Faculty Bibliography

The involvement of brain deoxyribonucleic acid (DNA) synthesis in adaptive neural events was studied in the adult rat during long-term habituation (LTH) or potentiation (LTP) of the perforant path-granule cell synapse. Male Long-Evans rats were given 50 muCi [3H]thymidine intraventricularly under urethane anesthesia. Soon thereafter, field excitatory postsynaptic potential (EPSP) slope and population spike were monitored from the right dentate gyrus before and at various times (5, 10, 15, 60 min) following the delivery to the ipsilateral perforant bundle of a low frequency (LFS: 1.0 Hz, 160 s) or a high-frequency train (HFS: 400 Hz, 200 ms), repeated once after 5 min. Unstimulated implanted rats served as controls. DNA synthesis was evaluated by the incorporation of the radioactive precursor into DNA of several brain areas at the end of a 1 h incorporation period. In CA1, LTH and LTP increased DNA synthesis by 30% on the stimulated side. In the entorhinal cortex, LTH but not LTP increased DNA synthesis (by 30%) on the stimulated side. Conversely, in the frontal cortex, LTP but not LTH increased DNA synthesis (by 100%) on both sides. Long-lasting changes in synaptic efficacy covaried non-linearly with DNA synthesis in mono- and polysynaptically stimulated hippocampal regions, and in functionally associated neocortical areas. The co-variations of population spike amplitude were positive for LTH and negative for LTP in the dentate gyrus and frontal cortex of both sides, and in CA3/CA1 of the stimulated side, indicating higher DNA synthesis at lower values of LTH and LTP, and viceversa. Further, regional cross-correlation analyses revealed a high degree of synchronization among brain sites, following low- or high-frequency train pulses, indicating that (i) extra-target sites participate on the stimulated and on the contralateral side, and (ii) small distributed changes take place across the sampled neural networks. A modulatory role of information flow on brain DNA synthesis is inferred to take place in a diffuse, distributed manner

Based on the experimental evidence from his laboratory and the relevant literature the Author outlines a formal model of memory trace formation. During exploratory (theta) behaviors the neocortical information is transmitted to the hippocampus via the fast-firing granule cells which may induce a weak and transient heterosynaptic potentiation in a subgroup of CA3 pyramidal cells. The weakly potentiated CA3 neurons will then initiate population bursts upon the termination of exploratory activity (sharp wave state). It is assumed that recurrent excitation during the population burst is strongest on those cells which initiated the population event. It is suggested that the strong excitatory drive brought about by the sharp wave-concurrent population bursts during consummatory behaviors, immobility, and slow wave sleep may be sufficient for the induction of long-term synaptic modification in the initiator neurons of the CA3 region and in their targets in CA1. In this two-stage model both exploratory (theta) and sharp wave states of the hippocampus are essential and any interference that might modify the structure of the population bursts (e.g., epileptic spikes) are detrimental to memory trace formation

