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.

Keywords: Cingulate; Entorhinal; Hippocampus; Parahippocampal; Perirhinal; Retrosplenial.

Fig. 1

Schematic representation of the novel environment, in which monkeys spent 15 minutes in order to trigger the activation of brain regions involved in spatial learning. The cage was 4.27 m long, 1.52 wide and 2.13 m high. The front and back panels were made of solid stainless steel panels, whereas the two sides and the ceiling were made of stainless steel wire mesh. Three 25 cm deep perches (in grey) made of PVC plastic bars were placed at different heights (0.91 m, 1.22 m, 1.52 m) against the back stainless steel panel. Attached to the left side wire mesh wall was a wire mesh chute with a remote controlled door, through which monkeys entered and exited the cage when prompted by the experimenter. The black lines represent stainless steel bars forming the structural frame of the room. They also served to delimitate the virtual zones used to score the monkeys’ locomotor activity while exploring the environment (see main text for details).

Fig. 2

Photomicrograph of c-fos positive cells, as they could be observed during the quantitative analyses, using a 20 X objective (N.A. 0.5) on a Nikon Eclipse 80i microscope (Nikon Instruments, Melville, NY, USA) linked to PC-based StereoInvestigator 11.0 (MBF Bioscience, Williston, VT, USA). Scale bar: 25 μm.

Fig. 3

Volumes of the different regions of the hippocampal formation (a) and cortical areas (b) analyzed in the current study. Control monkeys in black; Hippocampal-lesioned monkeys in white. Average ± SD; *: P < 0.05; **: P < 0.01; ***: P < 0.001.

Fig. 4

Number of c-fos positive cells: entorhinal cortex (a), perirhinal cortex (b), parahippocampal cortex (c), posterior cingulate cortex (e), and retrosplenial cortex (f). Panel (d): density of c-fos positive cells in the parahippocampal cortex (across regions and layers). ControlExplo (C_E), LesionExplo (L_E) and LesionCage (L_C) monkeys. Stacked bars represent the number of c-fos positive cells in the six cortical layers (light green: layer I; green: layer II; dark green: layer III; gray: layer IV (not present in entorhinal cortex); light red: layer V; dark red: layer VI). Average ± SD; *: P < 0.05; **: P < 0.01; ***: P < 0.001; in black: all layers; in green: superficial layers (I, II, III); in red: deep layers (V, VI).

Fig. 5

Two-dimensional unfolded map representations of the number of c-fos positive cells in the entorhinal cortex (areas Eo, Er, El, Ei, Ecaudal), perirhinal cortex (areas 35, 36d, 36r, 36c) and parahippocampal cortex (TH, TF). a: Unfolded map showing the different subdivisions considered in the study. b–d. ControlExplo monkeys. e–h: LesionExplo monkeys. i–k: LesionCage monkeys.

Fig. 6

Two-dimensional unfolded map representations of the number of c-fos positive cells in the posterior cingulate cortex (area 23) and retrosplenial cortex (areas 29, 30). a: Unfolded map showing the different subdivisions considered in the study. b–d. ControlExplo monkeys. e–h: LesionExplo monkeys. i–k: LesionCage monkeys.