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See biological psychiatry 2013  – stress, obesity and addiction.

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 Amygdala: a major structure leading to patterns of physiological

change which pause when emotion occurs. The connection isthalamus to cortex to amygdala. Thus, we may have an emotional

reaction/response before we’re aware what’s going on.

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Sensory inputs that can trigger an emotion arrive in the thalamus and are then

routed along a fast pathway directlyto the amygdala and along a slow pathway which allows the cortex time to

think about the situation. Activity in

the fast pathway also elicits the autonomic arousal and hormonal responses

that are part of the physiological

component of emotion.

What parts of the brain are principally involved in emotional responses?

Sensory information is transmitted from the thalamus to the hypothalamus  – if

that information is emotionallyrelevant it activates the cortex and the limbic system  – assess the emotional

relevance of the info and influence

subsequent hypothalamus response

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Homeostatic regulation extends far beyond the control of temperature. All animals also regulate their

blood glucose, as well as the concentration of their blood. Mammals regulate their blood glucose with

insulin and glucagon. The human body maintains glucose levels constant most of the day, even after a

24-hour fast. Even during long periods of fasting, glucose levels are reduced only very slightly.[5] Insulin,

secreted by the beta cells of the pancreas, effectively transports glucose to the body's cells by

instructing those cells to keep more of the glucose for their own use. seeDynamic equilibrium. If the

glucose inside the cells is high the cells will convert it to the insoluble glycogen to prevent the soluble

glucose interfering with cellular metabolism. Ultimately this lowers blood glucose levels, and Insulin

helps to prevent hyperglycemia. When insulin is deficient or cells become resistant to it, diabetes 

occurs. Glucagon, secreted by the alpha cells of the pancreas, encourages cells to break down stored

glycogen or convert non-carbohydrate carbon sources to glucose via gluconeogenesis, thus preventing

hypoglycemia. The kidneys are used to remove excess water and ions from the blood. These are then

expelled as urine. The kidneys perform a vital role in homeostatic regulation in mammals, removing

excess water, salt, and urea from the blood. These are the body's main waste products.

The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of

functions. One of the most important functions of the hypothalamus is to link the nervous system to the

endocrine system via the pituitary gland (hypophysis).

The hypothalamus is located below the thalamus, just above the brain stem. In the terminology of

neuroanatomy, it forms the ventral part of the diencephalon. All vertebrate brains contain a

hypothalamus. In humans, it is roughly the size of an almond.

The hypothalamus is responsible for certain metabolic processes and other activities of the autonomic

nervous system. It synthesizes and secretes certain neurohormones, often called hypothalamic-

releasing hormones, and these in turn stimulate or inhibit the secretion of pituitary hormones. Thehypothalamus controls body temperature, hunger , thirst,[1] fatigue, sleep, and circadian cycles.

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 A circadian rhythm is a roughly 24-hour cycle in the biochemical, physiological, or

behavioural processes of living entities

 Although circadian rhythms are endogenous ("built-in", self-sustained), they are adjusted to

the environment by external cues, the primary one of which is daylight.

Circadian rhythmicity is present in the sleeping and feeding patterns of animals, including

human beings. There are also clear patterns of core body temperature, brain wave activity,

hormone production, cell regeneration and other biological activities. In addition,

photoperiodism, the physiological reaction of organisms to the length of day or night, is vital to

both plants and animals, and the circadian system plays a role in the measurement and

interpretation of day length.

 After lesions to the lateral hypothalamus, animals do not eat spontaneously. Conversely

lesions to the ventromedial hypothalamus, the main satiety centre, cause animals to overeat

to excess, and become grossly obese

Neuropeptides are small protein-like molecules used by neurons to communicate with each

other. They are neuronal signaling molecules, influence the activity of the brain in specific

ways and are thus involved in particular brain functions, like analgesia, reward, food intake,

learning and memory.

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In physiology, the endocrine system is a system of glands, each of which secretes a type of

hormone directly into the bloodstream to regulate the body. The endocrine system is in

contrast to the exocrine system, which secretes its chemicals using ducts.

The autonomic nervous system (ANS or visceral nervous system) is the part of the peripheral

nervous system that acts as a control system functioning largely below the level of

consciousness, and controls visceral functions.[1] The ANS affects heart rate, digestion,

respiration rate, salivation, perspiration, diameter of the pupils, micturition (urination), and

sexual arousal. Whereas most of its actions are involuntary, some, such as breathing, work in

tandem with the conscious mind.

It s classically divided into two subsystems: the parasympathetic nervous system (PSNS) and

sympathetic nervous system (SNS).

The parasympathetic nervous system (PSNS) is one of the two main divisions of the

autonomic nervous system (ANS). The ANS is responsible for regulation of internal organs

and glands, which occurs unconsciously. The parasympathetic system specifically is

responsible for stimulation of "rest-and-digest" activities that occur when the body is at rest,

including sexual arousal, salivation, lacrimation (tears), urination, digestion and defecation. Its

action is described as being complementary to that of one of the other main branches of the

 ANS, the sympathetic nervous system, which is responsible for stimulating activities

associated with the fight-or-flight response.

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See paper by Dolan 2002 Science 298 no 5596 p1191-1194

 An evolutionary perspective on emotion suggests that environmental events of value should be susceptible to preferential perceptual processing. One means of achieving this is by emotion

enhancing attention, leading to increased detection of emotional events. The influence of emotion on attention can be studied in classic vi sual search and spatial orienting tasks. In a visualsearch, the standard finding is that the time taken to detect a specif ied target increases in direct proportion to the number of irrelevant distracters, indicating serial attentive processing.However, for emotional stimuli there is more rapid target detection for faces with positive or negative expressions, or for spiders or snakes, with the most consistent capture of attentionbeing evident for fear-relevant stimuli . Similar effects are seen in spatial orienting tasks where there is a faster response to targets appearing on the same side as an emotional cue (e.g.,faces, spiders, threat words, conditioned shapes) and a slower response to those appearing on the opposite side . Neuroimaging data, using spatial orienting paradigms, point to orbitalprefrontal cortex as a possible site of i nteraction .