Spontaneous hippocampal EEG activity and evoked field potentials were investigated in intact rats and in animals with fetal hippocampal grafts. Pieces of hippocampal grafts, derived from 15- to 16-day-old fetuses, were used to prepare cell suspensions and grafted directly into the intact hippocampus. Control animals received suspension grafts of the cerebellum derived from fetuses of identical age. Host hippocampal electrical patterns were monitored with chronic single electrodes or with a 16-microelectrode probe from 7 to 10 months after grafting. In contrast to previously reported high survival rates of fetal grafts in studies with damage to the host brain prior to grafting, survival of both hippocampal (60%) and cerebellar grafts (20%) was very poor in the intact hippocampus. In animals with cerebellar transplants or without surviving grafted neurons the electrical activity of the host hippocampus was indistinguishable from normal controls. In rats with hippocampal grafts short duration, large amplitude EEG spikes (up to 10 mV) were recorded, predominantly during immobility. When the EEG spikes (putative interictal spikes) were of large amplitude and contained population spikes, test evoked responses delivered to the perforant path were suppressed after the spontaneous events. In contrast, evoked responses were facilitated by interictal spikes without population spikes. The threshold of electrically induced afterdischarges did not differ significantly between groups of intact rats and animals with or without hippocampal grafts. However, in three rats with hippocampal grafts the evoked afterdischarges were associated with behavioral seizures. In two of these rats spontaneously occurring seizures were also observed. Synaptophysin-immunoreactivity demonstrated growth of the host mossy fibers into the graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous and evoked field potentials and cellular discharges of the subcortically denervated dorsal hippocampus were studied by multisite recordings in the freely behaving rat. Characteristic short-duration (< 100 ms), large-amplitude (up to 10 mV) transients, termed interictal spikes (IIS), were seen after fimbria-fornix (FF) lesion. Both pyramidal cells and putative interneurons fired maximally during IIS, with some interneurons sustaining long bursts (up to 400 ms) of high-frequency discharges (400-600 Hz) after the IIS. The speed of propagation of IIS along the longitudinal axis of the hippocampus varied from 0.2 m/s to > 3 m/s. The majority of IIS (type 1) could be accounted for by an enhanced activity of the intrahippocampal associational systems; a second class of IIS (type 2) had positive polarities in the stratum radiatum of CA1 and CA3 and propagated very rapidly (> 1.5 m/s). The authors propose that type 2 IIS reflect somatic depolarization and discharge of pyramidal neurons due to nonsynaptic (probably ephaptic) effects. Ephaptic interactions may also explain the longitudinal propagation of IIS at speeds higher than the conduction velocities (0.5 m/s) of hippocampal fiber systems. IIS emerged during the first 3 weeks after fimbria-fornix lesion, their incidence reaching a plateau of 2/min thereafter. During the same time period, paired-pulse suppression increased in the dentate gyrus. The amplitude of test responses to angular bundle stimulation was potentiated by small-amplitude IIS but suppressed by large-amplitude IIS. The incidence of IIS was significantly suppressed during walking relative to standing still. Tetanic stimulation of the angular bundle or handling-induced stress resulted in a 10- to 20-fold increase in the incidence of IIS that lasted for about 30 minutes. There was a negative correlation between evoked field PSP slope and population spike amplitude in the dentate gyrus of FF-lesioned rats; this correlation was positive in intact rats. The authors attribute the above pathophysiological changes to sprouting of both excitatory and inhibitory GABAergic pathways as a result of denervation of the intrahippocampal circuitry. They hypothesize that the majority of the observed physiological alterations can be traced to a weakening of feedforward inhibition coupled with an enhancement of feedback inhibition and excitation

The effects of alpha-adrenergic drugs on neocortical high voltage spike and wave spindles (HVS), reflecting thalamic oscillation, was investigated in freely moving rats. HVS occurred spontaneously in the awake but immobile animal. Peripheral administration of the alpha-1 antagonist, prazosin and alpha-2 agonists, xylazine and clonidine increased the incidence and duration of HVS in a dose-dependent manner. The alpha-2 antagonist, yohimbine and the tricyclic antidepressants, desipramine and amitriptyline, significantly decreased the incidence of the neocortical HVS. Bilateral microinjections of the alpha-2 agonists into the nucleus ventralis lateralis area of the thalamus, but not into the hippocampus or corpus callosum, was as effective as peripheral injection of these drugs. Xylazine was most effective in Fischer 344 rats that display high spontaneous rate of HVS and less effective in the Sprague - Dawley and Buffalo strains. The HVS-promoting effect of clonidine was antagonized by prior intrathalamic injection of the alpha-2 antagonist, yohimbine. The amplitude of the HVS was increased by picomole amounts of unilaterally-injected clonidine. Neurotoxic destruction of the thalamopetal noradrenergic afferents by intracisternal or intrathalamic injection of 6-hydroxydopamine, but not by peripheral administration of DSP-4, increased the incidence of HVS. Importantly, intrathalamic administration of xylazine continued to induce HVS after destroying the thalamic noradrenergic terminals. Following downregulation of the alpha-2 adrenoceptors by chronic administration (3 weeks) of amitriptylene the incidence of HVS decreased and the effectiveness of intrathalamic xylazine on the induction of HVS was significantly reduced. Based on these findings, we suggest that a major action of alpha-2 adrenergic drugs on thalamic oscillation may be mediated by postsynaptic alpha-2 adrenoceptors located on the thalamocortical neurons. We hypothesize that noradrenaline in the thalamus has a dual effect on the relay cells: blocking and promoting thalamic oscillation via alpha-1 and alpha-2 receptors, respectively. The final physiological effect is assumed to be a function of the relative density and affinity of these adrenergic receptor subtypes

