C21 – Neuroendocrine System Hypothalamus PDF

PHYSIO 21 – Hypothalamus - From autonomic actions to motivational states Parallel to the somatic system, the vegetative system has a sensory domain and a motor domain. -​ The sensory domain is fed by interceptors: o​ afferents enter the spinal cord by posterior roots (having cell b...

PHYSIO 21 – Hypothalamus - From autonomic actions to motivational states Parallel to the somatic system, the vegetative system has a sensory domain and a motor domain. -​ The sensory domain is fed by interceptors: o​ afferents enter the spinal cord by posterior roots (having cell bodies in dorsal root ganglia). The incoming information then activates the efferent branch or ascends towards the higher cortex. -​ Motor domain is through sympathetic and parasympathic system and are o​ Smooth muscle o​ Cardiac muscle o​ Glands o​ Adipose tissue The ANS mainly operates through refleexs, visceral reflexes under the model of: input sensory efferent output. These reflexes are much more complex and are under the control of supraspinous organs, who orchestrate the activity of the vegetative system. When running, the heart rate and the blood flow to muscles increases before the lack of CO2 due to inadequate ventilation. In stressed conditions, the system unbalances to sympathetic. In unstressed conditions, the system unbalances to parasympathetic. The vegetative system is not a passive system working only on reflexes but is complex and is controlled by supraspinous organs able to orchestrate its activities, and there must be a coherence between the activity of the vegetative system and the endocrine system. The coherence occurs ALO of the hypothalamus. 1.​ Visceral reflexes Slow and rapid responses to a sensory stimuli from an interoceptor. Within visceral reflexes exist neuroendocrine reflexes, triggering the release of hormones in response to a stimuli. Preganglionic neurons are the lower motoneurons of the vegetative system. Preganglionic neurons are excited by interoceptor inputs but also from autonomic upper motor neurons from the brainstem, hypothalamus, and limbic structures. They allow their coordination. The supraspinal structures can organize and tune the systems depending on the needs, that are transmitted through sensory information. Responsiveness are conveyed through these central autonomic regulatory systems which help coordinate appropriate autonomic responses. The central autonomic regulatory systems coordinate autonomic responses that affect visceral functions (reflexes) and neuroendocrine outflow. A hierarchy forms: 1)​ FOREBRAIN formed of the amygdala and limbic cortex and the hypothalamus a.​ Amygdala and limbic cortex: gives origin to the cognitive behaviours which can be motivationally or emotionally driven b.​ Hypothalamus: center for motivational and homeostatic drive states 2)​ BRAINSTEM centers of control for cardiac, respiratory and GI functions 3)​ SPINAL CORD autonomic reflexes triggered by cuntaneous and internal stimuli. Pathway 1 (lowest level): Sensory stimuli can act on the somatic and visceral sensory neurons, activating the spinal interneurons in the lateral horn (lamina VII) causing the autonomic response, a reflex. Pathway 2: the stimulus acts, via somatic sensory neurons, on the hypothalamus, driving the brainstem with the descending system (hypothalamic-spinal and reticulospinal). Interneurons act on preganglionic neurons, causing vegetative or endocrine responses. Pathway 3: together with the brainstem and hypothalamus, also the limbic system of the cortex is activated: in this case the cortex can act on the brainstem and hypothalamus or generate behavioural responses. 2.​ 3rd level 3.​ 2nd level At the level of the brainstem, respiratory, cardiac and GI centers are found. The interoceptors of the heart, lungs, and GU tract send information directly to the brain. The regulation of the CV, respiratory and GU systems is done via the brainstem. Each system receives information from -​ Upper brain stem -​ Hypothalamus -​ Telencephalon Homeostatic regulation of arterial blood pressure, respiration and gastrointestinal functions are represented in the lower brain stem. These control systems require temporally precise coordination and adaptation to somatic body functions and are therefore closely integrated. This integration is reflected in the anatomy and physiology of the neural substrates of these homeostatic regulations in the lower brain stem. Two different ponto-medullary respiratory networks and the cardiovascular network send information to respiratory premotor neurons (generating the respiratory cycle), parasympathetic premotor or preganglionic neurons, or sympathetic premotor or preganglionic neurons. The signals sent by the respiratory and cardiovascular networks connect with each other: these control systems require temporally precise coordination and adaptation to somatic body functions and are therefore integrated. Brainstem structures other than the centers are the periacqueductal grey, the medial and lateral paracore reticular formation and the second order neurons receiving from the periphery. 