sleep physiology pt 3 a ha ha haha

What is a hormone

A hormone is a chemical messenger secreted by an

An endocrine cell that travels through the circulation to

act on distant target tissues expressing specific

receptors.

what do circadian-controlled hormones do?

– Rhythmic across the 24-hour day

– Persist under a constant routine

– Sleep modulates amplitude but does not generate the

rhythm

What do sleep-dependent hormones do?

– Released primarily during sleep or specific sleep stages

– Strongly reduced by sleep loss or fragmentation

– Poorly predicted by clock time alone

why melatonin and cortisol are considered primarily circadian-regulated hormones

Melatonin: Why it is circadian

• Controlled directly by the SCN → pineal gland pathway

• Secretion rises at night based on internal clock timing, not because you are asleep

• Its role is to signal biological night

Cortisol: why it is circadian

• Controlled by the SCN via the HPA axis

• Shows a strong daily pattern:

  • Low at night

  • Peaks in early morning (before waking)

How does light differentially affect melatonin and cortisol secretion?

cortisol:

• Light has minimal direct effect on timing

• Cortisol rhythm is:

  • More stable

  • Less acutely suppressed by light compared to melatonin

melatonin:

• Strongly light-sensitive

• Light exposure at night:

  • Suppresses melatonin secretion

  • Can delay or shift circadian phase

How does sleep loss differentially affect melatonin and cortisol’s secretion

Melatonin

• Still occurs even if you don’t sleep

• Timing remains largely intact

• Sleep mainly affects how much is released (amplitude), not whether it happens

• not sleep dependent

Cortisol

• Persists during sleep deprivation

• Still rises to a morning peak even without sleep

• Even shifting sleep to daytime:

  • Does not shift the cortisol peak appropriately

  • Confirms it is clock-driven, not sleep-driven

Explain how growth hormone and prolactin secretion depend on sleep onset

GH:

• GH shows a large, rapid surge shortly after sleep begins

• This surge is:

  • Specifically tied to sleep onset

  • Strongest during early-night slow-wave sleep (SWS)

• The timing is not based on clock time → it happens whenever sleep starts

Prolactin:

• PRL levels:

  • Increase soon after sleep begins

  • Stay elevated across the sleep period

• Like GH, this rise is:

  • Linked to sleep onset

  • Not dependent on time of day

Explain how growth hormone and prolactin secretion depend on sleep architecture,

Growth Hormone

• GH release coincides with peaks in SWS/SWA

• Enhancing SWS → increases GH secretion

• Reducing SWS → reduces GH secretion

Prolactin

• PRL is less tightly linked to SWS than GH

• Instead:

  • It shows a sustained elevation across the entire sleep period

  • Not just during deep sleep

Describe how aging alters hormonal profiles GH and cortisol

Reduced Sleep-Dependent Growth Hormone (GH)

• Older adults show:

  • Much smaller GH peak after sleep onset

  • Reduced total GH secretion over 24 hours

• The large early-night GH pulse seen in young adults is blunted or absent

Cortisol

• Older adults show:

  • Higher cortisol levels in the evening and early night

  • A higher nadir (baseline) instead of the normal low nighttime levels

  • Sometimes a slightly earlier circadian phase (earlier peak timing)

Describe how testosterone exhibits mixed sleep-dependent and circadian regulation

Sleep-dependent component (dominant)

• Testosterone rises after sleep onset

• Peaks during the last part of the sleep episode

• This happens regardless of clock time

• Even though sleep drives secretion:

  • The timing of the peak is shaped by circadian rhythms

  • Typically aligns with early morning

So:

• Circadian system = sets timing window

• Sleep = enables actual secretion

How do estrogen and progesterone influence sleep despite being cycle regulated

• Estrogen and progesterone are driven by the menstrual cycle, not by sleep or circadian timing.

• Estrogen effects: Stable estrogen levels are

  generally associated with better sleep, while rapid

  declines before menses or during peri- and post-

  menopause often disrupts sleep.

