Current source density analysis of the potential evoked in hippocampus by perirhinal cortex stimulation

Previous anatomical research has demonstrated that the perirhinal cortex (PRC) projects to the dorsal hippocampal CA1 field. We have recently presented data (Liu and Bilkey, Hippocampus 1996; 6:125–135) which suggests that this pathway courses via the lateral perforant path (LPP). In the present study, laminar profiles of the average evoked potentials and current source density (CSD) analysis were used to study the input from the perirhinal cortex to the dorsal hippocampus in the urethane-anaesthetized rat. Stimulation of the lateral perforant path activated a current sink in the stratum lacunosum-moleculare of CA1 and the outer molecular layer of the dentate gyrus with an onset latency of 3.5 ms. Stimulation of the perirhinal cortex produced a very similar sink-source pattern with an onset latency of 4.0 ms. Higher-intensity stimulation of lateral entorhinal cortex also produced a similar pattern with an onset latency of 4.5 ms. Electrolytic lesions of PRC conducted 4–5 days prior to testing resulted in a major decrease (58%) in the amplitude of the LPP-elicited potentials and a corresponding reduction across the whole source-sink pattern. A similar result was observed following ibotenic acid lesions of PRC. In contrast, similar-sized electrolytic lesions of lateral entorhinal cortex produced a much smaller (16%) decrease in potential amplitude and little change in the source-sink pattern. These data provide further support for the hypothesis that perirhinal cortex projects to both the dentate gyrus and CA1 regions of the hippocampus via the lateral perforant path. Hippocampus 7:389–396, 1997. © 1997 Wiley-Liss, Inc.     

Parallel involvement of perirhinal and lateral entorhinal cortex in the polysynaptic activation of hippocampus by olfactory inputs

It has previously been shown that olfactory input to the hippocampus (HPC) is mediated polysynaptically via the lateral entorhinal cortex (LEC), the site of origin of the lateral perforant pathway (LPP). Because previous anatomical studies have shown that olfactory projections also terminate in perirhinal cortex and that this latter region projects directly to the hippocampus, we investigated the role of perirhinal cortex (PRC) in the mediation of the olfactory-hippocampal potential in the rat. Single-pulse stimulation of the lateral olfactory tract (LOT) resulted in a long onset latency (12–20 ms) evoked response in the dentate gyrus of the ipsilateral hippocampal formation. LOT-HPC potentials were rapidly and completely abolished following the microinfusion of procaine into the LPP, suggesting that they are ultimately mediated via this pathway. In support of this finding, a current source density analysis indicated that the LOT-HPC response was generated by a current sink at the outer molecular layer of both dorsal and ventral blades of the dentate gurus. Electrolytic and ibotenic acid lesions of PRC produced a significant decrease in the amplitude of LOT-HPC potentials when testing was conducted 4–7 days postlesion. Lesions of LEC produced similar effects and combined lesions of LEC and PRC resulted in an almost complete eradication of the potential, suggesting that parallel entorhinal-hippocampal and perirhinal-hippocampal pathways are involved. These data suggest, therefore, that a portion of the olfactory input to the hippocampus is mediated via polysynaptic connections routed through perirhinal cortex. Because recent research has suggested that PRC plays an important role within the temporal lobe memory system, this connectivity may be important for olfactory memory processes. Hippocampus 7:296–306, 1997. © 1997 Wiley-Liss, Inc.     