The “capture of attention” is not the sole means by which emotional stimuli inf luence perception, and emerging evidence indicates mechanisms independent of attention. Perceptualprocessing under conditions of limited attention as, for example, processing of stimuli at unattended spatial locations is often referred to as preattentive. In visual backward maskingparadigms, a briefly presented (ms) target can be rendered invisible if immediately followed by a second “masking stimulus.” In situations where the hidden target stimulus is an emotionalitem, for example a conditioned angry face or a spider, preserved processing can be i ndexed by differential skin conductance responses (SCRs) to fear-relevant compared with f ear-irrelevant targets, even though the target stimulus is not perceived (6). Simi lar findings are evident using the attentional blink paradigm. This refers to a situation where detection of an initialtarget stimulus in a visual stimulus str eam leads to impaired awareness, or “inattentional blindness,” for a successive second target. This inattentional blindness is greatly dim inished wherea second target is an emotional item (7). This finding suggests an advantage in detection of an emotional item even in circumstances where attentional resources are limited.

Studies of patients with focal brain lesions provide additional evidence for independence of emotional processing from attentional mechanisms. After brain damage to r ight inferior parietalcortex, patients frequently fail to perceive a stimulus presented in their contralesional hemifield (spatial neglect) or, in m ilder forms, fail to perceive a stimulus when a simultaneous stimulusis presented on the ipsilesional side (sensory extincti on). This contralesional deficit is greatly attenuated for emotional stimuli, such as faces with happy or angry expressions or images ofspiders . Noncon scious processing of emotion has also been demonstrated in the blindfield of patients with damage to primary v isual cortex . These findings indicate processing ofemotional stimuli occurs before the operation of selective attention and such “preattentive processing” results in enhanced stimulus detection.

Pre-attentive processing of emotional stimuli, such as faces, implies an early discrimination between the occurrence of emotional and nonemotional events. Using magneto-encephalography (MEG), discriminatory responses to emotional faces are seen in midl ine occipital cortex as early as 100 to 120 ms after stimulus onset, before the onset of a characteristicface-related response at approximately 170 m s . Intermodal binding of emotion for presentation of anger in v oice and face is associated with a distinct electroencephalographic potentialoccurring at about 100 ms . Short-latency responses (120 to 160 ms) to aversive stimulus presentation are also seen during direct intracerebral recordings within ventral prefrontal cortexThus, electrophysiological data point to rapid and widespread neuronal responses to emotional stimuli that precede responses associated with actual stim ulus identification which occur atapproximately 170 ms after stimulus onset.

 An important neurobiological question is how processing of emotional stimuli proceeds in the absence of attention. Accumulating evidence points to the amygdala as an important mediatorof emotional influences on perception (Fig. 1). In f unctional neuroimaging experiments using vi sual backward masking paradigms, where emotional stimuli are presented out of awareness,

an amygdala response discriminates between unseen emotional and unseen nonemotional targets In other experiments with overt stimulus presentation but where attention issystematically manipulated, an amygdala response to fearful faces is independent of the concurrent focus of attention . Studies involving patients with either blindsight or visual extinctiondemonstrate an amygdala response to emotional stimuli presented out of awareness in the damaged hemifield . Residual processing abil ities for unaware emotional stimulus presentationare associated with engagement of a subcortical retino-collicular-pulvinar pathway specific to unaware emotional stimulus processing . The involvement of this pathway i s of considerableinterest, because it is also im plicated in residual visual processing evident in patients with blindsight. One suggestion is that certain classes of emotional stimuli, for example coarse vi sualcues present in f earful faces, can be processed by a noncortical pathway to enable rapid adaptive responses to danger.

 A related neurobiological question is how preattentive processing of emotional events influences, and indeed enhances, perception. One possibility is that inputs from emotional processingregions, in particular the amygdala, modulate the function of regions involved in early object perceptual processing. Anatomically, the amygdala receives visual inputs from ventral visualpathways and sends feedback projections to all processing stages within this pathway (21). Neuroimaging data provide evidence for context-dependent enhancement of functionalconnectivity between amygdala and extrastriate visual regions expressed during processing of an emotional visual input (22, 23). There is now ev idence showing this connectivity haspsychological consequences in that after amygdala damage a v isual perceptual enhancement for emotional items is abolished

an emotional event, which may include automatic response repertoires, referred to as emotion, and their subjectiv e or experiential counterparts, referred to as feelings (43, 44). Feelings aredefined as mental representations of physiological changes that characterize and are consequent upon processing emotion-eliciting objects or states. In more extended form, the suggestionis that patterned neural responses provide for a differentiation of feeling states, this account assigns an important causal role to afferent feedback, sensory and neurochemical, to the brainregarding emotion-induced changes in body state. The importance of afferent feedback in the experience of emotion is supported by phenomenological evidence from patients with a rareacquired failure of peripheral autonomic regulation, pure autonomic failure (PAF), who have subtle blunting of emotional experience. However, the role of feeling states extends beyondproviding subjective coloring to experience, and it is proposed that feelings inf luence functions such as decision making and interpersonal interactions (43).

