Showing papers in "European Journal of Neuroscience in 1999"
TL;DR: Functional magnetic resonance imaging (fMRI) confirmed Brothers' prediction that the STG and amygdala show increased activation when using social intelligence, and provided support for the social brain theory of normal function, and the amygdala theory of autism.
Abstract: There is increasing support for the existence of 'social intelligence' [Humphrey (1984) Consciousness Regained], independent of general intelligence. Brothers et al. 1990) J. Cog. Neurosci., 4, 107-118] proposed a network of neural regions that comprise the 'social brain': the orbito-frontal cortex (OFC), superior temporal gyrus (STG) and amygdala. We tested Brothers' theory by examining both normal subjects as well as patients with high-functioning autism or Asperger syndrome (AS), who are well known to have deficits in social intelligence, and perhaps deficits in amygdala function [Bauman & Kemper (1988) J. Neuropath. Exp. Neurol., 47, 369]. We used a test of judging from the expressions of another person's eyes what that other person might be thinking or feeling. Using functional magnetic resonance imaging (fMRI) we confirmed Brothers' prediction that the STG and amygdala show increased activation when using social intelligence. Some areas of the prefrontal cortex also showed activation. In contrast, patients with autism or AS activated the fronto-temporal regions but not the amygdala when making mentalistic inferences from the eyes. These results provide support for the social brain theory of normal function, and the amygdala theory of autism.
1,390 citations
TL;DR: The present analysis showed that only a restricted portion of what had previously been labelled as area 46 in the monkey has the same characteristics as area46 of the human brain; the remaining part of this monkey region has the characteristics of a portion of the middle frontal gyrus in the humanbrain that had previously be included as part of area 9.
Abstract: The cytoarchitecture of the human and the macaque monkey dorsolateral prefrontal cortex has been examined in a strictly comparative manner in order to resolve major discrepancies between the available segmentations of this cortical region in the human and the monkey brain. In addition, the connections of the dorsolateral prefrontal cortical areas were re-examined in the monkey. The present analysis showed that only a restricted portion of what had previously been labelled as area 46 in the monkey has the same characteristics as area 46 of the human brain; the remaining part of this monkey region has the characteristics of a portion of the middle frontal gyrus in the human brain that had previously been included as part of area 9. We have labelled this cortical area as 9/46 in both species. These two areas (i.e. 46 and 9/46), which constitute the lower half of the mid-dorsolateral frontal cortex, have a well-developed granular layer IV, and can easily be distinguished from area 9, on the upper part of the mid-dorsolateral region, which does not have a well-developed granular layer IV. Area 9 has the same basic pattern of connections as areas 46 and 9/46, but, unlike the latter areas, it does not receive input from the lateral parietal cortex. Caudal to area 9, on the dorsomedial portion of the frontal cortex, there is a distinct strip of cortex (area 8B) which, unlike area 9, receives significant input from the prestriate cortex and the medial parietal cortex. The present results provide a basis for a closer integration of findings from functional neuroimaging studies in human subjects with experimental work in the monkey.
993 citations
TL;DR: It is suggested that a putative cross‐talk between cannabinoids and CCK might exist and will be relevant to better understanding of physiology and pharmacology of the cannabinoid system.
Abstract: Cannabinoids can modulate motor behaviour, learning and memory, cognition and pain perception. These effects correlate with the expression of the cannabinoid receptor 1 (CB1) and with the presence of endogenous cannabinoids in the brain. In trying to obtain further insights into the mechanisms underlying the modulatory effects of cannabinoids, CB1-positive neurons were determined in the murine forebrain at a single cell resolution. We performed a double in situ hybridization study to detect mRNA of CB1 in combination with mRNA of glutamic acid decarboxylase 65k, neuropeptide cholecystokinin (CCK), parvalbumin, calretinin and calbindin D28k, respectively. Our results revealed that CB1-expressing cells can be divided into distinct neuronal subpopulations. There is a clear distinction between neurons containing CB1 mRNA either at high levels or low levels. The majority of high CB1-expressing cells are GABAergic (gamma-aminobutyric acid) neurons belonging mainly to the cholecystokinin-positive and parvalbumin-negative type of interneurons (basket cells) and, to a lower extent, to the calbindin D28k-positive mid-proximal dendritic inhibitory interneurons. Only a fraction of low CB1-expressing cells is GABAergic. In the hippocampus, amygdala and entorhinal cortex area, CB1 mRNA is present at low but significant levels in many non-GABAergic cells that can be considered as projecting principal neurons. Thus, a complex mechanism appears to underlie the modulatory effects of cannabinoids. They might act on principal glutamatergic circuits as well as modulate local GABAergic inhibitory circuits. CB1 is very highly coexpressed with CCK. It is known that cannabinoids and CCK often have opposite effects on behaviour and physiology. Therefore, we suggest that a putative cross-talk between cannabinoids and CCK might exist and will be relevant to better understanding of physiology and pharmacology of the cannabinoid system.
864 citations
TL;DR: Surprisingly, VR1‐ir did not coexist substantially in nerve fibres and terminals that contain substance P and calcitonin gene‐related peptide, suggesting complex mechanisms for the release of these neuropeptides in response to capsaicin application.
Abstract: The vanilloid receptor (VR1) protein functions both as a receptor for capsaicin and a transducer of noxious thermal stimuli. To determine the expression and targetting of this protein, we have generated antisera against both the amino and carboxy termini of VR1. Within the dorsal root and trigeminal ganglia of rats, VR1-immunoreactivity (VR1-ir) was restricted to small and medium sized neurons. VR1-ir was transported into both the central and peripheral processes of these primary afferent neurons, as evidenced by: (i) the presence of VR1-ir in nerve fibres and terminals in lamina I and lamina II of the superficial dorsal horn, and the association of VR1-ir with small diameter nerve fibres in the skin and cornea; (ii) the reduction of VR1-ir in the spinal cord after dorsal rhizotomy; and (iii) the accumulation of VR1-ir proximal to sciatic nerve ligation. At the ultrastructural level, VR1-ir was associated with plasma membranes of neuronal perikarya in dorsal root ganglia and nerve terminals in the dorsal horn. VR1-ir was also seen in nerve fibres and terminals in the spinal trigeminal nucleus and nucleus of the solitary tract. Within a large proportion of dorsal root ganglion neurons and the terminals of their axons, VR1-ir was colocalized with staining for the P2X3 purinoceptor, and with binding sites for the lectin IB4. Surprisingly, VR1-ir did not coexist substantially in nerve fibres and terminals that contain substance P and calcitonin gene-related peptide, suggesting complex mechanisms for the release of these neuropeptides in response to capsaicin application.
