Faculty Bibliography

Fetal rat brain cell suspensions prepared from either the locus coeruleus region or hippocampus were implanted bilaterally into the subcortically denervated seizure-prone hippocampus of adult rats. Animals with locus coeruleus grafts were protected against picrotoxin-induced behavioral seizures and had significantly fewer interictal spikes. In contrast, in rats with fetal hippocampal grafts the incidence of interictal spikes was significantly higher than in lesion-only controls, and spontaneous behavioral seizures occurred in almost half of the animals. We suggest that neuronal grafting offers an alternative method for studying the mechanisms and control of epileptic brain activity

EEG and single-unit techniques have been used to study the EEG correlates of cellular firing in the neocortex, n. reticularis (RT) and 'specific' thalamic nuclei, and the cholinergic forebrain area (nucleus basalis, NB). Neuronal firing was related to the ongoing behavior of the rat. In addition, using a 16-channel neocortical recording/mapping system, we studied the effects of ibotenic acid lesion of NB, RT, and other thalamic nuclei on the patterns and spatial distribution of neocortical electrical activity. The majority of neurons in neocortex, NB, and RT increased their firing rates during walking, as compared to during immobility, with concurrent decrease of delta power in the neocortical EEG. During immobility, high-voltage spindles (HVS; greater than 1 mV) were occasionally recorded from the neocortex. Depth profiles of HVS and slow delta waves were different in the neocortex. Neocortical cells decreased their discharge frequency during the positive portion of delta waves recorded in layers V and VI. All cells in the neocortex and specific thalamic nuclei fired rhythmically and phase-locked to the spike component of HVS. RT neurons showed an opposite phase relationship and fired mainly during the wave component of HVS. Half of the NB neurons also showed phasic modulation with HVS. Circumscribed lesion of RT and extensive damage of other thalamic regions, including the intralaminar nuclei, suppressed HVS but had no effect on the neocortical EEG correlates of behavior. In sharp contrast, damage to the NB resulted in a dramatic increase of slow delta waves on the side of the lesion, mimicking the effect of scopolamine administration. We suggest that the NB plays a key role in neocortical arousal by directly activating the neocortex and by suppressing the rhythm generation in the RT-thalamocortical circuitry. We further suggest that the NB system may serve as a structural basis for the concept of the generalized ascending activation of Moruzzi and Magoun (1949)

Solid pieces of embryonic hippocampal tissue were implanted in a cavity formed by aspiration of the fimbria-fornix and the overlying cingulate cortex in adult rats. Six to 8 months after the transplantation, chronic recording electrodes were implanted into the graft and the host hippocampi for the recording of electroencephalogram and unit activity in the freely moving animal. Irregularly occurring sharp waves or electroencephalogram spikes and concurrent synchronous discharge of large groups of neurons dominated the electrical activity of the grafts, in contrast to the situation in normal animals. Light microscopy and GABA immunocytochemistry in the grafts revealed that the three major cell types of the hippocampal formation, i.e. pyramidal neurons, dentate granule cells and GABA-immunoreactive interneurons were present in the hippocampal grafts. At the ultrastructural level, however, significant alterations in connectivity were observed. The most striking finding was the absence or sparse occurrence of synapses on the axon initial segments of pyramidal neurons. The axon initial segments are normally densely covered by GABAergic synapses derived from a specialized type of interneuron, the chandelier or axo-axonic cell. On the other hand, numerous GABA-immunoreactive terminals were found in synaptic contact with somata of pyramidal neurons, suggesting that other types of GABAergic interneurons and their efferent connections may have developed in a normal manner. The cell bodies of pyramidal neurons received, in addition, several asymmetric synapses from GABA-negative terminals. These presumably excitatory synapses are not present on the somata of pyramidal cells in the normally developing hippocampus. We hypothesize that the somatic excitatory synapses originate, at least in part, from the axon collaterals of the neighbouring pyramidal cells in the graft. We suggest that the hyperexcitability of the neuronal circuitry within the graft is due to reduced inhibition (lack of axo-axonic synapses) coupled with increased collateral excitation of the pyramidal neurons

Electroencephalographic activity of the neocortex was evaluated in young (5-7 months) and aged (26-28 months) rats. All animals in the aged group showed behavioral impairment in a spatial task (water maze). A neocortical electroencephalogram was derived simultaneously from 16 different neocortical locations and was subjected to spectral analysis. The frequency of occurrence and duration of high-voltage spindles was determined in two sessions, each involving a total of 30 min alert immobility. Changes in spectral characteristics and high-voltage spindles in response to scopolamine administration were also evaluated. The power of high-frequency activity (8-20 Hz) was significantly reduced in the aged subjects. This was greatest in the temporo-occipital regions, while no significant changes were seen in the mediofrontal region. Scopolamine resulted in a large power increase in all frequency bands, but the increase in the higher-frequency range (8-20 Hz) was significantly less in the aged group. The incidence of high-voltage spindles was 6 times higher and their total duration was 9 times longer in aged rats, with virtually no overlap with the young group. In young rats, scopolamine increased the incidence and total duration of high-voltage spindles, while it decreased both parameters in the aged subjects. Cholinergic neurons in the nucleus basalis appeared shrunken in the aged animals. These findings demonstrate that reliable electroencephalographic changes are present in the neocortex of the aged rat, and that some of the physiological alterations may be due to the pathological changes in the cholinergic nucleus basalis

