Neural control of Motivational Behaviour: control of drinking & eating Flashcards
1
Q
What are circumventricular organs, what do they include and what do they do?
A
- In a few brain areas the blood-brain barrier is ‘leaky’. In these regions the capillaries are fenestrated and hormones in the blood can move out into the extracellular space of the brain.
- These areas are called circumventricular organs because they surround the ventricular system; they include the area postrema in the brainstem, posterior pituitary, median eminence, subfornical organ (SFO), subcommissural organ, and pineal gland .
2
Q
What is one mechanism of control of drinking linked directly to? How does the SFO allow for this?
A
- One mechanism of control of drinking is linked directly to the osmolarity of the blood. The higher the osmolarity, the stronger the urge to drink. Blood osmolarity is sensed by the subfornical organ (SFO) in the wall of the third ventricle near the interventricular formamen between the thalamus and hypothalamus.
- The SFO has fenestrated capillaries (ie capillaries with gaps between the endothelial cells); this allows it to detect various peptides in the blood. Changes in the osmolarity of the blood are detected by ”osmoreceptor cells” in the SFO which send axons to cells in the hypothalamus.
3
Q
What is activated by the stimulation of the osmoreceptors in the SFO? What does this project to and what does this cause us to feel?
A
- Stimulation of the osmoreceptors in the subfornical organ by hypertonic blood activates cells in the medial preoptic nucleus of the hypothalamus.
- This nucleus projects to the limbic system and regulates the sense of thirst. When the medial preoptic nucleus is activated we feel subjectively thirsty and will seek out water. The greater the activity of the nucleus, the thirstier we feel.
4
Q
Where else does the SFO activate cells? Where do the axons of these cells project to? How does this make us thirsty?
A
- The subfornical organ also activates cells in the paraventricular nucleus (around the third ventricle) and the supraoptic nucleus (above the optic chiasm). These cells have axons that project to the posterior pituitary and release ADH (antidiuretic hormone) and thus reduce urine flow.
- This reduces loss of water in urine and helps to prevent blood osmolarity rising even further. Angiotensin II is detected in the SFO and high levels of this peptide in the blood also triggers thirst
5
Q
What does high blood osmolarity trigger?
A
Thirst and ADH release
6
Q
What are the three effects of ADH that contribute to decreased loss of water in urine?
A
- ADH has three effects by which it contributes to decreased loss of water in urine. These are:
o ADH causes additional water channels (Aquaporins) to move into the membrane of the collecting duct epithelial cells. The aquaporins allow water to pass out of the collecting duct and into the renal medulla. This reduces the volume and increases the concentration of urine
o ADH also increases the permeability of the collecting duct to urea, allowing increased reabsorption of urea into the medullary interstitium, which helps to increase the reabsorption of water
o ADH stimulates sodium reabsorption in the thick ascending loop of Henle by increasing the activity of the Na+ K+ 2Cl- cotransporter. This increases the osmolarity of the medullary extracellular (interstitial) fluid, and allows even more water to be reabsorbed from the collecting ducts.
7
Q
A key idea in understanding feeding behaviour is that it is initiated by two factors. What are these two factors?
A
- A key idea in understanding feeding behaviour is that it is initiated by two factors.
o One is the immediate availability of food (i.e. is it there in front of you?). This is an EXTERNAL CUE.
o The second is the sense of hunger from inside your body. This is an INTERNAL CUE. (Cessation of eating is triggered by a separate, SATIETY system).
8
Q
A combination of what types of cues usually cause us to eat? Give examples.
A
- We normally eat due to a combination of internal and external cues. For example, we may not feel hungry but if appetizing food is presented we will eat it.
- On the other hand if we feel hungry enough we will eat what would normally be unappetising (e.g. raw meat)
9
Q
What type of tissue provides the major storage of energy in mammals? What model was proposed if body weight and fat are maintained at a constant level for long periods of time? How might weight also be regulated by intestinal absorption?
A
- Adipose tissue provides the major storage of energy in mammals.