  • Progesterone effects: Progesterone has more direct

  sleep-promoting effects via GABAergic mechanisms,

  making it the more strongly sleep-facilitating ovarian

  hormone

what are some of the consequences of insufficient or mistimed sleep

Disrupted sleep and hormonal signaling

contribute to age-related changes in

metabolism, stress regulation, recovery, and

overall health.

Explain why sleep is an active cardiovascular state, rather than a period of cardiovascular

shutdown,

During sleep, cardiovascular regulation is reorganized rather than shut down, with characteristic changes in blood pressure (BP), heart rate (HR), and autonomic balance that differ from wakefulness

How does nightly repetition of sleep across decades influence long-term cardiovascular health

Because sleep recurs every night for decades, even modest sleep-related changes in autonomic and vascular control can accumulate into meaningful protection or stress for the cardiovascular system.

Describe how autonomic nervous system balance regulates heart rate and blood pressure

• HR is regulated by the balance of parasympathetic and

sympathetic nervous system activity

• BP is primarily regulated by sympathetic control of

cardiac output and vascular tone

What are the distinct roles of sympathetic and parasympathetic activity during sleep

During sleep, parasympathetic activity predominates in NREM sleep to lower heart rate and blood pressure and promote cardiovascular recovery (rest and recover).

Sympathetic activity is suppressed during deep sleep but reemerges during REM sleep and arousals to produce variability and enable rapid cardiovascular responses (activation and responsiveness)

Why does the suppression of sympathetic activity during NREM sleep lower cardiovascular

load, leading to reduced heart rate, vascular resistance, and blood pressure

With sympathetic suppression:

• Heart pumps less frequently and with less force bc PNS is dominating

• Blood vessels offer less resistance (vasodilation)

• Since both HR and vascular resistance occur, this lowers BP (nocturnal dipping)

• Overall:

  • ↓ oxygen demand

  • ↓ mechanical stress on vessels

  • ↓ strain on the heart

what is nocturnal dipping and the morning surge

• Nocturnal dipping is the normal decline in BP during

sleep, typically about a 10–20% reduction from daytime

levels

• The morning surge is the physiological rise in BP that

occurs in the first few hours after waking

explain how nocturnal blood pressure dipping is shaped by sleep state and circadian timing

How sleep state shapes it

• During NREM sleep (especially slow-wave sleep):

  • ↓ Sympathetic activity

  • ↑ Parasympathetic activity

• This leads to:

  • ↓ Heart rate

  • ↓ Vascular resistance

  • ↓ Blood pressure

The deepest drops in BP:

• Occur during slow-wave sleep

• Align with periods of lowest sympathetic tone

So dipping is actively generated by sleep physiology, not just inactivity

explain how the morning surge is shaped by sleep state and circadian timing

How circadian timing shapes it

• The circadian system prepares the body for wakefulness by:

  • ↑ Sympathetic activity

  • ↑ Hormones like cortisol

• Upon waking:

  • The sympathetic system activates strongly

  • BP rises quickly

-The morning blood pressure surge occurs during the transition from sleep to wakefulness rather than a specific sleep stage, as circadian-driven increases in sympathetic activity combined with arousal from sleep rapidly elevate heart rate, vascular resistance, and blood pressure.

explain the linkage of sleep stage to sympathetic nerve activity and blood

pressure, including differences between NREM and REM sleep

NREM sleep (especially deep sleep / SWS)

• ↓ Sympathetic activity

• ↓ Blood pressure

• BP is low and stable

• Strongest cardiovascular recovery phase

REM sleep

• ↑ Sympathetic activity (more variable)

• BP becomes more unstable

• Transient spikes in BP

• Cardiovascular system is more active, not resting

Explain why cardiovascular events cluster at specific times of day

Cardiovascular events cluster at specific times of day because circadian rhythms produce predictable increases in sympathetic activity, blood pressure, and heart rate—especially during the early morning surge—creating periods of heightened cardiovascular stress and vulnerability.

Evaluate how circadian disruption and misalignment, such as daylight saving time transitions

and rapid time zone travel, acutely alter cardiovascular regulation and risk.

