABA mRNA in the brain, which may explain the behavioural changes.

Possible role of gut bacteria in autism spectrum disorder (ASD)

Believe it or not, the role of the microbiome has also been investigated in patients with autism. Autism patients often have gastrointestinal symptoms, an altered gut microbiome, and alterations in SCFA production. In animals, high doses of SCFAs has been shown to produce "autistic-like" behaviour which can be reversed by probiotic treatment.

The main animal model for ASD is maternal immune activation (MIA), in which pregnant mice are injected with poly(I:C), which is structurally similar to viral dsRNA. Offspring have gut barrier defects and microbiota alterations, as well as a large elevation in 4-ethylphenylsulfate (4EPS). 4EPS is secreted by gut bacteria in these "ASD mice," and when injected into healthy mice, 4EPS seems to result in higher levels of anxiety. Treatment with the probiotic bacteria Bacteroides fragilis (BF) appeared to correct gut permeability problems and normalise some communicative behaviours, though social interaction didn't change. It is hypothesised that increased gut permeability, combined with increased 4EPS, may lead to increased 4EPS in the circulation and in the CNS, which in turn may lead to autistic behavioural traits. Obviously, however, this area of research is still in its infancy, and these experiments were only done on mice. Additionally, autism is thought to be a result of many factors, including genetics, and so it is unlikely that there is a simple solution for all cases of autism.

Kisspeptin

In my last post, I wrote about GnRH (gonadotrophin releasing hormone), which stimulates the release of LH and FSH from the anterior pituitary. In this post, I will be talking about kisspeptin, which stimulates the release of GnRH from the hypothalamus.

Effects of kisspeptin on GnRH

Kisspeptin, which is encoded by the Kiss1 gene, comes in several forms, but the most common form is Kisspeptin-54 (a.k.a. metastin). Kisspeptin binds to the GPR54 receptor (a.k.a. Kiss1r), expressed on most GnRH neurons. In fact, GnRH neurons are almost always located next to kisspeptin neurons. Most kisspeptin-releasing neurons are located either in the more rostral AVPV (anteroventral periventricular nucleus) or in the more caudal ARC (arcuate nucleus). The AVPV and ARC neurons are thought to have somewhat different effects.

ARC kisspeptin neurons project to the median eminence, where they may impact the release of GnRH. ARC neurons, in contrast to AVPV neurons, also express neurokinin B and dynorphin, and are thus sometimes known as KNDy neurons (stands for "Kisspeptin, Neurokinin B, Dynorphin"). They also have receptors for these neurotransmitters, so they can act on themselves in an autocrine fashion. Neurokinin B is thought to stimulate pulse generation by KNDy neurons, whereas dynorphin is thought to inhibit it. KNDy neurons may be stimulated by pheromones (chemicals excreted by other animals).

ARC and AVPV kisspeptin neurons are also affected differently by sex steroids, as I will talk about in the next section.

Regulation by sex steroids

Kiss1 cells have receptors for sex steroids (GnRH neurons do not). These sex steroid receptors include ERα (oestrogen receptor α), ERβ (oestrogen receptor β), PR (progesterone receptor) and AR (androgen receptor). All four receptors are found in ARC kisspeptin neurons, but the AVPV neurons mainly have only ERα and ERβ receptors.

An interesting finding in female mice is that ARC neurons appear to be stimulated by low oestrogen, whereas AVPV neurons appear to be stimulated by high oestrogen. It has been suggested that ARC neurons may be responsible for negative feedback, whereas AVPV neurons may be responsible for positive feedback.

Another interesting finding is that androgen receptors, at least in mice, may be important in Kiss1 expression. Female mice with androgen receptor knockout have reduced Kiss1 expression in the AVPV and increased Kiss1 expression in the ARC relative to wild-type mice.

Puberty

I don't think there's much to say here, other than that puberty is thought to be stimulated by kisspeptin binding to GPR54 receptors. Moving on...

Energy balance

Kisspeptin may also be involved in energy balance and satiety, which is a topic that I've spoken about here and here. The main neurons involved in satiety are Agrp/Npy neurons, which are orexigenic (appetite-stimulating), and Pomc/Cart neurons, which are anorexigenic (appetite-inhibiting). Kiss1r knockout mice have been found to have an increase in Pomc expression, which means that they tend to eat less. Despite this, however, they tend to gain weight. The weight gain may be due to reduced energy expenditure due to less UCP1 expression (a protein I have spoken about here).

GnRH (Gonadotrophin Releasing Hormone)

This week we'll be delving into the details for two reproductive hormones: GnRH and kisspeptin! For the purposes of this post, we'll be discussing GnRH.

GnRH neurons are scattered throughout the hypothalamus, with the highest concentration in the preoptic area of the hypothalamus (the preoptic area is near the optic chiasm). Interestingly enough, GnRH neurons actually originated from the olfactory epithelium in the nose before migrating into the hypothalamus. It is thought that neural cell adhesion molecules and cytokines may help influence axonal outgrowth and brain development.

One of the most important cytokines in GnRH neuron development and migration is probably SDF-1. SDF-1 and its receptor, CXCR4, are highly expressed during development in the cerebellum, hippocampus, neocortex and nasal compartment. CXCR4 and/or SDF-1 gene deletions are embryolethal.

GnRH neurons are very unique in their morphology. They have two long, axonal-like projections that go to the median eminence (the network of blood vessels connecting the hypothalamus and anterior pituitary- see here), but a closer inspection of biotin-stained neurons suggests that these axonal-like projections might actually be more dendritic in nature as they have structures known as "dendritic spines." As such, these projections are sometimes called dendrites or "dendrons."

GnRH neuronal "dendrons" are mostly in close apposition to "dendrons" from other GnRH neurons, forming "dendritic bundles." "Dendrons" also share synapses (i.e. they synapse onto the same axon from another neuron). These features help GnRH neurons to communicate with each other, which might help coordinate the pulsatile release of GnRH. "Dendrons" also extend outside the blood-brain barrier into the OVLT, which might help these neurons to obtain input from external stimuli.

As mentioned before, "dendrons" have dendritic spines. Dendritic spines are areas where neurons receive input, and are usually found in areas with GABAergic or glutamatergic transmission. The number of spines can fluctuate- there is a dramatic increase before puberty, and there are also increases in spine density around the time of the GnRH/LH surge in activated neurons.

Welp, that was a short and sweet post. Less typing! Yay!

Determinants of Hormone Control

In my last post for PHYL3004, I spoke about one class of hormones (the steroids). In this post, I will be covering eicosanoid and protein hormones.

Eicosanoids

Eicosanoid hormones are derived from arachidonic acid, which is a constituent of cell plasma membranes. Eicosanoids include leukotrienes, thromboxanes, prostacyclin and prostaglandins. I have covered all of these hormones here. The most important eicosanoids for the reproductive system are prostaglandins, which are involved in ovulation and uterine contractions.

Proteins

Proteins are chains of amino acids. I've written far more detail than you need to know for this unit about protein structure here, and about protein synthesis here. Proteins are hydrophilic and generally don't need binding proteins to transport them around the blood. They cannot, however, readily diffuse into cells, so they usually bind to an external membrane-bound receptor, which then activates some second messengers. These second messengers usually increase calcium levels or act as transcription factors in order to carry out their effects.

