Efeito de variação gradual de fotoperíodo na modulação do comportamento associado à mania em camundongos C57BL/6

Abstract

Biological rhythms are characterized by cyclical variations in physiology and behavior. The systemthat generates and maintains rhythms that fluctuate around 24 hours is called the circadian timing system. This system is modulated by seasonal changes in the length of the day (photoperiod), which provide organisms with a reliable environmental clue to determine the time of year, particularly in animals with photoperiodic response. Several biological variables have circadian cyclic profiles that are affected by seasonal cycles, for example the wake and sleep cycles, the food profile, body temperature, blood pressure, reproductive profiles, annual fluctuations in triglyceride levels, changes in mood, in attention and cognitive performance. In addition, several diseases have been directly associated with seasonality, including psychiatric disorders, such as depression, seasonal depressive disorder and bipolar disorder. The incidence of suicide is higher in the spring and summer months and there is a greater number of hospitalizations for mania in the months with longer duration of ambiente light (during the spring months), in different latitudes. In addition, the suicide rate is higher at higher latitudes. Just as several diseases have been associated with disturbances and misalignments in the circadian rhythm, due to mismatches between the environmental cycle, the central timing system and the peripheral rhythms in the organisms, this seasonal modulation of the circadian rhythm may play an important role in triggering psychiatric disorders in vulnerable individuals, such as patients diagnosed with mood disorders. More specifically, a rapid increase in the photoperiod, as occurs in regions of greater seasonality, can promote a disturbance of the internal temporal order and trigger psychiatric symptoms. However, studies investigating this effect of increasing the photoperiod in patients or in animal models are scarce. Thus, we aim to investigate how the gradual increase in the photoperiod could affect circadian rhythm and the behavior associated with mood disorders in a murine model. For this, we developed a photoperiod variation protocol (TP – Transitional Photoperiod) in an animal model, using C57BL / 6 mice. The TP consists of a rapid but gradual variation of the photoperiod, from an 08: 16h regime (hours in light:dark), to a 16: 08h regime over 7 days, with an increase of 30 min per day at the beginning and at the end of the clear stage. For control, we used animals submitted to a 12: 12h regime and another group submitted to a 16: 08h long photoperiod regime, without photoperiod transition and after stabilization for 7 days in that regime. We evaluated the rhythm of activity and rest (N = 08), as well as behaviors associated with depression, anxiety, risk exposure and mania in consolidated behavioral tests (N = 30 - 10 animals per group). In addition, we evaluated whether TP modulates the expression of a clock gene (Per2) in the prefrontal medial córtex (n=48 per group – 1212 and TP), structure directly involved with executive functions and decision making. The results indicate that the animals are synchronized on the diferente days of the TP and when subjected to constant darkness these animals enter into free course from the last day of the protocol, which suggests synchronization and not just masking the rhythm. Animals in TP also have a higher risk exposure in the elevated plus maze test in the open field, as well as na effect considered to be an antidepressant type in the forced swim test and state similar to mania assessed by the plate test with holes. Per2 present a robust expression after TP with a phase delay of 1.8h in the acrophase compared to the EP group. Suggesting a circadian misalignment promoted by the photoperiodic variations. To the best of our knowledge, this is the first model for suicidal endophenotypes and mania-like behavior induced by photoperiodic changes.