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Key structures in the circuitry underlying emotion regulation. (A)Orbital prefrontal cortex in green and the ventromedial prefrontal

cortex in red. (B) Dorsolateral prefrontal cortex. (C) Amygdala. (D) Anterior cingulate cortex. Each of these interconnected structuresplays a role in different aspects of emotion regulation, andabnormalities in one or more of these regions and/or in theinterconnections among them are associated with failures of emotionregulation and also increased propensity for impulsive aggressionand violence. [Adapted from (9)]

From Davidson et al (2000) As reviewed recently , a circuit that

includes several regions of the prefrontal cortex (PFC), theamygdala, hippocampus, hypothalamus, anterior cingulate cortex(ACC) (8), insular cortex, ventral striatum, and other interconnectedstructures has been implicated in various aspects of emotion,affective style, and emotion regulation (Fig. 1). Emotion regulationincludes processes that amplify, attenuate, or maintain an emotion.

From Davidson et al (2000) Both the dorsolateral and ventromedial

sectors of the PFC have been associated with different aspects of

emotion. Asymmetries in the PFC have been linked to approach and

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withdrawal systems, with sectors of the left PFC more associated with the

approach system and certain forms of positiveaffect and other regions in the

right PFC more associated with negative affect and withdrawal. Studies of

patients with discrete PFC lesions, as well as studies using measures of

regional brain activation in neurologically intact normal subjects and patients

with psychiatric disorders, have provided evidence to support theseproposals. The PFC is likely to play a role in affective working memory, a

process critical to anticipating future affective outcomes (see, e.g.,

Watanabe, 1996). The amygdala is clearly important for several aspects of

emotional processing, though there still remain many questions about its

contributions to human emotion and affective style. It does appear to be the

case that the amygdala is activated by stimuli that elicit certain forms of

negative affect, particularly fear. It is also the case that individual differences

in amygdala activation, both at baseline and in response to negative affect-

arousing stimuli, account for significant variance in measures of emotion-related cognitive function (e.g., rapidity of aversive learning, recall of

negative affective stimuli) and in self-report measures of negative

dispositional mood. However, studies using discrete excitotoxic lesions of

the amygdala in nonhuman primates that preserve fibers of passage suggest

that the amygdala is not required for the expression of both behavioral and

biological components of an anxious temperament. Other evidence suggests

that the PFC may be a more critical site for the expression of these

individual differences. The final two sections above addressed issues related

to plasticity in the central circuitry of emotion and consequently, in affectivestyle. Evidence at the animal level was reviewed to illustrate the profound

impact of environmental events in shaping the neural circuitry of emotion.

Data are now available that reveal changes down to the level of gene

expression as a direct consequence of environmental manipulations.

Moreover, in addition to the critical role of the early environment, new

findings reveal neurogenesis in the human hippocampus in adults, indicating

that plasticity continues unabated

throughout the life course. The hippocampus and other interconnected

structures were highlighted for their contribution to context-dependentaffective responding. Stressors produce elevations in cortisol, which in turn

result in hippocampal cell death and/or decreases in hippocampal

neurogenesis. This chain of events provides one mechanism whereby

negative life events can result in abnormalities in context-dependent

emotional responses. We ended with a brief discussion of affect regulation.

There are many forms of affect regulation involving both automatic and

effortful/voluntary processing. It is likely that when traittike regulatory

strategies occur over a long duration of time, plastic changes in the central

circuitry of emotion are produced.

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 From Davidson et al (2000) a circuit that includes several regions ofthe prefrontal cortex (PFC), the amygdala, hippocampus,hypothalamus, anterior cingulate cortex (ACC) (8), insular cortex,ventral striatum, and other interconnected structures has beenimplicated in various aspects of emotion, affective style, and emotionregulation (Fig. 1). Emotion regulation includes processes thatamplify, attenuate, or maintain an emotion.

From Davidson et al (2000) Both the dorsolateral and ventromedial

sectors of the PFC have been associated with different aspects of

emotion. Asymmetries in the PFC have been linked to approach andwithdrawal systems, with sectors of the left PFC more associated

with the approach system and certain forms of positive affect and

other regions in the right PFC more associated with negative affect

and withdrawal. Studies of patients with discrete PFC lesions, as well

as studies using measures of regional brain activation in

neurologically intact normal subjects and patients with psychiatric

disorders, have provided evidence to support these proposals. The

PFC is likely to play a role in affective working memory, a process

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critical to anticipating future affective outcomes (see, e.g., Watanabe, 1996).

The amygdala is clearly important for several aspects of emotional

processing, though there still remain many questions about its contributions

to human emotion and affective style. It does appear to be the case that the

amygdala is activated by stimuli that elicit certain forms of negative affect,

particularly fear. It is also the case that individual differences in amygdalaactivation, both at baseline and in response to negative affect-arousing

stimuli, account for significant variance in measures of emotion-related

cognitive function (e.g., rapidity of aversive learning, recall of negative

affective stimuli) and in self-report measures of negative dispositional mood.

However, studies using discrete excitotoxic lesions of the amygdala in

nonhuman primates that preserve fibers of passage suggest that the

amygdala is not required for the expression of both behavioral and biological

components of an anxious temperament. Other evidence suggests that the

PFC may be a more critical site for the expression of these individualdifferences. The final two sections above addressed issues related to

plasticity in the central circuitry of emotion and consequently, in affective

style. Evidence at the animal level was reviewed to illustrate the profound

impact of environmental events in shaping the neural circuitry of emotion.

Data are now available that reveal changes down to the level of gene

expression as a direct consequence of environmental manipulations.

Moreover, in addition to the critical role of the early environment, new

findings reveal neurogenesis in the human hippocampus in adults, indicating

that plasticity continues unabatedthroughout the life course. The hippocampus and other interconnected

structures were highlighted for their contribution to context-dependent

affective responding. Stressors produce elevations in cortisol, which in turn

result in hippocampal cell death and/or decreases in hippocampal

neurogenesis. This chain of events provides one mechanism whereby

negative life events can result in abnormalities in context-dependent

emotional responses. We ended with a brief discussion of affect regulation.

