Effects of maternal separation, early handling, and gonadal sex on regional metabolic capacity of the preweanling rat brain.

This is the first study to assess the effects of mother-infant separation on regional metabolic capacity in the preweanling rat brain. Mother-infant separation is generally known to be stressful for rat pups. Holtzman adolescent rats show a depressive-like behavioral phenotype after maternal separation during the preweanling period. However, information is lacking on the effects of maternal separation on the brains of rat pups. We addressed this issue by mapping the brains of preweanling Holtzman rat pups using cytochrome oxidase histochemistry, which reflects long-term changes in brain metabolic capacity, following two weeks of repeated, prolonged maternal separation, and compared this to both early handled and non-handled pups. Quantitative image analysis revealed that maternal separation reduced cytochrome oxidase activity in the medial prefrontal cortex and nucleus accumbens shell. Maternal separation reduced prefrontal cytochrome oxidase to a greater degree in female pups than in males. Early handling reduced cytochrome oxidase activity in the posterior parietal cortex, ventral tegmental area, and subiculum, but increased cytochrome oxidase activity in the lateral frontal cortex. The sex-dependent effects of early handling on cytochrome oxidase activity were limited to the medial prefrontal cortex. Regardless of separation group, females had greater cytochrome oxidase activity in the habenula and ventral tegmental area compared to males. These findings suggest that early life mother-infant separation results in dysfunction of prefrontal and mesolimbic regions in the preweanling rat brain that may contribute to behavioral changes later in life.

Adolescent female rats are more resistant than males to the effects of early stress on prefrontal cortex and impulsive behavior.

We tested the hypothesis that adolescent Sprague-Dawley females may be more resistant than males to display impulsive behavior and lower prefrontal cortex thickness after mother-infant separation (MS). Starting at postnatal day 2 (P2), the MS group was separated 6 hr/day and the early handled (EH) group 15 min/day for 10 days, and another group was standard facility reared (SFR). Subjects were examined for novel open-field activity (P28), light-dark apparatus (P29), familiar open-field (P30) and frontal cortical thickness. This protocol resulted in impulsive behavior in MS rats relative to EH and SFR, but this effect was less pronounced in females than males. MS affected the two sexes differently in terms of decreased prefrontal cortex dorsoventral thickness, with this effect being significant in males but not females. Neuroanatomical and behavioral documentation that adolescent females are more resistant than males to ADHD-like effects of maternal separation have not been previously reported.

Juvenile male rats display lower cortical metabolic capacity than females.

The juvenile brain undergoes marked maturational changes accompanied by major sex hormone changes. In particular, sex differences in neural substrates could underlie male-specific dysfunction in behavioral responses related to the prefrontal cortex. Sex differences in regional metabolic capacity of the cerebral cortex were investigated in juvenile Sprague-Dawley rats. At 6 weeks of age the brains were processed for quantitative histochemistry of cytochrome oxidase, a rate-limiting enzyme in cellular respiration, which is an index of brain metabolic capacity. Quantitative image analysis revealed a main effect of sex with males displaying lower regional metabolic capacity than females in the dorsolateral and orbital prefrontal cortex and in the posterior parietal cortex. In addition, males separated for 6 h/day from their mothers as pups showed greater ambulatory behavior in the novel open field and higher metabolism in the posterior parietal cortex relative to males separated for 15 min/day. This is the first study to show sex differences in brain metabolic capacity in regions such as the prefrontal cortex that may be hypometabolic in juvenile males relative to females.