A New Neural Pathway from the Ventral Striatum to the Nucleus Basalis of Meynert with Functional Implication to Learning and Memory.

The cholinergic neurons in the nucleus basalis of Meynert (NBM) are among the first group of neurons known to become degenerated in Alzheimer's disease, and thus the NBM is proposed to be involved in learning and memory. The marginal division (MrD) of the striatum is a newly discovered subdivision at the ventromedial border of the mammalian striatum and is considered to be one part of the ventral striatum involved in learning and memory. The present study provided evidence to support the hypothesis that the MrD and the NBM were structurally connected at cellular and subcellular levels with functional implications in learning and memory. First, when wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) was stereotaxically injected into the NBM, fusiform neurons in the MrD were retrogradely labeled with WGA-HRP gray-blue particles and some of them were double stained in brown color by AchE staining method. Thus, cholinergic neurons of the MrD were shown to project to the neurons in the NBM. Second, in anterograde tract-tracing experiments where WGA-HRP was injected to the MrD, the labeled WGA-HRP was found to be anterogradely transported in axons from the MrD to the synaptic terminals with dendrites, axons, and perikaryons of the cholinergic neurons in the NBM when observed under an electronic microscope, indicating reciprocal structural connections between the MrD and the NBM. Third, when bilateral lesions of the MrD were injured with kainic acid in rats, degenerative terminals were observed in synapses of the NBM by an electronic microscope and severe learning and memory deficiency was found in these rats by the Y-maze behavioral test. Our results suggest reciprocal cholinergic connections between the MrD of the ventral striatum and the NBM, and implicate a role of the MrD-NBM pathway in learning and memory. The efferent fibers of cholinergic neurons in the NBM mainly project to the cortex, and severe reduction of the cholinergic innervation in the cortex is the common feature of Alzheimer's patients. The newly discovered cholinergic neural pathway between the MrD of the ventral striatum and the NBM is supposed involved in the memory circuitries of the brain and probably might play a role in the pathogenesis of the Alzheimer's disease.

Distribution of osmoregulatory peptides and neuronal-glial configuration in the hypothalamic magnocellular nuclei of desert rodents.

The desert rodents Psammomys obesus and Gerbillus tarabuli live under extreme conditions and overcome food and water shortage by modes of food and fluid intake specific to each species. Using immunohistochemistry and electron microscopy, we found that the hypothalamic magnocellular nuclei, and in particular, their vasopressinergic component, is highly and similarly developed in Psammomys and Gerbillus. In comparison to other rodents, the hypothalamus in both species contains more magnocellular VP neurons that, together with oxytocin neurons, accumulate in distinct and extensive nuclei. As in dehydrated rodents, many magnocellular neurons contained both neuropeptides. A striking feature of the hypothalamic magnocellular system of Psammomys and Gerbillus was its display of ultrastructural properties related to heightened neurosecretion, namely, a significant reduction in glial coverage of neuronal somata and dendrites in the hypothalamic nuclei. There were many neuronal elements whose surfaces were directly juxtaposed and shared the same synapses. Their magnocellular nuclei also showed a high level of sialylated isoform of the Neural Cell Adhesion Molecule (PSA-NCAM) that underlies their capacity for neuronal and glial plasticity. These species thus offer striking models of structural neuronal and glial plasticity linked to natural conditions of heightened neurosecretion.

Projections from basal forebrain to prefrontal cortex comprise cholinergic, GABAergic and glutamatergic inputs to pyramidal cells or interneurons.

