Neural transplantation and recovery of cognitive function

1995 ◽  
Vol 18 (1) ◽  
pp. 10-35 ◽  
Author(s):  
John D. Sinden ◽  
Helen Hodges ◽  
Jeffrey A. Gray
Keyword(s):  
Cognitive Function ◽  
Cognitive Deficits ◽  
Granule Cells ◽  
Hippocampal Formation ◽  
Fetal Brain ◽  
Pyramidal Cells ◽  
Local Injection ◽  
Projection System ◽  
Ca1 Pyramidal Cells ◽  
Neural Transplants

AbstractCognitive deficits were produced in rats by different methods of damaging the brain: chronic ingestion of alcohol, causing widespread damage to diffuse cholinergic and aminergic projection systems; lesions (by local injection of the excitotoxins, ibotenate, quisqualate, and AMPA) of the nuclei of origin of the forebrain cholinergic projection system (FCPS), which innervates the neocortex and hippocampal formation; transient cerebral ischaemia, producing focal damage especially in the CA1 pyramidal cells of the dorsal hippocampus; and lesions (by local injection of the neurotoxin, colchicine) of the granule cells of the dentate gyrus. Following chronic alcohol or lesions of the FCPS, transplants of cholinergically rich fetal brain tissue into the terminal areas (neocortex and/or hippocampus) restored performance almost to control levels, with a time course consistent with growth of the transplants and integration with host tissue; transplants of cholinergically poor fetal tissue (hippocampus) were without effect, as were transplants of cholinergically rich tissue into the region containing the nuclei of origin of the FCPS. Grafts of primary cells enriched in glia and cultured neuroblastoma cells into the terminal areas of the FCPS were equally effective, suggesting that there are multiple mechanisms by which neural transplants can restore cognitive function following diffuse cholinergic damage. In contrast, after ischaemia- or neurotoxin-induced damage to CA1 or dentate granule cells respectively, cholinergically rich fetal transplants into the damaged hippocampal formation were ineffective in restoring performance. After ischaemic damage, however, performance was restored by suspension grafts of CA1 cells but not by transplants containing CA3 pyramidal cells or granule cells; and after colchicine damage it was restored by solid grafts containing granule but not CA1 pyramidal cells. Furthermore, electrophysiological evidence has demonstrated functional, graft type-specific host-graft functional neuronal connectivity. Thus, restoration of cognitive function by neural transplants is possible after damage to either diffuse (cholinergic) or point-to-point (intrahippocampal) forebrain systems, but the transplant must be appropriate to the damage to be repaired. Because the different types of brain damage studied provide analogues of human alcoholic dementia, Alzheimer's disease, and heart attack, these results are encouraging with regard to the eventual application of neural transplant surgery to the treatment of cognitive deficits in humans.

Acetylcholine Sensitivity of Hippocampal Formation Neurons

1974 ◽  
Vol 52 (5) ◽  
pp. 966-971 ◽  
Author(s):  
B. H. Bland ◽  
G. K. Kostopoulos ◽  
J. W. Phillis
Keyword(s):  
Pyramidal Neurons ◽  
Granule Cells ◽  
Hippocampal Formation ◽  
Pyramidal Cells ◽  
Dentate Granule Cells ◽  
Ca1 Pyramidal Cells ◽  
Ca1 Pyramidal Neurons ◽  
Acetylcholine Sensitivity ◽  
Two Populations ◽  
Number Of Cells

Microiontophoretic application of acetylcholine to neurons in the CA1 pyramidal and dentate granule layers of the rabbit hippocampus revealed differences both in the number of cells excited and the nature of the excitation in the two populations of neurons. A smaller percentage (35.7%) of CA1 pyramidal neurons were found to be excited by acetylcholine, compared with the percentage (92.3%) of dentate granule cells excited. Excitation of CA1 pyramidal cells was slow in onset and antagonized by atropine. Excitation of dentate granule cells was rapid in onset and atropine did not specifically antagonize the action of acetylcholine on these cells.

scholarly journals Dendritic right/left asymmetries in the neurons of the human hippocampal formation: a quantitative Golgi study