Activation of perforant path neurons to field CA1 by hippocampal projections

Previous evidence showed that single-shock stimulation of dorsal hippocampal commissure (PSD) fibers to the entorhinal cortex led to sequential activation of perforant path neurons to the dentate gyrus, dentate granule cells, pyramidal neurons of hippocampal fields CA3 and CA1, and, through reentrant hippocampal impulses, neurons of deep and superficial layers of the entorhinal cortex. The aim of the present study was to ascertain whether perforant path neurons to CA1 are activated by the PSD input and/or by the reentrant hippocampal impulses in this model. Field potentials evoked by single-shock (0.1-Hz) or repetitive (1-4 Hz) PSD stimulation were recorded in anesthetized guinea pigs from the entorhinal cortex, dentate gyrus, fields CA1 and CA3, and subiculum. A current source-density analysis of the evoked potentials was used to localize the input to field CA1 and dentate gyrus. After either single-shock or repetitive PSD stimulation, an early current sink was found in the molecular layer of the dentate gyrus, but no sink was present in CA1. With low-frequency PSD stimulation, a late (approximately 40-ms) surface positive wave occurred in field CA1 alone. During this wave, a current sink was found in the stratum lacunosum-moleculare of CA1, but no sink was present in the dentate gyrus. The late wave had threshold and magnitude related to the building up of the response evoked by reentrant hippocampal impulses in layer III of the entorhinal cortex and was abolished by selective interruption of the perforant path to CA1. The results show that the commissural input to the entorhinal cortex activates perforant path neurons to the dentate gyrus, but not those to field CA1 which are recruited by repetitive hippocampal impulses. These findings show different frequency-dependent patterns of loop operation that might be related to different behaviors.     

Direct connection between perirhinal cortex and hippocampus is a major constituent of the lateral perforant path

Single-pulse stimulation of the perirhinal cortex (PRC) evoked field responses in the dorsal hippocampal CA1 region in urethane-anesthetized rats. In depth profiles conducted by moving the PRC stimulating electrode, the largest amplitude hippocampal potential was generated when the stimulating electrode was located within the perirhinal region. More dorsal (temporal cortex) or more ventral (lateral entorhinal cortex) stimulating sites elicited minimal hippocampal potentials. The hippocampal response was maintained during 100 Hz stimulation of the PRC, suggesting that it was monosynaptic, and high-frequency stimulation (400 Hz) of the PRC produced a significant potentiation of hippocampal CA1 field potentials (46.73 ± 4.14%). When the PRC and the lateral perforant path (LPP) were stimulated separately, the depth/amplitude profiles obtained from a roving recording electrode located within the dorsal hippocampus were similar. In order to determine if fibers from PRC project to the hippocampus via the LPP, the PRC-CA1 and LPP-CA1 potentials were recorded prior to and during procaine (20%, 0.5 μl) blockade of the LPP. A simultaneous loss of both potentials was observed immediately following procaine infusion, while a commissural control potential was unaffected. Both LPP and PRC potentials returned approximately 30–40 min later. Electrolytic lesions of PRC produced a significant decrease in the amplitude of LPP-hippocampal potentials when testing was conducted 4–5 days postlesion. Lesions of lateral entorhinal cortex or temporal cortex did not produce such effects. These data suggest that a direct pathway from perirhinal cortex to the dorsal hippocampal CA1 field can undergo long-term potentiation (LTP) and that this pathway makes a major contribution to the lateral perforant path. © 1996 Wiley-Liss, Inc.     

Parallel activation of field CA2 and dentate gyrus by synaptically elicited perforant path volleys

