Biological clocks and control of bioperiodic phenomena

Biological periodicities are driven by a genetic program to run according to a temporal duration (biotemporality) which causes a recursivity in a spectrum of frequencies ranging from milliseconds to years.

The temporal effect of genetic programming, the chronome, is the endogenous component for which the biological rhythms originate as «free-running» bioevents. The free-running rhythms reflect the «time of the body» which is independent from the environmental time measured by the clock, the «physical time». The free-running rhythms reflect the endogenous mechanisms of cyclic temporization whose expression is morphologically seen as an internal clock, a «biological or body clock».

Observing the animals integrated into their envi­ronment, it can be noted that the endogenous rhythms are usually not «free-running». The «time of the body» is masked, and the spontaneous biological rhythms are obliged by the exogenous cycles to adjust their period in accordance.

This means that the biological time has innately the capacity to uniform itself with the physical time. Therefore, events that perturbate the environ­ment can modulate the periodic cadence of the genetically determined endogenous rhythms. The strongest interferences are those provided by sys­tematic events having a cyclical character in their manifestation. The light-dark alternation, meal tim­ing schedule, social routines, including work shifts, etc. (see below) are deterministic as entraining agents.

In the entrainment of endogenous rhythms many structural entities intervene with a role of mediation (Table 2).

Table 2. - Central nervous structures involved in the chronoregulation of biological functions

Suprachiasmatic nuclei

Olfactory bulbs

Fornix

Septum

Limbic structure

Hippocampus

Preoptic area

Retino-hypothaiamic connection

Midbrain raphe nuclei

Ventromedial hypothalamus

Dorsomedial hypothalamus

Locus coeruleus

Brain stem

Autonomic nervous system

Superior cervical ganglic

Pineal giand

The most important determinants of biological timing are the endogenous oscillators, structures of the organism that function as rhythmic «pace­makers». Other machineries of synchronization are the «pace-resetters», elements of the organism that regulate the temporal structure of one or more rhythms in response to one or more environmental synchronizers. The informative relationships be­tween pacemakers and paceresetters are deter­mined by special connecting structures called «transducers» that translate the exogenous stimuli to the internal clocks. Transducers may have either negative or positive effects on the oscillators.. The series can be integrated by the «modifiers» and the «logic controllers» which act, respectively, in modifying arid controlling the exogenous and en­dogenous stimuli. /

With regard to biological clocks there exists an eternal diatribe between positivists arid negativists. The prevalent opinion is positivistic in the sense that the biological clocks are accepted as identifiable entities which reside inside tissues and organs. Those who believe in the' existence of biological clocks assert that these structures of self-sustaining timing play a primary role in coordinating the miriad of peripheral biological rhythms. Such a coordinative capacity presupposes a leadership with which the biological clocks drive the phase of the rhythms provided by each cell of the organism. This implies that the biological clocks are formally equipped to ubiquitarily interact with all the cells by means of neural, physical arid chemical messages. For this reason they are prominently located inside the non-mitotic-structures of the nervous system, both encephalic and spinal.

The structural organization of biological clocks is difficult to be deciphered. An attempt will be made here by presenting the principal models. The model I, the simplest, is made by an oscillator that times a second oscillator, and so forth. This primordial model proposes a linear cybernetic control. The model II describes a primary oscillator followed by a series of oscillators in succession. The model III proposes an interaction between various oscillators of equal hierarchical importance arranged in a cybernetic network. The control by nodal clocks explains the occurrence of collateral interactions conditioning the mechanisms of positive or negative feedback. This interactive mechanism of chronore­gulation has been called « feed-sideward».

C

Suprachiasmatic nuclei Olfactory bulbs Fornix Septum

Limbic structure Hippocampus Preoptic area

Retino-hypothaiamic connection Midbrain raphe nuclei Ventromedial hypothalamus Dorsomedial hypothalamus Locus coeruleus Brain stem

Autonomic nervous system Superior cervical ganglic Pineal giand

hronoanatomic research has brought to light a series of structures responsible for rhythmic pro­gramming and chronobiological integration of the organism with the environment. Information on the neuroanatomical structures involved in the central regulation of biological rhythms derive essentially from animal studies. Table 3 lists the structures which are presently recognized to play a rhythmogenic role as oscillators.

Table 3. - Central structures involved in the coordination of oscillating biological functions

Pacemakers
Paceresetters
Modifiers
Transducers
Logic-controllers
Synchronizers

Desynchronization, resynchronization, chronization

Chronobiological studies provided evidence that various environmental factors act hierarchically as synchronizers of biological rhythms. The most powerful synchronizer is the light-dark alternation. Isolated from geophysical temporality, human beings progressively tend to delay the resting time. This phenomenon occurs even in conditions of perennial light or darkness. A rapid change in time zones (passing through three or more time zones), as occurs in transmeridian flights, gives rise to a psychophysical disturbance commonly known as «jet lag syndrome» prominently due to the dyschronism between biological time and physical time. The resynchronization following geographical dyschron­ism occurs with a phase shift of about 90 min every 24 h. It is, however, necessary to keep in mind that the direction of time zone transiction is crucial. In east-west bound flights, travellers must recuperate a time span equal to the temporal difference between the time zones. In west-east bound flights, subjects must recuperate 24 h minus the difference in time zones, i.e., the physical time already passed in that zone , which was not biologically «lived» by the travellers. This implies that the resynchronization takes much more time. The resynchronization can be, however, accelerated or delayed by numerous factors (Table 4).

Acceleration	Retardation
Extroversion	Introversion
Serality	Manility
Phase advance	Phase delay
Delay shift	Advance shift
Labile rhythms	Stabile rhythms
Strong temporal pressures	Weak temporal pressures
Higher performance task	Lower temporal task
Yought	Ageing
Low neuroticism	High neuroticism
Low pulse/respiration ratio	High pulse/respiration ratio

The meal schedule is also a robust synchronizer. Subjects eating a complete meal only once a day will show a phase shift for many biological rhythms toward the hour that the meal is given. Social routines (sociotemporality) are also important, es­pecially shift work. A random shift can produce desynchronizing effects for many periodic functions, especially those related to physical and mental performance. Other environmental agents causing dyschronism are stress, fasting, fatigue, etc., if abnormally prolonged in time and/or cyclically repeated.

Several drugs can induce desynchronization as well. The lists of these drugs should compose a new chapter of pharmacology to be used in pharmacol­ogical surveillance.

Interestingly, some drugs may be used for resyn­chronizing the biological rhythms disturbed by exogenous interferences. These drugs are called «chronizing agents or chronizers».