2007 ◽  
Vol 65 (4b) ◽  
pp. 1105-1113 ◽  
Author(s):  
Maria José Sá ◽  
Carlos Ruela ◽  
Maria Dulce Madeira
Keyword(s):  
Pyramidal Neurons ◽  
Right Hemisphere ◽  
Granule Cells ◽  
Hippocampal Formation ◽  
Molecular Layer ◽  
Pyramidal Cells ◽  
Volumetric Analysis ◽  
Golgi Study ◽  
Dendritic Trees ◽  
The Right

OBJECTIVE: To search for right/left asymmetries in the dendritic trees of the neuronal populations and in the cell-free layer volumes of the human hipoccampal formation. METHOD: In necropsic material obtained from six male individuals we performed a quantitative Golgi study of the dendritic trees of dentate granules, CA3 and CA1 pyramidal neurons and a volumetric analysis of dentate gyrus molecular layer, strata oriens plus alveus and strata lacunosum-moleculare plus radiatum of CA3 and CA1 fields. RESULTS: We found inter-hemispheric asymmetries in the dendrites trees of all neurons, reaching the significant level in the number of granule cells dendritic segments (higher in the left than in the right hemisphere), dendritic branching density of CA3 pyramidal cells and mean dendritic length of CA1 apical terminal segments (higher in the right than in the opposite side). No volumetric differences were observed. CONCLUSION: This study points to different anatomical patterns of connectivity in the hippocampal formations of both hemispheres which may underlie functional asymmetries.

scholarly journals Conditionally Immortalized, Multipotential and Multifunctional Neural Stem Cell Lines as an Approach to Clinical Transplantation

2000 ◽  
Vol 9 (2) ◽  
pp. 153-168 ◽  
Author(s):  
J. A. Gray ◽  
G. Grigoryan ◽  
D. Virley ◽  
S. Patel ◽  
J. D. Sinden ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cell Suspension ◽  
Brain Damage ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Recovery Of Function ◽  
Fetal Brain ◽  
Nucleus Basalis ◽  
Ethanol Administration ◽  
Projection System

Experiments are described using rats with two kinds of brain damage and consequent cognitive deficit (in the Morris water maze, three-door runway, and radial maze): 1) ischemic damage to the CA1 hippocampal cell field after four-vessel occlusion (4VO), and 2) damage to the forebrain cholinergic projection system by local injection of excitotoxins to the nuclei of origin or prolonged ethanol administration. Cell suspension grafts derived from primary fetal brain tissue display a stringent requirement for homotypical cell replacement in the 4VO model: cells from the embryonic day (E)18–19 CA1 hippocampal subfield, but not from CA3 or dentate gyrus or from E16 basal forebrain (cholinergic rich) led to recovery of cognitive function. After damage to the cholinergic system, conversely, recovery of function was seen with cell suspension grafts from E16 basal forebrain or cholinergic-rich E14 ventral mesencephalon, but not with implants of hippocampal tissue. These two models therefore provided a test of multifunctionality for a clonal line of conditionally immortalized neural stem cells, MHP36, derived from the E14 “immortomouse” hippocampal anlage. Implanted above the damaged CA1 cell field in 4VO-treated adult rats, these cells (multipotential in vitro) migrated to the damaged area, reconstituted the gross morphology of the CA1 pyramidal layer, took up both neuronal and glial phenotypes, and gave rise to cognitive recovery. Similar recovery of function and restoration of species-typical morphology was observed when MHP36 cells were implanted into marmosets with excitotoxic CA1 damage. MHP36 implants led to recovery of cognitive function also in two experiments with rats with excitotoxic damage to the cholinergic system damage, either unilaterally in the nucleus basalis or bilaterally in both the nucleus basalis and the medial septal area. Thus, MHP36 cells are both multipotent (able to take up multiple cellular phenotypes) and multifunctional (able to repair diverse types of brain damage).

scholarly journals Effects of the AMPA-Receptor Antagonist, NBQX, on Neuron Loss in Dentate Hilus of the Hippocampal Formation after 8, 10, or 12 Min of Cerebral Ischemia in the Rat

