bluuebunny/crossref_metadata_2025 huggingface dataset:
Potentiation of amygdaloid and hippocampal auditory‐evoked potentials in a discriminatory fear‐conditioning task in mice as a function of tone pattern and context
Authors: Tang Jianrong , Wagner Stefanie , Schachner Melitta , Dityatev Alexander , Wotjak Carsten T.
Published: August 2003

According to the local memory storage hypothesis, information about the tone–shock association in an auditory fear‐conditioning paradigm is stored in synapses within the lateral amygdala. Thus, fear‐conditioning‐induced potentiation of auditory‐evoked potentials in response to a conditioned stimulus (CS+, a series of short lasting tones; patterned tone) has been interpreted as an in vivo correlate of amygdaloid synaptic plasticity. Here, we re‐examine the specificity of potentiation of auditory‐evoked potentials in terms of (i) local confinement to the lateral amygdala, (ii) parameters of CS+ and (iii) influence of context, using a discriminatory fear‐conditioning paradigm. Adult male C57BL/6J mice were implanted with recording electrodes aimed at the lateral amygdala, the CA1 region of the hippocampus and the neck muscles for simultaneous recordings of auditory‐evoked potentials and startle responses. In a neutral context, auditory‐evoked potentials within lateral amygdala and CA1 as well as startle and freezing responses to the CS+ were significantly potentiated following conditioning, as compared with pre‐conditioning values and responses to a neutral stimulus (CSn; tone of different frequency). Potentiation was only evident if CS+ was presented as a uniform series but not if presented mixed with CSn. Accordingly, mice failed to show intensified freezing to a patterned tone if a single lasting tone of the same frequency served as CS+. Both CA1 and lateral amygdala auditory‐evoked potentials were potentiated in response to CSn if presented in the conditioning context. These findings demonstrate that (i) potentiation of auditory‐evoked potentials is not restricted to the lateral amygdala, (ii) both tone frequency and pattern of tone presentation are essential for proper CS+ recognition and (iii) contextual memory leads to a general potentiation of auditory‐evoked potentials.
Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen
Authors: McCaffery P. J. , Adams J. , Maden M. , Rosa‐Molinar E.
Published: August 2003

Retinoic acid (RA) is essential for both embryonic and adult growth, activating gene transcription via specific nuclear receptors. It is generated, via a retinaldehyde intermediate, from retinol (vitamin A). RA levels require precise regulation by controlled synthesis and catabolism, and when RA concentrations deviate from normal, in either direction, abnormal growth and development occurs. This review describes: (i) how the pattern of RA metabolic enzymes controls the actions of RA; and (ii) the type of abnormalities that result when this pattern breaks down. Examples are given of RA control of the anterior/posterior axis of the hindbrain, the dorsal/ventral axis of the spinal cord, as well as certain sex‐specific segments of the spinal cord, using varied animal models including mouse, quail and mosquitofish. These functions are highly sensitive to abnormal changes in RA concentration. In rodents, the control of neural patterning and differentiation are disrupted when RA concentrations are lowered, whereas inappropriately high concentrations of RA result in abnormal development of cerebellum and hindbrain nuclei. The latter parallels the malformations seen in the human embryo exposed to RA due to treatment of the mother with the acne drug Accutane (13‐cisRA) and, in cases where the child survives beyond birth, a particular set of behavioural anomalies can be described. Even the adult brain may be susceptible to an imbalance of RA, particularly the hippocampus. This report shows how the properties of RA as a neural induction agent and organizer of segmentation can explain the consequences of RA depletion and overexpression.
Direction‐selective motion blindness after unilateral posterior brain damage
Authors: Blanke Olaf , Landis Theodor , Mermoud Christophe , Spinelli Laurent , Safran Avinoam B.
Published: August 2003

Motion blindness (MB) is defined as the selective disturbance of visual motion perception despite intact perception of other features of the visual scene. MB is characterized by a pandirectional deficit of motion direction discrimination and is assumed to result from damage to the visual motion pathway, especially area MT/V5. However, the most characteristic feature of primate MT/V5 neurons is not their motion selectivity but their preference for one direction of motion (direction selectivity), which changes incrementally at neighbouring columns. In addition to this microscopic directional organization, studies in nonhuman and human primates suggest that single directions of motion are also coded at a more macroscopic level. We thus hypothesized that if MB in humans results from damage to direction‐selective neurons in the visual motion pathway, posterior brain damage might cause MB which is direction selective, not pandirectional. The present study investigated motion direction discrimination in patients with posterior unilateral brain damage and determined separate psychophysical thresholds for the four cardinal directions. In addition, we analysed whether the direction of erroneous motion perception (i.e. the perception of right motion for upward motion) was random or showed a directional bias. We report three principal findings. First, motion direction discrimination was severely impaired in one or two directions while it was normal in the other directions. This constituted direction‐selective MB. Second, MB was characterized not only by a quantitative direction‐selective increase in psychophysical thresholds but also by a qualitative impairment of perceiving motion direction systematically in wrong directions. Both findings suggest that the cortical modules specialized for the perception of a single direction of motion might be larger than previously thought. Third, lesion analysis showed that unilateral damage, not only the human homologue of MT/V5 but also to parieto‐occipital cortex, leads to MB.
NMDA lesions of Ammon's horn and the dentate gyrus disrupt the direct and temporally paced homing displayed by rats exploring a novel environment: evidence for a role of the hippocampus in dead reckoning
Authors: Wallace Douglas G. , Whishaw Ian Q.
Published: August 2003

