Brain and Behaviour Flashcards
1
Q
What do emotions arise in response to?
A
changes in our surroundings that could have important consequences. These may be immediate (e.g., being confronted by a mug-
ger) or delayed (e.g., anticipating an examination). Some emotions are short-lived (surprise, humor) and these often arise when there is a discrepancy between what is expected and what actually happens, others are long-lived (e.g., jealousy, hatred).
1
Q
What do emotions arise in response to?
A
changes in our surroundings that could have important consequences. These may be immediate (e.g., being confronted by a mug-
ger) or delayed (e.g., anticipating an examination). Some emotions are short-lived (surprise, humor) and these often arise when there is a discrepancy between what is expected and what actually happens, others are long-lived (e.g., jealousy, hatred).
2
Q
Are emotional responses hard-wired or learnt?
A
some are hard wired—executed by neural circuits that are genetically specified during development—such as the universal aversive reaction of infants to bitter-tasting (potentially toxic) foods, but most (e.g., love) are probably learnt. Apparently hard-wired
responses need not be forever fixed; most adults come to like the bitter foods their culture teaches them is safe
3
Q
What are the three components to an emotional state?
A
● A conscious cognitive component
● Visceral sensations arising from autonomic and endocrine events (e.g., feeling a rise in heart rate)
● Motor actions (e.g., characteristic facial expressions)
4
Q
What makes the visceral sensations and cognitive aspects of the emotional state self-reinforcing?
A
There are learned associations between them.Realization of just how bad or good a situation is drives visceral changes, while conscious efforts to stem visceral sensation (e.g., controlled breathing) lessens emotional intensity.
5
Q
How do emotions enhance survival?
A
- They are arousing and direct attention to important aspects of a situation so that it can be assessed as threatening or beneficial.
- Emotions are goads to useful action. We usually avoid snakes.
- The motor component (e.g., laughing or crying) communicates our emotional state to others, altering their behavior. Before it acquires language an infant can only
communicate its needs and desires by expressing its emotions. But also in adults
emotions act as a powerful form of nonverbal communication. This is crucial for social interactions.
6
Q
What is an affect?
A
The subjective experience of emotion, especially that leading to action, is termed affect.
7
Q
The core of the limbic system consists of the affective striato-thalamo-cortical circuit and its connections with the amygdala what is the set up of this loop?
A
laid out in much the same
pattern as the motor loop, except that the striatal component is the ventral striatum (nucleus accumbens, nAc) which projects to the ventral pallidum (ventral part of the
globus pallidus). The ventral pallidum relays via the mediodorsal thalamus to the anterior cingulate cortex and medial orbital prefrontal cortex. The loop is closed by connections from the cortex back to the nucleus accumbens. The affective loop has reciprocal connections with the amygdala
8
Q
What is the amygdala responsible for?
A
responsible for fear learning, and is modulated by the dopaminergic mesolimbic system which is concerned with reward learning.
9
Q
Output of the nucleus accumbens goes to the compact part of the substantia nigra. What does this allow?
A
the activity of the motor and cognitive striato-thalamo-cortical circuits to be modified, providing for some of the motor and the cognitive aspects of emotional states.
10
Q
What is the affective motor pathway?
A
Output of the amygdala goes to the hypothalamus and a variety of brainstem structures that organize motor, arousal, and visceral aspects of emotions. Facial expressions engendered by emotions—smiling, crying, and so forth—are brought about by extrapyramidal
motor pathways that run in the brainstem reticular formation.
11
Q
What is a duchenne smile?
A
Patients with unilateral
damage to corticobulbar fibers descending from the motor cortex have voluntary motor paresis on the opposite side. When asked to smile on demand their smile is lopsided. However, when genuinely amused their smile is natural and bilateral (Duchenne smile) because different emotion-driven motor pathways are engaged.
12
Q
What is the Papez circuit?
A
The anterior cingulate cortex projects to the entorhinal cortex that acts as a gateway for all neocortical input to the hippocampus. Efferents leave the hippocampus by way of the fornix for the hypothalamus. Output from the mammillary bodies (by way of the mammillothalamic tract) goes via the anterior thalamic nuclei back to the anterior cingulate cortex. The hypothalamus also has connections with the prefrontal cortex.
13
Q
What is the role of the Papez circuit?
A
mediating explicit learning (learning that can be consciously recalled) during emotional states
14
Q
What is the amygdala?
A
a cluster of nuclei in the white matter of the temporal lobe.
15
Q
Where does sensory information enter the amygdala?
A
Olfactory input runs from the olfactory bulb to the corticomedial nucleus. Sensory information from other modalities (vision, hearing, somatosensory) enters the basolateral nuclei
from specific thalamic nuclei and their corresponding areas of sensory cortex.
16
Q
Other than sensory information, what other input does the basolateral nuclei receive?