1997 ◽  
Vol 17 (2) ◽  
pp. 147-152 ◽  
Author(s):  
Ping Hu ◽  
Nils Henrik Diemer ◽  
Torben Bruhn ◽  
Flemming Fryd Johansen
Keyword(s):  
Cerebral Ischemia ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Hippocampal Formation ◽  
Neuroprotective Effect ◽  
Pyramidal Cells ◽  
Ca1 Pyramidal Cells ◽  
Ampa Receptor Antagonist ◽  
Hippocampal Ca1 ◽  
Dentate Hilus

The α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinoxaline (NBQX), offers protection to hippocampal CA1 pyramidal cells after short episodes of transient cerebral ischemia. Besides CA1 pyramidal cells, neurons containing somatostatin (SS) and located in the dentate hilus of the hippocampal formation are lost after cerebral ischemia. We studied the protective effects of NBQX on SS neurons in the hilus and on hippocampal CA1 pyramidal cells following 8, 10, or 12 min of four-vessel occlusion ischemia during systemic hypotension. NBQX was administered 3 × 30 mg/kg at 0, 10, and 25 after induction of ischemia or sham, and all rats survived for 7 days. NBQX given to control rats without ischemia had no influence on number or morphology of hilar SS neurons and CA1 pyramidal cells. After 8 min of ischemia, NBQX prevented loss of hilar SS neurons. After 10 and 12 min of ischemia, NBQX had no significant effects on loss of SS neurons in the dentate hilus. However, in all ischemic groups, NBQX significantly reduced loss of CA1 pyramidal cells as compared to control rats. This neuroprotective effect decreased gradually and significantly as the time of ischemia increased. Our results support the observation that SS neurons in hilus are among the most ischemia-vulnerable neurons in the brain. We found that administration of NBQX in generally accepted dosages can protect the rapidly dying SS neurons in hilus from only brief episodes of ischemia.

scholarly journals Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sergio Valbuena ◽  
Álvaro García ◽  
Wilfrid Mazier ◽  
Ana V. Paternain ◽  
Juan Lerma
Keyword(s):  
Down Syndrome ◽  
Spatial Memory ◽  
Cognitive Deficits ◽  
Pyramidal Cells ◽  
Memory Deficits ◽  
Synaptic Inhibition ◽  
Ca1 Neurons ◽  
Ca1 Pyramidal Cells ◽  
Encoding Gene ◽  
Inhibitory Tone

Abstract Overinhibition is assumed one of the main causes of cognitive deficits (e.g. memory impairment) in mouse models of Down syndrome (DS). Yet the mechanisms that drive such exaggerated synaptic inhibition and their behavioral effects remain unclear. Here we report the existence of bidirectional alterations to the synaptic inhibition on CA1 pyramidal cells in the Ts2Cje mouse model of DS which are associated to impaired spatial memory. Furthermore, we identify triplication of the kainate receptor (KAR) encoding gene Grik1 as the cause of these phenotypes. Normalization of Grik1 dosage in Ts2Cje mice specifically restored spatial memory and reversed the bidirectional alterations to CA1 inhibition, but not the changes in synaptic plasticity or the other behavioral modifications observed. We propose that modified information gating caused by disturbed inhibitory tone rather than generalized overinhibition underlies some of the characteristic cognitive deficits in DS.

scholarly journals PKMζ traces hippocampal LTP maintenance and spatial long-term memory

2020 ◽  
Author(s):  
Changchi Hsieh ◽  
Panayiotis Tsokas ◽  
Ain Chung ◽  
Claudia Garcia-Jou ◽  
Edith Lesburguères ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Hippocampal Formation ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Memory Storage ◽  
Long Term Memory ◽  
Term Memory ◽  
Ca1 Pyramidal Cells

