Overview of the Integrative Functions of the Hypothalamus
The integrative functions of the hypothalamus include cardiovascular and temperature regulation and sexual, feeding, drinking, aggression, rage, and flight behaviors. The specific nature of each of these response patterns is highly complex, and our present understanding of the precise role of the underlying mechanisms remains incomplete. Our current knowledge of these functions is briefly reviewed here.
Regulation of Cardiovascular Processes
It was pointed out that the basic cardiovascular mechanisms present at the level of the intermediolateral cell columns of the thoracic and lumbar levels of the spinal cord are controlled extensively by other mechanisms residing in the ventrolateral medulla and solitary nucleus of the lower brainstem. Superimposed on these brainstem mechanisms are other mechanisms residing in the hypothalamus and limbic system. The most important region mediating sympathetic responses includes the posterior two thirds of the medial aspect of the hypoth-alamus. Sympathetic responses are also mediated by the lateral hypothalamus but are less intense than those mediated from the medial hypothalamus. Parasympathetic responses have been reported after stimulation of parts of the anterior hypothalamus and preoptic region. These autonomic responses are presumably mediated through descending pathways that reach the lower brainstem. Some investigators have even suggested that descending hypothalamic fibers may reach as far as the intermedi-olateral cell column of the thoracic cord, thus providing the basis for direct hypothalamic mediation of sympathetic functions.
Temperature Regulation
Temperature regulation requires the integration of a number of processes associated with hypothalamic functions. These include: (1) activation of temperature-sensitive neurons (thermoreceptors) that can respond to increases or decreases in blood temperature; (2) the capacity of the hypothalamus to activate TRH, which leads to secretion of TSH, with subsequent secretion of thyroid hormone for increases in metabolic rates; (3) activation of autonomic mechanisms, which, in turn, dilate or constrict peripheral blood vessels that serve to cause loss or conservation of body temperature, respectively; and (4) activation of behavioral responses, such as panting (to generate heat loss) and shivering (to conserve heat).
That body temperature normally remains relatively constant is the result of a balance between neuronal mechanisms subserving heat loss and heat conservation. A group of neurons situated in the anterior hypothalamus-preoptic region responds to changes in blood temperature. These neurons are specifically designed to prevent body temperature from rising above set values. When body temperature does increase, anterior hypothalamic neurons discharge, and efferent volleys are conducted down their axons to respiratory and cardiovascular neuronal groups of the lower brainstem and spinal cord. The net effect of such activation is initiation of vasodilation and perspiration, leading to heat loss. Therefore, this region of the hypotha-lamus is often referred to as a heat loss center (Fig. 24-8). Moreover, neurons in this region respond to substances called pyrogens (which cause marked increases in body temperature) by discharging in an attempt to reestablish normal body temperature. In addition, certain neurons in this region, as well as in adjoining regions of the septal area that contain vasopressin, are capable of counteracting the actions of pyrogens. Accordingly, this group of neurons is referred to as an antipyrogenic region.
Other neurons located in the posterior lateral hypotha-lamus appear to be more closely linked with heat conservation and are known as the heat conservation center. These neurons discharge when body temperature declines, and impulses are conducted down similar pathways to lower autonomic regions of the brainstem and spinal cord. The net effects include vasoconstriction, increases in cardiac rate, elevation of the basal metabolic rate, pilo-erection, and shivering. Shivering contributes to heat conservation because the rapid, involuntary contractions of the somatic musculature (through a multisynaptic descending pathway to ventral horn cells of the spinal cord) produce heat.
Feeding Behavior
Extensive research conducted in animals has demonstrated that feeding and ingestive behaviors are clearly regulated by the hypothalamus. Such studies have pointed out that two regions of the hypothalamus, the medial and lateral hypothalamus, play key roles in the regulation of feeding responses. Stimulation of the lateral hypothalamus has been shown to induce feeding behavior, whereas stimulation of the medial hypothalamus suppresses this behavior. Moreover, lesions of the lateral hypothalamus induce aphagia, while lesions of the medial hypothalamus result in hyperphagia. Based on such evidence, the lateral hypothalamus has often been referred to as a feeding center, while the ventromedial hypothalamus has been called a satiety center.
FIGURE 24-8 Sagittal view of the brain indicating the relationship of the regions of the hypothalamus associated with heat conservation and heat loss.