A
● The state of the viscera from the hypothalamus
● Arousal status from the locus coeruleus and nucleus basalis of Meynert
● Cognitive processing by the orbital prefrontal cortex
17
Q
What is the output from the amygdala?
A
It amygdala is from its central nucleus and follows two anatomical pathways. Efferents to the hypothalamus, septum, and several brainstem nuclei go via the stria terminalis, while the ventral amygdalofugal pathway conveys connections to the nucleus accumbens.
18
Q
How does the amygdala drive fear responses?
A
It has access to species-specific hard-wired neural representations of scary things
19
Q
How does fear conditioning occur?
A
occurs when a neutral stimulus (CS), such as a tone, is paired with a noxious stimulus (US), such as a brief electric foot shock. After several tone–shock pairings the tone becomes a negative reinforcer and it elicits conditioned fear responses (CR), including autonomic, endocrine, and behavioral
signs of fear.
20
Q
How has the role of amygdala in fear learning been documented?
A
● The connections of the amygdala supports its role in aversive learning because it activates the cholinergic attentional system, the sympathetic nervous system, and the release of stress hormones
● Firing of amygdala (central nucleus) neurons correlates with the development of the
fear responses.
● Lesions of the amygdala prevent acquisition of new conditioned fear responses or expression of preexisting ones, although they do not affect autonomic responses to aversive stimuli (e.g., the defense reaction) which are organized by the hypothalamus
● Electrical stimulation of the amygdala in humans during surgery evokes feelings of
apprehension and fear.
● Brain scans show increased activity in the amygdala in humans shown fearful faces.
This response is impaired in people in whom the amygdala is calcified, even though they are still able to identify individual faces. Hence the neural system for emotional memory is distinct from that for explicit memory of faces.
21
Q
When does evaluation of a stimulus by the amygdala occur?
A
It begins earlier than any conscious cognitive appraisal of the situation.
22
Q
Amygdala fear learning is implicit learning; what does this mean?
A
the fear responses cannot be consciously generated. The amygdala develops more rapidly during infancy than the hippocampus (responsible for explicit memory). During this time fearful memories may be acquired which cannot later be consciously accounted for. This could underlie specific phobias.
23
Q
Where are long-term emotional memories stored?
A
in the cerebral cortex rather than the amygdala: presentation of fear-evoking stimuli activates visual association cortex and orbital prefrontal cortex as well as the amygdala.
24
What does fear learning of the amygdala involve at a cellular level?
Involves NMDA receptor-dependent long-term potentiation similar to that underlying hippocampal learning.
25
What allows cognition to influence emotional states and vice versa?
Extensive interconnections between different parts of association neocortex. Lesions of the orbital prefrontal cortex reduce emotional responses (e.g., aggression) in primates, while in humans lesions of the anterior cingulate cortex reduce the emotional distress of chronic intractable pain.
26
What is motivated/ goal- directed behavior?
Behavior that is driven by internal states or external events and which is aimed at achieving a particular outcome. Some motivated behavior occurs in order to satisfy physiological needs. Goal-directed behaviors like this are homeostatic and normally self-limiting as the internal state is switched off (sated) by consumption. Much motivated behavior is not so straightforward because it occurs in the absence of any obvious physiological deficit.
27
What is a positive reinforcer?
Any stimulus that increases the probability of a motivated response occurring. An animal will work to get access to a positive reinforcer.
28
What is aversive behavior?
a reinforcer is said to be negative if the animal works to avoid the stimulus, in which case it is displaying aversive behavior.
29
The reinforcing quality of a stimulus depends on context. How is food an example of this?
food is a powerful reward to a hungry person but its positive reinforcing quality diminishes with satiety. However, a particular food may still be a positive rein- forcer if it is novel and sufficiently delicious even if the person is not hungry. Hence the motivation to eat is a complex interplay of internal state, external cues, and memory.
30
What are the two pathways that dopaminergic neurons ascend from the ventral tegmental area (VTA) as?
They ascend to the nucleus accumbens (nAc, ventral striatum) as the mesolimbic system and to the frontal cortex (including the cingulate and orbitofrontal cortex) as the mesocortical system
31
Why is the Mesolimbic system described as the reward system?
●Firing of mesolimbic neurons increases in the presence of natural reinforcers such as food.
●Conscious, behaving rats will forego food or sex in order to stimulate their own mesolimbic neurons by pressing a lever to deliver a small current through electrodes chronically implanted into the medial forebrain bundle; a technique termed intracranial self-stimulation (ICSS)
●Natural rewards, ICSS, and addictive drugs all increase the release of dopamine from mesolimbic terminals in the nucleus accumbens, and the reinforcing properties of all three are blocked by dopamine D1 receptor antagonists.
32
How do learned associations with a reward occur?