Gonadotrophins

The main gonadotrophins that you need to know are luteinising hormone (LH), released from the anterior pituitary, follicle-stimulating hormone (FSH), also from the anterior pituitary, and human chorionic gonadotrophin (hCG), from the syncytiotrophoblast (a structure formed during implantation of the blastocyst into the endometrium). All of these hormones have two chains (an alpha- and a beta-chain), and the alpha-chain is the same for all of the hormones. I've written more about LH and FSH here. hCG acts on luteal cells in the ovary to maintain progesterone, and on Leydig cells in the fetal testis in order to increase androgen production and testis development.

Somatomammotrophins

Somatomammotrophins are involved in tissue growth and function. The main somatomammotrophin is prolactin, released from the anterior pituitary. It is involved in lactation. If prolactin levels are high, fertility is suppressed.

Cytokines

Cytokines are often thought of as the main signalling molecules for the immune system, but they can do more than that. Inhibin is a cytokine that is involved in the reproductive system. It is released from granulosa cells (in females) or Sertoli cells (in males), and is involved in guiding gamete development and in gonad-pituitary interactions.

Oligopeptides

Oligopeptides are small peptides that are usually derived from cleaving a larger polypeptide precursor. Examples include GnRH, a highly-conserved 10 amino acid peptide that controls gonadotrophin secretion, and oxytocin, a posterior pituitary hormone involved in parturition, milk letdown and bonding.

Determinants of Hormone Action

The main determinants of hormone action are transport, blood concentration, secretion patterns and receptor expression, so let's get started!

Transport

As mentioned before, steroid hormones generally need a carrier protein to move around the blood, whereas proteins can normally move around by themselves. Only unbound hormones are biologically active.

Blood concentration

The blood concentration of hormone = production rate / clearance rate. Clearance may be due to hormone metabolism, which mainly occurs in the liver, but a small amount of metabolism can occur in the lung during respiration.

Secretion patterns

Most reproductive hormones are secreted in a pulsatile (on/off) manner. Some may follow a kind of circadian (~24hr) rhythm. Testosterone has a somewhat circadian pattern in younger males, but not so much in older males. However, the significance of this is still unknown. Pulsatile release is very important for some hormones, such as GnRH. If GnRH was secreted continuously, receptors would be down-regulated, and LH (a hormone "downstream" of GnRH in the signalling pathway) would decrease.

As you hopefully know by now, female fertility is episodic, with a monthly cycle in ovarian activity. Meanwhile, males pretty much have repeated pulsatile release of hormones from puberty onwards.

Receptor expression

Hormones can only have an effect if they bind to their target. Therefore, the number of targets (receptors) present is related to the strength of the effect. As I just mentioned, continuous release of GnRH can result in downregulation of GnRH receptors and therefore a decrease in the effectiveness of this hormone. Progesterone has the opposite effect: it can upregulate progesterone receptors on the endometrium.

Control of the Endocrine System

The main control systems are simple control, negative feedback, positive feedback and inhibitory control.

Simple control

In simple control, one hormone stimulates another. For example, GnRH stimulates LH.

Negative feedback

See previous post: Control Systems 1

Both males and female reproductive systems use negative feedback.

Positive feedback

See previous post: Control Systems 1

The female reproductive system can use positive feedback in ovulation and in childbirth.

Inhibitory control

In inhibitory control, an inhibitory factor prevents the release of a hormone. For example, dopamine acts as an inhibitory factor preventing the release of prolactin. Therefore, dopamine agonists such as bromocriptine may be considered in the treatment of hyperprolactinaemia (see here).

Reproductive Endocrinology

This lecture was mainly a refresher to get us stuck into the topic, so hopefully this post will be easy to write...! (Also- 500th post! 0_o)

Hormone Action

See previous post: Biochemical Messengers

Steroids

Steroids are lipid-soluble hormones that are derived from cholesterol. Some examples of steroid hormones include progesterone, aldosterone, cortisol, testosterone and oestradiol. As they do not dissolve well in water, roughly 95% of steroid hormone in the blood is bound to a carrier protein. The remaining 2-5% is free hormone that can diffuse into cells. Steroids usually bind to an intracellular receptor, which then diffuses into the nucleus and acts as a transcription factor. (For more details, see here.)

Progestagens

Progestagens are a type of steroid that includes progesterone. Progesterone is the most potent progestagen (i.e. has the highest affinity for its receptor). Other progestagens include 17α-hydroxyprogesterone (17α-OHP), which is around 40-70% as potent as progesterone, and 20α-hydroxyprogesterone (20α-OHP), which is only around 5% as potent as progesterone. Progestagens are particularly important in gestation, thickening of the endometrium in the second half of the menstrual cycle, and negative feedback on pituitary secretion of FSH and LH.

Androgens

Androgens include 5α-dihydrotestosterone (DHT), which is the most potent, testosterone, which is the most common but is only 50% as potent as DHT, androstenedione, which is 8% as potent as DHT, and dehydroepiandrosterone (DHEA), which is only around 4% as potent as DHT. Testosterone can be converted into DHT by 5α-reductase (see here for more information). Androgens are mainly important in the development of secondary sex characteristics, such as male genitalia, body hair, and so on. They are also anabolic and have negative feedback on pituitary secretion of FSH and LH.

Oestrogens

Oestrogens include oestradiol 17β, which is the most common and the most potent, oestriol, a common hormone in pregnancy which is only around 10% as potent as oestradiol, and oestrone, which is only around 1% as potent as oestradiol. Oestrogens are all formed from androgens via the action of an enzyme called aromatase. The functions of oestrogens include development of the endometrium during the first half of the menstrual cycle, increasing the water content of cervical mucus, and providing negative feedback to the pituitary.

Corticosteroids

Corticosteroids aren't normally associated with reproduction, but they may have some roles in the reproductive system. Corticosteroid levels increase during gestation and are important for fetal organ maturation. It has also been suggested that corticosteroids may be involved in the onset of parturition (labour), maternal behaviour, and suppression of the reproductive system, but further research is needed to confirm these.

Nociception and Pain

Review the physiology of nociception and forms of stimulus energy that activate them

Nociception (excitation of sensory neurons by potentially damaging stimuli) is caused by activation of nociceptors, which can be activated by mechanical, thermal, and/or chemical energy. Nociceptors are found in the skin and also in deep tissues, and respond to different stimuli (some respond to only one type of stimulus, while others are polymodal- that is, they respond to multiple types of stimuli). Nociceptors that respond to mechanical stimuli tend to have relatively high thresholds compared to the other types of nociceptors.

Define the difference between nociception and pain

Nociception, as I just mentioned, is the excitation of sensory neurons by potentially damaging stimuli. Pain is a subjective perception, which may or may not occur in the presence of nociception as it can be modulated independently.

Explain the physiological basis of fast and slow pain and central pain pathways

"Fast sharp" pain and "slow dull" pain are caused by different nerve fibres. "Fast sharp" pain is caused by Aδ fibres, which are myelinated (and therefore fast) and have small receptive fields. "Slow dull" pain is caused by C fibres, which are unmyelinated and have larger receptive fields.

I didn't quite understand the central pain pathways (neuroscience is not my forte), but to my understanding, the pathway that has been studied the most is the spinothalamic pathway. Sensory nerves cross over in the spinal cord and travel to the thalamus, and then to the primary somatosensory cortex, association cortex, and so on. There are also projections to the reticular formation and central lateral thalamus, which are responsible for arousal and autonomic responses, and projections to the insula and cingulate cortex, which are responsible for emotional responses.

