Comprehensive Physiology Wiley Online Library

Mechanisms of Learning in Complex Neural Systems

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Hippocampus as Model for Memory
1.1 Structural Features of Hippocampus
1.2 Synaptically Evoked Responses
1.3 Long‐Term Potentiation as Neuronal Model for Memory
1.4 Is LTP Primarily Presynaptic or Postsynaptic Phenomenon?
1.5 Comprehensive Hypothesis for LTP
1.6 Hypothesis of LTP Generation and Its Significance as Model for Memory
1.7 Further Questions Relating to Hypothesis
1.8 Difficulties for Hypothesis and Unexplained Phenomena
2 Role of Hippocampus in Memory
2.1 Anatomical Connectivities of Hippocampus
2.2 Types of Memory
2.3 Role of Hippocampus in Learning
2.4 Role of Hippocampus in Laying Down Memory Traces Elsewhere
2.5 Final Comments
3 Addendum
Figure 1. Figure 1.

Anatomy of hippocampal formation. A: lateral view of rabbit brain with parietal and temporal neocortex removed to expose hippocampal formation. B: section of hippocampal formation enlarged to show main neuronal elements. ento, Fibers from entorhinal cortex; pp, perforating pathway; mf, mossy fibers; Sch, Schaffer axon collaterals; CA1, CA3, pyramidal cells; fim, fimbria; alv, alveus. C, D: drawings of granule cell showing degeneration of pp fibers after lesion of entorhinal cortex. With lesion of lateral cortex (L) there is degeneration on distal third (d) of dendrites, shown in C. With additional lesion of medial entorhinal cortex (L + M) there is added degeneration of pp terminals on middle third (m) of dendrites, shown in D. p, Proximal.

A, B from Andersen et al. ; C, D adapted from Fifková .
Figure 2. Figure 2.

Stimulating electrodes located in Schaffer fibers both near their CA3 origin (O‐SC) and near their termination (A‐SC) and in stratum oriens (BC) for activating primary commissural fibers and on efferent fibers of CA1 pyramidal cells (ANTI). The 3 synaptic pathways rarely extended over complete mediolateral range of slice but were usually truncated in preparation, as represented in upper half. Outside central area of overlap (darker shading) are responses to stimulation via one but not both Schaffer electrodes.

From Dunwiddie and Lynch .
Figure 3. Figure 3.

Dentate granule cell showing 4 dendrites in outline, with synaptic spines on one with synapses at right. Ca2+ input across dendrite surface membrane is indicated for left dendrite; also indicated is intracellular flow of Ca2+ down to soma. Microtubules drawn in right dendrite extending upward from soma. Inset shows microtubules passing into spine through spine apparatus (cf. Fig. B).

From Eccles , © 1983, with permission from Pergamon Press, Ltd.
Figure 4. Figure 4.

Responses of dentate granule cells to stimulation of perforating path fibers. A: justthreshold excitatory postsynaptic potential (EPSP) and just‐suprathreshold EPSP recorded intracellularly. B: series of 6 intracellular EPSPs showing fluctuations in EPSP with low‐intensity stimulation. Note apparent response failure indicated by asterisk. Calibration: A, 30 mV, 5 ms; B, 1 mV, 10 ms. C, D: intracellular recording from CA1 pyramidal cell in response to stimulation of Schaffer collaterals (O‐SC in Fig. ) before and 5 min after tetanization of 10 bursts of 50 Hz for 0.4 s. In D a hyperpolarizing pulse of 0.4 nA was applied just before testing stimulation to reveal long‐term potentiation (LTP) increase in EPSP uncomplicated by initiation of spike potential seen in C.

A, B from McNaughton et al. ; C, D from Andersen et al. .
Figure 5. Figure 5.

