Internal Mechanisms Associated With Eating & Drinking

Part 1: Fluid Regulation

1. Stimuli (change in internal conditions), that stimulate both volumetric and osmotic thirst and experiments that disrupt normal thirst and drinking behavior.

We’ll start by differentiating between osmotic and hypovolemic thirst; Osmotic thirst is the most common type of thirst and hypovolemic literally means “low volume” (for instance, hypovolemic shock is when one goes to shock after losing blood). Molarity (the number of particles per unit of solution by volume) is closely related to osmotic thirst. Water is able to flow in and out of the membranes of our cells; i.e., they are semi-permeable. Because water can flow in and out, when the number of solutes increases outside of the cells, water flows out due to this “osmotic pressure”. When you eat something salty and the number of solutes in the extracellular fluid increases, certain neurons detect the shift when the water leaves their intracellular area. Osmotic thirst motivates us to drink water while our kidneys work to keep more water in our system by excreting more concentrated urine. The third ventricle is where our brain detects such discrepancies; surrounding receptors like the organum vasculosum laminae terminals and the subfornical organ (SFO) are aware of blood content as they aren’t subject to blood-brain-barrier as most of the brain is; that is to say that it is weaker there, not non-existent. The SFO has neurons that increase thirst and also neurons that suppress it. These axons take a combination of information from the OVLT (Organum Vasculosum Laminae Terminalis) and other relevant areas and send a message to the hypothalamus, where the lateral preoptic area lives. Thus far I’ve talked about how our cells react to dehydration to maintain homeostasis, but we also learned about allostasis. Our bodies anticipate our need for water and once we’ve filled that need the motivation to continue drinking is inhibited. Researchers found that in a mouse’s brain, a certain amount of time spent drinking will suppress the activity of the neurons responsible for thirst sensitivity in the SFO, before the water has reached the blood or brain. Drinking water is relevant to temperature regulation as well as molarity and volume. When vasopressin is released, this prompts the body to save water in preparation for sleep, but it also makes us thirsty.

Volumetric thirst is less common and can be satisfied by drinking slightly salty or non-pure water. Sodium-specific hunger is also triggered due to such imbalances. Bleeding, diarrhea and sweating can all cause hypovolemic thirst if we don’t maintain hydration. Low volume of bodily fluid creates low blood pressure, which signals the kidneys to send messages to the brain prompting release of vasopressin. One of the experiments Dr. Ettinger describes, works by restricting blood flow to the kidneys of an animal, which prompts the animal to drink immediately. The kidneys also release renin, an enzyme that separates the protein angiotensinogen into a new protein called angiotensin I which is then converted to angiotensin II. Angiotensin II constricts the blood vessels to further compensate for the decrease in blood pressure. When angiotensin II is detected by the third ventricle, axons to the hypothalamus prompt release of angiotensin II in the brain. Because we strive to maintain a certain level of sodium, pure water is not the best response to hypovolemic thirst. When we are low on sodium, salty food taste especially good due to changes in the taste receptors brought on by a combination of aldosterone and angiotensin II. Aldosterone is the hormone that initiates salt retention in the sweat glands, kidneys, and salivary glands.

There have been many animal experiments illuminating the importance of both osmotic and hypovolemic thirst alike. Fluid regulation is absolutely critical to many bodily systems, which may be why we are apt with mechanisms to keep our bodies aware.

There have also been experiments using polyethylene glycol (antifreeze). By injecting it into the gut of an animal, osmotic mechanisms were triggered due to the imbalance in fluids and cellular dehydration. When these thirst mechanisms are triggered the urge to drink is nearly immediate. Sadly, around 10,000 animals die each year from liver failure after drinking antifreeze. Companies have been asked to add bitterant so that animals will avoid drinking it, but despite the low cost, companies refuse to do so (Ettinger, 2020).

  • Neural structures that detect perturbations in fluid balance. What signals do they receive and how do they respond to them?

