Subcortical Brain Areas Research Articles

The sympathetic nervous system: the muse of primary hypertension.

Von Euler characterised the sympathetic neurotransmitter noradrenaline (NA) and postulated that excessive neural tone was a cause of primary hypertension (PH). Thirty years ago, we found raised NA levels in 30-40% of young patients with PH. Laragh found plasma renin activity (PRA) a risk marker for coronary artery disease. With Esler, Miura, and Campese, a close association was found of plasma NA with PRA. We found raised tyrosine hydroxylase activity (AC) in the hearts of a rabbit model of sinoaortic denervated hypertension and in PH with raised plasma NA. Esler utilised titrated NA infusion and described increased spillover of NA from heart, kidney and subcortical areas of brain of patients with PH. With Eide we found raised cerebrospinal fluid (CSF) NA in PH (not secondary hypertension) and with Kolloch and Miura, we found raised plasma/CSF NA in conjunction with reduced dopaminergic tone. With Shkvatsabaya, Yurenev and Davison, we found that relaxation therapy improved the anger ambience and blood pressure of PH with raised plasma NA vs those with normal NA levels. Campese found a hypothalamic source of raised blood pressure in two rat models - microphenol treated and ischaemic kidney. The resulting hypertension was associated with raised NA turnover of their hypothalamic centres. Finally, with Hsueh and Hodis, we found raised plasma NA in association with insulin resistance increased left ventricular mass and intimal medial hypertrophy in Mexican-American diabetics and their yet unaffected offspring. Reliable estimates of human sympathetic AC, including levels of plasma NA in the effluent of selected organs and peripheral venous and arterial sites, may eventually be displaced by techniques using genetic analysis and molecular biology. Never the less, the sympathetic nervous system appears to play an important role in the pathogenesis, sequelae and therapy of PH.

Long-term potentiation of single subicular neurons in mice.

Subicular neurons receive direct afferent connections from the vast majority of CA1 pyramidal cells and send their axons to the various brain areas. Because of this strategic position, subicular cells can modulate output of the hippocampus and, thus, play a significant part in memory, spatial processing, and seizure amplification and propagation from the hippocampus. Despite its important role as a hippocampal interface with different brain regions, present knowledge of the subiculum and the plastic properties of the synapses on the subicular neurons is rather limited. By using IR-DIC videomicroscopy and whole-cell patch-clamp recordings in mouse hippocampal slices, I demonstrated that long-term potentiation (LTP) in CA1-subicular cell synapses can be readily induced by high-frequency stimulation (HFS) of the afferents, but not by pairing of low-frequency stimulation with depolarization of postsynaptic cells. This tetanus-induced LTP is input specific, insensitive to the N-methyl-D-aspartate (NMDA) receptor antagonist 3-[(R)-2Carboxipiperazin-4-yl]-propyl-1-phosphonic acid (R-CPP), and reduces paired-pulse facilitation in potentiated synapses. Subsequent morphologic analysis of the recorded cells, which were filled either with Lucifer Yellow or Biocytin, revealed pyramidal-shaped neurons localized predominantly in the deep layer of the subiculum, close to the CA1 border. Axons of the majority of these neurons extended to the alveus and on toward the hippocampus, probably exiting it via the fornix. These data indicate that CA1-subicular cell synapses in mice exhibit LTP, which can be expressed presynaptically, and its induction does not require NMDA-receptor activation. The observed activity-dependent plasticity might play an important role in the integrative mechanisms of the subiculum and may influence transfer of information from the hippocampus to subcortical and cortical brain areas.

Leptin is released from the human brain: influence of adiposity and gender.