Previous studies showed that dorsal psalterium (PSD) volleys to the entorhinal cortex (ENT) activated in layer II perforant path neurons projecting to the dentate gyrus. The discharge of layer II neurons was followed by the sequential activation of the dentate gyrus (DG), field CA3, field CA1. The aim of the present study was to ascertain whether in this experimental model field, CA2, a largely ignored sector, is activated either directly by perforant path volleys and/or indirectly by recurrent hippocampal projections. Field potentials evoked by single-shock PSD stimulation were recorded in anesthetized guinea pigs from ENT, DG, fields CA2, CA1, and CA3. Current source-density (CSD) analysis was used to localize the input/s to field CA2. The results showed the presence in field CA2 of an early population spike superimposed on a slow wave (early response) and of a late and smaller population spike, superimposed on a slow wave (late response). CSD analysis during the early CA2 response showed a current sink in stratum lacunosum-moleculare, followed by a sink moving from stratum radiatum to stratum pyramidale, suggesting that this response represented the activation and discharge of CA2 pyramidal neurons, mediated by perforant path fibers to this field. CSD analysis during the late response showed a current sink in middle stratum radiatum of CA2 followed by a sink moving from inner stratum radiatum to stratum pyramidale, suggesting that this response was mediated by Schaffer collaterals from field CA3. No early population spike was evoked in CA3. However, an early current sink of small magnitude was evoked in stratum lacunosum-moleculare of CA3, suggesting the presence of synaptic currents mediated by perforant path fibers to this field. The results provide novel information about the perforant path system, by showing that dorsal psalterium volleys to the entorhinal cortex activate perforant path neurons that evoke the parallel discharge of granule cells and CA2 pyramidal neurons and depolarization, but no discharge of CA3 pyramidal neurons. Consequently, field CA2 may mediate the direct transfer of ENT signals to hippocampal and extrahippocampal structures in parallel with the DG-CA3-CA1 system and may provide a security factor in situations in which the latter is disrupted.     

Functional interconnections between CA3 and the dentate gyrus revealed by current source density analysis

The physiological interactions between the dentate gyrus (DG) and CA3 were studied in urethane-anesthetized rats by using field potential recording and current source density (CSD) analysis. Stimulation of CA3b resulted in a short-latency (<2.5-ms onset latency) antidromic population spike in both the DG and CA3c. An excitation (current sink) at the middle molecular layer (MML) was observed at 3-ms latency, possibly mediated by the backfiring of perforant path fibers that projected to both DG and CA3. CA3 stimulation also resulted in a sink at the dendritic layers of CA3c, which was likely mediated by excitatory CA3 recurrent collaterals. It was inferred that the DG was excited at the inner molecular layer (IML) after stimulation near the CA3b/CA3c border. This IML excitation (sink) probably resulted from orthodromic CA3 or hilar projections to the IML and not from mossy fiber backfiring. The IML and the CA3c dendritic sinks were blocked by an intracerebroventricular injection of a non-N-methyl-D-aspartate receptor antagonist, 6-cyano-7-nitroquinoxaline-2, 3-dione, but not by a gamma-aminobutyric acid type A (GABA_A) receptor antagonist, bicuculline. CA3b stimulation evoked population spike bursts (3–7-ms latency) in both DG and CA3c when GABA_A inhibition was suppressed by bicuculline, thus confirming that the excitatory afferents project from CA3b to DG and CA3c. A CA3 conditioning stimulus pulse given 30–200 ms before a perforant-path test pulse increased the amplitude of the perforant-path-evoked DG population spike (as compared with the test response without conditioning). After a moderate-intensity stimulation of CA3, a late (<20-ms latency) excitation of the MML of the DG was found. The late DG excitation was blocked by procaine injection at the medial perforant path, suggesting its origin from the medial entorhinal cortex. In conclusion, rich interactions between CA3 and other hippocampal structures were studied quantitatively by CSD analysis in vivo. We infer that CA3 provides an early excitatory feedback path to DG through recurrent collaterals or hilar interneurons and a late feedback through the medial entorhinal cortex. Hippocampus 1998;8:217–230. © 1998 Wiley-Liss, Inc.     

Monosynaptic activation of CA3 by the medial perforant path

The functional projection of the medial perforant path (MPP) to different CA3 subfields was studied in urethan-anesthetized rats using current source density analysis. MPP stimulation resulted in an early-latency (presumed monosynaptic) sink with onset of 2–3 ms at the distal apical dendritic layer of CA3 (stratum lacunosum molecule) and a long-latency (presumed disynaptic, >7 ms) sink at stratum lucidum and radiatum of CA3. The population spike (onset 5.3–6.1 ms), a sink at CA3 pyramidal cell layer, was observed 67% of the time (12 of 18 rats) in CA3a, 44% (8 of 18) in CA3b and 58% (7 of 12 rats) in CA3c following MPP stimulation. Population spike was not observed during presumed disynaptic excitation of CA3. Both early-latency sink (excitatory postsynaptic potential) and population spike in CA3 revealed robust paired-pulse facilitation (PPF). In contrast, little PPF was found for the MPP-evoked excitatory sink at the middle molecular layer of the dentate gyrus. The data suggested that the entorhinal cortex provides a strong monosynaptic excitation of different subfields of CA3. A direct entorhinal to CA3 input bypasses the dentate gyrus and may play a role in normal hippocampal signal processing and neural plasticity.     

