Faculty Bibliography

The effect of brain temperature and anesthesia on ischemic neuronal damage was studied in the hippocampal formation using the four vessel occlusion model in awake and anesthetized rats. Neuronal damage was assessed by immunocytochemistry and silver impregnation of tissue sections. The degree of ischemia was monitored by recording spontaneous and evoked electrical activity from the hippocampus and dentate gyrus in all animals. In addition, the hippocampal temperature and oxygen tension were also recorded using a chamber-type thin-film microelectrode in the anesthetized animals. Fifteen minutes ischemia in the awake animals caused greater neuronal damage and mortality of animals than 30 min ischemia in anesthetized rats. The temperature of the brain was found to drop by 4-6 degrees C during complete forebrain ischemia in the latter group. Neuronal damage was observed infrequently in the hippocampus of these animals. When the brain temperature was kept constant at the preischemic level during 30 min occlusion, all animals died within a day, while after 15 min occlusion the majority showed an almost complete degeneration of CA1 pyramidal cells and hilar somatostatin immunoreactive neurons. Following 15 min ischemia, the awake animals showed a similar cell loss in the CA1 region and the hilus. It is concluded that, in the anesthetized animals prepared for acute recording, the decreased temperature of the brain during ischemia is a major factor in protecting neurons from damage, but that Equithesin anesthesia also has a significant protective effect. Consistent ischemic degeneration occurs in awake animals by four vessel occlusion, if the brain temperature is controlled and the completeness of ischemia is monitored by recording spontaneous and evoked electrical activity with chronic electrodes

Fourteen months after receiving bilateral ibotenic acid lesions of the nucleus basalis magnocellaris (NBM), male rats demonstrated impairment in spatial learning in a water maze task, increased incidence of high voltage spindles, and significant depletion of cortical choline acetyltransferase (ChAT) activity. Histological evaluation revealed decreased acetylcholinesterase (AChE) staining but no plaque-like structures in the cortex

The relationship between neuronal calcium binding protein content (calbindin D28K: CaBP and parvalbumin: PV) and vulnerability to ischemia was studied in different regions of the rat brain using the four vessel occlusion model of complete forebrain ischemia. The areas studied, i.e. the hippocampal formation, neocortex, neostriatum and reticular thalamic nucleus (RTN), show a characteristic pattern of CaBP and PV distribution, and are involved in ischemic damage to different degrees. In the hippocampal formation CaBP is present in dentate granule cells and in a subpopulation of the CA1 pyramidal cells, the latter being the most and the former the least vulnerable to ischemia. Non-pyramidal cells containing CaBP in these regions survive ischemia, whereas PV-containing non-pyramidal cells in the CA1 region are occasionally lost. Hilar somatostatin-containing cells and CA3 pyramidal cells contain neither PV nor CaBP. Nevertheless, the latter are resistant to ischemia and the former is the first population of cells that undergoes degeneration. Supragranular pyramidal neurons containing CaBP are the most vulnerable cell group in the sensory neocortex. In the RTN the degenerating neurons contain both PV and CaBP. In the neostriatum, ischemic damage involves both CaBP-positive and negative medium spiny neurons, although the degeneration always starts in the dorsolateral neostriatum containing relatively few CaBP-positive cells. The giant cholinergic interneurons of the striatum contain neither CaBP nor PV, and they are the most resistant cell type in this area. These examples suggest the lack of a consistent and systematic relationship between neuronal CaBP or PV content and ischemic vulnerability. It appears that some populations of cells containing CaBP or PV are more predisposed to ischemic cell death than neurons lacking these proteins. These neurons may express high levels of calcium binding proteins because their normal activity may involve a high rate of calcium uptake and/or intraneuronal release

