Exercise ameliorates neurocognitive impairments in a translational model of pediatric radiotherapy

Sahnoune, Iman; Inoue, Taeko; Kesler, Shelli R.; Rodgers, Shaefali P.; Sabek, Omaima; Pedersen, Steen E.; Zawaski, Janice A.; Nelson, Katharine H.; Ris, M. Douglas; Leasure, J. Leigh; Gaber, M. Waleed

doi:10.1093/neuonc/nox197

Cited by 31 publications

(40 citation statements)

References 43 publications

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“…We did not observe any significant changes in FA or RD in the different brain regions following CRT or interactive effects between CRT and sex between the animals. These findings are similar to our results in rats when we did not find significant changes in FA but detected connectome differences due to CRT and exercise ( Sahnoune et al, 2018 ). Similarly, others have also reported difficulty in measuring differences in FA in animal models of CRT ( Wang et al, 2009 ).…”

Section: Discussionsupporting

confidence: 92%

“…Prior to examining long-term damage to the brain, we observed radiation-induced decreases in body lengths at 3 months post-CRT and weights over time. Our group has previously observed this in rats irradiated as juveniles ( Rodgers et al, 2016 ; Sahnoune et al, 2018 ), with a similar consistent lower body weight in irradiated animals in comparison to shams. Further, the present study demonstrated sex differences in body weight with no interaction with CRT: adult male mice consistently weighed more than females.…”

Section: Discussionsupporting

confidence: 82%

“…Mouse brains were DTI scanned using 20 distinct gradient directions on a Bruker BioSpec MRI scanner (Bruker, MA) and tractography information generated. All details of computational processing using ROIEditor, DTI studio ( Jiang et al, 2006 ), template maps from Duke Center for In vivo Microscopy ( Calabrese et al, 2013 ), DiffeoMap ( Zhang et al, 2009 ), AIR algorithm ( Woods et al, 1998 ), and LDDMM ( Ceritoglu et al, 2009 ) were presented previously ( Sahnoune et al, 2018 ). Briefly, the diffusion-weighted maps were used to generate a brain mask using the skull strip function encoded in ROIEditor 1 followed by manual editing of the mask.…”

Section: Methodsmentioning

confidence: 99%

“…The majority of behavioral CRT research employs standard tasks, such as spatial learning in the Morris water maze and novel object recognition, robust tests of learning and memory. Using a pediatric model of CRT, we have recently demonstrated executive function impairment observable at 3 and 12 months post-CRT using the five-choice serial reaction time task ( Sahnoune et al, 2018 ). Numerous other studies on the long-term effects of CRT demonstrate subtle cognitive impairments, such as spatial memory and/or object recognition memory impairments ( Rola et al, 2004 ; Wong-Goodrich et al, 2010 ; Rao et al, 2011 ; Warrington et al, 2012 ) which have been correlated with impaired hippocampal cell proliferation and neurogenesis ( Raber et al, 2004 ; Rola et al, 2004 ; Wong-Goodrich et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

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Olfactory Memory Impairment Differs by Sex in a Rodent Model of Pediatric Radiotherapy

Pérez

Rodgers

Inoue

et al. 2018

Front. Behav. Neurosci.

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Although an effective treatment for pediatric brain tumors, cranial radiation therapy (CRT) damages surrounding healthy tissue, thereby disrupting brain development. Animal models of pediatric CRT have primarily relied on visual tasks to assess cognitive impairment. Moreover, there has been a lack of sex comparisons as most research on the cognitive effects of pediatric CRT does not include females. Therefore, we utilized olfaction, an ethologically relevant sensory modality, to assess cognitive impairment in an animal model of CRT that included both male and female mice. Specifically, we used the novel odor recognition (NOdorR) task with social odors to test recognition memory, a cognitive parameter that has been associated with olfactory neurogenesis, a form of cellular plasticity damaged by CRT. In addition to odor recognition memory, olfactory ability or discrimination of non-social and social odors were assessed both acutely and 3 months after CRT. Magnetic resonance imaging (MRI) and histology were performed after behavioral testing to assess long-term damage by CRT. Long-term but not acute radiation-induced impairment in odor recognition memory was observed, consistent with delayed onset of cognitive impairment in human patients. Males showed greater exploration of social odors than females, but general exploration was not affected by irradiation. However, irradiated males had impaired odor recognition memory in adulthood, compared to non-irradiated males (or simply male controls). Female olfactory recognition memory, in contrast, was dependent on estrus stage. CRT damage was demonstrated by (1) histological evaluation of olfactory neurogenesis, which suggested a reduction in CRT versus control, and (2) imaging analyses which showed that the majority of brain regions were reduced in volume by CRT. Specifically, two regions involved in social odor processing (amygdala and piriform cortex) were damaged by cranial irradiation in males but not females, paralleling olfactory recognition findings.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Olfactory Memory Impairment Differs by Sex in a Rodent Model of Pediatric Radiotherapy

Pérez

Rodgers

Inoue

et al. 2018

Front. Behav. Neurosci.

