Biomedical subjects

L Zaborszky

Publications and source records attributed to L Zaborszky.

At least 19 recordsLinked to original sources

PubMed2005

Three-dimensional chemoarchitecture of the basal forebrain: spatially specific association of cholinergic and calcium binding protein-containing neurons.

The basal forebrain refers to heterogeneous structures located close to the medial and ventral surfaces of the cerebral hemispheres. It contains diverse populations of neurons, including the cholinergic cortically projecting cells that show severe loss in Alzheimer's and related neurodegenerative diseases. The basal forebrain does not display any cytoarchitectural or other structural features that make it easy to demarcate functional boundaries, a problem that allowed different investigators to propose different organizational schemes. The present paper uses novel three-dimensional reconstructions and numerical analyses for studying the spatial organization of four major basal forebrain cell populations, the cholinergic, parvalbumin, calbindin and calretinin containing neurons in the rat. Our analyses suggest that the distribution of these four cell populations is not random but displays a general pattern of association. Within the cholinergic space (i.e. the volume occupied by the cortically projecting cholinergic cell bodies) the three other cell types form twisted bands along the longitudinal axis of a central dense core of cholinergic cells traversing the traditionally defined basal forebrain regions, (i.e. the medial septum, diagonal bands, the substantia innominata, pallidal regions and the bed nucleus of the stria terminalis). At a smaller scale, the different cell types within the cholinergic space occupy overlapping high-density cell clusters that are either chemically uniform or mixed. However, the cell composition of these high-density clusters is regionally specific. The proposed scheme of basal forebrain organization, using cell density or density relations as criteria, offers a new perspective on structure-function relationship, unconstrained by traditional region boundaries.

Acetylcholine↗

PubMed2004

Alpha-adrenergic receptor (alpha(2 A )) is colocalized in basal forebrain cholinergic neurons: a light and electron microscopic double immunolabeling study.

A variety of data suggest that noradrenaline and acetylcholine may interact in the basal forebrain, however no morphological studies have addressed whether indeed cholinergic neurons express adrenergic receptors. We have investigated the presence of alpha-adrenergic receptor subtype alpha2A-AR in cholinergic neurons of the basal forebrain. Cholinergic neurons were identified with an antibody against choline acetyltransferase and the receptor with a polyclonal antibody raised against a 47 amino acid fragment of the third intracellular loop of the alpha2A-AR. For double labeling at the light microscopic level the Ni-DAB/DAB technique was used, and for electron microscopy an immunoperoxidase/immunogold method was applied. We detected the alpha2A-AR protein in cholinergic as well as in non-cholinergic neurons. Almost half of all cholinergic neurons contained this adrenergic receptor. Double-labeled neurons were distributed throughout the rostro-caudal extent of the basal forebrain cholinergic continuum, including the medial septum, vertical and horizontal diagonal band nuclei, pallidal regions, substantia innominata and the internal capsule. Non-cholinergic neurons that expressed the alpha2A-AR outnumbered cholinergic/alpha2A-AR neurons by several factors. Electron microscopy confirmed the presence of alpha2A-AR in cholinergic neurons in the medial septum, vertical and horizontal diagonal band nuclei. Gold particles (10 nm) indicative of alpha2A-AR were diffusely distributed in the cytoplasm and accumulated in cytoplasmic areas near the Golgi complex and cysterns of the endoplasmic reticulum and were associated with the cellular membranes at synaptic and non-synaptic locations. Since many of the alpha2A-AR+/non-cholinergic neurons we detected are likely to be GABAergic cells, our data support the hypothesis that noradrenaline may act via basal forebrain cholinergic and non-cholinergic neurons to influence cortical activity.

Acetylcholine↗

PubMed2003

Electrophysiological evidence for the existence of a posterior cortical-prefrontal-basal forebrain circuitry in modulating sensory responses in visual and somatosensory rat cortical areas.

