bluuebunny/crossref_metadata_2025_split huggingface dataset:
A combined pharmacological and genetic approach to investigate the role of orphanin FQ in learning and memory
Authors: Higgins G. A. , Kew J. N. C. , Richards J. G. , Takeshima H. , Jenck F. , Adam G. , Wichmann J. , Kemp J. A. , Grottick A. J. 
Published: March 2003

AbstractUsing a combination of the selective opioid receptor‐like1 (ORL1) receptor agonist, Ro 64‐6198, and orphanin FQ/nociceptin (OFQ/N) peptide knockout (KO) mice, the influence of OFQ/N on cognition has been studied in the rodent. In wild type, C57BL/6J mice, Ro 64‐6198 (0.3–1 mg/kg i.p.) impaired the acquisition of spatial learning in the Morris water maze, although a mild neurological impairment was evident which complicated precise interpretation. In Lister hooded rats, Ro 64‐6198 (6 mg/kg i.p.) produced delay dependent impairments in rats performing either a delayed matching or a delayed nonmatching to position task with only a modest (< 20%) effect on omissions – an effect consistent with a short‐term memory impairment. Electrophysiological studies demonstrated an inhibitory effect of OFQ/N on LTP recorded from the CA1 region of wild type mice, but not in ORL1 receptor knockout mice. In contrast to the ORL1 agonist, mice deficient in the OFQ/N peptide showed some evidence of improved spatial learning, fear conditioning and passive avoidance retention. However, CA1 LTP was similar between OFQ/N peptide KO mice and wild type controls. Subsequent receptor radioautography studies demonstrated the presence of ORL1 receptors within various regions of the medial temporal lobe system: i.e. CA1, dentate gyrus molecular layer, subiculum, perirhinal cortex. Taken together, these results suggest a bi‐directional effect of OFQ/N containing systems on aspects of cognitive behaviour, particularly those elements associated with hippocampal function. This is consistent with a likely modulatory role of OFQ/N on hippocampal and associated cortical circuitry.
Inhibition of spinal or hypoglossal motoneurons of the newborn rat by glycine or GABA
Authors: Marchetti Cristina , Pagnotta Sara , Donato Roberta , Nistri Andrea 
Published: March 2003

AbstractThe function of GABA or glycine during early postnatal development remains controversial as their action is reported as either excitatory or inhibitory. The present study addressed the question of the functional role of GABA or glycine on rat motoneurons shortly after birth. For this purpose, using in vitro preparations from immature rats (postnatal age, P0‐P4 days), we recorded from lumbar spinal motoneurons and hypoglossal motoneurons. All data were obtained under current clamp conditions (recording with potassium methylsulphate containing electrodes) from cells at about −70 mV resting potential. On spinal motoneurons we used the glycinergic and GABAergic recurrent postsysnaptic potential (PSP) mediated by Renshaw cells to assess its impact on excitatory synaptic inputs from dorsal afferent fibres. Despite its depolarizing nature, the recurrent PSP consistently inhibited synaptic excitation of lumbar motoneurons. On hypoglossal motoneurons, exogenously applied GABA or glycine produced depolarization with decreased input resistance. This response was always associated with inhibition of cell firing induced by intracellular current pulses. Even when the membrane potential was repolarized to resting level in the presence of GABA or glycine, hypoglossal motoneurons failed to generate spikes. Conversely, similar depolarization produced by glutamate consistently facilitated spike firing. GABAergic and glycinergic synaptic potentials evoked by focal stimulation of the reticular formation inhibited firing and/or increased firing latency in the majority of hypoglossal motoneurons. These results indicate that, immediately after birth, rat motoneurons were inhibited by synaptically released or exogenously applied GABA or glycine.
Circadian tryptophan hydroxylase levels and serotonin release in the suprachiasmatic nucleus of the rat
Authors: Barassin Stéphane , Raison Sylvie , Saboureau Michel , Bienvenu Christèle , Maître Michel , Malan André , Pévet Paul 
Published: March 2003