The spring shift is followed by a sharp increase in heart attacks,

while the fall shift is associated with a reduction, indicating that

even a one-hour change in sleep and timing can acutely alter

cardiovascular risk

Why disruption increases risk (core mechanism)

• Loss of coordinated timing between:

• Autonomic activity

• BP rhythms

• Hormone release

This leads to:

• Poor nighttime recovery

• Inappropriate daytime or nighttime activation

• Greater cardiovascular strain

Assess sleep duration as a modifiable regulator of blood pressure, using sleep extension

studies to distinguish causal effects from correlational associations

Sleep duration is a modifiable regulator of blood pressure because randomized sleep extension studies show that increasing sleep in habitual short sleepers lowers 24-hour systolic and diastolic blood pressure, demonstrating a causal effect (not correlational tho ) between short sleep and hypertension.

Why it’s hard to prove it’s correlational:

The studies cannot prove causation because short sleepers may also differ in stress, diet, activity, caffeine use, or health status. So correlation alone cannot tell us whether short sleep causes higher BP.

what is sleep arousal

Sleep arousal is a brief transition toward wakefulness marked by increased brain activity and

autonomic activation, often without full awakening

Explain how sleep fragmentation and arousals act as acute cardiovascular stressors and

how repeated sympathetic surges contribute to cardiovascular risk in conditions such as

restless legs syndrome and obstructive sleep apnea

Auditory arousals caused rapid increases in mean and diastolic blood pressure If arousals happen frequently

These repeated sympathetic surges lead to:

• Sustained ↑ blood pressure

• Increased vascular strain

• Conditions like restless leg syndrome or sleep apnea:

  • Show repeated systolic and diastolic BP spikes

  • Restless leg is linked to higher rise in hypertension

  • Sleep apnea is linked to an increased risk of hypertension, arrhythmias, and sudden cardiac death

Explain what wearable sleep trackers measure and how they infer sleep.

• Wearables estimate sleep using movement (accelerometry)

and cardiovascular signals such as heart rate and heart rate

variability (HRV) measured by photoplethysmography

• These signals are used to infer sleep timing and stages, but

wearables do not measure brain activity, eye movements, or

muscle tone

• As a result, they are most reliable for sleep duration and timing

and less accurate for arousals and sleep architecture

Explain why sleep is a vulnerable state for breathing

Loss of wake-related neural drive

During wake, breathing is supported by voluntary

control, upright posture, cortical input, and behavioral

backup.

• Sleep removes these stabilizing influences, allowing

latent respiratory instability and disease to emerge.

Reliance on automatic brainstem control

• In sleep:

  • Breathing is controlled only by:

    • Brainstem (medulla + pons)

• This system:

  • Maintains breathing using CO₂, O₂, and pH signals

It is the only control system during sleep

Differentiate between voluntary and automatic control of breathing

Voluntary

• Controlled by higher brain centers, primarily the cerebral cortex

• Allows conscious modification of breathing for speech, exercise, or breath holding

• Temporarily overrides brainstem respiratory signals

• Limited by rising CO₂, which restores involuntary breathing

Automatic control of breathing:

• Controlled by the brainstem centers in the medulla and pons

• Generates the automatic respiratory rhythm

• Driven by blood gas and pH regulation through chemical and reflex inputs

• Maintains O₂ delivery and CO₂ removal

• Sole control during sleep

identify the roles of cortical input versus medullary and pontine respiratory center for breathing

Cortical input:

• Function: Conscious control of breathing

  • Talking, singing, breath-holding, exercise adjustments

  • Can temporarily override automatic breathing

• The medulla oblongata generates the basic respiratory rhythm

  • – The dorsal respiratory group (DRG) produces rhythmic inspiratory bursts that activate the diaphragm and external intercostals during quiet breathing

  • – The ventral respiratory group (VRG) is recruited during increased demand to drive actively or forcefully expiration

• The pontine respiratory group (PRG) is a set of

neurons in the pons that modulate the medullary

breathing rhythm

• Apneustic activity promotes and prolongs inspiration

• Pneumotaxic activity terminates inspiration

• Their balance shapes the timing and smoothness of

breathing

Describe how breathing patterns and respiratory muscle activity change across wake, NREM

sleep, and REM sleep

Wake

• Faster and more irregular breathing due to cortical and

behavioral input

NREM sleep

• Breathing slows and becomes more regular

REM sleep

• Breathing speeds up and becomes irregular

How do we interpret breathing states through EMGs?

