bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral glucose utilization in transgenic mice overexpressing heat shock protein 70 is altered by dizocilpine
Authors: Kelly Stephen , Bieneman Alison , Uney James B. , McCulloch James
Published: March 2003

Heat shock protein (HSP70) a member of the 70 kDa HSP superfamily, has been widely implicated in the cellular stress response to numerous insults. HSP70 may be a significant factor in cell survival following stresses such as cerebral ischaemia. The precise mechanisms by which HSP70 facilitates cell survival remain unclear. The aim of this study was to ascertain whether any differences in local cerebral glucose utilization (LCGU) existed between transgenic mice overexpressing HSP70 (HSP70 Tg) and wild‐ type littermate (WT) mice. LCGU was assessed using 14C‐2‐deoxyglucose in HSP70 Tg and WT mice under basal conditions (intraperitoneal injection of saline) and during metabolic activation produced by NMDA receptor blockade (intraperitoneal injection of dizocilpine, 1 mg/kg). No significant alterations in LCGU were observed between saline injected HSP70 Tg and WT mice in any of the 35 brain regions analyzed. Dizocilpine injection produced significant heterogeneous alterations in LCGU in HSP70 Tg mice (24 of 35 brain regions) and in WT mice (22 of 35 brain regions) compared with saline injected mice. The distribution of altered LCGU produced by dizocilpine was similar in HSP70 Tg and WT mice. However in five brain regions, dizocilpine injected HSP70 Tg mice displayed significantly altered LCGU compared to dizocilpine injected WT mice (anterior thalamic nucleus +27%, dorsal CA1 stratum lacunosum molecularae+22%, dorsal CA1 stratum oriens+ 14%, superior olivary body −26%, and the nucleus of the lateral lemniscus −16%). These data highlight that while overexpression of HSP70 transgene does not significantly alter LCGU in the basal state, mice overexpressing the HSP70 transgene respond differently to metabolic stress produced by NMDA receptor blockade in some important brain regions.
Spinal cord repair in neonatal rats: a correlation between axonal regeneration and functional recovery
Authors: Hase Takao , Kawaguchi Saburo , Hayashi Hideki , Nishio Takeshi , Mizoguchi Akira , Nakamura Takashi
Published: March 2003

The present study aimed to analyse how anatomical regeneration contributes to functional recovery after experimental spinal cord repair. Thoracic spinal cord of neonatal rats was completely transected to make a gap and repaired by grafting a section of embryonic spinal cord. Six weeks after surgery, outcome of locomotor performance was assessed using an open field locomotor scale (BBB scale). Axonal regeneration across the repaired site was quantitatively assessed in the raphe, vestibular, and red nuclei and the sensorimotor cortex by a retrograde tracing method. The rats that had no labelled neurons in any of the supraspinal nuclei showed no hind–forelimb coordination. The rats that had labelled neurons in the brainstem nuclei but not in the sensorimotor cortex showed hind–forelimb coordination of varying grades depending on the amount of regeneration. The rats that had labelled neurons in all of the examined nuclei showed almost normal locomotion. In addition to a relationship between distribution of the labelled neurons and functional recovery, a positive correlation was observed between number of the labelled neurons in each of the supraspinal nuclei and locomotor performance of the rat. Thus the grade of restored function appeared to be regulated by distribution and number of fibres regenerated across the repaired site and into the target region. These results suggest that accurate reconstruction of neural connections is essential for significant functional recovery after spinal cord repair.
Synaptic depression improves coincidence detection in the nucleus laminaris in brainstem slices of the chick embryo
Authors: Kuba Hiroshi , Koyano Konomi , Ohmori Harunori
Published: March 2003

Neurons in the nucleus laminaris detect the coincidence of binaural signals, and are the first neurons to calculate the interaural time difference for the sound source localization in birds. In this paper, we have studied contributions of synaptic depression to the coincidence detection in the nucleus laminaris in a slice preparation of the chick embryo (E16–18), using the whole‐cell patch recording technique. Under voltage clamp, EPSCs decreased progressively in their amplitude during the course of tetanic stimuli. This synaptic depression was primarily ascribed to the reduction of transmitter release from the presynaptic terminal, because the depression was decreased by reducing transmitter release with 2.5 µm Cd2+ but was not affected by reducing desensitization of postsynaptic AMPA receptors with 20 µm cyclothiazide. Under current clamp, trains of 10 stimuli of 100 Hz were applied bilaterally with changing the time intervals systematically between both sides. Response window, defined as the time interval corresponding to the half‐maximum firing probability, was narrowed during the course of the stimulus train, and this occurred in parallel with a decrease in the EPSP amplitude. In addition, the reduction of the EPSP amplitude due to 2.5 µm Cd2+ or 2 µm CNQX improved the accuracy of coincidence detection. These results indicate that the synaptic depression may improve the coincidence detection in the chick laminaris neurons.
Forced swimming evokes a biphasic response in CREB phosphorylation in extrahypothalamic limbic and neocortical brain structures in the rat
Authors: Bilang‐Bleuel A. , Rech J. , De Carli S. , Holsboer F. , Reul J. M. H. M.
Published: March 2003

