Exploratory behavior and reaction to novelty in rats with hippocampal perforant path systems disrupted.

In this article, exploratory behavior and reaction to novelty were investigated in rats with either disruption of the total hippocampal perforant path projection (TPP), the medial perforant path (MPP), or lateral perforant path (LPP). All three experimental groups displayed increased locomotor activity, and the LPP group was even more active than the TPP and MPP groups. The TPP and LPP animals made more rearings than the control rats. The MPP and LPP groups exhibited less exploration of familiar objects than the TPP and control groups. TPP animals appeared unable to recognize novelty, LPP rats showed decreased preference for novelty, and MPP rats had only a slight deficit in recognition of novelty. It is suggested that perforant path disruptions reduce the hippocampal formation's access to sensory information of neocortical origin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociations of the medial and lateral perforant path projections into dorsal DG, CA3, and CA1 for spatial and nonspatial (visual object) information processing.

Medial perforant path plasticity can be attenuated by 2-amino-5-phosphonovaleric acid (APV) infusions, whereas lateral perforant path plasticity can be attenuated by naloxone infusions. The present experiment was designed to evaluate the role of each entorhinal efferent pathway into the dorsal hippocampus for detection of spatial and nonspatial (visual object) changes in the overall configuration of environmental stimuli. Dorsal dentate gyrus infusions of either APV or naloxone attenuated detection of a spatial change, whereas only naloxone infusions disrupted novel object detection. Either APV or naloxone infusions into dorsal CA3 disrupted both spatial and novel object detection. APV infusions into dorsal CA1 attenuated detection of a spatial change, whereas naloxone infusions into dorsal CA1 disrupted novel object detection. These data suggest that each dorsal hippocampal subregion processes spatial and nonspatial (visual object) information from perforant path efferents in a unique manner that is consistent with the intrinsic properties of each subregion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The projection from hippocampal area CA1 to the subiculum sustains long-term potentiation

Long-term potentiation (LTP) is a popular model of the synaptic plasticity which may be engaged by the biological processes underlying learning and memory. Most available studies of LTP have concentrated on the analysis of LTP occurring in 'early' components of the hippocampal circuit (for example, dentate gyrus and area CA1). We examine here, for the first time, LTP as it occurs in the massive, unidirectional projection from CA1 to the subiculum in vivo. We show that this projection sustains high-frequency stimulus-induced LTP (10 trains of 20 stimuli at 200 Hz; intertrain interval 2 s; LTP 181 +/- 9% at 30 min post-LTP induction). In addition, input-output (I/O) curves show a leftward shift for all stimulation values.     

Electrophysiological characterization of GABAergic neurons in the ventral tegmental area

GABAergic neurons in the ventral tegmental area (VTA) play a primary role in local inhibition of mesocorticolimbic dopamine (DA) neurons but are not physiologically or anatomically well characterized. We used in vivo extracellular and intracellular recordings in the rat VTA to identify a homogeneous population of neurons that were distinguished from DA neurons by their rapid-firing, nonbursting activity (19.1 +/- 1.4 Hz), short-duration action potentials (310 +/- 10 microseconds), EPSP-dependent spontaneous spikes, and lack of spike accommodation to depolarizing current pulses. These non-DA neurons were activated both antidromically and orthodromically by stimulation of the internal capsule (IC; conduction velocity, 2.4 +/- 0.2 m/sec; refractory period, 0.6 +/- 0.1 msec) and were inhibited by stimulation of the nucleus accumbens septi (NAcc). Their firing rate was moderately reduced, and their IC-driven activity was suppressed by microelectrophoretic application or systemic administration of NMDA receptor antagonists. VTA non-DA neurons were recorded intracellularly and showed relatively depolarized resting membrane potentials (-61.9 +/- 1.8 mV) and small action potentials (68.3 +/- 2.1 mV). They were injected with neurobiotin and shown by light microscopic immunocytochemistry to be multipolar cells and by electron microscopy to contain GABA but not the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH). Neurobiotin-filled dendrites containing GABA received asymmetric excitatory-type synapses from unlabeled terminals and symmetric synapses from terminals that also contained GABA. These findings indicate that VTA non-DA neurons are GABAergic, project to the cortex, and are controlled, in part, by a physiologically relevant NMDA receptor-mediated input from cortical structures and by GABAergic inhibition.     

Long-term potentiation facilitates behavioral responding to single-pulse stimulation of the perforant path.