Granule cells of fascia dentata. A: granule cells with their bodies, dendrites, and axons that form mossy fibers (mf). Fibers of perforating pathway (pp) shown traversing dendrites on which they make excitatory synapses. Recording field potentials at level of pp synapses results in large and prolonged negative potential, labeled population EPSP. When recording electrode is advanced to level of cell bodies, sharp negative spike (population spike) signals generation of impulses in cell bodies. B: relative amplitudes of population EPSPs plotted at up to 10 h after 4 conditioning trains of stimulation, indicated by arrows. At single arrows there was stimulation at 15/s for 15 s and at double arrows 100/s for 3 s. The 100% line is drawn through prestimulation responses at 0.5/s, and after conditioning tetanus same low rate was resumed. C: time course of poststimulation potentiation as in B, except for population spike and only single conditioning tetanus of 15/s for 15 s.

From Bliss and Lømo .
Figure 6. Figure 6.

A: hippocampal slice in plane of lamella, as in Fig. B, indicating electrode placements. Stimulating electrodes located for selectively stimulating Schaffer collaterals (Sch) and mossy fibers (mf). Electrode was placed to record extracellularly from somata of CA3 pyramidal cells; also shown is stimulating electrode in entorhinal cortex for exciting perforating pathway (PP) to granule cells of fascia dentata. B: electrical responses with Sch and mf stimulation at strength below twice threshold. Arrows on Sch trace mark double negative spike: first arrow, directly produced impulses; second arrow, monosynaptic response. C: mf‐ and Sch‐evoked responses in another experiment. Double negative spike marked by arrows. Lower responses in both mf and Sch frames show potentiation of second spike 20 min after conditioning tetanus to mf input at 300/s for 5 s. First spike was unaltered. D: sizes of second spike, in mV, plotted against times after conditioning mf tetanus.

From Misgeld et al. .
Figure 7. Figure 7.

A, B: stimulation of perforant path fibers and extracellular recording from dentate granule cells with testing effects of high‐frequency tetanization of different intensities. A: low‐intensity train of 128 pulses at 500 Hz produced only short‐lasting posttetanic potentiation (PTP). B: high‐intensity stimulation of 16 pulses at 100 Hz produced long‐term potentiation (LTP) after PTP. Tetanizing stimulations began at 10‐min mark. Ordinates are percentages of increase of spike responses to testing stimulation. C, D: height of extracellular excitatory postsynaptic potential (EPSP) to constant low‐intensity (30‐μs) test pulses is plotted in initial responses of two preparations. Conditioning tetani of 100 pulses at 100 Hz and at indicated strengths in μ were applied between testing EPSP responses, with summits shown as dots as in A and B. C: up to conditioning strength of 90 μs there was only brief PTP response as in A (note different time scale in min), and with further increase in conditioning strength up to 190 μs there was progressive increase in LTP. D: series similar to C, except that at asterisk there is reversion to initial conditioning strength of 30 μs. Vertical calibration bars, 0.5 mV; time scale in min for C and D.

From McNaughton et al. .
Figure 8. Figure 8.

Effect of entorhinal conditioning stimulation, S1 or S2, on testing responses evoked by a testing entorhinal cortex (EC) stimulation, S1. Extracellular recording from dentate granule cells gives population excitatory postsynaptic potentials (EPSPs) as in Fig. A. A: S1 stimulation of EC excites perforating path to ipsilateral granule cells for both testing and conditioning stimulation. Conditioning was by 8 trains of 8–10 pulses at 400 Hz delivered every 10 s. a, Population EPSP recorded by microelectrode, R1, before conditioning; b, at ∼2 min after conditioning tetanus; second conditioning tetanus was applied 16 min after first; c, population EPSP ∼2 min later, revealing slight further increase in long‐term potentiation (LTP). B: same EC stimulation procedures by S1, but recording by R2 was for population EPSP of contralateral side. Note absence of LTP in b and c. C: recording by microelectrode R2 as in B, but now there was conditioning by conjoint stimulation of both entorhinal cortices, S1 and S2, as indicated. Consequently in b and c there was large LTP of testing contralateral response S1 in contrast to absence of LTP in B.

Adapted from Levy and Steward .
Figure 9. Figure 9.

