UNIVERSITY OF JORDAN FACULTY OF MEDICINE DEPARTMENT OF PHYSIOLOGY & BIOCHEMISTRY NEUROPHYSIOLOGY (MEDICAL) Spring, 2014 Textbook of Medical Physiology by: Guyton & Hall, 12 th edition 2011 Eman Al-Khateeb, Professor of Neurophysiology No.10 Limbic system: Limbic = limbus in Latin and means arc, it means the border system. It is that part of the brain that consists of a rim of cortical tissue around the hilus of the cerebral hemisphere that start from the orbitofrontal area, subcallosal gyrus, cingulate gyrus, parahippocampal gyrus & uncus (Limbic cortex) and a group of interconnected complex of basal brain elements that includes amygdala, hippocampus, paraolfactory area, anterior nucleus of thalamus, septal nucleus and hypothalamus. Hypothalamus from the physiological point of view is one of the central elements of this system. The limbic system has connections with the reticular nuclei of brain stem; an important communication is the medial forebrain bundle, which extends from orbitofrontal and septal nuclei through hypothalamus to the reticular nuclei of brain stem. One of the characteristics of emotions is that it cannot be turned on and off at will, because limbic circuits have prolonged after - discharge following stimulation. This may explain why emotional response is prolonged and outlast the stimuli that initiate them. Function of the subcortical limbic structures: Hypothalamus: It is considered the major control headquarter for the limbic system. It has many endocrine and vegetative functions besides its major role in behavior. Behavioral functions of Hypothalamus & associated limbic structures: 1. Stimulation in the lateral hypothalamus leads to thirst, eating rage and fighting. Stimulation in the ventromedial nucleus of hypothalamus causes sense of satiety, decreased eating and 1
tranquility. Bilateral lesions of the ventromedial nucleus in animals and probably humans as well, result in overeating (hyperphagia) and extreme obesity as well as a chronically irritable mood and increase in aggressive behavior (termed hypothalamic rage). By contrast, bilateral lesions in the lateral hypothalamic area result in anorexia (lack of appetite). Animals with lesions in this area may die of starvation. The ventromedial nucleus has been referred to as a satiety center and the lateral hypothalamic area as a feeding center. It has been postulated that these opposing centers define a set point for body weight: the set point theory of weight control. According to this theory, when body weight goes below the set point, the lateral hypothalamus is activated and appetite is increased; when body weight goes above the set point, the ventromedial nucleus is activated and appetite is decreased. Their neurons respond to glucose, free fatty acid and insulin levels in a manner consistent with the set point theory, and activity levels in the two nuclei display a strict reciprocal relationship that is appropriately correlated with the level of hunger or satiety. 2
2. Stimulation in the anterior and posterior hypothalamus stimulates the sexual drive. SEXUAL DIMORPHISM IN THE HYPOTHALAMUS; As is well known, sexual differentiation is strongly influenced by the presence or absence of gonadal steriod hormones during certain critical periods of prenatal development in humans, certain regions of the brain have been found to be sexually dimorphic and differentially senstitive to steriods. Indeed it has now been well established that the amygdala and the hypothalamus (specifically the anterior commissure, anterior-preoptic, ventromedial and suprachiasmatic nuclei) are sexually differentiated and have sex specific patterns of neuronal and dendritic development. This is a consequence of the presence or absence of testosterone during fetal development in humans. In the absence of testosterone, the female pattern of neuronal development occurs. Indeed, it is the presence or absence of testosterone during these early critical periods that appear to be responsible for neurological alterations which greatly affect sex differences in thinking, sexual orientation, aggression, and cognitive functioning For example, if the testes are removed prior to differentiation, or if a chemical blocker of testosterone is administered thus preventing this hormone from reaching target cells in the limbic system, not only does the female pattern of neuronal development occur, but males so treated behave and process information in a manner similiar to females i.e. they develop female brains and think and behave in a manner similar to females. Conversely, if females are administered testosterone during this critical period, the male pattern of differentiation and behavior results. That the preoptic and other hypothalamic regions are sexually dimorphic is not surprising in that it has long been known that this area is extremely important in controlling the basal output of gonadotrophins in females prior to ovulation and is heavily involved in mediating cyclic changes in hormone levels (e.g. FSH, LH, estrogen, progesterone). Chemical and electrical stimulation of the preoptic and ventromedial hypothalamic nuclei also triggers sexual behavior and even sexual posturing in females and males. Specifically, the hypothalamic neurons secrete gonadotropin-releasing hormone, which acts on the anterior lobe of the pituitary which secretes gonadotropins. However, given that in females, this is a cyclic event, whereas in males sperms are constantly reproduced, is further evidence of the sexual dimorphism of the hypothalamus. Although the etiology of homosexuality remains in question, it has been shown that the ventromedial and anterior nuclei of the hypothalamus of male homosexuals demonstrate the female pattern of development. This raises the possibility that male homosexuals are in possession of limbic system that is more "female" than "male" in functional as well as structural orientation. 3. Stimulation in the lateral and ventromedial nuclei of hypothalamus (The Reward Center) leads to sense of satisfaction, feeling good and some times pleasure. In lateral hypothalamus weak stimulation gives the sense of reward while stronger stimulus leads to rage. Other reward centers are amygdala, septal nucleus, and parts of thalamus. Stimulation of other parts of hypothalamus in the periventricular zone lead to the feeling of punishment as displeasure, fear, terror, pain, punishment and even sickness (The Punishment Center). Stimulation in this center can inhibit the reward and pleasure centers completely. If we are doing something that is rewarding, we continue to do it; if it is punishing, we cease to do it. Therefore, the reward and punishment centers are one of the most important of all controllers of our bodily activities, drives, aversions and motivations. Bar - pressing experiments: In human, each bar press delivers stimulus to electrode implanted chronically in brain (usually schizophrenic, epileptics and few with visceral neoplasms or intractable pain), like animals human press the bar repeatedly; they report" relieve of pain", "Quiet" or "Relaxed" feelings. When electrodes are in the areas where stimulation is avoided, patients report sensation from vague fear to terror. It has been reported that in rats repeated 3
pressing is obtained from 35 % of the brain, avoidance from 5 % and indifferent response from 60 %. A variety of habits forming substances that produce addictive behavior may act by increasing dopaminergic activity in the reward system of the brain e.g. cocaine, amphetamines, nicotine, alcohol...etc Tranquilizers (chlorpromazine) inhibit both reward and punishment centers. Any sensory stimulus if does not stimulate the reward or the punishment centers will be ignored, and the repetition of this stimulus over and over lead to habituation. If the sensory stimulus excites either of these centers then it will be reinforced, memory traces are formed, and will be stored as a memory. Limbic system selects which information has to be stored, in fact 99 % of the information are discarded while the important 1 % will be stored (this is the role of limbic system in memory and learning). Many of addictive drugs can increase the levels of dopamine in the nucleus accumbens, some of them act directly in the VTA (ventral tegmental area) and others activate endogenous opioid pathways that ultimately lead to activation of the VTA dopaminergic neurons (e.g. alcohol, and nicotin). The craving for a drug long after withdrawal symptoms have vanished, and the relapse upon exposure to certain cues, strongly suggest the involvement of amygdale, cortex, hippocampus and nucleus accumbens. Uncontrolled Laughter ; Pathological laughter has frequently been reported to occur with hypophyseal and midline tumors involving the hypothalamus, aneurysm in this vicinity, hemorrhage, astrocytoma, or papilloma of the third ventricle (resulting in hypothalamic compression), as well as surgical manipulation of this nucleus For example, Martin (1950) describes a man who, while "attending his mother's funeral was seized at the graveside with an attack of uncontrollable laughter which embarrassed and distressed him considerably". Although this particular attack dissipated, it was soon accompanied by several further fits of laughter and he died soon thereafter. At postmortem examination, a large ruptured aneurysm was found compressing the mamillary bodies and hypothalamus. 4. paraventricular and supraoptic nuclei; synthesize Antidiuretic hormone (ADH) and oxytocin. 4
