Lecture I: The

• Overview of hypothalamus and limbic system purpose, function and some examples of clinical conditions mediated by hypothalamic and/or limbic system neural Hypothalamus and Limbic circuitry. System • Brief overview of hypothalamus anatomy. • Information flow into and out of the hypothalamus: Daniel Salzman inputs, outputs and pathways. Center for Neurobiology and Behavior • Servo-control systems as a model for hypothalamic [email protected] function. 212-543-6931 ext. 400 • Two detailed examples of hypothalamic function: Pages 972-1013 in PNS – Temperature regulation – Feeding behavior

Hypothalamus and Limbic System: Hypothalamus and Limbic System: and Motivated Behavior • A major function of the is to • and motivated behavior are crucial for maintain homeostasis, or the stability of the survival: internal environment. – Emotional responses modulate the to respond to threatening stimuli or • The hypothalamus, which comprises less than situations. 1% of the total volume of the , is intimately – Emotional responses are adaptive. If you are connected to a number of structures within the prepared to deal with threatening stimuli, you are limbic system and . more likely to survive and reproduce. – Motivated behavior underlies feeding, sexual and • Together the hypothalamus and the limbic other behaviors integral to promoting survival and system exert control on the reproduction. the autonomic nervous system to maintain – The hypothalamus and limbic system mediate these behaviors. homeostasis.

Hypothalamus and Limbic System: Hypothalamus and Limbic System: Clinical Context Clinical Context (cont.)

• A large number of clinical conditions have – Fever • Need to detect temperature changes and modulate the autonomic symptoms that arise from hypothalamic nervous system to either retain or dissipate heat. and/or limbic system brain circuits. – Addiction • Many recreational drugs work through neural pathways involved in reward and motivated behavior that form an important part of limbic • For example, regardless of medical or system function. – Anxiety Disorders dental specialty, all of you will encounter • Many anxiety disorders, such as and Post-traumatic disorder have physiological symptoms mediated by the patients who have one or more of the autonomic nervous system and by the limbic system. following: –Obesity. • Feeding behavior is in part controlled by the hypothalamus, and interactions between limbic reward circuitry and the hypothalamus are important to feeding behavior.

1 Hypothalamus: Integrative Hypothalamus Anatomy Functions • The hypothalamus helps regulate five basic physiological • Lines the walls of 3rd needs: 1) Controls blood pressure and electrolyte (drinking and salt ventricle, above the appetite). pituitary. 2) Regulates body temperature through influence both of the autonomic nervous system and of brain circuits directing • Divided into medial motivated behavior (e.g. behavior that seeks a warmer or cooler environment). and lateral regions by 3) Regulates energy metabolism through influence on feeding, digestion, and metabolic rate. the , bundles of 4) Regulates reproduction through hormonal control of mating, fiber tracts that pregnancy and lactation. 5) Directs responses to stress by influencing blood flow to specific connect the tissues, and by stimulating the secretion of adrenal stress to the hormones. mamillary bodies.

Hypothalamus Anatomy The Paraventricular Nucleus

• The hypothalamus is • Contains two types of cells: limited at the anterior – Parvocellular • Medially, parvocellular by the optic chiasm neurons secrete hypothalamic releasing hormones, such as and anterior CRH. commissure, and at • Dorsally and ventrally, neurons project to the the posterior by the medulla and to exert autonomic control. mamillary bodies. Some of these neurons secrete oxytocin and • The paraventricular vasopressin, which can act as nucleus is of particular neuromodulators. importance, as it – Magnocellular • Two distinct populations controls both control endocrine function by secreting oxytocin and endocrine and vasopressin directly into the autonomic processes. posterior pituitary.