Dead reckoning, a form of navigation used to locate a present position and to return to a starting position, is used by rats to return to their home base. The present experiment examined whether dead reckoning is displayed by rats during their first exploratory excursions in a novel environment and also examined whether the behaviour requires the integrity of the cells of the hippocampus. Experimental rats, those with NMDA (N‐methly d‐aspartate) lesions of Ammon's horn and the dentate gyrus, and control rats could leave a cage to explore a large circular table under light and dark conditions. Home base behaviour, use of olfactory cues, and thigmotaxic‐ based navigation were evaluated. Temporal, topographical and kinematic analyses were conducted on the first three exploratory excursions that extended at least halfway across the table. Groups did not differ in numbers of exits from the home base, lingering near the home base, distance travelled, or the use of surface cues as might be exemplified by thigmotaxic and olfactory behaviour. Temporal, topographical and kinematic reconstructions of homing behaviour, however, indicated that control rats, but not hippocampal rats, made direct high velocity return trips to the home base in both the light and the dark. Peak velocity of the trips occurred at the trip midpoint, independent of trip distance, suggesting the movements were preplanned. These results are discussed in relation to the ideas that dead reckoning is used in the homing of exploring rats and that this form of navigation involves the hippocampus.
Mechanisms of sensitization of the response of single dorsal root ganglion cells from adult rat to noxious heat
Authors: Galoyan Samuel M. , Petruska Jeffrey C. , Mendell Lorne M.
Published: August 2003

We investigated the regulation by nerve growth factor of the response of sensory neurons to noxious heat (>43 °C). In dissociated dorsal root ganglion neurons (<30 µm) from adult rat we demonstrated, using perforated patch clamp recording, that the inward current elicited in response to noxious heating is enhanced by nerve growth factor and reduced by capsazepine. The tachyphylaxis observed in response to the second of two heat pulses was reversed in most cells when nerve growth factor was introduced into the medium during the 5 min between the two heat stimuli, similar to findings using capsaicin [X. Shu & L.M. Mendell (1999) Neurosci. Lett.274, 159–162]. The threshold temperature did not change systematically after nerve growth factor. Using antibodies to TRPV1 and trkA in a subset of cells from which we recorded, we found a virtually perfect correlation between expression of TRPV1 and sensitivity to noxious heat. In addition, trkA expression was perfectly correlated with the ability of nerve growth factor to reverse tachyphylaxis. Thus, this physiological test is a reliable measure of trkA expression in cells sensitive to noxious heat. In agreement with studies in heterologous cells expressing trkA and TRPV1, pharmacologically blocking phospholipase C abolished the effect of nerve growth factor on heat‐evoked currents in cells verified to express trkA. We conclude that the response of dorsal root ganglion neurons to noxious heat is conditioned by nerve growth factor in the same way as their response to capsaicin and that these responses require the presence of trkA and TRPV1.
Corticotropin‐releasing factor receptor types 1 and 2 are differentially expressed in pre‐ and post‐synaptic elements in the post‐natal developing rat cerebellum
Authors: Swinny J. D. , Kalicharan D. , Blaauw E. H. , Ijkema‐Paassen J. , Shi F. , Gramsbergen A. , Van Der Want J. J. L.
Published: August 2003

Corticotropin‐releasing factor (CRF)‐like proteins act via two G‐protein‐coupled receptors (CRF‐R1 and CRF‐R2) playing important neuromodulatory roles in stress responses and synaptic plasticity. The cerebellar expression of corticotropin‐releasing factor‐like ligands has been well documented, but their receptor localization has not. This is the first combination of a light microscopic and ultrastructural study to localize corticotropin‐releasing factor receptors immunohistologically in the developing rat cerebellum. Both CRF‐R1 and CRF‐R2 were expressed in climbing fibres from early stages (post‐natal day 3) to the adult, but CRF‐R2 immmunoreactivity was only prominent throughout the molecular layer in the posterior cerebellar lobules. CRF‐R1 immunoreactivity was concentrated in apical regions of Purkinje cell somata and later in primary dendrites exhibiting a diffuse cytoplasmic appearance. In Purkinje cells, CRF‐R1 immunoreactivity was never membrane bound post‐synaptically in dendritic spines while CRF‐R2 immunoreactivity was found on plasmic membranes of Purkinje cells from post‐natal day 15 onwards. We conclude that the localization of these receptors in cerebellar afferents implies their pre‐synaptic control of the release of corticotropin‐releasing factor‐like ligands, impacting on the sensory information being transmitted from afferents. Furthermore, the fact that CRF‐R2 is membrane bound at synapses, while CRF‐R1 is not, suggests that ligands couple to CRF‐R2 via synaptic transmission and to CRF‐R1 via volume transmission. Finally, the distinct expression profiles of receptors along structural domains of Purkinje cells suggest that the role for these receptors is to modulate afferent inputs.
Heterogeneity and regulation of cellular prion protein glycoforms in neuronal cell lines
Authors: Monnet Céline , Marthiens Véronique , Enslen Hervé , Frobert Yveline , Sobel André , Mège René Marc
Published: August 2003