The prefrontal cortex (PFC) receives input from sensory neocortical regions and sends projections to the basal forebrain (BF). The present study tested the possibility that pathways from sensory cortical regions via the PFC-BF and from the BF back to specific sensory cortical areas could modulate sensory responses. Two prefrontal areas that responded to stimulation of the primary somatosensory and visual cortices were delineated: an area encompassing the rostral part of the cingulate cortex that responded to visual cortex stimulation, and a region dorso-lateral to the first in the precentral-motor association area that reacted to somatosensory cortex stimulation. Moreover, BF neurons responded to PFC electrical stimulation. They were located in the ventral pallidum, substantia innominata and the horizontal limb of the diagonal-band areas. Of the responsive BF neurons 42% reacted only to stimulation of 'visually-responsive,' 33% responded only to the 'somatosensory-responsive' prefrontal sites and the remaining neurons reacted to both prefrontal cortical areas. The effect of BF and PFC stimulations on somatosensory and visual-evoked potentials was tested. BF stimulation increased the amplitude of both sensory-evoked potentials. However, stimulation of the 'somatosensory-responsive' prefrontal area increased only somatosensory-evoked potentials while 'visually-responsive' prefrontal-area stimulation increased only visual-evoked potentials. Atropine blocked both facilitatory effects. The proposed cortico-prefronto-basalo-cortical circuitry may have an important role in cortical plasticity and selective attention.

Action Potentials↗

PubMed2001

Visualization of density relations in large-scale neural networks.

The topological organization of interfacing neuronal populations in the basal forebrain of rats was investigated in 3D by using computational methods for extracting information about the spatial distribution of cell densities and density relations. We claim that numerical and spatial constraints imposed by these methods may help to define neuronal clusters in this brain area where simple two-dimensional histology failed to reveal such an arrangement. Neuronal clusters have been suggested in many brain regions as sites of integrative operations. Taking advantage of computerized data acquisition methods in the 3D reconstruction of large cell populations we introduced four basic methods to visualize density relations on simple and combined cell markers: Differential Density 3D Scatter Plot, Iso-relational Scatter plot, Iso-density Surface Rendering and Iso-relational Surface Rendering. These methods are described and exemplified on a 3D neuronal database acquired from mapping different chemically or hodologically defined cell populations in serial sections of the rat basal forebrain.

Acetylcholine↗

PubMed2001

The midbrain dopaminergic system: anatomy and genetic variation in dopamine neuron number of inbred mouse strains.

The mesotelencephalic dopamine system is genetically variable and affects motor behavior, motivation, and learning. Here we examine the genetic variation of mesencephalic DA neuron number in a quasi-congenic RQI mouse strain and its background partner and in a recombinant inbred strain with different levels of mesencephalic tyrosine hydroxylase activity (TH/MES). We used B6.Cb4i5-alpha6/Vad, C57BL/6By, and CXBI, which are known to express high, intermediate, and low levels of TH/MES, respectively. Unbiased stereological sampling with optical disector counting methods were employed to estimate the number of TH-positive neurons in the A8-A9-A10 cell groups. Morphometric studies on the mesencephalic dopamine cell groups indicated that male mice of the B6.Cb4i5-alpha6/Vad strain were endowed with a significantly lower number of TH-positive cells than CXBI mice. In all strains studied, the right retrorubral field (A8 area) had a higher number of dopamine neurons compared to the left A8 area. The results suggest an inverse relationship between TH/MES and number of dopamine neurons in the A9-A10 cell groups and significant lateral asymmetry in the A8 cell group. A detailed anatomical atlas of the mesencephalic A8-A9-A10 dopaminergic cell groups in the mouse is also presented to facilitate the assignment of TH-positive neurons to specific cell groups.

Animals↗

PubMed2000

Local synaptic connections of basal forebrain neurons.

Single, biocytin filled neurons in combination with immunocytochemistry and retrograde tracing as well as material with traditional double-immunolabeling were used at the light and electron microscopic levels to study the neural circuitry within the basal forebrain. Cholinergic neurons projecting to the frontal cortex exhibited extensive local collaterals terminating on non-cholinergic, (possible GABAergic) neurons within the basal forebrain. Elaborate axon arbors confined to the basal forebrain region also originated from NPY, somatostatin and other non-cholinergic interneurons. It is proposed that putative interneurons together with local collaterals from projection neurons contribute to regional integrative processing in the basal forebrain that may participate in more selective functions, such as attention and cortical plasticity.

Animals↗

PubMed2000

EEG correlation of the discharge properties of identified neurons in the basal forebrain.