Leptin, a 16-kDa circulating protein primarily derived from adipocytes, is an important factor in the regulation of appetite and energy expenditure. Using simultaneous arterio-venous blood sampling, several organs were assessed with regard to their individual roles in leptin metabolism in healthy male and female subjects constituting a range of body mass indices. Plasma leptin levels were unchanged after passage through the hepatosplanchnic and forearm circulations. In contrast, concentrations in the renal vein were consistently lower than those in the renal artery (-15%; P<0.005), indicating net extraction, whereas the brain was observed to be a net leptin releaser. Concentrations in the internal jugular vein were significantly higher than arterial levels in lean females (change, 3.0+/-1.2 ng/mL; P<0.02) and in obese males (body mass index, >28 kg/m2), but not lean (change, 2.3+/-2.3 vs. 0.1+/-0.1 ng/mL, respectively; P<0.05), indicating a probable influence of both gender and adiposity on brain leptin release. An attempt to grossly localize the site of brain release by using cerebral venous scans to distinguish between jugular venous drainage from cortical and subcortical brain areas revealed no region-specific secretion. These data raise the possibility that the brain is a nonadipose source of leptin. In addition, the higher level of brain release observed in females may contribute to the well documented gender differences in overall plasma leptin levels.

Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study

Background: Patients with posttraumatic stress disorder (PTSD) show a reliable increase in PTSD symptoms and physiological reactivity following exposure to traumatic pictures and sounds. In this study neural correlates of exposure to traumatic pictures and sounds were measured in PTSD. Methods: Positron emission tomography and H 2[ 15O] were used to measure cerebral blood flow during exposure to combat-related and neutral pictures and sounds in Vietnam combat veterans with and without PTSD. Results: Exposure to traumatic material in PTSD (but not non-PTSD) subjects resulted in a decrease in blood flow in medial prefrontal cortex (area 25), an area postulated to play a role in emotion through inhibition of amygdala responsiveness. Non-PTSD subjects activated anterior cingulate (area 24) to a greater degree than PTSD patients. There were also differences in cerebral blood flow response in areas involved in memory and visuospatial processing (and by extension response to threat), including posterior cingulate (area 23), precentral (motor) and inferior parietal cortex, and lingual gyrus. There was a pattern of increases in PTSD and decreases in non-PTSD subjects in these areas. Conclusions: The findings suggest that functional alterations in specific cortical and subcortical brain areas involved in memory, visuospatial processing, and emotion underlie the symptoms of patients with PTSD.

Nicotinic receptor binding sites in rat primary neuronal cells in culture: characterization and their regulation by chronic nicotine

We have characterized high affinity neuronal nicotinic acetylcholine receptors labeled by [ 3 H ]cytisine in primary neuronal cell cultures from fetal rat brains. After 15 days in culture, the highest density of [ 3 H ]cytisine binding sites ( B max≈57 fmol/mg protein) was found in cells from the brainstem, which includes the following subcortical brain areas: the septum, thalamus, hypothalamus, midbrain, pons and medulla. A lower density of sites was found in cells from the cerebral cortex, hippocampus, and caudate nucleus. [ 3 H ]Cytisine binds to receptors in primary cells from the brainstem and cerebral cortex with a K d of ≈0.5 nM, and the binding is inhibited by the agonists nicotine, acetylcholine, and epibatidine with IC 50 values of 1 to 20 nM, and by carbachol and the antagonist dihydro-β-erythroidine with IC 50 values of 0.5 to 1.5 μM. Chronic treatment of neuronal cultures with nicotine for 7 days differentially affected the number of nicotinic receptors in cells from different brain areas; it significantly increased the number of nicotinic binding sites in cells from the cerebral cortex, hippocampus, and caudate, but not in cells from the brainstem. The nicotine-induced increase of receptors in cerebral cortical cultures was not blocked by either mecamylamine or dihydro-β-erythroidine. These results indicate that primary cultures of rat neuronal cells provide a good model system in which to study and compare the properties and regulation of native neuronal nicotinic acetylcholine receptors.

How does the human brain deal with a spinal cord injury?

