NEURAL BASIS OF INSTINCTUAL BEHAVIOR & EMOTIONS

INTRODUCTION Emotions have both mental and physical components. They involve cognition (embracing the mental activities associated with thinking, learning, and memory), an awareness of the sensation and usually its cause; affect (The emotional feeling, tone, and mood attached to a thought, including its external manifestations), the feeling itself; conation (The conscious tendency to act), the urge to take action; and physical changes such as hypertension, tachycardia, and sweating. The hypothalamus and limbic systems are intimately concerned with emotional expression and with the genesis of emotions.

ANATOMIC CONSIDERATIONS Introduction The term limbic lobe or limbic system is applied to the part of the brain that consists of a rim of cortical tissue around the hilum of the cerebral hemisphere and a group of associated deep structures-the amygdala (a nucleus in the temporal lobe), the hippocampus, and the septal nuclei. The region was formerly called the rhinencephalon because of its relation to olfaction, but only a small part of it is actually concerned with smell. Collective term denoting a heterogeneous array of brain structures at or near the edge (limbus) of the medial wall of the cerebral hemisphere, in particular the hippocampus, amygdala, and fornicate gyrus; the term is often used so as to include also the interconnections of these structures, as well as their connections with the septal area, the hypothalamus, and a medial zone of mesencephalic tegmentum. Histology - The limbic cortex is phylogenetically the oldest part of the cerebral cortex. - Histologically, it is made up of a primitive type of cortical tissue called allocortex, which in most regions has only three layers and surrounds the hilum of the hemisphere. - There is a second ring of transitional cortex called juxtallocortex between the allocortex and the neocortex. - It has three to six layers and is found in regions such as the cingulate gyrus and the insula. - The cortical tissue of the remaining nonlimbic portions of the hemisphere is called neocortex. - It generally has six layers and is the most highly developed type. - The actual extent of the allocortical and juxtallocortical areas has changed little as mammals have evolved, but these regions have been overshadowed by the immense growth of the neocortex, which reaches its greatest development in humans Afferent & Efferent Connections The fornix connects the hippocampus to the mamillary bodies, which are in turn connected to the anterior nuclei of the thalamus by the mamillothalamic tract. The anterior nuclei of the thalamus project to the cingulate cortex, and from the cingulate cortex there are connections to the hippocampus, completing a complex closed circuit. This circuit was originally described by Papez and has been called the Papez circuit. Correlations between Structure & Function One characteristic of the limbic system is the paucity of the connections between it and the neocortex. Nauta has aptly stated that "the neocortex sits astride the limbic system like a rider on a horse without reins." Actually, there are a few connections, and from a functional point of view, neocortical activity does modify emotional behavior and vice versa. However, one of the characteristics of emotion is that it cannot be turned on and off at will. Another characteristic of limbic circuits is their prolonged after-discharge following stimulation.

 This may explain in part the fact that emotional responses are generally prolonged rather than evanescent and outlast the stimuli that initiate them. LIMBIC FUNCTIONS\ Introduction In addition to its role in olfaction, the limbic system is concerned with autonomic responses. Along with the hypothalamus, it is also concerned with sexual behavior, the emotions of rage and fear, and motivation. Autonomic Responses & Feeding Behavior Limbic stimulation produces autonomic effects, particularly changes in blood pressure and respiration. These responses are elicited from many limbic structures, and there is little evidence of localization of autonomic responses. This suggests that the autonomic effects are part of more complex phenomena, particularly emotional and behavioral responses. Stimulation of the amygdaloid nuclei causes movements such as chewing and licking and other activities related to feeding. Lesions in the amygdala may cause moderate hyperphagia, with indiscriminate ingestion of all kinds of food, probably because of the inability to categorize objects as edible or inedible. SEXUAL BEHAVIOR Mating is a basic but complex phenomenon in which many parts of the nervous system are involved. Copulation is made up of a series of reflexes integrated in spinal and lower brain stem centers, but the behavioral components that accompany it, the urge to copulate, and the coordinated sequence of events in the male and female that lead to pregnancy are regulated to a large degree in the limbic system and hypothalamus. Learning plays a part in the development of mating behavior, particularly in primates, but in nonprimate mammals, courtship and successful mating can occur with no previous sexual experience. The basic responses are therefore innate and are undoubtedly present in all mammals. However, in humans, the sexual functions have become extensively encephalized and conditioned by social and psychic factors.