The normal cellular prion protein is a small sialoglycoprotein highly expressed in neurons, the physiological function of which is largely unknown. Due to extensive N‐glycosylations with a wide range of oligosaccharides, the prion protein displays a complex glycosylation pattern that could be of relevance for its function. The cellular prion protein patterns in adult mouse and rat brain, and in neuronal cell lines, appeared highly heterogeneous, as distinct levels and glycoforms of cellular prion protein were revealed by immunoblotting of corresponding samples. Amongst neuronal cell lines, mouse N2a neuroblastoma cells expressed low levels of endogenous prion protein. Mouse hypothalamic GT1‐7 cells and rat pheochromocytoma PC‐12 cells expressed highly glycosylated forms of cellular prion protein that were found neither in adult mouse and rat brain, nor in mouse brain during development. In contrast, rat B104 neuroblastoma cells abundantly expressed N‐glycosylated cellular prion protein forms similar to those observed in mouse and rat brain. In all these cell lines, the prion protein was normally exported to and expressed at the outer cell membrane. Our results suggest that B104 cells may represent an appropriate cell model to investigate the physiological role of cellular prion protein in further detail as they highly express the normal ‘brain‐like’ cellular prion protein glycoforms. In addition, we observed that the various prion glycoforms in B104 cells were tightly regulated both as a function of cell density and during neuronal differentiation, implying a potential role of cellular prion protein in cell–cell interactions and differentiation.
Involvement of platelet‐activating factor and LIS1 in neuronal migration
Authors: Tokuoka Suzumi M. , Ishii Satoshi , Kawamura Noriko , Satoh Mamoru , Shimada Atsuyoshi , Sasaki Shinji , Hirotsune Shinji , Wynshaw‐Boris Anthony , Shimizu Takao
Published: August 2003

Platelet‐activating factor (PAF, 1‐O‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphocholine) is a biologically active lipid mediator. We have previously shown the expression of PAF receptor in neurons and microglia. PAF is produced in the brain from its precursor, and degraded by the enzyme PAF acetylhydrolase. LIS1 is a regulatory subunit of PAF acetylhydrolase, and is identical to a gene whose deletion causes the human neuronal migration disorder, type I lissencephaly. Indeed, Lis1 mutant mice display defects in neuronal migration and layering in vivo, and also in cerebellar granule cell migration in vitro. However, the roles of PAF and the PAF receptor in the neuronal migration remain to be determined. Here, we show that PAF receptor‐deficient mice exhibited histological abnormalities in the embryonic cerebellum. PAF receptor‐deficient cerebellar granule neurons migrated more slowly in vitro than wild‐type neurons, consistent with the observation that a PAF receptor antagonist reduced the migration of wild‐type neurons in vitro. Synergistic reduction of neuronal migration was observed in a double mutant of PAF receptor and LIS1. Unexpectedly, PAF affected the migration of PAF receptor‐deficient neurons, suggesting a receptor‐independent pathway for PAF action. The PAF receptor‐independent response to PAF was abolished in granule neurons derived from the double mutant mice. Thus, our results suggest that the migration of cerebellar granule cells is regulated by PAF through receptor‐dependent and receptor‐independent pathways, and that LIS1 is a pivotal molecule that links PAF action and neuronal cell migration both in vivo and in vitro.
Different representations of pleasant and unpleasant odours in the human brain
Authors: Rolls Edmund T. , Kringelbach Morten L. , De Araujo Ivan E. T.
Published: August 2003

Odours are important in emotional processing; yet relatively little is known about the representations of the affective qualities of odours in the human brain. We found that three pleasant and three unpleasant odours activated dissociable parts of the human brain. Pleasant but not unpleasant odours were found to activate a medial region of the rostral orbitofrontal cortex. Further, there was a correlation between the subjective pleasantness ratings of the six odours given during the investigation with activation of a medial region of the rostral orbitofrontal cortex. In contrast, a correlation between the subjective unpleasantness ratings of the six odours was found in regions of the left and more lateral orbitofrontal cortex. Moreover, a double dissociation was found with the intensity ratings of the odours, which were not correlated with the BOLD signal in the orbitofrontal cortex, but were correlated with the signal in medial olfactory cortical areas including the pyriform and anterior entorhinal cortex. Activation was also found in the anterior cingulate cortex, with a middle part of the anterior cingulate activated by both pleasant and unpleasant odours, and a more anterior part of the anterior cingulate cortex showing a correlation with the subjective pleasantness ratings of the odours. Thus the results suggest that there is a hedonic map of the sense of smell in brain regions such as the orbitofrontal cortex, and these results have implications for understanding the psychiatric and related problems that follow damage to these brain areas.
A novel method of generating neuronal cell lines from gene‐knockout mice to study prion protein membrane orientation
Authors: Holme Andrea , Daniels Maki , Sassoon Judyth , Brown David R.
Published: August 2003