The ongoing micro-electroencephalogram was recorded with a chronically implanted comb-like array of 16 tungsten semi-microelectrodes 0.2 or 0.25 mm apart, spanning CA1 strata oriens, pyramidale and radiatum and into subiculum, in four behavioral states: walking, standing still, paradoxical and slow wave sleep and under scopolamine. Power, phase and coherence spectra were computed, the latter two for each of the 120 pairs, in frequency bands from 1 to 64 Hz. (1) Coherence is high for all frequencies within the same subfield, e.g. stratum radiatum, but falls with distance. Theta frequency (8 Hz), when prominent and widespread (during 'theta states' walking and paradoxical sleep), shows the most widespread synchrony: coherence falls slowly, from 1.0 at 0.2 mm to 0.7 at c. 2 mm longitudinally within stratum radiatum; all other frequencies fall two or three times faster. (2) An abrupt drop in coherence occurs across field borders (CA1-subiculum) and between stratum oriens and radiatum, across a line just under stratum pyramidale, between high coherence regions on each side of the coherence discontinuity. A less extreme drop occurs in stratum radiatum 0.4 mm from the subiculum border, without obvious histological correlate. The discontinuities in coherence are stable through all four behavioral states as well as under scopolamine. (3) Phase profiles diagonally across CA1 and into subiculum show abrupt, local shifts of phase (up to 125) at these same levels. No gradual shift reaching 180 (phase reversal) occurs in the span of loci examined. (4) The theta power peak in theta states is not necessarily due to additional energy in that band; in some conditions it is mainly due to reduced power in other frequencies. Root mean square voltage is generally less in the high theta ('synchronized') than in the non-theta states. Only the theta peak correlates with a peak in coherence. (5) Significant microstructure in the dynamics of neuronal cooperativity distinguishes behavioral states and regions of the hippocampal cortex

Rhythmic oscillation in neuronal systems may serve physiological purposes or may interfere with normal functions of the brain. In disorders of petit mal epilepsy and parkinsonian tremor, centrally and peripherally observable rhythmic patterns are due to network oscillations of thalamocortical cells. This article reviews the afferent mechanisms that might be critically involved in controlling the ionic conductances of thalamic neurons in the behaving organism. We propose that during active behavior the subcortical aminergic and cholinergic inputs to the thalamus act as anti-burst and anti-oscillation mechanisms. We suggest further that the thalamopetal GABAergic inputs (pars reticulata of substantia nigra, entopeduncular nucleus, pallidum) are burst- and oscillation-promoting systems, whose output is controlled by the striatum. Experimental or disease-related decrease of the striatal dopamine levels is hypothesized to increase the efficacy of the GABAergic burst-promoting systems resulting in rhythmic network oscillation of thalamocortical neurons during rest. The recognition of the overlapping neuronal mechanisms in petit mal epilepsy and parkinsonian tremor, and the multistage control of thalamic oscillation suggests that drugs effectively used in petit mal attacks may be effective in levodopa-refractory parkinsonian tremor, and conversely, epileptic patients may benefit from drugs acting on the extrapyramidal system

A combination of intracerebral grafting and intraventricular infusion of nerve growth factor was used to attempt to reconstruct the cholinergic component of the septohippocampal pathway following fimbria-fornix lesions in the rat. Four groups were tested: lesion only, lesion plus fetal hippocampal graft, lesion plus nerve growth factor, and lesion plus graft plus nerve growth factor. Choline acetyltransferase immunoreactivity, acetylcholinesterase fiber staining and behavior-dependent theta activity on electroencephalogram were used to assess the extent of pathway reconstruction. Nerve growth factor was infused for the first two weeks following the fimbria-fornix lesion, while electrophysiological measurements and histological analysis were conducted six to eight months later. The lesion plus graft plus nerve growth factor infusion group had long-term savings of choline acetyltransferase-immunoreactive cells as compared to the lesion only or lesion plus graft groups. In addition the lesion plus graft plus nerve growth factor infusion group had more extensive reinnervation of the hippocampus compared to all other groups. Behavioral-dependent theta activity on electroencephalogram was observed in some animals of both lesion plus graft and lesion plus graft plus nerve growth factor infusion groups, but not in other groups; however, unlike intact animals, the restored theta could be blocked completely by scopalamine. These results demonstrate that a combination of short-term intraventricular nerve growth factor infusion and fetal hippocampal grafts enhances reconstruction of the damaged septohippocampal circuit

While a variety of sprouting and regenerative responses have been investigated in the hippocampus, the cellular and molecular events responsible for these plastic responses have not been determined. One transmitter system, the cholinergic system, shows several distinct responses to damage in the septohippocampal circuit. Present evidence strongly supports a role for nerve growth factor (NGF) in these responses. NGF is not only important for the survival of the adult cholinergic neurons, but can also induce regrowth of the damaged fibers given an appropriate substratum for growth. These reparative effects of NGF can manifest themselves in functional recovery in the aged rat and the young rat with fimbria-fornix lesions. Finally, a role for glia cells is proposed to clarify how NGF availability may be regulated during the degenerative and regenerative events. While all plasticity events certainly cannot be explained by the coincidence of NGF and the cholinergic system, their interaction may provide a template for other transmitter/trophic factor interactions