- On the basis of the observation that body weight and fat are maintained at a constant level over long periods in spite of daily fluctuations in food intake, Kennedy in 1953* proposed an “adipostatic model” in which factors released by fat target the hypothalamus to control food intake and maintain weight.
- Weight may also be regulated by regulating intestinal absorption, by altering intestinal transit time and thus altering absorption of caloric material in the intestine.
10
Q
Where did early evidence for a role of the hypothalamus in appetite come from? What was demonstrated in this study? What ideas and studies did this lead to?
A
- Early evidence for a role of the hypothalamus in appetite came from studies of patients with pituitary tumors pressing upwards on the hypothalamus.
- These patients often demonstrated a voracious appetite, morbid obesity and hypogonadism. This was known as the “adiposogenital syndrome”.
- The hypogonadism led to the idea that hypothalamic damage was occurring; thus the voracious appetite could be due to damage to a ‘satiety centre’ in the hypothalamus.
- This led to studies where different parts of the hypothalamus were deliberately damaged in rats
11
Q
What did the studies on rats with hypothalamus damage show?
A
- Rat studies showed:
- Lesions in the Lateral hypothalamus produced anorexia (due to damage to orexigenic/feeding centre?)
- Lesions in the Medial hypothalamus lesions produced obesity (due to damage to satiety centre?)
12
Q
What does damage to the medial hypothalamic nuclei reduce a person’s ability to do? How is their feeding behaviour affected? What about damage to the lateral hypothalamus?
A
- Damage to the medial hypothalamic nuclei reduces a person’s ability to sense internal cues. Their feeding behaviour is then controlled by external cues alone. So if a rat or human has a ventromedial lesion, they will overeat if given palatable food but starve if given unpalatable food.
- Such individuals can become very ‘finicky’ in their diet, i.e. only eating particular kinds of food, if this food is unavailable they will starve, but if this food is available in quantity they will overeat and become obese.
- Lesions in the lateral hypothalamus can cause anorexia but these are harder to interpret as these lesions may interrupt several neuronal pathways. For example, dopamine pathways will be interrupted which may destroy the pleasure (reward) from eating.
13
Q
Which nuclei of the hypothalamus are damaged by medial lesions? What is the effect of this? What about the lateral lesions? What did lesions here lead to the idea of?
A
- The medial lesions involved the arcuate nucleus and periventricular nuclei of the hypothalamus. Animals with lesions here overate and became enormously obese. This led to the concept of an ventromedial ‘satiety centre’ that inhibited feeding when stimulated.
- The lateral hypothalamic lesions damaged the lateral hypothalamic nucleus. This led to the idea that there is a lateral hypothalamic ‘orexigenic’ (hunger) centre.
- N.B. Don’t confuse the periventricular nucleus (next to arcuate & to do with satiety) with the paraventricular nucleus (to do with release of ADH & oxytocin)
14
Q
What happened when unpalatable food was given to the rats with ventromedial lesions? What did this lead to the idea of?
A
- If unpalatable food (e.g. food tasting bitter but nutritious) was substituted for normal food, the animals with ventromedial lesions did not overeat but became anorexic! i.e. previously fat rats became anorexic
- This led to the idea that the hypothalamus regulates food intake depending on the balance between ‘internal’ and ‘external’ stimuli.
- Internal stimuli are things like contraction of the stomach (hunger pangs), and the levels of various blood chemicals like glucose, insulin, ghrelin, cholecytokinin and leptin.
- External stimuli are the sight and smell of food. In normal individuals eating is controlled by a balance between these two factors. If the internal stimuli are strong, we feel hunger, and depending on how intense, we will go and seek out food above all other actions.
- If the internal stimuli are very weak, we will not eat even if attractive and tasty food is presented to us. However, normally the internal stimuli are at some intermediate level, and whether or not we will eat food presented to us depends on the balance between the external stimuli (how attractive the food is) and the internal stimuli (how hungry we feel).
15
Q
Where are internal cues now known to be detected? What ‘centre’ are these part of? What effect does damage to these areas have?