Top trace shows summits of population excitatory postsynaptic potentials (EPSPs) to a testing entorhinal cortex stimulation at low frequency. Just beyond 3 min on scale there was brief conditioning high‐intensity tetanus, then testing stimulation was resumed. Brief posttetanic potentiation (PTP) and transient depression lead to long‐continued long‐term potentiation (LTP). Middle trace shows similar conditioning tetanus 17 min after first, which was followed by PTP and almost no additional LTP, showing that first conditioning tetanus had virtually saturated LTP mechanism. Bottom trace shows effect of subtracting run 2 from run 1 to reveal time course of onset of LTP uncomplicated by PTP and depression. Mean of 6 experiments and at higher amplification indicated by mV scale at left.

From McNaughton .
Figure 10. Figure 10.

Plot of effects of conditioning tetanus of 30/s for 30 s on sizes of synaptic spines and axon terminals, as measured in electron micrographs. Upper plot, synaptic spines (total 4,143), lower plot, axon terminals (total 3,009). Pooling of poststimulation intervals is indicated by horizontal bars, which are at mean percentage levels relative to controls. Standard errors are shown for each pooled series by vertical broken lines. Ordinate, percentages relative to controls. Abscissa, time from stimulation on logarithmic scale.

From Eccles .
Figure 11. Figure 11.

Effects of Ca2+ ‐free medium on long‐term potentiation (LTP) of CA1 populatìon spike amplitude. Dark bars along lower margin indicate periods during which flow of control medium was replaced with Ca2+ ‐free medium. Large arrows at bottom indicate interpolation of conditioning trains to pathway indicated by filled circles. Traces at right illustrate records derived from test pathway (filled circles) in left column and control pathway (open circles) in right column. Population spike (reflecting synchronous discharge of CA1 neurons) is small downward deflection on peak of positive field potential in both pathways (trace A at time indicated above figure to left) and is essentially unaffected by conditioning train (first arrow) in 0.0‐Ca2+ medium (C) but shows marked LTP (D) after initial train given 12 min earlier in control medium (second arrow) and was unchanged (F) after subsequent period of perfusion with Ca2+ ‐free medium. Traces B and E demonstrate complete suppression of synaptic responses observed in absence of Ca2+. Downward deflections of traces represent negative polarity. Calibrations, 8 mV, 5 ms. Vertical axis represents arbitrary scale units for measure of population spike amplitude; each point represents average of 2 responses evoked 5 s apart at indicated time points.

From Dunwiddie et al. .
Figure 12. Figure 12.

Extracellular recording of K+ and Ca2+ activity made with triple‐barreled ion‐selective electrode. Bath application of 10 μM 4‐aminopyridine (4‐AP) (hatched bar) led first to slow rise in K+ and small decline in Ca2+. Prior to seizure onset (upper trace) oscillations of ion activities occurred. [particularly clear on extracellular K activity (aKe) record]. Large rises of aKe and decline in aCae were seen during seizures, together with shifts in extracellular direct current field potential (FP). Three seizure activities were quickly abolished by washing in normal Krebs solution. Base‐line Ca2+ level refers to concentration of Ca2+ in bathing solution. Actual Cl in bicarbonate buffer system is 1.2 mM.

From Galvan et al. © 1982, Raven Press, New York.
Figure 13. Figure 13.

A: earliest diagram of synaptic contact (pre) on dendritic spine (spine) observed with electron microscope after osmium tetroxide fixation; den. t, dendritic microtubules; sv, synaptic vesicles; m, mitochondrion; a, spine apparatus; b, spine stalk; e, postsynaptic density; d, synaptic cleft; c, presynaptic membrane with clustered vesicles; st, presynaptic fiber. B: later diagram illustrating microtubules going into spine and spine apparatus. C: high‐power electron micrograph of isolated postsynaptic density showing peripheral planar array of round subunits whose median diameter is 18 nm. They enclose central fine granular material. Negative‐staining technique was used, in which subcellular particles are unstained and surrounded by electron‐dense background by uranyl acetate. D, E: illustrations of hypothesis of Lynch and Baudry. Influx of Ca2+ activates calpain, resulting in breakdown of fodrin and exposure of occluded glutamate receptors of postsynaptic density, shown in 2 stages.