852 citations
TL;DR: It is suggested that some of the persistent neurobehavioural consequences of repeated exposure to psychostimulant drugs may be due to their ability to reorganize patterns of synaptic connectivity in the nucleus accumbens and prefrontal cortex.
Abstract: Repeated treatment with psychostimulant drugs produces changes in brain and behaviour that far outlast their initial neuropharmacological actions. The nature of persistent drug-induced neurobehavioural adaptations is of interest because they are thought to contribute to the development of dependence and addiction, and other forms of psychopathology, e.g. amphetamine psychosis. There are many reports that psychostimulants produce biochemical adaptations in brain monoamine systems, especially dopamine systems. The purpose of the present study was to determine if they might also alter the morphology of neurons in brain regions that receive monoaminergic innervation. Rats were given repeated injections of either amphetamine or cocaine, or, to control for general motor activity, allowed access to a running wheel. They were then left undisturbed for 24-25 days before their brains were processed for Golgi-Cox staining. Treatment with either amphetamine or cocaine (but not wheel running experience) increased the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens, and on apical dendrites of layer V pyramidal cells in the prefrontal cortex. Cocaine also increased dendritic branching and spine density on the basilar dendrites of pyramidal cells. In addition, both drugs doubled the incidence of branched spines on medium spiny neurons. It is suggested that some of the persistent neurobehavioural consequences of repeated exposure to psychostimulant drugs may be due to their ability to reorganize patterns of synaptic connectivity in the nucleus accumbens and prefrontal cortex.
740 citations
TL;DR: It is suggested that a fronto‐parietal circuit for manipulation of objects exists in humans and involves basically the same areas as in the monkey and it is proposed that area SII analyses the intrinsic object characteristics whilst the superior parietal lobule is related to kinaesthesia.
Abstract: Functional magnetic resonance imaging (fMRI) was used to localize brain areas active during manipulation of complex objects. In one experiment subjects were required to manipulate complex objects for exploring their macrogeometric features as compared to manipulation of a simple smooth object (a sphere). In a second experiment subjects were asked to manipulate complex objects and to silently name them upon recognition as compared to manipulation of complex not recognizable objects without covert naming. Manipulation of complex objects resulted in an activation of ventral premotor cortex [Brodmann's area (BA) 44], of a region in the intraparietal sulcus (most probably corresponding to the anterior intraparietal area in the monkey), of area SII and of a sector of the superior parietal lobule. When the objects were covertly named additional activations were found in the opercular part of BA 44 and in the pars triangularis of the inferior frontal gyrus (BA 45). We suggest that a fronto-parietal circuit for manipulation of objects exists in humans and involves basically the same areas as in the monkey. It is proposed that area SII analyses the intrinsic object characteristics whilst the superior parietal lobule is related to kinaesthesia.
728 citations
TL;DR: Data indicate that, in addition to the resident population of quiescent oligodendrocyte progenitors of the adult CNS, neural precursors from the adult SVZ constitute a source of oligodendedrocytes for myelin repair.
Abstract: Identifying a source of cells with the capacity to generate oligodendrocytes in the adult CNS would help in the development of strategies to promote remyelination. In the present study, we examined the ability of the precursor cells of the adult mouse subventricular zone (SVZ) to differentiate into remyelinating oligodendrocytes. After lysolecithin-induced demyelination of the corpus callosum, progenitors of the rostral SVZ (SVZa) and the rostral migratory pathway (RMS), expressing the embryonic polysialylated form of the neural cell adhesion molecule (PSA-NCAM), increased progressively with a maximal expansion occurring after 2 weeks. This observation correlated with an increase in the proliferation activity of the neural progenitors located in the SVZa and RMS. Moreover, polysialic acid (PSA)-NCAM-immunoreactive cells arizing from the SVZa were detected in the lesioned corpus callosum and within the lesion. Tracing of the constitutively cycling cells of the adult SVZ and RMS with 3H-thymidine labelling showed their migration toward the lesion and their differentiation into oligodendrocytes and astrocytes but not neurons. These data indicate that, in addition to the resident population of quiescent oligodendrocyte progenitors of the adult CNS, neural precursors from the adult SVZ constitute a source of oligodendrocytes for myelin repair.
542 citations
TL;DR: It is proposed that the SCN utilizes neuronal pathways to spread its time of the day message, not only to the pineal, but also to other organs, including the adrenal, utilizing the autonomic nervous system.
Abstract: In view of mounting evidence that the suprachiasmatic nucleus (SCN) is directly involved in the setting of sensitivity of the adrenal cortex to ACTH, the present study investigated possible anatomical and functional connections between SCN and adrenal. Transneuronal virus tracing from the adrenal revealed first order labelling in neurons in the intermedio-lateral column of the spinal cord that were shown to receive an input from oxytocin fibres and subsequently second-order labelling in neurons of the autonomic division of the paraventricular nucleus. The latter neurons were shown to receive an input from vasopressin or vasoactive intestinal peptide (VIP) containing SCN efferents. The true character of this SCN input to second-order neurons was also demonstrated by the fact that third-order labelling was present within the SCN, vasopressin or VIP neurons. The functional presence of the SCN-adrenal connection was demonstrated by a light-induced fast decrease in plasma corticosterone that could not be attributed to a decrease in ACTH. Using intact and SCN-lesioned animals, the immediate decrease in plasma corticosterone was only observed in intact animals and only at the beginning of the dark period. This fast decrease of corticosterone was accompanied by constant basal levels of blood adrenaline and noradrenaline, and is proposed to be due to a direct inhibition of the neuronal output to the adrenal cortex by light-mediated activation of SCN neurons. As a consequence, it is proposed that the SCN utilizes neuronal pathways to spread its time of the day message, not only to the pineal, but also to other organs, including the adrenal, utilizing the autonomic nervous system.