There are many forms of affect regulation involving both automatic and

effortful/voluntary processing. It is likely that when trait tike regulatorystrategies occur over a long duration of time, plastic changes in the central

circuitry of emotion are produced.

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Klüver-Bucy syndrome is a behavioral disorder that occurs when both the right and left anterior temporal lobes of the brain malfunction. The amygdala has been a particularly implicated brain region in the pathogenesis of this syndrome. The syndrome isnamed for Heinrich Klüver  and Paul Bucy.

Docility. Characterized by exhibiting diminished fear responses or reacting with unusually low aggression. This has also been termed"placidity" or "tameness".[1][2][3] 

Dietary changes. Characterized by eating inappropriate objects and/or overeating (e.g. bulimia).[1][2][3] 

Hyperorality. This was described by Ozawa et al. as "an oral tendency, or compulsion to examine objects by mouth". [1][2][3] 

Hypersexuality. Characterized by a heightened sex drive or a tendency to seek sexual stimulation from unusual or inappropriateobjects.[1][2][3] 

Visual agnosia. Characterized by an inability to recognize familiar objects or people.[1][2][3] 

The syndrome in humans is due to bilateral destruction of the amygdaloid body and inferior temporal cortex, most commonly due toherpes simplex encephalitis.. It shares visual agnosia and loss of normal fear and anger responses in common with the monkeymodel but one also sees loss of memory with dementia, distractibility and seizures. The hypersexuality tends to be less gross thanwith the monkeys but may be public and unacceptable.

Epidemiology It is a very rare disorder and most of the literature relates to animal models rather than human cases:

Most literature relating to humans are isolated case reports and few papers report more than a small number of cases.

It is likely to become more common with greater survival of herpes encephalitis due to treatment with antiviral agents.

Risk factors

The most common cause is herpes simplex encephalitis, but it has also been associated with other infections such as tuberculousmeningitis or primary cerebral Whipples disease.2 

Other causes include:

Head injury (not necessarily very severe)

Dementia, especially fronto-temporal dementia (Pick's disease) but also Alzheimer's disease3 

Surgical lesions

Post-epilepsy4 

Cerebrovascular disease 

It has occasionally been described in children.5 

When the amygdala is damaged in humans, they lose their sensitivity to stimuli associated with strong emotions. For example, Adolphs, Russell, and Tranel (1999) found that a patient with "complete, bilateral damage restricted to the amygdala" was able to tellwhen a face was sad or happy, but he had lost his ability to discriminate between different levels of emotional arousal. He could nottell a slightly sad face from a very angry face: they all just looked "unhappy" to him. He had the same problem with happy

expressions: he could not tell the difference between a face that showed very mild happiness and one that expressed great joy

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 Alzheimer's disease affects the hippocampus first and severely, before other

parts of the cortex (later, the frontal lobes too). So memory is usually the firstthing to start to falter in Alzheimer's -- the ability to make new ones.

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Source: DEPRESSION: Perspectives from Affective Neuroscience

Richard J. Davidson, Diego Pizzagalli, Jack B. Nitschke, and KatherinePutnam

Source: Monk et al (2008) The development of emotion-related neural

circuitry in health and psychopathology. Development and Psychopathology

20 (2008), 1231 –1250

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Source: DEPRESSION: Perspectives from Affective Neuroscience

Richard J. Davidson, Diego Pizzagalli, Jack B. Nitschke, and KatherinePutnam

Source: Monk et al (2008) The development of emotion-related neural

circuitry in health and psychopathology. Development and Psychopathology

20 (2008), 1231 –1250

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Source: DEPRESSION: Perspectives from Affective Neuroscience

Richard J. Davidson, Diego Pizzagalli, Jack B. Nitschke, and KatherinePutnam

Source: Monk et al (2008) The development of emotion-related neural

circuitry in health and psychopathology. Development and Psychopathology

20 (2008), 1231 –1250

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See Sinha and Jastreboff Biological Psychiatry 2013

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 Act needs differ from all other levels in that they are not deficiency needs but

are growth needs –

 expand and develop.

Can spend life at one level without progressing e.g. People who are starving.

People at the highest level are free to pursue moral, cultural and aesthetic

concerns. - famous self-actualisers - Gandhi and Martin Luther King.

Idea is difficult to test.

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Leptin, a hormone secreted from adipocytes (fat cells) that circulates in the blood in proportion

to the energy stores of the body; leptin thus suppresses the desire to eat.

Mammals regulate their blood glucose with insulin and glucagon. Insulin, secreted by the beta

cells of the pancreas, effectively transports glucose to the body's cells by instructing those

cells to keep more of the glucose for their own use.

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Physiology

The hypothalamus is a very complex part of the brain, which contains many different types of specialised nerve cell and controls many differentphysiological functions. One important role of the hypothalamus is to regulate food intake and metabolism. Since the experiments of Lashley, it has beengenerally accepted that appetite for food is in part governed by a balance between hunger signals and satiety signals that converge at the hypothalamus. Apart from the lateral hypothalamus and the ventromedial nucleus, the arcuate nucleus of the hypothalamus has a particularly important role. The arcuatenucleus contains several different populations of nerve cells, one of which makes a neuropeptide, neuropeptide Y, which is a very potent orexigen (wheninjected into the brain i t causes animals to eat voraciously). These NPY neurons are activated by ghrelin, a hormone that is secreted from the emptystomach, and whose concentration in the blood falls after each meal and rises progressively until the next.

Ghrelin is thus a major physiological hunger signal. Conversely, the NPY cells are inhibited by leptin, a hormone secreted from adipocytes (fat cells) thatcirculates in the blood in proportion to the energy stores of the body; leptin thus suppresses the desire to eat. There are some cases of humans born withleptin deficiency due to a genetic mutation - these individuals are grossly obese, but their body weight will return to normal if they receive daily injections ofleptin. However these cases are extremely rare, in most cases of obesity, the individuals have high circulating concentrations of leptin (as expected from the large fat mass) but appear to be insensitive to leptin - this "leptin resistance" appears to be similar to the "insulin resistance" seen in type 2 diabetesmellitus.