Three experiments, with 32 male hooded Sprague-Dawley rats, examined whether long-term potentiation (LTP) could enhance the stimulus properties of electrical brain stimulation. In Exp I, a paradigm was developed in which single-pulse stimulation of the perforant path (PP) could acquire control over operant responses. Evoked potentials were recorded from the dentate gyrus (DG) to measure the postsynaptic consequences of the stimulus and to monitor synaptic efficacy in the PP–DG synapses. Exp II confirmed the relation between the amount of evoked activity and acquisition rate and also showed that transecting the PP impaired performance. In Exp III, high-frequency stimulation of the PP produced LTP and accelerated subsequent acquisition of behavioral responding to PP stimulation. Results document a link between increases in synaptic efficacy and changes in behavior and thereby demonstrate the ability of LTP to serve as at least 1 component of the neural bases of learning and memory. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interaction between paired-pulse facilitation and long-term potentiation in the projection from hippocampal area CA1 to the subiculum

Studies of the interaction between long-term potentiation (LTP) and paired-pulse facilitation (PPF) may throw light on the role of presynaptic factors in LTP. We examine here, for the first time, the nature of PPF in the CA1-subiculum projection. PPF peaks at a 50 ms interstimulus interval (ISI) and is evident at ISIs from 10 to 500 ms. There is no PPF effect at a 1000 ms ISI. PPF decreases in magnitude post-LTP induction across the middle range of ISI values tested (30, 50 and 100 ms). There is a positive correlation between initial PPF values and LTP; this correlation increases as the ISI increases. Initial values and the change in PPF post-LTP are also negatively correlated.     

Ethanol inhibition of AMPA and kainate receptor-mediated depolarizations of hippocampal area CA1

Longitudinal hippocampal slices were prepared from adult female rats. The excitatory amino acids, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainic acid, were applied to area CA1, and the resulting depolarizations were measured using the grease-gap electrophysiological technique. Agonist dose-response curves were generated in the presence and absence of various concentrations of ethanol. Ethanol (25-200 mM) significantly attenuated the depolarizations that were produced by each agonist. In addition, we found that ethanol potently antagonized kainate-induced depolarizations across the agonist concentration-response curve, whereas it significantly suppressed only AMPA responses that were induced with moderate-to-high agonist concentrations. These results indicate that ethanol has potent antagonist actions against non-N-methyl-D-aspartate (NMDA) excitatory amino acid-induced neuronal depolarizations in hippocampal area CA1. Moreover, the relative potency of ethanol depends on the specific excitatory agonist tested and the concentration of that agonist. This suggests that, in addition to the known effects of ethanol on NMDA receptor-mediated activity, it may also potently attenuate ongoing "fast" glutamatergic synaptic activity in the hippocampus.     

Self-sustaining status epilepticus after brief electrical stimulation of the perforant path

We examined the duration of intermittent perforant path stimulation (PPS) needed to induce self-sustaining status epilepticus (SSSE) in rats. Seven-minute PPS did not induce SSSE. Some rats receiving 15 min and all animals after 30 min PPS developed SSSE that continued for hours. The animals killed 3 days after SSSE showed extensive neuronal damage. Those which were allowed to survive for 6 weeks after SSSE displayed spontaneous seizures.     

Properties of spontaneous miniature GABAA receptor mediated synaptic currents in area CA3 of rat hippocampal slice cultures

Miniature, gamma-aminobutyric acid A receptor mediated inhibitory postsynaptic currents (mIPSCs) were recorded from CA3 pyramidal cells in hippocampal slice cultures using whole-cell techniques in the presence of tetrodotoxin. The kinetics and amplitudes of the mIPSCs were analyzed with the aim of determining whether subclasses of events arising from distinct populations of presynaptic interneurons could be distinguished. Histograms of mIPSC amplitude, rise time constant, and decay time constant were all positively skewed, but discrete subsets of events could not be distinguished. The positive skew did not appear to result from electrotonic filtering of distal synaptic currents because there was no correlation among mIPSC amplitudes and the kinetic parameters. Analysis of the intervals between mIPSCs indicated that each event occurred independently. The analysis of spontaneous mIPSCs does not provide evidence of the innervation of pyramidal cells by heterogeneous interneurons.     

