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Behavioral, hormonal, and neurochemical outcomes of neonatal repeated shaking brain injury in male adult rats

Tanaka, Hiromi, Ehara, Ayuka, Nakadate, Kazuhiko, Yoshimoto, Kanji, Shimoda, Kazutaka, Ueda, Shuich
Physiology & behavior 2019 v.199 pp. 118-126
adulthood, adults, amygdala, anxiety, brain damage, childhood, corticosterone, corticotropin, dopamine, elevated plus-maze test, glucocorticoid receptors, hippocampus, locomotion, males, mineralocorticoid receptors, models, neonates, neurons, norepinephrine, prefrontal cortex, rats, screening, secretion, serotonin, stress response
It is well known that an abusive environment in childhood is related to individual anxiety behavior in adulthood. Though an imbalance of adrenocorticosteroid receptors and a dysfunction of monoaminergic neuron systems have been proposed, the underlying mechanisms are not fully understood. To address these problems, we recently developed a new model of shaking brain injury (SBI) in neonatal rats. These model rats showed transient microhemorrhages in the gray matter of the cerebral cortex and hippocampus. Using this model, we assessed the effects of neonatal repeated mild SBI on subsequent behavior and the stress response, and we further examined the possible contribution of adrenocorticosteroid receptors in the hippocampus and central monoaminergic neuron systems mediating such abnormalities. Behavioral screening examination with a novel open-field test showed that the rats with postnatal day (P) 3–7 shaking had significantly reduced locomotor activity and exploration behaviors than those with late (P8–14) shaking periods, indicating a critical period for neonatal SBI. In the elevated plus maze (EPM) and the light/dark transition (L/D) tests, the model rats spent less time in the open arm of the EPM and the light box of the L/D test, indicating anxiety-like behavior as adults. In adults, the novel EPM-induced adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) responses were significantly increased by neonatal SBI. Further experiments showed that the expression of mineralocorticoid receptor (MR), but not glucocorticoid receptor (GR), was significantly downregulated in the hippocampus of this model rat. These results suggest that neonatal SBI-induced downregulation of MRs in the hippocampus attenuates negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which results in abnormal secretion of ACTH and CORT. Furthermore, the neurochemical analysis showed that shaken rats had higher dopamine (DA), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and noradrenaline (NA) levels in the dorsal part of the medial prefrontal cortex (dmPFC). In the amygdala, higher 5-HIAA and lower NA levels were observed. Both areas are known to be anxiety and stress-related. Taken together, the effects of neonatal SBI on the monoaminergic systems may also be involved in the changes of behavioral and hormonal responses in this model.