Abstract
Patients treated for cancer frequently experience chemobrain, characterized by impaired memory and reduced attention. These deficits often persist after treatment, and no preventive or curative interventions exist. In mice, we assessed the effect of cisplatin chemotherapy on attention using the 5-choice serial reaction time task and on synaptic integrity. We also assessed the capacity of mesenchymal stem cells to normalize the characteristics of chemobrain. Mice were trained in the 5-choice serial reaction time task. After reaching advancement criteria at a 4-second stimulus time, they were treated with cisplatin followed by nasal administration of mesenchymal stem cells. Cisplatin reduced the percentage of correct responses due to an increase in omissions, indicating attention deficits. Mesenchymal stem cell treatment reversed these cisplatin-induced deficits in attention. Cisplatin also induced abnormalities in markers of synaptic integrity in the prefrontal cortex. Specifically, cisplatin decreased expression of the global presynaptic marker synaptophysin and the glutamatergic presynaptic marker vGlut2. Expression of the presynaptic GABAergic marker vGAT increased. Nasal mesenchymal stem cell administration normalized these markers of synaptic integrity. In conclusion, cisplatin induces long-lasting attention deficits that are associated with decreased synaptic integrity in the prefrontal cortex. Nasal administration of mesenchymal stem cells reversed these behavioural and structural deficits.
Highlights
The American Cancer Society estimates that the number of cancer survivors in the United States will increase from more than 15.5 million in 2016 to more than 20 million by 20261
We recently showed that cisplatin treatment of young adult mice (10‒12 weeks old) impairs their performance in behavioural tasks examining short-term memory and spatial orientation, such as the novel object and place recognition task (NOPRT), and spontaneous alternations in the Y-maze[21,22]
To get more insight into the structural abnormalities associated with impaired performance in this behavioural task, we examined the effects of cisplatin and mesenchymal stem cells (MSCs) on synaptic integrity in the prefrontal cortex
Summary
The American Cancer Society estimates that the number of cancer survivors in the United States will increase from more than 15.5 million in 2016 to more than 20 million by 20261. We recently showed that cisplatin treatment of young adult mice (10‒12 weeks old) impairs their performance in behavioural tasks examining short-term memory and spatial orientation, such as the novel object and place recognition task (NOPRT), and spontaneous alternations in the Y-maze[21,22] These cognitive deficits were not associated with reductions in locomotor activity, food intake, total interaction times in the NOPRT, or total number www.nature.com/scientificreports/. The 5-choice serial reaction time task (5CSRTT) has been developed to assess attention deficits in rats and mice[24,25,26,27,28] We used this task in adult mice (7‒8 months old) to examine the effects of cisplatin treatment on these translationally relevant aspects of chemotherapy-induced deficits in cognitive function. To get more insight into the structural abnormalities associated with impaired performance in this behavioural task, we examined the effects of cisplatin and MSCs on synaptic integrity in the prefrontal cortex
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