• Regular diaphragm rhythm → NREM

• Irregular diaphragm + low airway tone → REM

• High, variable activity everywhere → Wake

• Sudden spikes → Arousal

Explain the role of serotonin in stabilizing breathing during sleep

• Serotonin stabilizes brainstem respiratory control

during sleep without generating the breathing rhythm

• Serotonergic neurons are in the raphe nuclei of the

brainstem and are part of the ARAS

• These neurons project to medullary respiratory

centers, including the DRG and VRG, to support

reliable breathing during sleep

explain serotonin’s effects on inspiratory neurons, chemoreflex sensitivity, and responses to hypoxia and hypercapnia.

• Serotonin increases the firing rate of inspiratory neurons in the DRG + strengthens diaphragm activation

• Serotonin affects chemoreflex sensitivity

• Enhances the responsiveness of these systems

  • Makes the brainstem more sensitive to changes in blood gases

• This leads to faster and stronger ventilatory responses to disturbances

how does serotonin affect the response to hypoxia

• ↓ Arterial O₂ (hypoxia) → activation of peripheral

chemoreceptors in carotid and aortic bodies →

excitatory input to medullary respiratory centers

(DRG/VRG) → 5-HT amplifies inspiratory neuron

firing → increased rate and depth of breathing →

restoration of arterial O₂

How does serotonin affect the response to hypercapnia

↑ CO₂ (hypercapnia) → ↓ CSF pH (acidosis) →

activation of serotonergic neurons in the medullary

raphe → increased 5-HT release → stimulation of

medullary respiratory centers (especially DRG) →

increased rate and depth of breathing → CO₂

removal and restoration of blood pH

How does orexin provide tonic excitatory drive?

• Orexin increases breathing rate and strength by

exciting brainstem respiratory centers

• These effects occur even when CO₂ and O₂ levels

are normal

• This indicates orexin provides tonic excitatory drive

independent of chemoreflexes

how does orexin help with maintenance of upper airway stability

• Orexin increases the activity of upper airway motor circuits

• This helps maintain airway openness during wake

• Loss of orexin signaling during sleep reduces airway tone, increasing the risk of hypoventilation and

obstruction

how does orexin support state-dependent respiratory control

• Orexin stabilizes brainstem respiratory control during

wake without generating the breathing rhythm

• Orexin neurons in the lateral hypothalamus (LH) are a

core component of the sleep-wake switch and arousal

network

• These neurons project widely, including to the respiratory

centers in the medulla and pons, supporting stable

breathing during wakefulness

Explain how do opioids disrupt respiratory control during sleep, including the μ-opioid receptor

effects on brainstem drive, REM sleep, and respiratory vulnerability.

Brainstem drive

μ-opioid receptors are expressed in the brainstem respiratory

control circuits

• Activation of μ-opioid receptors suppresses automatic

breathing (reduced breathing rate and depth)

Rem:

• Opioid use reduces both the percentage of REM sleep and the number of REM episodes across the night

• As a result, REM sleep becomes less frequent and less stable, altering normal sleep-state transitions

Respiratory vulnerability

• opioid-mediated inhibition of the brainstem

respiratory centers

• Automatic breathing is less controlled

what is apnea

Apnea is a temporary cessation of breathing lasting

≥10 seconds during sleep

• It reflects either loss of respiratory drive (central

apnea) or airway collapse (obstructive apnea)

Describe how developmental vulnerability of brainstem serotonin systems contributes to

SIDS

Impaired serotonergic function may reduce autoresuscitation and arousal, increasing risk

during sleep

Differentiate obstructive sleep apnea and central sleep apnea based on the underlying

physiological mechanisms, not just symptoms or definitions

OSA

Obstructive sleep apnea arises from sleep-related reductions in upper airway muscle tone and structural airway vulnerability that cause inspiratory collapse despite preserved respiratory drive

CSA

Central sleep apnea results from instability or suppression of brainstem respiratory control, often due to altered chemoreflex sensitivity and delayed CO₂ feedback, leading to absent inspiratory effort (no drive to breathe)

What is obstructive sleep apnea

OSA occurs when the upper airway repeatedly collapses or becomes blocked during sleep, despite normal neural signals to breathe

Describe how anatomical factors contribute to airway collapsibility in obstructive sleep

apnea

Anatomical factors increase airway collapsibility in obstructive sleep apnea by reducing airway size, increasing surrounding pressure, and weakening structural support.