The transcription factor cAMP response element‐binding protein (CREB) plays a critical role in plasticity processes underlying learning and memory. We investigated the phosphorylation of CREB in rat brain after forced swimming, a stressor known to impact on higher limbic and neocortical brain areas. As shown by immunohistochemistry, forced swimming increased phosphorylated CREB (P‐CREB) levels in the dentate gyrus, all neocortical areas, the medial, lateral and basolateral nuclei of the amygdala, cerebellum but not in the hypothalamic paraventricular nucleus. Distinct differences in the P‐CREB pattern were observed in the deeper vs. superficial layers of the neocortex. The response in P‐CREB was stressor type‐specific because exposure to either ether or a cold environment was ineffective. The forced swimming‐induced changes in P‐CREB levels showed a biphasic time‐course: an early peak detected at 15 min was followed by a marked drop at 60 min; a second rise starting after 1–2 h, reached maximal values between 6 and 8 h, and remained elevated for at least 48 h. Examination of the neuroanatomical induction pattern of the CRE‐inducible immediate early gene product c‐fos revealed that it was only partly overlapping with that of P‐CREB. Western analyses showed that only the 43‐kDa CREB protein (an enhancer of CRE‐containing promotors) was phosphorylated after forced swimming, while other members of the CREB/ATF family (CREM, ATF‐1 and ATF‐2) remained unaffected. The NF‐κB pathway was not activated, indicating that forced swimming does not unspecifically evoke transcription factor activation. Thus, in contrast to physical stressors, such as ether or cold exposure, forced swimming, a stressor with a strong psychological component, elicits the recruitment of the CREB pathway in a widespread manner in the limbic system and neocortex; brain regions known to be implicated in various forms of (stress‐related) learning and memory.
Superposition of horseshoe‐like periodicity and linear tonotopic maps in auditory cortex of the Mongolian gerbil
Authors: Schulze Holger , Hess Andreas , Ohl Frank W. , Scheich Henning
Published: March 2003

The segregation of an individual sound from a mixture of concurrent sounds, the so‐called cocktail‐party phenomenon, is a fundamental and largely unexplained capability of the auditory system. Speaker recognition involves grouping of the various spectral (frequency) components of an individual's voice and segregating them from other competing voices. The important parameter for grouping may be the periodicity of sound waves because the spectral components of a given voice have one periodicity, viz. fundamental frequency, as their common denominator. To determine the relationship between the representations of spectral content and periodicity in the primary auditory cortex (AI), we used optical recording of intrinsic signals and electrophysiological mapping in Mongolian gerbils (Meriones unguiculatus). We found that periodicity maps as an almost circular gradient superimposed on the linear tonotopic gradient in the low frequency part of AI. This geometry of the periodicity map may imply competitive signal processing in support of the theory of ‘winner‐takes‐all’.
Sensitization to the neuroendocrine, central monoamine and behavioural effects of murine tumor necrosis factor‐α: peripheral and central mechanisms
Authors: Hayley S. , Wall P. , Anisman H.
Published: March 2003

Systemic administration of murine tumour necrosis factor‐α (mTNF‐α; 0.1–2.0 µg, i.p.) dose‐dependently increased plasma corticosterone and augmented monoamine utilization within the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus, medial prefrontal cortex (PFC), central and medial amygdala. A time‐dependent sensitization was induced in mice, wherein reexposure to mTNF‐α 28 days (but not 1 day) following the initial cytokine treatment provoked marked signs of illness (diminished activity, ptosis, piloerection) and increased plasma corticosterone levels. Serotonin (5‐HT) activity was augmented upon mTNF‐α reexposure at the 1‐ or 28‐day intervals in the PFC and medial amygdala, respectively. Intracerebroventricular (i.c.v.; 1–500 ng) mTNF‐α did not promote illness, but modestly increased plasma corticosterone levels. Neither the illness nor the corticosterone changes were subject to a sensitization upon i.c.v. cytokine reexposure. Acute i.c.v. mTNF‐α increased norepinephrine (NE), 5‐HT and dopamine (DA) activity within the PVN and median eminence/arcuate nucleus complex (ME/ARC), and NE utilization within the central amygdala. Subsequent i.c.v. mTNF‐α further enhanced the hypothalamic monoamine variations. Finally, systemic (i.p.) mTNF‐α pretreatment did not proactively influence sickness or corticosterone responses upon later i.c.v. cytokine challenge, but augmented locus coeruleus NE activity and 5‐HT and DA utilization within the ME/ARC. It is suggested that the sensitization with respect to sickness and corticosterone activity in response to mTNF‐α reflect the involvement of peripheral mechanisms. Moreover, it appears that mTNF‐α promotes central neurochemical plasticity through independent central and peripheral mechanisms.
Acute cholinergic rescue of synaptic plasticity in the neurodegenerating cortex of anti‐nerve‐growth‐factor mice
Authors: Pesavento Emanuele , Capsoni Simona , Domenici Luciano , Cattaneo Antonino
Published: March 2003