Ghrelin acts on cells via a G-protein coupled receptor called the growth hormone secretagogue receptor  (GHS receptor) - discovered and named beforeghrelin itself was discovered and named in 2000. The GHS receptor is densely expressed in both the arcuate nucleus and the ventromedial hypothalamus,and it activates NPY-containing neurons. Leptin also acts through G-protein coupled membrane receptors, and leptin receptors are expressed in manybrain regions including particularly the arcuate nucleus. Leptin inhibits NPY neurons and activates ne urons that make alpha-MSH. Exactly how ghrelin andleptin reach their targets in the brain is not wholly clear: both are large peptides that do not cross the blood-brain barrier  readily. It is thought that there is aspecific mechanism for transporting leptin into the brain in the choroid plexus, but whether something similar exists for ghrelin is unclear. The arcuatenucleus is adjacent to the median eminence, an area of the brain which lacks a blood-brain barrier, so it is also possible that ghrelin and leptin gain directentry into the brain at this site.

Leptin and ghrelin are not the only signals that reach the hypothalamus; cells in the ventromedial nucleus and some in the lateral hypothalamus are directlysensitive to glucose concentrations - some are inhibited when glucose concentrations are high, others are facilitated. The hypothalamus also containsneurons that are sensitive to insulin - insulin is secreted overall in amounts proportional to the size of the body fat stores, so is another signal that the braincan use to evaluate its energy reserves. Other hormones ar e also produced by the stomach, pancreas and gastrointestinal tract, including pancreaticpolypeptide and the products of the gastrointestinal L cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY 3-36) which appear toact as satiety signals.

These signals are only part of the complex systems regulating when and how much we eat. In humans as in many other animals, we eat at generallyconsistent times of the day, and we are conditioned to expect food and become hungry at these times. Our appetite for food can also be potently stimulatedby the smell and taste of food. Experimental laboratory animals, even though food is freely available at all times, will still tend to confine their eating to mealtimes, according to a circadian rhythm; rats for example generally become active and start to eat soon after the lights are switched off. Such rhythms arecontrolled by another nucleus in the hypothalamus - the suprachiasmatic nucleus. How much we eat is also affected by our levels of stress and anxiety - socalled "comfort eating." Again, the hypothalamus is critically important - the paraventricular nucleus of the hypothalamus is the major control centre of thehypothalami-pituitary-adrenal axis (HPA axis) - the body systems that control our responses to stress.

Satiety, or the feeling of fullness and disappearance of appetite after a meal, is mediated by signals that arise from the stomach and gastrointestinal tract.These signals, which include signals arising from stretch receptors as the stomach is distended by food, and chemical signals arising in the stomach as theresult of secretion from cells regulating digestion, activate afferent fibres of the vagus nerve. For example, the gut hormone cholecystokinin (CCK) issecreted in the stomach during a meal, and activates specific receptors (CCK-A receptors) on the nerve endings of the gastric vagus nerve. The vagally-mediated signals reach the hypothalamus via nuclei in the caudal brainstem - notably the nucleus of the solitary tract. Noradrenergic neurons in this areaplay a particularly important role in carrying these signals; these neurons project to many different parts of the hypothalamus.

Eating appears to stop when the satiety signals reaching the hypothalamus are sufficiently strong to activate particular populations of neurons that make"anorexigenic" peptides - peptides that when injected into the brain are potent at suppressing hunger. There are many different anorexigenic peptides justas there are many different orexigenic peptides - the neural circuitry that regulates appetite is extremely complex. However one of the most importantanorexigenic peptides is alpha melanocyte-stimulating hormone (alpha-MSH) which is made in another population of neurons in the arcuate nucleus.These neurons project to many different parts of the hypothalamus where alpha-MSH is released and acts on other neurons via specific melanocortin

receptors.Genetic disorders that prevent alpha-MSH being made or which prevent its normal actions result in individuals who are grossly obese as a result of chronicovereating.

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See Sinha and Jastreboff Biological Psychiatry 2013

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Neuropeptides

In recent years, it has become apparent that many of the neural networks involved in regulating appetite use many

specific neuropeptides as chemical messengers. In the lateral hypothalamus, an important population uses apeptide that was called orexin because of its potent ability to evoke hunger, but other orexigenic neuropeptides

include NPY as mentioned above, melanin-concentrating hormone (MCH) which is produced in the dorsomedial

hypothalamus, and galanin, agouti-related peptide (AgRP) which is an endogenous antagonist of melanocortin

receptors, and the opioid peptide beta-endorphin, all of which are produced in the arcuate nucleus. Anorexigenic

neuropeptides include alpha-MSH, corticotropin releasing hormone (CRH), cocaine-and amphetamine regulated

transcript (CART), neuromedin U, galanin, galanin-like peptide and oxytocin. In addition, many of the factors

secreted from the periphery are also made in populations of nerve cells in the brain, and these populations are also

involved in regulating appetite and metabolism. These include neurons in the arcuate nucleus that synthesise the

orexigenic factor ghrelin, and the neurons in the hypothalamus and caudal brainstem that synthesize the

anorexigenic factors cholecystokinin, GLP-1 and oxyntomodulin.

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Pleasure Systems in the Brain

Michael A. Bozarth Behavioral Neuroscience Program Department of Psychology  State University of New York at Buffalo  Buffalo, New York 14260-4110 USA  Neurological research has identified a biological mechanism mediating behavior motivated by events commonly associated with p leasure in humans. These events are termed "rewards" and are viewed as primary factors governing normal behavior. The subjective i mpact ofrewards (e.g., pleasure) can be considered essential (e.g., Young, 1959) or irrelevant (e.g., Skinner, 1953) to their effect on behavior, but the m otivational effect of rewards on behavior is universally acknowledged by experimental psychologists.

