Increased granule cell neurogenesis in the adult dentate gyrus following mossy fiber stimulation sufficient to induce long-term potentiation

Neurons are continually added at a low rate to the granule cell layer of the dentate gyrus during adulthood in rats. The functional significance of this unusual feature is not completely understood, although recent studies suggest continued granule cell neurogenesis is essential for normal learning and memory. We report here that, in the adult rat, stimulation of the granule cell mossy fibers sufficient to induce long-term potentiation (LTP) increases the number of newly formed granule cells in the dentate gyrus, indicating that granule cell neurogenesis is regulated by efferent activity and, possibly, the induction of LTP.     

Involvement of calmodulin-dependent protein kinase II in carbachol-induced rhythmic activity in the hippocampus of the rat

The role of calcium and protein kinases in rhythmic activity induced by muscarinic receptor activation in the CA1 area in rat hippocampal slices was investigated. Extracellular recording showed that carbachol (20 microM) induced synchronized field potential activity with a dominant frequency of 7.39+/-0.68 Hz. Pretreatment with the membrane permeable Ca(2+) chelator BAPTA-AM (50 microM) or with thapsigargin (1 microM), a compound which depletes intracellular calcium stores, reduced the dominant power of carbachol-induced theta-like activity by 83% and 78%, respectively. Inhibition of calmodulin-dependent protein kinase II (CaMKII) by the cell permeable inhibitor KN-93 (10 microM) reduced the power of carbachol-induced theta-like activity by 80%. In contrast the protein kinase C (PKC) inhibitor calphostin C did not significantly (P>0.05) affect the effect of carbachol. Whole-cell recording indicated that KN-93 also blocked carbachol-induced suppression of slow I(AHP) and strongly inhibited the carbachol-induced plateau potential. Our data suggest that activation of CaMKII by carbachol is crucial for local theta-like activity in the CA1 area of the rat hippocampus in vitro. Furthermore, involvement of CaMKII in carbachol-induced suppression of the slow I(AHP) and the induction of plateau potentials could play a role in the induction of theta-like rhythmic activity by carbachol.     

吗啡对海马结构Bcl—Xs表达的影响

目的 研究吗啡对小白鼠海马结构Bcl—Xs表达厦神经元凋亡的影响。方法 免疫组化ABC法和图像分析与统计。结果 对照组小白鼠的海马结构有Bcl—Xs弱阳性表迭。注射吗啡10d后，小白鼠的海马结构有Bcl—Xs强阳性表迭：注射吗啡20d后。海马结构有Bcl—Xs极强的阳性表迭，并可见神经元凋亡；注射吗啡30d后，海马结构内神经元的凋亡加速，并有大量的空泡形成，Bcl—Xs的表迭减弱。结论 吗啡能促进Bel—Xs表迭，诱导神经元凋亡。     

Neuronal loss and neurofibrillary degeneration in the hippocampal cortex in late-onset sporadic Alzheimer's disease

To explore more fully the relationship between neuronal death and neurofibrillary degeneration, unaffected neurons, intracellular neurofibrillary tangles (i-NFT) and extracellular NFT (e-NFT) in 22 patients with late-onset sporadic Alzheimer's disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas hematoxylin-eosin stain. The subdivisions examined included CA4, CA3, CA2, CA1 (CA: cornu ammonis), prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). The unaffected neuron density was significantly lower and both i-NFT and e-NFT densities were significantly higher in subdivisions other than CA4 and CA3 in AD patients compared with those in the aged controls. Unaffected neuron density was significantly, inversely correlated with e-NFT density and with total NFT density in all subdivisions except for PRE in AD patients. Especially in CA2, CA1, PRO and ENT, there were strong correlations between the neuron density and these NFT densities. Both unaffected neuron and e-NFT densities in CA1 and ENT were significantly correlated with the disease duration. The i/e-NFT ratio, an index of the degree and/or rate of progress of neuronal death via neurofibrillary degeneration, showed the lowest value in ENT in AD patients. The findings suggest that neuronal death via neurofibrillary degeneration starts earliest and/or most rapidly progresses in ENT. Furthermore, the i/e-NFT ratios in both ENT and CA1 were significantly correlated with the disease duration, suggesting that the neuronal death pattern in the two subdivisions parallels disease progression.     