Deficits in cholinergic systems innervating cerebral cortex are associated with cognitive impairment during senescence and in age‐related neurodegenerative pathologies. However, little is known about the role of cholinergic pathways in modulating cortical plasticity. Basal forebrain cholinergic neurons are a major target for nerve‐growth factor (NGF). In order to investigate the relationship between cholinergic innervation and cortical synaptic plasticity, we exploited a transgenic mouse model in which the activity of NGF in the adult nervous system is neutralized by the expression of blocking antibodies to NGF itself (anti‐NGF mice) [Ruberti, F. et al. (2000). J. Neurosci. 20, 2589–2601]. In 6‐month‐old anti‐NGF mice, we show that the reduction in cholinergic innervation of the cortex is associated with different forms of synaptic plasticity impairment. A local, acute increase in the availability of acetylcholine rescues these synaptic plasticity deficits, thus indicating that a cholinergic system mediates the impairment of cortical plasticity at this early stage of the neurodegenerative process triggered by NGF neutralization. Our results represent an important step in unveiling the pivotal role of cholinergic transmission in modulating adult cortical plasticity.
Neuroinflammation of the nigrostriatal pathway during progressive 6‐OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging
Authors: Cicchetti F. , Brownell A. L. , Williams K. , Chen Y. I. , Livni E. , Isacson O.
Published: March 2003

We investigated the microglial response to progressive dopamine neuron degeneration using in vivo positron emission tomography (PET) imaging and postmortem analyses in a Parkinson's disease (PD) rat model induced by unilateral (right side) intrastriatal administration of 6‐hydroxydopamine (6‐OHDA). Degeneration of the dopamine system was monitored by PET imaging of presynaptic dopamine transporters using a specific ligand 11C‐CFT (2β‐carbomethoxy‐3β‐(4‐fluorophenyl) tropane). Binding of 11C‐CFT was markedly reduced in the striatum indicating dopaminergic degeneration. Parallel PET studies of 11C‐PK11195 (1‐(2‐chlorophenyl)‐N‐methyl‐N‐(1‐methylpropyl)‐3 isoquinoline carboxamide) (specific ligand for activated microglia) showed increased binding in the striatum and substantia nigra indicative of a microglial response. Postmortem immunohistochemical analyses were performed with antibodies against CR3 for microglia/macrophage activation. Using a qualitative postmortem index for microglial activation we found an initially focal, then widespread microglial response at striatal and nigral levels at 4 weeks postlesion. These data support the hypothesis that inflammation is a significant component of progressive dopaminergic degeneration that can be monitored by PET imaging.
Differential expression of phospholipase D1 in the developing retina
Authors: Lee E.‐J. , Min D. S. , Lee M.‐Y. , Chung J.‐W. , Chun M.‐H. , Oh S.‐J.
Published: March 2003

Expression patterns of phospholipase D1 (PLD1) in the developing rat retina were investigated using immunocytochemistry and Western blot analysis and compared with the expression patterns of glutamine synthetase. PLD1 immunoreactivity appeared first in a few neuroblasts in the middle of the mantle zone of the primitive retina by embryonic (E) day 13. PLD1‐immunoreactive primitive ganglion cells were characterized in the ganglion cell layer by E17. Faint immunoreactivity at E17 profiled radially orientated cells and this pattern appeared up to postnatal (P) day 7. In the ganglion cell layer at P3, displaced amacrine cells and ganglion cells were classified. At P5, presumptive horizontal cells and amacrine cells were identified. By P7, a thin outermost layer of newly formed segments of the photoreceptor cells was also PLD1 immunoreactive. PLD1 immunoreactivity at P8 was limited to radial Müller cells and the outer segment layer of the photoreceptor cells, and the expression pattern was conserved to adulthood. Western blot analysis showed relatively high amounts of PLD1 protein at E17 and P3, a decrease at P7, and moderate amounts from P8 onward. Co‐expression of PLD1 with glutamine synthetase in the retina appeared first after birth in differentiating neurons and in Müller cells by P8; thereafter the pattern was maintained. The expression pattern of the PLD1 during development of the retina suggests that PLD1 plays important roles in glutamate‐associated differentiation of both specific neurons and radial glial cells, and in glutamate‐mediated cellular signalling in Müller cells.
Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain
Authors: Ma Weiya , Eisenach James C.
Published: March 2003

Inflammatory mediators produced in the injured nerve have been proposed as contributing factors in the development of neuropathic pain. Prostaglandins (PGs) are probably included in these important inflammatory mediators. In the present study, 2 and 4 weeks following partial sciatic nerve ligation (PSNL), we observed a dramatic increase in the prostaglandin synthesizing enzyme cyclooxygenase (COX)2‐immunoreactive (IR) cell profiles in the injury site and adjacent region. Some of these COX2‐IR cells were identified as macrophages because they coexpressed ED1. None of these COX2‐IR cell profiles coexpressed the Schwann cell marker S100. In the contralateral sciatic nerve and sciatic nerve from normal rats, we failed to observe any of these COX‐IR cell profiles. We also observed COX1‐IR cell profiles (presumably Langerhans cells) in the epidermis of the footpad of both normal and PSNL rats. Interestingly, a greater number of COX1‐IR cell profiles were observed in the epidermis of the ipsilateral footpad of PSNL rats. Local injection of ketorolac, a nonselective COX inhibitor, into the ipsilateral plantar side or into the injury site of the sciatic nerve, effectively reversed the tactile allodynia induced by PSNL for > 5 days. Intraperitoneal or intramuscular injection of ketorolac had a similar but shorter antiallodynic effect. Intraplantar or peri‐neural injection of ketorolac dramatically suppressed the PSNL‐induced increase in the phosphorylation of a transcription factor cAMP response element binding protein (CREB) in the ipsilateral dorsal horn of L4 and L5 spinal cord of PSNL rats. Intraplantar or peri‐neural injection of ketorolac at the time of lesion did not prevent mechanical hypersensitivity but reduced it with a slow onset 3 weeks after lesion. Our data suggest that PSNL induces over‐production of PGs in peripheral tissues and that PGs probably sensitize nociceptors and are involved in central plasticity and sensitization at the spinal cord level, thus contributing to the maintenance of tactile allodynia.
Memory traces for inflectional affixes as shown by mismatch negativity
Authors: Shtyrov Yury , Pulvermüller Friedemann
Published: March 2003