A
- It is now known that the arcuate nucleus is where internal cues such as levels of blood hormones are detected. There is some uncertainty about where the arcuate nucleus ends and the periventricular nucleus begins. Probably both are part of the classic ‘satiety centre”
- Arcuate lesions destroy the animal’s ability to detect internal signals. So if presented with palatable food it will eat until it can physically eat no more; It has no ability to detect internal satiety signals. On the other hand if presented with unpalatable food it will starve to death, as it has no ability to detect internal hunger signals.
16
Q
What are the main cell types of receptors for hormones released from the gut to affect feeding behaviour?
A
- Both the the arcuate and periventricular nuclei, although small in size, contain a large number of neurons containing different neurotransmitters or hormones (some with odd names!) . These neurons have receptors for hormones released from the gut that affect feeding behaviour.
- Some of the main cell types are:
o ‘Agouti-related peptide*’ (AGRP) & ‘Neuropeptide Y’ neurons (NPY) neurons
o ‘Cocaine & amphetamine related transcript’ neurons (CART) & ‘Pro-opiomelanocortin (POMC)’ neurones
17
Q
What are enteroendocrine cells? What do they do and what are they stimulated by?
A
- Enteroendocrine cells are cells in the stomach wall and intestine that secrete hormones or neurotransmitters into the underlying blood vessels in response to the presence of nutrients in the lumen.
- Many different types exist, responding to different components (fats, carbohydrates, proteins) in the lumen
- Some types are also stimulated by vagal efferents to the gut
18
Q
What substances are released by enteroendocrine cells in the duodenum and ileum? Where can these compounds travel to?
A
- Compounds released by enteroendocrine cells In the duodenum and ileum include cholecystokinin (CCK) and glucagon-like peptides (GLP-1, GLP-2 etc)
- These compounds can activate vagal afferent nerve fibres and/or enter the bloodstream to travel to the hypothalamus
19
Q
What is ghrelin and what is its nickname? Where is it produced? When do its levels rise and fall?
A
- Ghrelin is sometimes called the ‘hunger hormone’
- Ghrelin is a protein hormone produced by enteroendocrine cells in the fundus of the stomach and to a lesser degree other parts of the gut including duodenum and ileum*
- Serum ghrelin concentrations rise before meals and fall after meals.
- Ghrelin levels increase at night and decrease after breakfast.
- Serum ghrelin increases steadily during long -term fasting and returns to normal after re-feeding
20
Q
How are the triggers of ghrelin release unlike most enteroendocrine cells? What are the triggers for its release? What pathway does ghrelin also stimulate?
A
- Unlike most enteroendocrine cells, ghrelin release is not triggered by chemicals in the gut lumen, but by low levels of blood glucose (exact mechanism unknown).
- Stomach contractions (hunger pangs) can also trigger ghrelin release.
- Ghrelin acts on cells in the hypothalamic arcuate nucleus to generate a sense of hunger.
o High levels of insulin in the blood inhibit ghrelin secretion
o High levels of leptin in the blood also inhibit ghrelin secretion - Clinical Note: Ghrelin also stimulates a dopamine pathway in the brain that is responsible for the pleasurable (hedonic) aspect of eating. It is possible that in anorexics this pathway is somehow disconnected and anorexics do not get the normal pleasurable sensations from eating.
21
Q
What does ghrelin stimulate in the arcuate nucleus? What do these in turn stimulate? How does this mediate a feeling of fullness?
A
- Ghrelin stimulates neurons in the arcuate nucleus that contain neuropeptide Y (NPY) and agouti-related peptide (AGRP). These cells stimulate cells in the limbic system that produce the sense of hunger. They also inhibit other cells (POMC & CART cells) that mediate a feeling of fullness (satiety). Thus ghrelin activates hunger and inhibits the sense of satiety, stimulating one set of hypothalamic neurons and inhibiting a second set.
See diagram in lecture notes
22
Q
What is cholecystokinin and how does it inhibit feeding?