Based on a review of anatomical and physiological findings, we suggest that the hippocampus may be viewed as a positive feedback device (autoassociator), which is capable of modifying the activity of the neocortical neurons. We examine the three-dimensional organization of evoked and spontaneous physiological patterns of the hippocampus and suggest rules how these patterns emerge during different behaviors from a hard-wired structural network. The high spatial coherence of theta activity is due to an external pacemaker, while the high synchrony of population bursts underlying hippocampal sharp waves is explained by the similar probability of recruitment of neurons by the burst-initiator cells along the whole extent of the hippocampus. We suggest that the burst-initiator cells are a group of CA3 neurons whose excitability is increased by a transient potentiation action of the neocortical activity during theta-concurrent exploratory behaviors. We hypothesize that sharp wave-concurrent population bursts result in a highly synchronous hippocampal output, converging preferentially on those entorhinal neurons which were instrumental in the creation of the burst-initiator neurons. The feedback action of population activity thus provides a selective mechanism for potentiation of connections between information-carrying neurons in the hippocampus and entorhinal cortex. The state-dependent operations of the anatomical hardware also point to the importance and advantage of studying the physiological activity of the intact brain

Recent studies provide evidence for a significant cholinergic projection from the nucleus basalis of Meynert (NbM) to the reticular and mediodorsal thalamic nuclei. We examined the incidence and distribution of plaques in the thalamus in order to determine whether in Alzheimer's disease degenerating cholinergic processes from the NbM induce the emergence of plaques according to the cholinergic hypothesis. The present study shows that degeneration of NbM neurons does not induce plaques in the thalamic nuclei it innervates, and that plaques appear more frequently in other thalamic nuclei that do not receive projections from the NbM

Field potentials and unitary activity were investigated in the grafted and the host hippocampi in freely moving rats and in vitro. The subcortical afferents and efferents of the hippocampus (fimbria-fornix, FF) were removed by aspiration. Solid pieces of hippocampal grafts derived from 15- to 16-day-old fetuses were placed in the lesion cavity in rats with unilateral FF lesions, and cell suspensions prepared from fetal hippocampi were grafted directly into the host hippocampi in animals with bilateral FF lesions. Reciprocal communication between the grafted and the host hippocampi was monitored with a 16-microelectrode probe from 7 to 10 months after grafting. The fluorescent retrograde tracer, Fluorogold, was used to examine graft-host projections and acetylcholinesterase staining to reveal host-derived fibers in the graft. The most typical neuronal pattern of the hippocampal graft was a highly synchronous population burst with concurrent EEG spike. The speed of propagation of the EEG spike within the graft and across the graft-host interface was either fast (greater than 3 m/s) or slow (less than 0.5 m/s). Large amplitude, short duration EEG spikes usually propagated with a high speed, while smaller amplitude, wider spikes with broad population bursts spread at a lower velocity. The direction of propagation was usually uniform indicating that the population burst was triggered by a localized subgroup of highly excitable neurons ('focus'). Spontaneous seizures were also present in the solid graft which frequently invaded the host hippocampus. The incidence of EEG spikes was three times higher in rats with bilateral suspension grafts than in animals with FF lesion only. In about half of the grafted rats spontaneous behavioral seizures were also observed. Intracellular recordings from putative pyramidal cells in the graft and in the host revealed large amplitude (10-12 mV), spontaneously occurring EPSPs. IPSPs were difficult to detect even during depolarizations of up to 20 mV from rest. We suggest that the increased excitability of the hippocampal graft is due to the high incidence of recurrent excitatory collaterals terminating on or close to the somata of pyramidal neurons. Population bursts may spread fast via extensively arborizing axon collaterals or slowly by successively activating new sets of neighboring neurons. Spontaneous behavioral convulsions are explained by assuming that the grafted hippocampus serves as an epileptic focus which is capable of kindling the host brain by repeated seizure induction.(ABSTRACT TRUNCATED AT 400 WORDS)