Another important point to touch on is the concept of "referred pain"- the idea that we might get pain in an area other than the affected area (e.g. pain in the left arm during a heart attack). "Referred pain" might be due to convergent wiring- sensory nerves from the skin and the affected organ synapse onto the same interneuron in the spine, and the brain can't figure out where the signal originated from, so you perceive the pain as coming from all of the regions that send signals to that interneuron.

Describe the mechanisms of hyperalgesia and allodynia

Hyperalgesia is increased intensity of pain from normally painful stimuli, whereas allodynia is pain from normally non-painful stimuli. Hyperalgesia and allodynia may be due to peripheral tissue damage, lesions to dorsal roots or alterations in the excitability of central circuits.

First, let's look at peripheral tissue damage. When tissue is damaged, it releases a whole bunch of stuff, like potassium, bradykinin, serotonin, and prostaglandins. All of these substances can increase the excitability of nociceptors. Nociceptors can also release substance P, which stimulates histamine release from mast cells, which also increases the sensitivity of nociceptors. Therefore, peripheral tissue damage can cause hyperalgesia. Even surrounding undamaged tissue can experience hyperalgesia.

I don't really have any examples of lesions to dorsal roots, but I do have an example for an alteration in the central circuit. Lesions to the thalamus can cause thalamic pain syndrome, which is chronic severe pain caused by lesions to the thalamus. Other kinds of pain that occur in the absence of nociception include phantom limb pain, and possibly also migraines.

Explain some mechanisms of modulation of pain and pain relief including intrinsic analgesic pathways

As well as nociceptive fibres, we also have non-nociceptive afferents, such as Aα and Aβ fibres. Non-nociceptive fibres can activate inhibitory interneurons, reducing the transmission of pain signals. Aα and Aβ fibres can be activated by rubbing the skin.

Descending "analgesic pathways" can also help modulate pain. These pathways mainly use norepinephrine and serotonin, and can act via two main pathways. Firstly, they can directly inhibit transmission of nociception (just like Aα and Aβ fibres), or they can indirectly inhibit it via enkephalin-releasing interneurons. Enkephalin binds to opiate receptors, and can influence the amount of Ca²⁺ uptake (and therefore neurotransmitter release) in presynaptic nociceptive neurons, as well as hyperpolarise post-synaptic neurons. Opiates relieve pain by activating the same pathway. (See here for more information on analgesic drugs.)

Sensorimotor Integration and Balance

Explain and compare the feed-forward and feed-back mechanisms of postural control

Feed-back mechanisms compensate for a loss of posture. When you lose posture, sensory systems detect this, and a compensatory response occurs. We seem to have a "bottom-up" strategy for this: we stabilise our ankles first, then our knees, then hips, trunk, and so on.

Feed-forward mechanisms are used in voluntary movements, and improve with learning. Feed-forward mechanisms can predict a disturbance, and over time reprogram your body's response so that you become better at handling said disturbance. For example, if you try roller-skating for the first time, there's a good chance that you'll fall on your arse pretty quickly because you're not used to it. Over time, however, your feed-forward mechanisms will predict the changes that occur when you're rolling, and you'll automatically compensate (and therefore stop falling on your arse).

Identify the primary sensory systems that contribute to balance and posture

The main sensory systems that contribute to balance and posture are the proprioceptive system, the visual system and the vestibular system. Let's start with proprioception!

The main proprioceptive receptors are the muscle spindle, the Golgi tendon organ, and joint receptors. Muscle spindles have "polar regions" (ends) made up of actin and myosin. Gamma motor endings, which are located in the middle of the spindle, maintain the sensitivity of muscle spindles. The Golgi tendon organ, located at the musculotendinous junction, is made up of mechanosensitive Ib fibres which are compressed during contraction, causing firing of action potentials. Finally, joint receptors change their firing rate as joint position changes.

The proprioceptive receptors are important in the stretch reflex: when muscle is stretched, the muscle spindles pick this up, causing inhibition of further stretch. The stretch reflex can be modulated by the gamma motor neurons, which regulate the sensitivity of the spindle and prevent it from completely slackening. In cases where there is high gain and/or latency (see here for explanations of these terms), oscillations can occur. An example of this is decerebrate rigidity, caused by lesions of the brain stem in the cerebellum and/or brain stem. Decerebrate rigidity is characterised by increased muscle stiffness, spasticity or clonus (rapid contractions and relaxations in response to stretch).

Describe the different types of eye movement and associated motor control processes

The visual system also contributes to balance and posture, so let's have a look at vision! There are a whole bunch of eye movements that can occur:

• Vestibulo-ocular: Vestibular input stabilises the eyes during rapid head movement
• Optokinetic: Visual input stabilises the eyes during slow head movement
• Saccades: Sharp movements that bring objects into focus
• Smooth pursuit: Eyes follow a moving target
• Vergence: Adjust for viewing at different depths/distances

Describe the vestibular contribution to the control of eye movement and postural reflexes

The main vestibular receptors are the otoliths and semicircular canals, all of which are located in the ear. The otolith organs include the utricle, which detects horizontal acceleration, and the saccule, which detects vertical acceleration. The semicircular canals detect rotational acceleration. As mentioned above, vestibular receptors are important in the vestibulo-ocular reflex, which stabilises the eyes during head movement. Vestibular problems may also generate nystagmus (a rapid, swinging motion of the eyes).

Aside from the vestibulo-ocular reflex, there are several other reflexes that are generated from the vestibular system. The vestibulocollic (neck) and vestibulospinal (limb) reflexes use input from the utricle and saccule. When the head moves back, arms and legs extend, but when the head moves forward, arms and legs flex.

Motor Control

This lecture had so many details :/

Describe the hierarchical organisation of motor system from a structural and functional perspective

I'm not really sure what we're supposed to know here, so here's a description of the diagram on the "Hierarchical organisation of motor control" slide. Motor areas in the cerebral cortex can send signals to the spinal cord, either directly or via the brainstem. From the spinal cord, motor neurons in the ventral horn can innervate muscles, causing movement. There are also accessory areas, such as the thalamus, basal ganglia, and cerebellum, which play roles in motor control.

There is also some kind of hierarchy of motor control when it comes to voluntary movement. The first step is the "strategy" (figuring out what needs to be done), which is carried out in the prefrontal cortex, posterior parietal cortex, and basal ganglia. The next step are "tactics" (figuring out how to do what needs to be done), which takes place in the pre-motor cortex and supplementary motor area (SMA). The SMA is important in mental rehearsal of actions (i.e. imagining what you need to do without actually doing it). The third and final step is execution (getting stuff done), which uses the primary motor cortex, brain stem, and spinal cord. Once again, other inputs are received by the somatosensory cortex, cerebellum, basal ganglia, and so on.

Describe the similarities and differences between voluntary movements, reflex movements and rhythmic motor patterns

Voluntary movements are, well, voluntary. We choose to do them, and we get better at them as we practice them. Reflex responses are rapid and involuntary, and the amplitude of response may depend on the eliciting stimulus. Rhythmic motor patterns combine aspects of both voluntary and reflex movements- initiation is usually voluntary, but continuation of the movement is usually reflexive. An example of a rhythmic motor pattern is walking- you usually choose to start walking somewhere, but then once you start walking, you can keep walking without having to think about what you're doing.

Describe the physiological properties of motor units and their recruitment during voluntary and reflex movements.

Motor units consist of a motor neuron and all of the muscle fibres that it innervates. The innervation ratio is the number of muscle fibres innervated by a single motor neuron. Different muscles have different innervation ratios: for example, eye muscles have a low innervation ratio for fine control, whereas muscles that need powerful (but not necessarily accurate) movements, such as the gastrocnemius, have a much higher innervation ratio.