Medial and lateral perforant path evoked potentials are selectively modulated by pairing with glutamatergic activation of locus coeruleus in the dentate gyrus of the anesthetized rat

Norepinephrine (NE) in vitro produces long-lasting potentiation of medial perforant path input and depression of lateral perforant path input to dentate gyrus in the rat. Similar, but highly transient, effects have been reported in vivo using paragigantocellular stimulation to release NE. The present study uses alternate stimulation of the medial perforant path and lateral olfactory tract (eliciting a lateral perforant path-evoked potential) to examine the effects of glutamatergic activation of locus coeruleus (LC) on the two pathways for up to 3 h post-LC activation. In the first experiment, the expected potentiation of the medial perforant path population spike in dentate gyrus was observed, but without accompanying depression of the lateral perforant path-mediated evoked potential (lateral olfactory tract stimulation, 60 s ISI). In a second experiment, with more frequent pairing of input with NE release (10 s ISI), significant potentiation of lateral perforant path-mediated input to dentate gyrus occurred, but potentiation of medial perforant path input was not seen. A third experiment with a 30 s ISI again produced potentiation of lateral perforant path-mediated input without potentiation of the medial perforant path population spike. The size of effects with the 30 s ISI was intermediate between that seen with 10 s and 60 s ISI. Potentiation of lateral perforant path over medial perforant path input has previously been reported with acute nicotinic activation of the LC. This outcome also resembles heterosynaptic modulation previously reported with tetanic potentiation. The data argue for a competitive relationship between medial and lateral perforant path inputs to dentate gyrus and suggest pairing with increased NE produces a bias favoring one or the other pathway depending on parameters such as strength and frequency. NE potentiating effects on lateral perforant path input here may also have occurred in entorhinal cortex (EC) given the system-wide NE release with LC activation.     

The entorhinal cortex of the mouse: organization of the projection to the hippocampal formation

The origin and the terminations of the projections from the entorhinal cortex to the hippocampal formation of the mouse (C57BL/6J strain) have been studied using anterogradely and retrogradely transported tracers. The entorhinal cortex is principally divided into two areas, the lateral entorhinal area (LEA) and the medial entorhinal area (MEA). LEA is the origin of the lateral perforant path that terminates in the outer one-third of the molecular layer of the dentate gyrus, and MEA is the origin of the medial perforant path that ends in the middle one-third of the molecular layer of the dentate gyrus. This projection is mostly to the ispsilateral dentate gyrus; only a few labeled axons and terminals are found in the contralateral dentate gyrus. The projection to the dentate gyrus originates predominantly from neurons in layer II of the entorhinal cortex. The entorhinal cortex also projects to CA3 and CA1 and to subiculum; in both CA3 and CA1, the terminals are present in stratum lacunosum-moleculare, whereas in the subiculum the terminals are in the outer part of the molecular layer. The projection from the entorhinal cortex to CA3, CA1, and subiculum is bilateral, and it originates predominantly from neurons in layer III, but a small number of neurons in the deeper layers of the entorhinal cortex contributes to this projection. The projection of entorhinal cortex to the hippocampus is topographically organized, neurons in the lateral part of both LEA and MEA project to the dorsal part (i.e., septal pole) of the hippocampus, whereas the projection to the ventral (i.e., temporal pole) hippocampus originates from neurons in medial parts of the entorhinal cortex.     