Relation to Endocrine Function In nonprimate mammals, removal of the gonads leads eventually to decrease or absent sexual activity in both the male and the femalealthough the loss is slow to develop in the males of some species. Injections of gonadal hormones in castrate animals revive sexual activity. Testosterone in the male and estrogen in the female have the most marked effect. Large doses of testosterone and other androgens in castrate females initiate female behavior, and large doses of estrogens in castrate males trigger male mating responses.

Effects of Hormones in Humans In adult women, ovariectomy does not necessarily reduce libido (defined in this context as sexual interest and drive) or sexual ability. Postmenopausal women continue to have sexual relations, often without much change in frequency from their premenopausal pattern. This persistence is probably due to secretion of steroids from the adrenal cortex that are converted to circulating estrogens but may also be due to the greater contribution of learning

sexual functions in humans and their relative emancipation from instinctual and hormonal control. Treatment with sex hormones increases sexual interest and drive in humans. Testosterone, for example, increases libido in males, and so does estrogen used to treat diseases such as carcinoma of the prostate. The behavioral pattern that was present before treatment is stimulated but not redirected. Thus, administration of testosterone to homosexuals intensifies their homosexual drive but does not convert it to a heterosexual drive.

Neural Control in the Male - In male animals, removal of the neocortex generally inhibits sexual behavior. - Partial cortical ablations also produce some inhibition, the degree of the inhibition being independent of the coexisting motor deficit and most marked when the lesions are in the frontal lobes. - On the other hand, cats and monkeys with bilateral limbic lesions localized to the piriform cortex overlying the amygdala develop a marked intensification of sexual activity. - These animals not only mount adult females; they also mount immature females and other males and attempt to copulate with animals of other species and with inanimate objects. - Despite some claims to the contrary, such behavior is clearly abnormal in the species studied. The behavior is dependent upon the presence of testosterone but is not due to any increase in its secretion. - The hypothalamus is also involved in the control of sexual activity in males. - Stimulation along the medial forebrain bundle and in neighboring hypothalamic areas causes penile erection with considerable emotional display in monkeys. - In castrated rats, intrahypothalamic implants of testosterone restore the complete pattern of sexual behavior, and in intact rats, appropriately placed anterior hypothalamic lesions abolish interest in sex. - The extent to which the findings in male animals with periamygdaloid lesions are applicable to men is, of course, difficult to determine, but there are reports of hypersexuality in men with bilateral lesions in or near the amygdaloid nuclei. Sexual Behavior in the Female In mammals, the sexual activity of the male is more or less continuous, but in many species, the sexual activity of the female is cyclic. Most of the time, the female avoids the male and repulses his sexual advances. Periodically, however, there is an abrupt change in behavior and the female seeks out the male, attempting to mate. These short episodes of heat or estrus are so characteristic that the sexual cycle in mammalian species that do not menstruate is named the estrous cycle. This change in female sexual behavior is brought on by a rise in the circulating blood estrogen level. Some animals, notably the rabbit and the ferret, come into heat and remain estrous until pregnancy or pseudopregnancy results. In these species, ovulation is due to a neuroendocrine reflex. Stimulation of the genitalia and other sensory stimuli at the time of copulation provokes release from the pituitary of the LH that makes the ovarian follicles rupture. In many other species, spontaneous ovulation occurs at regular intervals, and the periods of heat coincide with its occurrence. This is true in monkeys and apes. In captivity, these species mate at any time; but in the wild state, the females accept the male more frequently at the time of ovulation. In women, sexual activity occurs throughout the menstrual cycle, but careful studies indicate that, as in other primates, there is more spontaneous female-initiated sexual activity at about the time of ovulation.