A from Gray , reprinted by permission from Nature, copyright 1959, Macmillan Journals Limited; B from Gray ; C from Matus ; D, E from Lynch and Baudry .
Figure 14. Figure 14.

Drawing of spine synapses showing evolution of shape from small disk to larger annular shape in 2 stages, to horseshoe shape, and finally to beginning of fragmentation.

From Carlin and Siekevitz .
Figure 15. Figure 15.

Diagrammatic representation of cascade of connectivities for somesthetic system (A), principal connections 3, 1, 2, and visual system (B), principal connections 17, 18, 19, in cerebrum. Numbers refer to Brodmann's areas; other areas are SM, supplementary motor; STS, superior temporal sulcus; PrCo, precentral agranular; TG, temporal pole; OF, orbital surface frontal lobe.

From Popper and Eccles .
Figure 16. Figure 16.

Scheme in monkey brain of pathways involved in flow of information from primary sensory areas via sensory association areas of temporal and parietal lobes and cortex of frontal convexity to limbic system and then the loop back via mediodorsal nucleus of thalamus (MD) and frontal cortex to temporal and parietal areas for long‐term storage. Primary sensory areas: Vi, visual; A, auditory; S, somatosensory.

From Kornhuber .
Figure 17. Figure 17.

Schematic drawing of medial surface of right cerebral hemisphere showing connectivities from neocortex to and from mediodorsal thalamus (MD) and limbic system. OF, orbital surface of prefrontal cortex; HI, hippocampus; S, septum; EC, entorhinal cortex; A, amygdala; CG, cingulate gyrus; M, mammillary body; AT, anterior thalamus; 46 and 20 are Brodmann's areas.

From Popper and Eccles .
Figure 18. Figure 18.

Distribution of CA3 and CA1 axons. A: diagram of dorsal view of hippocampal formation showing distribution and orientation of axons of CA3 cells (large filled circles) and CA1 cells (open circles). Dashed lines, CA3–CA1 border and border between CA1 and subiculum (Sub.); small filled circles, Schaffer synapses; Sept., septum. B: semidiagrammatic transverse section of hippocampal formation showing approximation of histological relationship of CA3 and CA1 cells and axons.

From Andersen et al. .
Figure 19. Figure 19.

A, B: some anatomical interconnections between limbic system and brain stem. H, hypothalamus; S, septal area; M, mammillary body; A, amygdala; P, pituitary; MFB, medial forebrain bundle.

From McGeer et al. .
Figure 20. Figure 20.

Scheme of anatomical structures involved in selection of information between short‐term memory (STM) and long‐term memory (LTM). MB, mammillary body; A, anterior thalamic nucleus; MD, mediodorsal thalamic nucleus.

From Kornhuber .
Figure 21. Figure 21.

Scheme of structures participating in circuits involved in cerebral learning; Fig. is redrawn to show two circuits emanating from CA3 and CA1 hippocampal pyramidal cells. Connections within hippocampus are entorhinal cortex (ent. cort.) by perforating pathway to fascia dentata (fasc. dent.); granule cells of fascia dentata by mossy fibers to CA3 pyramidal cells; axon collaterals of CA3 pyramidal cells to CA1 pyramidal cells; CA1 cells to subiculum (sub) to mammillary bodies (mam. b.); CA3 by fimbria to septal nucleus (sept. nuc.) to mediodorsal thalamus (md thal.) to prefrontal cortex.

From Popper and Eccles .
Figure 22. Figure 22.