Mismatch negativity (MMN), an index of experience‐dependent memory traces, was used to investigate the processing of grammatical affixes in the human brain. The MMN was elicited by either a verb stem or an inflected verb form, phonetic contrasts being identical in both conditions. The topography of the mismatch responses showed clear left‐hemispheric laterality in both conditions. However, the MMN to the inflected form occurred later than that for the stem. Furthermore, the inflected stimulus produced MMN maximal in centroparietal sites, whereas stem‐elicited MMN was more profound at more frontal sites. We suggest that these features of the MMN to inflected form indicate delayed activation of left‐lateralized perisylvian cell assemblies that function as cortical memory traces of inflectional affixes.
Neuronal activation and corticotropin‐releasing hormone expression in the brain of obese (fa/fa) and lean (fa/?) Zucker rats in response to refeeding
Authors: Timofeeva Elena , Picard Frédéric , Duclos Martine , Deshaies Yves , Richard Denis
Published: March 2003

The present study was conducted to investigate the pattern of neuronal activation and corticotropin‐releasing hormone (CRH) expression in fed, food deprived and refed lean (Fa/?) and obese (fa/fa) Zucker rats. The pattern of neuronal activation was studied by measuring the expression of the immediate‐early gene c‐fos. Expression of c‐fos and CRH mRNA was determined by in situ hybridization histochemistry. In both lean and obese rats, one hour of refeeding led to a transient increase in c‐fos mRNA levels which was detected in the paraventricular hypothalamic nucleus (PVH), the dorsomedial hypothalamic nucleus, the supraoptic nucleus, the paraventricular thalamic nucleus, the central nucleus of amygdala (CeA), the lateral and medial parabrachial nuclei, the nucleus of the solitary tract, and the area postrema. In addition, refeeding led to strong activation of the arginine‐vasopressin neurons located in the magnocellular part of the PVH. Following 24 h of food deprivation, CRH expression in the parvocellular division of the PVH was significantly higher in obese rats compared to lean animals. During refeeding, PVH CRH mRNA levels in obese rats decreased to reach control values. The decrease in CRH expression in obese rats was accompanied by the alleviation of the hypercorticosteronemia that characterized obese Zucker rats. CRH mRNA levels in the central nucleus of the amygdala were significantly higher in lean rats than in obese animals, when the rats were fed ad libitum During food deprivation, CeA CRH mRNA levels decreased in lean rats and gradually returned to predeprivation values during refeeding. In refed obese rats, CeA levels of CRH mRNA were higher than those of ad libitum fed or food‐deprived obese mutants. In the perifornical region of the lateral hypothalamic area (LHA), the expression of CRH mRNA rose significantly in response to refeeding in lean rats, but not in obese animals. Following the first hour of refeeding, the number of neurons expressing CRH mRNA in the LHA in lean rats almost doubled. The present results demonstrate that refeeding has a stimulating effect in obese Zucker rats in a pattern of activation similar to that seen in lean Fa/? rats. They also demonstrate differences in CRH expression between Fa/? and fa/fa rats after refeeding. The most apparent of these differences was seen in the lateral hypothalamus in which refeeding failed to up‐regulate CRH expression in obese rats.
Transistor array with an organotypic brain slice: field potential records and synaptic currents
Authors: Besl Brigitte , Fromherz Peter
Published: March 2003

Linear transistor arrays on a silicon chip were used to map evoked extracellular field potentials in organotypic brain slices of rat hippocampus. The shape and amplitude of the transients were similar to those from records with micropipette electrodes. The spatial resolution was 21 and 4.6 µm. The sampled profile of the field potential showed a wide and shallow trough of transients in the stratum radiatum and a narrow but higher ridge in the stratum pyramidale. Due to the high resolution, the profile could be interpreted quantitatively in terms of synaptic currents. Transistor chips may become a novel tool for neurophysiological and pharmacological studies in brain slices.
Sub‐chronic treatment with classical but not atypical antipsychotics produces morphological changes in rat nigro‐striatal dopaminergic neurons directly related to ‘early onset’ vacuous chewing
Authors: Marchese Giorgio , Casu Maria Antonietta , Bartholini Francesco , Ruiu Stefania , Saba Pierluigi , Gessa Gian Luigi , Pani Luca
Published: March 2003

In the present work, we investigated if an impairment of dopaminergic neurons after subchronic haloperidol treatment might be a possible physiopathologic substrate of the ‘early onset’ vacuous chewing movements (VCMs) in rats. For this purpose, different antipsychotics were used to analyse a possible relationship between VCMs development and morphological alterations of tyrosine‐hydroxylase‐immunostained (TH‐IM) neurons.