The technology of gene knockout and transgenic mice has allowed the study of the role of genes and their proteins in animal physiology and metabolism. However, these techniques have often been found to be limited in that some genetic manipulations of mice led either to a fatal phenotype or to compensations that mask the loss of function of the target protein. The experimentation on neurons from transgenic mice is particularly critical in the study of key proteins that may be involved in neurodegeneration. The cell fusion technique has been implemented as a novel way to generate cell lines from prion protein knockout mice. Fusion between neonatal mouse neurons and a neuroblastoma cell line have led to a Prnp°/° cell line that facilitates the study of the knockout phenotype. These cells are readily transfectable and allowed us to study the expression of prion protein mutants on a PrP‐knockout background. Using this cell line we have examined the effect of PrP mutations reported to alter PrPc to a transmembrane form. Our results suggest that these mutations do not create transmembrane forms of the protein, but block normal transport of PrP to the cell membrane.
Age‐related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype
Authors: Thiruchelvam Mona , McCormack Alison , Richfield Eric K. , Baggs Raymond B. , Tank A. William , Di Monte Donato A. , Cory‐Slechta Deborah A.
Published: August 2003

While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb‐induced reductions in locomotor activity and motor coordination were age dependent, with 18‐month‐old mice most affected and exhibiting failure to recover 24 h post‐treatment. Three months post‐treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5‐month‐old and further reduced in 18‐month‐old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18‐month‐old paraquat + maneb and paraquat groups 3 months post‐treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6‐week‐old and 5‐month‐old, but not 18‐month‐old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18‐month‐old paraquat and paraquat + maneb groups between 2 weeks and 3 months post‐exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
The medullary dorsal reticular nucleus enhances the responsiveness of spinal nociceptive neurons to peripheral stimulation in the rat
Authors: Dugast Christophe , Almeida Armando , Lima Deolinda
Published: August 2003

Single‐unit spinal recordings combined with application of glutamate into the medullary dorsal reticular nucleus were used to assess the action of this nucleus upon deep dorsal horn neurons in rats. Injection of high glutamate concentrations (10 and 100 mm) induced a dramatic and long‐lasting increase of the responses of wide‐dynamic range neurons to electrical stimulation of the sciatic nerve in the noxious range, without affecting ongoing discharges. Post‐stimulus time histograms revealed that this increase concerned the post‐discharge, but not A‐ or C‐fibre‐mediated responses, which remained unchanged independently of the stimulation frequency applied. The onset of the glutamate‐induced response enhancement occurred with a concentration‐dependent time delay and developed slowly until its maximum. These data indicate that the medullary dorsal reticular nucleus exerts a facilitating action upon deep dorsal horn wide‐dynamic range neurons by enhancing their capacity to respond to peripheral stimulation through prolongation of their discharge. This action is accompanied by the strengthening of wind‐up of deep dorsal horn wide‐dynamic range neurons, hence providing a plausible substrate for chronic pain states. These results are in agreement with previous behavioural studies suggesting a pronociceptive role for the dorsal reticular nucleus [Almeida et al. (1996) Brain Res. Bull., 39, 7–15; Almeida et al. (1999) Eur. J. Neurosci., 11, 110–122], and support the involvement of a reverberating circuit, previously described in morphological studies [Almeida et al. (1993) Neuroscience, 55, 1093–1106; Almeida et al. (2000) Eur. J. Pain, 4, 373–387], which probably operates only at a certain threshold of activation.
Connexin30‐deficient mice show increased emotionality and decreased rearing activity in the open‐field along with neurochemical changes
Authors: Dere E. , De Souza‐Silva M. A. , Frisch C. , Teubner B. , Söhl G. , Willecke K. , Huston J. P.
Published: August 2003

Gap‐junction channels in the brain, formed by connexin (Cx) proteins with a distinct regional/cell‐type distribution, allow intercellular electrical and metabolic communication. In astrocytes, mainly the connexins 43, 26 and 30 are expressed. In addition, connexin30 is expressed in ependymal and leptomeningeal cells, as well as in skin and cochlea. The functional implications of the astrocytic gap‐junctional network are not well understood and evidence regarding their behavioural relevance is lacking. Thus, we have tested groups of Cx30−/−, Cx30+/−, and Cx30+/+ mice in the open‐field, an object exploration task, in the graded anxiety test and on the rotarod. The Cx30−/− mice showed reduced exploratory activity in terms of rearings but not locomotion in the open‐field and object exploration task. Furthermore, Cx30−/− mice exhibited anxiogenic behaviour as shown by higher open‐field centre avoidance and corner preference. Graded anxiety test and rotarod performance was similar across groups. The Cx30−/− mice had elevated choline levels in the ventral striatum, possibly related to their aberrant behavioural phenotypes. The Cx30+/− mice had lower dopamine and metabolite levels in the amygdala and ventral striatum and lower hippocampal 5‐hydroxyindole acid (5‐HIAA) concentrations relative to Cx30+/+ mice. Furthermore, the Cx30+/− mice had lower acetylcholine concentrations in the ventral striatum and higher choline levels in the neostriatum, relative to Cx30+/+ mice. Our data suggest that the elimination of connexin30 can alter the reactivity to novel environments, pointing to the importance of gap‐junctional signalling in behavioural processes.
Normal prism adaptation but reduced after‐effect in basal ganglia disorders using a throwing task
Authors: Fernandez‐Ruiz J. , Diaz R. , Hall‐Haro C. , Vergara P. , Mischner J. , Nuñez L. , Drucker‐Colin R. , Ochoa A. , Alonso M. E.
Published: August 2003

