Biological Rhythms and Introduction to Hormonal Control 9-18

Biological Rhythms: Definition and Characteristics

• Definition: Biological rhythms are predictable cycles of activity.

• Cycle Lengths: Can occur hourly, daily, monthly, or annually. The most commonly studied are circadian rhythms, which occur approximately every $24$ hours.

• Rules/Characteristics of Biological Rhythms:

  • Endogenous: The mechanism for telling time is internal to the organism.

  • Persist Under Constant Conditions: Rhythms continue even in constant light or darkness (e.g., $24$ hours of darkness). However, the period of the rhythm changes, often drifting.

    • Free-running conditions: Occur when an animal is in constant conditions, and its rhythm's period drifts. This drift signifies the animal's endogenous and natural period, which is never exactly $24$ hours.

    • Phase delay/advance: Refers to the shift in the onset of activity. If activity starts later each day, it's a phase delay. If it starts earlier, it's a phase advance.

  • Entrainable: Rhythms can be set to be the same across individuals, typically near $24$ hours. This is crucial for survival (e.g., nocturnal animals predicting sunrise to avoid predators) and for ecological interactions (e.g., predator/prey synchronization).

Zeitgebers: Synchronizing the Clock

• Definition: Zeitgeber (German for "time giver") is a major cue animals use to synchronize their internal clocks.

• Most Significant Zeitgeber: Light is the most prominent and important zeitgeber for most species, including humans, due to its consistency.

  • Animals use light to "rewind" or synchronize their clocks.

  • Sources include the sun (natural) and artificial lights (lab settings).

  • Animals primarily synchronize to major light events like the onset of dark or morning, or seasonal changes (e.g., shorter days from June $20$ to December $22$, longer days from December $22$ to June $19$).

• Other Zeitgebers: Anything that occurs on a predictable basis can serve as a zeitgeber (e.g., daily feeding schedules, arrival of research assistants in a lab).

The Master Clock and Peripheral Clocks

• Master Clock (Pacemaker):

  • The main clock that drives observable biological rhythms (e.g., locomotor activity, feeding, hormonal release).

  • Located in the brain (in mammals, the Suprachiasmatic Nucleus or SCN).

• Peripheral Clocks:

  • Smaller versions of clocks located in nearly every tissue throughout an animal's body.

  • Communicate with the master clock.

• Relationship and Role: The master clock ensures all peripheral clocks are working synchronously and are properly coordinated. A major ongoing question in circadian biology is how the master clock communicates with peripheral clocks and ensures their synchronization.

Evidence for the SCN as the Master Clock

• In mammals, the Suprachiasmatic Nucleus (SCN), a bilateral collection of neurons in the hypothalamus, is the master/pacemaker clock.

  • Anatomical Location: "Supra" (above) the optic "chiasm" (crossing point of optic nerves). These axons from the eyes are myelinated (white matter), staining lighter.

• Experimental Evidence:

  • In Vitro Studies: When SCN tissue is removed and cultured in a petri dish, it still exhibits rhythmic activity, indicating the rhythms originate within this tissue.

  • Lesion Studies: Complete ablation (destruction using chemicals or electricity) of the SCN in an animal's brain results in arrhythmia—the animal exhibits no predictable pattern of activity whatsoever.

  • Transplant Studies:

    • Removal of SCN causes arrhythmia, but transplanting SCN tissue from another animal restores rhythmicity to the recipient.

    • Tau Mutant Hamster Studies (Dr. Michael Menaker's work):

      • Identified a genetic mutation in the casein kinase one epsilon gene (which produces the tau protein) in hamsters that significantly altered free-running periods.

      • Hamsters heterozygous (single mutation) for this gene showed a free-running period of approximately $22$ hours (exceptionally short).

      • Hamsters homozygous (double mutation) for this gene showed an even shorter free-running period of approximately $20$ hours.

      • Cross-transplant experiment: Lesioning the SCN of a wild-type hamster (with a $\approx 24$-hour free-running period) and then transplanting SCN tissue from a tau-mutant hamster resulted in the wild-type animal adopting the free-running period of the donor (e.g., $22$ or $20$ hours). This strongly demonstrates that the endogenous periodicity resides within the SCN tissue.

Detection of Light Information: Direct and Indirect Pathways

• Animals utilize distinct pathways to detect light and entrain the SCN.

• Direct Pathway (Retinal Hypothalamic Tract):

  • A specific connection between the retina and the hypothalamus (where the SCN is located).

  • Photoreceptors: Light information for entrainment is NOT captured by rods and cones (responsible for vision and color detection, respectively).

  • It is detected by non-image-forming retinal ganglion cells (a subset of retinal ganglion cells not attached to rods and cones), which capture light but are not important for vision.

  • These cells transmit light information via the optic nerve. SCN neurons have long dendrites that reach into the optic chiasm to intercept this passing light information.

  • Evidence: Blind animals (with non-functional rods and cones) can still entrain. However, if the entire eye (including these retinal ganglion cells) is removed, entrainment ceases.

• Indirect Pathway (Pineal Gland and Melatonin):

  • The pineal gland secretes the hormone melatonin, which signals light/dark presence to the SCN.

  • Melatonin Secretion: High during darkness (nighttime), low during light (daytime). This cycle repeats every $24$ hours.

  • Mechanism: Melatonin circulates in the bloodstream and is detected by receptors in the SCN. High melatonin signals darkness; low melatonin signals light.