    Rats treated twice a day with haloperidol displayed a significant increase of VCMs that was both time‐ (2–4 weeks) and dose (0.1–1 mg/kg) dependent. Immunocytochemical analysis showed a shrinkage of TH‐IM cell bodies in substantia nigra pars compacta and reticulata and a reduction of TH‐immunostaining in the striatum of haloperidol treated rats with the arising of VCMs. No differences were observed in TH‐IM neurons of ventral tegmental area and nucleus accumbens vs. control rats. The atypical antipsychotics risperidone (2 mg/kg, twice a day), amisulpride (20 mg/kg, twice a day) and clozapine (10 mg/kg, twice a day) did not produce any nigro‐striatal morphological changes or VCMs. TH‐IM nigro‐striatal neuron morphological alterations and VCMs were still present after three days of withdrawal in rats treated for four weeks with haloperidol (1 mg/kg). Both the main morphological changes and the behavioural correlate disappeared after three weeks of withdrawal. These results suggest that haloperidol induces a morphological impairment of the dopaminergic nigro‐striatal neurons which is directly associated with the arising, permanency and disappearance of VCMs in rats.
Contribution of amygdala neurons containing peptides and calcium‐binding proteins to fear‐potentiated startle and exploration‐related anxiety in inbred Roman high‐ and low‐avoidance rats
Authors: Yilmazer‐Hanke Deniz M. , Faber‐Zuschratter Heidi , Linke Rüdiger , Schwegler Herbert
Published: March 2003

The purpose of this study was to investigate amygdala‐related fear and anxiety in two inbred rat lines differing in emotionality (RHA/Verh and RLA/Verh), and to relate the behaviour of the animals to neuronal types in different nuclei of the amygdala. The behavioural tests used were the motility test, elevated plus‐maze and fear‐potentiated startle response. The neurons investigated were immunoreactive for the anxiogenic peptide corticotropin‐releasing factor (CRF‐ir), the anxiolytic peptide neuropeptide Y (NPY‐ir), and the calcium‐binding proteins parvalbumin (PARV‐ir) and calbindin (CALB‐ir). The NPY‐ir, PARV‐ir and CALB‐ir neurons studied were subpopulations of GABAergic neurons. RLA/Verh rats, which showed a significant fear‐potentiation of the acoustic startle response, had more CRF‐ir projection neurons in the central nucleus of the amygdala. The same RLA/Verh rats were either less or equally anxious in the motility test (similar to open field) and elevated plus‐maze as compared with RHA/Verh rats. In accordance with this behaviour, the RLA/Verh rats had more NPY‐ir neurons in the lateral, and more PARV‐ir neurons in basal nuclei of the amygdala than RHA/Verh rats, but no differences were detected in the number of CRF‐ir and CALB‐ir neurons of the basolateral complex. In conclusion, the RLA/Verh rats displayed an opposite behaviour in the fear‐potentiated startle model and the exploratory tests measuring anxiety based on choice behaviour. Thus, the anxiogenic systems in the central nucleus and anxiolytic systems in the basolateral complex of the amygdala might be differentially involved in the fear‐potentiated startle paradigm and exploratory tests in the Roman rat lines.
Glycinergic and GABAergic calcium responses in the developing lateral superior olive
Authors: Kullmann Paul H. M. , Ene F. Aura , Kandler Karl
Published: March 2003

The lateral superior olive (LSO), a binaural nucleus involved in sound localization, receives tonotopically organized inhibitory inputs from the medial nucleus of the trapezoid body (MNTB). During development, the tonotopic organization of this glycinergic/GABAergic MNTB–LSO pathway is established by activity‐dependent axonal reorganization. However, the underlying mechanisms by which this reorganization takes place have remained largely unknown. As cytosolic calcium is one of the most important second messengers responsible for inducing synaptic plasticity and reorganization, we examined whether and how activity in the MNTB–LSO pathway changes the intracellular calcium concentration ([Ca2+]i) in developing LSO neurons. By applying calcium imaging techniques to Fura‐2‐labelled slices from neonatal rats and mice, we found that glycine and GABA (γ‐aminobutyric acid) affect [Ca2+]i in LSO neurons in an age‐dependent manner; during the first postnatal week, the period at which glycine and GABA are depolarizing in the LSO, glycine and GABA always increased [Ca2+]i. However, in 2‐week‐old animals, the time around hearing onset when glycine and GABA are hyperpolarizing, glycine and GABA slightly decreased [Ca2+]i. Calcium responses could also be elicited by stimulation of afferent fibres from the MNTB, and these synaptic responses were mediated by glycine and GABAA receptors. Furthermore, GABA, which is a neurotransmitter only in the immature MNTB–LSO pathway, played a major role in generating MNTB‐elicited Ca2+ responses. The direct link of glycinergic/GABAergic synaptic activity to intracellular calcium signalling during the period of inhibitory synaptic plasticity could be one of the mechanisms by which tonotopic MNTB–LSO connections become established.
Seizure‐dependent modulation of mitochondrial oxidative phosphorylation in rat hippocampus
Authors: Kudin Alexei P. , Kudina Tatiana A. , Seyfried Jan , Vielhaber Stefan , Beck Heinz , Elger Christian E. , Kunz Wolfram S.
Published: March 2003