VTA neurons fire in response to a natural reward and the dopamine release facilitates
learned associations with the reward, in animal studies a conditional stimulus with which the reward has been paired. The learning occurs via the nucleus accumbens and the affective basal ganglia circuit. Subsequent firing of the VTA neurons depends on the predictability of the reward. Unexpected or novel rewards elicit a strong response, although this declines with repeated presentation. Predicted rewards have little effect, though conditioned stimuli associated with them continue to elicit dopamine release.
33
What happens with Omission of a predicted
reward?
reduces mesolimbic activity. The immediate response to omission of an expected
reward is to persevere with the activity that usually provides it. So, low activity of mesolimbic neurons when a predicted reward is missed promotes reward-seeking behavior.
34
What is the major target of the mesolimbic system?
The nucleus accumbens. Has GABAergic medium spiny neurons.
35
What is the output of the nucleus accumbens?
project to the GABAergic cells of the ventral pallidum (VP). Phasic dopamine release from terminals of VTA cells excites the MSNs, particularly if this coincides with excitatory input from the cortex or amygdala. Activity of the MSNs inhibits the GABAergic VP cells, hence disinhibiting the affective basal ganglia circuit. Distinct ensembles of MSNs respond differentially to cues associated with specific rewards.
36
What is the role of the cingulate and orbitofrontal cortices in reward pathways?
respond to rewards and associated stimuli in a manner that depends on their predictability and seems to be concerned with evaluating their overall salience (importance) and determining the intensity of the behavioral response. In some cases at least the prefrontal cortex initiates goal-directed behavior via glutamatergic connections to the nucleus accumbens.
37
How are the positive reinforcing properties of a drug assessed?
by self-stimulation studies which measure the extent to which animals (usually rats or monkeys) will work to get a dose of the drug.
38
What are conditioned place preference studies?
reveal that the context in which drugs are taken is important. Animals are first exposed to one environment when drugged and to a different environment when non-drugged. Next, the animals are given a choice
between the two environments (they can now move freely between them) and the time spent in each is recorded. With positively reinforcing drugs, animals spend more time in the environment they experienced in the drugged state. This is context-dependent learning and shows that learning is important in addictive behavior.
39
What is the concept of tolerance?
On repeated administration a drug becomes progressively less effective, so the dose has to be increased if the original action is to be maintained. The precise mechanism for tolerance depends on the drug, but includes enzyme induction, changes in receptor numbers, and alterations to second messengers. Tolerance does
not necessarily lead to addiction
40
What is dependence?
This occurs when biological changes brought about by the drug are such that normal functioning is only possible when the drug is present.
41
What is abstinence/ withdrawal syndrome?
If a drug is withheld after dependence is estab-
lished an abstinence syndrome results which is extremely unpleasant and lasts until the long-term biological changes that brought about dependence have abated. Hence, addiction (the need to take the drug repeatedly) can be driven as much by the aver-
sion to withdrawal as by the positive reinforcing qualities of the drug. In rare cases with some drugs (e.g., alcohol) withdrawal can be fatal.
42
What is craving?
The intense longing for a drug felt by addicts is a learned response that long outlasts the abstinence syndrome. Addicts form memories which associate the pleasure produced by the drug with the environment and cues that accompany the drug taking. Subsequent exposure to the same context causes craving.
43
What feature of craving corresponds with the much more intense motivation of addicts to seek the drug than natural rewards?
Brain imaging shows that cocaine-addicted subjects have increased activity in the cingulate and orbitofrontal cortices in response to stimuli associated with cocaine availability but decreased activity when presented with stimuli associated with natural rewards, compared to
non-addicts.
44
How does the effect of addictive drugs on the brain reward system differ from that of natural rewards?
unlike natural rewards, which when familiar cease to elicit dopamine release, addictive drugs continue to cause dopamine release with repeated exposure, resulting in dysregulation of the reward and affective basal ganglia circuits, and eventually long-term neuroplasticity that underpins craving and compulsive drug-seeking behavior.
45
How does cocaine produce tolerance?
by blocking the dopamine transporter (DAT) in the presynaptic terminals of mesolimbic neurons, limiting dopamine reuptake, so the concentration of transmitter in the synaptic cleft is raised. This causes downregulation of postsynaptic dopamine receptors. In addition dopamine binding to presynaptic receptors reduces dopamine synthesis and release. The overall effect is that higher amounts of transmitter, and hence drug, are needed to achieve the same level of dopamine transmission. When drug use stops, dopamine transmission in the mesolimbic system drops below normal.
46
how does creb overexpression contribute to abstinence syndrome?