Motor units may be made up of predominantly slow-twitch or fast-twitch muscle fibres. (All of the fibre types are described here.) Again, the types of muscle fibres depend on the muscle type. A muscle that plays a more postural role, such as the soleus, has more slow-twitch fibres. A muscle that requires more power, such as the gastrocnemius, has more fast-twitch fibres.

According to Henneman's size principle, smaller motor neurons have the lowest threshold for synaptic activation, so they are recruited first. As smaller motor neurons are more likely to innervate slow-twitch muscle fibres, slow motor units tend to be recruited first. As intensity increases, more fast units will be recruited.

Identify the muscle receptors and explain their role in spinal reflexes.

The main muscle receptors involved in spinal reflexes are muscle spindles (which detect muscle length) and Golgi tendon organs (which, if I remember correctly, detect the amount of force on the muscle). Cutaneous receptors may also be involved in these reflexes, and descending inputs from the brain stem and cortex may also provide input into the reflex response. Reflexes can be classified according to a three-level hierarchy: control of individual muscles, control of muscles around a joint, and control of muscles at several joints.

A common example of a spinal reflex is the muscle tendon reflex. When a muscle is stretched, it sends signals to the spinal cord via Ia afferent neurons. In the spinal cord, Ia afferent neurons synapse with motor neurons that stimulate the agonist muscle, causing reflex contraction. At the same time, Ia afferent neurons synapse with inhibitory motorneurons, which synapse with another motor neuron, causing reflex relaxation of the antagonist muscle.

Since rhythmic locomotor behaviour also has some things in common with reflex movements, I'm going to discuss it here. To my understanding, rhythmic locomotor behaviour is mainly due to inhibitory interneurons in the spinal cord. When the flexor is activated, the extensor is inhibited, and vice versa. Tonic descending input can also play a role, but it is not necessary: cats with a spinal transection will still display rhythmic locomotor behaviour.

Identify the principal descending pathways in the spinal cord.

Before I talk about descending pathways, I'm going to talk about the layout of the spinal cord itself. As I mentioned earlier, motor neurons are located in the ventral horn of the spinal cord. "Pools" of motor neurons refer to all of the neurons that go to a muscle or to a group of muscles. These "pools" of neurons are laid out in a certain way: motor neurons innervating proximal muscles are located medially, neurons innervating distal muscles are located laterally, neurons innervating extensor muscles are located ventrally (i.e. towards the front), and neurons innervating flexor muscles are located dorsally (i.e. towards the back).

Aside from motor neurons, there are also interneurons and propriospinal neurons within the spinal cord. Medial propriospinal neurons project bilaterally (i.e. on both sides), span large lengths of the spinal cord, and coordinate trunk muscles on both sides of the body. Lateral propriospinal neurons project ipsilaterally (i.e. on the same side) and over shorter distances, and are used to innervate distal limb muscles.

Now it's time to info-dump a bunch of stuff about descending pathways! Tighten your seatbelts, because there's a lot to learn.

Descending pathways can be divided into two main categories: indirect pathways, which run from the brainstem to the spinal cord, and direct pathways, which run from the cortex to the spinal cord. Indirect pathways, which include the vestibulospinal and reticulospinal tracts, are mostly important in complex polysynaptic pathways regulating posture. Direct pathways, which include the corticospinal tract, are mostly important in innervating lateral motor neurons that innervate distal limb muscles, which are important for voluntary movements.

Vestibulospinal Tract

The vestibulospinal tracts arise from the vestibular nucleus, which in turn receives input from the vestibular system (balance organs in the ear). The vestibular nucleus also has connections with the cerebellum and reticular formation. There are both lateral and medial vestibulospinal tracts. The lateral vestibulospinal tract acts ipsilaterally, and excites extensor muscles. The medial tract acts bilaterally, and excites axial muscles. The vestibulospinal tracts are largely responsible for reflexes that help align the head and body.

Reticulospinal Tract

The reticulospinal tracts receive input from the vestibular system, cerebellum, lateral hypothalamus, globus pallidus, and sensorimotor cortex. The medial, or pontine (i.e. arising from the pons) tract acts ipsilaterally, and excites axial and extensor muscles. The lateral, or medullary (i.e. arising from the medulla) tract acts bilaterally, and inhibits extensor muscles while it excites flexor muscles.

Corticospinal Tract

The corticospinal tracts receive input from the primary motor cortex, supplementary motor area (SMA), and primary somatosensory cortex. The lateral corticospinal tract crosses over at the medulla, so it innervates contralateral distal limb muscles. The ventral corticospinal tract projects ipsilaterally and innervates the axial and proximal limb muscles. The corticobulbar tract, which terminates in the brainstem, innervates the motor neurons of the head and face muscles.

Describe the role of the cerebellum and basal ganglia in movement control.

The basal ganglia had a very complicated slide, but I think all we need to know is that it regulates motor control by concentrating information from different structures and feeding back to the motor cortex and SMA.

The cerebellum is important for comparing executed movements with motor commands (i.e. comparing what you actually did with what you intended to do), timing and coordination of movements, balance, muscle tone, and regulating eye movements. There are three main regions of the cerebellum: the spinocerebellum, the cerebrocerebellum, and the vestibulocerebellum. The spinocerebellum is important in motor execution and signals to the vestibulospinal and reticulospinal tracts. The cerebrocerebellum is important in motor planning. Finally, the vestibulocerebellum has roles in balance, and signals to the vestibular nuclei.

Thermal Physiology II: Fever and Acclimation

This post is going to contain a tiny bit of the next lecture (Thermal Physiology III). The lectures all ran overtime to the point that the lecturer only got to talk about the third lecture for a grand total of five minutes :P

Describe and understand a standard heat acclimatisation procedure in humans

In heat acclimatisation procedures, a subject is placed in a hot room for a certain number of hours each day for a certain number of days in a row. Fun. (Not.)

Describe and understand what physiological changes occurs during the process of heat acclimatisation in humans

In the process of heat acclimatisation, sweat loss increases and contains fewer electrolytes (like sodium). This may be due to the effect of aldosterone on sodium reabsorption. Plasma volume also increases. As someone acclimatises to heat, their heart rate and rectal temperature in the hot environment decrease.

Describe and understand how heat flow is affected by insulation and temperature gradient
Describe and understand the inverse relationship between insulation and thermal conductance

Heat flow is related to insulation and temperature gradient according to the following equation:

Heat Flow = Temperature Gradient / Insulation

This can also be rearranged to give an equation in terms of conductance (which is the inverse of insulation):

Heat Flow = Temperature Gradient * Conductance

Describe and understand the various components of the heat balance diagram

There are several different curves on the heat balance diagram:

• Deep body temperature: Stays relatively constant at a range of environmental temperatures. Decreases if temperature is too low and increases if temperature is too high.
• Non-evaporative heat loss: Heat loss due to conduction, convection and radiation. Depends on the temperature gradient (if insulation is constant), so heat loss decreases as temperature increases. The slope of the line is not constant- it flattens out in the temperature range between maximum vasoconstriction and maximum vasodilation, before becoming steep again. (Maybe I should draw a diagram, but I really can't be bothered.)
• Heat production: Prior to the point of maximum vasoconstriction, heat production increases with decreasing temperature. After the point of maximum vasoconstriction, the curve flattens out as you are at your basal metabolism rate and can't decrease your heat production further.
• Evaporative heat loss: Heat loss due to sweating and some other factors, such as breathing. Stays relatively flat for a while. Increases slightly between the points of maximum vasoconstriction and maximum vasodilation, before increasing more sharply.

