Influence of Early-Life Stress on Sleep and Attention Regulation in Mice

• In Event: 2-068 - Social Origins of Developmental Risk for Mental and Physical Illnesses

Integrative Statement

Children who have experienced early-life stress (ELS). such as emotional disturbances or neglect, display increased rates of psychiatric conditions and behavioral features consistent with attention
deficit / hyperactivity disorder (ADHD). Research on ELS in animal models has shown altered brain development and associated changes in psychological/behavioral functioning. In particular, the objectives of this study were to explore the impact of ELS on attentional performance and sleep regulation in a mouse model of neglect. Male C57Bl6/J mice were raised under control care or a fragmented care paradigm (limited nesting and bedding material during the first postnatal week), then tested as adults (>P90) on a variety of behavioral and physiological assays. Notably, we utilized a two-choice touchscreen visual attention (2-CVA) task with / without sleep deprivation (SD; 4 hours by gentle handling/novel objects). Pupillometry was used to assess arousal levels as well. To investigate the effect of ELS on adult sleep per se and the associated cortical activity, mice were implanted with electrodes over the right prefrontal cortex and nuchal muscle for electroencephalogram / -myogram (EEG/EMG) recordings, respectively. Finally, brains were harvested for molecular analysis of prefrontal cortex by real-time quantitative reverse transcription PCR (qRTPCR). Adult male mice displayed a variety of externalizing behaviors following ELS, including social dominance (tube test victories, urine marking), compulsive marble burying and social memory deficits. Although baseline pupil diameter was enlarged, size fluctuations were largely blunted. Moreover, while these mice showed a trend toward decreased attention levels on the 2-CVA task, they were notably immune to reduced attentional performance post-SD, as typically seen in control mice. Baseline circadian modulation of wake/sleep rhythms was largely unchanged in ELS mice, but they exhibited heightened EEG gamma power during wake periods, which may underlie their altered attention sensitivity. Potential molecular correlates contributing to the gamma power changes investigated by qRTPCR revealed a persistent enhancement of the dopamine D2 receptor (D2R) following ELS. Male mice exhibit primarily externalizing behaviors following early life fragmented care, as well as altered attention regulation and sleep EEG oscillations. Notably, ELS may bestow a potential resistance to attentional decline under conditions of increased sleep need. This suggests adaptations to adversity during critical periods of early life may determine later sleep and arousal regulation, consistent with human studies implicating D2 receptor signaling.

Author

• Takao Hensch, Harvard University
  Presenting Author