Activation of D1receptors, which are positively coupled to cAMP, switches on transcription of the creb gene. CREB (cAMP response element binding protein) is itself a transcription factor that influences the expression of genes with the cAMP response elements (cre) in their regulatory domains; that is, genes switched on by increases in cAMP. When the drug is withheld, the CREB changes reverse with a time course that matches the abstinence syndrome
47
What is the neurobiology behind transition from acute drug responses to chronic plastic changes in addiction?
due to a gradual increase in the expression of a Fos family transcription factor, DFosB, in the nucleus accumbens. This molecule increases the expression of GluR2 AMPA receptors, cell signaling molecules, and brain-derived neurotrophic factor (BDNF), which can stimulate dendritic growth. the mesolimbic system
becomes more sensitive to the effects of the drug, overwriting the preexisting tolerance.
48
How does the origin of craving differ in the early and later stages of addiction?
In the early stages of drug use craving arises from the release of dopamine in the nucleus accumbens. As addiction takes hold and dopamine transmission in the mesolimbic system reduces, increased metabolic activity in the orbitofrontal cortex contributes to craving. This transition is due to glutamate-mediated plastic changes in ventral tegmental area, nucleus accumbens, and cortex akin to that which underpins learning in the hippocampus and elsewhere, namely long-term potentiation (LTP) and long-term depression
49
How does a recent history of drug experience alter the direction of direction of plasticity at nAc excitatory synapses?
LTP occurs in the medium spiny neurons during a drug-free period after cocaine addiction has been established. This is accompanied by increased numbers of AMPA receptors and dendritic spines on MSN cells, making them more sensitive to excitatory inputs from the orbitofrontal and cingulate cortex, and amygdala, some of which encode drug-contextual learning. Remarkably, just a single dose of cocaine reverses this to bring about LTD, a reduced responsiveness to glutamate, most probably by NMDA
receptor-controlled endocytosis of AMPA receptors.
50
How does inhibition of nucleus accumbens MSNs (GABAergic projection neurons), for example by
LTD, promote reward-seeking behavior?
inhibition of nucleus accumbens MSNs (GABAergic projection neurons), for example by LTD, promotes reward-seeking behavior,
51
What does reinstatement of drug-seeking now depend on?
depends on dopamine release not in the nucleus accumbens but in the amygdala and prefrontal cortex, probably due to plastic changes there.
52
Eating is a goal-directed behavior, what is it controlled by?
controlled in the shorter term by hunger signals, which motivate feeding, and satiety signals, which reduce it.
53
What two types of agents affect appetite?
An agent, neuron or pathway which stimulates appetite is said to be orexigenic, those which suppress appetite are anorexigenic.
54
Food intake and energy expenditure are additionally regulated by which hormones?
Those released from white fat cells (adipokines).
55
Where do the neural networks responsible for central regulation of feeding and energy expenditure lie?
in the hypothalamus and in the nucleus of the solitary tract, which lies in the medulla.
56
The control of eating is complex- what does it involve?
involves the reward system, affect, learning, and memory, all of which is colored by social and cultural contexts.
57
What is the peptide ghrelin?
is a hunger signal that acts in both the hypothalamus and the reward system to increase food intake.
58
What affects ghrelin blood concentrations?
In general blood concentrations of ghrelin are
lower in obese and higher in anorexic individuals compared to those with normal body mass implying that ghrelin release is inversely related to energy intake. There is also an
inverse relation between hours of sleep per night and blood ghrelin concentrations. The fewer hours slept the higher the ghrelin, and individuals who sleep less are more likely to be obese.
59
Ghrelin cannot cross the blood–brain barrier. How does it exert its effects?
● As a peripheral signal secreted from the epithelium of the empty stomach it enters the circulation (i.e., it is a gut hormone) and acts on ghrelin receptors on the area postrema.
● Locally in the gut it acts on terminals of vagus nerve axons that run to the NST.
● It is a transmitter of neurons in the hypothalamus. It acts presynaptically to excite
orexigenic (NPY/AgRP) neurons, and on corticotrophin releasing hormone (CRH) neurons in the hypothalamus.
60
What is neuropeptide y?
It is a gut hormone and the most potent orexigenic agent known. It is also a transmitter in hypothalamic orexigenic pathways.
61
What is the area postrema?
It is a circumventricular organ located adjacent to the nucleus of the solitary tract (NST). It has chemosensory cells that respond to a variety of peptides. In response to toxins in the blood it triggers vomiting.
62
What are gut hormone satiety signals?
Cholecystokinin (CCK) is secreted by the gut in response to food. As a circulating gut hormone it acts at the area postrema. As a local hormone it acts on gut vagal afferents that project to the NST. CCK also inhibits feeding by acting as a transmitter in hypothalamic anorexigenic pathways. Somatostatin and peptide YY are also gut hormone satiety signals.
63
What are short-term neural satiety signals?
Afferent input from taste buds and pharynx, stomach distension, and neural signals related to energy metabolism from the liver all inhibit eating. Stretch receptor afferents conveying gastric distension signals from the gut run in the vagus nerve to the NST.
