Nucleus Basalis Complex Research Articles

Early Failure of the Default‐Mode Network and the Pathogenesis of Alzheimer's Disease

The default-mode network (DMN) is a major resting-state network that supports most of the baseline brain activity. Recent studies revealed that DMN cortical hub regions, including the medial prefrontal cortex, parietal cortex, posterior cingulum, and precuneus, are all affected early during Alzheimer’s disease (AD) and exhibit high amounts of A-beta deposits. The cells generating A-beta are chiefly cortical and some brainstem projection neurons. Because processing of the amyloid precursor protein is activity-dependent, it can be speculated that due to their constant activity, DMN neurons produce and release more A- beta than occur elsewhere in the neocortex, thus leading to an increase in production, oligomerization, and aggregation of Ab as well as tau hyperphosphorylation, which presumably is caused by the released A-beta oligomers. DMN cortical regions are richly innervated by long projection fibers from the noradrenergic locus coeruleus (LC), the serotonergic dorsal raphe nucleus (DRN), as well as the cholinergic basal forebrain (nucleus basalis complex, NB), which all may release high amounts of A-beta in the vicinity of glutamatergic projection neurons in the DMN cortical regions that are vulnerable to tau pathology and neurofibrillary degeneration. Recent findings provide converging evidence that the amyloid accumulation and DMN functional alterations are closely linked with the changes of sleep–wake cycle (particularly in regard to lesser amount of shortwave deep sleep when metabolic demands are about 50% lower in comparison with awake state and when presumably less amyloid is produced) and pretangle changes of LC, thus opening new promising area for future research.

Response to Boban et al: computer-assisted 3D reconstruction of the nucleus basalis complex, including the nucleus subputaminalis (Ayala's nucleus)

We appreciate the suggestions of Boban et al . (2006) in clarifying the designation of a circumscribed basophilic nuclear complex as depicted in Fig. 2 (Ch4 p?) of our recent publication (Teipel et al ., 2005). The basophilia of the neurons forming this cluster was the main reason why we decided to include this cluster into a Ch4al–Ch4p continuum. Furthermore, Hedreen et al . (1984) preferred the Mesulam et al . (1983) terminology as a thorough and very useful description which may prove to be definitive. At the time of our joint MRI-cytoarchitectonic study of the NBC we had no gapless serial sections from the single case investigated because every second section of this series was either stored in formalin or used for paraffin embedding and neuropathological diagnosis (cf. Fig. 1A in Teipel et al ., 2005). Fig. 1 Computer-assisted 3D reconstruction of the left nucleus basalis complex (NBC) and neighboring structures of a 50-year-old non-demented woman. ( A ) view from the occiptal pole, ( B ) ventral view from the anterior perforate substance. In ( A ) the first of a total of 44 gallocyanin-stained 400 μm thick sections used for the 3D reconstruction was left in situ . Putamen, nucl. accumbens, globus pallidus and anterior commissure are displayed in a transparent mode. Meanwhile, we could cut and stain complete 400 μm thick serial sections [details on the method are given in Heinsen et al . (2000)] from two control cases, a 50-year-old female who died due to aspiration and a 43-year-old-male who died due to embolism of the pulmonary artery. Our 3D reconstructions (Fig. …

Direct, complex effects of estrogens on basal forebrain cholinergic neurons

Although controversial, estrogens remain one of the few agents purported to influence the incidence of Alzheimer's disease and one of their postulated mechanisms of action is their effects on basal forebrain cholinergic neurons. However, it is unclear whether the responses of cholinergic neurons to estrogens are direct or mediated via the retrograde influences of neurotrophins, known to be induced by estrogens in the hippocampus and neocortex. In the present study, we explore the issue of the primary site of action of estrogens by studying the regulation of expression of genes that characterize mature cholinergic neurons, i.e., choline acetyltransferase, trkA, and p75 NTR in the medial septum and the nucleus basalis complex. In parallel, we study the hippocampal expression of NGF, BDNF, and NT-3, i.e., neurotrophins with known trophic roles on cholinergic neurons. Gene expression is studied by RT-PCR in ovariectomized female rats with and without estrogen supplementation within the physiological estradiol range and in rats with complete fimbria-fornix transactions treated with estrogen or vehicle. To clarify mechanisms of estrogen transduction in cholinergic neurons, we study the effects of estrogen treatment on fimbria-fornix-lesioned mice with genetic ablations of ER subtypes α and β. The results of the present study suggest that, while estrogens do regulate BDNF expression in the hippocampus and neocortex, they also exert stimulatory non-trophic effects on basal forebrain cholinergic neurons, primarily on ChAT expression. Cholinergic neurons retain their ability to respond to estrogens after their complete separation from the hippocampus. The elimination of ERα alters significantly the phenotypic responsiveness of cholinergic neurons to estrogens, whereas elimination of ERβ appears to have no effect. Our findings support the idea that estrogens directly enhance cholinergic neuron function and that ERα plays a significant role in transducing these regulatory effects.