PKMζ is an autonomously active, atypical PKC isoform crucial for maintaining synaptic long-term potentiation (LTP) and long-term memory. Unlike other PKCs that are transiently activated by short-lived second messengers, PKMζ is persistently activated by long-lasting increases in the amount of the autonomously active kinase during LTP and long-term memory maintenance. Thus, localizing persistent increases in PKMζ might reveal traces of physiological LTP maintenance in the circuitry of the brain during long-term memory storage. Using quantitative immunohistochemistry validated by the lack of staining in PKMζ-null mice, we visualized the amount and distribution of PKMζ during LTP maintenance and spatial long-term memory storage in the hippocampal formation of wild-type mice. Strong afferent stimulation of Schaffer collateral/commissural fibers inducing LTP maintenance increases PKMζ in CA1 pyramidal cells for 2 hours in hippocampal slices. Active place avoidance spatial conditioning increases PKMζ in CA1 pyramidal cells of the hippocampal formation from 1 day to at least 1 month. The increases in PKMζ coincide with the location of cells marked during long-term memory training by Arc promoter-mediated expression of a fluorescent protein, including at dendritic spines. We conclude that increased PKMζ forms persistent traces in CA1 pyramidal cells that are sites of molecular information storage during LTP maintenance and spatial long-term memory.Graphical AbstractPKMζ-immunohistochemistry reveals persistent increased PKMζ in the hippocampus during (A) LTP maintenance, and (B) spatial long-term memory storage.

Changes in inhibitory neurotransmission in the CA1 region and dentate gyrus in a chronic model of temporal lobe epilepsy

1995 ◽  
Vol 74 (2) ◽  
pp. 829-840 ◽  
Author(s):  
P. S. Mangan ◽  
D. A. Rempe ◽  
E. W. Lothman
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Dentate Gyrus ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Ca1 Pyramidal Cells ◽  
Ca1 Region ◽  
Stratum Lacunosum Moleculare ◽  
Reversal Potentials

1. In this report we compare changes in inhibitory neurotransmission within the CA1 region and the dentate gyrus (DG) in a model of chronic temporal lobe epilepsy (TLE). Extracellular and intracellular recordings were obtained in combined hippocampal-parahippocampal slices > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. 2. Polysynaptic inhibitory postsynaptic potentials (IPSPs) were induced by positioning electrodes to activate specific afferent pathways and evoking responses in the absence of glutamate receptor antagonists [D(-)-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)]. Polysynaptic IPSPs were evoked in CA1 pyramidal cells from electrodes positioned in stratum radiatum and in stratum lacunosum/moleculare. Polysynaptic IPSPs were evoked in DG granule cells from electrodes positioned over the perforant path located in the subiculum. Monosynaptic IPSPs were induced by positioning electrodes within 200 microns of the intracellular recording electrode (near site stimulation) and stimulating in the presence of APV and CNQX to block ionotropic glutamate receptors. Monosynaptic IPSPs were evoked in CA1 pyramidal cells with electrodes positioned in the stratum lacunosum/moleculare and stratum pyramidale. Monosynaptic IPSPs were evoked in DG granule cells with electrodes positioned in the stratum moleculare. 3. Population spike (PS) amplitudes were employed to assure that a full range of stimulus strengths, from subthreshold for action potentials to an intensity giving maximal-amplitude PSs, was used to elicit polysynaptic IPSPs in CA1 pyramidal cells in both post-SSLSE and control slices. In control tissue, polysynaptic IPSPs were biphasic, composed of early and late events. In post-SSLSE tissue, polysynaptic IPSPs were markedly diminished. The diminution of polysynaptic IPSPs was detected at all levels of stimulus intensity. Both early IPSPs [mediated by gamma-aminobutyric acid-A (GABAA) receptors] and late IPSPs (mediated by GABAB receptors) were diminished. Polysynaptic IPSPs were diminished with both stratum radiatum and with stratum lacunosum/moleculare stimulation. 4. Reversal potentials for either polysynaptic early or polysynaptic late IPSPs evoked in CA1 pyramidal cells by stratum radiatum stimulation were not different in slices from post-SSLSE animals as compared with control animals. Likewise, reversal potentials for either polysynaptic early or polysynaptic late IPSPs evoked by stratum lacunosum/moleculare stimulation did not differ in the two groups. These findings excluded changes in driving force as an explanation for the diminished amplitude of IPSPs in CA1 pyramidal cells in the post-SSLSE model.(ABSTRACT TRUNCATED AT 400 WORDS)

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