465 citations
TL;DR: There is clear evidence that the acute inflammatory response to traumatic injury is significantly greater in the spinal cord than in the cerebral cortex.
Abstract: Lesion-induced inflammatory responses in both brain and spinal cord have recently become a topic of active investigation. Using C57BL/6J mice, we compared the tissue reaction in these two central nervous system (CNS) compartments with mechanical lesions of similar size involving both grey and white matter. This evaluation included the quantitative assessment of neutrophils, lymphocytes and activated macrophages/microglia, as well as astrocyte activation, upregulation of vascular cell adhesion molecules (ICAM-1, VCAM-1, PECAM) and the extent of blood-brain barrier (BBB) breakdown. Time points analysed post-lesioning included 1, 2, 4 and 7 days (as well as 10 and 14 days for the BBB). We found clear evidence that the acute inflammatory response to traumatic injury is significantly greater in the spinal cord than in the cerebral cortex. The numbers of both neutrophils and macrophages recruited to the lesion site were significantly higher in the spinal cord than in the brain, and the recruitment of these cells into the surrounding parenchyma was also more widespread in the cord. The area of BBB breakdown was substantially larger in the spinal cord and vascular damage persisted for a longer period. In the brain, as in spinal cord, the area to which neutrophils were recruited correlated well with the area of BBB breakdown. It will be of interest to determine the extent to which the infiltration of inflammatory cells contributes, either directly or indirectly, to the vascular permeability and secondary tissue damage or, conversely, to local tissue repair in the brain and the spinal cord.
418 citations
TL;DR: Electroencephalography results provide evidence that observation and execution of movement share the same cortical network and indicate that the motor cortex and the frontal cortex are specifically activated by both observation and executed of finger movements.
Abstract: Quantified electroencephalography (qEEG) was used to compare cerebral electrical variations while human subjects (10 males and 10 females) were observing and executing finger movements and while they were resting Video recording enabled elimination of subjects performing involuntary movements EEGs were recorded from 14 sites in seven frequency bands: theta 1, theta 2, alpha 1, alpha, beta 1, beta 2 and beta 3 Analyses were performed on logarithmically transformed absolute spectral power values Both observation and execution of finger movements involved a decrease in spectral power compared with resting This decrease was significant only for the alpha 1 frequency band (75-105 Hz) and it involved nine of the 14 electrode locations (F7, F8, F4, T6, T5, C3, C4, P3 and P4) This indicates that the motor cortex and the frontal cortex are specifically activated by both observation and execution of finger movements These results provide evidence that observation and execution of movement share the same cortical network
416 citations
TL;DR: The first study which determines and compares the mRNA expression of all four cloned functional Y‐receptor subtypes in consecutive sections of the rat brain on a cellular level, using a uniform in situ hybridization technique, suggests that some of neuropeptide Y's effects may be mediated through one particular subtype, whereas other physiological processes might require the coordinated action of different subtypes within the same or discrete areas.
Abstract: Molecular cloning techniques have recently led to the identification of a growing number of neuropeptide Y-receptor subtypes, suggesting possible subtype-specific involvement in different physiological processes. Here we report the first study which determines and compares the mRNA expression of all four cloned functional Y-receptor subtypes (Y1, Y2, Y4 and Y5) in consecutive sections of the rat brain on a cellular level, using a uniform in situ hybridization technique. Our results demonstrate that Y-receptor subtype mRNA expression is widely distributed throughout the rat brain. Interestingly, coexpression of all four Y-receptors, at different levels, is particularly evident within the limbic system, including the hypothalamus, hippocampus, amygdala, piriform and cingulate cortices and tegmental areas, all of which are heavily involved in behaviour, emotion and homeostatic regulation. Particularly interesting is the demonstration that Y5-receptor mRNA expression always coincides with the presence of Y1-receptor mRNA (although not vice versa), possibly due to the overlapping organization and transcriptional control of their genes. However, it is also clear that several brain nuclei display preferential expression of one or a selective combination of Y-receptor subtype mRNAs. Furthermore, it is evident that there is regionalization of expression within certain loci which express all four receptor subtype mRNAs, particularly within the paraventricular and arcuate hypothalamic nuclei. Our results suggest that some of neuropeptide Y’s (NPY) effects may be mediated through one particular subtype, whereas other physiological processes might require the coordinated action of different subtypes within the same or discrete areas.
TL;DR: This is the first study to show induction of HIF‐1 after focal ischaemia in brain, and it is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces Hif‐1 and its target genes.
Abstract: HIF-1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF-1alpha and HIF-1beta protein subunits. It binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes, including glucose transporter-1 and the glycolytic enzymes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of permanent middle cerebral artery occlusion on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes were up-regulated in the peri-infarct penumbra. This was observed by 7.5 h after the onset of ischaemia and increased further at 19 and 24 h. Regional cerebral blood flow was moderately decreased at 1 and 24 h after the ischaemia in areas of HIF-1 and HIF-1 target gene induction. Because hypoxia induces HIF-1 in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. This is the first study to show induction of HIF-1 after focal ischaemia in brain. Increased expression of HIF-1 target genes as a result of HIF-1 activation by hypoxia may contribute to tissue viability in the hypoxic/ischaemic penumbra by increasing glucose transport and glycolysis.