Visualisation of somatostatin receptor sst3 in the rat central nervous system

Somatostatin actions are mediated through G-protein coupled receptors named sst1 to sst5. We used an affinity-purified polyclonal antibody AS-69, directed against a specific N-terminal peptide sequence of sst3 to determine the immunohistochemical distribution of the sst3 receptor in the rat and human brain. The specificity of the antibody was shown by Western blotting experiments using an N-terminal sst3 fusion protein. Enzymatic deglycosylation experiments were combined to blotting experiments on a sst3-transfected cell line and rat brain membrane proteins and with immunocytochemistry on the sst3-transfected cell line. These studies showed that the antibody detected the deglycosylated sst3 receptor protein. Immunohistochemical staining showed that sst3 immunoreactivity recognised by this N-terminal antiserum was widely distributed throughout the brain with cells and processes labelled in the cerebral cortex, regions of the limbic system (including the hippocampal formation, some amygdaloid regions, some basal ganglia nuclei and regions from the nucleus basalis complex), the habenula, the hypothalamus, the thalamus, different mesencephalic structures (substantia nigra, zona incerta, superior colliculus), the reticular formation, the cerebellum. The distribution of immunoreactivity was in good general agreement with that predicted from the localisation of sst3 mRNA and radio-ligand binding studies; however, due to the preference of AS-69 towards the deglycosylated receptor, it appears that the sst3 immunoreactivity detected may correspond largely to the deglycosylated receptor. This study on the immunohistochemical distribution of the sst3 receptor in the brain may provide a better understanding of the central actions of somatotropin release-inhibiting factor (SRIF).

M2 muscarinic acetylcholine receptor-immunoreactive neurons are not reduced within the nucleus basalis in Alzheimer's disease: Relationship with cholinergic and galaninergic perikarya

The distribution of profiles containing the m2-muscarinic acetylcholine receptor within the aged human basal forebrain and its relationship to cholinergic and noncholinerigc neurons and alterations in Alzheimer's disease (AD) was investigated by using an m2-specific monoclonal antibody (Levey et al. [1995] J. Comp. Neurol. 351:339-356). Immunocytochemistry revealed that the m2 receptor protein is expressed primarily in noncholinergic multipolar neurons (mean+/-S.E.M.; 355.7+/-15.4 microm2) located primarily outside the cholinergic nucleus basalis subfields. Dual-stained sections from the septal/diagonal band complex revealed that m2 was detected in only 14% of choline acetyltransferase-labeled neurons, whereas only 13% of m2-stained neurons colocalized choline acetyltransferase. Within the nucleus basalis, choline acetyltransferase was found in 35% of the m2-labeled neurons, whereas only 6% of choline acetyltransferase-stained perikarya were dual labeled for m2. Although we did not visualize colocalization of m2+/choline acetyltransferase-immunonegative neurons and the inhibitory neuropeptide galanin, galaninergic fibers coursed in close apposition to m2+ cells. Cell counts demonstrated that 90% of choline acetyltransferase-labeled striatal neurons expressed the m2 receptor. Despite the extensive reduction in cholinergic basal forebrain neurons, cell counts of the relative number ofm2-immunoreactive neurons within the nucleus basalis complex from aged controls and AD patients revealed that the m2 neurons are spared. Finally, our findings suggest that most m2 receptors in the cholinergic basal forebrain are located on noncholinergic structures; therefore, they are not the major source of m2 receptors in the cortex. Thus, the reduced levels of the m2 receptor seen in AD cortex probably reflect changes in other neuronal populations.