Now for some more terminology! The lower critical temperature is the temperature at which your arteries are maximally vasoconstricted. The upper critical temperature is the temperature at which your arteries are maximally dilated. The thermoneutral zone, also known as the Zone of Vasomotor Adjustment, is located between these two points.

Describe and understand the underlying mechanistic basis of heat stroke

"Heat stroke" is defined as a core body temperature of more than 41°C, but I'm not really sure about the mechanistic basis. I'm assuming that the main idea is that, when the amount of heat you are gaining exceeds the amount you are losing, your body temperature heats up over time until it gets to the point that your body just can't handle it any more (enzymes denature etc.)?

Describe and understand the limits to human heat tolerance
Describe and understand the prescriptive zone, how it is measured and what it means

The "prescriptive zone" is the point at which you can no longer thermoregulate. It is measured by putting subjects in a room with gradually increasing temperature or humidity and then finding the point at which the subjects' temperatures begin to increase. Several factors can influence the prescriptive zone- heat acclimatisation can increase the prescriptive zone, as can wind.

Understand the terms ‘torpor’ and ‘hibernation’

'Torpor' is a state in which heat production and metabolic rate drop. Hibernation is similar to torpor, but occurs for a longer period of time. Torpor is mainly found in small animals, some of which have to produce their own "antifreeze" to prevent their cells from freezing at sub-zero temperatures.

Describe and understand the relationship between surface area and body mass for animals of different sizes

As animals get larger, mass increases faster than surface area. Therefore, smaller animals will tend to have a relatively high surface area, and larger animals will tend to have a relatively low surface area. Since heat loss is proportional to surface area, smaller animals are more likely to struggle in the cold (as they are losing a lot of heat), and larger animals are more likely to struggle in the heat.

Describe the tissue known as brown adipose tissue and its role in non-shivering thermogenesis

Babies are unable to shiver, but they are able to produce heat via brown adipose tissue (a.k.a. "brown fat"). Brown adipose tissue has a lot of mitochondria that are capable of producing heat.

Describe and understand the role of UCP1 in non-shivering thermogenesis

UCP1 (uncoupling protein), also called "thermogenin," is found on the inner mitochondrial membrane in brown fat. UCP1 is essentially a H+ channel. Unlike ATP synthase, which is also an H+ channel, UCP1 does not produce ATP. Instead, UCP1 produces heat.

It was originally thought that adults don't have brown fat. This has been found to be untrue. Some adults do have brown fat, mainly in the supraclavicular and neck regions.

Describe and understand the mechanistic basis of fever, including the role of endogenous pyrogens, and how they operate to alter the thermoregulatory set-point

Fever is usually stimulated by some kind of invading microorganism. Various toxic products of microorganisms, such as lipopolysaccharide, are called exogenous pyrogens as they can stimulate fever. Exogenous pyrogens stimulate phagocytes to make and secrete endogenous pyrogens, such as IL-1β, IL-6, IFNβ, IFNγ and TFNα. It has been suggested that endogenous pyrogens cross the blood-brain barrier at the organism vasculosum of the lamina terminalis (OVLT), which is kind of like a "leakier" part of the blood-brain barrier.

After passing through the OVLT, endogenous pyrogens stimulate phospholipase A2, which cleaves phospholipids to form arachidonic acid. Arachidonic acid is then converted into prostaglandins via cyclooxygenase. (I've described these pathways in more detail here.) One of the more important prostaglandins in fever signalling is prostaglandin E2. Prostaglandin E2 changes the firing rate of cold-sensitive neurons, essentially tricking your body into thinking that it's cold so that thermoregulatory processes can kick in and raise your body temperature.

Interestingly enough, injecting exogenous pyrogen, endogenous pyrogen and prostaglandin E into the hypothalamus can all cause fever. However, the time it takes to cause fever is different. Exogenous pyrogen has the longest latency (i.e. delay before onset of fever), followed by endogenous pyrogen and then prostaglandin E2. In fact, prostaglandin E2 causes fever immediately after injection into the hypothalamus.

What's the point of fever? It's been suggested that fever might play a role in fighting infection. Yay...!

Describe and understand the mechanistic basis for some anti-pyretics

Most anti-pyretics work by blocking either cyclooxygenase or phospholipase A2. Paracetamol and NSAIDs (e.g. ibuprofen) block cyclooxygenase. Steroidal anti-inflammatory drugs (I assume these are just corticosteroids) block phospholipase A2.

Describe and understand how the various components of the heat balance equation change from rest to exercise

If you can't remember from my last post, the heat balance equation is as follows:

S = M ± Cond ± Conv ± Rad ± E - W

During exercise, our metabolic rate (M) increases. Therefore, to stop our temperature from increasing too much, we need to lose heat in some other way (e.g. increasing our evaporative heat loss (E) by sweating).

Describe and understand some of the arguments that the thermoregulatory relies on negative feedback regulation during exercise

During exercise, we make more heat as our metabolic rate increases. In early stages of exercise, our heat loss mechanisms (vasodilation and sweating) are still operating at their resting levels, which is insufficient for the increased metabolism during exercise. Therefore, body temperature rises, stimulating heat loss until heat loss is equal to heat gain. In other words, it's a negative feedback loop. Yay!

Describe and understand the effect of increased thermoregulatory demands on exercise performance

Pretty much all we got up to here is that increased muscle temperature does seem to increase performance, but if muscle temperature increases, body temperature also increases, which isn't necessarily good. There's also a battle between the muscles and the skin- the muscles want blood so they can do their job, and the skin wants blood so it can get rid of the excess heat. Overall, heat tends to reduce exercise performance. I think that's all we got up to in this lecture, so I'll end this post here.

Thermal Physiology I: Heat Balance

Describe and understand the different definitions of animal thermoregulation

There are many different terms that can be used to describe how animals regulate body heat:

• Poikilothermic- Literally means "change heat." Body temperature changes according to ambient temperature.
• Homeothermic- Literally means "same heat." Body temperature remains constant despite changes in ambient temperature.
• Heterothermic- Somewhere between poikilothermic and heterothermic.
• Endothermic- Body heat is generated from metabolic processes.
• Ectothermic- The animal seeks an external source of body heat.

Describe, understand, and be able to calculate the Q10 effect of temperature on processes
Understand why changes in body temperature have profound effects on all life processes

The Q10 effect is basically a ratio of the reaction rates at a given temperature, and at another temperature that is 10 degrees higher than the given temperature. It is calculated as (reaction rate at higher temperature) / (reaction rate at given temperature). Generally, increasing temperature increases reaction rate (as the energy of the particles is brought closer to activation energy), but at high enough temperatures you might also have problems with denaturation of enzymes. As we're basically just big bags of chemical reactions, this is pretty bloody important.

Describe and understand the relationship between heat capacity and temperature

Heat capacity is the amount of energy that it takes to raise body temperature by 1 degree. For most animal tissue, heat capacity is around 3.5 joules/gram/°C. In other words, if the amount of heat energy generated (by metabolic processes etc.) in 1g of animal tissue is 3.5J higher than the amount of heat that is lost, then that 1g of animal tissue will become 1°C warmer.

