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INTRODUCTION The entorhinal cortex (ERC) and perforant path (PP) fibers are critical structures in the pathology of Alzheimer's disease (AD). This study aims to explore these regions using high‐field magnetic resonance imaging (MRI), with the goal of identifying reliable biomarkers based on histopathological observations. METHODS Twenty post mortem brain specimens were scanned with 11.7T MRI, including diffusion tensor imaging and tractography, and were cut for subsequent histological examinations. The entorhinal cortical thickness and number of PP fibers derived from MRI were compared across neuropathological and premortem clinical diagnoses of AD. RESULTS The entorhinal cortical thickness and number of PP fibers decreased along with severities of neurofibrillary tangles in the ERC. Meanwhile, a reduction in the number of PP fibers, but not the entorhinal cortical thickness, was observed during the preclinical stage of AD. CONCLUSIONS Degeneration of PP fibers was observed in early AD and progressed along with neuropathological changes. Highlights Twenty post mortem brain tissues were scanned with 11.7T MRI. Degeneration of PP fibers was observed at 250 µm isotropic resolution. PP fiber indices were linked with severities of NFTs. The number of PP fibers was decreased in preclinical AD.

The selective hyperpolarization-activated cyclic nucleotide-gated（HCN） channel blocker 4-（N-ethyl-N-phenylamino）-1,2-dimethyl-6-（methylamino） pyrimidinium chloride（ZD7288） blocks the induction of long-term potentiation in the perforant path-CA3 region in rat hippocampus in vivo. To explore the mechanisms underlying the action of ZD7288, we recorded excitatory postsynaptic potentials in perforant path-CA3 synapses in male Sprague-Dawley rats. We measured glutamate content in the hippocampus and in cultured hippocampal neurons using high performance liquid chromatography, and determined intracellular Ca2＋ concentration（[Ca2＋]i） using Fura-2. ZD7288 inhibited the induction and maintenance of long-term potentiation, and these effects were mirrored by the nonspecific HCN channel blocker cesium. ZD7288 also decreased glutamate release in hippocampal tissue and in cultured hippocampal neurons. Furthermore, ZD7288 attenuated glutamate-induced rises in [Ca2＋]i in a concentration-dependent manner and reversed 8-Br-c AMP-mediated facilitation of these glutamate-induced [Ca2＋]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both glutamate release and resultant [Ca2＋]i increases in rat hippocampal neurons.

Converging data from rodents and humans have demonstrated an age-related decline in pattern separation abilities (the ability to discriminate among similar experiences). Several studies have proposed the dentate and CA3 subfields of the hippocampus as the potential locus of this change. Specifically, these studies identified rigidity in place cell remapping in similar environments in the CA3. We used high-resolution fMRI to examine activity profiles in the dentate gyrus and CA3 in young and older adults as stimulus similarity was incrementally varied. We report evidence for \"representational rigidity\" in older adults' dentate/CA3 that is linked to behavioral discrimination deficits. Using ultrahigh-resolution diffusion imaging, we quantified both the integrity of the perforant path as well as dentate/CA3 dendritic changes and found that both were correlated with dentate/CA3 functional rigidity. These results highlight structural and functional alterations in the hippocampal network that predict age-related changes in memory function and present potential targets for intervention.

The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer’s disease. Here, we studied whether the lack of APP affects the synaptic properties in the dentate gyrus by measuring granule cell field potentials evoked by perforant path stimulation in anesthetized 9–11-month-old APP-deficient mice in vivo. We found decreased paired-pulse facilitation, indicating altered presynaptic short-term plasticity in the APP-deficient dentate gyrus. In contrast, excitatory synaptic strength and granule cell firing were unchanged in APP knockout mice. Likewise, long-term potentiation (LTP) induced by a theta-burst stimulation protocol was not impaired in the absence of APP. These findings suggest that the deletion of APP may affect presynaptic plasticity of synaptic transmission at the perforant path–granule cell synapse but leaves synaptic efficacy intact and LTP preserved, possibly due to functional redundancy within the APP gene family.