Learning and memory of cue-reward association meaning by modifications of synaptic efficacy in dentate gyrus and piriform cortex

This article begins with a review of recent experiments investigating the synaptic efficacy changes occurring in rat dentate gyrus and piriform cortex during an associative olfactory task. In all these experiments, animals were trained to discriminate among an artificial cue, a patterned electrical stimulation distributed to the lateral olfactory tract associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral olfactory tract were recorded in the ipsilateral piriform cortex before and just after each training session. Monosynaptic field and polysynaptic field potentials evoked by single electrical stimuli applied respectively to the lateral perforant pathway and lateral olfactory tract were also recorded in ipsilateral dentate gyrus. The results showed an increase in synaptic efficacy subsequent to the first training session in the dentate gyrus network when compared with piriform cortex at the later stage of the learning. The early increase of monosynaptic response in the dentate gyrus was observed immediately after the first learning session but disappeared 24 h later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of the last (fifth) session. The polysynaptic potential recorded in this structure increased substantially when rats began to discriminate the leaming cues, usually after the second or third learning session. Then, from the third to the fifth session, an LTP like-phenomenon appeared in piriform cortex when rats perfectly mastered the associations. Experiments using high-frequency stimulation to prevent changes in gyrus dentatus indicated that the onset of the observed depression was necessary for the learning of the olfactory associations. The fact that hippocampal and cortical neuronal networks exhibited different timing in synaptic efficacy changes could physiologically explain learning and memory processes.     

Simultaneous activation and opioid modulation of long-term potentiation in the dentate gyrus and the hippocampal CA3 region after stimulation of the perforant pathway in freely moving rats

Recent investigations indicate monosynaptic activation by the perforant pathway (pp) of the dentate gyrus and the CA3 region. While short-term potentiation and long-term potentiation (LTP) and its opioid modulation are frequently described for the dentate gyrus, data for the CA3 region are rare. Therefore, evoked potentials and opioid modulation of LTP were directly compared in both target regions of the pp. Male Wistar rats were chronically implanted with a bipolar stimulation electrode in the pp (angular bundle) and two recording electrodes in the dorsal dentate gyrus and the CA3 region. Stimulation of the pp in the freely behaving animals induced short-latency evoked potentials in both target structures which were compared with respect to waveform, latency, amplitude and signs of short- and long-term neuronal plasticity. The short-latency potential in the CA3 region seemed to be a monosynaptic potential which displayed LTP sensitive to the N-methyl-D-aspartate receptor antagonist, MK 801, and depotentiating stimulation. After application of specific opioid antagonists at the mu-, delta- and kappa-opioid receptor subtypes, naloxone, funaltrexamine, naltrindole and binaltorphimine, different effects on induction and maintenance of LTP of the population spike were found both within the dentate gyrus and between the dentate gyrus and the CA3 region. The results show marked diminution of LTP in the dentate gyrus only for naloxone and naltrindole and only small, if any, effects of naloxone on LTP in the CA3 region. Thus, neuronal plasticity in the direct perforant pathway input to the CA3 region seems not to be under such substantial opioidergic control. LTP would be inducible in that region even when LTP in the input formation, the dentate gyrus, and transsynaptic LTP via the mossy fibres are blocked.     

Physiological studies of the reciprocal connections between the hippocampus and entorhinal cortex

Neurophysiological recordings were obtained from the hippocampus, entorhinal cortex, and dentate gyrus under conditions of controlled electrostimulation at interconnecting pathways in order to confirm their bidirectional nature as suggested by recent anatomical findings. The existence of a hippocampal to entorhinal pathway was confirmed physiologically by the presence of evoked field potentials and unitary driving of the entorhinal cortex following stimulation of the CA3 subfields of the ipsilateral and contralateral hippocampus. Activation of the entorhinal cortex by such procedures led to a subsequent excitation of the granule cells of the dentate gyrus through the axonal projections of the perforant pathway. The findings are discussed in the context of known anatomical circuitry which might provide the basis for such bidirectional interactions. The functional significance of the demonstrated physiological connections is indicated by the fact that the entorhinal cortex responds to hippocampal activation in a consistent manner and transmits that information back to the dentate gyrus; thereby completing an important three chain loop between three major components of limbic system circuitry.     