Increased osmotic pressure of blood draws water out of cells, dehydrating them. When this happens, Neurons in the OVLT and SFO detect changes and send information to hypothalamic structures that release vasopressin. The SFO works to anticipate future needs but decreases thirst signals after we drink even before the water has reached our blood or brain. Thirst brought on by loss of blood volume is much less common; furthermore, we have to replace the solutes as well, not only the liquid, so this type of thirst is better satisfied with a combination of water and solutes. Volumetric dependent thirst is triggered by angiotensin II. The kidneys release renin, which separates the protein angiotensinogen into angiotensin I, which is then converted to angiotensin II. Angiotensin II constricts the blood vessels to further compensate for the decrease in blood pressure. When angiotensin II is detected by the third ventricle, axons to the hypothalamus prompt release of angiotensin II in the brain. Because we strive to maintain a certain level of sodium, pure water does not satisfy hypovolemic thirst. When we are low on sodium salty food taste especially good due to changes in the taste receptors brought on by a combination of aldosterone and angiotensin II. Aldosterone is the hormone that initiates salt retention in the sweat glands, kidneys, and salivary glands.

Part 2: Feeding Regulation

3. How early (1940s-1980s) theories regarded the roles of the ventromedial and lateral hypothalamus in feeding and how they are implicated today. 

Lesions studies between the 1940’s -1980’s show the effects of electrolytic ablation of the lateral hypothalamus. Chemical lesions of the LHA suppress feeding and drinking but lesioning of the VMH (Ventromedial Hypothalamus) promote feeding and body weight gain according to the classical studies. Chemical lesions that ablate LHA (Lateral Hypothalamus) somata, but spare passing fibers, also suppressed feeding and drinking. Early studies that used electrical stimulation of the LHA in rodents showed that electrical activation of the region caused voracious feeding and reinforced food seeking behaviors to gain additional stimulation, suggesting that the LHA region is not only critical for feeding behavior, but also reinforcement processes. A 1958 study “Hippocampal projections and Related Neural Pathways to the Mid-Brain in The Cat”, states that the fornix system is expanded by secondary neural pathways arising from recipient structures of the direct hippocampal projections. According to the study, secondary pathways including those arising in the septal area had been analyzed in some detail in the rat by experimental methods. It is apparent in these studies that in the rat both structures project directly to the mid-brain by way of the medial fore-brain bundle, while an additional pathway of septal origin follows the stria medullaris to the medial nucleus of the habenular complex (Nauta,1958).

The introduction of optogenetic stimulation greatly improved accuracy and differentiation in these studies. While electrical stimulation allows little differentiation, optogenetic methods allow researchers to activate specific areas. Contemporary research tells us that output from the PVN (Paraventricular Nucleus) acts upon the LHA, which controls insulin secretion and controls feeding habits in many ways. An animal with damage to the LHA will refuse to eat or drink to the point of starvation without intervention. Stimulation of the LHA, inversely, increases hunger drive. Damage to the area impacts axons containing dopamine that pass through the area. To differentiate the role of the cells and the axons passing through, researchers used chemicals that damage the cell bodies or experimented on young rats in which case the axons had not yet reached the hypothalamus, which inhibited feeding without disrupting physical activity. The axons that pass through the lateral hypothalamus are associated with arousal and reward. The VMH sends signals that inhibit feeding, damage to this area leads to overeating and weight gain. People with a tumor in this area have been shown to gain substantial amounts of weight rapidly and rats with damage to the area gain weight as well. Damage that is limited explicitly to the VMH does not always increase body weight and feeding habits; the lesion must extend beyond the ventromedial nucleus and affect the nearby axonal pathways. Rats that have damage to this area eat the same amount per meal as normal, but they eat far more often. Insulin production is increased in an animal with this type of damage, so while they are eating plenty, much of their nutrition is being stored as fat and they are essentially starving; so they would gain weight even if they were prevented from eating extra (Kajal, 2019).

  • The role of leptin in regulating hunger and food intake.

Leptin (which is only found in invertebrates) is a hormone released by fat molecules to helps us monitor our fat supply. Unless you have a mutation in the gene that prompts you to produce leptin, the amount of leptin you have will depend on the amount of fat you have. When your fat reserves decrease and leptin levels lower causing a need to eat more and do less physical activity. Unfortunately, while decreasing levels of leptin make us want to eat—increasing our level of leptin does not do much to reduce appetite. Historically, it has been more important to eat than to reduce our diets, so from an evolutionary standpoint, it makes perfect sense that we have more in the way of biological mechanisms that prevent starvation but less so for obesity (Kajal, 2019). 