The present study was undertaken to characterize the pre- and postsynaptic constituents of the basal forebrain (BF) projection to the prefrontal cortex in the rat, and determine whether it includes glutamatergic in addition to established gamma-aminobutyric acid (GABA)ergic and cholinergic elements. BF fibres were labelled by anterograde transport using biotin dextran amine (BDA) and dual-stained for the vesicular transporter proteins (VTPs) for glutamate (VGluT), GABA (VGAT) or acetylcholine (VAChT). Viewed by fluorescence microscopy and estimated by stereology, proportions of BDA-labelled varicosities were found to be stained for VGluT2 (and not VGluT1 or 3), VGAT or VAChT (representing, respectively, approximately 15%, approximately 52% and approximately 19% within the infralimbic cortex). Each type was present in all, though commonly most densely in deep, cortical layers. Material was triple-stained for postsynaptic proteins to examine whether BDA+VTP+ varicosities might form excitatory or inhibitory synapses, respectively, labelled by postsynaptic density-95 kDA (PSD-95) or gephyrin (Geph). Viewed by confocal microscopy, a majority of BDA+/VGluT2+ varicosities were found to be apposed to PSD-95+ elements, and a majority of BDA+/VGAT+ varicosities to be apposed to Geph+ elements. Other series were triple-stained for cell marker proteins to assess whether the varicosities contacted interneurons or pyramidal cells. Viewed by confocal microscopy, BDA-labelled VGluT2+, VGAT+ and VAChT+ BF terminals were all found in contact with calbindin+ interneurons, whereas VGAT+ BF terminals were also seen in contact with parvalbumin+ interneurons and non-phosphorylated neurofilament+ pyramidal cells. Through distinct glutamatergic, GABAergic and cholinergic projections, the BF can thus influence cortical activity in a diverse manner.

Synaptologic and fine structural features distinguishing a subset of basal forebrain cholinergic neurons embedded in the dense intrinsic fiber network of the caudal extended amygdala.

Cholinergic basal forebrain neurons confined within the intrinsic connections of the extended amygdala in the caudal sublenticular region and anterior amygdaloid area (cSLR/AAA) differ from other basal forebrain cholinergic neurons in several morphological and neurochemical respects. These cSLR/AAA cholinergic neurons have been subjected to additional investigations described in this report. First, fibers traced anterogradely following injections of Phaseolus vulgaris-leucoagglutinin in the central amygdaloid nucleus were shown to contact cSLR/AAA cholinergic neurons and dendrites. Second, these neurons were shown to be contacted by numerous GABAergic boutons with symmetric synaptic specializations. Third, the numbers of synaptic densities of morphologically characterized symmetric contacts on the somata and proximal dendrites of cSLR/AAA cholinergic neurons were shown to significantly exceed those of extra-cSLR/AAA cholinergic neurons. Fourth, fine structural features distinguishing cSLR/AAA cholinergic neurons from other basal forebrain cholinergic neurons were revealed. Specifically, cSLR/AAA cholinergic neurons have less abundant cytoplasm and a less well-organized system of rough endoplasmic reticulum than their counterparts in other parts of the basal forebrain. Thus, morphologically and neurochemically distinct cSLR/AAA cholinergic neurons exhibit robust proximal inhibitory inputs, of which a significant number originate in the extended amygdala, while cholinergic neurons outside this region lack a substrate for strong proximal inhibitory input. The implications of these findings for interaction of fear, anxiety, and attention are considered.

More attention must be paid: the neurobiology of attentional effort.

Increases in attentional effort are defined as the motivated activation of attentional systems in response to detrimental challenges on attentional performance, such as the presentation of distractors, prolonged time-on-task, changing target stimulus characteristics and stimulus presentation parameters, circadian phase shifts, stress or sickness. Increases in attentional effort are motivated by the expected performance outcome; in the absence of such motivation, attentional performance continues to decline or may cease altogether. The beneficial effects of increased attentional effort are due in part to the activation of top-down mechanisms that act to optimize input detection and processing, thereby stabilizing or recovering attentional performance in response to challenges. Following a description of the psychological construct "attentional effort", evidence is reviewed indicating that increases in the activity of cortical cholinergic inputs represent a major component of the neuronal circuitry mediating increases in attentional effort. A neuronal model describes how error detection and reward loss, indicating declining performance, are integrated with motivational mechanisms on the basis of neuronal circuits between prefrontal/anterior cingulate and mesolimbic regions. The cortical cholinergic input system is activated by projections of mesolimbic structures to the basal forebrain cholinergic system. In prefrontal regions, increases in cholinergic activity are hypothesized to contribute to the activation of the anterior attention system and associated executive functions, particularly the top-down optimization of input processing in sensory regions. Moreover, and influenced in part by prefrontal projections to the basal forebrain, increases in cholinergic activity in sensory and other posterior cortical regions contribute directly to the modification of receptive field properties or the suppression of contextual information and, therefore, to the mediation of top-down effects. The definition of attentional effort as a cognitive incentive, and the description of a neuronal circuitry model that integrates brain systems involved in performance monitoring, the processing of incentives, activation of attention systems and modulation of input functions, suggest that 'attentional effort' represents a viable construct for cognitive neuroscience research.