Simplified diagram of connectivities in neocortex showing pathways and synapses in proposed theory of cerebral learning. AC: 3 modules that are vertical functional elements of neocortex, each with ∼4,000 neurons. In laminae I and II, horizontal fibers arise as bifurcating axons of commissural (COM) and association (ASS) fibers and also of Martinotti axons (MA) from C. Horizontal fibers make synapses with apical dendrites of stellate pyramidal cells in C and of pyramidal cells in A and B. Deeper there is spiny stellate cell (Sst) with axon (Ax) making cartridge synapses with shafts of apical dendrites of pyramidal cells (Py). Because of conjunction hypertrophy, association fiber from C has enlarged synapses on apical dendrites of pyramidal cell in A.

From Eccles .


Figure 1.

Anatomy of hippocampal formation. A: lateral view of rabbit brain with parietal and temporal neocortex removed to expose hippocampal formation. B: section of hippocampal formation enlarged to show main neuronal elements. ento, Fibers from entorhinal cortex; pp, perforating pathway; mf, mossy fibers; Sch, Schaffer axon collaterals; CA1, CA3, pyramidal cells; fim, fimbria; alv, alveus. C, D: drawings of granule cell showing degeneration of pp fibers after lesion of entorhinal cortex. With lesion of lateral cortex (L) there is degeneration on distal third (d) of dendrites, shown in C. With additional lesion of medial entorhinal cortex (L + M) there is added degeneration of pp terminals on middle third (m) of dendrites, shown in D. p, Proximal.

A, B from Andersen et al. ; C, D adapted from Fifková .


Figure 2.

Stimulating electrodes located in Schaffer fibers both near their CA3 origin (O‐SC) and near their termination (A‐SC) and in stratum oriens (BC) for activating primary commissural fibers and on efferent fibers of CA1 pyramidal cells (ANTI). The 3 synaptic pathways rarely extended over complete mediolateral range of slice but were usually truncated in preparation, as represented in upper half. Outside central area of overlap (darker shading) are responses to stimulation via one but not both Schaffer electrodes.

From Dunwiddie and Lynch .


Figure 3.

Dentate granule cell showing 4 dendrites in outline, with synaptic spines on one with synapses at right. Ca2+ input across dendrite surface membrane is indicated for left dendrite; also indicated is intracellular flow of Ca2+ down to soma. Microtubules drawn in right dendrite extending upward from soma. Inset shows microtubules passing into spine through spine apparatus (cf. Fig. B).

From Eccles , © 1983, with permission from Pergamon Press, Ltd.


Figure 4.

Responses of dentate granule cells to stimulation of perforating path fibers. A: justthreshold excitatory postsynaptic potential (EPSP) and just‐suprathreshold EPSP recorded intracellularly. B: series of 6 intracellular EPSPs showing fluctuations in EPSP with low‐intensity stimulation. Note apparent response failure indicated by asterisk. Calibration: A, 30 mV, 5 ms; B, 1 mV, 10 ms. C, D: intracellular recording from CA1 pyramidal cell in response to stimulation of Schaffer collaterals (O‐SC in Fig. ) before and 5 min after tetanization of 10 bursts of 50 Hz for 0.4 s. In D a hyperpolarizing pulse of 0.4 nA was applied just before testing stimulation to reveal long‐term potentiation (LTP) increase in EPSP uncomplicated by initiation of spike potential seen in C.

A, B from McNaughton et al. ; C, D from Andersen et al. .


Figure 5.

Granule cells of fascia dentata. A: granule cells with their bodies, dendrites, and axons that form mossy fibers (mf). Fibers of perforating pathway (pp) shown traversing dendrites on which they make excitatory synapses. Recording field potentials at level of pp synapses results in large and prolonged negative potential, labeled population EPSP. When recording electrode is advanced to level of cell bodies, sharp negative spike (population spike) signals generation of impulses in cell bodies. B: relative amplitudes of population EPSPs plotted at up to 10 h after 4 conditioning trains of stimulation, indicated by arrows. At single arrows there was stimulation at 15/s for 15 s and at double arrows 100/s for 3 s. The 100% line is drawn through prestimulation responses at 0.5/s, and after conditioning tetanus same low rate was resumed. C: time course of poststimulation potentiation as in B, except for population spike and only single conditioning tetanus of 15/s for 15 s.

