Circadian Rhythms: Hormones and Behavior

Circadian Rhythms: Endocrine Regulation and Behavioral Aspects

• Circadian rhythms, driven by an internal timing system or "circadian clock", adapt organisms to rhythmic environments.
• Hormones play a key role in mediating behavioral outputs related to rhythms.
• Molecular clocks are present inside tissues/organs in mammals
• The SCN is located in the rostro-ventral hypothalamus in mammals, it is the main circadian rhythm coordinator.
• Hormones such as melatonin and cortisol strongly regulate sleep-wake cycles.
• Food intake is modulated by hormones such as leptin, ghrelin, insulin, and orexin.

The Role of the SCN

• SCN is reset by external light
• SCN projections regulate subordinate clocks in the CNS and periphery.
• Disrupted rhythms can result from the external signals conflicting the internal time.
• These disruptions speed up adaptation and differ among tissues.
• Disruptions can result in the active-time sleepiness, insomnia, mood problems and gastrointestinal.
• Disruptions like those caused by jet lag are resided internal and external time become realigned.
• Jetlag risks metabolic and cardiovascular diseases or risks certain cancers.

Molecular Mechanisms and Essential Functions

• Interlocked transcription-translation feedback loops (TTFLs) of clock genes and proteins generate circadian rhythms at the molecular level.
• CLOCK and BMAL1 activate transcription of three period (Per1-3) and two cryptochrome (Cry1/2) genes during activity phase.
• Per/Cry proteins create inactive phase complexes to shut down activity.
• The most important behaviors are energy intake, mating, and sleeping, they are clock-controlled
• Hormones function as messengers between the SCN, peripheral organs, and other brain regions.
• Circadian time regulates hormonal secretion as well as external signals like light, energy intake, or stress.
• Hormones control behavior/metabolic functions and include insulin/leptin/glucocorticoids/steroids/oxytocin.

Sleep-Wake Cycle and Hormonal Influence

• The sleep-wake rhythm relies on strict circadian behavioral production.
• Sleep drive depends on time spent awake, while muscle clocks contribute to peripheral feedback
• Interaction of sleep-promoting galaninergic nuclei and arousal-stimulating noradrenergic nuclei coordinate sleep-wake rhythms.
• Melatonin facilitates sleep adaptation, and is secreted in the dark.
• Melatonin can help with defining sleep/wake rhythms.
• Cortisol influences sleep/wake depending on HPA axis stimulation
• Cortisol secretion: CRH in the paraventricular nucleus releases cortisol which shows nadir/peak concentrations to promote wakefulness.

Hormones and Sleep Regulation

• GHRH stimulates growth hormone release promotes NREMS.
• Gonadal hormones, such as oestrogen and testosterone affect sleep.
• Oestrogen affects rapid eye movement while testosterone levels oscillate diurnally regarding sleep quality.
• Sleep-wake integrates circadian clock rhythms and hormonal signals, adapting to the menstrual or metabolic state.

Food Intake and Endocrine Regulation

• Food Timing/Sleep Cycles are related
• Hormones drive both homeostatic or hedonic appetite pathways.
• Leptin is a long term signal indicating body fat, acute leptin responses also reflect post meal.
• Leptin primarily suppresses hunger during rest.
• Leptin inhibits Npy/Agrp genes, and activates POMC in the hypothalamus to curb appetite/promote anorexigenic signals
• Leptin targets midbrain dopaminergic neurons, inhibiting reward, and resulting in leptin resistance for obese patients.
• SCN affects leptin rhythms through sympathetics.
• Ghrelin stimulates NPY/AgRP to increase hunger and promote feeding.
• Ghrelin opposes leptin effects through same dopaminergic neurons
• Ghrelin impairs STAT3, affects circadian activity, and can modulate other behavioural patterns.
• Insulin modulates food intake and acts like leptin by signaling in the CNS and periphery to reduce appetite.
• Altered SCN causes blunting of Insulin Sentivity
• The central clock controls cortisol/releasing growth hormone.
• Cortisol in stressed patients increases desire to eat which has been proven in humans.
• Orexin regulates anxiety as well as homeostatic and hedonic food intake.

Mating Behavior

• Critical for genetics diversity and almost every species relies on a successful mating and reproduction.
• Reproduction and mating have seasonal effects.
• Steroid hormones are critical for mating-related behaviors.
• There are various mating behavior dependencies that depend on the time of day; these are regulated.
• The hypothalamus releases gonadotropin-releasing hormone (GnRH).
• It stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release.
• LH promotes ovulation as FSH promotes oestrogen syntheses.
• Oxytocin, Testosterone and Estrogen are involved in mating.
• Oestrogen upregulates Cry2, and phase advances Per2.
• Oestrogens influence time window through with receptivity of the female is apparent.
• The HPG axes is very important for mating, while the SCN also controls it

Testosterone and Bonding

• The limbic system receives testosterone signals while oxytocin and vasopressin may be upregulated
• Testosterone mediates aggression,dominance,social vigilance via the amygdala etc
• Oxytocin induces caring and less aggression
• The need for sexual interest and motivation correlates positively.
• Pairing and bonding rely on memory which may be mediated by oxytocin in the hippocampus.

Conclusion and Future Directions

• Basic behavior of evolutionary impact is eating, sleeping and mating they depend on hormones and hormones depend on the circadian clock
• Interaction network is key
• Medical intervention points include:
• Time-restricted feeding/light and sleep hygiene
• Endocrinological and choronotype profiling
• Drugs (chronobiotics)
• Melatonin
• Other clock protein targets