64
what is the inhibition of food intake by CCK and gastric distention is mediated by?
by the paraventricular nucleus (PVN) of the hypothalamus which receives input from the NST.
65
How are people able to match energy input and output closely over years, despite day-to-day imbalances between food intake and energy expenditure?
This is done largely by defending the size of the body store of white adipose tissue
66
What is the function of leptin?
It is secreted by fat cells and crosses the blood–brain barrier to act at the hypothalamus where it inhibits feeding (i.e., it is a satiety factor) and increases energy expenditure. Leptin acts as an adipostat. It has a plasma concentration that correlates well with fat content and so is a molecule that reflects the size of the fat store and regulates
it homeostatically.
67
How does leptin regulate fat mass?
Leptin secretion is enhanced by the insulin-stimulated lipogenesis that occurs on feeding and is suppressed by the glucocorticoid-stimulated lipolysis that accompanies fasting, so leptin regulates fat mass by means of a negative feedback loop.
68
How does leptin increase energy expenditure and therefore basic metabolic rate?
expenditure by increasing the expression of uncoupling proteins in mitochondria of fat and skeletal muscle, and by acting centrally to increase sympathetic activity to brown adipose tissue.
69
Other than leptin what is a long term satiety signal?
Insulin
70
What are the two brain pathways originating in the arcuate nucleus of the hypothalamus that regulate food intake?
An orexigenic pathway promotes feeding and reduces energy expenditure whilst an anorexigenic pathway reduces feeding and increases energy expenditure
71
How do the food intake pathways exert their effects?
by modulating the nucleus of the solitary tract (NST). This structure organizes feeding reflexes and regulates energy expenditure by altering sympathetic nervous system output, basal metabolic rate,
and locomotor activity.
72
What are the first-order neurons in the orexigenic
pathway?
Arcuate nucleus NPY/AgRP neurons, so called because they use neuropeptide Y and
agouti-related protein as co-transmitters, NPY secretion from the NPY/AgRP neurons is stimulated by ghrelin.
73
What is the effect of the NPY/AgRP neurons?
project to the lateral hypothalamus, synapsing with second-order neurons that use peptides termed orexins as neurotransmitters. These relay to neurons in the nucleus of the solitary tract (NST). NPY/AgRP cells also produce GABA and inhibit the anorexigenic pathway.
74
Why is the anorexigenic pathway often described as the melanocortin system?
First-order cells in the anorexigenic pathway in the arcuate nucleus contain
pro-opiomelanocortin (POMC), the precursor protein for several biologically active peptides, one of which, melanocortin, is a neurotransmitter of these neurons.
75
Other than POMC cells, what are the other first order cells in the anorexiogenic pathway?
Other first- order cells in the anorexigenic pathway express cocaine- and amphetamine-related transcript (CART).
76
Where do POMC/CART cells of the anorexiogenic pathway run?
run to the paraventricular nucleus (PVN) of the hypothalamus which contains neurons that use oxytocin, thyrotrophin releasing hormone, or corticotrophin releasing hormone as transmitters.
77
What is the function of the melanocortinin system?
melanocortin system gets a wealth of inputs relaying short- and long-term satiety signals, and also possibly from a glucostat in the arcuate nucleus. Activation of the melanocortin system inhibits feeding and increases basal metabolic rate via outputs from the NST.
78
What is the effect of leptin and insulin on the feeding pathways?
Leptin and insulin receptors exist on first-order neurons of both orexigenic and anorexigenic pathways. Leptin and insulin inhibit the orexigenic pathway and stimulate the anorexigenic pathway, thereby reducing feeding.
79
How is stress a key component of anorexia nervosa?
Stress and neuropeptide Y stimulate CRH neurons in the PVN which synapse with melanocortin system neurons to inhibit feeding. Brain imaging shows that anorexics produce amygdala fear responses to their own body image. Once established, starvation naturally maintains high activity in the hypothalamic pituitary stress axis
80
How are endocannabinoid pathways activated in fasting and stimulate feeding?
by modulating the action of leptin on the melanocortin system, and by stimulating the mesolimbic reward system.
81
What are the mechanisms of genetic obesity?
animals and humans that lack either functional leptin or leptin receptors (and hence have leptin resistance) are obese, as are those with excessive ghrelin concentrations.
82
What are the mechanisms of obesity (non-genetic)?
long term their energy expenditure is lower than their energy intake. Experiments suggest they respond more to external cues (how appetizing food seems) than to internal cues (hunger and satiety) than lean people. Basal metabolic rate (BMR) is related to lean body mass and because obese people have much the same lean body mass as lean individuals their BMRs do not differ on average. However, they have poorer capacity for energy expenditure.
83
What are potential pharmacological agents for obesity?