Mitochondrial function is a key determinant of both excitability and viability of neurons. Here, we demonstrate seizure‐dependent changes in mitochondrial oxidative phosphorylation in the epileptic rat hippocampus. The intense pathological neuronal activity in pilocarpine‐treated rats exhibiting spontaneous seizures resulted in a selective decline of the activities of NADH–CoQ oxidoreductase (complex I of the respiratory chain) and cytochrome c oxidase (complex IV of respiratory chain) in the CA3 and CA1 hippocampal pyramidal subfields. In line with these findings, high‐resolution respirometry revealed an increased flux control of complex I on respiration in the CA1 and CA3 subfields and decreased maximal respiration rates in the more severely affected CA3 subfield. Imaging of mitochondrial membrane potential using rhodamine 123 showed a lowered mitochondrial membrane potential in both pyramidal subfields. In contrast to the CA1 and CA3 subfields, mitochondrial oxidative phosphorylation was unaltered in the dentate gyrus and the parahippocampal gyrus. The changes of oxidative phosphorylation in the epileptic rat hippocampus cannot be attributed to oxidative enzyme modifications but are very likely related to a decrease in mitochondrial DNA copy number as shown in the more severely affected CA3 subfield and in cultured PC12 cells partially depleted of mitochondrial DNA. Thus, our results demonstrate that seizure activity downregulates the expression of mitochondrial‐encoded enzymes of oxidative phosphorylation. This mechanism could be invoked during diverse forms of pathological neuronal activity and could severely affect both excitability and viability of hippocampal pyramidal neurons.
The role of hippocampal dopamine receptors in prepulse inhibition
Authors: Ellenbroek Bart A. , Lubbers Luuk J. , Cools Alexander R.
Published: March 2003

Although it has long been realized that the hippocampal formation receives a projection from the midbrain dopaminergic cell groups and contains mRNA for all five dopamine receptors, the functional role of this dopaminergic projection has not been studied so far. The present study aimed to investigate the role of dopamine receptors in the dorsal CA1 area of the hippocampus in prepulse inhibition. The results show that local application of amphetamine reduced prepulse inhibition without affecting the baseline startle amplitude. This effect of amphetamine could be reversed by coadministration of the D1 antagonist SCH23390. Moreover, local application of the D1 agonist SKF81297 also disrupted prepulse inhibition without altering basal startle amplitude. These data clearly suggest that the hippocampal D1 receptor plays an important role in prepulse inhibition. The effects of amphetamine could not be reversed by coadministration of the D2 antagonist sulpiride. Interestingly, the D2/3 agonist quinpirole did reduce prepulse inhibition, again without affecting basal startle amplitude. Because quinpirole has a much higher affinity for the D3 receptor than does sulpiride, it is suggested that the D3 receptor might be involved in this effect.
Opposing effects of head position on sound localization in blind and sighted human subjects
Authors: Lewald Jörg
Published: March 2003

Up to now, there is an unsolved contradiction between the view that the development of an auditory spatial representation needs calibration by vision and the psychophysical demonstration of quite precise sound localization in early blind humans. The present study provides a link between these two competing conceptions. Two experiments were conducted with congenitally or early blind subjects and sighted controls. In the first experiment, subjects pointed with their head to actual sound sources located in the azimuthal plane. In the second experiment, lateralization of dichotic sound stimuli, presented via headphones, was investigated with variation of head‐to‐trunk position. The results showed opposing systematic errors of sound localization or lateralization, depending on head position, made by blind and sighted subjects. These differences suggest that audiomotor feedback replaces vision so as to calibrate auditory space in blind individuals. That is, in contrast to the widespread opinion of compensation of visual loss by a general sharpening of audition, compensatory plasticity in the blind may specifically be related to enhanced processing of proprioceptive and vestibular information with the auditory spatial input.
Intrinsic GABA neurons inhibit proenkephalin gene expression in slice cultures of rat neostriatum
Authors: Mörl Franz , Gröschel Michael , Leemhuis Jost , Meyer Dieter K.
Published: March 2003

In the neostriatum, the proenkephalin gene is expressed in medium spiny GABA neurons, which project to the globus pallidus. The expression is activated by glutamatergic projections from the neocortex via NMDA receptors. In these experiments we have used slice cultures of rat neostriatum to study the role of GABA in proenkephalin gene expression. Our results show that GABA is released from neostriatal neurons and negatively regulates the proenkephalin gene expression induced by NMDA receptor stimulation. The GABAA receptors involved seem to be colocalized with NMDA receptors on the projection neurons, which express the proenkephalin gene. In further experiments, we have found that the proenkephalin gene expression is not only activated by neocortical projection neurons but also by intrinsic striatal neurons as well as by projections from the thalamus. All these glutamatergic afferents enhance the proenkephalin gene expression via NMDA receptors. Their efficacy is regulated by endogenous GABA.
The histaminergic system in human thalamus: correlation of innervation to receptor expression
Authors: Jin C. Y. , Kalimo H. , Panula P.
Published: March 2003

