Sex differences in the effects of mother-infant separation on brain metabolism and behavior
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Mother-infant separation (MS) is an early-life stressor which affects stress-related processes in brain and behaviors in rats. Changes associated with MS were investigated in the brain and behavior of two rat strains, Holtzman and Sprague-Dawley, at three points in development. The hypothesis was that MS would affect the prefrontal cortex (PFC), both in metabolic capacity and PFC-related behaviors across the lifespan. First, cytochrome oxidase (CO), an enzyme that directly reflects metabolic capacity in the brain, was quantified in two-week old Holtzman rats after MS, early handling (EH), or nohhandled controls. MS reduced CO activity in the PFC of female rats but not males. Path analysis of the CO data revealed a stronger descending influence of the medial PFC, a region associated with behavioral inhibition, in females; contrasted with a stronger descending influence of the lateral PFC, a region associated with motor output, in males. Second, adolescent rats were tested in the open field to assess MS effects on ambulatory activity and impulsivity. MS increased ambulatory activity and impulsivity in Sprague-Dawley males. In a separate study, MS reduced ambulation and impulsivity in Holtzman rats in the open field. Brains of Sprague- Dawley adolescents showed reduced PFC thickness in MS males relative to EH males. Across groups, male adolescents had reduced metabolic capacity relative to females in the PFC. Finally, extinction of Pavlovian fear, a PFC-related behavior, was not affected by sex or separation group in adult Holtzman rats. Across groups, males showed greater fear renewal than females, despite the extinction process. An unexpected finding was that EH attenuated fear renewal. Findings from these MS studies in Sprague-Dawley rats are similar to human psychopathology of ADHD, which is reported more frequently in young males and is related to PFC dysfunction. The opposite behavioral findings between Holtzman and Sprague-Dawley rats suggest that genetic predisposition can affect long-term responses to the same early-life stressor. Knowledge about baseline sex differences in brain and behavior gained from the studies on Holtzman rats may help future research to consider sex-dependent effects of disruptions during development, as it appears that some basic neural substrates are sexually dimorphic.