NPY, orexin, or endo- cannabinoid receptor antagonists, and melanocortin, CART, or CRH receptor agonists. Some of these interventions are likely to be problematic; for example, orexins are involved in wakefulness as well as feeding, and CRH receptor agonists are anxiogenic.
84
What is free running?
Humans isolated from all external time cues show intrinsic circadian rhythms with a period of about 25 hours initially. This decoupling of circadian rhythms from the normal 24-hour period is called free running
85
What are zeitgebers?
Environmental cues that entrain intrinsic circadian clocks. Zeitgebers include light, exercise, social interactions, and work schedules. Light is the strongest. A powerful light pulse given during subjective night, produces shifts in the circadian rhythm.
86
What is the effect on circadian rhythm when a light pulse is experienced at night?
In humans with normal sleep patterns the nadir in core temperature occurs at about 5 a.m. A light pulse given during the night before this time causes circadian rhythms to be delayed (phase delay) whereas a light pulse after this time causes phase advance.
87
What phenomenon suggests that there are two circadian clocks, both normally entrained by light–dark cycles of day and night?
After 1–2 weeks free running, physiological variables often desynchronize from each other. For example, typically, fluctuations in core temperature, secretion of ACTH and glucocorticoids, and rapid eye movement (REM) sleep continue with a period of about 25 hours, but the cycles of sleep–wakefulness and secretion of growth hormone (GH) lengthen to over 30 hours.
88
The circadian clock that regulates sleep–waking cycles resides in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. What is the mechanism of its clock function?
It is due to pacemaker neurons which fire with a frequency that varies in a circadian fashion even
when isolated from the rest of the nervous system. The firing frequency of SCN neurons varies sinusoidally with a period of 24 hours, peaking during the day, and dropping to its lowest rate during the night.
89
What is the output of the suprachiasmatic nucleus?
projects largely to other hypothalamic structures to
regulate sleep–wake cycles, autonomic, and endocrine functions, but also sends output to the thalamus and basal forebrain (e.g., septal nucleus) which probably accounts for circadian variation in memory and cognitive functions. Most SCN neurons are GABAergic and co-release peptides, and are assumed to be inhibitory on their targets.
90
how are light signals encoding total luminance relayed to the SCN?
by the retinohypotha-
lamic tract (RHT). This pathway consists of the axons of a population of small retinal ganglion cells driven by cone photoreceptors over a wide area, which synapse directly
with neurons in the core of the SCN. The RHT uses glutamate as a transmitter.
91
What is the pineal gland?
is a circumventricular organ which secretes melatonin into the blood during the hours of darkness. Melatonin secreted into the blood is transported across the blood–brain barrier to act on the SCN.
92
What is the duration of pineal melatonin a direct measure of?
of the length of night, and hence also of day length, the photoperiod.
93
For animals living at latitudes other than the equator, day length varies during the year, so melatonin secretion acts as a signal which codes for the time of the year, what is the significance of this?
For seasonal breeders, the length of the melatonin pulse regulates the hypothalamic–
pituitary–gonadal (HPG) axis of both males and females via its action on the SCN.
94
What is the pathway by which light inhibits melatonin synthesis?
Neurons in the SCN which get retinal input from the RHT inhibit central autonomic neurons in the
paraventricular nucleus (PVN). The PVN sends axons through the brainstem to synapse with preganglionic sympathetic neurons in the intermediolateral horn of spinal cord segments T1 and T2. These project to the superior cervical ganglion (SCG), the postganglionic cells of which innervate the pineal gland.
95
At night, what happens to the activity of the SCG neurons?
the activity is increased, and the secretion of noradrenaline (norepinephrine) from sympathetic terminals acts on b adrenoceptors of pinealocytes to synthesize melatonin.
96
what are the functions of melatonin?
Melatonin can entrain the circadian clock in the SCN, reset sleep–wake cycles in animals and humans, and reduce the symptoms of jet-lag, the sleep disturbance that arises when light–dark cycles and circadian rhythms are suddenly desynchronized by air travel over several time zones.
97
What are the two sleep states?
non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep,
98
What does electroencephalography (EEG) record?
Large numbers of cerebral cortical cells fire in synchrony and consequently their summed activity produces potentials large enough that they can be recorded with an array of scalp electrodes as electroencephalography (EEG).
99
EEG waveform varies in frequency, what are the groupings of these frequencies?
alpha (8–13 Hz), beta (13–30 Hz), delta (0.5–2 Hz), and theta (4–7 Hz).
100
How do the EEG waveforms differ when awake vs when asleep?
When awake, the EEG waveforms are of low amplitude and high (alpha) frequency and are described as desynchronized. Non-REM (NREM) sleep, has high amplitude, low-frequency (synchronized) EEG waveforms.