Sensory modulation of hippocampal transmission. I. Opposite effects on CA1 and dentate gyrus synapsis

Neuronal transmission through hippocampal subfields exhibits a high degree of modulation and appears dependent on the behavioral state and hippocampal EEG. Sensory inputs, which profoundly modify the hippocampal EEG, may be involved in modulating hippocampal excitability. Field responses of the CA1 region, evoked by ipsilateral CA3 or perforant path stimulation, as well as dentate gyrus potentials evoked by perforant path stimulation were recorded in paralyzed and locally anesthetized rats and studied before, during and after sensory stimulation, consisting of gentle stroking of the animal's fur. On some occasions the CA1 was also antidromically driven from the posterior alveus in order to study the recurrent inhibitory loop and paired pulses were applied to the perforant pathway to study recurrent inhibition in the dentate gyrus. Evoked responses were averaged and field excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude measured. In addition the positive wave which follows the population spike, which corresponds in part to the recurrent IPSP, was also evaluated. Sensory stimulation, which evoked a high-amplitude 5-6 Hz theta (theta)-rhythm in the hippocampal EEG, drastically depressed the efficacy of Schaffer collateral volleys in discharging the CA1 cells. The EPSP-PS curves, however, were not altered revealing that cellular excitability was unaffected. The inhibitory CA1 loop appeared to be unaltered. In contrast, the dentate gyrus responses to perforant pathway stimulation were enhanced during periods of sensory stimulation and the cellular excitability increased, as judged by the shift to the left of EPSP-PS relation. In addition, the recurrent inhibition appeared to be reduced during sensory stimulation. Present results demonstrate that sensory stimulation causes modulation of information transfer through the hippocampus. This modification of hippocampal transmission may serve to properly gate the information reaching the CA1 and dentate gyrus.     

Reduced nicotinamide adenine dinucleotide phosphate-diaphorase/nitric oxide synthase profiles in the human hippocampal formation and perirhinal cortex

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-stained profiles were evaluated throughout the human hippocampal formation (i. e., dentate gyrus, Ammon's horn, subicular complex, entorhinal cortex) and perirhinal cortex. NADPH-d staining revealed pleomorphic cells, fibers, and blood vessels. Within the entorhinal and the perirhinal cortices, darkly stained (type 1) NADPH-d pyramidal, fusiform, bipolar, and multipolar neurons with extensive dendrites were scattered mainly within deep layers and subjacent white matter. Moderately stained (type 2) NADPH-d round or oval neurons were seen mainly in layers II and III of the entorhinal and perirhinal cortices, in the dentate gyrus polymorphic layer, in the CA fields stratum pyramidal and radiatum, and in the subicular complex. The distribution of type 2 cells was more abundant in the perirhinal cortex compared to the hippocampal formation. Lightly stained (type 3) NADPH-d pyramidal and oval neurons were distributed in CA4, the entorhinal cortex medial subfields, and the amygdalohippocampal transition area. Sections concurrently stained for NADPH-d and nitric oxide synthase (NOS) revealed that all type 1 neurons coexpressed NOS, whereas types 2 and 3 were NOS immunonegative. NADPH-d fibers were heterogeneously distributed within the different regions examined and were frequently in close apposition to reactive blood vessels. The greatest concentration of fibers was in layers III and V–VI of the entorhinal and perirhinal cortices, dentate gyrus polymorphic and molecular layers, and CA1 and CA4. A band of fibers coursing within CA1 divided into dorsal and ventral bundles to reach the presubiculum and entorhinal cortex, respectively. Although the distribution of NADPH-d fibers was conserved across all ages examined (28–98 years), we observed an increase in the density of fiber staining in the aged cases. These results may be relevant to our understanding of selective vulnerability of neuronal systems within the human hippocampal formation in aging and in neurodegenerative diseases. © 1995 Wiley-Liss, Inc.     