The primary sensorimotor cortex of the adult brain is capable of significant reorganization of topographic maps after deafferentation and de-efferentation. Here we show that patients with spinal cord injury exhibit extensive changes in the activation of cortical and subcortical brain areas during hand movements, irrespective of normal (paraplegic) or impaired (tetraplegic patients) hand function. Positron emission tomography ([15O]-H2O-PET) revealed not only an expansion of the cortical 'hand area' towards the cortical 'leg area', but also an enhanced bilateral activation of the thalamus and cerebellum. The areas of the brain which were activated were qualitatively the same in both paraplegic and tetraplegic patients, but differed quantitatively as a function of the level of their spinal cord injury. We postulate that the changes in brain activation following spinal cord injury may reflect an adaptation of hand movement to a new body reference scheme secondary to a reduced and altered spino-thalamic and spino-cerebellar input.

Transplantation of fetal neocortex ameliorates sensorimotor and locomotor deficits following neonatal ischemic-hypoxic brain injury in rats.

Ischemic brain injury in neonates can result in the degeneration of cortical and subcortical areas of brain and is associated with neurologic deficits. One approach to restoring function in conditions of ischemic brain injury is the use of neural transplants to repair damaged connections. This approach has been shown to reestablish neural circuitry and to ameliorate associated motor deficits in models of neonatal sensorimotor cortex damage. In this study, we utilized the Rice et al. rodent model of neonatal ischemic-hypoxic (IH) brain injury to assess whether transplantation of fetal neocortical tissue can promote functional recovery in tests of sensorimotor and locomotor ability throughout development and as adults. We show that animals that received neocortical grafts 3 days following the IH injury performed significantly better as adults on two measures of motor ability, the Rota-Rod treadmill and apomorphine-induced rotations, than did control animals that received sham transplants after the IH injury. Transplants were identifiable in 72% of the animals 10-12 weeks after implantation. Histochemical studies revealed that while the transplanted tissue did not establish normal cortical cytoarchitecture, cells and fibers within the grafts stained for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), choline acetyl transferase (ChAT), cholecystokinin (CCK), and glial fibrillary acidic protein (GFAP). These results suggest that transplantation of fetal neocortical tissue following IH injury in the neonatal period is associated with amelioration of motor deficits and that the grafted tissue demonstrated a neurochemical phenotype that resembled normal neocortex. This approach warrants continued investigation in light of potential therapeutic uses.

Neuropsychological deficits in adults with neurofibromatosis type 1.

To examine neuropsychological deficits in adults with Neurofibromatosis type 1 (NF1) with and without an affective mental disorder (i.e. dysthymia). Seventy adult NF1 patients were followed-up after a 12-year period. Of 65 patients assessed earlier with the Comprehensive Psychopathological Rating Scale (CPRS), 19 patients had died. The remaining patients were assessed by the CPRS with the exception of 4 patients, and were psychiatrically diagnosed according to DSM III-R. Twelve patients were excluded because of advanced age, and psychiatric illness other than affective disorder. The remaining 30 NF1 patients (7 with affective disorder and 23 psychiatrically healthy), and a control group of 23 normal adults were assessed on a variety of neuropsychological tests. Results indicated NF1-related deficits in inductive reasoning, visuoconstructive skill, visual and tactual memory, logical abstraction, coordination, and mental flexibility, although basic motor speed and vocabulary were not affected by NF1. An affective disorder exacerbated the neuropsychological deficits associated with NF1 only with regard to tests assessing motor functions. NF1 results in a relatively global cognitive impairment among adults, and additional depressive symptoms appear to slow down basic motor processes. It was speculated that the NF1-related cognitive deficits may partly result from white-matter lesions in subcortical brain areas, due to proliferation of glial tissue, aberrant myelination or hamartomas.

Correlation of evoked potentials in cortical and subcortical areas of human brain during psychological tasks

Correlation of evoked potentials in cortical and subcortical areas of human brain during psychological tasks

Effects of intracerebroventricular administration of atrial natriuretic peptide on subcortical EEG activity in conscious rabbits.