Pheromones Substances produced by an animal that act at a distance to produce hormonal, behavioral, or other physiologic changes in another animal of the same species have been called pheromones. The sex attractants of certain insects are particularly well-known examples, as are the odorant pheromones that act via the vomeronasal organ in rodents In monkeys, the sex drive of the male is greater when he is exposed to a female at the time of ovulation than when he is exposed to a female at another time of her cycle. The "message" sent by the female to the male in this situation is olfactory, and the substances responsible are certain fatty acids in the vaginal secretions. In women, there is also solid evidence for the production of odorant pheromones. For example, women who are good friends or roommates tend to synchronize their menstrual cycles, and armpit odor of women has been shown to be capable of modifying the menstrual cycle. Also, infants prefer breast or axillary pads from their own mothers over pads from unfamiliar mothers. Neural Control in the Female In female animals, removal of the neocortex and the limbic cortex abolishes active seeking out of the male ("enticement reactions") during estrus, but other aspects of heat are unaffected. Periamygdaloid lesions do not produce hypersexuality as they do in the male. However, discrete anterior hypothalamic lesions abolish behavioral heat without affecting the regular pituitary-ovarian cycle Implantation of minute amounts of estrogen in the anterior hypothalamus causes heat in ovariectomized rats. Implantation in other parts of the brain and outside the brain does not have this effect. Apparently, therefore, some element in the hypothalamus is sensitive to estrogen and is stimulated by the hormone to initiate estrous behavior. Effects of Sex Hormones in Infancy on Adult Behavior In female experimental animals, exposure to sex steroids in utero or during early postnatal development causes marked abnormalities of sexual behavior when the animals reach adulthood. Female rats treated with a single relatively small dose of androgen before the fifth day of life do not have normal heat periods when they mature. They do not show the cyclic release of pituitary gonadotropins characteristic of the adult female but, rather the tonic, steady secretion characteristic of the adult male; their brains have been "masculinized" by the single brief exposure to androgens. They also show increased male sexual behavior. Conversely, male rats castrated at birth develop the female pattern of cyclic gonadotropin secretion and show considerable female sexual behavior when given doses of ovarian hormones that do not have this effect in intact males. Thus, the development of a "female hypothalamus" depends simply on the absence of androgens in early life rather than on exposure to female hormones. Rats are particularly immature at birth, and animals of other species in which the young are more fully developed at birth do not show these changes when exposed to androgens during the postnatal period. However, these animals develop genital abnormalities when exposed to androgens in utero Female monkeys exposed to androgens in utero do not lose the female pattern of gonadotropin secretion but do develop abnormalities of sexual behavior in adulthood.

Exposure of human females to androgens in utero does not change the cyclic pattern of gonadotropin secretion in adulthood. However, there is evidence that masculinizing effects on behavior do occur.

