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The mechanisms governing how the hippocampus selects neurons to exhibit place fields are not well understood. A default assumption in some previous studies was the uniform random draw with replacement (URDWR) model, which, theoretically, maximizes spatial "pattern separation", and predicts a Poisson distribution of the numbers of place fields expressed by a given cell per unit area. The actual distribution of mean firing rates exhibited by a population of hippocampal neurons, however, is approximately exponential or log-normal in a given environment and these rates are somewhat correlated across multiple places, at least under some conditions. The advantage of neural activity-dependent immediate-early gene (IEG) analysis, as a proxy for electrophysiological recording, is the ability to obtain much larger samples of cells, even those whose activity is so sparse that they are overlooked in recording studies. Thus, a more accurate representation of the activation statistics can potentially be achieved. Some previous IEG studies that examined behavior-driven IEG expression in CA1 appear to support URDWR. There was, however, in some of the same studies, an under-recruitment of dentate gyrus granule cells, indicating a highly skewed excitability distribution, which is inconsistent with URDWR. Although it was suggested that this skewness might be related to increased excitability of recently generated granule cells, we show here that CA1, CA3, and subiculum also exhibit cumulative under-recruitment of neurons. Thus, a highly skewed excitability distribution is a general principle common to all major hippocampal subfields. Finally, a more detailed analysis of the frequency distributions of IEG intranuclear transcription foci suggests that a large fraction of hippocampal neurons is virtually silent, even during sleep. Whether the skewing of the excitability distribution is cell-intrinsic or a network phenomenon, and the degree to which this excitability is fixed or possibly time-varying are open questions for future studies. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The time when an event occurs can become part of autobiographical memories. In brain structures that support such memories, a neural code should exist that represents when or how long ago events occurred. Here we describe a neuronal coding mechanism in hippocampus that can be used to represent the recency of an experience over intervals of hours to days. When the same event is repeated after such time periods, the activity patterns of hippocampal CA1 cell populations progressively differ with increasing temporal distances. Coding for space and context is nonetheless preserved. Compared with CA1, the firing patterns of hippocampal CA3 cell populations are highly reproducible, irrespective of the time interval, and thus provide a stable memory code over time. Therefore, the neuronal activity patterns in CA1 but not CA3 include a code that can be used to distinguish between time intervals on an extended scale, consistent with behavioral studies showing that the CA1 area is selectively required for temporal coding over such periods.

The hippocampus maintains the remarkable ability to generate new neurons throughout the lifespan. Progenitor cells in the subgranular zone give rise mainly to granule cells that migrate to the granule cell layer and become mature, functionally integrated neurons. Numerous factors are capable of regulating the proliferation and survival of new neurons in the adult hippocampus. Corticosterone is one of the most potent factors. Stress results in a significant decrease in the number of dividing cells and exogenous corticosterone administration produces a similar result. Conversely, removal of circulating glucocorticoids via adrenalectomy has been shown to dramatically increase cell proliferation. However, no studies have examined the long-term effects of adrenalectomy on cell proliferation in the hippocampus. In addition to increasing cell proliferation in the hippocampus, chronic adrenalectomy induces ongoing cell death in the dentate gyrus. In order to determine the time course of cell proliferation and cell death in the dentate gyrus following corticosterone removal we examined the dentate gyrus of rats at several time points following adrenalectomy. We analyzed the number of proliferating cells based on Ki67 labeling and visualized cell death using Fluoro-Jade B. Here we show that although cell proliferation is initially enhanced by adrenalectomy, but the increase is transient; it is no longer apparent by 4 weeks after adrenalectomy. Furthermore, we demonstrate that cell death is pronounced by 3 days after adrenalectomy and continues for at least 23 weeks., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Chronic adrenalectomy (ADX) causes a gradual and selective loss of granule cells in the dentate gyrus (DG) of the rat. Here, we administered replacement corticosterone to rats beginning 10 wk after ADX. We then tested them in three discrimination tasks based on object novelty, location, or object/context association. Only during testing of the object/context association did ADX rats demonstrate deficits. These findings add to a body of evidence that the hippocampus is necessary when contextual information is important. We also confirm that memory deficits after chronic adrenalectomy are not a result of loss of corticosterone per se.

Immunofluorescence is the basis for many techniques used to quantify phenomena in neuroscience research, in both normal and pathological tissue. Autofluorescence (non-specific, broad spectrum background fluorescence) is an unfortunate consequence of damage to brain tissue. Damage-induced autofluorescence potentially confounds analyses of tissue labeled with fluorescent markers in many experiments. This is especially problematic in protocols that utilize co-localization methods such as BrdU/NeuN in which autofluorescence might lead to overestimates of the number of double-labeled cells. Techniques to reduce autofluorescence are variable and relatively ineffective in damaged brain tissue. Here we show using confocal microscopy that damage-induced autofluorescence does not co-localize with the nuclear specific markers DAPI or Hoechst. Further co-localization of nuclear markers such as Ki67 or BrdU/NeuN with DAPI or Hoechst should serve to help discriminate between intended and spurious fluorescent signal.

The dentate gyrus continues to produce new neurons in adult rodents. The possibility of differential regulation of neurogenesis within regions of the dentate gyrus is largely unexplored, despite several other aspects of this phenomenon being well characterized in a large number of studies. In this report, we describe an area located at the anterior pole of the dentate gyrus that consistently lacks neurogenesis. This neurogenically quiescent zone invariably lacks expression of the neuroblast marker doublecortin (DCX), bromodeoxyuridine and Ki-67, though DCX expression can be elicited in response to a combined paradigm of environmental enrichment and wheel running. We propose that this region may provide a valuable model system to discern the factors that regulate the process of neurogenesis.

Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampus-dependent cognition.