The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis.

In 27 of 28 children with congenital lactic acidosis, cerebrospinal fluid lactate was higher than venous blood lactate. The mean +/- SEM difference between these variables was 2.4 +/- 0.3 mmol/L (P =.0001). Girls or patients with pyruvate dehydrogenase deficiency had higher cerebrospinal fluid lactate concentrations than boys or patients with respiratory chain defects or mitochondrial DNA mutations.

NMDA receptor blockade alters the topography of naturally occurring ganglion cell death in the rat retina.

During the first 10 days after birth around half the rat's retinal ganglion cells die. Previous work has shown that ganglion cells whose axons have made large topographic targeting errors are preferentially eliminated during this period and that the selection of such cells for preferential elimination is dependent on an activity-driven mechanism: this process is one way in which the postnatal refinement of the topography of the retinocollicular projection is achieved. We have given systemic injections of the NMDA channel blocker MK801 during the first 14 days of life to see whether this activity-dependent process works via the NMDA channel. We assessed the topographic pattern of retinal ganglion cell death by making localized injections of fast blue into the superior colliculus at birth and measuring the distribution of labeled ganglion cells either at Postnatal Day 2 or at Day 14. We find that overall retinal ganglion cell death, measured by optic nerve axon counts, is not prevented by MK801 treatment. However, whereas in untreated animals ganglion cells whose axons have reached the most topographically inappropriate target area are preferentially eliminated, in MK801-treated animals ganglion cell death appears to be random, in that we see no evidence of the preferential elimination of retinal ganglion cells whose axons have made large topographic targeting errors in MK801-treated animals. NMDA receptor blockade therefore has the same effect on the pattern of retinal ganglion cell death as tetrodotoxin blockade of the retina.

A comparison of the initial retinal ganglion cell projection to the contralateral superior colliculus in albino and pigmented rats.

Newborn albino and pigmented rats received localised Fast blue (FB) injections into the most caudal part of the contralateral superior colliculus (SC). A proportion of retinal ganglion cells (RGC's) from the temporal retina which in the adult projects exclusively to the rostral half of the colliculus are labelled by injections to the caudal colliculus in neonatal animals. The majority of these cells die during the period of naturally occurring cell death in the retina, which occurs during the first 10 postnatal days. The object of this experiment was to see whether albino rats, which have well documented abnormalities in axon pathfinding in their visual system, had a larger number of cells in temporal retina which initially project to caudal colliculus than pigmented animals. On postnatal day 2 (P2), the ratio of temporal to nasal RGCs projecting to the caudal SC is greater in albino than pigmented rats (6.2% vs 2.65%). After the wave of naturally occurring cell death, at P14, when many of the neonatal errors have been eliminated, the ratio of temporal to nasal RGC's is reduced to 1.71% for albinos versus 1.53% for pigmented rats.

Functional consequences of embryonic neocortex transplanted to rats with prefrontal cortex lesions.

In four experiments we reexamined the recent report by Labbe, Firl, Mufson, and Stein (1983) that fetal cortical tissue transplanted to an aspirative prefrontal cortical cavity in rats can ameliorate the learning impairments induced by the aspirative lesions. Healthy surviving grafts from young (E16) embryonic donors had no immediate effects on the rats' impairments in T-maze alternation, spatial navigation in the Morris swimming pool task, or locomotor activity, and they produced even greater impairments than the lesions alone when all three tests were conducted after longer (3-5 month) survival periods. Grafts taken from older (E21) donors did produce a short-lasting improvement in the T-maze alternation performance, replicating the previous report. However, this effect was not seen in the other two behavioral tests; the grafts survived poorly, and the beneficial effect was no longer apparent in the long-term tests. It is concluded that (a) functional benefits of embryonic cortical grafts are dependent on a precise combination of conditions rather than being a general phenomenon, and (b) the short-lasting recovery in delayed alternation performance is attributable to diffuse influences of the embryonic tissue on the lesioned host brain rather than to a reconnection of damaged circuitries.

Impairments in the acquisition, retention and selection of spatial navigation strategies after medial caudate-putamen lesions in rats.

Using the Morris swimming pool test of spatial navigation, medial caudate-putamen lesions in rats produce impairments in the acquisition and retention of both place and cue tasks, and impair the selection of normal navigation strategies. Also described are some novel features of spatial navigation behaviour displayed by control animals in cue and place tasks that provide insights into the performance of the caudate-putamen rats. Analyses of the swim patterns on postacquisition probe trials, in which the target platform was removed or relocated, showed that the strategy used by the caudate-putamen lesioned rats was dependent upon the task that they were required to solve. Control rats used a place strategy and distal visual cues to identify the location of the start points, the routes from the start points to the platform, and the location of the platform on both the cue and place tasks. The caudate-putamen lesioned rats used distal visual cues and a place strategy only to acquire the place task. They solved the cue task using a taxon strategy consisting of a combination of proximal and position response cues. The results suggest that when necessary, medial caudate-putamen lesioned rats, like normal rats, can use place strategies for spatial navigation, but if an alternate, perhaps simpler, taxon solution is available they seemingly ignore place information and navigate using the simpler strategy. The deficit, which has features of a neglect rather than a loss of ability per se, suggests that medial caudate-putamen neural systems are involved in the selection of alternative strategies in spatial navigation tasks.

Behavioural, biochemical and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats.