The mRNA expression of three histamine receptors (H1, H2 and H3) and H1 and H3 receptor binding were mapped and quantified in normal human thalamus by in situ hybridization and receptor binding autoradiography, respectively. Immunohistochemistry was applied to study the distribution of histaminergic fibres and terminals in the normal human thalamus. mRNAs for all three histamine receptors were detected mainly in the dorsal thalamus, but the expression intensities were different. Briefly, H1 and H3 receptor mRNAs were relatively enriched in the anterior, medial, and part of the lateral nuclei regions; whereas the expression level was much lower in the ventral and posterior parts of the thalamus, and the reticular nucleus. H2 receptor mRNA displayed in general very low expression intensity with slightly higher expression level in the anterior and lateropolar regions. H1 receptor binding was mainly detected in the mediodorsal, ventroposterolateral nuclei, and the pulvinar. H3 receptor binding was detected mainly in the dorsal thalamus, predominantly the periventricular, mediodorsal, and posterior regions. Very high or high histaminergic fibre densities were observed in the midline nuclear region and other nuclei next to the third ventricle, ventroposterior lateral nucleus and medial geniculate nucleus. In most of the core structures of the thalamus, the fibre density was very low or absent. The results suggest that histamine in human brain regulates tactile and proprioceptory thalamocortical functions through multiple receptors. Also, other, e.g. visual areas and those not making cortical connections expressed histamine receptors and contained histaminergic nerve fibres.
Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal‐based model of schizophrenia
Authors: Ballmaier Martina , Zoli Michele , Leo Giuseppina , Agnati Luigi Francesco , Spano PierFranco
Published: March 2003

Based on a number of neuroanatomical and behavioural similarities, recent evidence suggests that heterozygous reeler mice, haploinsufficient for reelin expression, represent a useful model of psychosis vulnerability. As brain mesolimbic dopamine pathways have been proposed to be associated with the pathophysiology of psychotic disorders, we thought it would be of interest to examine whether these animals present disturbances in the mesolimbic dopamine system. To this end we studied by immunocytochemical, in situ hybridization procedures and receptor autoradiography, several markers of the mesotelencephalic dopamine pathway in heterozygous reeler mice and controls. We report that heterozygous reeler mice exhibit a reduction in the number of tyrosine hydroxylase‐immunoreactive cell bodies and tyrosine hydroxylase mRNA levels in the ventral tegmental area, as well as a reduction of tyrosine hydroxylase and dopamine transporter immunoreactivity in the dopamine terminal fields of the limbic striatum. In these areas we also observed a reduction of dopamine D2 receptor mRNA. Finally, a marked increase in D3 receptor mRNA levels was observed concomitant with a significant increase in D3 binding sites. On the contrary, the nigrostriatal pathway did not show any significant alteration in heterozygous reeler mice with regards to the dopaminergic markers examined in substantia nigra cell bodies and dorsal striatum dopamine terminal fields. These results suggest a specific link between reelin‐related neuronal pathology and dopamine involvement in the pathophysiology of psychotic disorders.
Developmental expression of the cellular prion protein in elongating axons
Authors: Salès Nicole , Hässig Raymonde , Rodolfo Katia , Di Giamberardino Luigi , Traiffort Elisabeth , Ruat Martial , Frétier Philippe , Moya Kenneth L.
Published: March 2003

PrPc, a sialoglycoprotein present in the normal adult hamster brain, is particularly abundant in plastic brain regions but little is known about the level of expression and the localization of the protein during development. Western blot analysis of whole brain homogenates with mab3F4 show very low levels of the three main molecular weight forms of the protein at birth, in contrast to the strong and wide expression of mRNA transcripts. The PrPc levels increase sharply through P14 and are diminished somewhat in the adult. Regional analysis showed that in structures with ongoing growth or plasticity such as the olfactory bulb and hippocampus, PrPc remains high in the adult, while in areas where structural and functional relationships stabilize during development, such as the cortex and the thalamus, PrPc levels decline after the third postnatal week. In the neonate brain PrPc was prominent along fiber tracts similar to markers of axon elongation and in vitro experiments showed that the protein was present on the surface of elongating axons. PrPc is then localized to the synaptic neuropil in close spatio‐temporal association with synapse formation. The localization of PrPc on elongating axons suggests a role for the protein in axon growth. In addition, the relative abundance of the protein in developing axon pathways and during synaptogenesis may provide a basis for the age‐dependent susceptibility to transmissible spongiform encephalopathies.
Whole‐cell recording from honeybee olfactory receptor neurons: ionic currents, membrane excitability and odourant response in developing workerbee and drone
Authors: Laurent Stéphanie , Masson Claudine , Jakob Ingrid
Published: March 2003

Whole‐cell recording techniques were used to characterize ionic membrane currents and odourant responses in honeybee olfactory receptor neurons (ORNs) in primary cell culture. ORNs of workerbee (female) and drone (male) were isolated at an early stage of development before sensory axons connect to their target in the antennal lobe. The results collectively indicate that honeybee ORNs have electrical properties similar, but not necessarily identical to, those currently envisaged for ORNs of other species. Under voltage clamp at least four ionic currents could be distinguished. Inward currents were made of a fast transient, tetrodotoxin‐sensitive sodium current. In some ORNs a cadmium‐sensitive calcium current was detected. ORNs showed heterogeneity in their outward currents: either outward currents were made of a delayed rectifier type potassium current, which was partially blocked by tetraethyl ammonium or quinidine, or were composed of a delayed rectifier type and a transient calcium‐dependent potassium current, which was cadmium‐sensitive and abolished by removal of external calcium. The proportion of each of the two outward currents, however, was different within the ORNs of the two sexes suggesting a gender‐specific functional heterogeneity. ORNs showed heterogeneity in action potential firing properties: depolarizing current steps elicited either one action potential or, as in most of the cells, it led to repetitive spiking. Action potentials were tetrodotoxin‐sensitive suggesting they are carried by sodium. Odourant stimulation with different mixtures and pure substances evoked depolarizing receptor potentials with superimposed action potentials when spike threshold was reached. In summary, honeybee ORNs are remarkably mature at early stages in their development.
Gradients in the circadian expression of Per1 and Per2 genes in the rat suprachiasmatic nucleus
Authors: Yan Lily , Okamura Hitoshi
Published: March 2003