The basal forebrain (BF) is a heterogeneous structure located in the ventral aspect of the cerebral hemispheres. It contains cholinergic as well as different types of noncholinergic corticopetal neurons and interneurons, including GABAergic and peptidergic cells. The BF constitutes an extrathalamic route to the cortex, and its activity is associated with an increase in cortical release of the neurotransmitter acetylcholine, concomitant with electroencephalographic (EEG) low-voltage fast activity (LVFA). However, the specific role of the different BF cell types has largely remained unknown due to the lack of chemical identification of the recorded neurons. Here we show that the firing rate of immunocytochemically identified cholinergic and parvalbumin-containing neurons increase during cortical LVFA. In contrast, increased neuropeptide Y neuron firing is accompanied by cortical slow waves. Our results, furthermore, indicate that BF neurons posses a distinct temporal relationship to different EEG patterns and suggest a more dynamic interplay within BF as well as between BF and cortical circuitries than previously proposed.

Action Potentials↗

PubMed1999

The basal forebrain corticopetal system revisited.

The medial septum, diagonal bands, ventral pallidum, substantia innominata, globus pallidus, and internal capsule contain a heterogeneous population of neurons, including cholinergic and noncholinergic (mostly GABA containing), corticopetal projection neurons, and interneurons. This highly complex brain region, which constitutes a significant part of the basal forebrain has been implicated in attention, motivation, learning, as well as in a number of neuropsychiatric disorders, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Part of the difficulty in understanding the functions of the basal forebrain, as well as the aberrant information-processing characteristics of these disease states lies in the fact that the organizational principles of this brain area remained largely elusive. On the basis of new anatomical data, it is proposed that a large part of the basal forebrain corticopetal system be organized into longitudinal bands. Considering the topographic organization of cortical afferents to different divisions of the prefrontal cortex and a similar topographic projection of these prefrontal areas to basal forebrain regions, it is suggested that several functionally segregated cortico-prefronto-basal forebrain-cortical circuits exist. It is envisaged that such specific "triangular" circuits could amplify selective attentional processing in posterior sensory cortical areas.

Alzheimer Disease↗

PubMed1998

Morphological and electrophysiological characteristics of noncholinergic basal forebrain neurons.

Cholinergic neurons in the basal forebrain are the focus of considerable interest because they are severely affected in Alzheimer's disease. However, both cholinergic and noncholinergic neurons are intermingled in this region. The goal of the present study was to characterize the morphology and in vivo electrophysiology of noncholinergic basal forebrain neurons. Neurons in the ventral pallidum and substantia innominata were recorded extracellularly, labeled juxtacellularly with biocytin and characterized for the presence of choline acetyltransferase immunoreactivity. Two types of ventral pallidal cells were observed. Type I ventral pallidal neurons had axons that rarely branched near the cell body and tended to have smaller somata and lower spontaneous firing rates than did type II ventral pallidal neurons, which displayed extensive local axonal arborizations. Subtypes of substantia innominata neurons could not be distinguished based on axonal morphology. These noncholineregic neurons exhibited local axon arborizations along a continuum that varied from no local collaterals to quite extensive arbors. Substantia innominata neurons had lower spontaneous firing rates, more variable interspike intervals, and different spontaneous firing patterns than did type II ventral pallidal neurons and could be antidromically activated from cortex or substantia nigra, indicating that they were projection neurons. Ventral pallidal neurons resemble, both morphologically and electrophysiologically, previously described neurons in the globus pallidus, whereas the substantia innominata neurons bore similarities to isodendritic neurons of the reticular formation. These results demonstrate the heterogeneous nature of noncholinergic neurons in the basal forebrain.

Acetylcholine↗

PubMed1997

Parvalbumin-containing neurons in the basal forebrain receive direct input from the substantia nigra-ventral tegmental area.