M2 muscarinic acetylcholine receptor‐immunoreactive neurons are not reduced within the nucleus basalis in Alzheimer's disease: Relationship with cholinergic and galaninergic perikarya

The distribution of profiles containing the m2-muscarinic acetylcholine receptor within the aged human basal forebrain and its relationship to cholinergic and noncholinerigc neurons and alterations in Alzheimer's disease (AD) was investigated by using an m2-specific monoclonal antibody (Levey et al. [1995] J. Comp. Neurol. 351:339–356). Immunocytochemistry revealed that the m2 receptor protein is expressed primarily in noncholinergic multipolar neurons (mean ± S.E.M.; 355.7 ± 15.4 μm2) located primarily outside the cholinergic nucleus basalis subfields. Dual-stained sections from the septal/diagonal band complex revealed that m2 was detected in only 14% of choline acetyltransferase-labeled neurons, whereas only 13% of m2-stained neurons colocalized choline acetyltransferase. Within the nucleus basalis, choline acetyltransferase was found in 35% of the m2-labeled neurons, whereas only 6% of choline acetyltransferase-stained perikarya were dual labeled for m2. Although we did not visualize colocalization of m2+/choline acetyltransferase-immunonegative neurons and the inhibitory neuropeptide galanin, galaninergic fibers coursed in close apposition to m2+ cells. Cell counts demonstrated that 90% of choline acetyltransferase-labeled striatal neurons expressed the m2 receptor. Despite the extensive reduction in cholinergic basal forebrain neurons, cell counts of the relative number of m2-immunoreactive neurons within the nucleus basalis complex from aged controls and AD patients revealed that the m2 neurons are spared. Finally, our findings suggest that most m2 receptors in the cholinergic basal forebrain are located on noncholinergic structures; therefore, they are not the major source of m2 receptors in the cortex. Thus, the reduced levels of the m2 receptor seen in AD cortex probably reflect changes in other neuronal populations. J. Comp. Neurol. 392:313–329, 1998. © 1998 Wiley-Liss, Inc.

Long-term effects of cholinergic basal forebrain lesions on neuropeptide Y and somatostatin immunoreactivity in rat neocortex

The effect of cholinerfic basal forebrain lesions on immunoreactivity to somatostatin (SOM-i) and neuropeptide-Y (NPY-i) was investigated in the rat parietal cortex, 16–18 months after multiple bilateral ibotenic acid injections in the nucleus basalis complex. As a result of the lesion, the cholinergic fiber density in the cortex decreased by 66% with a concurrent increase in SOM-i fibers by more than 50% and a 124% increase in NPY-i fiber innervation. The neuropeptidergic sprouting response on cholinergic denervation does not match the concurrent cholinergic and peptidergic decline in Alzheimer's disease and as such does not support the cholinergic lesion alone as an animal model for this neurodegenerative disorder.

Prenatal development of nucleus basalis complex and related fiber systems in man: A histochemical study