Maternal Behavior Maternal behavior is depressed by lesions of the cingulate and retrosplenial portions of the limbic cortex in animals. Hormones do not appear to be necessary for its occurrence, but prolactin, which is secreted in large amounts during pregnancy and lactation, facilitates it. In female mice, knockout of the fos-B gene, one of four immediate early fos genes, is associated with failure to retrieve and care for pups after delivery. The neglected pups die, though if they are nourished by a normal foster mother they develop and flourish. Thus, genetic factors also appear to be involved in the control of maternal behavior. FEAR & RAGE Introduction The relation of the limbic system to fear and rage was demonstrated by Kluver and Bucy, who showed that bilateral temporal lobectomy in monkeys, produced a characteristic set of abnormalities ("Kluver-Bucy animals"). Their animals were docile and the males hypersexual because of removal of limbic structures in the temporal lobes. They also had visual agnosia (inability to recognize objects by sight). They would repeatedly pick up all moveable objects in their environment. They would manipulate each object in a compulsive way; mouth, lick, and bite it; and then, unless it was edible, discard it. However, discarded objects were picked up again in a few minutes as if the animal had never seen them before and subjected to the same manipulation and oral exploration. Fear and rage are in some ways closely related emotions. The external manifestations of the fear, fleeing, or avoidance reaction in animals are autonomic responses such as sweating and pupillary dilation, cowering, and turning the head from side to side to seek escape. The rage, fighting, or attack reaction is associated in the cat with hissing, spitting, growling, piloerection, pupillary dilation, and well-directed biting and clawing. Both reactions-and sometimes mixtures of the two-can be produced by hypothalamic stimulation. When an animal is threatened, it usually attempts to flee. If cornered, it fights. Thus, fear and rage reactions are probably related instinctual protective responses to threats in the environment. Fear The fear reaction can be produced in conscious animals by stimulation of the hypothalamus and the amygdaloid nuclei. Conversely, after destruction of the amygdalas, the fear reaction and its autonomic and endocrine manifestations are absent in situations in which they would normally be evoked. There is considerable evidence that the amygdaloid nuclei are concerned with the encoding of memories that evoke fear. Fear learning is blocked when LTP is disrupted in pathways to the amygdalas In humans with amygdala damage, there are deficient fear responses to auditory and visual stimuli. In normal humans, viewing faces that have fearful expressions activates the left amygdala. The degree of activation is proportionate to the intensity of fear in the facial expression, and happy faces fail to produce a response.

Afferent sensory inputs that trigger conditioned fear responses may pass directly to the amygdalas without going through the neocortical sensory areas.

Anxiety Anxiety is associated with a bilateral increase in blood flow in a discrete portion of the anterior end of each temporal lobe. It is relieved by benzodiazepines, which bind to GABAA receptors and increase the Clconductance of these ion channels. Patients with anxiety disorders have decreased sensitivity to benzodiazepines. These drugs bind to the subunits of the GABAA receptors. However, the 2 subunit is also required for full sensitivity to benzodiazepines, and mice heterozygous for knockout of this subunit show decreased sensitivity to the drugs and increased anxiety behavior. Rage & Placidity Most animals, including humans, maintain a balance between rage and its opposite, the emotional state that for lack of a better name is referred to here as placidity. Major irritations make normal individuals "lose their temper," but minor stimuli are ignored. In animals with certain brain lesions, this balance is altered. Some lesions produce a state in which the most minor stimuli evoke violent episodes of rage; others produce a state in which the most traumatic and anger-provoking stimuli fail to ruffle the animal's abnormal calm. Rage responses to minor stimuli are observed after removal of the neocortex and after destruction of the ventromedial hypothalamic nuclei and septal nuclei in animals with intact cerebral cortices. On the other hand, bilateral destruction of the amygdaloid nuclei in monkeys causes a state of abnormal placidity. The placidity produced by amygdaloid lesions in animals is converted into rage by subsequent destruction of the ventromedial nuclei of the hypothalamus. Rage can also be produced by stimulation of an area extending back through the lateral hypothalamus to the central gray area of the midbrain. Gonadal hormones appear to affect aggressive behavior. In male animals, aggression is decreased by castration and increased by androgens. It is also conditioned by social factors; it is more prominent in males that live with females and increases when a stranger is introduced into an animal's territory.

"Sham Rage" Although rage attacks in animals with diencephalic lesions are induced by minor stimuli, they are usually directed with great accuracy at the source of the irritation. Furthermore, hypothalamic stimulation that produces the fear-rage reaction is apparently unpleasant to animals, because they become conditioned against the place where the experiments are conducted and try to avoid the experimental sessions. They can easily be taught to press a lever or perform some other act to avoid a hypothalamic stimulus that produces the manifestations of fear or rage. The fact that hypothalamic stimulation is a potent unconditioned stimulus for the formation of conditioned avoidance responses and the fact that the avoidance responses are extremely persistent indicate that the stimulus is unpleasant. There is therefore little doubt that rage attacks include the mental as well as the physical manifestations of rage, and the term "sham rage" should be dropped. Clinical Correlates Although emotional responses appear to be more complex and subtle in humans than in animals, the neural substrates are probably the same. Rage attacks in response to trivial stimuli have been observed in patients with brain damage.

