Early life circadian rhythm disruption in mice alters brain and behavior in adulthood

Abstract

Healthy sleep supports robust development of the brain and behavior. Modern society presents a host of challenges that can impair and disrupt critical circadian rhythms that reinforce optimal physiological functioning, including the proper timing and consolidation of sleep. While the acute effects of inadequate sleep and disrupted circadian rhythms are being defined, the adverse developmental consequences of disrupted sleep and circadian rhythms are understudied. Here, we exposed mice to disrupting light-dark cycles from birth until weaning and demonstrate that such exposure has adverse impacts on brain and behavior as adults. Mice that experience early-life circadian disruption exhibit more anxiety-like behavior in the elevated plus maze, poorer spatial memory in the Morris Water Maze, and impaired working memory in a delayed match-to-sample task. Additionally, neuron morphology in the amygdala, hippocampus and prefrontal cortex is adversely impacted. Pyramidal cells in these areas had smaller dendritic fields, and pyramidal cells in the prefrontal cortex and hippocampus also exhibited diminished branching orders. Disrupted mice were also hyperactive as adults, but otherwise exhibited no alteration in adult circadian locomotor rhythms. These results highlight that circadian disruption early in life may have long lasting and far-reaching consequences for the development of behavior and the brain.

Figure 1

Actograms depicting locomotor activity of adult male mice housed under the control LD cycle (left) or disrupting LD cycle (right) under which the litters were raised from birth until weaning. The graphs are F-periodograms representing the strength of the rhythm at each period.

Figure 2

The mean number of entries into the exposed arms of the Elevated Plus Maze (EPM) task by the control and disrupted animals (A). The mean time in seconds spent by the control and disrupted groups in the open arms during the EPM task (B). The error bars represent the standard error of the mean. The difference between the groups was significant at p < 0.05. N = 12/group.

Figure 3

The mean latency, in seconds, to the platform on the four training days of MWM task between the control and disrupted mice (A). The latency in seconds to the target quadrant between the control and the disrupted animals on the testing day (day 5) (B). The mean number of passing through the target area by the control and disrupted animals on the testing day (day 5) (C). The time spent in the target quadrant (quadrant 1) by control and disrupted animals on testing day (day 5) (D). The platform was located in quadrant 1 of the apparatus during training. Error bars represent the standard error of the mean. * = p < 0.05. N = 12/group.

Figure 4

The mean number of entries into the wrong arms between the control and disrupted groups, across the 8 days of the Delayed Match-to-Sample (DMS) task (A). Day 5 is statistically significant (p < 0.05). The mean number of entries into the wrong arms between the control and disrupted groups, across the 6 trials of the DMS task (B). The mean Latency in seconds to the platform on the 8 days of the DMS task between the control and disrupted (C), days 1, 3, 5, and 6 are statistically significant (p < 0.05). The mean Latency in seconds to the platform on the 6 trials of the DMS task between the control and disrupted (D), trials 2, 4, 5, and 6 are statistically significant, (p < 0.05). Error bars represent the standard error of the mean. N = 12/group.

Figure 5

Graphical representation of Golgi-Cox neuroanatomical analyses for disrupted and control animals perfused at P90-110. Neurons of the medial prefrontal cortex (mPFC), dorsal hippocampus (dHC), and basolateral amygdala (BLA) from control and disrupted animals depicted in photomicrographs and camera lucida tracings. The bar graphs represent results from branching order and the dendritic length for control and disrupted animals (*p < 0.001) (3 cells/region/animals were assessed and averaged, n = 4 control, n = 8 disrupted).

Figure 6

Circadian assessment. Actograms represent wheel running activity of the animals under a light–dark cycle (12–12 LD) and in complete darkness (DD), of controls and disrupted animals. Bar graphs represent activity in 4 h bins during in LD and DD between control and disrupted animals (n = 6 control, n = 10 disrupted).