Describe and understand the heat balance equation including its individual components, what they mean, and how they are affected by various environmental and biological factors
Be able to calculate the heat balance and its effect on body temperature given the relevant information

The heat balance equation is as follows:

Heat storage (S) = Metabolic heat production (M) ± Conductive heat exchange ± Convective heat exchange ± Radiative heat exchange ± Evaporative heat exchange (E) - External work (W)

which can be abbreviated to:

S = M ± Cond ± Conv ± Rad ± E - W

In order for body temperature to remain constant, S must be equal to 0. If S is not equal to 0, then body temperature will change. As mentioned above, since the heat capacity of animal tissue is 3.5 joules/gram/°C (or 3.5 kJ/kg/°C), for every 3.5J increase in S, 1g of animal tissue will increase in temperature by 1°C.

If you haven't done physics (like me :P), here are some quick definitions for the four main methods of heat exchange (conduction, convection, radiation, evaporation):

• Conduction- Transfer of thermal energy by direct contact (i.e. you transfer heat to things that you touch, and things that you touch transfer heat to you).
• Convection- Transfer of thermal energy to a moving fluid. This can be natural, like the buoyancy effect (heat rising), or forced (e.g. wind).
• Radiation- Transfer of thermal energy by electromagnetic radiation. The amount of radiation emitted depends on their surface temperature. The temperature and maximum wavelength are related according to Wien's law: λ_max = 2.898 * 10⁶ / T (°K).
• Evaporation- Transfer of thermal energy as latent heat of evaporation (2400J/g of water).

Describe and understand body temperature classifications of hypo- and hyperthermia

Hypothermia: Body temperature less than around 36°C.
Hyperthermia: Body temperature greater than around 38°C.

Describe and understand the basic components of the thermoregulatory control system in homeothermic animals

Just a warning from here on out: I wasn't able to attend this lecture in person, and the lecture recorded without sound. A lot of the other points on this post were not covered in the replacement lectures, so I'm basically just gonna wing the rest of this post by looking at the lecture slides.

Just like in other control systems, the thermoregulatory control system needs certain components. These components are: the variable to be regulated (skin temperature), receptors that measure the variable (thermosensors in the skin and hypothalamus), some kind of command centre where the information is integrated and then new information is sent out (presumably the CNS???), and the effectors that regulate the variable (skin blood flow, sweating, shivering and behavioural changes).

Describe and understand how peripheral and central temperatures are integrated by the control system to stimulate effector mechanisms that result in the regulation of body temperature

Both the skin and hypothalamus have cold and warm thermosensors. In the skin, the cold receptors are called A delta, and the warm receptors are C fibres. (Not sure if they have different names in the hypothalamus.) Warm sensors increase firing when they are warm, and cool sensors increase firing when they are cool.

Describe and understand the four main effector systems in thermoregulation and how they are controlled 

The four main effector systems are control of skin blood flow, sweating, shivering and behaviour changes.

Skin blood flow

At a comfortable temperature, our skin blood flow is around 25 mL/min.100g. This can decrease to 1 mL/min.100g in the cold, and increase to 150mL/min.100g in heat. The skin of the hands, feet, ears and nose have arteriovenous anastomoses (AVAs) which, when open, shunt blood directly to the veins (and not to the skin). AVAs are opened when warm, and closed when cold, thus directing blood flow to meet our needs for warmth. Indeed, changing skin temperature can adjust heat loss by a factor of 8.

Sweating

As you may (or may not) remember from second year, nerves that innervate sweat glands are part of the sympathetic nervous system, but they secrete acetylcholine rather than noradrenaline. These nerves are also called sudomotor nerves. There are two types of sweat gland: eccrine glands, which cover most of the body surface and are mainly responsible for thermoregulation, and apocrine glands, which are pretty much only found on the armpit and pubis. Sweating increases pretty much linearly once head temperature is higher than a set point. (Skin temperature also helps to determine the set point.)

Shivering

Shivering is essentially heat production by moving your muscles. It begins once head temperature drops below a set point. (Once again, skin temperature also plays a role in determining set point.)

Behavioural Changes

This wasn't covered at all, but I'm pretty sure that this just entails wearing more clothes when you're cold, and taking off clothes when you're hot.

Exercise Physiology III: The Urge to Breathe

This post is going to be kind of incomplete as we ran out of time (the first half of this lecture was basically the back end of Exercise Physiology II). As such, I'll just write about all of the stuff that we have learned about, and when we learn the rest, I'll update this post. Updated now :)

Describe and understand normal chemoreceptor control of ventilation

See previous post: Control of Ventilation

Describe and understand what happens to blood gasses during exercise

During exercise, venous PCO2 increases, but arterial PCO2 remains fairly steady. If anything, arterial PCO2 decreases a bit. This indicates that all excess CO2 produced during exercise is removed in the first pass through the lungs. The other consequence of this is that it suggests that chemoreceptors are probably not the main drivers of an increase in ventilation during exercise, as chemoreceptors are located in the arterial system, not the venous system.

Describe and understand what happens to blood gasses during exercise in the absence of normal chemoreceptor input

To study whether or not CO2 sensitivity is actually important during exercise, children with central congenital hypoventilation syndrome (CCHS) have been studied. Children with CCHS are insensitive to CO2, and while they breathe normally when awake, they stop breathing when asleep. Despite this, children with CCHS still have increased ventilation during exercise. The increase in ventilation is increased to a greater extent in fast than in slow exercise (matched for work rate), suggesting that mechanoreceptors detecting limb movements might be responsible in exercise.

Describe and understand alternative ventilator stimuli during exercise

Ventilation increases to a fairly large extent at the beginning of exercise. It has been suggested that this may be due to central command, as well as mechanoreceptors. The initial rise in Ve is larger in trained than in untrained individuals. Ventilation then gradually increases during exercise, which may be due to metaboreceptors, which are chemoreceptors in the muscle.

Describe and understand the alveolar gas equation and how ventilation and chemoreceptor input are causes and effects of each other 

The alveolar gas equation discussed in this lecture was different to the equation discussed in other units. Why not make things simple when you can make them confusing, right?

Anyway, the equation discussed in this lecture was as follows:

P_aCO₂ = K (V_CO2/V_A)
where P_aCO₂ is the arterial partial pressure of CO₂, and I think V_CO2 and V_A are the ventilation rates for carbon dioxide and for alveolar air, respectively.

As discussed previously, P_aCO₂ affects ventilation via the action of chemoreceptors. Conversely, ventilation can affect P_aCO₂, as higher ventilation rates result in lower partial pressures of CO₂, and vice versa. P_aCO₂ vs. ventilation and ventilation vs. P_aCO₂ can be graphed simultaneously (sort of like the cardiac and vascular function curves), and the equilibrium point is where the two curves intersect.

Describe and understand how work intensity and muscle fibre type recruitment affects the relationship between VE and VCO2

As mentioned here, type I fibres are activated at all intensity levels. As intensity increases, type IIa and IIb fibres are also activated. Type II fibres, especially IIb fibres, rely a lot on anaerobic respiration (e.g. glycolysis) to produce energy. One of the main downsides of glycolysis production is that lactic acid is produced. We do have a buffering system to reduce lactate levels, but this produces carbon dioxide, increasing ventilation:

Lactic acid + Carbonic acid <--> Water + Carbon Dioxide

Because of this buffering system, respiration increases more rapidly following the Onset of Blood Lactate Accumulation (OBLA), which occurs when blood lactate levels are around 4mM. Eventually, this buffering system is pushed to its limit, and the pH starts to decrease. The decrease in pH (increase in H+ ions) drives ventilation further, causing an even steeper increase in ventilation rate.

