Heterogeneity of Age-Related Neural Hyperactivity along the CA3 Transverse Axis
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Abstract:
Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from young and aged, male, Long–Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite, decreasing trend, in that CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared with young (Y) rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus (DG), the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote abnormal, bistable representations under certain conditions. SIGNIFICANCE STATEMENT Prior work suggested that age-related CA3 hyperactivity enhances pattern completion, resulting in rigid representations. Implicit in prior studies is the notion that hyperactivity is present throughout a functionally homogeneous CA3 network. However, more recent work has demonstrated functional heterogeneity along the CA3 transverse axis, in that proximal CA3 is involved in pattern separation and distal CA3 is involved in pattern completion. Here, we show that age-related hyperactivity is present only in proximal CA3, with potential hypoactivity in distal CA3. This result provides new insight in the role of CA3 in age-related memory impairments, suggesting that the rigid representations in aging result primarily from dysfunction of computational circuits involving the dentate gyrus (DG) and proximal CA3.Keywords:
Entorhinal cortex
Background: MRI measures of the entorhinal cortex and the hippocampus have been used to predict which nondemented individuals with memory problems will progress to meet criteria for AD on follow-up, but their relative accuracy remains controversial. Objectives: To compare MRI measures of the entorhinal cortex and the hippocampus for predicting who will develop AD. Methods: MRI volumes of the entorhinal cortex and the hippocampus were obtained in 137 individuals comprising four groups: 1) individuals with normal cognition both at baseline and after 3 years of follow-up (n = 28), 2) subjects with memory difficulty but not dementia both at baseline and after 3 years of follow-up (n = 73), 3) subjects with memory difficulty at baseline who were diagnosed with probable AD within 3 years of follow-up (n = 21), and 4) patients with mild AD at baseline (n = 16). Results: Measures of both the entorhinal cortex and the hippocampus were different for each of the pairwise comparisons between the groups (p < 0.001) and were correlated with tests of memory (p < 0.01). However, the volume of the entorhinal cortex differentiated the subjects from those destined to develop dementia with considerable accuracy (84%), whereas the measure of the hippocampus did not. Conclusion: These findings are consistent with neuropathologic data showing substantial involvement of the entorhinal cortex in the preclinical phase of AD and suggest that, as the disease spreads, atrophic change develops within the hippocampus, which is measurable on MRI.
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Objective To investigate the role of neuro-specific DNA repair gene Nbn in mouse hippocampus development by observing the morphological differences in Nbn-CNS-Del and Nbn-CNS-Ctr mice.Methods Serial sections and stereology were used to quantitatively analyze the development of mouse hippocampus on postnatal day 7,14 and 21.Results Compared with that of the control group,the hippocampus development of Nbn-CNS-Del mice lagged behind.In Nbn-CNS-Del mice,on day 21,the profile area of pyramidal layer of hippocampus and granular layer of dentate gyrus decreased(P0.05),and the volume densities in granular layer and polymorphic layer of dentate gyrus,and CA4 had significant differences(P0.05).Conclusion DNA repair gene Nbn,an important gene in mouse hippocampus development,affects the development and maturation of hippocampus and granular layer of DG in mice.
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Stereotactic lesioning of the rat entorhinal cortex leads to an induction of β-amyloid precursor protein (APP) immunoreactivity in non-neuronal cells of the deafferented dentate gyrus. Double immunofluorescence against APP and the microglia-binding isolectin B4 fromGriffonia simplicifoliarevealed that APP immunoreactivity was confined to activated microglia. The microglial APP expression became detectable 3 days after lesioning, reached its peak after 7 days and disappeared after 10 days. The early accumulation of APP in microglia supports the view that microglia play an important role in the initial stages of amyloid plaque formation. Such a glial APP accumulation occurs rapidly in distant but anatomically connected areas. This is in line with the preferential localization of amyloid plaques in the dentate gyrus, which is the projection field of the degenerating neurones of the entorhinal cortex in patients with developing dementia.
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Why distinct neurodegenerative disorders affect specific neuronal populations is largely unknown. Granule cells of the dentate gyrus are particularly vulnerable to Aβ-induced molecular and functional impairments. Aβ may exert these effects within granule cells, in their immediate extracellular milieu after being released from granule cells or synaptic contacts, or by affecting neurons in distant regions that provide afferent input to granule cells. To identify where Aβ first acts within the entorhinal-hippocampal network to ultimately elicit molecular and behavioral deficits. We engineered lentiviral vectors to express either green fluorescent protein (lenti-GFP) or human amyloid precursor protein (lenti-hAPP) carrying Swedish and London mutations under control of the human ubiquitin C promoter. Wildtype mice received injections of lenti-hAPP into one dentate gyrus (or entorhinal cortex) and of lenti-GFP into the opposite dentate gyrus (or entorhinal cortex) at 2–3 months of age. The distribution and cellular localization of lentivirus-mediated expression of hAPP was analyzed 2 and 6 weeks later by immunohistochemistry, and compared with hAPP transgenic mice from line J20. Six weeks after a single viral injection, hAPP was specifically expressed within the dentate gyrus at high levels throughout the rostral-caudal extent of the hippocampus. Granule neurons represented the clear majority of immunolabeled cells, with little to no labeling of pyramidal neurons in CA regions. Within granule neurons, hAPP was expressed in a punctate pattern that was practically indistinguishable between lentivirus-infected cells and uninfected granule cells from hAPP transgenic mice. In the entorhinal cortex, lentivirus-mediated expression of hAPP was also localized primarily to neurons. Deposition of Aβ into plaques was not detected at these early time points. Ongoing experiments are analyzing the effects of this region-specific neuronal expression of hAPP on molecular alterations previously correlated with behavioral deficits in hAPP transgenic mice. Lentivirus-mediated expression of hAPP/Aβ may be an effective tool with which to probe the source of selective vulnerability within the entorhinal-hippocampal network. Understanding where APP/Aβ first triggers network dysfunction may enable the design of new strategies to better protect the most vulnerable brain regions in AD patients. Supported by NIA grant AG022074.