Rats exhibit morphological, biochemical, and metabolic changes in their brains, as well as cognitive deficits, with aging. Aged rats were found to be significantly impaired compared to young rats in a water maze task and test of motor coordination, and show reduced locomotor activity and exploration. Although aged rats did exhibit deficits as a group, not all aged rats were impaired. Additionally, the subgroup that was impaired on one task was not necessarily the subgroup that was impaired on another task. The cholinergic projection neurons in the basal forebrain region were significantly atrophied in the aged rodent. The degree of atrophy was highly correlated with the cognitive impairment exhibited on the Morris water maze task. Swollen choline acetyltransferase (ChAT)-positive 'plaque-like' structures were observed in the neocortex of the aged but not the young rats. Declines in cholinergic activity in the brain has also been observed during aging. Biochemical measurements of ChAT in the basal forebrain region of aged rats revealed small but consistent decreases in ChAT activity compared to young rats. General metabolic activity, measured by the 2-deoxyglucose method, was also decreased in the hippocampal CA1 and CA3 fields, the dentate gyrus, the medial septal-diagonal band area, and the prefrontal cortex of aged rats. There was a significant correlation between the decrease in glucose utilization and deficits on the Morris water maze. Most aged rats exhibit pathological EEG patterns as reflected by frequent long-duration high voltage neocortical spindles (HVS) during immobility. Bilateral lesions of the nucleus basalis and scopolamine treatment increased the incidence of HVS, thereby mimicking changes in the aged brain. We attempted to ameliorate the cognitive deficits observed in subgroups or impaired rats by either: (1) implanting fetal cells of basal forebrain origin into the hippocampus, or (2) infusing nerve growth factor (NGF) chronically into the lateral ventricle. The grafts appeared to facilitate an improvement in the ability of the impaired aged rats to perform in the Morris water maze. This improved performance was reversed by injections of atropine at doses that did not affect the behavior of young animals that performed well in the same task. These results suggest that enhancement of the cholinergic system could have an effect on the performance of the impaired aged animals. The study of the effects of infusions of NGF clearly demonstrate that the ability of impaired aged rats to remember what they had previously learned was increased after NGF treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic stimulating and recording electrodes were implanted in the perforant path (PP), the dentate gyrus, and the CA3 and CA1 regions in adult rats. Input-output curves were constructed from PP-dentate, dentate-CA3, and CA3-CA1 responses before and after 9 high-frequency trains (400 Hz, 20 ms) delivered to PP. The stimulations produced enhancement of the population spikes at each pathway tested, lasting from 1 to 24 h. It is hypothesized that the potentiating effect in the test pathways (dentate-CA3, CA3-CA1) occurred as a result of coupling the tetanizing trains via the direct PP-CA3/CA1 synapses with the asynchronous polysynaptic volleys occurring in the intrahippocampal circuitry. The findings suggest that the physiological role of the direct PP-pyramidal cell synapse may be to enhance the effectiveness of other inputs to these neurons

It has been debated whether or not decapitation of conscious animals is a humane procedure. This problem may be clarified on the basis of recent research that has indicated that neocortical low voltage fast activity (LVFA) and hippocampal rhythmical slow activity (RSA) can result from activity in either the cholinergic corticipetal projections from the basal forebrain or the serotonergic corticipetal projections from the brainstem. These inputs appear to produce, respectively, atropine-sensitive LVFA and RSA and atropine-resistant LVFA and RSA. In waking animals, atropine-resistant LVFA and RSA occur only in close correlation with motor activities such as spontaneous changes in posture, walking or struggling (Type 1 behavior). Painful stimuli readily elicit both Type 1 behavior and LVFA and RSA in atropine-treated rats. Atropine-sensitive LVFA and RSA may occur in anesthetized as well as in conscious animals, but atropine-resistant LVFA and RSA are generally absent during anesthesia. In the experiments reported here, rats were decapitated: (1) in the normal waking state; (2) after pretreatment with atropine or scopolamine; or (3) following induction of anesthesia with ethyl ether. Clear hippocampal RSA and neocortical LVFA were observed in conditions 1 and 3 but not in condition 2. It is concluded: (A) that atropine-sensitive LVFA and RSA are not good indices of conscious perception of pain since these waveforms occur during anesthesia as well as in the waking state; and (B) that the cerebral reaction to decapitation does not resemble the usual cerebral reaction to painful stimuli. This is consistent with the view that decapitation is not inhumane

This review summarizes the range of possible mechanisms of action of neuronal grafts in the central nervous system. It aims to illustrate the capacity and limitations of the transplanted tissue in the promotion of neurological recovery after experimental surgical insults

Spatial distribution of field responses evoked by perforant path stimulation were studied in the hippocampus of both anaesthetized and drug-free rats. Simultaneous recordings with an array of 4 electrodes allowed us to construct a 2-dimensional map of the evoked field potentials. In addition, we examined the effects of atropine-SO4 and urethane on the amplitude of the dentate response. Trisynaptic activation of the CA1 region occurred regularly in the drug-free rat while CA1 population spikes were rarely seen in the anaesthetized animal. The latency of the CA1 population spike was shortest at the fimbrial side and increased gradually towards the subicular side. In the dentate gyrus atropine increased the amplitude of the population spike. We suggest that atropine may interfere with the septo-hippocampal feed-forward inhibition, and urethane may decrease the effectiveness of the perforant path-granule cell synapse, as well as the intrahippocampal excitatory circuit