From Bliss and Lømo .


Figure 6.

A: hippocampal slice in plane of lamella, as in Fig. B, indicating electrode placements. Stimulating electrodes located for selectively stimulating Schaffer collaterals (Sch) and mossy fibers (mf). Electrode was placed to record extracellularly from somata of CA3 pyramidal cells; also shown is stimulating electrode in entorhinal cortex for exciting perforating pathway (PP) to granule cells of fascia dentata. B: electrical responses with Sch and mf stimulation at strength below twice threshold. Arrows on Sch trace mark double negative spike: first arrow, directly produced impulses; second arrow, monosynaptic response. C: mf‐ and Sch‐evoked responses in another experiment. Double negative spike marked by arrows. Lower responses in both mf and Sch frames show potentiation of second spike 20 min after conditioning tetanus to mf input at 300/s for 5 s. First spike was unaltered. D: sizes of second spike, in mV, plotted against times after conditioning mf tetanus.

From Misgeld et al. .


Figure 7.

A, B: stimulation of perforant path fibers and extracellular recording from dentate granule cells with testing effects of high‐frequency tetanization of different intensities. A: low‐intensity train of 128 pulses at 500 Hz produced only short‐lasting posttetanic potentiation (PTP). B: high‐intensity stimulation of 16 pulses at 100 Hz produced long‐term potentiation (LTP) after PTP. Tetanizing stimulations began at 10‐min mark. Ordinates are percentages of increase of spike responses to testing stimulation. C, D: height of extracellular excitatory postsynaptic potential (EPSP) to constant low‐intensity (30‐μs) test pulses is plotted in initial responses of two preparations. Conditioning tetani of 100 pulses at 100 Hz and at indicated strengths in μ were applied between testing EPSP responses, with summits shown as dots as in A and B. C: up to conditioning strength of 90 μs there was only brief PTP response as in A (note different time scale in min), and with further increase in conditioning strength up to 190 μs there was progressive increase in LTP. D: series similar to C, except that at asterisk there is reversion to initial conditioning strength of 30 μs. Vertical calibration bars, 0.5 mV; time scale in min for C and D.

From McNaughton et al. .


Figure 8.

Effect of entorhinal conditioning stimulation, S1 or S2, on testing responses evoked by a testing entorhinal cortex (EC) stimulation, S1. Extracellular recording from dentate granule cells gives population excitatory postsynaptic potentials (EPSPs) as in Fig. A. A: S1 stimulation of EC excites perforating path to ipsilateral granule cells for both testing and conditioning stimulation. Conditioning was by 8 trains of 8–10 pulses at 400 Hz delivered every 10 s. a, Population EPSP recorded by microelectrode, R1, before conditioning; b, at ∼2 min after conditioning tetanus; second conditioning tetanus was applied 16 min after first; c, population EPSP ∼2 min later, revealing slight further increase in long‐term potentiation (LTP). B: same EC stimulation procedures by S1, but recording by R2 was for population EPSP of contralateral side. Note absence of LTP in b and c. C: recording by microelectrode R2 as in B, but now there was conditioning by conjoint stimulation of both entorhinal cortices, S1 and S2, as indicated. Consequently in b and c there was large LTP of testing contralateral response S1 in contrast to absence of LTP in B.

Adapted from Levy and Steward .


Figure 9.

Top trace shows summits of population excitatory postsynaptic potentials (EPSPs) to a testing entorhinal cortex stimulation at low frequency. Just beyond 3 min on scale there was brief conditioning high‐intensity tetanus, then testing stimulation was resumed. Brief posttetanic potentiation (PTP) and transient depression lead to long‐continued long‐term potentiation (LTP). Middle trace shows similar conditioning tetanus 17 min after first, which was followed by PTP and almost no additional LTP, showing that first conditioning tetanus had virtually saturated LTP mechanism. Bottom trace shows effect of subtracting run 2 from run 1 to reveal time course of onset of LTP uncomplicated by PTP and depression. Mean of 6 experiments and at higher amplification indicated by mV scale at left.

