Moderate recurrent hypoglycemia during early development leads to persistent changes in affective behavior in the rat

Abstract

Recurrent hypoglycemia is a common problem among infants and children that is associated with several metabolic disorders and insulin-dependent diabetes mellitus. Although studies have reported a relationship between a history of juvenile hypoglycemia and psychological health problems, the direct effects of recurrent moderate hypoglycemia have not been fully determined. Thus, in this study, we used an animal model to examine the effects of recurrent hypoglycemia during the juvenile period on affective, social, and motor function (assessed under euglycemic conditions) across development. To model recurrent hypoglycemia, rats were administered 5 U/kg of insulin or saline twice per day from postnatal day (P)10 to P19. Body weight gain was retarded in insulin-treated rats during the treatment period, but recovered by the end of treatment. However, insulin-treated rats displayed increases in affective reactivity that emerged early during treatment and persisted after treatment into early adulthood. Specifically, insulin-treated pups showed increased maternal separation-induced vocalizations as infants, and an exaggerated acoustic startle reflex as juveniles and young adults. Moreover, young adult rats with a history of recurrent juvenile hypoglycemia exhibited increased fear-potentiated startle and increases in behavioral and hormonal responses to restraint stress. Some of these effects were sex-dependent. The changes in affective behavior in insulin-exposed pups were accompanied by decreases in adolescent social play behavior. These results provide evidence that recurrent, transient hypoglycemia during juvenile development can lead to increases in fear-related behavior and stress reactivity. Importantly, these phenotypes are not reversed with normalization of blood glucose and may persist into adulthood.

Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain

“…Similar to previous studies (4,5,16,26), neuronal injury was primarily seen in the anterior regions of the cerebral cortex, confirming the vulnerability of this brain region during moderate hypoglycemia. Contrary to our expectation, hyperglycemia accentuated the severity of injury, likely via glucose reperfusion and PARP-1 overactivation.…”

Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats

“…Decreased PPI on P29 suggests impaired sensorimotor gating in the post-hypoglycemia period. This finding differs from the intact PPI reported in a previous study of recurrent hypoglycemia in younger rats [10]. Differences in timing of hypoglycemia in the two studies may explain the discrepant results.…”

“…Differences in timing of hypoglycemia in the two studies may explain the discrepant results. Recurrent hypoglycemia occurred during the period of peak PFC development (P24 to P30) [12] in the present study, whereas hypoglycemia episodes (from P9 to P20) had ceased prior to this period in the Moore et al study [10]. Lower BDNF/TrkB expression in the PFC may explain the impaired PPI in the present study.…”

“…This is not surprising given that three-week-old rats and adult rats have comparable vulnerability to hypoglycemia-induced brain injury [7,14]. It is possible that testing under hypoglycemia conditions [59] or testing for more complex cognitive or affective behaviors [10] would have uncovered additional functional deficits.…”

“…Studies in developing rats demonstrate that the medial prefrontal cortex (PFC) is highly vulnerable to injury during moderate hypoglycemia [7–10]. The effects beyond neuronal injury are not well characterized.…”