By means of anterograde tracing of Phaseolus vulgaris-leucoagglutinin (PHA-L) it was determined if parvalbumin-immunoreactive neurons in the basal forebrain receive a direct synaptic input from the A9-A10 dopaminergic nuclei of the substantia nigra and ventral tegmental area. Forebrain sections were processed for immunocytochemical detection of PHA-L and parvalbumin (PV) at light and electron microscopic levels. At the ultrastructural level, PHA-L-labeled terminals were found to establish synaptic contacts with PV-immunoreactive neuronal somata in the ventromedial globus pallidus, the ventral pallidum, the internal capsule, and the substantia innominata. PV-containing neurons in pallidal and adjacent basal forebrain territories are thus directly targeted by presumably A9-A10 dopaminergic neurons and represent a novel aspect of midbrain dopaminergic control of basal forebrain neuronal activity.

Animals↗

PubMed1997

3-Nitropropionic acid neurotoxicity: visualization by silver staining and implications for use as an animal model of Huntington's disease.

The neuronal damage produced by the mitochondrial toxin 3-nitropropionic acid (3NPA) has been suggested to replicate much of the neuropathology seen in Huntington's disease (HD) and therefore might be used in an animal model. We investigated the susceptibility to this toxin of different neuronal populations in addition to the commonly studied caudate putamen by injecting 3NPA into seven different brain regions as well as systemically. After different survival times, rats were intracardially perfused, brain sections were processed with the Gallyas silver technique, and impregnated neurons were mapped with a computerized microscope. Intracerebral administration of 3NPA resulted in a lesion, the center of which was devoid of tissue while the area was surrounded by a halo of Golgi-like impregnated neurons. In addition to local damage, rats receiving microinjections into the frontal cortex, caudate putamen, basal forebrain, and amygdala displayed argyrophilic neurons in the thalamus corresponding to the topography of thalamofugal neurons projecting to the individual injection sites. On the other hand, negligible secondary damage was seen after injections into the internal capsule, thalamus, or substantia nigra, implicating that thalamofugal axons are especially vulnerable to the local effect of this toxin. Two and a half days after systemic administration of 3NPA, a diffuse argyrophilic neuronal reaction was seen in the dorsolateral part of the caudate putamen, together with a more regionally selective staining of neurons in different cortical areas and the hippocampus. These morphopathological changes were also accompanied by motor deficits. The affected neurons in the cortical regions were primarily in those layers (V and VI) and areas (medial prefrontal, caudal insular/periphinal, and ventral temporal) that do not project toward the lesioned striatal area; therefore, the cortical pathology may represent another primary site of action of the toxin. Among the affected neurons in the hippocampal complex were pyramidal neurons in the CA1 region as well as various neurons in the CA3 region and dentate hilar area. These studies suggest that a combination of 3NPA administration and a sensitive silver-impregnation method may unravel the potential site of primary neuronal damage in this animal model. Furthermore, these findings may contribute to the understanding of how the disease progresses in HD from the originally affected neuronal population(s) by the recruitment of closely related systems and pathways.

Animals↗

PubMed1997

Cortical input to the basal forebrain.

The arborization pattern and postsynaptic targets of corticofugal axons in basal forebrain areas have been studied by the combination of anatomical tract-tracing and pre- and postembedding immunocytochemistry. The anterograde neuronal tracer Phaseolus vulgaris leucoagglutinin was iontophoretically delivered into different neocortical (frontal, parietal, occipital), allocortical (piriform) and mesocortical (insular, prefrontal) areas in rats. To identify the transmitter phenotype in pre- or postsynaptic elements, the tracer staining was combined with immunolabeling for either glutamate or GABA, or with immunolabeling for choline acetyltransferase or parvalbumin. Tracer injections into medial and ventral prefrontal areas gave rise to dense terminal arborizations in extended basal forebrain areas, particularly in the horizontal limb of the diagonal band and the region ventral to it. Terminals were also found to a lesser extent in the ventral part of the substantia innominata and in ventral pallidal areas adjoining ventral striatal territories. Similarly, labeled fibers from the piriform and insular cortices were found to reach lateral and ventral parts of the substantia innominata, where terminal varicosities were evident. In contrast, descending fibers from neocortical areas were smooth, devoid of terminal varicosities, and restricted to the myelinated fascicles of the internal capsule en route to more caudal targets. Ultrastructural studies obtained indicated that corticofugal axon terminals in the basal forebrain areas form synaptic contact primarily with dendritic spines or small dendritic branches (89%); the remaining axon terminals established synapses with dendritic shafts. All tracer labeled axon terminals were immunonegative for GABA, and in the cases investigated, were found to contain glutamate immunoreactivity. In material stained for the anterograde tracer and choline acetyltransferase, a total of 63 Phaseolus vulgaris leucoagglutinin varicosities closely associated with cholinergic profiles were selected for electron microscopic analysis. From this material, 37 varicosities were identified as establishing asymmetric synaptic contacts with neurons that were immunonegative for choline acetyltransferase, including spines and small dendrites (87%) or dendritic shafts (13%). Unequivocal evidence for synaptic interactions between tracer labeled terminals and cholinergic profiles could not be obtained in the remaining cases. From material stained for the anterograde tracer and parvalbumin, 40% of the labeled terminals investigated were found to establish synapses with parvalbumin-positive elements; these contacts were on dendritic shafts and were of the asymmetrical type. The present data suggest that corticofugal axons innervate forebrain neurons that are primarily inhibitory and non-cholinergic; local forebrain axonal arborizations of these cells may represent a mechanism by which prefrontal cortical areas control basal forebrain cholinergic neurons outside the traditional boundaries of pallidal areas.