TL;DR: Results show that the altered glucocorticoid secretion induced by early environmental manipulations is primary to the cognitive alterations observed only later in life and could be one cause of age‐related memory deficits.
Abstract: There is growing evidence that stress during prenatal and postnatal periods of life can modify adaptive capacities in adulthood. The hypothalamo-pituitary-adrenal axis may mediate an animal's responses to perinatal stressful events and thus serve as a neurobiological substrate of the behavioural consequences of these early events. However, little is known about the long-term effects of prenatal stressors throughout the entire life of the animals. The focus of the present study was to examine the long-term influences of a prenatal and postnatal stress on glucocorticoid secretion and cognitive performance. Prenatal stress of rat dams during the last week of pregnancy and postnatal daily handling of rat pups during the first 3 weeks of life were used as stressors. The long-term effects of these manipulations were analysed using a longitudinal approach throughout the entire life of the animals, and were repeatedly tested in adulthood (4-7 months), middle age (13-16 months) and in later life (20-24 months). The study demonstrated that prenatal stress and postnatal handling induced opposite effects on both glucocorticoid secretion and cognitive performance. Prenatal stress accelerated the age-related hypothalamo-pituitary-adrenal axis dysfunctions; indeed, circulating glucocorticoids levels of prenatally stressed middle-aged animals are similar to old control ones, and also induced cognitive impairments. In contrast, postnatal handling protected from the age-related neuroendocrine and behavioural alterations. These results show that the altered glucocorticoid secretion induced by early environmental manipulations is primary to the cognitive alterations observed only later in life and could be one cause of age-related memory deficits.
TL;DR: The role of GABAB‐receptors in vivo extends beyond synaptic GABAergic neurotransmission and may, in the cerebellum, involve taurine as a ligand.
Abstract: GABAB (gamma-aminobutyric acid)-receptors have been implicated in central nervous system (CNS) functions, e.g. cognition and pain perception, and dysfunctions including spasticity and absence epilepsy. To permit an analysis of the two known GABAB-receptor splice variants GABAB-R1a (GB1a) and GABAB-R1b (GB1b), their distribution pattern has been differentiated in the rat brain, using Western blotting and immunohistochemistry with isoform-specific antisera. During postnatal maturation, the expression of the two splice variants was differentially regulated with GB1a being preponderant at birth. In adult brain, GB1b-immunoreactivity (-IR) was predominant, and the two isoforms largely accounted for the pattern of GABAB-receptor binding sites in the brain. Receptor heterogeneity was pronounced in the hippocampus, where both isoforms occurred in CA1, but only GB1b in CA3. Similarly, in the cerebellum, GB1b was exclusively found in Purkinje cells in a zebrin-like pattern. The staining was most pronounced in Purkinje cell dendrites and spines. Using electron microscopy, over 80% of the spine profiles in which a synaptic contact with a parallel fibre was visible contained GB1b-IR at extrasynaptic sites. This subcellular localization is unrelated to GABAergic inputs, indicating that the role of GABAB-receptors in vivo extends beyond synaptic GABAergic neurotransmission and may, in the cerebellum, involve taurine as a ligand.
TL;DR: Findings provide the first direct evidence that it is the medial rather than the central amygdala that is critical to hypothalamic neuroendocrine cell responses during an emotional response, and also provides the first evidence that the amygdala governs oxytocin as well as HPA axis responses to an emotional stressor.
Abstract: The amygdala plays a pivotal role in the generation of appropriate responses to emotional stimuli. In the case of emotional stressors, these responses include activation of the hypothalamic-pituitary-adrenal (HPA) axis. This effect is generally held to depend upon the central nucleus of the amygdala, but recent evidence suggests a role for the medial nucleus. In the present study, c-fos expression, amygdala lesion and retrograde tracing experiments were performed on adult rats in order to re-evaluate the role of the central as opposed to the medial amygdala in generating neuroendocrine responses to an emotional stressor. Brief restraint (15 min) was used as a representative emotional stressor and was found to elicit c-fos expression much more strongly in the medial than central nucleus of the amygdala; relatively few Fos-positive cells were seen in other amygdala nuclei. Subsequent experiments showed that ibotenic acid lesions of the medial amygdala, but not the central amygdala, greatly reduced restraint-induced activation of cells of the medial paraventricular nucleus, the site of the tuberoinfundibular corticotropin-releasing factor cells that constitute the apex of the HPA axis. Medial amygdala lesions also reduced the activation of supraoptic and paraventricular nucleus oxytocinergic neurosecretory cells that commonly accompanies stress-induced HPA axis activation in rodents. To assess whether the role of the medial amygdala in the control of neuroendocrine cell responses to emotional stress might involve a direct projection to such cells, retrograde tracing of amygdala projections to the paraventricular nucleus was performed in combination with Fos immunolabelling. This showed that although some medial amygdala cells activated by exposure to an emotional stressor project directly to the paraventricular nucleus, the number is very small. These findings provide the first direct evidence that it is the medial rather than the central amygdala that is critical to hypothalamic neuroendocrine cell responses during an emotional response, and also provide the first evidence that the amygdala governs oxytocin as well as HPA axis responses to an emotional stressor.
TL;DR: It is hypothesize that a necessary condition for place‐specific discharge of hippocampal pyramidal cells is the presence of theta oscillation, and relevant stimuli can tonically and selectively activate hippocampusal pyramsidal cells as long as theta activity is present.