A
Cholecystokinin (CCK) , is a peptide synthesised by enteroendocrine cells in the mucosal epithelium of the small intestine and secreted in the duodenum when food (chyme) moves from the stomach to the duodenum.
o It causes the release of digestive enzymes from the pancreas and bile from the gallbladder. It is released into the blood and travels to the hypothalamus as well as the pancreas. CCK acts on cells in the arcuate nucleus to produce satiety. Thus it is a satiety signal.
o CCK acts rapidly to induce a sense of satiety or even nausea. Thus it may one of the main hormones whose rise signals satiety at the end of a meal,
23
Q
What is glucagon-like peptide 1 (GLP-1) and how does it inhibit feeding?
A
Glucagon like peptide 1 (GLP-1) is another hormone released as a consequence of nutrients in the gut and it also produces satiety by an action on the arcuate cells. GLP-1 inhibits gastric emptying (part of the ‘duodenal brake’ mechanism) and stimulates insulin and inhibits glucagon secretion.
- GLP-1 is an incretin. Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin r from pancreatic beta cells by a blood glucose-dependent mechanism. Thus incretins help prevent glucose overshoot and hyperglycemia after a meal.
See diagram in lecture notes
* GIP in the diagram is gastric inhibitory peptide. Its main role is to stimulate insulin secretion. It is also a weak inhibitor of gastric acid secretion. (hence the name)
24
Q
What do CCK, GLP-1 and other peptides inhibiting feeding stimulate? What is the effect of this?
A
- CCK, GLP-1 and other peptides inhibiting feeding (eg PYY) stimulate neurons in the arcuate nucleus that contain POMC & CART. These neurons stimulate a sense of satiety & stop feeding behaviour. A rise in insulin (triggered by a rise in blood glucose) also activates these ‘satiety neurons’.
See useful flowchart in lecture notes
25
What is pancreatic peptide YY (PYY) and how does it inhibit feeding?
- Pancreatic peptide YY (PYY) is a large peptide hormone synthesized within the gastrointestinal tract in a set of enteroendocrine cells named L cells.
- Within the gastrointestinal tract, PYY increases ileal absorption, slows gastric emptying and delays gallbladder and pancreatic secretion. PYY also enters the bloodstream and acts to inhibit NPY cells and reduce a sense of hunger.
See useful flowchart in lecture notes
26
What is leptin and what do its circulating levels reflect? What does this signal to the hypothalamus? What can deletion of leptin receptors induce? Why is it not a 'satiety signal' to stop eating? What is it instead? Who has a reduced sensitivity to leptin? What else can leptin levels affect?
- Leptin (from the Greek word leptos, meaning thin) is a protein hormone that is produced by adipose tissue.
- The amount of circulating leptin appears to reflect the total amount of adipose tissue in the body. Thus the circulating leptin levels gives the hypothalamus a reading of total energy storage. This is a feedback signal to tell the hypothalamus whether the body is above its ‘set point’ weight or below it. Deletion of leptin receptors in the hypothalamus induces chronic obesity in rats.
- Leptin levels do NOT rise rapidly after a meal, therefore leptin cannot be a ‘satiety signal’ to stop eating.
- Instead it acts as a long-term regulator of appetite. In a normal individual leptin levels control the person’s sensitivity to satiety hormones like CCK and GLP-1
- Obese people may have a reduced sensitivity to leptin and thus have a reduced response to normal satiety signals. (Perhaps like type 2 diabetics have a reduced sensitivity to insulin)
- Clinical note: ** Leptin levels affect fertility. A woman ceases to menstruate and ovulate if circulating leptin decreases below a certain level, as happens in anorexia. The low level of leptin prevents gonadotrophic hormones from being released.
27
Summarise the activity of internal feeding inhibitors.
- Ghrelin is released from stomach enteroendocrine cells into the bloodstream when blood glucose is low. It acts in the arcuate nucleus of the hypothalamus to trigger a sense of hunger. Ghrelin is also released by stomach contractions (hunger pangs).
