Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment.

Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE), are activated by novelty and changes in environmental contingencies. Based on the role of monoamines in reconfiguring invertebrate networks, and data from mammalian systems, a network reset hypothesis for the effects of LC activation has been proposed. We used the cellular compartmental analysis of temporal FISH technique based on the cellular distribution of immediate early genes to examine the effect of LC activation and inactivation, on regional hippocampal maps in male rats, when LC activity was manipulated just before placement in a second familiar (A/A) and/or novel environment (A/B). We found that bilateral phasic, but not tonic, activation of LC reset hippocampal maps in the A/A condition, whereas silencing the LC with clonidine before placement in the A/B condition blocked map reset and a familiar map emerged in the dentate gyrus, proximal and distal CA1, and CA3c. However, CA3a and CA3b encoded the novel environment. These results support a role for phasic LC responses in generating novel hippocampal sequences during memory encoding and, potentially, memory updating. The silencing experiments suggest that novel environments may not be recognized as different by dentate gyrus and CA1 without LC input. The functional distinction between phasic and tonic LC activity argues that these parameters are critical for determining network changes. These data are consistent with the hippocampus activating internal network representations to encode novel experiential episodes and suggest LC input is critical for this role.SIGNIFICANCE STATEMENT Burst activation of the broadly projecting novelty signaling system of the locus coeruleus initiates new network representations throughout the hippocampus despite unchanged external environments. Tonic activation does not alter network representations in the same condition. This suggests differences in the temporal parameters of neuromodulator network activation are critical for neuromodulator function. Silencing this novelty signaling system prevented the appearance of new network representations in a novel environment. Instead, familiar representations were expressed in a subset of hippocampal areas, with another subset encoding the novel environment. This "being in two places at once" argues for independent functional regions within the hippocampus. These experiments strengthen the view that internal states are major determinants of the brain's construction of environmental representations.

Dissociation of spatial representations within hippocampal region CA3.

Classic models of the hippocampus uniformly ascribe pattern completion to CA3, but recent data suggest CA3c (enclosed by the dentate gyrus) may act in a manner more consistent with the dentate and aid in pattern separation. The ideal test for functional distinction within CA3, however, is to compare the responses in these regions in the same animal in multiple contexts. To accomplish this, animals visited two contexts with varying degrees of similarity and the pattern of repeated Arc expression was examined across the pyramidal cell layer. Under conditions of partial cue change, responses in CA3c are far more distinct than CA3a/b, consistent with evidence for functional diversity along the transverse axis of CA3. These data add to the mounting evidence that "classic" roles ascribed to CA3 in learning and memory require re-evaluation.

Hippocampal spatial mapping and the acquisition of competing responses.

Response reversal learning is facilitated in many species, including humans, when competing responses occur in separate contexts. This suggests hippocampal maps may facilitate the acquisition of competing responses and is consistent with the hypothesis that contextual encoding permits rapid acquisition of new behaviors in similar environments. To test this hypothesis, the pattern of Arc expression was examined after rats completed a series of left/right response reversals in a T-maze. This reversal training occurred in the same room, two different rooms, or within a single room but with the maze enclosed in wall-length curtains of different configurations (i.e., black/white square or circle). Across CA1 and CA3, successive T-maze exposures in the same room recruited the same cells to repeatedly transcribe Arc, while a unique population of cells transcribed Arc in response to each of two different rooms as well as to the two unique curtain configurations in the same room. The interference from original learning that was evident on the first reversal in animals without a context switch was absent in groups that experienced changes in room or curtain configuration. However, only the use of unique rooms, and not changes in the curtained enclosure, facilitated learning across response reversals relative to the groups exposed to only one room. Thus, separate hippocampal maps appear to provide protection from the original learning interference but do not support improved reversals over trials. The present data suggest changes in heading direction input, rather than remapping, are the source of facilitation of reversal learning.

Location is everything: neurons born during fluoxetine treatment accumulate in regions that do not support spatial learning.

It is well known that antidepressants both improve mood and increase the rate at which the dentate gyrus (DG) generates new neurons. In addition to the implications of neurogenesis for mood regulation, the production and survival of granule cells has also been implicated in learning and memory. Despite this evidence, the results of studies on the effect of antidepressants on memory have been mixed. A critical piece of data that may be missing from previous studies, however, is insight into (a) the location that newborn neurons migrate to following fluoxetine administration and (b) their ability to express normal patterns of activity-related genes. Here we demonstrate a finding that may resolve the discrepancy in the effects fluoxetine-induced neurogenesis on mood and memory: after 5 weeks delay, the net additional neurons generated in animals given the antidepressant fluoxetine during treatment are functionally normal, but preferentially accumulate (due to changes in migration and/or survival) in an area of the DG that is not recruited by spatial memory tasks.