•Mesoscale mapping of connectivity in the human hippocampus.•Visualization of canonical pathway, such as the perforant path.•Mapping of non-canonical pathway along the anterior-posterior axis.•Visualization of intra- and trans-lamellar connectivity.•Detailed description of ROI segmentations. The connectivity of the hippocampus is essential to its functions. To gain a whole system view of intrahippocampal connectivity, ex vivo mesoscale (100 μm isotropic resolution) multi-shell diffusion MRI (11.7T) and tractography were performed on entire post-mortem human right hippocampi. Volumetric measurements indicated that the head region was largest followed by the body and tail regions. A unique anatomical organization in the head region reflected a complex organization of the granule cell layer (GCL) of the dentate gyrus. Tractography revealed the volumetric distribution of the perforant path, including both the tri-synaptic and temporoammonic pathways, as well as other well-established canonical connections, such as Schaffer collaterals. Visualization of the perforant path provided a means to verify the borders between the pro-subiculum and CA1, as well as between CA1/CA2. A specific angularity of different layers of fibers in the alveus was evident across the whole sample and allowed a separation of afferent and efferent connections based on their origin (i.e. entorhinal cortex) or destination (i.e. fimbria) using a cluster analysis of streamlines. Non-canonical translamellar connections running along the anterior-posterior axis were also discerned in the hilus. In line with “dentations” of the GCL, mossy fibers were bunching together in the sagittal plane revealing a unique lamellar organization and connections between these. In the head region, mossy fibers projected to the origin of the fimbria, which was distinct from the body and tail region. Mesoscale tractography provides an unprecedented systems view of intrahippocampal connections that underpin cognitive and emotional processing. [Display omitted]

Background Amyloid beta (A[beta]) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to \"spread\" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied. Methods To genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP). Results It is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, A[beta] production in the perforant path and levels of soluble A[beta] and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the [alpha]-secretase and [beta]-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway. Conclusions Our findings demonstrate that perforant path NgR plays an important role in regulating APP/A[beta] level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression. Keywords: Alzheimer's disease, Nogo receptor, Perforant path, Amyloid precursor protein (APP), Amyloid beta, Rho/ROCK signaling pathway

The Papez circuit has been considered as an important anatomical substrate involved in emotional experience. However, the circuit remains difficult to elucidate in the human brain due to the resolution limit of current neuroimaging modalities. In this article, for the first time, we report the direct visualization of the Papez circuit with 7-Tesla super-resolution magnetic resonance tractography. Two healthy, young male subjects (aged 30 and 35 years) were recruited as volunteers following the guidelines of the institutional review board (IRB). Track density imaging (TDI) generation with track tracing was performed using MRtrix software package. With these tools, we were able to visualize the entire Papez circuit. We believe this is the first study to visualize the complete loop of the Papez circuit, including the perforant path (PP), thalamocortical fibers of the anterior nucleus (AN), and mammillothalamic tract (MTT), which were hitherto difficult to visualize by conventional imaging techniques.

Denervation of neurons is a network consequence of brain injury. The effects of denervation on neurons can be readily studied in vitro using organotypic slice cultures of entorhinal cortex and hippocampus. Following transection of the entorhino-dentate projection, granule cells (GCs) are denervated and show on average a transient loss of spines on their denervated distal dendrites but not on their non-denervated proximal dendrites. In the present study, we addressed the question how single GCs and their denervated and non-denervated segments react to entorhinal denervation. Local adeno-associated virus (AAV)-injections were employed to transduce dentate GCs with tdTomato and entorhinal projection neurons with EGFP. This made it possible to visualize both innervating entorhinal fibers and their target neurons and to identify dendritic segments located in the “entorhinal” and the “hippocampal” zone of the dentate gyrus. Confocal time-lapse imaging was used to image distal and proximal segments of single GCs after entorhinal denervation. Time-matched non-denervated cultures served as controls. In line with previous reports, average dendritic spine loss was ~30% (2–4 days post-lesion) in the denervated zone. However, individual GCs showed considerable variability in their response to denervation in both layers, and both decreases as well as increases in spine density were observed at the single cell level. Based on the standard deviations and the effect sizes observed in this study, a computer simulation yielded recommendations for the minimum number of neurons that should be analyzed in future studies using the entorhinal in vitro denervation model.

The axon initial segment (AIS) is the site of action potential initiation and important for the integration of synaptic input. Length and localization of the AIS are dynamic, modulated by afferent activity and contribute to the homeostatic control of neuronal excitability. Synaptopodin is a plasticity-related protein expressed by the majority of telencephalic neurons. It is required for the formation of cisternal organelles within the AIS and an excellent marker to identify these enigmatic organelles at the light microscopic level. Here we applied 2 h of high frequency stimulation of the medial perforant path in rats in vivo to induce a strong long-term potentiation of dentate gyrus granule cells. Immunolabeling for βIV-spectrin and synaptopodin were performed to study structural changes of the AIS and its cisternal organelles. Three-dimensional analysis of the AIS revealed a shortening of the AIS and a corresponding reduction of the number of synaptopodin clusters. These data demonstrate a rapid structural plasticity of the AIS and its cisternal organelles to strong stimulation, indicating a homeostatic response of the entire AIS compartment.

Background Amyloid beta (Aβ) which is recognized as a main feature of Alzheimer’s disease (AD) has been proposed to “spread” through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied. Methods To genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP). Results It is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway. Conclusions Our findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.