Rhythmical oscillation of thalamic neuronal populations occurs under physiological conditions and in several disease states. In the present experiments we examined the network properties of population rhythmicity and the possible involvement of N-methyl-D-aspartate receptors in the frequency regulation and maintenance of rhythmic thalamic bursts. Multisite recording of neuronal activity and local microinjections of drugs were performed on the freely moving rat. Rhythmic thalamic population bursts at 6 to 9 Hz and concurrent neocortical high voltage spike-and-wave spindles were observed during awake immobility, with the thalamic rhythm leading the neocortical high voltage spindle. Even though all individual thalamocortical neurons fired in a phase-locked manner to the high-voltage spindle, the majority discharged at a significantly lower frequency than that of the population (multiunit) activity. In contrast, neurons in the nucleus reticularis thalami discharged at the frequency of the population bursts. Neurons in the extrapyramidal system and neocortex but not the hippocampal formation also fired in a phase-locked manner to the high-voltage spindle. Systemic administration or local microinjection of either non-competitive or competitive N-methyl-D-aspartate blockers (ketamine or ap-5) slowed the frequency of thalamic multiunit bursts and associated high-voltage spindles from 8 to 2 Hz, or completely blocked rhythmicity. Unilateral thalamic injection of ketamine or ap-5 resulted in a suppression of the amplitude of high-voltage spindles in the injected hemisphere. It is concluded that thalamic rhythmicity is not due to the 'pacemaker' properties of thalamic cells but is rather an emergent property of the relay thalamus-nucleus reticularis network. Furthermore, we hypothesize that the frequency of network oscillation is regulated by the interplay between two major classes of voltage-dependent conductances in the thalamocortical cells: low-threshold calcium channels and high-threshold N-methyl-D-aspartate channels

Spontaneously occurring and drug-induced high voltage spike-and-wave electroencephalogram patterns were examined in inbred rats of the Fischer 344 and Buffalo strains and of the random-bred Sprague-Dawley strain at different ages. In addition, tyrosine hydroxylase activity and dopamine D2 receptor density were determined in the substantia nigra, corpus striatum, olfactory tubercle and ponsmedulla areas of Fisher 344 and Buffalo animals. High voltage spike-and-wave episodes were present in 87.5% of the 3-month-old and in 100% of the older Fischer 344 rats. High voltage spike-and-wave episodes were completely absent in 3-month-old Buffalo and Sprague-Dawley animals but could be induced by systemic injection of pentylenetetrazol and at an older age they appeared in 58.3% (12-month) and 71.4% (greater than 26-month) of the subjects of these strains. The incidence and duration of high voltage spike-and-wave episodes were significantly higher/longer in Fischer 344 rats than in the age-matched Buffalo and Sprague-Dawley animals. The dopamine blocker acepromazine induced a several-fold increase of the incidence and duration of high voltage spike-and-wave episodes in 3-month-old Fischer 344 rats, but failed to induce high voltage spike-and-wave episodes in Buffalo animals at this age. However, acepromazine also triggered high voltage spike-and-wave episodes in Buffalo rats when they were pretreated with subthreshold doses of pentylenetetrazol. Tyrosine hydroxylase activity was significantly higher in the substantia nigra, corpus striatum and olfactory tubercle of the Fischer 344 strain than in Buffalo rats. The higher tyrosine hydroxylase activity was paralleled with significantly higher D2 binding values in the corpus striatum and olfactory tubercle of Fischer 344 rats. These findings suggest that the neocortical high voltage spike-and-wave phenotype is genetically mediated and that the inbred Fischer 344 and Buffalo rats with defined bilineal origin will facilitate future works aimed at the identification of genetic elements involved in the generation of neocortical high voltage spike-and-wave episodes. The significant genotype x age interaction supports the suggestion, however, that high voltage spike-and-wave episodes are likely to be influenced by more than one gene; some of them are probably related to the regulation of brain aminergic systems