Expression of GABA(B) receptor in the avian auditory brainstem: ontogeny, afferent deprivation, and ultrastructure.

Nucleus magnocellularis (NM), nucleus angularis (NA), and nucleus laminaris (NL), second- and third-order auditory neurons in the avian brainstem, receive GABAergic input primarily from the superior olivary nucleus (SON). Previous studies have demonstrated that both GABA(A) and GABA(B) receptors (GABA(B)Rs) influence physiological properties of NM neurons. We characterized the distribution of GABA(B)R expression in these nuclei during development and after deafferentation of the excitatory auditory nerve (nVIII) inputs. We used a polyclonal antibody raised against rat GABA(B)Rs in the auditory brainstem during developmental periods that are thought to precede and include synaptogenesis of GABAergic inputs. As early as embryonic day (E)14, dense labeling is observed in NA, NM, NL, and SON. At earlier ages immunoreactivity is present in somas as diffuse staining with few puncta. By E21, when the structure and function of the auditory nuclei are known to be mature, GABA(B) immunoreactivity is characterized by dense punctate labeling in NM, NL, and a subset of NA neurons, but label is sparse in the SON. Removal of the cochlea and nVIII neurons in posthatch chicks resulted in only a small decrease in immunoreactivity after survival times of 14 or 28 days, suggesting that a major proportion of GABA(B)Rs may be expressed postsynaptically or on GABAergic terminals. We confirmed this interpretation with immunogold TEM, where expression at postsynaptic membrane sites is clearly observed. The characterization of GABA(B)R distribution enriches our understanding of the full complement of inhibitory influences on central auditory processing in this well-studied neuronal circuit.

Developmental changes in the subcellular localization of calretinin.

Brainstem auditory neurons in the chick nucleus magnocellularis (NM) express high levels of the neuron-specific calcium-binding protein calretinin (CR). CR has heretofore been considered a diffusible calcium buffer that is dispersed uniformly throughout the cytosol. Using high-resolution confocal microscopy and complementary biochemical analyses, we have found that during the development of NM neurons, CR changes from being expressed diffusely at low concentrations to being highly concentrated beneath the plasma membrane. This shift in CR localization occurs at the same time as the onset of spontaneous activity, synaptic transmission, and synapse refinement in NM. In the chick brainstem auditory pathway, this subcellular localization appears to occur only in NM neurons and only with respect to CR, because calmodulin remains diffusely expressed in NM. Biochemical analyses show the association of calretinin with the membrane is detergent-soluble and calcium-independent. Because these are highly active neurons with a large number of Ca2+-permeable synaptic AMPA receptors, we hypothesize that localization of CR beneath the plasma membrane is an adaptation to spatially restrict the calcium influxes.

Pathological characteristic of Alzheimer's disease produced by lesion in nucleus basalis of Meynert in rats.

OBJECTIVE: To find out if the lesion in nucleus basalis of Meynert (nbM) can induce some morphological changes characteristic of Alzheimer's disease. METHODS: Kainic acid was injected into nbM of the rats, and the behavioral deficiency and the morphological changes in the cortex and hippocampus were observed by methenamine silver staining and electron microscopical examination. RESULTS: After 9-15 months of breeding following nbM-lesion, we observed many pathological changes in this animal model, which were characteristic of Alzheimer's disease in human, and especially we could find for the first time the formation of senile plagues after 15-month breeding. CONCLUSION: It is proposed that the degeneration of nbM neurons might be primary and responsible for the pathological changes in other brain tissues in sporadic Alzheimer's disease.