Motivation & Reward

Motivation can be considered under two general rubrics—

appetitive and aversive motivation. Appetitive motivation concerns behavior directed toward goals that are usually associated with positive hedonic processes; food, sex, and wine are three such goal objects. Aversive motivation involves escaping from somehedonically unpleasant condition; the pain from a headache, the chill from a cold winter night are a mong the list of conditions that give rise to aversive motivation. The notion that hedonic mechanisms might provide direction to be havior can be traced at least to the Greeks (e.g., Epicures); Spencer (1880) formalizedthis notion into psychological theory and suggested that tw o fundamental forces governed motivation—pleasure and pain. Troland (1928) suggested that pleasure was associated with beneception, events that contributed to the survival of the organism (or species) and thus 'benefited' the organism from anevolutionary biology perspective; pain was suggested to be associated with nociception, events that had undesirable consequences for the organism. This schem a—emphasizing hedonic processes in the regulation of b ehavior —lost favor with the advance of the Freudian and later behavioristic schools, althoughvariations on this theme have occasionally resurfaced among motivational psychologists (e.g., Bindra, 1969; Young, 1959).

Behaviorism traditionally rejects the notion that subjective experience has a critical role in determining behavior. Specifically, behaviorism describes the relationship between behavior and external factors governing that behavior without reference to internal states, albeit it does help to have a hungry (i.e., fooddeprived) rat when studying the ability of food to serve as a reward. Behaviorism, or more properly operant conditioning theory, postulates three fundamental principles of behavior —positive reinforcement, negative reinforcement, and punishment. Positive reinforcement  describes the situation whe re presentation ofsome stimulus event (e.g., food ) increases the probability or frequency of the behavior it follows. Negative reinforcement  describes the situation where the termination of so me stimulus event (e.g., electric shock) increases the probability or freq uency of the behavior its termination follows. Both positive and negativereinforcers increase behavioral responses; they differ in the temporal relationship between the behavior and the reinforcing event—positive reinforcers follow the behavior they reinforce, while negative reinforcers precede the behavior they reinforcement. (In collo quial terms, the organism is said to w ork to receive apositive reinforcer and to work to escape from a negative reinforcer.) Punishment is the third general principle of operant conditioning. Punishment  describes the situation where presentation of an aversive stimulus following a behavior decreases the probability or frequenc y of that behavior. Unlike reinforcers,punishers suppress behavior. Radical behaviorism describes the effects of reinforcement and punishment on behavior devoid of thei r subjective impact. Indeed, the emoti onal states associated with reinforcement and punishment are usually viewed as the result of behavioral conditioning and not a cause ofbehavior.

In general, events that serve as positive reinforcers produce approach behavior defined as appetitive motivation. Events that serve as negative reinforcers or punishers produce withdrawal behavior defined as aversive motivation. Positive reinforcement is usually associated with a pleasant hedonic impact (andhence frequently termed reward  connoting this pleasant affective component), while negative reinforcement and punishment are usually associated w ith an unpleasant hedonic impact. Whethe r the subjective experience of reward (viz., pleasure) plays an important role in determining beha vior is moot for the presentdiscussion. The same principles apply whether the emotional impact of a reward precedes or follows the behavioral response. Furthermore, events that serve as positive reinforcers in humans and other anima ls are generally described by humans as pleasant; thus, there is an intimate association between rewardand pleasure despite controversy regarding the role of the su bjective experience of pleasure in determining behavior.

 A Biological Basis of Appetitive Motivation and Reward

Physiological psychology research has identified separate but interactive neural pathways mediating reward and aversion (i.e., functioning as positive and negative reinforcement systems, respectively). Direct activation of brain reward mechanisms through elec trical and chemical stimulation provides a tool fo relucidating these neural systems. During the past four decades, considerable knowledge has been gained regarding the anatomical and neurochemical basis of these pathw ays. This brief presentation addresses only brain mechanisms involved in positive reinforcement because they are closely identified withpleasure in humans and because they underlie the primary process governing much of normal behavior. Reward Substrate Identified by Electrical Brain Stimulation

Olds and Milner (1954) first identified brain sites where direct electrical stimulation is reinforcing. Laboratory animals will lever press at high rates (> 6,000 times pe r hour) to obtain brief stim ulation pulses to certain brain regions. The reinforcement from direct ele ctrical activation of this reward substrate is morepotent than other rew ards, such as food or w ater. The potency of thi s electrical stimulation is most dramatically illustrated in a classic experiment where the subjects suffered self -imposed starvation when forced to make a choice between obtaining food and wa ter or electrical brain stimulation (Routtenberg & Lindy,1965). A second distinguishing feature of reward from electrical brain stimulation is the lack of satiation; anim als generally respond continuously, taking only brief breaks from lever pressing to obtain the electrical stimulation. These two fea tures (i.e., super-potent reward and lack of satiation) are importantcharacteristics of direct activation of brain reward mechanisms. Initial work suggested th at a number of brain regions could produce rewarding effects, but many of these seemingly diverse stimulation sites were quickly linked through a common n eural pathway—the medial forebrain bundle (Olds, 1977). Although itis true that ac tivation of other brain systems can produce rewarding e ffects, activation of the med ial forebrain bundle as it courses through the lateral hypothalamus to the ventral tegmentum produces the m ost robust rewarding effects. And several neuro transmitters may be involved in the rewarding effects fromvarious electrode placements, but dopamine appears to be the neurotransmitter essential for reward from activation of the m edial forebrain bundle system (see Fibiger & Phillips, 1979; Wise, 1978). The neuroanatomical elements of rewarding stimulation have been identified using electrophysiologicaland neurochemical techniques: electrical stimulation activates a descending component of the medial forebrain bundle which is synaptically coupled at the ventral tegmentum to the asc ending mesolimbic dopamine system. Rewarding electrical stimulation thus activa tes a circuitousreward pathway, first involving a descending medial forebrain bundle component and then involving the ascending mesolimbic dopamine pathway (Bozarth, 1987a; Wise, & Bozarth, 198 4). The terms mesolimbic  and ventra l tegmental dopamine system are used interchangeably in thiscontext, both denoting the same dopamine system involved in reward and motivation.

