Research reportPossible regeneration of rat medial frontal cortex following neonatal frontal lesions
Introduction
A large literature now shows that when rats are given frontal cortical lesions over the first 7–12 days of life they show substantial recovery of function 11, 13, 14, 20, 22, 23. In fact, under optimal circumstances rats can nearly completely compensate for the loss of midline frontal cortical tissue [20]. This functional recovery is most extensive if the cortex is injured between the postnatal ages of 7 and 12 days and if they do not include extensive amounts of adjoining motor cortex. Under these circumstances the lesion cavity is filled over a 7–14 day period after the injury ([20]; see Fig. 1). Although the disappearance of the cavity might be thought to be due to collapse of adjacent tissue, it is also possible that there is a generation of new neurons to `regrow' the lost region. The production of cortical neurons is largely confined to the prenatal period in the mammalian brain. Nonetheless, the mammalian brain is capable generating neurons postnatally as granule cells in both the olfactory bulb and hippocampus of rodents, and stem cells in the subventricular zone of rodents and primates, are capable of growing well into adulthood 4, 10, 25, 27. In addition, there are a number of reports of limited neural generation after cortical injury in the rat 1, 8. There is, however, no evidence of substantial neuronal regeneration, reconstitution of complex circuitry, or restoration of pyramidal cells, which are the major output neurons of the cerebral cortex, following postnatal cortical injury in mammals. Nor is there any evidence that lesion-induced neurogenesis plays any role in functional recovery after postnatal injury.
The current series of experiments asked (1) about the characteristics of the replacement tissue; (2) can the replacement be blocked; (3) are the cells filling the lesion cavity newly generated neurons and, if so; (4) do the new neurons form connections to other cerebral regions as in normal control rats. We examined the first two questions by measuring the volume of tissue in normal versus frontal-lesioned brains and by blocking regrowth with E13 bromodeoxyuridine (BrdU) injections. To answer the third question we combined immunohistochemical labeling with the mitotic marker BrdU and the neuron antibody NeuN to identify newly generated neurons. To answer the fourth question we combined BrdU labeling and retrograde tracing techniques to identify the connections of newly generated neurons. Finally, since the behavioral viability of the tissue is the ultimate question in our studies, we compared the forelimb reaching performance of rats with and without regenerated tissue.
Section snippets
Subjects
The animals included 136 Long-Evans rats (64 male, 82 female) raised derived from Charles River breeding stock. The rats were given medial frontal lesions on the 10th day of life (P10), or sham operations, and were sacrificed on various postoperative days ranging from day 1 to 20, or in adulthood (day 120 or later).
A subgroup of 37 animals was allowed to survive until maturity (120 days), at which time they were either given injections of a retrograde tracer (n=5) or were tested in a behavioral
Anatomical results
All rats given either P10 frontal lesions or sham procedures survived and were suckling within hours of surgery. Rats given BrdU postlesion lost their fur, however, and completely regrew it over the ensuing days. This fur loss presumably reflects the toxicity of the BrdU and has led us to be cautious in giving repeated doses of BrdU over an extended period of time.
Forelimb reaching
The normal rats rapidly learned to reach for food and were successful in retrieving food about 50% of the time (Fig. 10). When normal animals made failed reaching attempts it was usually because they grasped more than one piece of food, and then dropped them en route back through the cage bars. Rats with medial frontal cortex lesions in adulthood are severely impaired at this task and seldom performed better than about 25% accuracy [12]. As with normal rats, failed reaches sometimes occurred
Discussion
This study shows that removal to the midline frontal region is followed by the cavity filling with new tissue that partially fills in the lesion cavity and contains neurons that connect appropriately with other brain regions. The cavity filling is correlated with functional recovery. Both the cavity filling and functional recovery can be blocked by pretreatment with BrdU on E13. We consider each result separately.
Acknowledgements
This work was supported by grants from the Canadian Neuroscience Network and the NSERC and MRC of Canada to B.K. and I.Q.W. We thank Dr Richard Mullen for kindly providing the NeuN antibodies.
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