The data in support of two opposing regions that regulate feeding is significant, although interpretation of the data might be somewhat oversimplified. It appears that a number of different mechanisms might be operative within these hypothalamic nuclei. The ventromedial nucleus appears to play a critical role here. For example, it has recently been shown that the ventromedial nucleus responds to changes in caloric intake. There is believed to be a set-point governing hypothalamic regulation of food intake. The set-point is governed by such factors as metabolic rate of the organism, immediate past history of food intake, and present level of food intake. Lesions of the medial hypothalamus disrupt this set-point, leading to large increases in food intake and weight gain. The ventro-medial hypothalamus and adjoining nuclei have been linked to several neurotransmitter and hormonal systems. For example, inhibition of feeding behavior occurs after administration of CCK to the paraventricular region. This finding suggests that part of the satiety mechanism involves a release of CCK from the medial hypothalamus following food intake. Other compounds associated with the medial hypothalamus, such as glucagon and neurotensin, appear to have similar functions. Thus, lesions of the medial hypothalamus could result in hyperphagia because of disruption of these compounds and may affect the release of other hormones, such as ACTH and insulin, that normally regulate metabolic rates.
Several mechanisms may also be operative with respect to food intake functions involving several nuclei of the hypothalamus. Sensory processes play an important role in feeding behavior. Of particular significance are the learned sensory cues associated with olfaction and taste. These signals, which intensify the drive for food, involve signals that reach the amygdala, which, in turn, are relayed to the lateral hypothalamus via the ventral amygdalofugal pathway. The loss of motivation for food following lesions of the lateral hypothalamus may be related, in part, to the disruption of inputs to the lateral hypothalamus from the amygdala triggered by sensory signals associated with food.
In addition to the lateral hypothalamus, the paraven-tricular nucleus also appears to contribute to feeding behavior. Recent studies have shown that several different peptides (galanin, neuropeptide Y, orexins, and opioids) and norepinephrine can induce feeding responses in rats when microinjected into the paraventricular nucleus. Other recent studies have revealed a feedback and integrating mechanism linking the arcuate nucleus (located at the ventromedial base of the hypothalamus) and paraventricular nucleus. For example, anabolic neurons in the arcuate nucleus can release neuropeptide Y, which then binds to a neuropeptide Y receptor, leading to an increase in food intake. In contrast, there are other neurons in the arcuate nucleus that synthesize pro-opiomelanocortin, whose cleavage product, a-melanocyte stimulating hormone, interacts with melanocyte receptors, and results in a decrease in food intake. Another protein, leptin, has been shown to regulate weight gain and home-ostasis as well. This compound is secreted by adipocytes in plasma, circulates in the blood, and crosses the blood-brain barrier, and binds to the leptin receptor within the arcuate nucleus, resulting in a reduction in food intake. It apparently reduces food intake by increasing thermogenesis and the expenditure of energy by its activation of the sympathetic nervous system. Current research is attempting to identify the precise role of these and other compounds present within the forebrain; the precise mechanisms governing how these compounds interact with neuronal pools within the hypothalamus to affect feeding responses and weight change remain unknown.
Drinking Behavior
The basic mechanisms governing drinking behavior were described previously in this topic. They include the role of the paraventricular nucleus in releasing ADH in response to increases in tissue osmolarity and the role of the subfornical organ in responding to the presence of angiotensin II by exciting neurons in the anterior hypoth-alamus and preoptic region. As noted earlier, stimulation of the paraventricular nucleus activates a mechanism that induces water retention from the kidneys. A separate mechanism has also been described: Activation of the tissue surrounding the anteroventral aspect of the third ventricle, which includes the preoptic region, is believed to excite a process that induces the behavioral process of drinking. However, the specific neural circuits underlying how drinking behavior occurs remain obscure.
Sexual Behavior
Female sexual behavior is directly dependent on the relationship between endocrine function, the presence of hormonal-neural interactions, and activation of neural circuits that govern the elicitation of species-specific sexual responses. One of the key structures controlling sexual behavior is the ventromedial hypothalamus. It contains estrogen and progesterone receptors. In fact, experimental studies in rats have shown that stimulation of the ventromedial nucleus by chemicals (i.e., choliner-gic stimulation) induces a sexual response referred to as lordosis. This response is characterized by arching of the back (by the female) coupled with a rigid posture and a deflection of the tail, all of which allows intromission by the male. In contrast, lesions of the ventromedial nucleus significantly reduce sexual behavior.