- Nutrients in the stomach and small intestine (especially duodenum) acts on enteroendocrine cells which release various hormones into the blood stream. These include cholecystokinin (CCK) Glucagon like peptide (GLP-1) & pancreatic peptide PYY . These hormones act in the arcuate nucleus to decrease hunger and generate a sense of satiety. The enteroendocrine cells can also stimulate vagal afferents which add to the sense of satiety
- Damage to the arcuate and paraventricular nuclei leads to a loss of the ability to detect hormones released from the gut. This leads to overeating and obesity due to insensitivity to internal cues when food is readily available.
- Leptin is present in the blood in proportion to total fat stores. It normally acts as a long-term appetite regulator, possibly by changing the sensitivity of arcuate cells to the various gut hormones.
28
Why do humans often drink more than we need to? How do reward pathways work in the brain?
- In normal life most people drink far more than they need to maintain normal body hydration. For example, why do we drink socially in a pub? The answer is that feeding and especially drinking is pleasant and enjoyable, or as the psychologists say “intrinsically rewarding”
- Neurophysiologists have identified a ‘reward pathway’ in the brain, i.e. a brain system that is active when you feel happy, pleased, satisfied, etc.
- Drinking is ‘hard wired’ to this system, so you enjoy the act of drinking, regardless of whether you are dehydrated or not. This pathway is important in a baby; the act of suckling activates this pathway; if it did not, there is a risk that the baby would not feed and hence die. The act of chewing is also intrinsically rewarding; (this is probably why chewing gum is pleasurable despite having no calories).
- Actions of the orofacial muscles during drinking or feeding activate dopamine neurons in the ventral tegmental area of the brainstem. These project to and activate neurons in the nucleus accumbens, a structure deep in the frontal lobe. It seems that activation of the accumbens neurons is the neuronal correlate of feelings of pleasure or reward.
29
What is anorexia nervosa and what are its characteristics? What are its suggested causes within the brain?
- Often referred to simply as anorexia, this is an eating disorder characterized by low weight, fear of gaining weight, and a strong desire to be thin, resulting in voluntary food restriction. Complications may include osteoporosis, infertility, and heart damage. Women will stop having menstrual periods.
- The severity of disease is based on body mass index (BMI). Mild disease is a BMI of 17-18, moderate a BMI of 16-17, severe a BMI of 15-16, and extreme a BMI less than 15.
- Anorexics weigh themselves frequently, eat only small amounts, and become very ‘finicky’ and only eat certain foods. This is similar behavior to rats with medial hypothalamic lesions, and there is evidence for hypothalamic dysfunction in some anorexic patients
- Several studies have shown that anorexics also have reduced pleasure from the smell and taste of food. They also have reduced pleasure from orofacial activity. (drinking and chewing food).
- This suggests that the reward pathway in the limbic system may somehow have become disconnected from the system for food intake in these subjects; feeding and drinking is no longer rewarding and may even become repugnant to them.
- Some recent studies* have suggested that dopamine reward neurons have become ‘rewired’ in anorexics so they are paradoxically activated by hunger and inhibited by eating
30
Summarise the main points of this lecture.
1. The hypothalamus controls eating and drinking.
2. Water intake is controlled by osmoreceptors. Thirst increases and ADH is released when plasma osmolarity is too high. ADH release is suppressed and ANP release is increased when osmolarity is too low.
3. Food intake is controlled by several factors. Lesion studies initially suggested a ‘satiety centre’ in the medial hypothalamus (nuclei around the third ventricle) and a ‘hunger centre’ in the lateral hypothalamus. It is now accepted that all the nuclei controlling feeding are in the medial (arcuate) nuclei of the hypothalamus.
4. Grhelin is released from enteroendocrine cells in the stomach when it contracts and act on certain arcuate cells to produce the sensation of hunger.
5. CCK, PYY GLP-1 and other peptides are released from other enteroendocrine cells in the gut during feeding and trigger a sense of satiety by acting on other arcuate neurons.
6. The ‘hunger’ neurons (AGRP & NPT) and the ‘satiety’ neurons (POMC & CART) mutually inhibit each other.
