Impairment in Extinction of Contextual and Cued Fear Following Post-Training Whole-Body Irradiation

Abstract

Because of the use of radiation in cancer therapy, the risk of nuclear contamination from power plants, military conflicts, and terrorism, there is a compelling scientific and public health interest in the effects of environmental radiation exposure on brain function, in particular hippocampal function and learning and memory. Previous studies have emphasized changes in learning and memory following radiation exposure. These approaches have ignored the question of how radiation exposure might impact recently acquired memories, which might be acquired under traumatic circumstances (cancer treatment, nuclear disaster, etc.). To address the question of how radiation exposure might affect the processing and recall of recently acquired memories, we employed a fear conditioning paradigm wherein animals were trained, and subsequently irradiated (whole-body X-ray irradiation) 24 h later. Animals were given 2 weeks to recover, and were tested for retention and extinction of hippocampus-dependent contextual fear conditioning or hippocampus-independent cued fear conditioning. Exposure to irradiation following training was associated with reduced daily increases in body weights over the 22-days of the study and resulted in greater freezing levels and aberrant extinction 2 weeks later. This was also observed when the intensity of the training protocol was increased. Cued freezing levels and measures of anxiety 2 weeks after training were also higher in irradiated than sham-irradiated mice. In contrast to contextual freezing levels, cued freezing levels were even higher in irradiated mice receiving 5 shocks during training than sham-irradiated mice receiving 10 shocks during training. In addition, the effects of radiation on extinction of contextual fear were more profound than those on the extinction of cued fear. Thus, whole-body irradiation elevates contextual and cued fear memory recall.

Post-training gamma irradiation-enhanced contextual fear memory associated with reduced neuronal activation of the infralimbic cortex

“…The next day, or 24 hours after training, the mice were tested for recall of conditioned fear during a six min trial. All freezing data were analyzed using Med Associates software (Georgia and St. Albans, Vermont), as previously described [44]. The software analyzes freezing based on a proprietary algorithm scoring with freezing defined as no movement except respiration.…”

Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

“…Neurogenic areas are particularly susceptible to ionizing radiation, and this is especially true for the hippocampus [10], a structure of the brain involved in the formation of explicit memories [11]. Although most studies have found reduced cognitive performance after irradiation, there are also conflicting reports, including one where 4-Gy whole-body X-ray irradiation of young mice resulted in an impaired extinction of memories acquired 2 weeks earlier [12] and another one where 0.25-Gy whole-body 28 Si irradiation enhanced long-term potentiation (LTP) and contextual fear conditioning [13]. The first of these studies is compatible with the recent study by Akers et al [14], demonstrating that hippocampal neurogenesis positively regulates forgetting.…”

Enhanced cued fear memory following post-training whole body irradiation of 3-month-old mice

“…Half of the mice (randomly sorted into two groups until any differences in baseline measurements were non-significant) were placed in a new mouse cage fitting in the irradiator and received whole body irradiation at a dose of 4 Gy (dose rate: 1.25 Gy/min). This dose was selected as that was the dose we used previously to assess post-training irradiation effects on cognitive performance in one-month-old mice [10]. This dose could be relevant in the context of radiation therapy in cancer patients, nuclear contamination from power plants, military conflicts, and bioterrorism.…”

“…Therefore, it would be important to assess whether memory alterations due to radiation exposure could be retrograde. Previously, we showed enhanced contextual and cued fear memory prior to and during extinction following post-training irradiation of one-month-old male mice [10]. Due to the established age-sensitivity of radiation effects in mice with increased sensitivity in younger mice, the prior observed enhanced contextual and cued fear memory prior to and during extinction following post-training irradiation following post-training irradiation of one-month-old male mice could be age-dependent.…”