Animals↗

PubMed1996

Direct catecholaminergic-cholinergic interactions in the basal forebrain. I. Dopamine-beta-hydroxylase- and tyrosine hydroxylase input to cholinergic neurons.

Immunocytochemical double-labeling techniques were used at the light and electron microscopic levels to investigate whether dopamine-beta-hydroxylase and tyrosine hydroxylase-containing axons contact basal forebrain cholinergic neurons. Dopamine-beta-hydroxylase- and tyrosine hydroxylase-positive fibers and terminals were found in close proximity to cholinergic neurons throughout extensive basal forebrain areas, including the vertical and horizontal limb of the diagonal band nuclei, the sublenticular substantia innominata, bed nucleus of the stria terminalis, ventral pallidum, and ventrolateral globus pallidus. Cholinergic cells in some aspects of the globus pallidus appeared to be contacted by tyrosine hydroxylase-positive but not dopamine-beta-hydroxylase-positive fibers, suggesting dopaminergic input to cholinergic neurons in these regions. Direct evidence for the termination of dopamine-beta-hydroxylase and tyrosine hydroxylase-positive fibers on cholinergic neurons was obtained in electron microscopic double-immunolabeling studies. Using high magnification light microscopic screening, both qualitative and quantitative differences were noted in the catecholaminergic innervation of forebrain cholinergic neurons. For example, while many cholinergic neurons were in close proximity to single dopamine-beta-hydroxylase-positive varicosities, others, particularly those located in the substantia innominatabed nucleus of the stria terminalis continuum, were apparently contacted by labeled fibers in repetitive fashion. The findings of the present study, together with our preliminary biochemical experiments (Zaborszky et al. [1993] Prog. Brain Res. 98:31-49) suggest that catecholaminergic afferents can differentially modulate forebrain cholinergic neurons. Such interactions may be important in learning and memory processes, and their perturbations may contribute to the cognitive decline seen in aging and in disorders such as Alzheimer's and Parkinson's diseases.

Animals↗

PubMed1996

Direct catecholaminergic-cholinergic interactions in the basal forebrain. II. Substantia nigra-ventral tegmental area projections to cholinergic neurons.

Previous observations indicate that the basal forebrain receives dopaminergic input from the ventral midbrain. The present study aimed at determining the topographic organization of these projections in the rat, and whether this input directly terminates on cholinergic neurons. Injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) into discrete parts of the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC) labeled axons and terminals in distinct parts of the basal forebrain, including medial and lateral septum, diagnoal band nuclei, ventral pallidum, globus pallidus, substantia innominata, globus pallidus, and internal capsule, where PHA-L-labeled terminals abutted cholinergic (choline acetyltransferase = ChAT-containing) profiles. Three-dimensional (3-D) computerized reconstruction of immunostained sections clearly revealed distinct, albeit overlapping, subpopulations of ChAT-immunoreactive neurons apposed by PHA-L-labeled input from medial VTA (mainly in vertical and horizontal diagonal band nuclei), lateral VTA and medial SNC (ventral pallidum and anterior half of substantia innominata), and lateral SNC (caudal half of the substantia innominata and globus pallidus). At the ultrastructural level, about 40% of the selected PHA-L-labeled presynaptic terminals in the ventral pallidum and substantia innominata were found to establish synaptic specializations with ChAT-containing profiles, most of which on the cell body and proximal dendritic shafts. Convergent synaptic input of unlabeled terminals that formed asymmetric synapses with the ChAT-immunoreactive profiles were often found in close proximity to the PHA-L-labeled terminals. These observations show that the cholinergic neurons in the basal forebrain are targets of presumably dopaminergic SNC/VTA neurons, and suggest a direct modulatory role of dopamine in acetylcholine release in the cerebral cortical mantle.