Long-term and short-term plasticity in the CA1, CA3, and dentate regions of the rat hippocampal slice

Subregions of the rat hippocampal slice were investigated in relation to (a) the presence of long-term potentiation and (b) responsiveness to low-frequency stimulation. Long-term potentiation was observed in CA1, CA3 and dentate. The effect occasionally lasted up to 6 h, developed gradually, and depended upon repeated low-frequency tetani for maximal effect. To low-frequency monosynaptic stimulation, areas CA3 and CA1 exhibit response facilitation whereas the dentate gyrus exhibits response depression. Reponsiveness in all areas was influenced by stimulus frequency. Recovery was rapid in all areas.     

Characterization of perforant path lesions in rodent models of memory and attention

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.     

Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1

Long-term potentiation (LTP) of the Schaffer collateral/commissural inputs to CA1 in the hippocampus was shown to consist of N-methyl-D-aspartate receptor (NMDAR) and voltage-dependent calcium channel (VDCC) dependent forms. In this study, the relative contributions of these two forms of LTP in in vitro hippocampal slices from young (2 mo) and old (24 mo) Fischer 344 rats were examined. Excitatory postsynaptic potentials (EPSP) were recorded extracellularly from stratum radiatum before and after a tetanic stimulus consisting of four 200-Hz, 0.5-s trains given 5 s apart. Under control conditions, a compound LTP consisting of both forms was induced and was similar, in both time course and magnitude, in young and old animals. NMDAR-dependent LTP (nmdaLTP), isolated by the application of 10 microM nifedipine (a voltage-dependent calcium channel blocker), was significantly reduced in magnitude in aged animals. The VDCC dependent form (vdccLTP), isolated by the application of 50 microM D,L-2-amino-5-phosphonvalerate (APV), was significantly larger in aged animals. Although both LTP forms reached stable values 40-60 min posttetanus in young animals, in aged animals vdccLTP increased and nmdaLTP decreased during this time. In both young and old animals, the sum of the two isolated LTP forms approximated the magnitude of the compound LTP, and application of APV and nifedipine or genestein (a tyrosine kinase inhibitor) together blocked potentiation. These results suggest that aging causes a shift in synaptic plasticity from NMDAR-dependent mechanisms to VDCC-dependent mechanisms. The data are consistent with previous findings of increased L-type calcium current and decreased NMDAR number in aged CA1 cells and may help explain age-related deficits in learning and memory.     

Intrinsic oscillations in CA3 hippocampal pyramids: physiological relevance to theta rhythm generation

The theta rhythm is the most remarkable hippocampal activity correlated with various physiological and behavioral phenomena. Although analyzed by numerous investigators, during the last five decades, the mechanisms that lead to its generation still remain reason of debate. In the present report it is shown that hippocampal neurons, recorded from juvenile and adult slices, are endowed with intrinsic properties that allow the generation of a steady oscillatory activity. The frequency of this rhythmic ongoing process is highly sensitive to the level of the membrane potential, reaching values in the theta range, up to 6 Hz, for more depolarized values of membrane potential. Membrane potential oscillations are unmasked by loading pyramidal neurons with intracellular cesium, are sodium-independent, and are generated by the sequential activation of calcium and potassium conductances. Finally, like theta rhythm, regularly occurring membrane potential oscillations can be detected since postnatal day 10 and their frequency increases with age, i.e., during the following 2 weeks.     

Synaptic target selectivity and input of GABAergic basket and bistratified interneurons in the CA1 area of the rat hippocampus

To assess the position of interneurons in the hippocampal network, fast spiking cells were recorded intracellularly in vitro and filled with biocytin. Sixteen non-principal cells were selected on the basis of 1) cell bodies located in the pyramidal layer and in the middle of the slice, 2) extensive labeling of their axons, and 3) a branching pattern of the axon indicating that they were not axo-axonic cells. Examination of their efferent synapses (n = 400) demonstrated that the cells made synapses on cell bodies, dendritic shafts, spines, and axon initial segments (AIS). Statistical analysis of the distribution of different postsynaptic elements, together with published data (n = 288) for 12 similar cells, showed that the interneurons were heterogeneous with regard to the frequency of synapses given to different parts of pyramidal cells. When the cells were grouped according to whether they had less or more than 40% somatic synaptic targets, each population appeared homogeneous. The population (n = 19) innervating a high proportion of somata (53 +/- 10%, SD) corresponds to basket cells. They also form synapses with proximal dendrites (44 +/- 12%) and rarely with AISs and spines. One well-filled basket cell had 8,859 boutons within the slice, covering an area of 0.331 mm2 of pyramidal layer tangentially and containing 7,150 pyramidal cells, 933 (13%) of which were calculated to be innervated, assuming that each pyramidal cell received nine to ten synapses. It was extrapolated that the intact axon probably had about 10,800 boutons innervating 1,140 pyramids. The proportion of innervated pyramidal cells decreased from 28% in the middle to 4% at the edge of the axonal field. The other group of neurons, the bistratified cells (n = 9), showed a preference for dendritic shafts (79 +/- 8%) and spines (17 +/- 8%) as synaptic targets, rarely terminating on somata (4 +/- 8%). Their axonal field was significantly larger (1,250 +/- 180 microns) in the medio-lateral direction than that of basket cells (760 +/- 130 microns). The axon terminals of bistratified cells were smaller than those of basket cells. Furthermore, in constrast to bistratified cells, basket cells had a significant proportion of dendrites in stratum lacunosum-moleculare suggesting a direct entorhinal input. The results define two distinct types of GABAergic neuron innervating pyramidal cells in a spatially segregated manner and predict different functions for the two inputs. The perisomatic termination of basket cells is suited for the synchronization of a subset of pyramidal cells that they select from the population within their axonal field, whereas the termination of bistratified cells in conjunction with Schaffer collateral/commissural terminals may govern the timing of CA3 input and/or voltage-dependent conductances in the dendrites.     

