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

Abstract

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.

Disruption of behavior and brain metabolism in artificially reared rats

“…Our results are coincident with current literature regarding maternal separation before weaning (Sanchez et al, ; Meagher et al, ; Spivey et al, ; Bonab et al, ; Wall et al, ; Vetulani ; Melo, ; Segura et al, ; Sieben et al, ).…”

“…Once again, all these authors find changes mainly in hippocampus and amygdala, although in this case, the thalamus and medial prefrontal cortex (PFC) is also altered. Some authors have found changes in the metabolism of PFC (Spivey et al, ) even in short‐term separations (handling), despite the so‐called “positive effect” (Melo, ); and in some cases, there are changes that depend on gender (León‐Rodríguez and Dueñas, ). As can be seen, the wide variety of protocols makes difficult to have a big panorama of the effects of social isolation, both before‐ and after‐weaning, and in some cases, contradictory recalls of the observed changes.…”

“…Behavioral and neurodevelopment changes can be obtained by intermittent or even a single period of separation from the mother and siblings before or after weaning (Braun et al, 2009;Spivey et al, 2011;Kozlov et al, 2013;Barrett et al, 2015;Schiavone et al, 2017).…”

“…However, not all brain areas seem to be affected. Main changes have been detected in regions involved with learning (Braun et al, 2009;Bonab et al, 2012), emotions (Lukkes et al, 2012;Toda et al, 2014), and social interaction (Braun et al, 2009;Spivey et al, 2011;Wang et al, 2015). Fos immunoreactivity is reduced in different brain regions such as medial preoptic area, ventromedial hypothalamus, thalamus, habenula, dentate gyrus, lateral septum, and basolateral amygdala (Akbari et al, 2008;Wall et al, 2012;Ahern et al, 2016).…”

Resilience priming: Translational models for understanding resiliency and adaptation to early life adversity

“…This reduced stress response was again associated with reduced CRH expression in the hypothalamus and increased GR in the hippocampus (Avishai-Eliner, Eghbal-Ahmadi, Tabachnik, Brunson, & Baram, 2001;Meaney et al, 1996), suggesting a similar pattern of alteration in the brain due to different manipulations that all seem to result in resilience. Further, early handling also led to improved cognitive function and reduced risk for depressive-like behavior (Dinces, Romeo, McEwen, & Tang, 2014;Meaney et al, 1991;Reeb-Sutherland & Tang, 2012;Spivey, Padilla, Shumake, & Gonzalez-Lima, 2011;Tang, 2001), suggesting that the extra stimulation early in life leads to a more resilient phenotype that is based on alterations in HPA axis functioning.…”