1. A smaller upper airway provides less space for airflow, so even minor reductions in muscle tone during sleep can lead to complete obstruction.

2. Increased soft tissue volume, such as enlarged tonsils, tongue, or soft palate, further narrows the airway and adds internal pressure that promotes collapse.

3. Craniofacial structure also plays a key role, as features like a recessed jaw or shortened lower face reduce the skeletal support that normally helps keep the airway open.

4. In addition, a larger neck circumference, often associated with excess fat deposition around the airway, applies external pressure that further compresses and narrows the airway.

Together, these anatomical factors create a structurally narrow and unstable airway that becomes highly susceptible to collapse during sleep when neuromuscular tone is reduced, leading to obstructive events.

What is central sleep apnea

Breathing pauses occur due to reduced or absent neural drive from the brainstem respiratory centers, not airway obstruction

Explain how instability in brainstem ventilatory control leads to central sleep apnea,

including reduced versus excessive chemosensitivity and periodic breathing patterns

Central sleep apnea arises from instability in brainstem ventilatory control, particularly in how the system regulates breathing in response to changes in carbon dioxide (CO₂). Under normal conditions, medullary respiratory centers adjust ventilation to maintain stable CO₂ levels, increasing breathing when CO₂ rises and decreasing it when CO₂ falls. In central sleep apnea, this feedback system becomes unstable in two key ways.

1. In cases of reduced chemosensitivity, the brainstem has a blunted response to rising CO₂, resulting in insufficient stimulation of inspiratory neurons and a failure to generate adequate respiratory drive, which can lead to periods of absent breathing.

2. In contrast, excessive chemosensitivity produces an overactive response to small increases in CO₂, causing hyperventilation that lowers CO₂ below the threshold required to sustain breathing.

3. When CO₂ falls too low, respiratory drive is temporarily suppressed, resulting in apnea. As CO₂ rises again, the system overcorrects once more, creating a repeating cycle of hyperventilation followed by apnea known as periodic breathing, commonly seen as Cheyne–Stokes respiration. These oscillations are often exacerbated by delayed feedback in the system, such as prolonged circulation time in heart failure, which causes mismatches between blood gas levels and the brainstem response. During sleep, the absence of wake-related neural input further increases reliance on this unstable automatic control system, making these fluctuations more pronounced and increasing the likelihood of central apneas.

Compare major treatment strategies by identifying their primary physiological targets, such

as airway splinting, ventilatory support, neuromuscular activation, or anatomical

modification.

Airway Splinting

– Continuous positive airway pressure (CPAP) delivers

continuous positive pressure that splints the airway open

– Oral appliances advance the mandible to enlarge the upper

airway

– Oral pressure therapy (OPT) pulls the tongue and soft

palate forward using negative oral pressure

Ventilatory Support

– Bilevel positive airway pressure (BIPAP) provides

inspiratory pressure support and reduces work of breathing

– Adaptive servo ventilation (ASV) adjusts pressure support

breath by breath to stabilize ventilation

Neuromuscular activation

- Hypoglossal nerve stimulation activates tongue muscles

to maintain airway patency

Anatomical Modification

These interventions permanently alter airway structure

to reduce obstruction.