Evidence from simultaneous intracellular recordings in rat hippocampal slices that area CA3 pyramidal cells innervate dentate hilar mossy cells

1. Simultaneous intracellular recordings of area CA3 pyramidal cells and dentate hilar "mossy" cells were made in rat hippocampal slices to test the hypothesis that area CA3 pyramidal cells excite mossy cells monosynaptically. Mossy cells and pyramidal cells were differentiated by location and electrophysiological characteristics. When cells were impaled near the border of area CA3 and the hilus, their identity was confirmed morphologically after injection of the marker Neurobiotin. 2. Evidence for monosynaptic excitation of a mossy cell by a pyramidal cell was obtained in 7 of 481 (1.4%) paired recordings. In these cases, a pyramidal cell action potential was followed immediately by a 0.40 to 6.75 (mean, 2.26) mV depolarization in the simultaneously recorded mossy cell (mossy cell membrane potentials, -60 to -70 mV). Given that pyramidal cells used an excitatory amino acid as a neurotransmitter (Cotman and Nadler 1987; Ottersen and Storm-Mathisen 1987) and recordings were made in the presence of the GABAA receptor antagonist bicuculline (25 microM), it is likely that the depolarizations were unitary excitatory postsynaptic potentials (EPSPs). 3. Unitary EPSPs of mossy cells were prone to apparent "failure." The probability of failure was extremely high (up to 0.72; mean = 0.48) if the effects of all presynaptic action potentials were examined, including action potentials triggered inadvertently during other spontaneous EPSPs of the mossy cell. Probability of failure was relatively low (as low as 0; mean = 0.24) if action potentials that occurred during spontaneous activity of the mossy cell were excluded. These data suggest that unitary EPSPs produced by pyramidal cells are strongly affected by concurrent synaptic inputs to the mossy cell. 4. Unitary EPSPs were not clearly affected by manipulation of the mossy cell's membrane potential. This is consistent with the recent report that area CA3 pyramidal cells innervate distal dendrites of mossy cells (Kunkel et al. 1993). Such a distal location also may contribute to the high incidence of apparent failures. 5. Characteristics of unitary EPSPs generated by pyramidal cells were compared with the properties of the unitary EPSPs produced by granule cells. In two slices, pyramidal cell and granule cell inputs to the same mossy cell were compared. In other slices, inputs to different mossy cells were compared. In all experiments, unitary EPSPs produced by granule cells were larger in amplitude but similar in time course to unitary EPSPs produced by pyramidal cells. Probability of failure was lower and paired-pulse facilitation more common among EPSPs triggered by granule cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Organization of direct hippocampal efferent projections to the cerebral cortex of the rhesus monkey: projections from CA1, prosubiculum, and subiculum to the temporal lobe