What pathways deliver visceral What pathways control autonomic information to the hypothalamus? responses? • The nucleus of the • Direct control of solitary tract receives autonomic preganglionic visceral information from neurons arises from the VII, IX, and hypothalamus, the X. parabrachial nucleus, the • Besides directly nucleus of the solitary regulating certain tract, and neurons in the autonomic functions, the ventrolateral medulla. nucleus of the solitary • Indirect control of tract relays information to autonomic responses the parabrachial nucleus, originates from the which projects to the cortex, , and hypothalamus and other the periqueductal gray limbic structures. matter.

2 Neural Input and Hormonal Output: Hypothalamus: Inputs and Outputs oxytocin release and lactation Neural Output Hormonal • Supraoptic and paraventricular nuclei contain Output magnocellular neurons that secrete oxytocin into the general circulation in the posterior pituitary. • When a baby sucks on a mother’s nipples, Neural Input Controls the Controls mechanoreceptors are stimulated. These autonomic release of receptors activate neurons that project to the nervous system oxytocin for milk magnocellular hypothalamic neurons, causing (e.g. emotion) lactaction those cells to fire brief bursts, releasing oxytocin. Hormonal Input Used for drives Controls • Oxytocin, in turn, increases contraction of and motivated release of myoepithelial cells in the mamillary glands, leading to milk ejection. behavior vasopressin for fluid regulation

Vasopressin release: an example of humoral input Hormonal input and Neural output: and humoral output Endocrine Control of Behavior • Magnocellular neurons containing vasopressin • Classic experiments by Geoffrey Harris demonstrated are sensitive to changes in blood tonicity, how hormones may influence motivated behavior. • Harris and colleagues implanted crystals of stilboestrol releasing more vasopressin upon water loss. esters in the hypothalamus of ovariectomized cats. Vasopressin increases water resorption in the These cats had atrophic genitalia. Implantation of these kidney. esters elicited full mating behavior from the cats. Thus although the cats were anestrous from the point of view • Transecting the neural inputs to the of the endocrine system in the periphery, the animals hypothalamus does not disrupt the ability to were estrous from the point of view of the CNS. increase vasopressin release upon water loss. • These experiments established the concept that the brain is a target for specific feedback action from This finding confirms that the signal used by gonadal steroids, leading to modulations in motivated hypothalamic neurons is humoral, and not behavior through neural circuits almost certainly neural, to modulate vasopressin release. connected to the hypothalamus.

What hypothalamic pathways How do we know that regulatory factors travel influence endocrine function? through the portal circulation to the pituitary? • The hypothalamus controls the • Geoffrey Harris was a famous neurobiologist endocrine system by secreting oxytocin and vasopressin into responsible for showing that that the the general circulation from hypothalamus exerts control of the pituitary nerve terminals ending in the posterior pituitary (5 in figure). gland. • The hypothalamus also • In the 1950s, Harris and colleagues carried out a secretes regulatory hormones into local portal circulation that series of transplantation experiments. drains into the anterior pituitary – It had already been shown that endocrine glands (e.g. (3 and 4). testes, ovaries, adrenal cortex) can function in a • Finally, some hypothalamic regulated manner when transplanted to a remote neurons influence peptidergic location in the body. neurons, synapsing at those neurons cell bodies or axon – Harris showed that when the anterior pituitary was terminals (1 and 2). transplanted away from its original site, it did not function normally.

3 How do we know that regulatory factors travel through the portal circulation to the pituitary (2)? Homeostatic processes: servo- control systems • Harris and colleagues then transplanted the anterior • 3 main mechanisms in pituitary back under the midline hypothalamus, near the the hypothalamus make portal vessels. Normal endocrine function was restored, its function analogous to and subsequent histology showed that the restoration of servo-control systems – Receives sensory function depended upon the successful revascularization information from external of the anterior pituitary by the primary capillary plexus of body portal vessels in the median eminence. – Compares sensory information with biological • These experiments provided definitive proof of the set points. functional importance of the portal vascular system in – Adjusts an array of connecting hypothalamic regulation to anterior pituitary autonomic, endocrine and behavioral responses function. aimed at maintaining homeostasis