The correlation between sexual behavior and estrogen levels is quite high. Therefore, it is reasonable to conclude that increased levels of estrogen act on estrogen receptors within the ventromedial hypothalamus to trigger a neural mechanism that excites other neurons in lower regions of the CNS, such as the midbrain PAG and spinal cord, which serve to induce the expression of sexual behavior. Progesterone also likely acts on ventromedial neurons, the net effect of which is to intensify the sexual response to estrogen. Experimental studies have also shown that the lordosis reaction is also modulated by monoaminergic inputs and acetylcholine. In particular, lordosis behavior is enhanced by norepinephrine, suppressed by serotonin, and induced by acetylcholine when each of the agonists for these transmitters is microinjected directly into the rat ventromedial hypothalamus.
Part of the overall hypothalamic mechanism underlying sexual behavior may involve the release of GnRH from the anterior hypothalamus (preoptic region). These neurons project to the median eminence, where the peptide is released into the portal circulation. The peptide is then transported to the anterior pituitary, resulting in increases in estrogen levels. In addition, the gonadotropin pathway from the anterior hypothalamus also reaches the midbrain PAG, where the release of gonadotropin-releasing hormone can induce lordosis. It is reasonable to conclude that all of these mechanisms come into play when sexual behavior occurs normally in humans.
Male sexual behavior is induced or augmented by the presence of testosterone. Testosterone appears to act on the preoptic region to produce the various behavioral characteristics of sexual behavior. This suggests that the preoptic region plays an important role in sexual behavior in both males and females. It is of interest to note that the morphological appearance of the preoptic region differs between males and females (at least in rodents), and the appearance is dependent on the extent of release of LH from the anterior pituitary. For this reason, the preoptic region contains the sexually dimorphic nucleus, which is a somewhat rounded, compact structure that is larger in males than in females. It might be that the kind of morphology present in the preoptic region provides the neural substrate for the kind of sexual behavior that is expressed by a given organism. Like the female, male sexual responses are modulated by various neurotransmitters, such as dopamine, and by neuropeptides (gonadotropin-releasing hormone, substance P, and neuropeptide Y).
Aggression and Rage
We have previously pointed out the role of the hypotha-lamus in regulating cardiovascular and related autonomic functions of the nervous system. These functions comprise components of the various forms of emotional behavior that are integrated within different regions of the hypothalamus.
Several forms of emotional behavior have been identified, mainly from feline models of aggression and rage. Stimulation of the medial hypothalamus produces a ragelike response called defensive rage behavior. In cats, for example, the response includes piloerection, marked vocalization, such as hissing and growling, retraction of the claws, significant pupillary dilatation and other forms of sympathetic reactions, arching of the paws, and striking out at a moving object within its visual field (Fig. 24-9). The response is essentially defensive in nature and occurs naturally when the cat perceives itself as being threatened by another animal.
The pathways and putative neurotransmitters that regulate defensive rage behavior have recently been described. The primary pathway mediating defensive rage behavior from the medial hypothalamus projects to the dorsal aspect of the midbrain PAG from which this response can also be elicited. Excitatory amino acids that act on N-methyl-D-asparate receptors have been identified as the neurotransmitters associated with this pathway. Because the most caudal level of the brainstem at which this response is integrated is the PAG, the auto-nomic and somatomotor components that comprise the defensive rage response are activated by descending fibers from the PAG that reach autonomic regions of the lower brainstem and somatomotor regions of the brainstem (e.g., trigeminal and facial motor nuclei for vocalization) and spinal cord (for paw striking).
FIGURE 24-9 Defensive rage and predatory behavior. (A) Defensive rage behavior elicited by electrical stimulation of the medial hypothalamus. (B) Predatory attack behavior elicited by electrical stimulation of the lateral hypothalamus of the cat.
Other regions of the brain play important roles in modulating defensive rage behavior. Perhaps the most significant group of structures includes the limbic system.Structures, such as the amygdala, hippocam-pal formation, septal area, and prefrontal cortex, powerfully control this response through direct or indirect connections with the hypothalamus or midbrain PAG. For example, the medial amygdala generates a very powerful excitatory effect on defensive rage behavior by virtue of a direct excitatory pathway to the medial hypothalamus, which uses substance P as a neurotransmitter. Inhibitory effects on defensive rage behavior become manifest when the central nucleus is stimulated. This structure provides a direct, inhibitory pathway to the midbrain PAG, which is mediated by opioid peptides acting through receptors. Monoamine neurotransmitters have also been studied, and the results indicate that dopamine and norepinephrine facilitate defensive rage, whereas serotonin is inhibitory.