Animals↗

PubMed1989

Hypothalamic axons terminate on forebrain cholinergic neurons: an ultrastructural double-labeling study using PHA-L tracing and ChAT immunocytochemistry.

A correlated light and electron microscopic study combining choline acetyltransferase immunocytochemistry with anterograde tracing of Phaseolus vulgaris leucoagglutinin revealed that axons of lateral hypothalamic neurons terminate on forebrain cholinergic projection cells. This finding is discussed in relation to direct and indirect corticopetal systems.

Animals↗

PubMed1989

Afferent connections of the forebrain cholinergic projection neurons, with special reference to monoaminergic and peptidergic fibers.

Earlier light microscopic data on afferent connections to the cholinergic forebrain neurons are reconsidered in the light of EM cross-identification of neurons and synapses by combinations of tracer and immunocytochemical techniques. Such studies suggest that brainstem monoaminergic afferents terminate on cholinergic forebrain neurons, and may modulate the activity of choline acetyltransferase levels in the postsynaptic neurons. A monosynaptic relationship between cholinergic forebrain neurons and neuropeptide Y and somatostatin containing axons is also supported by studies using double immunolabeling techniques at the EM level. These peptidergic afferents originate in part from locally arborizing neurons. Based upon the new data a circuit model for basal forebrain cholinergic neurons is proposed.

Acetylcholine↗

PubMed1987

The ventral striatopallidothalamic projection: I. The striatopallidal link originating in the striatal parts of the olfactory tubercle.

The projections from the striatal part of the olfactory tubercle were examined in rats, both with the aid of experimental silver impregnation methods following superficial laminar heat lesions of the tubercle and by the use of anterograde transport of Phaseolus vulgaris-leucoagglutinin (PHA-L) following injections of the lectin in the dense cell layer of the tubercle. Retrograde transport of fluorescent substances following injections of the tracer in the multiform layer of the tubercle were used to corroborate the results obtained by the anterograde transport and degeneration methods. The main and apparently only significant termination from the striatal cells in the olfactory tubercle is located immediately deep to the dense cell layer in areas that could be identified as part of the ventral pallidum on the basis of either the Nissl method or glutamate decarboxylase immunocytochemistry. Whereas a mediolateral topography is generally maintained by the ventral striatopallidal pathway originating in the dense cell layer, there is a considerable spread of the projection in the rostrocaudal direction. The dense projection field of the olfactory tubercle component of the ventral striatopallidal pathway permeates the ventrolateral part of the ventral pallidum, thereby complementing the termination of the accumbens projection to the more mediodorsal parts of the ventral pallidum.

Animals↗

PubMed1987

The ventral striatopallidothalamic projection: II. The ventral pallidothalamic link.

The projection of ventral pallidal neurons to the mediodorsal nucleus of the thalamus (MD) was examined in rats by combined retrograde transport of horseradish peroxidase (HRP) after injections in the MD and glutamate decarboxylase (GAD) immunocytochemistry at light and electron microscopic levels, with and without prior exposure of the brains to colchicine. HRP was transported to the soma of medium-sized and large ventral pallidum neurons, which along with their long, large dendrites were contacted by many glutamate decarboxylase immunoreactive synaptic boutons. The retrograde tracer positive neurons bore a remarkable resemblance to the projecting cells of the globus pallidus and entopeduncular nucleus. When colchine exposure was included in the tissue preparation, some but not all tracer positive cells also exhibited cytoplasmic GAD immunoreactivity.

Animals↗