Atrial natriuretic peptide (ANP) influences the activity of rat hypothalamic neurons, modifies the membrane excitability of the rat forebrain neurons, and induces changes in membrane potentials in cultured rat glioma cells. In order to explore whether these effects are reflected in the electrical activity of larger subcortical brain areas, we investigated the electroenceophalographic activity (EEG) recorded from 20 male albino (New Zealand White) rabbits. Recordings of EEG were made on restrained, conscious animals 1 week after the implantation of an indwelling intracerebroventricular (i.c.v.) cannula (lateral right ventricle) and two stainless steel electrodes, implanted in the paraventricular (PVN) and supraoptic (SON) nuclei. Animals were classified into two main groups: those with water available ad libitum (group A) and those which were dehydrated for 24 h before EEG recordings (group B). Each group was divided into two subgroups (1 and 2) of five animals each. EEG was recorded at 0 min (control) and 30, 60, and 90 min following the i.c.v. injection of either 25 microliters artificial cerebrospinal fluid (aCSF; subgroup 1) or 1 microgram alpha-human ANP in 25 microliters a CSF (subgroup 2). Each EEG record duration was 6 s. For each EEG record the power spectrum of the digitized waveform was estimated in the frequencies 0.5-48 Hz using the fast Fourier transform, and the energy of each waveform was subsequently calculated. The results were analyzed by repeated-measures ANOVA and by the t-test. The analysis revealed that (1) water deprivation does not affect mean EEG energy and value (2) ANP attenuates (P < 0.05; in comparison with zero time) the mean energy value of EEG recorded from SON at 30 min and 60 min in the frequencies 8-48 Hz, whilst it tends to decrease (P < 0.1) the mean energy of EEG recorded from PVN at 30 min in the frequencies 8-15 Hz. Mean EEG energy changes caused by ANP would reflect its various (mainly inhibitory) effects on the electrical activity recorded from PVN and SON neurons in in vitro and in vivo studies.

An improved methodology for routine in vivo microdialysis in non-human primates

A new method was developed to carry out in vivo microdialysis experiments repetitively and routinely within an individual monkey. We designed and built a dialysis probe guide and holding device (‘guide holder’) which permits accurate placement of dialysis probes into cortical (e.g., prefrontal, hippocampus, and parietal cortices) and subcortical target areas (e.g., caudate nucleus, amygdala, and nucleus accumbens) of the rhesus monkey brain without extensive and repetitive surgery needed to expose a desired brain region. The guide holder is positioned, using MRI-guided coordinates, and fixed to the skull over an intended targeted region. This design provides an opportunity to conduct several experiments in a single monkey over an extended period and permits placement of several probes accurately into ‘fresh’ or ‘experienced’ tissue during repeated microdialysis experiments. In addition, during repeated dialysis experiments tissue trauma is minimized because no surgical procedure is necessary on the day of dialysate collection. This procedure can be readily adapted for use with an awake monkey.

Nerve Growth Factor and the Monosialoganglioside GM1: Analogous and Different in Vivo Effects on Biochemical, Morphological, and Behavioral Parameters of Adult Cortically Lesioned Rats