101
What physiological changes in the body occur during non-rem sleep?
muscle tone is retained and postural adjustments (turning over) are
occasionally made. Respiration rate, heart rate, and mean arterial blood pressure all fall, though gastrointestinal motility increases. Most growth hormone secretion occurs during NREM sleep. Brain scan shows that cerebral blood flow and glucose utilization fall by as much as 40% in NREM sleep.
102
What are the EEG characteristics of the 4 phases of NREM sleep?
Stage 2 is interspersed by higher frequency bursts called sleep spindles and large spikes called K complexes. Sleep spindles may have a role in motor
learning. K complexes are brief synchronized episodes of widespread cortical inactivity (cortical down time). Stages 3 and 4 are collectively referred to as slow-wave sleep because it is characterized by delta waves.
103
What are the characteristics of EEG in REM sleep?
EEG resembles that of the awake state. In REM sleep the brain is as metabolically active as it is when awake.
104
What are the physiological changes occuring in REM sleep?
Muscle tone is absent, except for transient contractions of extraocular eye muscles (hence rapid eye movement sleep). Respiration rate, heart rate, mean arterial blood pressure, and core temperature become irregular. People aroused from REM sleep usually report that they were dreaming. At this time dream content is in short-term memory and is rapidly forgotten unless rehearsed. Dreaming can also occur in NREM sleep.
105
During a typical night's sleep, how long does one spend in REM/NREM sleep?
adults drop rapidly into deep (stage 4) NREM sleep and then REM and NREM sleep alternate about every 90 min with increasingly longer periods of REM sleep as the night progresses. After sleep deprivation an individual spends more time in NREM.
106
How does the proportion of time spent asleep change dramatically during development?
Human fetuses sleep (mostly REM) almost all the time. This falls to 17–18 hours sleep (50% REM) for babies born at term. The amount of time spent in stage 4 sleep falls exponentially with age. Between 10 and 70 years the proportion of REM sleep is constant at about 25% of
total sleep time and declines in the elderly.
107
What constitutes the ascending arousal system?
Monoaminergic neurons in the ascending reticular formation, required to generate the awake state and to increase arousal and the responsiveness of the cortex to sensory input
108
The ascending arousal system splits into two branches at the level of
the diencephalon. One branch projects through the lateral hypothalamus to
the cerebral cortex from which sources?
● Noradrenergic neurons of the locus coeruleus
● Serotonergic cells in the raphe nuclei
● Histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus
109
The branch of the ascending arousal system projecting to the cortex is augemented by which cells?
by cholinergic neurons in the basal forebrain. The noradrenergic and serotonergic neurons fire at the highest rate in alert animals, have low firing rates during NREM sleep and go silent during REM sleep, hence are called wake-on/REM-off cells.
110
A second branch of the ascending arousal system projects to the thalamus, what does it contain?
● Histaminergic neurons in the TMN which make excitatory synapses with thalamic relay neurons
● Cholinergic neurons in the pons (pedunculopontine nucleus, PPN, and lateral dor-
sal tegmental nucleus, LdT) which inhibit GABAergic thalamic reticular neurons and hence excite thalamic relay cells
111
Why are the pontine cholinergic cells called wake-on/REM -on cells?
They are active during wakefulness and REM sleep—and are responsible for the desynchronization of the EEG in these states—but become quiescent during NREM sleep,
112
What is the purpose of neurons using orexin, located in the tuberal region of the hypothalamus?
excite all the groups of neurons in arousal pathways and are active during the awake state and REM sleep. Orexigenic neurons probably stabilize whichever state (awake or REM) the brain is in.
113
What is the main function of the thalamus?
Most of the thalamus is concerned with controlling which sensory information is sent to the cortex (attention). Thalamic relay cells project to the cortex and get reciprocal connections from the cortex. Specific sensory input directly excites the relay
cells.
114
What neurotransmitter does thalamus neurons use?
Both relay cells and cortical projection neurons use glutamate and are excitatory.
115
The relay cells are subject inhibition by which cells?
GABAergic interneurons and from the thalamic reticular nucleus (TRN), a sheet of GABAergic neurons covering the thalamus.
116
Thalamic neurons have two modes of firing, tonic and burst firing, when does tonic firing occur?
Tonic firing of single action potentials occurs in the awake state when the relay cells are depolarized by input from the ascending arousal system. In this mode, transmission of sensory input from thalamus to cortex takes place.
117
When is burst firing of thalamic relay cells seen?
seen during NREM sleep when the relay cells are hyperpolarized by a
loss of input from the ascending arousal system.
118
What is the mechanism of the burst firing of thalamic relay cells?
Burst firing occurs because relay cells have T-type Ca2+ channels that are activated by hyperpolarization. Opening these channels causes a calcium depolarization that triggers a burst of 4–5 conventional
action potentials.