Lesions of the nucleus basalis magnocellularis in rats have been used to investigate functions of the extrinsic cortical cholinergic system which originates from these neurons. These lesions also produce extensive non-specific subcortical damage and associated regulatory and neurological impairments, causing doubt about the specificity of consequent functional impairments. Here, nucleus basalis magnocellularis lesions made with four different neurotoxic amino acids (kainic acid, ibotenic acid, N-methyl-D-aspartate, and quisqualic acid) have been compared. Quisqualic acid produced less subcortical damage and lesser neurological and regulatory impairments than the other toxins at doses that produced comparable cholinergic deafferentation of the neocortex, as assessed both histologically and biochemically. This suggests that these impairments are non-specific rather than specific consequences of cholinergic cell loss. The effects on learning a spatial navigation task were more ambiguous, suggesting the involvement of both cholinergic and non-cholinergic systems. Impairment of a passive shock avoidance task was as great following quisqualic acid as the other neurotoxins, which may suggest a more direct relationship specifically with the decline in cortical cholinergic activity. It is concluded that in the absence of availability of a specific cholinergic neurotoxin, quisqualic acid produces less non-specific neuroanatomical and neurological side effects than the more widely used toxins N-methyl-D-aspartate, kainic acid or ibotenic acid.

Acetylcholine-rich neuronal grafts in the forebrain of rats: effects of environmental enrichment, neonatal noradrenaline depletion, host transplantation site and regional source of embryonic donor cells on graft size and acetylcholinesterase-positive fibre outgrowth.

The importance of several factors influencing the survival of cholinergic-rich embryonic tissue transplanted to the adult rat forebrain and the extent of acetylcholinesterase-positive fibre innervation of the host brain was investigated in 3 experiments. In the first two experiments, embryonic ventral forebrain tissue was grafted to the neocortex of rats in which the intrinsic cortical cholinergic innervation had been removed by nucleus basalis lesions. Housing the host rats in an enriched environment produced a temporary enhancement of fibre outgrowth 4 weeks after transplantation, but this was not maintained after 10 weeks. Fibre outgrowth was greater when the grafts were transplanted to the noradrenaline-depleted neocortex than to the intact neocortex. Neither environmental enrichment nor noradrenaline depletion influenced graft survival or size. In the third experiment, the embryonic donor tissue was dissected to separate regions containing precursors of the nucleus basalis cholinergic cells from regions containing precursors of the septal cholinergic cells, and transplanted to either the neocortex following nucleus basalis lesions or to the hippocampus following fimbria-fornix lesions. Nucleus basalis grafts showed greater growth in size than septal grafts, and grafts placed into the hippocampus showed greater growth in size than grafts placed into the neocortex. More interestingly, the extent of fibre outgrowth depended on the appropriateness of the donor tissue to the host transplantation site: nucleus basalis tissue showed greater acetylcholinesterase-positive outgrowth than septal tissue in the neocortex, whereas septal tissue showed greater outgrowth than nucleus basalis tissue in the hippocampus.

Dopamine-rich transplants in rats with 6-OHDA lesions of the ventral tegmental area. I. Effects on spontaneous and drug-induced locomotor activity.

In order to investigate the relative contribution of dopaminergic projections to the nucleus accumbens and prefrontal cortex in the regulation of spontaneous and drug-induced locomotor activity, separate groups of rats were prepared with 6-OHDA lesions of the ventral tegmental area alone, or additional grafts of dopamine-rich tissue reinnervating either the nucleus accumbens or medial prefrontal cortex. A fourth unoperated group served as normal controls. The lesions induced no change in spontaneous, daytime activity, but increased overnight activity. The lesioned rats were also hyperactive to apomorphine, while the activational effects of amphetamine were blocked. Grafts of dopamine-rich tissue, whether into the prefrontal cortex or nucleus accumbens, resulted in a significant normalization of both drug responses towards control levels. Neither graft influenced overnight hyperactivity, whereas spontaneous daytime activity was increased above both control and lesion levels by the accumbens grafts alone. The results are interpreted as suggesting that dopaminergic projections to prefrontal cortex and nucleus accumbens are similarly rather than antagonistically involved in the regulation of drug-induced locomotor activation.

The distribution of acetylcholinesterase in the lateral geniculate nucleus of the cat and monkey.

The distribution of acetylcholinesterase (AChe) has been examined histochemically in the lateral geniculate nucleus (LGN) of the cat and the monkey, and in the cat visual cortex. It was found that in the cat, AChE is most concentrated in laminae A and A1. Lamina C-proper possessed a weak band of AChE in its ventral part. Only restricted patches of activity were observed in the medial interlaminar nucleus. Laminae C1-3 and the central interlaminar nucleus possessed very little AChE. This pattern of enzyme distribution suggests that in the cat LGN, AChe activity coincides with the sites of neurophysiologically recorded X-cells, which are predominantly found in laminae A and A1 and are scarce in the C laminae and the medial interlaminar nucleus. The presence of AChE over neurones in layer VI of both areas 17 and 18 of the cerebral cortex in the cat suggests the corticothalamic pathway as one possible source of geniculate AChE activity. In the monkey LGN, AChE activity was observed in the parvocellular and magnocellular layers. The activity was greatest in the magnocellular layers, which are believed to contain neurones driven predominantly by retinal Y-cells. Thus, for this species the correlation between AChE activity and X-cells does not seem to hold.