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.

Loss of sleep when it is needed most – Consequences of persistent developmental sleep disruption: A scoping review of rodent models

“…A week of gentle handling between P29-35 lead to increased latency to find the platform in the MWM in rats aged P31-44 ( Yang et al, 2012 ). A DCCD protocol with 8 h light shifts every other day from P0–P22 worsens performance in the MWM task: increased latency to the platform as well as the platform in a delayed match-to-sample task ( Ameen et al, 2022 ). Intermittent hypoxia (IH), a model of obstructive sleep apnea, exposure from P10-24 in rats leads to deficits in performance in Morris Water Maze, increased time and distance to the platform in adolescence ( Row et al, 2002 ).…”

“…P35-42 sleep-disruption in mice had no effect on spine density in VTA dopamine projecting neurons in the mPFC ( Bian et al, 2022 ). Early-life light advances produced lower branching order of pyramidal dendrites in the mPFC and dHPC, with a concomitant reduced length of dendrites in P90-110 animals ( Ameen et al, 2022 ). Branching order and dendritic lengths are proxies for complexity of morphology, or maturity ( Coleman and Riesen, 1968 ).…”

“…Cage manipulation presents the opportunity for potential automated disruption that is either continuous, targeting only the light-phase (when rodents are most likely to be asleep), and/or using closed loop delivery of disruption based on EEG/EMG activity ( Jones et al, 2019a , 2019b , 2020 , 2021 ; Lord et al, 2022 ; Bian et al, 2022 ; Feng et al, 2000 ; Nagai et al, 2021 ). An animal's cage includes its light source, the developmental chronic circadian disruption (DCCD) paradigm mimics severe shift-work with the light cycle advances dramatically every other or every fourth day ( Smarr et al, 2017 ; Ameen et al, 2022 ). Animal manipulation involves either gentle handling ( Medina et al, 2022 ; Weisman et al, 2011 ; Saré et al, 2016 , 2019 , 2022a ; Araujo et al, 2018 ; Yang et al, 2012 ; Murack et al, 2021 ) when the animal enters a sleep state, placing the animal on a platform over water where they are required to stay awake to avoid falling into the water ( da Silva Rocha-Lopes et al, 2018 ; Shaffery et al, 2006 ; Shaffery et al, 2002 ; Chen et al, 2015 ), or installing a sweeping bar that moves through the cage to enforce wakefulness ( Wallace et al, 2015 ; Atrooz et al, 2019 ).…”

“…During sleep manipulations, not all studies validated DSD with the gold standard EEG/EMG recordings. Some paradigms were validated based on video scoring or cage-activity, finding differences in rest (bout) duration, but without EEG-based sleep staging ( Lord et al, 2022 ; Ameen et al, 2022 ). The timing and duration of sleep disruption is also an important consideration in assessing the behavioral and neuropathological consequences.…”

Circadian rhythms as modulators of brain health during development and throughout aging

“…Preclinical rodent studies also support the association between sleep disruption in early life and impaired cognition that is manifest sometimes much later in life. For example, mouse pups placed under rapidly changing light/dark cycles until weaning (21 days), display impaired spatial and problem-solving tasks as well as increased anxiety-like behavior and decreased neuronal complexity in the prefrontal cortex ( Ameen et al, 2022 ). In another study, researchers exposed mice to ambient light via an 8:8-h light/dark cycle from embryonic day one to postnatal day 42.…”