From McNaughton .


Figure 10.

Plot of effects of conditioning tetanus of 30/s for 30 s on sizes of synaptic spines and axon terminals, as measured in electron micrographs. Upper plot, synaptic spines (total 4,143), lower plot, axon terminals (total 3,009). Pooling of poststimulation intervals is indicated by horizontal bars, which are at mean percentage levels relative to controls. Standard errors are shown for each pooled series by vertical broken lines. Ordinate, percentages relative to controls. Abscissa, time from stimulation on logarithmic scale.

From Eccles .


Figure 11.

Effects of Ca2+ ‐free medium on long‐term potentiation (LTP) of CA1 populatìon spike amplitude. Dark bars along lower margin indicate periods during which flow of control medium was replaced with Ca2+ ‐free medium. Large arrows at bottom indicate interpolation of conditioning trains to pathway indicated by filled circles. Traces at right illustrate records derived from test pathway (filled circles) in left column and control pathway (open circles) in right column. Population spike (reflecting synchronous discharge of CA1 neurons) is small downward deflection on peak of positive field potential in both pathways (trace A at time indicated above figure to left) and is essentially unaffected by conditioning train (first arrow) in 0.0‐Ca2+ medium (C) but shows marked LTP (D) after initial train given 12 min earlier in control medium (second arrow) and was unchanged (F) after subsequent period of perfusion with Ca2+ ‐free medium. Traces B and E demonstrate complete suppression of synaptic responses observed in absence of Ca2+. Downward deflections of traces represent negative polarity. Calibrations, 8 mV, 5 ms. Vertical axis represents arbitrary scale units for measure of population spike amplitude; each point represents average of 2 responses evoked 5 s apart at indicated time points.

From Dunwiddie et al. .


Figure 12.

Extracellular recording of K+ and Ca2+ activity made with triple‐barreled ion‐selective electrode. Bath application of 10 μM 4‐aminopyridine (4‐AP) (hatched bar) led first to slow rise in K+ and small decline in Ca2+. Prior to seizure onset (upper trace) oscillations of ion activities occurred. [particularly clear on extracellular K activity (aKe) record]. Large rises of aKe and decline in aCae were seen during seizures, together with shifts in extracellular direct current field potential (FP). Three seizure activities were quickly abolished by washing in normal Krebs solution. Base‐line Ca2+ level refers to concentration of Ca2+ in bathing solution. Actual Cl in bicarbonate buffer system is 1.2 mM.

From Galvan et al. © 1982, Raven Press, New York.


Figure 13.

A: earliest diagram of synaptic contact (pre) on dendritic spine (spine) observed with electron microscope after osmium tetroxide fixation; den. t, dendritic microtubules; sv, synaptic vesicles; m, mitochondrion; a, spine apparatus; b, spine stalk; e, postsynaptic density; d, synaptic cleft; c, presynaptic membrane with clustered vesicles; st, presynaptic fiber. B: later diagram illustrating microtubules going into spine and spine apparatus. C: high‐power electron micrograph of isolated postsynaptic density showing peripheral planar array of round subunits whose median diameter is 18 nm. They enclose central fine granular material. Negative‐staining technique was used, in which subcellular particles are unstained and surrounded by electron‐dense background by uranyl acetate. D, E: illustrations of hypothesis of Lynch and Baudry. Influx of Ca2+ activates calpain, resulting in breakdown of fodrin and exposure of occluded glutamate receptors of postsynaptic density, shown in 2 stages.

A from Gray , reprinted by permission from Nature, copyright 1959, Macmillan Journals Limited; B from Gray ; C from Matus ; D, E from Lynch and Baudry .


Figure 14.

Drawing of spine synapses showing evolution of shape from small disk to larger annular shape in 2 stages, to horseshoe shape, and finally to beginning of fragmentation.

From Carlin and Siekevitz .


