Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects

Abstract

Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes. Adult male rats (10/group) received a single dose of 0, 11, 14, 17, or 20 Gy irradiation (the 20 Gy group was not used because 50% died). Rats were tested once/week for 5 weeks post-irradiation for activity, coordination, and startle. Cognitive assessment began 6-weeks post-irradiation with novel object recognition (NOR), egocentric learning, allocentric learning, reference memory, and proximal cue learning. Proton exposure had the largest effect on activity and prepulse inhibition of startle 1-week post-irradiation that dissipated each week. 6-weeks post-irradiation, there were no effects on NOR, however proton exposure impaired egocentric (Cincinnati water maze) and allocentric learning and caused reference memory deficits (Morris water maze), but did not affect proximal cue learning or swimming performance. Proton groups also had reduced striatal levels of the dopamine transporter, tyrosine hydroxylase, and the dopamine receptor D1, effects consistent with egocentric learning deficits. This new model will facilitate investigations of different proton dose rates and drugs to ameliorate the cognitive sequelae of proton radiotherapy.

Review of Conventional and High Dose Rate Brain Radiation (FLASH): Neurobehavioural, Neurocognitive and Assessment Issues in Rodent Models

“…There were no significant effects on acoustic or tactile startle or rotorod. Only minor effects were found on prepulse inhibition of acoustic startle 5 weeks postirradiation, with no effects on tactile prepulse inhibition [34].…”

“…The effect was larger in the 11 and 14 Gy groups than in the 17 Gy group, for reasons we do not yet understand but are investigating. Striatal tyrosine hydroxylase protein was reduced in the 14 Gy group and striatal dopamine transporter was reduced in all three proton-exposed groups; there was a dose-dependent reduction in dopamine D1 receptor that was significant only in the 17 Gy group [34].…”

“…Another manifestation of neurotoxicity is through activation of proinflammatory cytokines [47]. As noted above, there are effects of radiation on neurotransmitters, transporters and receptors involving dopamine [34,48,49] and other neurotransmitter systems. In addition to neurochemical changes, proton radiation can induce morphological changes on the cell structure of the hippocampus [50,51].…”

“…In contrast to their studies, our emphasis was on tests assessing cognitive domains. We placed less emphasis on object preference tests for the reasons outlined above and used methods to assess egocentric and allocentric (spatial) navigation, working memory, and conditioned contextual and cued freezing [34]. We included NOR but used a fourobject method rather than the two-object method used in [20].…”

Models for Translational Proton Radiobiology—From Bench to Bedside and Back

“…For example, recent studies have established proton irradiation of mouse brain subvolumes [42,59] to investigate the underlying causes of radiation-induced brain lesions appearing after proton therapy [10,18]. Overall, central nervous system (CNS) toxicity studies in rodent models are of increasing interest and performed from both a behavioral [213][214][215] and histological perspective [59,216,217]. Using clinically relevant settings is crucial in developing protocols that reduce normal tissue complications.…”