This study examined the behavioral effects of maximal doses of exogenous NGF and/or GM1 when given intracerebroventricularly to adult rats with unilateral cortical lesions. In addition, the long-term effects of these agents on choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) activity, and choline uptake, as well as on ChAT and NGF receptor (p75NGFR) immunoreactivity in various brain regions, were also investigated. When retested in passive avoidance and Morris water maze tasks, 30 days postlesion (i.e., 2 weeks after termination of treatment), decorticated vehicle-treated rats showed retention and reacquisition deficits which were equally attenuated by NGF (6 μg/day, 14 days) or NGF + GM1 (750 μg/day, 14 days) treatment. By contrast, lesioned animals which received GM1 alone only showed improved reacquisition of the two tasks. After behavioral testing (52 days postlesion) lesioned vehicle-treated animals had decreased ChAT activity in the ipsilateral nucleus basalis magnocellularis (NBM) but not in other subcortical brain areas examined. Neuronal loss was observed only in the ventrolateral nucleus of the ipsilateral dorsal thalamus. However, using quantitative image analysis a significant shrinkage of ChAT immunoreactive (IR) and p75NGFR-IR NBM neurons as well as a decrease in their neuritic network was noted, particularly in the mid portion of the NBM. GM1 and NGF equally prevented these deficits in the NBM and, furthermore, enhanced ChAT activity and choline uptake in the remaining cortex ipsilateral to the lesion site. These alterations in NBM and cortical cholinergic markers were even more augmented in rats which received both NGF and GM1 treatment. By contrast, the noted NGF-induced increase in striatal ChAT activity was not further increased by concomitant GM1 treatment. GAD activity in all brain areas examined was unaltered by the lesion or any of the treatments and the apparent thalamic neuronal retrograde degeneration was not prevented by any of the treatments. It is concluded that GM1 or NGF treatment can distinctly affect performance of cortically lesioned rats in passive avoidance and Morris water maze tasks despite their equal ability to serve as long-term neuroprotective agents for the basalo-cortical cholinergic pathway.

Abnormal Tau proteins in progressive supranuclear palsy

We have previously shown that abnormal Tau species are produced during the neurofibrillary degeneration of the Alzheimer type. These abnormal Tau proteins consist of a characteristic triplet named Tau 55, Tau 64 and Tau 69 which are constantly found in Alzheimer's disease (AD) and Downs syndrome brain regions with tangles. To determine if abnormal Tau species are also produced in other neurodegenerative conditions where intraneuronal filamentous Tau aggregates are observed, we have undertaken an immuno-blot study of brain homogenates from patients with progressive supranuclear palsy (PSP), a neurological disorder characterized by the presence of tangles in subcortical and cortical brain areas. We show here that abnormal Tau species are produced in PSP but that they are different from those in AD. Indeed, although Tau 64 and 69 were present in PSP brain homogenates, possibly as the result of an abnormal phosphorylation as in AD, they were detected in smaller amounts (three times lower) than in AD. In addition Tau 55 was undetected by the immunological tools, such as the absorbed anti-PHF antisera, which specifically label the abnormal Tau proteins. Also the two-dimensional analysis revealed different isoelectric properties. Our results suggest that the production of abnormal Tau species is a very important event during all types of neurofibrillary degeneration. The differences in the pathological Tau-variant profile that were observed between PSP and AD possibly reflect different etiopathogenetic pathways and might explain the formation of different types of filamentous Tau aggregates.

Biochemical Membrane Constituents and Activities of Alkaline and Acid Phosphatase and Cathepsin in Cortical and Subcortical Brain Areas in Dementia of the Alzheimer Type

Biochemical substrates and activities of three enzymes were determined in cortical and subcortical brain areas from neuropathologically proven cases with dementia of the Alzheimer type (DAT) and age-matched control cases. Protein and total lipid content, lecithin, triglycerides, cholesterol, uric acid, alkaline and acid phosphatases and cathepsin activity were determined in homogenates from frontal, temporal, and occipital cortex, hippocampus, the amygdaloid nucleus and the putamen. Protein content was reduced in the frontal cortex only. In the hippocampus, total lipids, triglycerides, lecithin, cholesterol, and acid phosphatase activity were reduced. Cathepsin activity was reduced in the putamen, and increased in the amygdaloid body. The other brain areas appeared unaltered. Neuropathological changes were most pronounced in the hippocampus. The data indicate that only in the hippocampus, the most severely affected brain region, major alterations of membrane constituents occur. Among the neocortical brain regions, only the frontal cortex showed some signs of degradation of cell membranes. The activity of cathepsin, a lysosomal protease potentially involved in amyloidogenesis, was differentially altered. The biochemical observations do not follow the classical pattern of neuropathological degeneration in DAT.