This study investigates direct hippocampal efferent projections to the temporal lobe of the rhesus monkey. Tritiated amino acid injections were placed into the hippocampal formation to identify terminal fields, and complementary fluorescent retrograde tracer injections were placed into the cortex to identify the cells of origin. Tritiated amino acid injections into CA1, prosubicular, or subicular subfields produced anterograde label over parts of the parahippocampal gyrus and temporal pole. Injections of fluorescent retrograde tracers demonstrated that these projections originate from longitudinal strips of neurons that occupy part of the CA1 subfield as well as from strips of neurons in adjacent prosubicular and subicular subfields. Thus, an injection into area TH of the posterior parahippocampal gyrus labeled neurons in a longitudinal strip of proximal CA1 (i.e., near CA2) as well as a strip in the subiculum; injections into areas TF, TL, 35, or Pro labeled neurons in a longitudinal strip of distal CA1 (i.e., near the prosubiculum) as well as one in the prosubiculum; and an injection into area TFO labeled neurons in a longitudinal strip in the middle of CA1. These strips of neurons extended longitudinally throughout the entire rostrocaudal length of the hippocampus. These results demonstrate that, in the monkey, CA1 projections to cortex arise topographically from longitudinally oriented strips of neurons that occupy only a part of the transverse extent of CA1 but that cover most of the anteroposterior extent of the hippocampus. Thus, in the monkey, CA1 is not a single uniform entity and may have a unique role as a source of direct hippocampal projections to the cerebral cortex.     

Degeneration of hippocampal CA3 pyramidal cells induced by intraventricular kainic acid

Degeneration of hippocampal CA3 pyramidal cells was investigated by light and electron microscopy after intraventricular injection of the potent convulsant, kainic acid. Electron microscopy revealed evidence of pyramidal cell degeneration within one hour. The earliest degenerative changes were confined to the cell body and proximal dendritic shafts. These included an increased incidence of lysosomal structures, deformation of the perikaryal and nuclear outlines, some increase in background electron density, and dilation of the cisternae of the endoplasmic reticulum accompanied by detachment of polyribosomes. Within the next few hours the pyramidal cells atrophied and became electron dense. Then these cells became electron lucent once more as ribosomes disappeared and their membranes and organelles broke up and disintegrated. Light microscopic changes correlated with these ultrastructural observations. The dendritic spines and the initial portion of the dendritic shaft became electron dense within four hours and degenerated rapidly, whereas the intermediate segment of the dendrites swelled moderately and became more electron lucent. No degenerative changes were evident in pyramidal cell axons and boutons until one day after kainic acid treatment. Less than one hour after kainic acid administration, astrocytes in the CA3 area swelled, initially in the vicinity of the cell body and mossy fiber layers. It is suggested that the paroxysmal discharges initiated in CA3 pyramidal cells by kainic acid served as the stimulus for this response. Phagocytosis commenced between one and three days after kainic acid administration, but remained incomplete at survival times of 6-8 weeks. Astrocytes, microglia, and probably oligodendroglia phagocytized the degenerating material. These results point to the pyramidal cell body and possibly also the dendritic spines as primary targets of kainic acid neurotoxicity. In conjunction with other data, they support the view that lesions made by intraventricular kainic acid can serve as models of epileptic brain damage.     

Active summation of excitatory postsynaptic potentials in hippocampal CA3 pyramidal neurons

The manner in which the thousands of synaptic inputs received by a pyramidal neuron are summed is critical both to our understanding of the computations that may be performed by single neurons and of the codes used by neurons to transmit information. Recent work on pyramidal cell dendrites has shown that subthreshold synaptic inputs are modulated by voltage-dependent channels, raising the possibility that summation of synaptic responses is influenced by the active properties of dendrites. Here, we use somatic and dendritic whole-cell recordings to show that pyramidal cells in hippocampal area CA3 sum distal and proximal excitatory postsynaptic potentials sublinearly and actively, that the degree of nonlinearity depends on the magnitude and timing of the excitatory postsynaptic potentials, and that blockade of transient potassium channels linearizes summation. Nonlinear summation of synaptic inputs could have important implications for the computations performed by single neurons and also for the role of the mossy fiber and perforant path inputs to hippocampal area CA3.     

Comparison of the short- and long-lasting effects of perforant path kindling on radial maze learning.

Compared the long-lasting with the short-lasting effects of kindling the perforant path input to the hippocampal formation on the acquisition of 2 radial maze tasks. Animals in the long-term group were fully kindled (i.e., Stage 5 motor seizures were evoked) prior to a stimulation-free training period. Animals in the short-term group were kindled 30–45 min prior to each learning trial. A 3rd group of animals served as controls and were never kindled. On both 8-arm and 4/8-arm radial maze tasks, learning impairments were apparent only in the short-term group. Thus, the impaired learning is more likely related to the short-term aftereffects of an afterdischarge than to any long-term alterations in the neuronal status of the brain caused by kindling. (PsycINFO Database Record (c) 2010 APA, all rights reserved)