To provide parameters for study of the “cholinergic” innervation of a human fetal cerebrum, we have analyzed the prenatal development of histochemical reactivity in the nucleus basalis complex (a magnocellular complex known to contain a high concentration of cholinergic perikarya). Brains from fetuses and premature infants ranging between 8 and 35 weeks of gestation were frozen cut and processed by the thiocholine method for the demonstration of acetylcholinesterase activity. Since no consistent results were obtained with inhibitors on the material younger than 15 weeks, the histochemical reactivity for early stages was expressed as the total cholinesterase reactivity. The first sign of histochemical differentiation of the basal telencephalon is the appearance of a dark cholinesterase reactive “spot” situated between the developing lenticular nucleus and basal telencephalon surface as early as 9 weeks of gestation. The first cholinesterase reactive bundle connects this reactive area (nucleus basalis complex anlage) with the strongly reactive fiber system situated along the dorsal side of the optic tract. During the next “stage” (10.5 weeks), there is a significant increase in the size of the nucleus basalis complex and strongly cholinesterase reactive neuropil occupies the sublenticular, diagonal and septal areas. At this stage we have seen two new cholinesterase-reactive bundles: one well developed cholinesterase reactive fiber stratum approaching (but not penetrating) the neocortical anlage through the external capsule and another minute bundle running towards the medial limbic cortex through the precommissural septum. The supraoptic fiber system can be traced now to the pregeniculate area and the tegmentum. At 15 weeks, the first acetylcholinesterase reactive perikarya appear and the nucleus basalis complex anlage becomes segregated into several strongly reactive territories, corresponding in position to the medial septal, diagonal and basal nuclei as defined on adjacent Nissl stained sections. At this stage, fibers from the nucleus basalis complex enter the “white” matter of frontal, temporal, parietal and occipital parts of the cerebral hemisphere via the external capsule. Between 15 and 18 weeks, acetylcholinesterase fibers spread throughout the “white” matter of the cerebral hemisphere. In the next “stage” (18–22 weeks), strongly reactive fibers can be followed from the nucleus basalis below the putamen and through the external capsule to the transient, synapse-rich subplate zone of frontal, temporal, parietal and occipital cortices. Fibers from rostromedial divisions of the nucleus basalis complex extend above the developing corpus callosum and form “limbic” bundles—longitudinal striae and the ventral cingulum or run below the corpus callosum as a part of the ventral fornix. These supracallosal fibers penetrate the dorsal archicortex and reach the subplate zone of the parahippocampal gyrus. In addition, strongly reactive fibers can be traced from the nucleus basalis complex to subcortical structures: the amygdaloid, putamen, caudate and the mediodorsal thalamic nuclei. Between 22 and 30 weeks (preterm infants age) there is a significant increase in the number of large, strongly reactive neuronal perikarya in all divisions of the nucleus basalis complex: rostromedial, intermediate and caudolateral. The most prominent part of the nucleus basalis complex is the nucleus basalis which contains the largest and the most numerous neurons. It can be divided into the small rostromedial part (pars diffusa), the main intermediate part (pars compacta) and the posterior lateral division which consists of numerous (7–10) cell aggregations (pars aggregata), the most rostral corresponding to the nucleus subputaminalis and the most caudal intermingling with the amygdala. Concomitantly, the strong acetylcholinesterase reactivity was observed in the deepest layers and in the marginal zone of the neocortex, parahippocampal gyrus and hippocampal formation. In conclusion, the nucleus basalis complex develops the earliest acetylcholinesterase activity in the telencephalon and sends widely distributed fibers to the anlage of neocortex and limbic cortex by the end of the second trimester of gestation. The development of cortical layer innervation coincides with the appearance of the “adult” pattern of topographical relationships. These results provide new data on the development of the nucleus basalis complex and on the early, prenatal “cholinergic” innervation of cerebral cortex. These findings also suggest developmental interaction of basal forebrain fibers with other cortical afferents and offer a new explanation for the anatomical substrate of regulation of behavioural states in the human preterm infant.

Alzheimer's disease

Alzheimer's disease is a complex and fascinating entity, clinically and neurobiologically. Although originally described as a form of accelerated aging in an article that emphasized neuropathology, it is now considered a specific age-related disease entity, at whatever age it occurs. It is the most common cause of the dementia syndrome, probably the fourth most common cause of death in the United States and is likely to become more common as the population ages. The course is typically an insidious onset of cognitive and behavioral impairment progressing more or less steadily over years to profound disability. The classic pathologic changes are Alzheimer plaques, neurofibrillary tangles, and loss of subcortical cells, including particularly the cholinergic cells of the nucleus basalis complex. The functional disability can be correlated with the site and extent of brain damage, but why these cells deteriorate and die is not known. Diagnosis depends on identifying the dementia syndrome in a patient whose course is compatible with Alzheimer's disease and in whom no other factors adequate to explain the dementia are found. NIH consensus diagnostic criteria are now available. Care is symptomatic optimal care of intercurrent illness, and pharmacologic, behavioral, and social “splints” to maximize the function of the remaining brain. Specific treatments are still in the realm of research, and both clinical and basic research on this challenging disorder are active and accelerating.

Chemical Nature of Synaptic Transmission in Vertebrates

Chemical Nature of Synaptic Transmission in Vertebrates