Stimulation of the lateral hypothalamus in the cat produces a different form of aggressive behavior. It is called quiet biting (predatory) attack behavior. In this form of attack behavior, cats, which do not normally attack rats, will stalk and then bite the back of the neck of the rat and/ or strike it with its forepaw (Fig. 24-9). This form of aggressive behavior resembles the natural predatory response of a cat on a prey object. This response is accompanied by few overt autonomic signs other than some pupillary dilation and increases in heart rate and blood pressure.
The pathways mediating this response descend through the medial forebrain bundle from the lateral hypothalamus and synapse in several areas of the brainstem, including the ventral aspect of the midbrain PAG, tegmental fields, and motor nucleus of the trigeminal nerve. Secondary fibers from the brainstem descend to lower levels of the brainstem and spinal cord, where they synapse with somatomotor and autonomic nuclei, which must be activated for this response to occur. In addition, because of the complexity of the response, it is also likely that the senso-rimotor cortex also becomes activated following stimulation of the lateral hypothalamus, which may account for the precise character of the behavioral response. The anatomical pathway by which the cerebral cortex becomes activated following stimulation of the lateral hypothalamus remains obscure.
Predatory attack behavior is also powerfully modulated by different regions of the limbic system that project directly or indirectly to the lateral hypothalamus. Monoam-ine neurotransmitters appear to have effects on predatory attack behavior that are similar to those mediated on defensive rage behavior.
The relationship between the medial and lateral hypothalamus with respect to these two forms of aggression is mutual inhibition. When the predatory attack mechanism is activated in the lateral hypothalamus, neurons in the medial hypothalamus subserving defensive rage are suppressed, and, likewise, when the defensive rage mechanism is activated, neurons mediating predatory attack are suppressed. These opposing effects likely involve inhibitory connections between the medial and lateral hypothalamus. Such an interactive mechanism would be of obvious survival value to an organism: An animal about to display predatory attack on a prey object would not find it useful to elicit vocalization associated with defensive rage behavior. Similarly, predatory attack-like responses would be of little survival value when an animal’s life space is threatened by another organism of the same or different species.
A third type of emotional response elicited by electrical stimulation of wide regions of the hypothalamus and dorsal aspect of the midbrain PAG gray is flight behavior. It is characterized by an attempt of the cat to escape from its cage after electrical stimulation is applied to either of these brain regions. The pathways mediating flight behavior have been described and indicate that direct descending fibers to the midbrain PAG most likely mediate this response. The neurotransmitters associated with elicitation or modulation of this response have yet to be identified.
Biological Rhythms
As indicated earlier, specific regions of the hypothalamus play an important role in pacemaker activities (i.e., setting and maintaining biological rhythms) for different endocrine and behaviorally related functions. Of particular importance are the suprachiasmatic nucleus and the preoptic area. The suprachiasmatic nucleus receives retinal inputs that appear to be critical for triggering cir-cadian rhythms for a number of sex hormones, corticos-terone, and the pineal hormone melatonin.Associated with these hormonal rhythms are circadian rhythms for body temperature and sexual behavior. It is possible, and even likely, that the preoptic area also plays an important role in governing the circadian rhythm for the release of LH from the anterior pituitary because GnRH neurons are located within the preoptic region. Recent research has provided new knowledge concerning the basis for these rhythms. Specific genes, called clock genes have been identified, which exhibit short or long arrhythmic periods, driving or otherwise regulating their transcription, and attempts have been made to characterize their protein products. These genes are now known to be present in the suprachiasmatic nucleus and perhaps elsewhere and are believed to form the basis for the rhythms observed in these neurons.
Sleep
The hypothalamus and the reticular formation have been associated with the regulation of sleep. Thus, a brief summary of the role of the hypothala-mus in sleep is considered here.
Early experiments conducted in rats demonstrated that lesions of the posterior hypothalamus produced prolonged periods of sleep. This led to the view that mechanisms regulating sleep involve the hypothalamus. Subsequent experiments have revealed that such lesions may have produced sleep because of the disruption of ascending fibers from the reticular formation rather than because of the cell damage within the hypothalamus. However, more recent studies have suggested that portions of the cholin-ergic basal forebrain region, such as the preoptic area and substantia innominata, are likely involved and function in concert with other cholinergic and monoaminergic mechanisms within the reticular formation of the brainstem to regulate sleep and wakefulness cycles.