Prism adaptation is a form of visuomotor learning in which the visual and motor systems need to be adjusted because a visual perturbation is produced by horizontally displacing prisms. Despite being known for over two centuries, the neuronal substrates of this phenomenon are not yet completely understood. In this article the possible role of the basal ganglia in this kind of learning was analysed through a study of Huntington's and Parkinson's disease patients. A throwing technique requiring the use of open loop feedback was used. The variables analysed were visuomotor performance, adaptation rate and magnitude, and the after‐effect. The results clearly showed that both Huntington's and Parkinson's disease groups learned at the same rate as control subjects. In addition, despite having a disturbed visuomotor performance, both experimental groups showed the same adaptation magnitude as the control group. Finally, the after‐effect, which is measured after removing the prisms, is reduced in both patients groups. This reduction leads to a disruption in the normal adaptation–after‐effect correlation found in normal volunteers. These results suggest that basal ganglia are not involved in this type of open‐looped visuomotor learning. The large number of patients studied as well as the similarity of the findings between both populations support this hypothesis. By contrast, there is an impairment in the after‐effect on both basal ganglia patient populations. This impairment may be the result of the deterioration of the perceptual recalibration process involved in visuomotor learning.
Contrasting expression of Kv4.3, an A‐type K+ channel, in migrating Purkinje cells and other post‐migratory cerebellar neurons
Authors: Hsu Yi‐Hua , Huang Hsin‐Yi , Tsaur Meei‐Ling
Published: August 2003

Kv4.3, an A‐type K+ channel, is the only channel molecule showing anterior–posterior (A–P) compartmentalization in the granular layer of mammalian cerebellum known so far. Kv4.3 mRNA has been detected from the posterior but not anterior granular layer in adult rat cerebellum. To characterize this A‐P compartmentalization further, we examined Kv4.3 protein expression in rat cerebellum by immunohistochemistry at the embryonic, early postnatal and adult stages. Specificity of the Kv4.3 antibody was confirmed by both Western blot and immunoprecipitation analysis. In adulthood, Kv4.3 was detected from the somatodendritic domain of posterior granule cells, with a restriction boundary in the vermal lobule VI extending laterally to the hemispheric crus 1 ansiform lobules. At the early postnatal stage, this A–P pattern first appeared on postnatal day 8, when significant numbers of granule cells had migrated into the posterior granular layer and started to express Kv4.3. Similar Kv4.3 expression in the somatodendritic domain of post‐migratory neurons in the cerebellum was also observed in basket cells, stellate cells, a subset of GABAergic deep neurons, Lugaro cells and, probably, deep Lugaro cells. However, none of them showed A–P compartmentalization. Strikingly, we found Kv4.3 in several clusters of migrating Purkinje cells with mediolateral compartmentalization. These Purkinje cells no longer expressed Kv4.3 after completing the migration. By contrasting the expression in migrating and post‐migratory neurons, our results suggest that Kv4.3 may play an important role in the development of cerebellum, as well as in the mature cerebellum.
Alpha 2 adrenergic receptors on GABAergic, putative sleep‐promoting basal forebrain neurons
Authors: Manns Ian D. , Lee Maan Gee , Modirrousta Mandana , Hou Yiping P. , Jones Barbara E.
Published: August 2003

The basal forebrain plays an important role in the modulation of cortical activity and sleep‐wake states. Yet its role must be multivalent as lesions reportedly diminish cortical fast activity and also cortical slow activity along with slow wave sleep (SWS). Basal forebrain cholinergic vs. GABAergic cell groups could differentially influence these processes. By labelling recorded neurons with Neurobiotin (Nb) using the juxtacellular technique and identifying them by immunostaining, we previously found that whereas all cholinergic cells increased their firing, the majority of GABAergic neurons decreased their firing in association with evoked cortical activation in urethane‐anaesthetized rats. Here, we examined the possibility that such GABAergic, cortical activation ‘off’ cells might bear alpha 2 adrenergic receptors (α2AR) through which noradrenaline (NA) could inhibit them during cortical activation. First using simple dual‐immunostaining for glutamic acid decarboxylase (GAD) and the α2AAR, we found that the majority (≈60%) of GAD‐immunopositive (GAD+) neurons through the magnocellular preoptic nucleus (MCPO) and substantia innominata (SI) were labelled for the α2AAR. Second, in urethane‐anaesthetized rats, we examined whether Nb‐labelled, GAD+ cortical activation ‘off’ neurons that discharged maximally in association with cortical slow wave activity, were immunopositive for α2AAR. We found that all the Nb+/GAD+‘off’ cells were labelled for the α2AAR. Such cells could be inhibited in association with cortical activation and waking when noradrenergic locus coeruleus (LC) neurons discharge and be disinhibited with cortical slow waves and SWS when these neurons become inactive. We thus propose that α2AR‐bearing GABAergic basal forebrain neurons constitute sleep‐active and sleep‐promoting neurons.
Altered responses to orexigenic (AGRP, MCH) and anorexigenic (α‐MSH, CART) neuropeptides of paraventricular hypothalamic neurons in early postnatally overfed rats
Authors: Davidowa Helga , Li Yuzhen , Plagemann Andreas
Published: August 2003

