BEHAVIORAL NEUROSCIENCE COMMENTARY Chemotherapy modulates specific aspects of cognition parallel to neurogenesis (Commentary on Nokia et al.) P. J. Lucassen Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands Prolonged chemotherapy significantly impacts a range of cognitive functions, including attention, working memory and processing speed. These undesired side-effects are often referred to as ‘chemobrain’, and are a common yet poorly understood occurrence in clinical settings (Padovani et al., 2012). In this issue of EJN, Nokia et al. (2012) set out to address potential neuronal mechanisms underlying the emergence of such symptoms, by focusing not only on adult hippocampal neurogenesis (Monje & Dietrich, 2012), but also on hippocampal oscillatory activity within the theta range and in relation to associative learning. Adult-generated hippocampal neurons have been implicated in various forms of (spatial) learning and memory, including pattern separation. Modulating neurogenesis by various factors (Lucassen et al., 2010) can, for example, impair or promote performance in hippocampal-depen- dent tasks, in particular if these tasks are stringent and compressed in time (Castilla-Ortega et al., 2011; Marín-Burgin & Schinder, 2012). Cancer drugs that cross the blood–brain barrier in patients will also target dividing cells inside the brain. Therefore, changes in neurogenesis have been expected to contribute to at least some of the cognitive deficits occurring after chemotherapy. In an elegant approach, Nokia et al. (2012) tested whether a previously acquired trace-conditioned response that is stored by mature, but not young, neurons would relate to new learning and task acquisition. Similar to clinical protocols, the authors used prolonged and repeated cyclic application of the commonly used chemotherapy drug temozolomide. They combined this treatment with bromodeoxyuridine pulse- labeling to show that long-term chemotherapy reduces newborn cell numbers. Interestingly, in parallel, the hippocampal theta-band responses to the conditioned stimulus during trace eye blink conditioning were dis- rupted, but not those elicited during delay or very long delay conditioning, or during retention of an already acquired trace memory. As syn- chronized oscillatory activity may facilitate communication between related structures during learning, a disruption in theta activity after chemotherapy could prevent interregional communication from occurring, and hence explain deficits in learning. In conclusion, chemotherapy seems to disrupt learning in a very selective manner, sparing forms of learning that appear to rely on mature neurons in the cerebellum, as well as sparing memories stored by mature neurons in the neocortex. Although targeted to affect mainly proliferating cells, temozolomide may also have affected network integrity by detrimentally affecting the mature population of neurons and/or glia cells. Moreover, future studies should investigate how systemic administration of the drug can induce such selective theta-band responses in the hippocampus. Yet, as granule cells in the dentate gyrus are ‘gatekeepers’ of the signals entering the hippocampal tri-synaptic circuit, even small disruptions in dentate structure may already lead to functional deficits. These results from Nokia et al. (2012) are promising as they indicate that certain cognitive deficits after chemotherapy might not be irre- versible. Indeed, long-lasting reductions in neurogenesis are generally not permanent (Crews et al., 2004; Lafenetre et al., 2011; Van Bokho- ven et al., 2011; Hu et al., 2012), and even adverse effects of cancer treatment on cognition in animals may be rescued by stimulation of neurogenesis through exercise (Naylor et al., 2008; Hamani et al., 2011; Fardell et al., 2012). From a neurogenesis/cognition perspective, these data open up a new avenue of exploration; furthermore, the question of how adult neuro- genesis might regulate oscillatory activity is important for a better understanding of cognitive/mnemonic processing. As such, the paper by Nokia et al. (2012) represents an important and timely addition to the field. References Castilla-Ortega, E., Pedraza, C., Estivill-Torrús, G. & Santín, L.J. (2011) When is adult hippocampal neurogenesis necessary for learning? Evidence from animal research. Rev. Neurosci., 22, 267–283. Crews, F.T., Nixon, K. & Wilkie, M.E. (2004) Exercise reverses ethanol inhibition of neural stem cell proliferation. Alcohol, 33, 63–71. Fardell, J.E., Vardy, J., Shah, J.D. & Johnston, I.N. (2012) Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity. Psychopharmacology, 220, 183–193. Hamani, C., Stone, S.S., Garten, A., Lozano, A.M. & Winocur, G. (2011) Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone. Exp. Neurol., 232, 100–104. Hu, P., Oomen, C., van Dam, A.M., Wester, J., Zhou, J.N., Joëls, M. & Lucassen, P.J. (2012) A single-day treatment with mifepristone is sufficient to normal- ize chronic glucocorticoid induced suppression of hippocampal cell proliferation. PLoS One, 7, e46224. Lafenetre, P., Leske, O., Wahle, P. & Heumann, R. (2011) The beneficial effects of physical activity on impaired adult neurogenesis and cognitive performance. Front. Neurosci., 5, 51. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, Vol. 36, pp. 3519–3520, 2012 doi:10.1111/ejn.12056 European Journal of Neuroscience