Abstract: In contrast to sensory cortical areas of the brain, the relevant physiological inputs to the hippocampus, leading to selective activation of pyramidal cells, are largely unknown. Pyramidal cells are thought to be phasically activated by spatial cues and a variety of sensory and motor stimuli. Here, we used a behavioural 'space clamp' method, which involved the confinement of the actively running animal in a defined position in space (running wheel) and kept sensory inputs constant. Twelve percent of the recorded CA1 pyramidal cells were selectively active while the rat was running in the wheel. Cell firing was specific to the direction of running and disappeared after rotating the recording apparatus. The discharge frequency of pyramidal cells and interneurons was sustained as long as the rat ran continuously in the wheel. Furthermore, the discharge frequency of pyramidal cells and interneurons increased with increasing running velocity, even though the frequency of hippocampal theta waves remained constant. The discharge frequency of some 'wheel-related' pyramidal cells could increase more than 10-fold between 10 and 100 cm/s, whereas the firing rate of 'non-wheel' cells remained constantly low. We hypothesize that: (i) a necessary condition for place-specific discharge of hippocampal pyramidal cells is the presence of theta oscillation; and (ii) relevant stimuli can tonically and selectively activate hippocampal pyramidal cells as long as theta activity is present.
TL;DR: PET dissociation provides unambiguous evidence that the mid‐dorsolateral and mid‐ventrolateral frontal cortical areas make distinct functional contributions to spatial working memory and corresponds with a fractionation of working memory processes in psychological terms.
Abstract: It is widely held that the frontal cortex plays a critical part in certain aspects of spatial and non-spatial working memory. One unresolved issue is whether there are functionally distinct subdivisions of the lateral frontal cortex that subserve different aspects of working memory. The present study used positron emission tomography (PET) to demonstrate that working memory processes within the human mid-dorsolateral and mid-ventrolateral frontal regions are organized according to the type of processing required rather than according to the nature (i.e. spatial or non-spatial), of the information being processed, as has been widely assumed. Two spatial working memory tasks were used which varied in the extent to which they required different executive processes. During a 'spatial span' task that required the subject to hold a sequence of five previously remembered locations in working memory a significant change in blood-flow was observed in the right mid-ventrolateral frontal cortex, but not in the anatomically and cytoarchitectonically distinct mid-dorsolateral frontal-lobe region. By contrast, during a '2-back' task that required the subject to continually update and manipulate an ongoing sequence of locations within working memory, significant blood flow increases were observed in both mid-ventrolateral and mid-dorsolateral frontal regions. When the two working memory tasks were compared directly, the one that emphasized manipulation of information within working memory yielded significantly greater activity in the right mid-dorsolateral frontal cortex only. This dissociation provides unambiguous evidence that the mid-dorsolateral and mid-ventrolateral frontal cortical areas make distinct functional contributions to spatial working memory and corresponds with a fractionation of working memory processes in psychological terms.
TL;DR: The results indicate that glucocorticoids induce a rapid and transient increase in hippocampal EAA levels in vivo that might be exerted through a novel non‐genomic mechanism of action.
Abstract: Glucocorticoids can rapidly affect neuronal function and behaviour in mammals. Several studies have suggested the possible existence of rapid, non-genomic effects of glucocorticoids in the hippocampus. To investigate whether glucocorticoids could affect neurotransmission in the hippocampus through rapid, non-genomic mechanisms, we studied the effects of acute glucocorticoid administration on extracellular amino acid levels in the CA1 area of the hippocampus. By means of microdialysis on freely moving rats, we observed that an intraperitoneal injection of corticosterone (2.5 mg/kg) induced a rapid (within 15 min) and transient (returning to basal levels by 35-45 min) increase in extracellular aspartate and glutamate levels ( approximately 155-160%), both in sham-operated and adrenalectomized rats. These effects occurred in parallel with a rise in corticosterone concentration, also detected by microdialysis, in this hippocampal area. Intrahippocampal perfusion of corticosterone by retrodialysis also produced the same fast and reversible effects on excitatory amino acid (EAA) levels. Extracellular concentrations of taurine and gamma-aminobutyric acid (GABA) were unchanged after intrahippocampal glucocorticoid administration. This corticosterone-mediated rise in EAA levels was not inhibited by the presence of specific antagonists for the two types of intracellular corticosteroid receptors, nor by a protein synthesis inhibitor, anisomycin. Perfusion of dexamethasone, a synthetic glucocorticoid, elicited a similar effect to that observed with corticosterone treatment in all studied cases. However, non-glucocorticoid steroids did not affect amino acid transmission in this hippocampal area. These results indicate that glucocorticoids induce a rapid and transient increase in hippocampal EAA levels in vivo that might be exerted through a novel non-genomic mechanism of action.
TL;DR: It is demonstrated that a tissue cable containing grafted SCs formed an effective bridge between the two stumps of the hemicord 1 month after transplantation, and that the mini‐channel model may be appropriate for further investigation of axonal re‐entry, synaptic reconnection and functional recovery following spinal cord injury.
Abstract: Schwann cells (SCs) have been shown to be a key element in promoting axonal regeneration after being grafted into the central nervous system (CNS). In the present study, SC-supported axonal regrowth was tested in an adult rat spinal cord implantation model. This model is characterized by a right spinal cord hemisection at the eighth thoracic segment, implantation of a SC-containing mini-channel and restoration of cerebrospinal fluid circulation by suturing the dura. We demonstrate that a tissue cable containing grafted SCs formed an effective bridge between the two stumps of the hemicord 1 month after transplantation. Approximately 10 000 myelinated and unmyelinated axons (1 : 9) per cable were found at its midpoint. In addition to propriospinal axons and axons of peripheral nervous system (PNS) origin, axons from as many as 19 brainstem regions also grew into the graft without additional treatments. Most significantly, some regenerating axons in the SC grafts were able to penetrate through the distal graft-host interface to re-enter the host environment, as demonstrated by anterograde axonal labelling. These axons coursed toward, and then entered the grey matter where terminal bouton-like structures were observed. In channels containing no SCs, limited axonal growth was seen within the graft and no axons penetrated the distal interface. These findings further support the notion that SCs are strong promotors of axonal regeneration and that the mini-channel model may be appropriate for further investigation of axonal re-entry, synaptic reconnection and functional recovery following spinal cord injury.
TL;DR: The results show that the phasic responsiveness of NAc DA transmission to an unfamiliar palatable food is under strong modulatory control by primary (consummatory) and secondary (appetitive) stimuli, and that the sign and extent of this control depends on the nature of the appetitive stimulus, delay of reward and motivational state (deprivation).