Research with laboratory animals generally uses an operant conditioning perspective when studying reward processes (viz., w ithout reference to possible subjective effects), but research in human subjects has revealed that com parable electrical brain stimulation is associated with profoundly pleasurable effects(e.g., Heath, 1964). Indeed, some experimental subjects liken the effect of electrical brain stimulation to intense sexual orgasm, and anecdotal reports suggest that human subjects have developed a strong romantic attraction to the researchers performing the experiments. For obvious ethical reasons, research withhuman subjects has been very lim ited. But the available data suggest that the principles learned from animal experimentation are valid for human subje cts; studies of electrical stimulation of reward pathways in human s provide direct evidence that stimulation that is reinforcing in animals is both reinforcing andintensely pleasurable in humans.

Reward Substrate Identified by Chemical Brain Stimulation

 Another approach to studying brain reward systems is to determine the neurochemical coding of these pathways. This can be accomplished by identifying the neurochemical mechanisms whereby various drugs serve as rewards following either systemic or intracranial administration. Essentially, reinforcing drugscan be used as tools for studying brain reward mechanisms in much the same manner as electrical stimulation. Experimental procedures have been developed where animals can lev er press to obtain various drug re wards (see Bozarth, 1987b). Some drugs delivered intravenously can serve asrewards. Most drugs that are self-administered by humans are also self-administered by laboratory animals. The most potent drug rew ards include the psychomotor stimulants (e.g., amphetamine, cocaine) and the opia tes (heroin, morphine). These drugs are self-administered by laboratory animals thathave surgically implanted intravenous catheters. Animals quickly learn to press a lever to intravenously self-administer drugs such as cocaine and heroin. This experimental preparation provides an animal model of human drug-taking behavior and hence a method to study the reinforcing properties ofdrugs; this reinforcing drug-action forms the basis for drug addiction in humans (see Bozarth, 1987b, 1990). It is im portant to note that addiction is defined as a beha vioral syndrome where a drug seems to exert extreme control over the individual's behavior and is not defined b y physiological withdrawalreactions such as those accompanying abstinence from some drugs. Drug use is seen as developing along a continuum, beginning with casual/recreational use where the drug has a modest influence on behavior to the extreme condition (i.e., addiction) where the drug use seems to dom inate the individual'sbehavior (see Bozarth, 1990).

Reward from psychomotor stimulants and from opiates appears to involve a ctivation of the same brain reward system as that activated by electrical stimulation. Dopamine is the neurotransmitter most consistently linked with reward from these drugs, and the ventral tegmental dopaminesystem has been specifically implicated in psychomotor stimulant a nd opiate rewards. Other drugs that may serve as reinforcers (e.g., alcohol, barbiturates, caffeine, marijuana, nicotine) also activate the v entral tegmental dopamine system, although the data suggesting this activation iscritical for their reinforcing effects are not conclusive. Furthermore, abstinence from cocaine or from morphine after repeated administration may decrease dopamine levels in this brain system (Bozarth, 1989; Rossetti, Hmaidan, & Gessa, 1992); this diminished dopamine function may berelated to the intense craving associated with withdrawal in drug dependent humans. The subjective experience of craving is probably related to relapse into drug-taking behavior following abstinence and therefore is an important factor in drug addiction.

Integrative Aspects of the Ventral Tegmental "Reward" System

Research has progressed to where several distinct rewarding ev ents can be explained by their abilities to activate a common brain reward mechanism: electrical brain stimulation reward, psychomotor stimulant reward, and opiate reward all appear to involve activation of the ventraltegmental dopamine system (Bozarth, 1987a; Wise & Bozarth, 1984). Several other drug rewards, such as alcohol and nicotine, may also involve activation of this brain pathway. This has lead to the asse rtion that various addictive drugs share the common feature of activating the samebrain reward system and this action has been related to their appetitive motivational effects (Wise & Bozarth, 1987). This theoretical perspective deviated sharply from prevailing thought in that (i) it suggested a co mmon neural basis for tw o distinctively different pharmacological drug classes (i.e.,psychomotor stimulants and opiates) and (ii) it suggested that appetitive motivation rather than av ersive motivation (such as that associated with physical dependence and overt withdrawal reactions) motivated drug-taking behavior and addiction. From this perspective, addictive drugs are seen topharmacologically activate brain reward mechanisms involved in the control of normal behavior (see Bozarth, 1990; Wise & B ozarth, 1987). Thus, addictive drugs may be used as tools to study brain mechanisms involved in normal motivational and reward processes. Other, natural rewards can bemodulated by the activity of this system: feeding can be elicited (Hamilton & Bozarth, 1988), sexual behavioral can be aroused (Mitchell & Stewart, 1990), and maternal behavior can be facilitated (Thompson & Kristal, 1992) by opiate activation of this r eward system. The origin of the ventraltegmental dopamine system (i.e., ventral tegmen tum) appears to provide an important neurochemical interface where exogenous opiates (e.g., heroin, m orphine) and endogenous opioid peptides (e.g., endorphins, enkephalins) can activate a brain mechanism involved in appetitive motivation and reward. These andother empirical findings are consistent with the notion that the ventral tegmental dopam ine system may serve as an appetitive motivation system for diverse behaviors. This is not to suggest that all motivational effects of these rewards emanate from this single brain system, but rather this dopaminesystem represents one important mechanism for the control of both normal and pathological behaviors. (For a more technical review, see Bozarth, 1987a, 1991).