Describe and understand some experiments designed to investigate the phenomenon of ‘central command’ in ventilator control 

In the first experiment, researchers attached a vibrator to the bicep muscle tendon. This stimulated reflex contraction of the bicep via the muscle tendon reflex. While the muscle tendon reflex was stimulating the bicep, not as much input from the brain was required to lift a weight (as compared to participants who didn't have the vibrator). When central command required was reduced, ventilation also decreased.

The second experiment had a similar setup to the first experiment, but in the second experiment, participants were asked to use their tricep muscle to pull something down to lift a weight via a pulley system, rather than use their bicep to lift something up. As the vibrator was still attached to the bicep muscle, the muscle reflex actually made it harder to contract the tricep (as the bicep and tricep are antagonistic muscles). Therefore, in this setup, participants with the vibrator needed more input from the brain in order to lift the weight. When central command required was increased, ventilation also increased.

Exercise Physiology II: The Cardiovascular System

Understand the distribution of cardiac output and how it is controlled in different situations

At rest, only around 20% of cardiac output goes to the muscles. Around half goes to the liver and kidneys, around 14% to the brain, and the rest goes to the heart, skin, and other organs. Distribution depends on the opening and closing of pre-capillary sphincters, and local vasodilation/vasoconstriction, as discussed here.

Describe and understand what happens to cardiac output during exercise

Cardiac output, as I'm sure you know, increases dramatically during exercise. The distribution of cardiac output also changes: a larger proportion of cardiac output goes to the muscle, and less goes to other organs. Because cardiac output has increased so much, though, the absolute amount of blood that most organs get increases. There are two exceptions to this rule: the liver and kidneys both experience a decrease in cardiac output (both absolute and proportional).

Describe and understand the determinants of cardiac output during exercise

During exercise, sympathetic stimulation increases, causing vasoconstriction. This seems counterproductive given that vasoconstriction will reduce the flow of blood, but thankfully there's also something called "functional sympatholysis" (i.e. the "breaking off" of sympathetic stimulation). Areas of the body undergoing high levels of metabolism, such as working muscle, can produce local mediators that cause vasodilation, counteracting the vasoconstricting effects of sympathetic stimulation.

Describe the known determinants of local blood flow mediation

See previous post: Microcirculation and Blood Flow

Nitric oxide (NO) may also play a role. It has been discovered that haemoglobin releases NO when it becomes deoxygenated.

Describe and understand how the local control of blood flow conflicts with blood pressure regulation

Vasodilation of capillaries causes a decrease in blood pressure, which would be bad if unchecked. (The opposite is true during vasoconstriction.) Thankfully, total peripheral resistance isn't the only determinant of blood pressure, the other being cardiac output. An increase in cardiac output can counteract a decrease in blood pressure due to local vasodilation (within limits, of course).

Understand the relationships between work rate and cardiovascular variables

As work rate increases, so too does heart rate and stroke volume (and hence cardiac output), arterial pressure (systolic increases to a much greater extent than diastolic), oxygen consumption, and arterio-venous oxygen difference. Peripheral resistance, however, decreases due to the vasodilation of capillaries in working muscle.

Describe and understand the origin of changes in the arterio-venous oxygen difference during exercise

As you might recall from PHYL2001, the haemoglobin saturation curve shifts to the right when temperature is high and pH is low (which is what happens during exercise). A rightward shift indicates that more oxygen is released from haemoglobin at the same partial pressure of oxygen in solution. As more oxygen is being released from haemoglobin during exercise, the arterio-venous oxygen difference increases.

Describe and understand the changes in cardiovascular variables during exercise

During exercise, the baroreceptor's set point is reset to a higher blood pressure. Stimuli that reset the baroreceptors may include feedback from muscle chemosensors, muscle mechanoreceptors, or the motor cortex. Our normal blood pressure is then sensed as being too low, reducing the firing rate of baroreceptors. The nervous system then responds by increasing sympathetic stimulation and decreasing sympathetic stimulation. These changes in sympathetic and parasympathetic stimulation cause an increase in certain cardiovascular variables, such as heart rate.

Describe and understand adaptations in cardiovascular variables after repeated exercise

Our bodies can adapt to repeated exercise. Fit people will tend to have a lower resting and exercise heart rate, but a greater oxygen uptake (a.k.a. VO2 max). I'm not entirely sure what the mechanisms are, though- maybe we'll find out in the next lecture?

Describe and understand the determinants of stroke volume

See previous post: Cardiac Loads

End-diastolic volume changes more in exercise than end-systolic volume. Interestingly enough, end-systolic volume changes even less when you are exercising in a supine (lying down) position, compared to exercising while standing up.

Describe and understand Starling’s capillary fluid balance and how it is affected by exercise

See previous post: Microcirculation and Blood Flow

Remember, the switch from filtration to reabsorption depends on the pressure drop across the length of an arteriole. In exercise, this pressure drop is decreased, so the outward hydrostatic presssure is greater than the inward oncotic pressure over a longer distance. This leads to increased filtration during exercise, which in turn leads to oedema and a decrease in plasma volume during exercise.

Describe and understand cardiac drift

Cardiac drift refers to the phenomenon in which heart rate increases during exercise, even when work rate remains the same. Cardiac drift occurs because of the decrease in plasma volume during exercise (see above). A decrease in plasma volume lowers blood pressure, and heart rate increases in order to compensate (baroreceptor reflex).

Describe and understand blood pressure changes in exercise

Not really sure what to say here, other than that a higher heart rate leads to a higher diastolic pressure during exercise (my understanding was that it's because the next heart beat comes along before pressure can drop all the way down to resting diastolic pressure?). Mean arterial pressure also increases during exercise.

Describe and understand blood boosting

In blood doping (or blood boosting), athletes remove a litre of their blood around a month or so prior to a competition, and then reinfuse it. As such, their haematocrit (% of blood with red blood cells) increases. Blood doping increases VO2 max and exercise performance, but if you overdo it, the blood can become very viscous and difficult to pump around (as also mentioned here).

An alternative to blood doping is to add erythropoietin (EPO) to increase production of red blood cells. Recombinant EPO, made in the lab by microbes, can be detected as microbes glycosylate EPO differently to humans.

Exercise Physiology I: Cells and Organs

This lecture shared quite a lot of content with some of the lectures in PHYL3001 and BIOC3004. Hopefully that means that this post will be easy to write!

Describe and understand the three systems used to replenish ATP in muscle contraction
Describe and understand the physiological differences between these three systems, and how that affects performance

See earlier post: Exercise Metabolism

Phosphocreatine (PCr), mentioned in the above post, is also known as creatine phosphate (CP). Together, CP and ATP make up the "phosphagen" system. Dephosphorylation of creatine phosphate via creatine kinase (yeah, its name doesn't really make sense in this context, but I think it's a reversible enzyme) can produce energy by itself, or it can donate its phosphate group to ADP to regenerate ATP.

Describe and understand the role of muscle glycogen in endurance exercise and its effect on fatigue
Describe and understand the physiological basis of carbo-loading

Glycogen is one of the main ways in which muscles store energy. Glycogen can be broken down into glucose via glycogen phosphorylase, which in turn is activated by Ca²⁺ influx. In addition to glycogen, muscles also have a store of triglycerides, and can obtain even more fuel from passing blood.