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Objective
To explore the effect of lentiviral delivery green fluorescent protein in different brain regions on the transfection of dentate gyrus neurons.
Methods
Lenti-pSyn-EGFP was stereotaxic injected into dentate gyrus (DG), Cornu Ammonis 1 (CA1) of hippocampus and medial entorhinal cortex (EC) of rats. All animals were perfused with 4% paraformaldehyde. Their brains were cut into 30 μm sections which were performed with Nissl fluorescent staining.
Results
The resuts showed that the GFP positive cells in DG area of DG, CA1, EC, DG-EC groups were (18.0±1.0), (17.0±0.6), (17.3±0.6), (18.3±0.6) respectively, and there was no statistical difference among each group(P>0.05).
Conclusion
Lentivirus delivery in EC and CA1 both can transfect DG neurons. This is a useful method to transfect dentate gyrus neurons instead of injecting lentivirus into DG directly and avoid the lesion of DG.
Key words:
Lentivirus; Dentate gyrus; Hippocampus; Medial entorhinal cortex
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By using three-dimensional computer reconstruction techniques and the production of two-dimensional unfolded maps, we analyzed the topographic organization of projections from the entorhinal cortex of the rat to the dentate gyrus. The retrograde tracers, Fast blue and Diamidino yellow, were injected at all septotemporal levels of the dentate gyrus, and the distribution of retrogradely labeled layer II cells in the entorhinal cortex was plotted by using computer-aided microscopy systems. Discrete injections of fluorescent dyes into the dentate gyrus labeled bands of layer II neurons in the entorhinal cortex that covered approximately 45% of its surface area. Injections confined to the septal half of the dentate gyrus resulted in a band that occupied the most lateral and caudomedial portions of the entorhinal cortex. Although there were subtle changes in the density of labeled cells in this region, essentially the same region of cells was labeled after any injection into the septal half of the dentate gyrus. Injections into mid-septotemporal levels of the dentate gyrus (50–75% of the distance from the septal pole) led to a distinctly different pattern of retrograde labeling. A more medial portion of the lateral entorhinal cortex and a more rostral portion of the medial entorhinal area were labeled in these cases. Another change in entorhinal labeling occurred when the injection involved the most temporal quarter of the dentate gyrus. Injections into this area led to a constrained region of entorhinal labeling that included the most medial portion of the lateral entorhinal area and the most rostral portion of the medial entorhinal area. Although the domains of cells projecting to septal, mid-septotemporal, and temporal levels of the dentate gyrus were not entirely segregated, there was relatively little overlap of the three populations of neurons. These data raise the possibility that different portions of the entorhinal-hippocampal circuit are capable of semiautonomous information processing, at least at the stage of input to the dentate gyrus. J. Comp. Neurol. 398:25–48, 1998. © 1998 Wiley-Liss, Inc.
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Abstract The goal of this study was to answer the question of whether repeated administration of electroconvulsive shock (ECS) seizures causes structural changes in the entorhinal‐dentate projection system, whose neurons are known to be particularly vulnerable to seizure activity. Adult rats were administered six ECS seizures, the first five of which were spaced by 24‐hr intervals, whereas the last two were only 2 hr apart. Stereological approaches were employed to compare the total neuronal and synaptic numbers in sham‐ and ECS‐treated rats. Golgi‐stained material was used to analyze dendritic arborizations of the dentate gyrus granule cells. Treatment with ECS produced loss of neurons in the entorhinal layer III and in the hilus of the dentate gyrus. The number of neurons in the entorhinal layer II, which provides the major source of dentate afferents, and in the granular layer of the dentate gyrus, known to receive entorhinal projections, remained unchanged. Despite this, the number of synapses established between the entorhinal layer II neurons and their targets, dentate granule cells, was reduced in ECS‐treated rats. In addition, administration of ECS seizures produced atrophic changes in the dendritic arbors of dentate granule cells. The total volumes of entorhinal layers II, III, and V–VI were also found to be reduced in ECS‐treated rats. By showing that treatment with ECS leads to partial disconnection of the entorhinal cortex and dentate gyrus, these findings shed new light on cellular processes that may underlie structural and functional brain changes induced by brief, generalized seizures. © 2007 Wiley‐Liss, Inc.
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