AbstractSerotonin (5‐HT) plays an important role in the regulation of the time‐keeping system in rodents. In the present study, we have investigated the interplay between the rhythms of 5‐HT synthesis and release in the suprachiasmatic nuclei (SCN) of the rat. The quantitative distribution of tryptophan hydroxylase (TpH) protein was used as an index of 5‐HT synthesis, in perikarya and terminals areas. In the raphe medianus, the maximal levels of TpH was reached in the early daytime period, followed by a decrease before the onset of darkness. Conversely, in the axon terminals of the SCN the highest levels of TpH were found before the onset of the dark‐period. Furthermore, TpH amount in SCN displays variations depending on the anatomical area of the SCN. Extracellular 5‐HT peaked at the beginning of the night, as evidenced byin vivomicrodialysis in the SCN. The 5‐HT metabolite, 5‐HIAA, presented a similar pattern, but the acrophase occurred in the middle of the dark period. These results suggest that TpH is transported from the soma to the nerve terminals in which 5‐HT is synthesized during daytime. This would fill the intracellular stores of 5‐HT to provide for its nocturnal release.
Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation
Authors: Ohno‐Shosaku Takako , Shosaku Jumpei , Tsubokawa Hiroshi , Kano Masanobu 
Published: March 2003

AbstractEndocannabinoids are retrograde messengers that are released from central neurons by depolarization‐induced elevation of intracellular Ca2+ concentration [Ca2+]I or by activation of a group I metabotropic glutamate receptor (mGluR). We studied the interaction between these two pathways for endocannabinoid production in rat hippocampal neurons. We made a paired whole‐cell recording from cultured hippocampal neurons with inhibitory synaptic connections. Activation of group I mGluRs, mainly mGluR5, by the specific agonist (RS)‐3,5‐dihydroxyphenylglycine (DHPG), suppressed inhibitory postsynaptic currents (IPSCs) in about half of the neuron pairs. A cannabinoid agonist, WIN55,212–2, suppressed IPSCs in all DHPG‐sensitive pairs but not in most of DHPG‐insensitive pairs. The effects of both DHPG and WIN55,212–2 were abolished by the cannabinoid antagonists, AM281 and SR141716A, indicating that activation of group I mGluR releases endocannabinoids and suppress inhibitory neurotransmitter release through activation of presynaptic cannabinoid receptors. Depolarization of the postsynaptic neurons caused a transient suppression of IPSCs, a phemomenon termed depolarization‐induced suppression of inhibition (DSI) that was also abolished by cannabinoid antagonists. Importantly, DSI was enhanced significantly when group I mGluRs were activated simultaneously by DHPG. This enhancement was much more prominent than expected from the simple summation of depolarization‐induced and group I mGluR‐induced endocannabinoid release. DHPG caused no change in depolarization‐induced Ca2+ transients, indicating that the enhanced DSI by DHPG was not due to the augmentation of Ca2+ influx. Enhancement of DSI by DHPG was also observed in hippocampal slices. These results suggest that two pathways work in a cooperative manner to release endocannabinoids via a common intracellular cascade.
Dynamics of nitric oxide during simulated ischaemia‐reperfusion in rat striatal slices measured using an intrinsic biosensor, soluble guanylyl cyclase
Authors: Griffiths Charmaine , Garthwaite Giti , Goodwin David A. , Garthwaite John 
Published: March 2003

AbstractNitric oxide (NO) may act as a toxin in several neuropathologies, including the brain damage resulting from cerebral ischaemia. Rat striatal slices were used to determine the mechanism of enhanced NO release following simulated ischaemia and, for estimating the NO concentrations, the activity of guanylyl cyclase served as a biosensor. Exposure of the slices for 10 min to an oxygen‐ and glucose‐free medium caused a 70% fall in cGMP levels. On recovery, cGMP increased 2‐fold above basal, where it remained for 40 min before declining. The pattern of changes matched those of cGMP or NO oxidation products measured during and after brain ischaemia in vivo. The increase observed during the recovery period was blocked by inhibition of NO synthase or NMDA receptors and was curtailed by tetrodotoxin, implying that it was caused by glutamate release leading to activation of the NMDA receptor‐NO synthase pathway. Calibration of the cGMP levels against NO‐stimulated guanylyl cyclase yielded a basal NO concentration of 0.6 nm. The peak NO concentration achieved on recovery from simulated ischaemia was estimated as 0.8 nm. These values are compatible with the low micromolar concentrations of NO oxidation products (chiefly nitrate) found by microdialysis in vivo, providing the NO inactivation rate (forming nitrate) is accounted for. NO at a concentration around 1 nm is unlikely to be toxic to cells. However, if the NO inactivation mechanism were to fail (as it can) the NO production rate normally providing only subnanomolar NO could readily generate toxic (µM) NO concentrations.
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

AbstractHeat 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

AbstractThe 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

AbstractNeurons 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

AbstractThe 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

AbstractThe 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

AbstractSystemic 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

AbstractDeficits 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

AbstractWe 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.