Figure 15.

Diagrammatic representation of cascade of connectivities for somesthetic system (A), principal connections 3, 1, 2, and visual system (B), principal connections 17, 18, 19, in cerebrum. Numbers refer to Brodmann's areas; other areas are SM, supplementary motor; STS, superior temporal sulcus; PrCo, precentral agranular; TG, temporal pole; OF, orbital surface frontal lobe.

From Popper and Eccles .


Figure 16.

Scheme in monkey brain of pathways involved in flow of information from primary sensory areas via sensory association areas of temporal and parietal lobes and cortex of frontal convexity to limbic system and then the loop back via mediodorsal nucleus of thalamus (MD) and frontal cortex to temporal and parietal areas for long‐term storage. Primary sensory areas: Vi, visual; A, auditory; S, somatosensory.

From Kornhuber .


Figure 17.

Schematic drawing of medial surface of right cerebral hemisphere showing connectivities from neocortex to and from mediodorsal thalamus (MD) and limbic system. OF, orbital surface of prefrontal cortex; HI, hippocampus; S, septum; EC, entorhinal cortex; A, amygdala; CG, cingulate gyrus; M, mammillary body; AT, anterior thalamus; 46 and 20 are Brodmann's areas.

From Popper and Eccles .


Figure 18.

Distribution of CA3 and CA1 axons. A: diagram of dorsal view of hippocampal formation showing distribution and orientation of axons of CA3 cells (large filled circles) and CA1 cells (open circles). Dashed lines, CA3–CA1 border and border between CA1 and subiculum (Sub.); small filled circles, Schaffer synapses; Sept., septum. B: semidiagrammatic transverse section of hippocampal formation showing approximation of histological relationship of CA3 and CA1 cells and axons.

From Andersen et al. .


Figure 19.

A, B: some anatomical interconnections between limbic system and brain stem. H, hypothalamus; S, septal area; M, mammillary body; A, amygdala; P, pituitary; MFB, medial forebrain bundle.

From McGeer et al. .


Figure 20.

Scheme of anatomical structures involved in selection of information between short‐term memory (STM) and long‐term memory (LTM). MB, mammillary body; A, anterior thalamic nucleus; MD, mediodorsal thalamic nucleus.

From Kornhuber .


Figure 21.

Scheme of structures participating in circuits involved in cerebral learning; Fig. is redrawn to show two circuits emanating from CA3 and CA1 hippocampal pyramidal cells. Connections within hippocampus are entorhinal cortex (ent. cort.) by perforating pathway to fascia dentata (fasc. dent.); granule cells of fascia dentata by mossy fibers to CA3 pyramidal cells; axon collaterals of CA3 pyramidal cells to CA1 pyramidal cells; CA1 cells to subiculum (sub) to mammillary bodies (mam. b.); CA3 by fimbria to septal nucleus (sept. nuc.) to mediodorsal thalamus (md thal.) to prefrontal cortex.

From Popper and Eccles .


Figure 22.

Simplified diagram of connectivities in neocortex showing pathways and synapses in proposed theory of cerebral learning. AC: 3 modules that are vertical functional elements of neocortex, each with ∼4,000 neurons. In laminae I and II, horizontal fibers arise as bifurcating axons of commissural (COM) and association (ASS) fibers and also of Martinotti axons (MA) from C. Horizontal fibers make synapses with apical dendrites of stellate pyramidal cells in C and of pyramidal cells in A and B. Deeper there is spiny stellate cell (Sst) with axon (Ax) making cartridge synapses with shafts of apical dendrites of pyramidal cells (Py). Because of conjunction hypertrophy, association fiber from C has enlarged synapses on apical dendrites of pyramidal cell in A.

From Eccles .
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John C. Eccles. Mechanisms of Learning in Complex Neural Systems. Compr Physiol 2011, Supplement 5: Handbook of Physiology, The Nervous System, Higher Functions of the Brain: 137-167. First published in print 1987. doi: 10.1002/cphy.cp010505