Food intake and energy expenditure are regulated by neuropeptides in the hypothalamus. While cocaine‐ and amphetamine‐regulated transcript (CART) peptide and melanocortins such as α‐melanocyte‐stimulating hormone (α‐MSH) are anorexigenic and increase energy expenditure, the endogenous melanocortin receptor antagonist agouti gene‐related protein (AGRP), melanin‐concentrating hormone (MCH) and neuropeptide Y (NPY) are orexigenic, anabolic peptides. Alterations in the regulatory balance may promote excessive weight gain. The action of these peptides on paraventricular hypothalamic neurons was studied in brain slices of overweight, adult rats previously subjected to early postnatal overfeeding in small litters of only three pups per mother, compared to 12 pups per dam in control litters. CART, melanocortins and NPY significantly excited paraventricular neurons of controls, whereas neurons of small‐litter rats were mainly inhibited. Inhibition was dominant following administration of AGRP, MCH and NPY. The altered responses of paraventricular neurons in adult small‐litter rats might reflect a general mechanism of neurochemical plasticity and ‘malprogramming’ of hypothalamic neuropeptidergic systems acquired during the postnatal critical differentiation period, thus leading to permanently altered function of these regulatory systems of body weight.
Low molecular weight constituents of male mouse urine mediate the pregnancy block effect and convey information about the identity of the mating male
Authors: Peele P. , Salazar I. , Mimmack M. , Keverne E. B. , Brennan P. A.
Published: August 2003

Mouse urine contains a complex mixture of chemosignals including a variety of small volatile molecules that are bound to major urinary proteins. In addition to signalling maleness, male urine also conveys information about individuality, which allows recently mated female mice to distinguish the urinary chemosignals of the mating male from those of an unfamiliar male. The highly polymorphic nature of the major urinary proteins makes them a likely candidate for conveying individuality information in the context of the pregnancy block effect. This was investigated by comparing the pregnancy‐blocking effectiveness of a high molecular weight urinary fraction, containing major urinary proteins, with that of a low molecular weight fraction containing volatile ligands. Not only was the high molecular weight fraction ineffective in blocking pregnancy, but it also appeared to be less important in signalling individuality than the low molecular fraction. The high molecular weight fraction was ineffective in inducing expression of the immediate early gene product egr‐1 in the accessory olfactory bulb. In contrast, the low molecular weight fraction induced egr‐1 expression in the mitral/tufted neurons in the anterior subregion of the accessory olfactory bulb, suggesting that they activate the V1R class of vomeronasal receptor neuron.
Neural activity related to the processing of increasing monetary reward in smokers and nonsmokers
Authors: Martin‐Soelch C. , Missimer J. , Leenders K. L. , Schultz W.
Published: August 2003

This study investigated the processing of increasing monetary reward in nonsmoking and smoking subjects. The choice of the subject populations has been motivated by the observation of differences between nonsmokers and smokers in response to rewarding stimuli in a previous study. Subjects performed a pattern recognition task with delayed response, while rCBF was measured with [\mathrm{H}^{15}_{2}O] PET. Correct responses to the task were reinforced with three different amounts of monetary reward. The subjects received the sum of the rewards at the end of the experiment. The results show that a cortico‐subcortical loop, including the dorsolateral prefrontal cortex, the orbitofrontal cortex, the cingulate gyrus and the thalamus is involved in processing increasing monetary reward. Furthermore, the striatal response differentiates nonsmokers from smokers. Thus, we found significant correlations between rCBF increases in striatum and increasing monetary reward and between striatal rCBF increases and mood in nonsmokers, but not in smokers. Moreover, no significant mood changes among the different monetary rewards could be observed in smokers. We infer that the response of the striatum to reward is related to changes in subjective feelings. The differences between smokers and nonsmokers confirm our previous conclusions that the association between blood flow, performance, mood and amount of reward is more direct in nonsmokers.
Neural substrates of microstimulation‐evoked tingling: a chronaxie study in human somatosensory thalamus
Authors: Kiss Zelma H. T. , Anderson Trent , Hansen Terry , Kirstein Dolen , Suchowersky Oksana , Hu Bin
Published: August 2003

Intra‐operative micro‐electrode stimulation of sensorimotor thalamus produces paraesthesia or tingling in various body regions and is used to map somatotopy prior to implantation of deep brain‐stimulating electrodes in awake patients. The neural elements affected by such microstimulation are unknown. Using paraesthesia as the behavioural–physiological response threshold, we measured chronaxie times for microstimuli applied to both somatosensory thalamic nuclei (cellular region) and its axonal afferents, the medial lemniscus. White matter chronaxie times were relatively unimodal, whereas two different clusters of chronaxie times were identified in grey matter: one corresponding to that of the medial lemniscus and the other about five times longer and compatible with that obtained from cell somata. Therefore, excitations of local axons and/or cell bodies can both contribute to the paraesthesia evoked during intra‐operative thalamic mapping.
A role for the periaqueductal grey in opioidergic inhibition of maternal behaviour
Authors: Miranda‐Paiva Cláudia M. , Ribeiro‐Barbosa Erika R. , Canteras Newton S. , Felicio Luciano F.
Published: August 2003

