Circadian Forced Desynchrony of the Master Clock Leads to Phenotypic Manifestation of Depression in Rats.

In mammals, a master circadian clock within the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the phase coherence among a wide array of behavioral and physiological circadian rhythms. Affective disorders are typically associated with disruption of this fine-tuned "internal synchronization," but whether this internal misalignment is part of the physiopathology of mood disorders is not clear. To date, depressive-like behavior in animal models has been induced by methods that fail to specifically target the SCN regulation of internal synchronization as the mode to generate depression. In the rat, exposure to a 22-h light-dark cycle (LD22) leads to the uncoupling of two distinct populations of neuronal oscillators within the SCN. This genetically, neurally, and pharmacologically intact animal model represents a unique opportunity to assess the effect of a systematic challenge to the central circadian pacemaker on phenotypic manifestations of mood disorders. We show that LD22 circadian forced desynchrony in rats induces depressive-like phenotypes including anhedonia, sexual dysfunction, and increased immobility in the forced swim test (FST), as well as changes in the levels and turnover rates of monoamines within the prefrontal cortex. Desynchronized rats show increased FST immobility during the dark (active) phase but decreased immobility during the light (rest) phase, suggesting a decrease in the amplitude of the normal daily oscillation in this behavioral manifestation of depression. Our results support the notion that the prolonged internal misalignment of circadian rhythms induced by environmental challenge to the central circadian pacemaker may constitute part of the etiology of depression.

Fragmentation of Rapid Eye Movement and Nonrapid Eye Movement Sleep without Total Sleep Loss Impairs Hippocampus-Dependent Fear Memory Consolidation.

STUDY OBJECTIVES: Sleep is important for consolidation of hippocampus-dependent memories. It is hypothesized that the temporal sequence of nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep is critical for the weakening of nonadaptive memories and the subsequent transfer of memories temporarily stored in the hippocampus to more permanent memories in the neocortex. A great body of evidence supporting this hypothesis relies on behavioral, pharmacological, neural, and/or genetic manipulations that induce sleep deprivation or stage-specific sleep deprivation. METHODS: We exploit an experimental model of circadian desynchrony in which intact animals are not deprived of any sleep stage but show fragmentation of REM and NREM sleep within nonfragmented sleep bouts. We test the hypothesis that the shortening of NREM and REM sleep durations post-training will impair memory consolidation irrespective of total sleep duration. RESULTS: When circadian-desynchronized animals are trained in a hippocampus-dependent contextual fear-conditioning task they show normal short-term memory but impaired long-term memory consolidation. This impairment in memory consolidation is positively associated with the post-training fragmentation of REM and NREM sleep but is not significantly associated with the fragmentation of total sleep or the total amount of delta activity. We also show that the sleep stage fragmentation resulting from circadian desynchrony has no effect on hippocampus-dependent spatial memory and no effect on hippocampus-independent cued fear-conditioning memory. CONCLUSIONS: Our findings in an intact animal model, in which sleep deprivation is not a confounding factor, support the hypothesis that the stereotypic sequence and duration of sleep stages play a specific role in long-term hippocampus-dependent fear memory consolidation.