Abstract: We have previously shown in non-deprived rats that feeding of an unfamiliar palatable food (Fonzies(R)) phasically stimulates in vivo dopamine (DA) transmission in the medial nucleus accumbens (NAc) and this effect undergoes habituation after a previous (24 h) Fonzies meal (Bassareo & Di Chiara 1997, J Neurosci, 17, 851-861) The present study shows that an unfamiliar food (Kinder(R)) with a taste and composition (milk chocolate) different from that of Fonzies, also induces a release of DA in the NAc subjected to one-trial habituation Habituation was taste specific as no cross-habituation was observed between Fonzies and Kinder In undeprived rats, a 40-min exposure to an intrinsic appetitive stimulus (food smell arising from a Fonzies-filled plastic box) also prevented the increase in dialysate DA associated with Fonzies feeding, and this effect was partially reversed by food deprivation Food deprivation also prevented habituation of Fonzies-induced increase of dialysate DA in the NAc Predictive association of an empty plastic box to Fonzies feeding resulted in the acquisition of appetitive properties by the box and in facilitation (rather than inhibition) of the phasic responsiveness of DA transmission to Fonzies feeding A 10-min pre-exposure to appetitive olfactory stimuli intrinsic to Fonzies still prevented, like a 40-min pre-exposure, the NAc DA response to Fonzies feeding; however, a 5-min pre-exposure to these appetitive stimuli did not prevent the DA response in the NAc These results show that the phasic responsiveness of NAc DA transmission to an unfamiliar palatable food is under strong modulatory control by primary (consummatory) and secondary (appetitive) stimuli, and that the sign and extent of this control depends on the nature of the appetitive stimulus, delay of reward and motivational state (deprivation)
TL;DR: Optically measured glomerular calcium activities in vivo in the honeybee Apis mellifera during olfactory stimulation with 36 pure chemicals differing systematically in carbon chain length and functional group (aldehyde, ketone, alcohol, carboxylic acid and alkane) to allow conclusions about the interactions between o aroma receptors and odour molecules, and about the AL network.
Abstract: Odours are represented by specific ensembles of activated glomeruli in a combinatorial manner within the olfactory bulb of vertebrates or the antennal lobe (AL) of insects. Here, we optically measured glomerular calcium activities in vivo in the honeybee Apis mellifera during olfactory stimulation with 36 pure chemicals differing systematically in carbon chain length (C-5-10) and functional group (aldehyde, ketone, alcohol, carboxylic acid and alkane). We show their glomerular representations in 38 morphologically identified glomeruli out of the honeybee's 160. We measured the molecular receptive range of identified glomeruli averaging up to 21 individuals. Of the 38 glomeruli measured, 23 show maximal activity in a specific range of chain length. Glomeruli preferentially responding to a functional group are also always broadly tuned to particular chain lengths. Furthermore, glomeruli with similar response spectra are often direct neighbours. The results allow conclusions about the interactions between olfactory receptors and odour molecules, and about the AL network.
TL;DR: GDNF is highly effective as a neuroprotective and axon growth‐stimulating agent in the IS 6‐OHDA lesion model after both IS and ICV administration, and the lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
Abstract: Both glial cell line-derived neurotrophic factor (GDNF) and its recently discovered congener, neurturin (NTN), have been shown to exert neuroprotective effects on lesioned nigral dopamine (DA) neurons when administered at the level of the substantia nigra. In the present study, we have explored the relative in vivo potency of these two neurotrophic factors using two alternative routes of administration, into the striatum or the lateral ventricle, which may be more relevant in a clinical setting. In rats subjected to an intrastriatal (IS) 6-hydroxydopamine (6-OHDA) lesion, GDNF and NTN were injected every third day for 3 weeks starting on the day after the 6-OHDA injection. GDNF provided almost complete (90-92%) protection of the lesioned nigral DA neurons after both IS and intracerebroventricular (ICV) administration. NTN, by contrast, was only partially effective after IS injection (72% sparing) and totally ineffective after ICV injection. Although the trophic factor injections protected the nigral neurons from lesion-induced cell death, the level of expression of the phenotypic marker, tyrosine hydroxylase (TH), was markedly reduced in the rescued cell bodies. The extent of 6-OHDA-induced DA denervation in the striatum was unaffected by both types of treatment; consistent with this observation, the high rate of amphetamine-induced turning seen in the lesioned control animals was unaltered by either GDNF or NTN treatment. In the GDNF-treated animals, and to a lesser extent also after IS NTN treatment, prominent axonal sprouting was observed within the globus pallidus, at the level where the lesioned nigrostriatal axons are known to end at the time of onset of the neurotrophic factor treatment. The results show that GDNF is highly effective as a neuroprotective and axon growth-stimulating agent in the IS 6-OHDA lesion model after both IS and ICV administration. The lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
TL;DR: The specific expression pattern ofretinoid‐binding proteins and nuclear retinoid receptors as well as the presence of RA in striatum suggests that retinoids are important in many brain structures and emphasizes a role for retinoidal in gene regulatory events in postnatal and adult striatum.