5. The article on obesity by Page et al.

Found interesting neural correlates of hunger. What did they find and why this is important as we develop strategies to decrease obesity in this country?

According to the study, fasting increases activation of the hypothalamus, insula and striatum which are important reward/motivating systems. Generally, eating a meal activates the prefrontal cortex which is important for executive function and decision making. The study connected glycemic (hypo vs eu) state to the former body of research and used blood glucose levels in combination with food cues to determine a connection. During periods in which blood glucose levels were normal, in non-obese individuals, the prefrontal cortex activation and decreased wanting of food was consistent, not dependent upon caloric density of the food; when blood glucose levels were low, reward systems were indicated in association with high-calorie foods. In obese individuals, reward systems were activated during hypoglycemic and euglycemic states without PFC, higher order thought process, activation. The study found that obese individuals may be more affected by food related striatal activation when their blood sugar starts to drop. Small decreases in blood glucose decrease PFC inhibitory control and promote overeating of foods dense in calories. The study confirmed that individuals with higher BMI (body mass index) show less prefrontal activation after a meal and at rest. Furthermore, the obese individuals showed reduced postprandial (after meal) deactivation of the hypothalamus. Essentially the neural circuitry of the individuals was related to BMI and dissimilar in ways that could contribute to overeating. The study indicates that a good strategy to minimize this would be to eat smaller meals more often to avoid sharp decrease in circulating blood-glucose levels. This study is important because it elucidates the connection between blood-glucose levels and our feelings towards food while also showing that declining blood glucose levels override insulin related satiety signals.

  • Why don’t we expect a new drug to be developed that reduces both motivation to eat and body weight significantly? Remember the last attempt was fen-Phen. Why not leptin or some other hormone?

Drugs that reduce motivation to eat and body weight often have severe consequences and are not safe. We have so many neural circuits that tell us we need to eat and fewer that tell us when not to eat; moreover, the ones that do tell us when not to eat are not as strong as those that tell us to eat (hunger signals are stronger than satiety signals). Essentially, there are too many systems involved in food motivation to inhibit them all safely while still eating enough to stay healthy. Illicit drugs such as methamphetamine excite the reward system and also hinder appetite, but destroy the body in the process. Obesity is not only a matter of will-power but of the types of foods available to us today. We are surrounded by high-calorie foods and we have evolved to enjoy eating. In one study, students swallowed a tube and fed themselves without eating the food and they tended not to like it. Fen-phen was considered extremely promising before it was found to be damaging heart valves. 

Binge eating is known to excite the same neural circuits as drug addiction, so image being a drug addict where drugs were offered several times per day and depicted in magazines and on tv. Alcoholics have to exercise much willpower to eliminate drinking from their lives; imagine how much worse it would be if you had to drink a certain amount of alcohol to be healthy but if you drank too much you would be unhealthy as it is with food. For those that don’t have a problem with weight gain and control it’s already a non-issue, but for those that do it can be a lifelong struggle. Most obese people are not obese because of leptin deficiency, so leptin would not help. Gastric bypass surgery is one of the best medical interventions regarding obesity and often times patients must prove that they can lose a certain amount of weight by abiding by a stricter diet before doctors will go to such an extreme because relapse is so common. Another interesting study indicates that the type of micro-organisms present in lean mice can be implanted into overweight mice to help them lose weight; while the outcome was good, they did so by taking the feces of one mouse and implanting it into the digestive tract of another mouse. There are most certainly be some hurdles to cross before this becomes a viable option for humans, and there is still the impulse control problem to overcome or the weight lost will simply return!

Kalat, J. W. (2019). Biological psychology (13th ed). Boston, MA: Cengage.    

Page, K. A., Seo, D., Belfort-DeAguiar, R., Lacadie, C., Dzuira, J., Naik, S., Amarnath, S., Constable, R. T., Sherwin, R. S., & Sinha, R. (2011). Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. The Journal of Clinical Investigation 121(10), 4161-4169. to an external site.

Stuber, G, D., & Wise, R. A. (2016). Lateral Hypothalamic Circuits for Feeding and Reward. US Natioal Library of Medicing National Institutes of Health (2), 198-205. http://doi.org10.1038/nn.4220


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