Opiates are known to be involved in the regulation of various events surrounding parturition and lactation, such as maternal behaviour in rats. The onset of this behaviour has been closely linked to opiate action in the medial pre‐optic area, where administration of morphine disrupts maternal behaviour during lactation. By combining the use of Fos protein immunohistochemical detection and pharmacological manipulations, in the present paper we show that the periaqueductal grey (PAG) is another region critically involved in the opioidergic blockade of maternal behaviour. According to our observations, a critical level of morphine‐induced activation of the rostral lateral PAG appears to be required to inhibit maternal behaviour in lactating rats. This hypothesis was further confirmed in experiments showing that morphine's inhibitory effect on maternal responsiveness was blocked by unilateral naloxone injection into the rostral PAG, but not into nearby regions of the mesencephalic reticular nucleus. Therefore, only a partial inhibition of the opiate's effect on the rostral PAG was needed to block the inhibitory effect of morphine on maternal behaviour. Further studies are needed to ascertain whether the rostral lateral PAG plays a role in the natural onset of maternal behaviour, playing a complementary role to the medial pre‐optic area, or merely inhibits maternal behaviour in response to this specific pharmacological challenge. Conversely, the present findings may well reflect a more general role of the PAG, seemingly providing an important piece of information for proposing a hitherto unexplored concept of the PAG as an important centre for the selection of adaptive behavioural responses.
Myocardial Connections Between Left Atrial Myocardium and Coronary Sinus Musculature in Man
Authors: KASAI ATSUNOBU , ANSELME FREDERIC , SAOUDI NADIR
Published: August 2003

Connections Between LA Myocardium and CS Musculature.
Introduction: Anatomic studies have shown that muscle morphologically identical to that of the atrial myocardium consistently surrounds the coronary sinus (CS). The CS musculature is connected to the left atrial (LA) myocardium in a variable fashion, with fewer connections in its distal portion. The aim of this study was to document the presence of connections between the LA myocardium and the CS musculature, using pacing maneuvers in man, and to study their potential association with natural atrial arrhythmia occurrence.

Methods and Results: Thirty patients (19 men; mean age 50.5 years) underwent electrophysiologic study, during which a decapolar catheter with 2‐mm interelectrode spacing every 10 mm was inserted into the CS, with the proximal electrode pair positioned at the ostium. Associated atrial arrhythmias were paroxysmal atrial fibrillation in 5, typical atrial flutter in 13, LA flutter in 1, and other in 11. Baseline S1 and a single extrastimulus were delivered during distal and proximal CS pacing, while recordings were obtained from the four remaining bipoles. During distal CS pacing, double potentials with increasing interpotential interval from proximal to distal CS as a function of extrastimulus prematurity were detected in nine patients, suggesting block in a discrete local pathway distally connecting the CS to the LA and leading to reversion of low LA activation. Local delay in this pathway without complete CS‐LA block resulting in LA activation fusion was observed in eight patients. A single nonfractionated potential at the distal CS, even at the shortest attainable S1‐S2 coupling interval, which was interpreted as no block within distal CS‐LA connection(s), was observed in the other 13 patients. History of atrial fibrillation or atypical atrial flutter was found in 8 of 9 patients with block at the distal CS‐LA connection but in only 3 of 13 patients with no CS‐LA connection block (P = 0.004).

Conclusion: The ability to dissociate the LA from the distal CS suggests the presence of discrete connections between these structures in man. This observation appears to be associated with the clinical occurrence of atrial arrhythmias.
Effect of Gender on Atrial Electrophysiologic Changes Induced by Rapid Atrial Pacing and Elevation of Atrial Pressure
Authors: TSE HUNG‐FAT , ORAL HAKAN , PELOSI FRANK , KNIGHT BRADLEY P. , STRICKBERGER S. ADAM , MORADY FRED
Published: August 2003

Atrial Electrical Remodeling.
Introduction: The incidence of atrial fibrillation is greater in men than in women, but the reasons for this gender difference are unclear. The purpose of this study was to evaluate the effects of gender on the atrial electrophysiologic effects of rapid atrial pacing and an increase in atrial pressure.

Methods and Results: Right atrial pressure and effective refractory period (ERP) were measured during sinus rhythm and during atrial and simultaneous AV pacing at a cycle length of 300 msec in 10 premenopausal women, 11 postmenopausal women, and 24 men. The postmenopausal women were significantly older than the premenopausal women (61 ± 8 years vs 34 ± 10 years; P < 0.01). During sinus rhythm, mean atrial ERP in premenopausal women was shorter (211 ± 19 msec) than in postmenopausal women and age‐matched men (242 ± 18 msec and 246 ± 34 msec, respectively; P < 0.05). Atrial ERPs in all patients shortened significantly during atrial and simultaneous AV pacing. However, the degree of shortening during atrial pacing (43 ± 8 msec vs 70 ± 20 msec and 74 ± 21 msec; P < 0.05) and during simultaneous AV pacing (48 ± 16 msec vs 91 ± 27 msec and 84 ± 26 msec; P < 0.05) was significantly less in premenopausal women than in postmenopausal women or age‐matched men.

