To determine how spatial scale is represented in the pyramidal cell population of the hippocampus, we recorded neural activity at multiple longitudinal levels of this brain area while rats ran back and forth on an 18-meter-long linear track. CA3 cells had well-defined place fields at all levels. The scale of representation increased almost linearly from <1 meter at the dorsal pole to approximately 10 meters at the ventral pole. The results suggest that the place-cell map includes the entire hippocampus and that environments are represented in the hippocampus at a topographically graded but finite continuum of scales.

Place cells in hippocampal area CA1 may receive positional information from the intrahippocampal associative network in area CA3 or directly from the entorhinal cortex. To determine whether direct entorhinal connections support spatial firing and spatial memory, we removed all input from areas CA3 to CA1, thus isolating the CA1 area. Pyramidal cells in the isolated CA1 area developed sharp and stable place fields. Rats with an isolated CA1 area showed normal acquisition of an associative hippocampal-dependent spatial recognition task. Spatial recall was impaired. These results suggest that the hippocampus contains two functionally separable memory circuits: The direct entorhinal-CA1 system is sufficient for recollection-based recognition memory, but recall depends on intact CA3-CA1 connectivity.

ABSTRACT:Grid cells are topographically organized in the sense that, within the dorsal part of the medial entorhinal cortex, the scale of the grid increases systematically with anatomical distance from the dorsal border of this brain area. The ventral limit of the spatial map is currently not known. To determine if the grid map extends into the intermediate and ventral parts of the medial entorhinal cortex, we recorded activity from entorhinal principal cells at multiple dorsoventral levels while rats shuttled back and forth on an 18 m long linear track. The recordings spanned a range of more than 3 mm, covering approximately three quarters of the dorsoventral extent of the medial entorhinal cortex. Distinct periodic firing fields were observed at all recording levels. The average interpeak distance between the fields increased from $50 cm in the most dorsal part to $3 m at the most ventral recording positions. The increase in grid scale was accompanied by a decrease in the frequency of theta modulation and the rate of phase precession. The increase in average spacing and field size was approximately linear but this relationship coincided with a substantial increase in the variability of each measure. Taken together, the observations suggest that the spatial scale of the grid representation increases progressively along most of the dorsoventral axis of the medial entorhinal cortex, mirroring the topographical scale expansion observed in place cells in the hippocampus. V V C 2008 Wiley-Liss, Inc.

Place-specific firing in the hippocampus is determined by path integration-based spatial representations in the grid-cell network of the medial entorhinal cortex. Output from this network is conveyed directly to CA1 of the hippocampus by projections from principal neurons in layer III, but also indirectly by axons from layer II to the dentate gyrus and CA3. The direct pathway is sufficient for spatial firing in CA1, but it is not known whether similar firing can also be supported by the input from CA3. To test this possibility, we made selective lesions in layer III of medial entorhinal cortex by local infusion of the neurotoxin gamma-acetylenic GABA. Firing fields in CA1 became larger and more dispersed after cell loss in layer III, whereas CA3 cells, which receive layer II input, still had sharp firing fields. Thus, the direct projection is necessary for precise spatial firing in the CA1 place cell population.

If information is stored as distributed patterns of synaptic weights in the hippocampal formation, retention should be vulnerable to electrically induced long-term potentiation (LTP) of hippocampal synapses after learning. This prediction was tested by training animals in a spatial water maze task and then delivering bursts of high-frequency (HF) or control stimulation to the perforant path in the angular bundle. High-frequency stimulation induced LTP in the dentate gyrus and probably also at other hippocampal termination sites. Retention in a later probe test was disrupted. When the competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) was administered before the high-frequency stimulation, water maze retention was unimpaired. CPP administration blocked the induction of LTP. Thus, high-frequency stimulation of hippocampal afferents disrupts memory retention only when it induces a change in the spatial pattern of synaptic weights. The NMDA receptor dependency of this retrograde amnesia is consistent with the synaptic plasticity and memory hypothesis.