4.​ 1st level Composed of -​ Limbic cortex and amygdala: responsible of the emotional and motivational cognitive behaviour -​ Hypothalamus: controls motivational and emotional “drive states”. The amygdaloid nucleus and forebrain structures project to hypothalamus. Hypothalamus is split into 2 parts: -​ Vegetative part: projects to o​ the brainstem centers, who in turn project to the preganglionic sympathetic neurons in lateral horn of the spinal cord o​ preganglionic sympathetic neurons in lateral horn of the spinal cord directly targets the vegetative system -​ puituitary part: prekects to the pituitary gland; causing the hypophysis to release hormones. Hypothalamus therefore projects to the endocrine and the vegetative systems. 5.​ Hypothalamus Anatomical division The hypothalamus is a very tiny stucture, weighing about 4g, located in the brain. It is a group of nuclei, that can be divided with different classifications. One possibility is to divide it anatomically in three regions containing different nuclei: -​ Anterior region: o​ Preoptic nucleus ▪​ Medial ▪​ Lateral o​ Supraoptic nucleus o​ Paraventricular nucleus o​ Anterior nuclei o​ suprachiasmatic nucleus -​ Middle region: o​ Dorsomedial nucleus o​ Ventromedial nucleus -​ Posterior region: o​ Mamillary nucleus o​ Posterior nuclei Functional division This is a horizontal section of the hypothalamus surrounding the third ventricle, that divides the nuclei sagittaly around itself. A right and a left symmetrical sectors can be recognized. Three mediolaterally distributed zones can be recognized: -​ periventricular, -​ medial -​ lateral The periventricular zone is organized in -​ anterior portion -​ periventricular portion The yellow portion is endocrine, while the red spots are part of the autonomic system. Neurons of the hypothalamus are organized in -​ nuclei that are part of the prime mover of the endocrine system -​ nuclei that are part of the vegetative system. In endocrine portion, we can recognize three endocrine nuclei: -​ supraventricular -​ paraoptic -​ arcuate This region is divided in two portions: -​ the supraoptic nucleus and the pars magnocellularis of the paraventricular nucleus end up into the neurohypohysis, -​ the arcuate nucleus and pars parvicellularis of the paraventricular nucleus communicate with the adenohypophysis. The paraventricular nucleus is split in two parts, the magnocellularis (working w supraoptic neurohypophysis) and the parvicellularis (working w the arcuate nucleus adenohypophysis). In the autonomic portion, instead, there is the hypothalamic generator of autonomic motor activity, in which the nuclei act on the preganglionic sympathetic neurons, either directly or via the brainstem.  6.​ Hypophysis (neurohypophysis) The endocrine portion of the hypothalamus is connected mainly to the pituitary gland, and receives info from the hippocampus, thalamus and neocortex, amygdala, other regions of the hypothalamus such as the suprachiasmatic nucleus. The neurohypophysis originates from the supraoptic and magnocellularis nuclei. This part of the pituitary gland is not composed by epithelial tissue but by the axons of the neurons of these nuclei, descending in the bulk and ending up in the hypophysis. Thus, this gland is itself an appendix of the hypothalamus. The axons terminate on a capillary bed formed by the Hypophyseal artery and a venule. By looking at the synaptic portion of the axon, it can be seen that the synapsis occurs with a vessel, and the neurotransmitters running in it are released into the blood, becoming hormones. This is called neuro-endocrine secretion. The hormones released are: -​ Oxytocin: Oxytocin acts at the level of the uterus during labour and on mammary glands when the mother is feeding the baby. o​ In the first case, the target is smooth muscle, inducing contractions of the uterus o​ the aim is to help the “sucking” of the baby, not causing a sufficient negative pressure by itself, to extract milk from the breast. As soon as the mouth of the baby touches the breast, receptors induce a reflex that projects to the hypothalamus inducing the release of Oxytocin, that targets the smooth muscles on the mammillary ducts, constricting them and pushing milk toward the baby.  -​ Anti-Diuretic Hormone (ADH): it is primarily involved in the maintainance of osmolarity of interstitial and cellular body fluids. Intracellular and extracellular fluid are very similar from the point of view of osmolarity. The aim of our body is to avoid having cell swelling or shrinkage because of changes in osmolarity, so the osmolarity must be kept constant. -​ In most of the tissues, water and solutes can pass through the membrane; therefore, in order to correct the osmolarity, water and ions can be moved. -​ However there are some cells (eg: in the brain) where only water can be moved; problems in brain osmolarity would cause it to swell or shrink, leading to very dangerous brain damages. So, unbalances of ions, among which the most important is sodium, must be corrected. It is necessary to cure these problems slowly, since an immediate shrinkage or swelling would damage the brain too. The hypothalamic nuclei where this neurotransmitter/hormone is released are themselves the osmo-receptors, since they are equipped with a special membrane able to sense movements of water. As soon as an imbalance in homeostatic pressure is perceived, more or less ADH is released. ADH targets the kidneys, where it acts at the level of the collecting ducts, reabsorbing only water (not salts!). together with this function, it also is a vasoconstrictor. However, cell nuclei are more sensitive to imbalances in osmolarity rather than in pressure. The release of this hormone is triggered in case of a drop in arterial pressure, since the absorption of water counterbalances hypotension. ADH The target of vasopressin (also known as anti-diuretic hormone) is the collecting duct of the nephrons of the kidney. They are tiny peptides which connect with receptors on the membrane of the cells of the collecting duct and request the expression of aquaporins in the membrane. This allows the reabsorption of water without salt. This is the only hormone able to correct the osmolarity of body fluids: blood, interstitial fluid, and extracellular fluid. The same neurons which release the hormone are also osmolarity sensors – so they have both functions. As soon as they detect a change is osmolarity they then modulate the release of vasopressin, and this regulates the reabsorption of pure water. When the aquaporins are opened, water flows from the tubule into the blood system. In the medullary portion of the kidney we have a gradient of hypo-osmolarity which allows, when you open the door, the pure water to flow out without the salts. This is the only way to dilute the interstitial fluid. If the salt came too, it would just add volume, but the osmolarity would stay the same. So vasopressin increases water retention. Vasopressin can also vasoconstrict arterioles and can stimulate the release of adrenocorticotropic hormone. Oxytocin Oxytocin is needed for labour and for lactation. It can increase uterine muscle contraction. During pregnancy the uterus keeps increasing the number of receptors for oxytocin. When the fetus signals that it is time for labour, oxytocin is released. If labour doesn’t start when expected, oxytocin can be administered to the mother. Contractions behave as a syncytium. They are fast and homogenous. The cervix has stretch sensors, which signal to the hypothalamus to release more oxytocin, so it is an example of positive feedback. When the baby comes out, the positive feedback loop stops because there is no more stretch, and the release of oxytocin stops. A strong post labour uterine contraction is needed to push out the placenta and also in order to prevent the blood-filled villi of the placenta causing a hemorrhage. The contraction helps to keep the blood contained. Oxytocin isn’t involved in the production of milk, it helps with the ejection of milk, by causing the myoepithelial cells around the gland to contact, because the sucking pressure of baby isn’t enough to eject the milk. It also contributes to regression of corpus luteum and in males may also contribute to sperm progression during ejaculation. ​ 7.​ Hypothalamic-hypophyseal axis (adenohypophysis) Unlike the posterior lobe of the pituitary gland, the ante- rior lobe does not receive axon terminals from hypothalamic neurons. The hypothalamus communicates with the adenohypophysis via the hypophyseal portal system. The axons travel to the median eminence which is also the site of a capillary bed from the hypophyseal artery. But the venule doesn’t go out in systemic circulation. The venule goes down to the anterior hypophysis and generates a second capillary bed, and the venule from this capillary bed then goes into systemic circulation. This is called hypothalamic/hypophyseal portal system. This is portal system because there are 2 capillary beds in series. This portal system can be seen as private lift. The blood from the first capillary bed goes down in private lift then exchanges with interstitial fluid via the second capillary bed, then goes out into systemic circulation. It is a chemical private lift because the neurotransmitters are released at the first capillary bed, and they are not mixed with the systemic blood or diluted, and then go straight down to the anterior hypophysis where they can act and result in the secretion of hormones. This is called the hypothalamic-hypophyseal axis.  