– Surgery (uvuloplasty) removes or repositions obstructing

tissue or modifies airway anatomy

Predict appropriate treatment approaches for different patient phenotypes based on PSG

features and underlying pathophysiology rather than disease labels alone

Explain how thermoregulation is controlled by the hypothalamus

Thermoregulation by the hypothalamus

• The preoptic area of the hypothalamus (POA) is the

primary integrator of thermal information

– Receives input from peripheral & central thermoreceptors

– Generates coordinated autonomic and behavioral responses

Peripheral effectors regulate production through

• Cutaneous vasodilation

– Warm-sensitive POA neurons

(primarily GABAergic) increase

firing as local temperature rises →

GABAergic inhibition reduces

sympathetic vasoconstrictor tone →

increased skin blood flow promotes

heat loss at the body surface

• Sweating

– Warm-sensitive POA neurons

activate downstream sympathetic

pathways to eccrine sweat glands

→ evaporative cooling dissipates

excess heat

peripheral effectors regulate heat loss through

• Cutaneous vasoconstriction

– Cold-sensitive POA neurons increase

activity as local temperature falls →

increased sympathetic vasoconstrictor

tone → reduced skin blood flow limits

heat loss

• Shivering thermogenesis (ST)

– Cold-sensitive POA pathways increase

somatic motor output → rhythmic

skeletal muscle contractions generate

heat

• Non-shivering thermogenesis (NST)

– Cold-sensitive POA pathways increase

sympathetic drive to brown adipose

tissue → increased metabolic heat

production

define the thermoneutral zone

The thermoneutral zone (TNZ) is the range of ambient temperatures where:

• The body maintains core temperature

• With minimal metabolic effort

predict how moving above or below the thermoneutral zone alters metabolic cost and sleep architecture

Describe how the circadian regulation of body temperature and melatonin release promotes

sleep onset.

Circadian regulation promotes sleep onset through the coordinated timing of a

• decline in core body temperature

• and an increase in melatonin release.

Melatonin

• increases sleep propensity but also

• facilitates peripheral vasodilation, particularly in distal regions such as the hands and feet, which enhances heat loss from the body. This redistribution of heat from the core to the periphery accelerates the decline in core body temperature. The combined effects of reduced core temperature, increased heat loss, and rising melatonin levels create a physiological state that lowers metabolic activity and promotes the transition from wakefulness to sleep.

Explain how distal skin vasodilation and the distal–proximal temperature gradient facilitate

sleep initiation.

Distal skin vasodilation increases blood flow to the hands and feet, promoting heat transfer from the core to the periphery and raising distal skin temperature, which creates a positive distal–proximal temperature gradient that reflects enhanced heat loss; this redistribution of heat lowers core body temperature and facilitates sleep initiation by promoting a physiological state conducive to sleep

Compare thermoregulatory control during NREM and REM sleep, including which responses

are preserved, reduced, or suspended.

• NREM sleep

– Body shifts toward heat loss at sleep onset

– Thermoregulation remains active but less sensitive

– System prioritizes thermal stability and low energy use

– Lower metabolism and cooler core temperature support

restoration

• REM sleep

– Active thermoregulation is suspended (not occuring)

– Body temperature becomes less actively regulated

Predict how ambient temperature and brain temperature differently affect NREM and REM

sleep.

Ambient

• Below the TNZ, NREM predominates while REM is suppressed

• Within the TNZ, both NREM and REM sleep are maximized

• Above the TNZ, both NREM and REM decline, with REM most affected

Brain temp

• Brain temperature is highest during wake due to sustained neuronal firing and high metabolic demand

• During NREM sleep, the brain temperature falls as neuronal activity and metabolism decrease

• During REM sleep, brain temperature rises again due to intense cortical activation and increased cerebral blood flow, despite muscle atonia

what are night sweats

Night sweats are episodes of excessive sweating

during sleep that soak clothing or bedding

• They occur even when the room is not hot, and the

individual is not overdressed

• Night sweats reflect abnormal activation of

thermoregulatory or autonomic systems during sleep,

not simple overheating

Apply thermoregulatory principles to explain real world phenomena such as night sweats,

exercise timing, and the effects of cooling sleep environments.

Thermoregulatory principles explain that sleep is promoted by a decline in core body temperature and increased peripheral heat loss, so excessive or dysregulated heat loss can cause night sweats and disrupt sleep, elevated core temperature from late exercise can delay sleep onset, and appropriately cool sleep environments enhance heat dissipation and facilitate sleep initiation, whereas extreme temperatures can impair sleep by increasing thermoregulatory demands.