Importance of Control Groups for Evaluating Long-Term Behavioral and Cognitive Outcomes of Controlled Cortical Impact in Immature Rats

Abstract

Therapies are limited for pediatric traumatic brain injury (TBI), especially for the very young who can experience long term consequences to learning, memory, and social behavior. Animal models of pediatric TBI have yielded mechanistic insights, but demonstration of clinically relevant long-term behavioral and/or cognitive deficits has been challenging. We characterized short- and long-term outcomes in a controlled cortical impact (CCI) model of pediatric TBI using a panel of tests between 2 weeks and ~4 months after injury. Male rats with CCI at postnatal day (PND) 10 were compared with 3 control groups: Naïve, Anesthesia, and Craniotomy. Motor testing (PND25-33), novel object recognition (NOR, PND40-50), and multiple tasks in water maze (WM, PND65-100) were followed by social interaction tests (PND120-140). Anesthesia rats performed the same as Naïve rats in all tasks. TBI rats, when compared to Naïve controls, had functional impairments across most tests studied. The most sensitive cognitive processes affected by TBI included those that required fast one-trial learning (NOR, WM), flexibility of acquired memory traces (reversals in WM), response strategies (WM) or recognition memory in the setting of reciprocal social interactions. Both TBI and Craniotomy groups demonstrated increased rates of decision making across several WM tasks, suggesting disinhibition of motor responses. When the TBI group was compared to the Craniotomy group, however, deficits were detected in a limited number of outcomes. The latter included learning speed (WM), cognitive flexibility (WM) and social recognition memory. Notably, effects of craniotomy, when compared to Naïve controls, spanned across multiple tasks, and, in some tasks, could reach the effect sizes observed in TBI. These results highlight the importance of appropriate control groups in pediatric CCI models. In addition, the study demonstrates the high sensitivity of comprehensive cognitive testing to detect long-term effects of early-age craniotomy and TBI and provides a template for future testing of experimental therapies.