During exercise, muscle glycogen is the first fuel to be used. Over time, fatty acids and glucose are taken up in order to continue to supply the muscle with energy. Once glycogen stores are depleted, however, exhaustion occurs and further exercise becomes impossible. Increasing glycogen stores by increasing the amount of carbohydrate in the diet may help in increasing the time for fatigue to set in. Therefore, a lot of endurance athletes will participate in "carbo-loading"- increasing their glycogen stores so that they will have more stamina.

High carbohydrate diets will also assist in replenishing glycogen after exercise. Interestingly, not eating will replenish a little bit of glycogen too (around as much as for a fat and protein diet following exercise). This may be due to the breakdown of muscle.

Describe and understand the morphology and physiology of the different muscle fibre types

Another topic that I mentioned in my good ol' post about exercise metabolism!

Now for some stuff that I didn't mention in that post:

• The types are distinguished based on their isoform of myosin ATPase
• Type I fibres have a lower calcium-handling capacity than type II fibres
• Type I fibres have a higher capillary density and mitochondrial volume than type II fibres

Describe and understand the recruitment of the different fibre types during exercise of different intensity

As exercise intensity increases, more fibres are recruited. At low intensity, only type I fibres are needed, but as intensity increases, type IIa and IIb fibres join in on the action.

Describe and understand how differences in fibre type makeup affect exercise performance between individuals

I thought I'd mentioned this before, but apparently not. Sprinters and other athletes involved in short, highly-intense activity tend to have a higher proportion of type II fibres. Endurance athletes, on the other hand, tend to have a higher proportion of type I fibres. The next question is whether people become a certain type of athlete because their fibre type proportions are more suitable, or whether they have a certain fibre type proportion because of their training (i.e. is it nature or nurture)?

Describe and understand what is VO2 max
Describe how training changes VO2 max
Describe and understand the potential morphological and physiological limits to VO2 max

I don't think VO2 max was even mentioned in this lecture (there are two slides, but I don't think he actually talked about them at all), but I have talked about it briefly in a previous post: Exercise Metabolism. (Yep, it's that post again.) As VO2 max is a measure of the maximum capacity to take up and use oxygen, I would assume that all of the systems that are involved in oxygen transport and uptake could represent limits to VO2 max. For example, the ability of the circulatory system to transport blood, and the amount of mitochondria able to take up and use oxygen, could both limit VO2 max.

Control Systems 2

Describe how referenced negative feedback can become unstable

Negative feedback, which I discussed in my previous post for PHYL3004, does have its limitations. For example, phenomena under negative feedback control may oscillate around a set point rather than remaining stable at that point. There is also an issue with latency (delay before negative feedback kicks in) and range over which negative feedback can operate (for example, if you lose too much blood, no compensatory system can save you).

Define Power, Integral, Derivative, range, Input/output function and PID in reference to control systems

• Input/output function- I'm going to start with this one, and you'll appreciate why in a moment. The input/output function relates an input (for example, blood pressure) to an output (for example, number of impulses generated by the baroreceptors).
• Power- Power is the slope of the input/output function. In other words, how much does the output change after a change in input?
• Integral- The integral in this context is the integral of the error signal (i.e. deviation from the set point). This basically adds up the amount of error over time.
• Derivative- The derivative here is the derivative of the error signal. The rate of change of error can give an indication as to how much power is actually needed for stability. If the amount of error is falling, you don't need a lot of power- in fact, if you have too much power, you'll overshoot.
• Range- The range of values over which a feedback control system will operate.
• PID- Power, Integral, Derivative (though my engineer dad says that it's meant to be Proportion, Integral, Derivative). Basically, there are three main factors that determine output: power multiplied by the error signal, derivative of the error signal, and the integral of the error signal.

Give examples of input/output functions for a control system

I've already given an example above, which is blood pressure and firing rate of baroreceptors, but there are many others. Another such example is the partial pressure of carbon dioxide and pulmonary ventilation.

Explain how increasing power improves gain but reduces sensitivity

If you don't remember what gain is, it's basically the amount of change that is prevented by the feedback system. As power is the slope of the input/output curve, and smaller changes in input cause larger changes in output, an increase in power causes an increase in gain. If you keep increasing power, eventually you'll actually overshoot your set point. When power is increased too much, length overshoots so much that the system then needs to correct itself, but it may overcorrect due to the high power. This causes growing oscillations, which can be quite problematic. (I'm not sure how power affects sensitivity, because sensitivity was only mentioned in the "learning outcomes" slide. Maybe he's referring to the large oscillations that miss the mark every time? Or maybe he meant to say "stability," given that the slide says "More power more gain; more power less stable.")

Oscillations can also be maintained by latency, or the delay before the response starts. For example, when a variable is at its peak, the system might prepare to respond to that peak value by attempting to decrease it, but by the time this response kicks in, the variable might not be at its peak any more. In other words, while the response was suitable at the time the input was received, it wasn't suitable any more by the time the system responded. If the latency and oscillations are out of phase, oscillations can become bigger. This can be especially bad if the oscillations are 90 degrees out of phase, probably because the constructive interference would look like this (image taken from http://astronomy.swin.edu.au/cosmos/C/Constructive+Interference):

Describe ways to limit instability in negative feedback control

There are a couple of main ways to limit instability in negative feedback control. PID control, mentioned in that list of definitions above, is one method. The derivative of the error signal can be used to predict the amount of error, which in turn can be used to control the amount of power, improving stability. The integral takes into account the amount of error over time. Therefore, all three factors in PID- power multiplied by error signal, integral of error signal, and derivative of error signal- can all add up to give a control system that is more stable than a system with only the first component alone.

Another way to limit instability is to use antagonistic pairs. There are many antagonistic pairs throughout the body: flexor and extensor muscles, parasympathetic and sympathetic nerves, insulin and glucagon, and so on. Each component of an antagonistic pair has its own oscillations, but they often cancel each other out.

Give an example of positive feedback control and how it is regulated
Explain how platelet activation occurs and is inhibited

Platelet activation is an example of positive feedback control. Platelets are activated by von Willebrand factor (vWF), which in turn is activated by binding to exposed collagen on a damaged vessel wall. As described here, activated platelets release ADP and thromboxane A₂ (TxA₂), which in turn stimulate activation of platelets and further release of ADP and TxA₂. Of course, there is a limit to this, otherwise our entire circulation would clot every time we got a little cut. ADP can also stimulate the release of nitric oxide (NO) and prostacyclin from healthy endothelium cells. As NO and prostacyclin inhibit platelet activation, the clot will remain restricted to the damage site.

Distinguish between feedback and feed-forward control

Feedback control: some kind of variable is measured, and that information is then used to control the same variable. Responds to past or present conditions, with a limited amount of anticipation.

Feedforward control: some kind of variable is measured, and that information is used to control something else. Responds to something that will probably happen in the future (anticipation).

Define feed-forward control and anticipation

I just did...

Give an example of a feed-forward control system in physiology

I'm going to be super-duper and give you three examples:

1. Respiration rate increases even before exercise begins.
2. Vestibular ocular reflex: semicircular canals allow us to keep track of our head movements, and this affects our eye muscles. Our eye movements coordinate to our head movements so that our visual field is kept stable.
3. Catching a ball uses both feed-forward and feedback. Feed-forward allows us to figure out where we need to put our hands (the "set point" in this system). Feedback lets us figure out where our hands are and how far they are from the "set point" determined by feed-forward.

Explain how delayed feedback control is used in learning motor skills

When we perform an action, such as throwing a ball, we can remember the outcome and use that to inform future actions. For example, if we throw a ball and it goes slightly left, we can try aiming differently the next time. Over time, we become more accurate.