In a new study published in Science Translational Medicine (PDF), the Hensch Lab shares evidence that erratic maternal caregiving during a critical period leads to attention deficits in male mice. Interestingly, they did not find the same effect in female mice. The attention deficits were associated with disrupted sleep and unbalanced expression of dopamine receptors in the anterior cingulate cortex (ACC).
The work is part of the NIMH Conte Center and campus-wide Center on the Developing Child, which has a mission of finding science-based approaches to address early life stress in children and was founded by Jack Shonkoff. “We aspired to understand how adverse early life experiences ‘get under the skin’ to impact behavior,” says MCB faculty Takao Hensch, who led the Science Translational Medicine study. “Neglect is by far the most prevalent form of adversity worldwide – from war-torn nations or natural disasters to the challenges of poverty or single-parenting. Notably, studies of Romanian orphans had found attention deficits to be a pervasive hallmark of neglect unless responsive caregiving was introduced before the age of two. What underlies such a critical period for cognitive function was unknown.”
To find out, the Hensch Lab turned to attention experiments in mice. Postdoc Yuichi Makino of the Hensch Lab used a simplified test where thirsty mice are trained to touch a screen where a visual stimulus appears in order to receive a drink reward. Then to probe attention, the experimenters increase the waiting time between stimuli or shorten the duration in which the stimulus appears. As the task becomes more challenging, the researchers measure the drop-off in rodent performance.
In collaboration with Judy Cameron’s team (University of Pittsburgh) and investigators from the University of Calgary, the scientists compared these results to data from a group of young children and found that once again, early life adversity correlated with attention deficits primarily in boys. They then confirmed that the attention deficits were also mediated by disrupted sleep patterns in the human children.
“We established an animal model of fragmented maternal care (induced by limited nesting resources) and revealed the first postnatal week in mice to be vital for proper development of attention,” Hensch explains. “Strikingly, this was observed only in males, consistent with a sex bias for ADHD in boys. What stood out was that adverse childhood experiences (ACEs) already impact attention mediated by sleep deficits by age 3-5 in human children. This suggests that the underlying biology could be corrected by similar cellular targets as in our mice.”
He adds, “Why female attention is resilient to the very same early adversity remains an exciting open question. We found that males carry a lifelong oxidative stress burden at the cellular level, which may regulate orexin (an arousal peptide) and dopamine receptor expression. In parallel studies, females adopt a strategy of maturing their brain circuitry faster, which protects them from oxidative stress on the one hand, but deprives them of normally protracted developmental trajectories (e.g. adolescence).”
The study incorporates contributions from three undergraduate alumni of the Hensch Lab. “We are proud of the hard work by three senior thesis writers featured here: critical period mapping by Anna Victoria Serbin Neuro ’22 (now at Georgetown Medical School), sleep deprivation studies by Koya Osada Neuro ’18 (now at Harvard Medical School), and female resilience by Matthew Dickey MCB and Neuro (minor) ‘23 ,” Hensch says.
Because both the early life adversity and attention deficits due to sleep loss were traced to particular dopamine receptor levels in the ACC, further investigating circuits in that area provides a clear next step for this line of research. Hensch plans to look into how to rescue the ACC from the effects of sleep deprivation and look into female brains as a potential source of resilience factors.
(PDF)