Temperature regulation is a good example Distinct regions of the hypothalamus mediate heat of a hypothalamic servo-control system dissipation and heat conservation

• To regulate temperature, integration of autonomic, • The anterior endocrine, and skelatomotor systems must occur. The hypothalamus (preoptic hypothalamus is positioned anatomically to accomplish area) mediates this control and integration. decreases in heat. • The set point for the system is normal body temperature. • Lesions cause: • The hypothalamus contains “feedback detectors” that collect information about body temperature. These – Chronic hyperthermia come from two sources: • Electrical stimulation – Peripheral receptors transmit information through temperature causes: pathways to the CNS. – Dilation of blood vessels in – Central receptors are located mainly in the anterior the skin hypothalamus. Temperature-sensitive neurons in the hypothalamus modulate their activity in relation to local – Panting temperature (blood temperature). – Suppression of shivering

Distinct regions of the hypothalamus mediate heat Endocrine responses to dissipation and heat conservation (2) temperature change • The posterior • Long-term exposure to cold can lead to hypothalamus mediates heat conservation. increased hypothalamic secretion of • Lesions cause: thyrotropin-releasing hormone. – Hypothermia if an animal is • This results in increased release of placed in a cold environment. thyroxine, which in turns increases body • Microstimulation causes: heat by increasing tissue metabolism. – Shivering – Constriction of blood vessels in the skin

4 Behavioral responses to The hypothalamus integrates peripheral and temperature change central temperature information • Increases in room • can be trained to press a button for temperature lead to an cool air if placed in a hot environment. increased in button pushing (response rate) After training, if in a cool environment, the to receive cool air. will not push the button. • Increases and decreases in hypothalamic • If you warm the anterior hypothalamus temperature also locally by perfusing it with warm water modulate response rate locally, the rat will push the button for cool in a predictable manner. • The behavioral response air, even though it is already in a cool rate appears to sum environment. inputs from the periphery and the hypothalamus.

Feeding behavior can also resemble a servo- Feeding behavior can also resemble a control mechanism servo-control mechanism (2)

• Animals tend to adjust • These data demonstrate their food intake to a biological set point for achieve a normal body weight control. weight. • But…in humans, we • Curve b = control rats on know that: a normal diet. – Weight set point can vary • Curve a = rats force fed by individual. for 15 days. – Weight set point can vary depending upon a variety • Curve c = rats on a of factors, including stress, restricted diet for 15 days. taste, emotions, social factors, convenience, • All rats returned to their exercise and other normal body weight after environmental and genetic either force feeding or factors. restriction.

How does the hypothalamus contribute to the How does the hypothalamus contribute to control of food intake? the control of food intake? (2)

• Early studies of the hypothalamus • But…subsequent work provided the insight that the demonstrated that lesions of the results from lesion studies may have been due to ventromedial hypothalamus damage of fibers of passage rather than due to loss of produced hyperphagia and cell bodies in distinct parts of the hypothalamus. obesity. • Lesions of the • In particular, hypothalamus lesions may damage fibers lateral hypothalamus of: produced aphagia, leading to – the trigeminal system which affect sensory processing important starvation. for feeding Stimulation produced the – Dopaminergic neurons projecting from the substantia nigra to the opposite effect of these lesions. striatum, as wells as those that project from the ventral • These findings lead tegmental area to innervate parts of the limbic system. to the theory that the hypothalamus Dopaminergic neurons are thought to be important for reward contains a “feeding center” and a processing and , and therefore may affect feeding “satiety center”. behavior.

