Functional organization of the medial temporal lobe memory system following neonatal hippocampal lesion in rhesus monkeys
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.
KeywordsHippocampus Entorhinal Perirhinal Parahippocampal Cingulate Retrosplenial
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).
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.
- Amaral DG, Lavenex P (2007) Hippocampal neuroanatomy. In: Amaral DG, Andersen P, Bliss T, Morris RGM, O’Keefe J (eds) The hippocampus book. Oxford University Press, Oxford, pp 37–114Google Scholar
- Bartsch T, Dohring J, Rohr A, Jansen O, Deuschl G (2011) CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousness. Proc Natl Acad Sci USA 108(42):17562–17567. doi: 10.1073/pnas.1110266108 CrossRefPubMedPubMedCentralGoogle Scholar
- Bohbot VD, Allen JJ, Dagher A, Dumoulin SO, Evans AC, Petrides M, Kalina M, Stepankova K, Nadel L (2015) Role of the parahippocampal cortex in memory for the configuration but not the identity of objects: converging evidence from patients with selective thermal lesions and fMRI. Front Hum Neurosci 9:431. doi: 10.3389/fnhum.2015.00431 CrossRefPubMedPubMedCentralGoogle Scholar
- Howard LR, Javadi AH, Yu Y, Mill RD, Morrison LC, Knight R, Loftus MM, Staskute L, Spiers HJ (2014) The hippocampus and entorhinal cortex encode the path and Euclidean distances to goals during navigation. Curr Biol 24(12):1331–1340. doi: 10.1016/j.cub.2014.05.001 CrossRefPubMedPubMedCentralGoogle Scholar
- Lavenex P, Amaral DG (2000) Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus 10(4):420–430. doi: 10.1002/1098-1063(2000)10:4<420:AID-HIPO8>3.0.CO;2-5 CrossRefPubMedGoogle Scholar
- Morris RGM (2007) Theories of hippocampal function. The hippocampus book. Oxford University Press, Oxford, New York, pp 581–713Google Scholar
- Moscovitch M, Rosenbaum RS, Gilboa A, Addis DR, Westmacott R, Grady C, McAndrews MP, Levine B, Black S, Winocur G, Nadel L (2005) Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory. J Anat 207(1):35–66CrossRefPubMedPubMedCentralGoogle Scholar
- O’Keefe J, Nadel L (1978) The hippocampus as a cognitive map. Clarendon Press, OxfordGoogle Scholar
- Parslow DM, Rose D, Brooks B, Fleminger S, Gray JA, Giampietro V, Brammer MJ, Williams S, Gasston D, Andrew C, Vythelingum GN, Ioannou G, Simmons A, Morris RG (2004) Allocentric spatial memory activation of the hippocampal formation measured with fMRI. Neuropsychology 18(3):450–461CrossRefPubMedGoogle Scholar
- Suzuki WA, Amaral DG (1996) The construction of straight-line unfolded two-dimensional density maps of neuroanatomical projections in the monkey cerebral cortex. Neurosci Protoc 96:7–19Google Scholar