Parvocelluar neurons (small cells) located in the arcuate nucleus and other periventricular zone nuclei, and cells of the paraventricular, suprachiasmatic, tuberal, and medial preoptic nuclei of the hypothalamus give rise to fibers hat become incorporated in the tuberohypophyseal tract. These cells synthesize various releasing hormones (factors) and release-inhibiting hormones (factors). The target of these hormones is usually other endocrine glands. The hypothalamus is the one which drives the release of hormones in hypophysis. The hypophysis doesn’t decide when to release hormones, it only produces them. The releasing hormone from the hypothalamus goes down the private lift and acts on the anterior hypophysis, which releases hormones, which then act on other endocrine organs, which then release a second hormone, which finally acts on the target. The organ in charge is the hypothalamus, followed by the hypophysis, followed by the endocrine gland. The hypophysis is sometimes called the conductor of the endocrine system, but this conductor is controlled by the hypothalamus. So it is the nervous system which controls the endocrine system. Hormones are always constantly/tonically being released. They are in charge of maintenance of tissue trophism, metabolism, renewal of the extracellular matrix, and they act on widespread targets. So the hypothalamic-hypophyseal axis is always active. It is the modulation of the axis which is important. Sometimes the system needs more of something, so a hormone is increased or decreased according to environmental needs. The hormones are in constant communication with the tissues. Because the action of these hormones is global and there are loads of targets, there is no one parameter to check that the hormone is working. Other hormones have a single parameter, like insulin or glucagon, where the parameter is the level of glucose in blood. Depending on the modulation of glucose in blood, Langerhans cells release the correct hormone to keep the correct level of glucose in blood. It is similar for calcium homeostasis, involving parathyroid hormone and calcitonin, which act on kidney, intestine and bones. Here calcium level is the parameter. a.​ Hormones released The RELEASING hormones produced by the hypothalamus are: -​ somatotropin-releasing hormone (SRH), which stimulates the release of somatotropin (GH) o​ produced in the periventricular and arcuate nuclei -​ prolactin-releasing hormone (PRH), which stimulates the release of prolactin (PRL)  -​ corticotropin-releasing hormone (CRH), which stimulates the release of adrenocorticotropin (ACTH) o​ neurons are located in the parvocellular paraventricular nucleus; -​ gonadotropin-releasing hormone (GnRH), which stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); -​ thyroid-stimulating hormone-releasing hormone (thyrotropin-releasing hormone, TRH), which stimulates the release of thryoid stimulating hormone (TSH) o​ neurons are located in the periventricular, ventromedial and dorsomedial nuclei of the hypothalamus; -​ melanocyte-stimulating hormone-releasing hormone, which releases melanocyte-stimulating hormone (MSH). The RELEASE-INHIBITING hormones produced by the hypo thalamus are: -​ somatostatin, which inhibits growth hormone (GH) and TSH release o​ produced by neurons in the periventricular nucleus -​ prolactin-inhibitory factor (PIF, dopamine), which inhibits the release of prolactin; -​ melanocyte-stimulating hormone inhibitory factor (MSHIF), which inhibits melanocyte-stimulating hor mone (MSH) release. 8.​ Autonomic zone of the hypothalamus a.​ Periventricular zone The periventricular autonomic zone is shown by the red dots in the below image, representing 6 nuclei. They receive INPUTS from -​ the solitary tract nucleus, -​ medial hypothalamus -​ prefrontal cortex  -​ amygdala. The prefrontal cortex is the origin of the networks that allow people to have higher cognitive function/executive function, they allow people to have appropriate behavior with respect to environmental context e.g. inhibition of instinctual behavior that is not appropriate for social context. If there is damage to the prefrontal lobes, there can be behavior which is not appropriate. The amygdala is part of limbic system which is related to emotional drive. The solitary tract is part of the autonomic system, so it is natural that it inputs here. In terms of OUTPUT, these autonomic nuclei communicate with the rest of the hypothalamus and brain stem premotor autonomic neurons. They organize the balance between parasympathetic and sympathetic systems and adjust the activity of autonomic system to the context. b.