新型胆碱酯酶抑制剂对AD大鼠空间记忆及海马结构胆碱能纤维的影响

目的探讨新型胆碱酯酶抑制剂(NAI)及水迷宫训练对AD大鼠海马结构胆碱能纤维的影响。方法用36只Wistar♂大鼠制作AD动物模型,随机分成3组:NAI组、石杉碱甲组(Hup组)、单纯损伤组(SO组)。水迷宫训练后,采用组织化学方法测定海马结构胆碱能纤维密度。结果①定位航行实验中,NAI组逃避潜伏期较SO组显著缩短(P<0.01)。②空间探索实验中,NAI组跨越各象限平台相应位置次数占总次数百分率较SO组明显增高(P<0.01)。③组化结果显示:NAI组海马结构胆碱能纤维密度较SO组明显增加(P<0.05)。尽管NAI组胆碱能纤维密度高于Hup组,但无统计学意义。结论经NAI治疗及水迷宫行为训练后的AD大鼠,海马结构内胆碱能纤维密度明显增加,提示NAI及水迷宫训练联合作用可促进AD大鼠海马结构胆碱能纤维重建。     

Hippocampal BOLD response during category learning predicts subsequent performance on transfer generalization

To test a prediction of our previous computational model of cortico‐hippocampal interaction (Gluck and Myers [1993, 2001]) for characterizing individual differences in category learning, we studied young healthy subjects using an fMRI‐adapted category‐learning task that has two phases, an initial phase in which associations are learned through trial‐and‐error feedback followed by a generalization phase in which previously learned rules can be applied to novel associations (Myers et al. [2003]). As expected by our model, we found a negative correlation between learning‐related hippocampal responses and accuracy during transfer, demonstrating that hippocampal adaptation during learning is associated with better behavioral scores during transfer generalization. In addition, we found an inverse relationship between Blood Oxygenation Level Dependent (BOLD) activity in the striatum and that in the hippocampal formation and the orbitofrontal cortex during the initial learning phase. Conversely, activity in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal lobes dominated over that of the hippocampal formation during the generalization phase. These findings provide evidence in support of theories of the neural substrates of category learning which argue that the hippocampal region plays a critical role during learning for appropriately encoding and representing newly learned information so that that this learning can be successfully applied and generalized to subsequent novel task demands. Hum Brain Mapp 35:3122–3131, 2014. © 2013 Wiley Periodicals, Inc .     

Overlapping but distinct TDP‐43 and tau pathologic patterns in aged hippocampi

Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP‐43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration. A specific question for this study was whether neurofibrillary tangle (NFT) pathology outside of the Braak NFT staging scheme is characteristic of brains with TDP‐43 pathology but lacking AD, that is those with cerebral age‐related TDP‐43 with sclerosis (CARTS). We also tested whether TDP‐43 pathology is associated with comorbid AD pathology, and whether argyrophilic grains are relatively likely to be present in cases with, vs. without, TDP‐43 pathology. Consistent with prior studies, hippocampal TDP‐43 pathology was associated with advanced AD – Braak NFT stages V/VI. However, argyrophilic grain pathology was not more common in cases with TDP‐43 pathology in this data set. In brains with CARTS (TDP‐43[+]/AD[−] cases), there were more NFTs in dentate granule neurons than were seen in TDP‐43[−]/AD[−] cases. These dentate granule cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. Immunofluorescent experiments in a subsample of cases found that, in both advanced AD and CARTS, approximately 1% of dentate granule neurons were PHF‐1 immunopositive, whereas ∼25% of TDP‐43 positive cells showed colocalized PHF‐1 immunoreactivity. We conclude that NFTs in hippocampal dentate granule neurons are often present in CARTS, and TDP‐43 pathology may be secondary to or occurring in parallel with tauopathy.     

Enhancing the interaction of central nervous system neurons with poly(tetrafluoroethylene-co-hexafluoropropylene) via a novel surface amine-functionalization reaction followed by peptide modification

Poly(tetrafluoroethylene-co-hexafluoropropylene) (FEP) surfaces were modified with cell adhesive peptides, via a novel amination reaction, to enhance the neuron-substrate interaction. Amination of FEP surfaces was achieved by exposing FEP film samples to a UV-activated mercury/ammonia system for either 3 or 24 h, yielding nitrogen compositions of 3.5 and 13.2%, respectively. By labeling the nitrogen functionality with trichlorobenzaldehyde, the surface amine compositions were calculated to be 14 and 4.3% for the 3 and 24 h amination reactions, respectively. Three oligopeptide sequences derived from laminin (GYIGSR, GRGDS, and SIKVAV) were coupled to the aminated FEP (FEP-NH₂) surfaces and found to have almost identical surface concentrations as determined by XPS. Using radiolabeled GYIGSR, three coupling agents were compared and the concentration of peptide per surface area was calculated to be 3 and 6 fmol cm^-2 for surfaces aminated for 3 and 24 h, respectively, regardless of the coupling agent. The interaction of embryonic hippocampal neurons with the modified surfaces was compared to that with the positive poly(L-lysine)/laminin control in terms of number and length of extended neurites. After 1 day incubation, neurite extension on the GYIGSR- and SIKVAV-coupled surfaces was similar to that on the positive control but significantly greater than that on FEP and FEP-NH₂ control surfaces. These peptide-coupled fluoropolymer surfaces enhance the neuron-fluoropolymer interaction, similar to that observed with PLL/laminin.