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“…Brain-derived neurotropic factor plays a key role in supporting neuronal development and function, so this phenomenon may be clinically relevant. A recent report showed preliminary evidence that reduction in neuroinflammation might be one of the effects of voluntary exercise that works toward ameliorating the radiation-induced cognitive decline observed in a rodent model of cranial irradiation [51]. This persistent neuroinflammation may also be in part responsible for shunting remaining viable neuronal precursor cells toward a glial fate [52,53].…”

Section: Particle Therapy Induced Neuroinflammation and Effects On Glmentioning

confidence: 99%

Particle Radiation Induced Neurotoxicity in the Central Nervous System

Grosshans

Duman

Gaber

et al. 2018

International Journal of Particle Therapy

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For patients with primary or metastatic brain tumors, radiation therapy plays a central role in treatment. However, despite its efficacy, cranial radiation is associated with a range of side effects ranging from mild cognitive impairment to overt brain necrosis. Given the negative effects on patient quality of life, radiation-induced neurotoxicities have been the subject of intense study for decades. Photon-based therapy has been and largely remains the standard of care for the treatment of brain tumors. This is particularly true for patients with metastatic tumors who may need treatment to the whole brain or those with very aggressive tumors and a limited life expectancy. Particle therapy is now becoming more widely available for clinical use with the two most common particles used being protons and carbon ions. For patients with favorable prognoses, particularly childhood brain tumors, proton therapy is increasingly used for treatment. This is, in part, driven by the desire to reduce the potential for radiation-induced side effects, including lasting cognitive impairment, which may potentially be achieved by reducing dose to normal tissues using the unique physical properties of particle therapy. There is also interest in using carbon ion therapy for the treatment of aggressive brain tumors, as this form of particle therapy not only spares normal tissues but may also improve tumor control. The biological effects of particle therapy, both proton and carbon, may differ substantially from those of photon radiation. In this review, we briefly describe the unique physical properties of particle therapy that produce differential biological effects. Focusing on the effects of various radiation types on brain parenchyma, we then describe biological effects and potential mechanisms underlying these, comparing to photon studies and highlighting potential clinical implications.

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Adulthood effects of developmental exercise in rats

Perez,

Gehm,

Lobo

et al. 2023

Developmental Psychobiology

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Exercise is known to promote efficient function of stress circuitry. The developing brain is malleable and thus exercise during adolescence could potentially exert lasting beneficial effects on the stress response that would be detectable in adulthood. The current study determined whether adolescent wheel running was associated with reduced stress response in adulthood, 6 weeks after cessation of exercise. Male and female adolescent rats voluntarily ran for 6 weeks and then were sedentary for 6 weeks prior to 10 days of chronic restraint stress in adulthood. Fecal corticosterone levels were measured during stress, and escape from the restraint tube was assessed on the final day as a proxy for depressive‐like behavior. Anxiety‐like behavior was measured 24 h later with the elevated plus maze and locomotor behaviors with the open field. Brain and body measurements were taken immediately following behavioral testing. Developmental exercise and adulthood stress both exerted independent effects on physiological and behavioral outcomes in adulthood. Exercise history increased the odds ratio of escape from restraint stress in males, but did not influence other stress‐induced behaviors. In summary, exercise early in life exerted lasting effects, but did not substantially alter the adulthood response to restraint stress.

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Exercise ameliorates neurocognitive impairments in a translational model of pediatric radiotherapy

Abstract: Our data strongly suggest that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT.

Cited by 31 publications

References 43 publications

Olfactory Memory Impairment Differs by Sex in a Rodent Model of Pediatric Radiotherapy

Olfactory Memory Impairment Differs by Sex in a Rodent Model of Pediatric Radiotherapy

Particle Radiation Induced Neurotoxicity in the Central Nervous System

Adulthood effects of developmental exercise in rats

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