​ Medial zone The medial zone contains what is called the biological clock, the suprachiasmatic nucleus. It organizes the time course of the activation of all the functions of the body which is called the circadian rhythm, which adapts our systems to the rhythms of the earth. It has connections to: -​ the periventricular zone, so it can influence the endocrine and autonomic systems. -​ other parts of the medial zone, which are involved in sleep/wake cycles, -​ the parts of the lateral zone involved in food ingestion. The suprachiasmatic nucleus can communicate with all of the hypothalamus, and therefore all of the body. ​ ​ The behavioral column, represented in green in the image below, is made up of six nuclei. ​ The anteroposterior part is involved o​ in death stimulation, which is a way to escape a predator, o​ in signaling whether it is time for reproduction or not. ​ The preoptic premamillary area is involved in thermoregulation ​ the pars parvicellularis paraventricular nucleus is involved in water and food intake. ​ These nuclei are in contact with the mesencephalic substantia nigra and ventral tegmental mesencephalic area which are involved in explorative behavior. The substantia nigra fires according to environment context rather than with a big background discharge. c.​ Lateral zone The lateral zone is the most complex area of the hypothalamus and the least well understood. It connects the hypothalamus to other brain structures. It releases hypocretin/orexins which control hunger, food intake and are involved in cardiovascular control. The lateral zone has a diffuse effect on CNS so hard to figure out what it does specifically. OVERVIEW: An general overview/list of hypothalamic functions from endocrine/ visceral to behavioural responses includes: 1)​ control of blood pressure 2)​ control of blood electrolyte composition 3)​ control of body temperature 4)​ control of energy metabolism 5)​ control of stressors 6)​ control of reproduction. Because the hypothalamus is involved in such a wide array of functions it needs: -​ Information: and it does receive a lot of inputs. -​ A system of comparison between the desired state and current state. -​ Ability to act on the vegetative and endocrine systems. 9.​ Inputs to the hypothalamus Circumventricular organs are structures near the midline, around the third and fourth ventricles which contain vessels without the blood brain barrier. There are receptors for hormones contained in the circumventricular organs. There are secretory interruptions in the blood brain barrier in the median eminence, and this is how axons from the arcuate nucleus can release peptides into the blood. Without these interruptions there could be no cross talk between the anterior hypophysis and the blood. In the sensory domain of the vegetative system, there are second order neurons located in lamina 1,5, 7, 8 that go to -​ brainstem, o​ solitary tract nucleus, o​ dorsal motor nucleus of the vagus nerve o​ reticular formation. -​ Pons o​ parabrachial nucleus, o​ raphe nucleus, o​ reticular formation, o​ periaqueductal gray -​ hypothalamus directly -​ Thalamus: goes then to the limbic lobe (insula and cingulate) and to the hypothalamus  -​ The image also shows that the hypothalamus not only receives input from the solitary tract nucleus but also raw data from second order neurons. So it receives info that has been computed and integrated by the brain stem but also raw data from spinal cord that has not. Then there are also third order neurons go to the thalamus then to the hypothalamus or forebrain insula/cingulate gyrus. 10.​Set point concept In relation to the hypothalamus, there is also the concept of the set point. There is a desired target and range of tolerance, and the hypothalamus compares the desired value with actual value of parameter and if needed it modulates the tonic release of a releasing hormone. For example, when it is cold, hypothalamus will -​ force an instinctual behavior to put on more clothes. -​ act on an unconscious level to try and reduce heat loss by vasoconstriction. This is why people, when it’s cold, will have white hands, because blood is being sent to the core and the blood vessels near the skin close in order to stop the exchange of heat with the environment. -​ Shivering is also an unconscious reaction to cold. They are all driven by hypothalamus even though 2 are autonomic, and one is behavioral (instinctual behavior rather than cognitive). There is a sinusoidal variation of values determined by the suprachiasmatic nucleus of the hypothalamus, who acts as a internal clock. For example the body temperature will have a different temperature set point at 3am compared to 3pm. The hypothalamus is not merely monitoring a constant set point for different parameters throughout the day. The set point oscillates, and the hypothalamus needs to know the set point for different times of the day. The suprachiasmatic is what tells the others that the set point has changed. ​ The vegetative system is not just made up of preganglionic/ postganglionic neurons in the periphery. It includes part of brain, listed in the image below. The CNS portion of the vegetive system also talks with the associative cortices and parts of limbic system that are associated with emotional drive, e.g. the amygdala. ​