The suprachiasmatic nucleus (SCN) is the mammalian circadian pacemaker, which consists of thousands of oscillator cells. It is believed that the circadian oscillation in each cell is generated by the transcription/(post)‐translation feedback loop of a set of clock genes. However, little is known about how these oscillator cells are organized to produce the robust circadian rhythms in the SCN. In the present study, we examined the expression of the clock genes Per1 and Per2 paying particular attention to the topographic compartmentalization of the SCN. In the rat SCN, the dorsomedial (SCNDM) and ventrolateral (SCNVL) compartments are clearly delineated by chemical characteristics of neurons and neuronal afferents. In the SCNDM, Per1 mRNA was initially expressed at the most dorsomedial region along the third ventricle (SCNDMPV, periventricular part of the dorsomedial compartment of the SCN) at CT0, and then spread laterally to the central dorsomedial region (SCNDMCe, central part of the dorsomedial compartment of the SCN), reaching peaks at subjective day and troughs at subjective night. In contrast, in the SCNVL, Per1 expression showed a weak, two‐peak pattern in one circadian cycle. Per2 expression was also robust in the SCN, showing very similar circadian profiles among these three subdivisions with a slightly earlier phase in SCNDMPV than that in SCNDMCe. We also investigated the Per1 and Per2 expression in response to a light exposure at early subjective night. The light pulse induced both Per1 and Per2 expression, which was restricted in the SCNVL neurons. The present findings suggest that the phase and amplitude of the circadian expression of clock genes are not uniform, and there are topographic neuron groups that have different properties in the SCN.
Excitotoxic lesions of the rhinal cortex in the baboon differentially affect visual recognition memory, habit memory and spatial executive functions
Authors: Chavoix C. , Blaizot X. , Meguro K. , Landeau B. , Baron J.C.
Published: March 2003

To specify the functional role of the rhinal cortex, baboons with bilateral excitotoxic lesions of the rhinal cortex (RH group) were tested on a series of computerized memory and learning tasks. Preoperatively, they were trained to and then tested on a delayed nonmatching‐to‐sample (DNMS) task with trial‐unique stimuli. Postoperatively, this visual recognition memory task was given twice. As compared to a sham‐operated group, the RH group showed good retention of rule learning and were unimpaired on the Delay memory subtest. Performance on the List Length memory subtest was, however, severely impaired at both postoperative evaluations, with a significant negative correlation between cognitive performance and neuronal loss in rhinal areas. Visual habit memory and spatial working memory were assessed postoperatively only, using a concurrent discrimination learning task and both a delayed‐response task (with a two‐ and four‐location choice) and a delayed alternation task, respectively. The RH group was unimpaired on the first two tasks and was even faster than the controls in learning the delayed‐response task with four locations. Finally, most RH baboons failed to learn the delayed alternation task within the limits of testing. These results indicate that neuronal loss in the rhinal cortex is sufficient to impair visual recognition memory, and extend the implication of this area to spatial executive functions. Furthermore, the observation of impaired recognition memory and executive processes with preserved procedural memory and retrograde memory suggests that damage to the rhinal cortex probably participates in the cognitive deficits typical of the early stages of Alzheimer's disease.
Age‐related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour
Authors: Maccarrone Mauro , Valverde Olga , Barbaccia Maria L. , Castañé Anna , Maldonado Rafael , Ledent Catherine , Parmentier Marc , Finazzi‐Agrò Alessandro
Published: March 2003

Anandamide (N‐arachidonoylethanolamine, AEA) and 2‐arachidonoylglycerol (2‐AG) are the most active endocannabinoids at brain (CB1) cannabinoid receptors. CD1 mice lacking the CB1 receptors (‘knockout’[KO] mutants) were compared with wildtype (WT) littermates for their ability to degrade AEA through an AEA membrane transporter (AMT) and an AEA hydrolase (fatty acid amide hydrolase, FAAH). The age dependence of AMT and FAAH activity were investigated in 1‐ or 4‐month‐old WT and KO animals, and found to increase with age in KO, but not WT, mice and to be higher in the hippocampus than in the cortex of all animals. AEA and 2‐AG were detected in nmol/mg protein (µm) concentrations in both regions, though the hippocampus showed approximately twice the amount found in the cortex. In the same regions, 2‐AG failed to change across groups, while AEA was significantly decreased (≈ 30%) in hippocampus, but not in cortex, of old KO mice, when compared with young KO or age‐matched WT animals. In the open‐field test under bright light and in the lit‐dark exploration model of anxiety, young KO mice, compared with old KO, exhibited a mild anxiety‐related behaviour. In contrast, neither the increase in memory performance assessed by the object recognition test, nor the reduction of morphine withdrawal symptoms, showed age dependence in CB1 KO mice. These results suggest that invalidation of the CB1 receptor gene is associated with age‐dependent adaptive changes of endocannabinoid metabolism which appear to correlate with the waning of the anxiety‐like behaviour exhibited by young CB1 KO mice.