Conclusion: The results of this study demonstrate a significant gender difference in atrial electrophysiologic changes in response to rapid atrial pacing and an increase in atrial pressure. The effect of menopause on the observed changes suggests that the gender differences may be mediated by the effects of estrogen on atrial electrophysiologic properties.
Follow‐Up of Patients with Unexplained Syncope and Inducible Ventricular Tachyarrhythmias: Analysis of the AVID Registry and an AVID Substudy
Authors: STEINBERG JONATHAN S. , BECKMAN KAREN , GREENE H. LEON , MARINCHAK ROGER , KLEIN RICHARD C. , GREER STEPHEN G. , EHLERT FREDERICK , FOSTER PETER , MENCHAVEZ EDITH , RAITT MERRITT , WATHEN MARK S. , MORRIS MARY , HALLSTROM ALFRED
Published: August 2003

Unexplained Syncope in AVID.
Introduction: A prospective registry and substudy were conducted in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study to clarify the prognosis and recurrent event rate, risk factors, and impact of implantable cardioverter defibrillator (ICD) therapy in patients with unexplained syncope, structural heart disease, and inducible ventricular tachyarrhythmias.

Methods and Results: Included in the AVID registry were patients from all participating sites who had “out of hospital syncope with structural heart disease and EP‐inducible VT/VF with symptoms.” In addition, 13 collaborating sites provided more in‐depth clinical and electrophysiologic data as part of a formal prospective substudy. Patients in the substudy were followed by local investigators for recurrent arrhythmic events and mortality. Registry patients were tracked for fatal outcomes by the National Death Index. A total of 429 patients with syncope were entered in the AVID registry, of whom 80 participated in the substudy. Of the substudy patients, 21 patients (26%) had inducible polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF), 11 patients (14%) had sustained monomorphic VT < 200 beats/min, and 48 patients (60%) had sustained monomorphic VT ≥200 beats/min. The ICD was used as sole therapy in 75% of the syncope substudy patients (and with antiarrhythmic drug in an additional 9%) and in 59% of the syncope registry patients. Survival rates at 1 and 3 years were 93% and 74% for the substudy patients and 90% and 74% for the registry patients, respectively. Survival of the syncope substudy patients (predominantly treated by ICD) was similar to the VT patients treated by ICD and superior to the VT patients treated by an antiarrhythmic drug (P = 0.05) in the randomized main trial. Mortality events in the substudy were marginally predicted by ejection fraction (P = 0.06) but not by electrophysiologic study‐induced arrhythmia. The significant predictor of increased mortality in the registry was age (P = 0.003) and of reduced mortality was treatment with ICD (P = 0.006).

Conclusion: The results of these analyses support the role of the ICD as primary antiarrhythmic therapy in patients with unexplained syncope, structural heart disease, and inducible VT/VF at electrophysiologic study.
Flecainide Widens the Excitable Gap at Pivot Points of Premature Turning Wavefronts in Rabbit Ventricular Myocardium
Authors: DANSE PETER W. , GARRATT CLIFFORD J. , ALLESSIE MAURITS A.
Published: August 2003

Widening of the Excitable Gap by Flecainide.
Introduction: The mechanisms by which Class IC drugs slow the rate of functional reentrant arrhythmias are not completely understood. We hypothesized that flecainide widens the excitable gap beyond the pivot point of premature turning wavefronts.

Methods and Results: In eight perfused subepicardial layers of rabbit left ventricle, a linear lesion was made by radiofrequency (RF) ablation parallel to the fiber orientation. One end of the RF lesion was extended by a short incision. Pacing next to the lesion induced a wavefront propagating with a sharp U‐turn around the end of the lesion in either the clockwise or counterclockwise direction. A high‐density mapping electrode (240 electrodes, 350‐μm resolution) was used to record unipolar electrograms at the pivot point. During control, the shortest V1‐V2 interval proximal to the pivot point was 162 ± 12 msec compared with 173 ± 13 msec distal to the pivot point (difference 11 ± 8 msec; P < 0.01). After infusion of flecainide 2 mg/L, the shortest V1‐V2 interval proximal and distal to the pivot point were 217 ± 29 msec and 244 ± 36 msec (difference 27 ± 16 msec; P < 0.01). Due to the increase in V1‐V2 interval at the pivot point, flecainide widened the temporal excitable gap in the returning limb of the turning wavefront from 30 ± 11 msec to 55 ± 22 msec (P < 0.01). High‐density mapping at the pivot point revealed that this widening of the excitable gap was due to both macroscopic discontinuous conduction and functional conduction block at the pivot point.

Conclusion: Flecainide widens the excitable gap in the returning limb of premature U‐turning wavefronts by causing macroscopic discontinuous conduction and functional conduction block at the pivot point.