Direct determination of homovanillic acid release from the human brain, and indicator of central dopaminergic activity

The plasma concentration of the dopamine (DA) metabolite, homovanillic acid (HVA), is used as an indicator of central nervous system dopaminergic activity. Using percutaneously inserted catheters we were able to obtain blood samples simultaneously from the right and left internal jugular veins. Veno-arterial HVA plasma concentration differences combined with adjusted organ plasma flows were used, according to the Fick Principle, to determine the HVA overflow from the brain. The HVA overflow from the liver was also measured. HVA overflow from the brain represented 12% of the total body HVA production. A similar amount was released from the liver, illustrating the limited validity of peripheral plasma HVA measurements as an indicator of central dopaminergic activity. HVA release from the human brain displayed a degree of asymmetry, the overflow into the left internal jugular vein being 36% greater than that into the right. Cerebral venous blood flow scans indicated that cortical cerebral regions drained preferentially into the right internal jugular; by inference the higher HVA overflow on the left originated from dopamine-rich subcortical brain areas. Since HVA in plasma may arise from the metabolism of DA existing either as a neurotransmitter or a norpinephrine (NE) precursor we measured the internal jugular vein plasma concentrations of NE, and its metabolite dihydroxyphenylglycol (DHPG), to determine whether they displayed a similar pattern of release to HVA. The overflow of both NE and DHPG into the right internal jugular vein was approximately double that on the left. Since the overflow of HVA did not parallel that of NE and DHPG it may be inferred that the origin of much of the subcortically produced HVA is from dopaminergic neurons and not from the metabolism of precursor DA in noradrenergic neurones or cerebrovascular sympathetic nerves.

Molecular forms of acetylcholinesterase in subcortical areas of normal and Alzheimer disease brain

We have previously reported that the 10s molecular form (G4) of acetylcholinesterase (AChE) is selectively lost from several cortical areas of Alzheimer's disease (AD) brain. In the current follow-up study, we microdissected several areas of nondemented and AD brain, including the hippocampus, amygdala, and cingulate gyrus. Tissue homogenates were separated on sucrose density gradients and the resulting fractions were analyzed for AChE activity in order to define the ratios of the predominant AChE molecular forms (G4/G1). Both the hippocampus and amygdala exhibited distinct patterns of alterations in the G4/G1 ratio which correlate with the known distribution of histopathological changes in AD brain. In order to further define the major pool of AChE that is depleted in AD, we separated fractionated tissue homogenates into salt-soluble and detergent-soluble fractions. The G4/G1 ratios were only altered in the detergent-soluble fractions, indicating that the loss of the G4 AChE molecular form involves a selective depletion of the membrane pool. Available evidence would suggest that this form is the AChE molecular form physiologically relevant at the cholinergic synapse.

Effects of the D-1 Agonist SKF-38393 Combined With Haloperidol in Schizophrenic Patients

To the Editor.— The original dopamine (DA) hypothesis of schizophrenia suggested that D-2 receptor densities are augmented in subcortical brain areas and that the therapeutic effects of antipsychotic drugs are mediated by the antidopaminergic properties of these drugs. However, the notion that augmented dopaminergic activity is a consistent and pervasive phenomenon in schizophrenic patients is probably too simplistic. More recent elaboration of the DA hypothesis suggests that, depending on the brain area, dopaminergic activity could be increased or decreased. 1 In fact, clinical observations attribute some schizophrenic symptoms to frontal cortical dopaminergic deficits, and cerebral blood flow studies in schizophrenic patients indicate that frontal DA activity is reduced rather than augmented. 2 Animal experiments support the notion that reduced dopaminergic activity in cortical brain regions can coexist with, or even be the cause of, increased dopaminergic activity in subcortical areas. Lesions of dopaminergic innervation of the medial prefrontal cortex

Preferential Metabolic Activation of Subcortical Brain Areas by Acute Administration of Nicotine to Rats