5. Suprachiasmatic nucleus; visual input from retina via optic tract terminate in this nucleus, this information helps set certain body rhythms to the 24 hour light-dark cycle (circadian rhythm). 6. Mammillary bodies; lesions here occur in Korsakoff syndrome. Korsakoff syndrome results in both anterograde and retrograde amnesia with confabulation. Korsakoff syndrome is seen mainly in alcoholics with who have a thiamine deficiency and often follows an acute presentation of Wernicke encephalopathy. Wernicke encephalopathy presents with ocular palsies, confusion, and gait ataxia and is also related to a thiamine deficiency. In Wernicke-Korsakoff syndrome, lesions are always found in the mammillary bodies and the dorsomedial nuclei of the thalamus. Thiamine treatment improves signs of Wernicke encephalopathy, but it does not reverse amnesia in Korsakoff syndrome. 7. Anterior hypothalamic zone; senses an elevation of body temperature and mediates the response to dissipate heat. Lesions to the anterior hypothalamic zone lead to hyperthermia. Posterior hypothalamic zone senses a decrease of body temperature and mediates the conservation of heat. An individual with a lesion to this area has a body temperature that varies with the environmental temperature. 8. Preoptic area; lesion here before puberty may arrest sexual development, while after puberty may result in amenorrhea and impotence. Function of Hippocampus: The hippocampus is a part of the forebrain, located in the medial temporal lobe. The name, in fact, derives from the Greek word for seahorse (Greek: hippos = horse, campos = sea). In Alzheimer s disease, the hippocampus is one of the first regions of the brain to suffer damage; memory problems and disorientation appear among the first symptoms. Alzheimer's patient loses episodic memory (events in time) earliest and most severe. Also impaired may be working memory (short-term retention) and semantic memory (objects or facts). Procedural memory (how to use tools) is affected late. Damage to hippocampus can also result from anoxia, encephalitis or temporal lobe epilepsy. People with extensive hippocampal damage may experience amnesia, that is, inability to form or retain new memories. 1. Stimulation of different areas in the hippocampus can cause any of the behavioral patterns as pleasure, rage, passivity or excess sex drive. 2. It can become hyper-excitable easily leading to focal epileptic seizures; during the fit all hallucinations are likely to take place, hallucinations can not be suppressed as long as the seizure persists even without loss of consciousness and knows that these hallucinations to be unreal. 3. It has a role in learning and memory. 5
Function of the Amygdala: Amygdala is a complex of multiple small nuclei lies beneath the cerebral cortex of the medial anterior pole of the temporal lobes. It is believed to make the person's behavioral response appropriate to each occasion. If you remember only one word about the amygdala, the word is FEAR. (The amygdala is the nucleus responsible for the lurch you feel in your stomach when you turn around in a dark alley and notice someone following you). It couples a learned sensory stimulus (man in ski mask in alley = danger) to an adaptive response (fight or flight). On the basis of this information, you should be able to guess the primary inputs to and outputs from the amygdala. Inputs: the amygdala must get sensory input, and it must be fairly highly processed input to recognize the elements of a scene that signal danger. The association areas of visual, auditory, and somatosensory cortices are the main inputs to the amygdala. Outputs: the amygdala must be able to control the autonomic system, to provoke such an instant sympathetic response. The main outputs of the amygdala are to the hypothalamus and brainstem autonomic centers, including the vagal nuclei and the sympathetic neurons. The amygdala is also involved with mood and the conscious emotional response to an event, whether positive or negative. The amygdala is also extensively interconnected with frontal cortex, mediodorsal thalamus, and the medial striatum. Its stimulation can cause almost all the same effects as those elicited by direct stimulation to hypothalamus plus other effects; 1. It has a vegetative control similar to hypothalamus. 2. One of the major olfactory tracts terminates at the corticomedial nuclei of the amygdala. Different types of movements associated with olfaction and eating such as licking, chewing and swallowing can be seen after stimulating the amygdala. 3. It is a Reward center at a given part and a Punishment center at other parts of the amygdala. 4. "Kluver - Bucy syndrome" takes place in damage to both temporal lobes including the amygdala, the animal become placid (there is marked decrease in aggressive behavior), fearless, objects in visual field are treated inappropriately (Psychic blindness) e.g. monkeys may approach a snake or human with inappropriate docility, tends to forget (anterograde 6
amnesia), curious, has the tendency to discover things by mouth (oral exploratory behavior), and hypersexual. Similar lesions in human can lead to similar behavior. Functions of limbic cortex: It functions as a cerebral association area for control of behavior. 1. Damage to the anterior temporal cortex is always associated with damage to amygdala leading to "Kluver - Bucy syndrome" 2. Damage to the posterior orbital frontal cortex lead to insomnia. 3. Damage to the anterior cingulate gyri and the subcallosal gyri lead to rage. 7