Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat

doi:10.1016/S0306-4522(03)00199-4

Neuroscience

Volume 119, Issue 3, 4 July 2003, Pages 635-642

https://doi.org/10.1016/S0306-4522(03)00199-4 Get rights and content

Abstract

The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.

Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.

Section snippets

Animals and treatment

Adult (approximately 2 month of age) male Wistar rats (M&B breeding center, Ll. Skensved, Denmark), weighing from 260 to 290 g at the beginning of the study were used. They were given free access to ordinary laboratory chow and water. All experimental procedures used in this experiment were in accordance with Danish Animal Experimentation Inspectorate (“Dyreforsøgstilsynet”) regulations. All efforts were made to minimize the number of animals used and their suffering.

Fractionated brain irradiation

Under general anesthesia

Brdu immunoreactivity

In the hippocampi of rats that received BrdU injections and fractionated irradiation on the same days, virtually no BrdU-positive cells were present and this number was significantly lower than that observed in sham-treated controls (t₁₀=−5.029, P=0,001). Also in the groups of animals that received injections of BrdU on days 11–14 and days 32–35 after irradiation, the number of BrdU-labeled cells was significantly lower than in the respective control groups (t₁₂=−3.473, P=0,005 and t₁₁=−6.826, P

Discussion

Here, we show that adult neurogenesis can be completely arrested by fractionated brain irradiation, but resumes somewhat within the following weeks. This halt in neurogenesis is associated with a deficit in a hippocampus-dependent test of spatial short-term memory.

The number of neurons generated daily in the dentate gyrus of the adult rat hippocampus has been disputed, but has been estimated to be up to 9000 under normal circumstances (Cameron and McKay, 2001). However large, the number is

Acknowledgements

Birgit H. Hansen is thanked for expert technical assistance. Supported by The Ivan Nielsen foundation, the Theodore and Vada Stanley foundation, and a stipend from the NeuroScience PharmaBiotec Center (The Danish Medical Research Council) to G.W.

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Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat

Abstract

Section snippets

Animals and treatment

Fractionated brain irradiation

Brdu immunoreactivity

Discussion

Acknowledgements

Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

J Comp Neurol

Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remissionProphylactic Cranial Irradiation Overview Collaborative Group

N Engl J Med

Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees

Proc Natl Acad Sci USA

Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus

J Comp Neurol

Spatial but not object recognition is impaired by aging in rats

Physiol Behav

Hippocampal lesions and activity

Psychon Sci

Neuronal plasticity and survival in mood disorders

Biol Psychiatry

A new one-trial test for neurobiological studies of memory in ratsI. Behavioral data

Behav Brain Res

Neurogenesis in the adult human hippocampus

Nat Med

Multipotent progenitor cells in the adult dentate gyrus

J Neurobiol

Learning enhances adult neurogenesis in the hippocampal formation

Nat Neurosci

New neurons in old brainslearning to survive?

Nat Neurosci

Rapid extension of axons into the CA3 region by adult-generated granule cells

J Comp Neurol

Adult brain neurogenesis and psychiatrya novel theory of depression

Mol Psychiatry

Effects of adrenal medulla grafts on memory capacities of rats after hippocampal lesions

Neuroscience

Genetic influence on neurogenesis in the dentate gyrus of adult mice

Proc Natl Acad Sci USA

Activity-dependent regulation of neuronal plasticity and self repair

Prog Brain Res

The stressed hippocampus, synaptic plasticity and lost memories

Nat Rev Neurosci

Prophylactic cranial irradiation in small cell lung canceran update

Lung Cancer

Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus

Proc Natl Acad Sci USA