119
What is the function of burst firing of thalamic relay cells?
drives synchronized bursting of cortical cells. The conventional argument is that this limits information transmission between
thalamus and cortex. With deepest NREM sleep the thalamocortical neurons become so hyperpolarized they go silent and cortical neurons, now completely decoupled from the thalamus, fire with their own intrinsic (delta) rhythm.
120
The start of NREM sleep is organized by hypothalamic nuclei and involves suppressing both branches of the ascending reticular formation- how does this occur?
GABAergic neurons in the
ventrolateral pre-optic area (VLPO) inhibit histaminergic neurons in the tuberomam-
millary nucleus. The loss of excitation on thalamic relay neurons causes them to hyperpolarize so they go into burst firing, NREM sleep, mode. VLPO cells suppress the cortical branch of the ascending reticular formation by inhibiting all the monoaminergic and the
orexigenic neurons.
121
What is the effect of inhibition of orexigenic neurons in the initiation of NREM sleep?
● Shuts off the cholinergic basal forebrain cortical arousal system
● Reduces activity of the noradrenergic and serotonergic (wake-on/REM-off) cells and of the pontine cholinergic (wake-on/REM-on) cells
122
What are the the triggers for NREM sleep, which activate the GABAergic VLPO cells?
not well understood but include the biological clock in the suprachiasmatic nucleus, and elevated core temperature detected by warm receptors in the hypothalamus. A number of molecules have also been proposed as candidate endogenous sleep-producing substances including adenosine, melatonin, and interleukin-1.
123
How is adenosine produced?
derived from ATP by
neural activity is secreted by astrocytes into the brain extracellular space; an example of gliotransmission.
124
What is the role of adenosine in sleep/ wake cycles?
Adenosine concentration rises during wakefulness and it decreases the activity of the cholinergic cells of the basal forebrain cortical arousal system by acting at adenosine A1 receptors. During sleep, adenosine concentrations decrease as it is degraded by adenosine deaminase.
125
During REM sleep, where does GABAergic inhibition come from?
REM-on cells, possibly located in the periaqueductal gray matter. These shut down the noradrenergic and serotonergic (wake-on/REM-off) neurons, but not the orexin cells.
126
How are pontine cholinergic wake-on/REM-on cells activated during REM sleep?
by the combination of continued excitation by orexinergic cells plus disinhibition from the aminergic neurons.
127
What is the consequence of activation of wake-on/REM-on cells?
● High levels of activity in these cholinergic neurons causes depolarization of the thalamic relay neurons which go into tonic firing mode.
● The continual activity of the orexin neurons keeps the basal forebrain cholinergic cells responsive.
Both of the above effects conspire to desynchronize the EEG.
128
Which two major features of REM sleep do pontine cholinergic neurons also organize—via relays through pontine and medullary reticular nuclei?
The first is the powerful suppression of sensory input and motor output. Presynaptic GABAergic inhibition on afferent terminals reduces sensory input. Glycinergic postsynaptic inhibition of motor neurons is the route by which muscle atonia (loss of muscle tone) is brought about. A second major feature of REM sleep are periodic pontine geniculate occipital (PGO) spikes in the EEG.
129
What suggests that during REM sleep motor patterns are generated but not executed?
Lesions of the pons which prevent the muscle atonia produces animals which express stereotyped
behaviors during REM sleep.
130
Periodic pontine geniculate-occipital (PGO)
spikes in the EEG originate from cholinergic (PGO-on) cells in the pons, what is the function of these?
drive vestibular and reticular neurons to excite oculomotor neurons (causing the rapid eye movements) and other cells to produce the phasic alterations in respiration, heart rate, blood flow, and muscle twitches seen in REM sleep. PGO-on cells also initiate the spread of activity to the lateral geniculate nucleus and visual cortex recorded as PGO spikes.
131
What is the status of PGO-On cells in wakefullness?
usually inhibited by serotonergic cells, however, PGO spikes can be produced in awake subjects by sudden stimuli, so they may underlie startle responses.
132
What defecits have been found in humans with narcolepsy (where patients experience frequent and undesired flips into REM sleep during the day)?
deficits in orexin neurotransmission. it is thought that orexigenic neurons stabilize the waking or REM state once the brain has made the transition.
133
What is the metabolic hypothesis of the function of sleep?
postulates that NREM sleep provides a period of low metabolic demand needed to replenish neural energy resources depleted during waking. One possibility is that wakefulness decreases the ATP:AMP ratio, resulting in accumulation of extracellular adenosine which, acting through adenosine A1 receptors, inhibits neuronal activity and lowers brain metabolic demand.
134
sleep may have global anabolic functions that conserve energy stores and core temperature. What is the circumstantial evidence for this?
● Smaller mammals (with the highest metabolic rates) sleep the most.
● Heat stress or experimental warming of the pre-optic hypothalamus (which is involved in both thermoregulation and triggering NREM sleep) can trigger or prolong NREM
sleep.
