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Functional organization of the medial temporal lobe memory system following neonatal hippocampal lesion in rhesus monkeys

Abstract

Hippocampal damage in adult humans impairs episodic and semantic memory, whereas hippocampal damage early in life impairs episodic memory but leaves semantic learning relatively preserved. We have previously shown a similar behavioral dissociation in nonhuman primates. Hippocampal lesion in adult monkeys prevents allocentric spatial relational learning, whereas spatial learning persists following neonatal lesion. Here, we quantified the number of cells expressing the immediate–early gene c-fos, a marker of neuronal activity, to characterize the functional organization of the medial temporal lobe memory system following neonatal hippocampal lesion. Ninety minutes before brain collection, three control and four adult monkeys with bilateral neonatal hippocampal lesions explored a novel environment to activate brain structures involved in spatial learning. Three other adult monkeys with neonatal hippocampal lesions remained in their housing quarters. In unlesioned monkeys, we found high levels of c-fos expression in the intermediate and caudal regions of the entorhinal cortex, and in the perirhinal, parahippocampal, and retrosplenial cortices. In lesioned monkeys, spatial exploration induced an increase in c-fos expression in the intermediate field of the entorhinal cortex, the perirhinal, parahippocampal, and retrosplenial cortices, but not in the caudal entorhinal cortex. These findings suggest that different regions of the medial temporal lobe memory system may require different types of interaction with the hippocampus in support of memory. The caudal perirhinal cortex, the parahippocampal cortex, and the retrosplenial cortex may contribute to spatial learning in the absence of functional hippocampal circuits, whereas the caudal entorhinal cortex may require hippocampal output to support spatial learning.

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Acknowledgements

This research was supported by grants from the Swiss National Science Foundation (P00A-106701, PP00P3-124536, and 310030_143956), the US National Institutes of Health (NIH; MH041479; and NS16980); and conducted, in part, at the California National Primate Research Center (OD011107).

Significance statement

We characterized the functional organization of the medial temporal lobe memory system following neonatal hippocampal lesions in nonhuman primates. After exploration of a novel environment, c-fos expression, a marker of neuronal activity, was found in the intermediate and caudal regions of the entorhinal cortex, the caudal perirhinal cortex, and the parahippocampal and retrosplenial cortices of control monkeys. In lesioned monkeys, spatial exploration induced increased c-fos expression in the intermediate field of the entorhinal cortex, the caudal perirhinal cortex, and the parahippocampal and retrosplenial cortices. These findings suggest that the caudal perirhinal, parahippocampal, and retrosplenial cortices may contribute to spatial learning in the absence of functional hippocampal circuits, whereas the caudal entorhinal cortex may require hippocampal output to support spatial learning.

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Correspondence to Pierre Lavenex.

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Chareyron, L.J., Banta Lavenex, P., Amaral, D.G. et al. Functional organization of the medial temporal lobe memory system following neonatal hippocampal lesion in rhesus monkeys. Brain Struct Funct 222, 3899–3914 (2017). https://doi.org/10.1007/s00429-017-1441-z

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Keywords

  • Hippocampus
  • Entorhinal
  • Perirhinal
  • Parahippocampal
  • Cingulate
  • Retrosplenial