  • Light Input to Pineal Gland:

    • In Mammals: The pineal gland is deep within the brain ("deep brain photoreceptor") and receives indirect light information via a branch of the optic nerve that passes by it.

    • In Reptiles, Amphibians, Birds: The pineal gland is more superficial, closer to the skull. Light can directly penetrate their translucent skulls to activate the pineal gland.

• Importance of Multiple Pathways: Animals often use both direct and indirect pathways for light detection, providing redundancy and robustness to ensure accurate and synchronized clock function.

  • Blind individuals, for example, can still have melatonin cycles and entrain due to the non-image-forming retinal ganglion cells.

The Molecular Basis of Circadian Rhythms

• The ability of animals to tell time is based on a defined molecular mechanism occurring at the cellular level, completing one cycle approximately every $24$ hours.

• Step-by-step Cycle (within a cell, involving cytoplasm and nucleus):

  1. Protein Synthesis and Dimerization: In the cytoplasm, Clock and BMAL proteins are produced and then dimerize (bind together).

  2. Translocation to Nucleus: The Clock/BMAL dimer moves into the nucleus.

  3. Gene Activation: Inside the nucleus, the Clock/BMAL dimer binds to specific DNA elements on the Period and Cryptochrome genes, activating their transcription.

  4. mRNA and Protein Production: This leads to the production of Period and Cryptochrome messenger RNA (mRNA) and subsequently, their respective proteins.

  5. Trimer Formation: The Period and Cryptochrome proteins join with a third protein, Tau (the product of the casein kinase one epsilon gene, mutations in which lead to disrupted rhythms), to form a trimer.

  6. Negative Feedback: As the trimer concentration builds up, it translocates back into the nucleus and inhibits the binding of Clock and BMAL to the Period and Cryptochrome genes, effectively putting a "brake" on further transcription.

  7. Trimer Degradation: Over time, a protein called Double Time degrades the trimer.

  8. Cycle Restart: Once the trimer is degraded, the inhibitory effect is lifted, allowing Clock and BMAL to bind to the Period and Cryptochrome genes again, restarting the $ext{about } 24 ext{-hour }$ cycle.

• Master Clock Role: The master clock regulates the synchronicity of this molecular process across all clocks in the body.

Importance of Circadian Rhythm Synchronization

• Well-being: Maintaining synchronized circadian rhythms is crucial for physical and mental well-being (e.g., consistent energy, concentration).

• Disruption Causes: Inconsistent sleep patterns, irregular eating times, and particularly light exposure from electronic devices (like cell phones) in dark rooms right before bed, disrupt melatonin secretion and desynchronize rhythms.

• Health Consequences: Prolonged disruption of circadian rhythms (e.g., in shift workers, airline pilots) is correlated with increased risk of:

  • Mental disorders (e.g., schizophrenia).

  • Other physical abnormalities (e.g., heart attacks).

• Jet Lag: Traveling across time zones rapidly shifts the master clock (SCN), but peripheral clocks (especially those related to digestion) take longer to resynchronize, leading to issues like digestive problems.

  • Tip: Adjust eating habits before travel to help peripheral clocks adapt more smoothly.

Introduction to Hormonal Control of Behavior

Early Experiments Suggesting Hormonal Influence

• Aristotle: Observed that castration (removal of testes) in male birds altered their physical characteristics and sexual behavior, suggesting the testes were important.

• Arnold Adolf Berthold ($1849$): Systematically investigated the importance of testes in roosters.

  • Observation: Adult roosters develop large combs/wattles, crow loudly, fight vigorously, and mate with hens—behaviors absent in young males.

  • Experiments:

    1. Castration: Castrating young male chickens resulted in adults with small combs/wattles, no mating interest, weak crowing, and no aggression (non-normal development and behavior).

    2. Castration + Re-implantation: Castrating young males and re-implanting their own testes into their abdomen resulted in normal adult rooster development and behavior.

    3. Castration + Cross-Transplant: Castrating two young males and cross-transplanting their testes into each other's abdome also resulted in normal adult development and behavior.

  • Conclusion: Berthold noted that the transplanted testes had rich vascular connections but no neural connections, implying a blood-borne substance was responsible for the observed effects. This substance was later understood to be hormones.

What are Hormones?

• Characteristics:

  • Secreted by ductless glands directly into the bloodstream.

  • Travel in tissue fluids (e.g., blood in animals, sap in plants).

  • Interact with specific target receptors, which can be nearby or far away from the secretion site.

  • Act in very small quantities (a little goes a long way).

• Impact on Behavior: Hormones do not cause an animal to perform a behavior; they only alter the probability that a behavior will occur under certain circumstances (similar to genes).

Classes of Hormones: Peptides and Proteins

• Definition: Peptide and protein hormones are chains of amino acids.

  • Peptide hormones: Shorter amino acid chains.

  • Protein hormones: Longer amino acid chains.

  • The distinction is relative, not based on a strict numerical cutoff.

• Examples:

  • Oxytocin:

    • A peptide hormone consisting of $9$ amino acids.

    • Behavioral Roles: Important for social behaviors and pair bonding.

    • Physiological Roles: Regulates uterine contractions during childbirth and milk production during nursing. Present in both males and females.

  • Vasopressin:

    • Also a $9$-amino acid peptide hormone, differing from oxytocin by only $1$ amino acid.

    • Behavioral Roles: Also plays a role in regulating social behavior.

    • Physiological Roles: Important for regulating blood pressure by affecting the kidneys' reabsorption or secretion of water.