Cerebral metabolic and behavioral effects of acutely administered nicotine were measured in rats in relation to dose. Nicotine 0.1, 1, or 10 mg/kg or vehicle was administered intraperitoneally to 3-month-old male Fischer-344 rats that had been pretreated with hexamethonium bromide 5 mg/kg i.p. to reduce peripheral autonomic effects. Regional CMRglc (rCMRglc) values were measured, using the quantitative autoradiographic [14C]-2-deoxy-D-glucose method, in 71 brain regions, beginning 3 min after nicotine or vehicle administration. Intensity of body tremor, scored by a blinded rater, was dose related and peaked at 3 min after nicotine injection. rCMRglc rose in a dose-related manner: Nicotine 0.1 mg/kg had no significant effect in any region, whereas 1 mg/kg elevated rCMRglc significantly in 21 regions (mean rise 20%) and 10 mg/kg produced generalized (56 regions) and greater (mean rise 50%) increases in rCMRglc. Nicotine 1 mg/kg activated thalamic nuclei, cerebellum, geniculate nuclei, superior colliculus, median raphe, reticular formation, and the habenulointerpeduncular pathway, but was without effect in the telencephalon. Effects of nicotine in the hindbrain were related anatomically to reported distributions of [3H]nicotine and [3H]acetylcholine but not [125I]alpha-bungarotoxin binding sites, implying that the former ligands label functional nicotine receptors. The pattern of change in rCMRglc after nicotine administration suggests that its cognitive effects in humans are due to augmented arousal/attention and visual processing rather than to direct neocortical or hippocampal activation.

Non-Alzheimer-type pattern of brain cholineacetyltransferase reduction in dominantly inherited olivopontocerebellar atrophy.

We recently reported reduced activity of the cholinergic marker enzyme cholineacetyltransferase (ChAT) in several brain regions of patients with dominantly inherited olivopontocerebellar atrophy (OPCA). To document the regional extent of these changes we performed a comprehensive examination of the behavior of ChAT throughout both cerebral cortical and subcortical brain areas in 5 patients from one large OPCA pedigree. As compared with the controls, mean ChAT activities in OPCA were reduced by 39 to 72% in all (n = 27) cerebral cortical areas examined and in several thalamic subdivisions, caudate head, globus pallidus, red nucleus, and medial olfactory area. In contradistinction to findings in Alzheimer's disease (AD), mean ChAT levels in OPCA amygdala and hippocampal subdivisions were either normal or only mildly reduced. The lack of severe disabling dementia in our OPCA patients compared with AD patients having a similar cortical cholinergic reduction could be explained by an absence of either a marked cholinergic loss in amygdala or hippocampus or significant loss of noncholinergic cerebral cortical and limbic neurons as occurs in AD brain. We suggest that this and other OPCA pedigrees having a cortical cholinergic reduction represent a unique model for the study of behavioral consequences of a more selective cerebral cortical cholinergic lesion rather than a limbic cholinergic lesion.

Localization of the growth-associated phosphoprotein GAP-43 (B-50, F1) in the human cerebral cortex

The growth-associated phosphoprotein GAP-43 is a component of the presynaptic membrane that has been linked to the development and functional modulation of neuronal connections. A monospecific antibody raised against rat GAP-43 was used here to study the distribution of the protein in cortical and subcortical areas of the human brain. On Western blots, the antibody recognized a synaptosomal plasma membrane protein that had an apparent molecular weight and isoelectric point similar to GAP-43 of other species. In brain tissue reacted with the antibody, the heaviest immunoreactivity was found in associative areas of the neocortex, particularly within layers 1 and 6, in the molecular layer of the dentate gyrus, the caudate putamen, and the amygdala. In contrast, primary sensory or motor regions of the cortex, portions of dorsal thalamus, and cerebellum showed only light staining. Staining was generally confined to the neuropil, which showed punctate labeling, whereas most neuronal somata and fiber bundles were unreactive. The pronounced variations in GAP-43 immunostaining among various areas of the human brain may reflect different potentials for functional and/or structural remodeling.