Abstract: Retinoic acid (RA), a retinoid metabolite, acts as a gene regulator via ligand-activated transcription factors, known as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both existing in three different subtypes, alpha, beta and gamma. In the intracellular regulation of retinoids, four binding proteins have been implicated: cellular retinol binding protein (CRBP) types I and II and cellular retinoic acid binding protein (CRABP) types I and II. We have used in situ hybridization to localize mRNA species encoding CRBP- and CRABP I and II as well as all the different nuclear receptors in the developing and adult rat and mouse central nervous system (CNS), an assay to investigate the possible presence of RA, and immunohistochemistry to also analyse CRBP I- and CRABP immunoreactivity (IR). RXRbeta is found in most areas while RARalpha and -beta and RXRalpha and -gamma show much more restricted patterns of expression. RARalpha is found in cortex and hippocampus and RARbeta and RXRgamma are both highly expressed in the dopamine-innervated areas caudate/putamen, nucleus accumbens and olfactory tubercle. RARgamma could not be detected in any part of the CNS. Using an in vitro reporter assay, we found high levels of RA in the developing striatum. The caudate/putamen of the developing brain showed strong CRBP I-IR in a compartmentalized manner, while at the same time containing many evenly distributed CRABP I-IR neurons. The CRBP I- and CRABP I-IR patterns were closely paralleled by the presence of the corresponding transcripts. The specific expression pattern of retinoid-binding proteins and nuclear retinoid receptors as well as the presence of RA in striatum suggests that retinoids are important in many brain structures and emphasizes a role for retinoids in gene regulatory events in postnatal and adult striatum.
TL;DR: The intrathecal delivery of NT‐3 or other neurotrophic molecules has obvious advantages in clinical applications, as it is shown for the first time that dorsal column axonal regeneration can be achieved without the use of graft implantation or nerve lesions.
Abstract: The regeneration capacity of spinal cord axons is severely limited. Recently, much attention has focused on promoting regeneration of descending spinal cord pathways, but little is known about the regenerative capacity of ascending axons. Here we have assessed the ability of neurotrophic factors to promote regeneration of sensory neurons whose central axons ascend in the dorsal columns. The dorsal columns of adult rats were crushed and either brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) or a vehicle solution was delivered continuously to the lesion site for 4 weeks. Transganglionic labelling with cholera toxin beta subunit (CTB) was used to selectively label large myelinated Abeta fibres. In lesioned rats treated with vehicle, CTB-labelled fibres were observed ascending in the gracile fasciculus, but these stopped abruptly at the lesion site, with no evidence of sprouting or growth into lesioned tissue. No CTB-labelled terminals were observed in the gracile nucleus, indicating that the lesion successfully severed all ascending dorsal column axons. Treatment with BDNF did not promote axonal regeneration. In GDNF-treated rats fibres grew around cavities in caudal degenerated tissue but did not approach the lesion epicentre. NT-3, in contrast, had a striking effect on promoting growth of lesioned dorsal column axons with an abundance of fibre sprouting apparent at the lesion site, and many fibres extending into and beyond the lesion epicentre. Quantification of fibre growth confirmed that only in NT-3-treated rats did fibres grow into the crush site and beyond. No evidence of terminal staining in the gracile nucleus was apparent following any treatment. Thus, although NT-3 promotes extensive growth of lesioned axons, other factors may be required for complete regeneration of these long ascending projections back to the dorsal column nuclei. The intrathecal delivery of NT-3 or other neurotrophic molecules has obvious advantages in clinical applications, as we show for the first time that dorsal column axonal regeneration can be achieved without the use of graft implantation or nerve lesions.
TL;DR: Treatment with antioxidants such as idebenone and α‐tocopherol prevents learning and memory deficits caused by Aβ, and suggests that oxidative stress is involved in the mechanisms of Aβ‐induced neurotoxicity in vitro.
Abstract: Amyloid beta-peptide (A beta), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of A beta-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of A beta-(1-42). In the A beta-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with A beta-(40-1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with A beta-(1-42). Potent antioxidants idebenone and alpha-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in A beta-(1-42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of A beta infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of A beta-(1-42)-infused rats did not differ from those in control animals, and neither idebenone nor alpha-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and alpha-tocopherol prevents learning and memory deficits caused by A beta.
TL;DR: A probability map of the pars opercularis was constructed by averaging its location and extent in each individual normalized brain into Talairach space to aid in localization of activity changes in functional neuroimaging studies.
Abstract: The pars opercularis occupies the posterior part of the inferior frontal gyrus. Electrical stimulation or damage of this region interferes with language production. The present study investigated the morphology and morphometry of the pars opercularis in 108 normal adult human cerebral hemispheres by means of magnetic resonance imaging. The brain images were transformed into a standardized proportional steoreotaxic space (i.e. that of Talairach and Tournoux) in order to minimize interindividual brain size variability. There was considerable variability in the shape and location of the pars opercularis across brains and between cerebral hemispheres. There was no significant difference or correlation between left and right hemisphere grey matter volumes. There was also no significant difference between sex and side of asymmetry of the pars opercularis. A probability map of the pars opercularis was constructed by averaging its location and extent in each individual normalized brain into Talairach space to aid in localization of activity changes in functional neuroimaging studies.
TL;DR: The brain location, extent and functional organization of the cortical visual area V6A was investigated in macaque monkeys by using single cell recording techniques in awake, behaving animals in the view that this area could be involved in the control of reaching out and grasping objects.
Abstract: The brain location, extent and functional organization of the cortical visual area V6A was investigated in macaque monkeys by using single cell recording techniques in awake, behaving animals. Six hemispheres of four animals were studied. Area V6A occupies a horseshoe-like region of cortex in the caudalmost part of the superior parietal lobule. It extends from the medial surface of the brain, through the anterior bank of the parieto-occipital sulcus, up to the most lateral part of the fundus of the same sulcus. Area V6A borders on areas V6 ventrally, PEc dorsally, PGm medially and MIP laterally. Of 1348 neurons recorded in V6A, 61% were visual and 39% non-visual in nature. The visual neurons were particularly sensitive to orientation and direction of movement of visual stimuli. The inferior contralateral quadrant was the most represented one. Visual receptive fields were also found in the inferior ipsilateral quadrant and in the upper visual field. Receptive fields were on average smaller in the lower visual field than in the upper one. Both central and peripheral parts of the visual field were represented. Large parts of the visual field were represented in small regions of area V6A, and the same regions of the visual field were re-represented many times in different parts of this area, without any apparent topographical order. The only reliable sign of retinotopic organization was the predominance of central representation dorsally and far periphery ventrally. The functional organization of area V6A is discussed in the view that this area could be involved in the control of reaching out and grasping objects.