 They are a complication of pituitary surgery when there is inadvertent damage to the base of the brain. They also follow a number of diseases of the nervous system, especially epidemic influenza and encephalitis, which destroy neurons in the limbic system and hypothalamus. MOTIVATION & ADDICTION Self-Stimulation The points where stimulation leads to repeated bar pressing are located in a medial band of tissue extending from the frontal cortex through the hypothalamus to the midbrain tegmentum The area most concerned is the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. The points where stimulation is avoided are in the lateral portion of the posterior hypothalamus, the dorsal midbrain, and the entorhinal cortex. The latter points are sometimes close to points where bar pressing is repeated, but they are part of a separate system. The areas where bar pressing is repeated are much more extensive than those where it is avoided. It has been calculated that in rats repeated pressing is obtained from 35% of the brain, avoidance from 5%, and indifferent responses (neither repetition nor avoidance) from 60%. Drugs that block postsynaptic D3 dopaminergic receptors reduce the rate of selfstimulation, and dopamine agonists increase it. The main site of the relevant receptors appears to be the nucleus accumbens. Behavior is motivated not only by reduction or prevention of an unpleasant affect but also by primary rewards such as those produced by stimulation of the approach system of the brain. Stimulation of the reward system provides a potent motivation for learning mazes or performing other tasks. The implications of these facts are great in terms of the classic drive-reduction theory of motivation, the disruption and facilitation of ongoing behavior, and addiction. Addiction Addiction, defined as the repeated compulsive use of a substance despite negative consequences, can be produced by a variety of different drugs. Not surprisingly, addiction is associated with the reward system, and particularly with the nucleus accumbens, located at the base of the striatum and the mesocortical dopaminergic neurons that project from the midbrain to this nucleus and the frontal cortex The best-studied addictive drugs are opiates such as morphine and heroin, cocaine, amphetamine, ethyl alcohol, and nicotine. All these affect the brain in different ways, but all have in common the fact that they increase the amount of dopamine available to act on D3 receptors in the nucleus accumbens. Thus, acutely they stimulate the reward system of the brain. Long term, however, addiction involves the development of tolerance, i.e., the need for increasing amounts of a drug to produce a "high." Withdrawal produces psychologic and physical symptoms. One of the characteristics of addiction is the tendency of addicts to relapse after treatment. For opiate addicts, for example, the relapse rate in the first year is about 80%. Relapse often occurs upon exposure to sights, sounds, and situations that were previously associated with drug use. The medial-prefrontal cortex, the hippocampus, and the amygdala send excitatory glutaminergic fibers to the nucleus accumbens, and it may be that activity in these inputs contributes to the relapses produced by environmental cues and memories.

BRAIN CHEMISTRY & BEHAVIOR Introduction Drugs that modify human behavior include hallucinogenic agents, drugs that produce hallucinations and other manifestations of the psychoses; tranquilizers, drugs that allay anxiety and various psychiatric symptoms; and antidepressants, drugs that elevate mood and increase interest and drive. These and many other drugs act by modifying transmission at synaptic junctions in the brain. Aminergic Systems in the Brain There are four large aminergic systems in the brain that have in common the presence of their cell bodies in relatively few locations with multiple branched axons projecting to almost all parts of the nervous system These are the serotonergic, nor-adrenergic, adrenergic, and histaminergic systems. Dopaminergic neurons have their cell bodies in more locations, but their axons also project to many different areas. Serotonin Serotonin-containing neurons have their cell bodies in the midline raphe nuclei of the brain stem and project to portions of the hypothalamus, the limbic system, the neocortex, the cerebellum, and the spinal cord The hallucinogenic agent lysergic acid diethyl-amide (LSD) is a serotonin agonist that produces its effects by activating 5-HT2 receptors in the brain.