The hypothesized activation of the ventral tegm ental reward system by endogenous opioid peptides can offer an explanation of seemingly paradoxical behavior —the voluntary self-infliction of stress or pain. Events normally considered stressful and thus aversive m ay activate the ventral tegmental reward systemthrough the release of endogenous opioid peptides induced by the stressor. (Stress-induced release of endogenous opioid peptides was one of the earliest identified effects for these neuromodulators.) This could explain the attraction some individuals display to seemingly aversive stimulation (e.g., risk-takingbehavior, self-infliction of painful stimuli). In some situations the appetitive motivational effect of these behaviors may override the norm al aversive motivational effect that usually produces withdrawal behavior; thus in certain pathological conditions, approach behavior indicative of appetitive motivation may beproduced by an aversive stimulus normally avoided and described as painful. This is mos t likely perhaps in situations where the effec ts of the s tress-induced endogenous opioid peptide release out last the abrupt termination of the pai nful stimulus. Also, cognitive processes may label the stressor as nonthreatening,thereby permitting the pleasurable effects to dom inate affective tone.

The Pursuit of Pleasure: When Does it Become Pathological?

Activation of brain reward systems can be considered a natural component of normal behavior. Indeed, brain reward systems serv e to direct the organism's behavior toward goals that are normally beneficial and promote surviv al of the individual (e.g., food and water intake) or the species(e.g., reproductive behavior) as suggested by Troland's (1928) concept of beneception. The notion that the brain influences b ehavior is not particularly radical for twentieth century scientists nor is the notion that many rewards activate such mechanisms through various sense modalities such as taste or touch. Thedirect chemical activation of these reward pathways does not in itself represent any severe departure from the normal control reward systems exert over behavior. Inhalation of a substance (e.g., nico tine) is no less natural than the ingestion of sugar, although the former has no direct survival value to the organismnor to the sp ecies. But both involve activation of brain reward m echanisms and both may be subje ctively experienced as pleasurable in humans. So what constitutes the pathological control of behavior termed "addictio n"? Certainly not the fact that a substance activates a brain reward system nor the fact that thissame system may be involved in the potent reward produced by addictive drugs. Sim ple activation of brain reward systems does no t constitute addiction! Rather, the extreme control of behavior —exemplified by a deterioration in the a bility of normal rewards to govern behavior (termed motivationaltoxicity )—is the distinguishing feature of an addiction.  Some drugs quickly and uniformly exert extreme control over behavior (e.g., cocaine, heroin), while other substances exert a m uch less potent influence on behavior (e.g., mo derate alcohol consumption, occasional nicotine use). The fact that a chem ical(e.g., nicotine) influences behavior does not constitute addiction any more than the chemical reaction that produces a taste (e.g., sugar-associated sweetness) which influences behavior constitutes addiction. Motivational toxicity is apparent when rewards normally effective in influencing behavior lose their ability tomotivate the organism. This is typically seen in human drug addicts that neglec t formerly potent rewards (e.g., career, sex) a nd focus their behavior on the acquisition and ingestion of drug. The neural mechanisms responsible for this disruption of the motivational hierarchy have not been identified; one poten tialmechanism involves decreased dopaminergic function following chronic drug use (see Bozarth, 1989). In a reward system wi th decreased dopaminergic function, natural rewards that activate reward processes much less potently than some drug rewards (e.g., c ocaine, heroin) may lose their abilities to engage theorganism's behavior. In contradistinction, direct pharmacological activation of a reward system dominates the organism's moti vational hierarchy at the expense of other rewards that promote survival. The ensuing motivational toxicity distinguishes drug addiction from simple drug activation of rewardmechanisms. Motivational toxicity may develop from neuroadaptive responses to chronic intake of some drugs, but it is not a general property of chem ical activation of brain reward mechanisms.

Epilogue on the Role of Pleasure

Brain systems involved in what the behaviorist terms positive reinforcement are also involved in th e sensation of pleasure in humans. Although radical behaviorism ignores the hedonic impact of positive reinforcers, the subjective experience of pleasure is a usual concomitant of positive reinforcement. Becausehumans most often de scribe their own behavior in terms of subjective experience instead of the behavioristic terms of operant conditioning theory (e.g., positive reinforcement), it is appropriate to use reward and pleasure as descriptors of events g overning human behavior. Indeed, the phrase introduced by Olds(1956), "pleasure centers in the brain," remains generally descriptive of the neu ral basis of reward, but the word center  (suggesting a single neuroanatomical focus) has been replaced by the w ord systems (emphasizing multiple neural elements) as additional n eural linkages have been identified. Appetitivemotivation is most often associated with goals that have benefited the species from an evolutionary biology perspective. Specialized brain systems have evolved that direct the organism tow ard historically beneficial goals, and these systems could be termed  pleasure systems in colloquial language. Whether thesensation of pleasure is a critical determinant of be havior or a simple concomitant of reward activation remains to be resolved: appetitive motivational is intimately linked with the subjective experience of pleasure.

Much of behavior can be explained by simple processes of approaching pleasant stimuli and avoiding painful stimuli as described by Spencer (1880) in the nineteenth century. The ventral tegmental dopamine system is an important neural substrate for reward, and it has a central role in regulatingappetitive motivation: several distinct rewarding events activate this reward system, and activ ation of this system elicits a ppetitive motivation. The ventral tegmental dopamine system, along with its various neural inputs and outputs, can be aptly desi gnated a "pleasure system in thebrain" with an important role regulating many normal and pathological behaviors.

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