TL;DR: A distinct pattern of EP2 and EP4 expression throughout the rat brain under both basal and immune‐challenged conditions is provided, and underlie the possible role of the EP4 subtype in mediating the effects of PGE2 on different autonomic and neuroendocrine functions.
Abstract: It is currently believed that prostaglandin (PG) of E2 type plays a crucial role in transferring the information received from circulating immune factors to brain parenchymal cells. Although PGE2 is synthesized quite essentially by cells of the blood-brain barrier, the organization and regulation of its receptor subtypes within neuronal elements remain unknown. In this study, intravenous (i.v.) injection of the endotoxin lipopolysaccharide (LPS) or recombinant rat interleukin-1beta (IL-1beta), and intramuscular (i.m.) injection of turpentine were used as different models of systemic immune stimuli. Rats were perfused at various times after the insults (30 min to 24 h), their brains cut and hybridized with full-length rat cRNA probes. Double-labelling procedures were accomplished to determine the cellular phenotype and activity. A very distinct distribution of both EP2 and EP4 receptors was found across the brain under basal conditions; the hybridization signal for the type 2 was detected in the bed nucleus of the stria terminalis (BNST), lateral septum, subfornical organ (SFO), ventromedial hypothalamic nucleus (VMH), central nucleus of the amygdala (CeA), locus coeruleus (LC) and the area postrema (AP), whereas the ventral septal/anterior preoptic area, the magnocellular paraventricular nucleus (PVN), supraoptic nucleus, parabrachial nucleus, LC, the nucleus of the solitary tract (NTS) and the ventrolateral medulla (VLM) exhibited moderate to strong levels for the EP4 mRNA under basal conditions. Upregulation of the genes encoding EP2 and EP4 receptors was detected in selective regions and neuronal populations during systemic inflammatory challenges. The most dramatic one being the robust transcriptional activation of the EP4 subtype within corticotropin-releasing factor (CRF) neurons of the parvocellular PVN following i.v. LPS and IL-1beta injection, and the localized i.m. aggression. These neurons of the endocrine hypothalamus as well as those of numerous autonomic-related nuclei were activated by the proinflammatory cytokine, as they were immunoreactive (ir) to Fos nuclear protein. The EP4 transcript was also present in activated catecholaminergic neurons of the LC, NTS and VLM, although only the A1 cell group exhibited an increase in EP4 transcription in response to circulating IL-1beta. Moreover, the systemic immunogenic insults caused a significant increase in the EP2 mRNA levels in the CeA, SFO, AP and the leptomeninges. These data provide a distinct pattern of EP2 and EP4 expression throughout the rat brain under both basal and immune-challenged conditions, and underlie the possible role of the EP4 subtype in mediating the effects of PGE2 on different autonomic and neuroendocrine functions. The presence of Fos-ir nuclei in various populations of EP4 neurons of IL-1beta-treated animals clearly supports this concept and suggests that the selectivity of the neuronal response during systemic inflammation may depend on the expression of specific PGE2 receptors in key structures of the brain.
TL;DR: It is found that nerve growth factor (NGF) and neurotrophin‐3 (NT3) synthesis is upregulated in satellite cells surrounding neurons in lesioned DRG as early as 48 h after nerve injury, and this response lasts for at least 2 months.
Abstract: Injury to a peripheral nerve induces in the dorsal root ganglia (DRG) sprouting of sympathetic and peptidergic terminals around large-diameter sensory neurons that project in the damaged nerve. This pathological change may be implicated in the chronic pain syndromes seen in some patients with peripheral nerve injury. The mechanisms underlying the sprouting are not known. Using in situ hybridization and immunohistochemical techniques, we have now found that nerve growth factor (NGF) and neurotrophin-3 (NT3) synthesis is upregulated in satellite cells surrounding neurons in lesioned DRG as early as 48 h after nerve injury. This response lasts for at least 2 months. Quantitative analysis showed that the levels of mRNAs for NT3 and NGF increased in ipsilateral but not contralateral DRG after nerve injury. Noradrenergic sprouting around the axotomized neurons was associated with p75-immunoreactive satellite cells. Further, antibodies specific to NGF or NT3, delivered by an osmotic mini-pump to the DRG via the lesioned L5 spinal nerve, significantly reduced noradrenergic sprouting. These results implicate satellite cell-derived neurotrophins in the induction of sympathetic sprouting following peripheral nerve injury.
TL;DR: The visuotopic organization of area V6 suggests a role in the analysis of the flow field resulting from self‐motion, in selecting targets during visual searching as well as in the control of arm‐reaching movements towards non‐foveated targets.
Abstract: The brain location and topographical organization of the cortical visual area V6 was studied in five hemispheres of four awake macaque monkeys. Area V6 is located in the caudal aspect of the superior parietal lobule (SPL). It occupies a 'C'-shaped belt of cortex whose upper branch is in the depth of the parieto-occipital sulcus (POS) and lower one is in the depth of the medial parieto-occipital sulcus (POM), with the medial surface of the brain as a zone of junction between the two branches. Area V6 contains a topographically organized representation of the contralateral visual field up to an eccentricity of at least 80 degrees. The lower visual field representation is located dorsally, in the ventral part of POS, and the upper field ventrally, in the dorsal wall of POM. The representation of the horizontal meridian forms the posterior border of V6. It is adjacent to area V3 in POS as well as in the caudal part of POM, on the ventral convexity of the brain. The lower vertical meridian forms the anterior border of V6, adjacent to area V6A. The upper vertical meridian is in the depth of POM. The representation of the central visual field is not magnified relative to that of the periphery. The central visual field (below 20-30 degrees of eccentricity) is represented in the medial-most aspect of the annectant gyrus, in the lateral part of the posterior bank of POS. The visuotopic organization of area V6 suggests a role in the analysis of the flow field resulting from self-motion, in selecting targets during visual searching as well as in the control of arm-reaching movements towards non-foveated targets.