The effects of traumatic brain injury on inhibition in the hippocampus and dentate gyrus

Changes in inhibitory neuronal functioning may contribute to morbidity following traumatic brain injury (TBI). Evoked responses to orthodromic paired-pulse stimulation were examined in the hippocampus and dentate gyrus at 2 and 15 days following lateral fluid percussion TBI in adult rats. The relative strength of inhibition was estimated by measuring evoked paired pulses in three afferent systems: the CA3 commissural input to the CA1 region of the hippocampus; the entorhinal cortical input to the ipsilateral CA1 area (temporoammonic system); and the entorhinal input to the ipsilateral dentate gyrus (perforant path). In addition to quantitative electrophysiological estimates of inhibitory efficacy, levels of γ-aminobutyric acid (GABA) were qualitatively examined with immunohistochemical techniques. Effects of TBI on paired-pulse responses were pathway-specific, and dependent on time postinjury. At 2 days following TBI, inhibition of population spikes was significantly reduced in the CA3 commissural input to CA1, which contrasted with injury-induced increases in inhibition in the dentate gyrus seen at both 2 and 15 days postinjury. Low-level stimulation, subthreshold for population spikes, also revealed changes in paired-pulse facilitation of field extracellular postsynaptic potentials (fEPSPs), which depended on fiber pathway and time postinjury. Significant injury-induced electrophysiological changes were almost entirely confined to the hemisphere ipsilateral to injury. Intensity of GABA immunobinding exhibited a regional association with electrophysiological indices of inhibition, with the most pronounced increases in GABA levels and inhibition found in the dentate gyrus. TBI-induced effects showed a regional pattern within the hippocampus which corresponds closely to inhibitory changes reported to follow ischemia and kindling. This degree of similarity in outcome following dissimilar injuries may indicate common mechanisms in the nervous system response to injury.     

Input-output relations in the entorhinal-hippocampal-entorhinal loop: Entorhinal cortex and dentate gyrus

The pattern of impulse transfer along the entorhinal-hippocampal-entorhinal loop has been analyzed in the guinea pig by field potential analysis. The loop was driven by impulse volleys conducted by presubicular commissural fibers, directly stimulated in the dorsal psalterium, which monosynaptically activated perforant path neurons in the medial entorhinal cortex. Perforant path volleys activated in sequence the dentate gyrus, field CA3, field CA1, subiculum, and entorhinal cortex. Input-output curves were reconstructed from responses simultaneously recorded from different stations along the loop. The entorhinal response to the presubicular volley was found to increase gradually with respect to its input. The population excitatory postsynaptic potential (EPSP) of the dentate gyrus granule cells had a similar behavior. By contrast, the input-output relation between the granule cell population spike and population EPSP was described by a very steep sigmoid curve. The population spike of CA3 and CA1 pyramidal neurons as well as the response evoked in the entorhinal cortex by the hippocampal output had slightly higher threshold than the granule cell population spike and, like the latter, abruptly reached maximum amplitude. These findings show that the entorhinal-hippocampal-entorhinal loop transforms a linear input in a non-linear, almost all-or-none output and that the dentate gyrus is the critical site where the transformation occurs. Beyond the dentate gyrus, the loop appears very permeant to impulse traffic. © 1995 Wiley-Liss, Inc.     

“Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies

Sustained electrical stimulation of the perforant path in urethane-anesthetized rats evoked hippocampal granule cell population spikes and epileptiform discharges. After stimulation, recurrent inhibition in the granule cell layer was abolished. Light microscopic analysis revealed a highly reproducible pattern of hippocampal damage to dentate pyramidal basket cells, hilar cells in general and CA3 and CA1 pyramidal cells. CA2 pyramidal cells and dentate granule cells were relatively unaffected. When perforant path stimulation on one side of the brain evoked bilateral granule cell discharges, damage was bilateral. Unilateral hippocampal seizures were associated with unilateral hippocampal damage. Rapid Golgi-stained hippocampi exhibited spherical dendritic swellings at the sites of termination of excitatory entorhinal afferents to the hippocampus and in the mossy fiber region. Electrical stimulation of a single excitatory afferent to the hippocampus appears to reproduce the “epileptic” pattern of hippocampal damage without using convulsant drugs and without causing motor convulsions. It is suggested that seizure-associated brain damage in caused by excessive pre-synaptic release of excitatory transmitter that induces intracellular post-synaptic changes that lead to dendritic swelling and cell death.     

Perirhinal cortex projections to the amygdaloid complex and hippocampal formation in the rat

The differential efferent projections of the perirhinal cortex were traced by using anterograde and retrograde tracing techniques. The dorsal bank cortex (area 36) projected lightly to the lateral entorhinal cortex and more strongly to the lateral, posterolateral cortical, and posterior basomedial amygdaloid nuclei and amygdalostriatal transition zone. The ventral bank (dorsolateral entorhinal cortex) projected to the lateral entorhinal cortex, dorsal subiculum, and subfield CA1 and mainly targeted the basolateral amygdaloid nucleus. Corticocortical projections from the dorsal and ventral banks targeted different cortical areas. The fundus of the rhinal sulcus (area 35) projected to both lateral and medial entorhinal cortices, ventral subiculum, lateral and basolateral nuclei, and amygdalostriatal transition zone. Corticocortical projections targeted areas projected to by both dorsal and ventral banks and also by second somatosensory area, first temporal cortical area, and striate cortex. Neurons projecting to the lateral nucleus were distributed in all layers of the dorsal bank, wheras those projecting to CA1 and subiculum were found in superfical layers (mostly layer III) of the ventral bank. Projections to the basolateral nucleus arose from superfical layers (mostly layer II) of the fundus and deep layers of the ventral bank. Furthermore, projections to the amygdala mostly arose from rostral levels, whereas hippocampal projections primarily originated caudally. The rat perirhinal cortex is heterogeneous in its efferent connectivity, and distinct projections arise from the dorsal and ventral banks and fundus of the rhinal sulcus. The widespread cortical connectivity of the fundus suggests that only this part of the perirhinal cortex is similar to area 35 of the primate brain.     

Cooperation and competition between lateral and medial perforant path synapses in the dentate gyrus

It has been suggested that non-spatial and spatial pieces of information are transmitted to the dentate gyrus from entorhinal cortex layer II through the lateral and medial perforant paths (LPP and MPP), which establish synapses on granule cell dendrites in the outer and middle one-thirds of the dentate molecular layer, respectively. In the present paper, we first investigated cooperation and competition between MPP and LPP synapses being subject to STDP rules, using a four-compartmental granule cell model. MPP and LPP were stimulated simultaneously by periodic and random pulse trains, respectively. Both synapses were gradually enhanced by cooperation between those synapses in the early stage, and then either the MPP or the LPP synapse was rapidly enhanced through synaptic competition in the following stage, depending on their initial synaptic conductances. The dominant cause of synaptic competition is that the distance between the MPP synapse and the soma is shorter than that between the LPP synapse and the soma. These results suggest that the LPP and MPP synapses tend to be enhanced in the dentate supra- and infrapyramidal blades, respectively, taking account of the thickness of each of the LPP and MPP fiber laminae in the blades. The dentate gyrus may select spatial and non-spatial pieces of information through synaptic cooperation, and may open a gate for each piece of information through synaptic competition. Then we investigated the role of inhibitory local circuits in synaptic competition in the dentate gyrus. The feed-forward GABA_B inhibition suppressed unusual high-frequency firing of the granule cell, and consequently prevented excessive synaptic depression due to synaptic competition through STDP. The feed-forward and feedback GABA_A inhibitions tend to reduce synaptic conductance fluctuations resulting from large increments and decrements due to very small spike-timings happening occasionally.