5 How does the hypothalamus contribute to the control of food intake? (3) A model for energy homeostasis

• The modern view of energy homeostasis now proposes that discrete neuronal pathways generate integrated responses to afferent input • Adiposity signals modulate anabolic and related to energy storage. The hypothalamus plays a prominent role catabolic pathways in the CNS. in this integration. • The hypothalamus is sensitive to adiposity signals supplied by the • These pathways control food intake and energy hormones leptin and insulin, secreted by fat cells and the pancrease respectively. expenditure by influencing behavior, autonomic • Insulin and leptin both modulate neural activity in the arcuate nucleus of the hypothalamus, which transduces afferent hormonal activity, and metabolic rate. signals into a neural response. • Satiety signals terminate feeding, and energy • Leptin may also play a role in establishing a biological set point for body weight by modifying the strength and number of synapses onto balance and fat storage mechanisms control the arcuate neurons and by inducing projections from the arcuate nucleus to the PVN during development. amounts of leptin and insulin circulating in the blood (adiposity signals).

How do satiety signals control meal A model for energy homeostasis size? • Two sets of • Meal size tends to be more biologically controlled than signals are meal timing, that depends important for on numerous emotional modulating food and social factors. • Satiety signals are probably intake in initially processed by the response to body nucleus of the solitary tract (NTS), which receives adiposity and afferent input from the food intake: vagus nerve and from afferents passing into the – Satiety signals spinal cord from the upper • Short-term gastrointestinal tract. control • Adiposity signals can modulate the response to – Adiposity signals satiety signals, either • Long-term indirectly through the control hypothalamic pathways we have discussed, or directly, since the NTS does have some leptin receptors.

Hypothalamic neuropeptides that Hypothalamic neuropeptides that influence caloric homeostasis influence caloric homeostasis (2) • Two adiposity signals, insulin • NPY/AgRP neurons inhibit the and leptin, are produced in paraventricular nucleus (PVN) and the periphery and travel stimulate the lateral hypothalamic through the blood-brain area (LHA). α-MSH/CART barrier to influence neurons in neurons do the opposite. the arcuate nucleus. • The PVN has a net catabolic action, releasing CRH and oxytocin • Some arcuate neurons and thereby decreasing food intake synthesize and release and increasing energy expenditure. neuropeptide Y (NPY) and Plasma levels of oxytocin, which agouti-related protein (AgRP) we previously discussed with and are inhibited by adiposity reference to the milk let-down signals. reflex, have also been correlated with food intake in male and female • Other arcuate neurons rats. synthesize and release α- • The LHA has a net anabolic action, melanocyte-stimulating releasing two additional hormone (α−MSH) and neuropeptides, orexin A and cocaine-amphetamine-related melanin-concentrating hormone transcript (CART) and are (MCH), both of which stimulate stimulated by adiposity food intake. signals.

6 Leptin deficiency disrupts the normal developmental Leptin treatment during development can rescue pattern of projections from the arcuate nucleus to PVN in projections from the arcuate nucleus to PVN mice Bouret et al., (2004) Science 304:108-110

Bouret et al., (2004) Science 304:108-110

Effects of leptin on hypothalamic Summary of Hypothalamus Lecture neurocircuitry • Reviewed basic hypothalamus anatomy. • Reviewed basic hypothalamic function: – Hormonal and neural inputs and outputs – Control of autonomic, endocrine, and behavior to maintain homeostasis • Temperature regulation is an excellent example of a servo-control mechanism operating in the hypothalamus. The hypothalamus is sensitive both to hypothalamic and peripheral temperature, and it mediates changes in autonomic, endocrine and behavioral responses in order to maintain homeostasis. • Feeding behavior is a less good example of a servo-control system, in part because of variable biological set points depending upon numerous factors. Nonetheless, feeding behavior appears to be influenced by short-term satiety signals, and long- term adiposity signals. Adiposity signals influence catabolic and anabolic pathways in the hypothalamus that can control a variety of autonomic, endocrine, and behavioral functions to maintain homeostasis. Emerging evidence implicates leptin as playing an important role in modulating the neurocircuity of the hypothalamus to influence feeding behavior. • Fever and obesity are two major clinical conditions that are mediated by these neural pathways.

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