bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired spatial and sequential learning in rats treated neonatally with d‐fenfluramine
Authors: Morford L. L. , Inman‐Wood S. L. , Gudelsky G. A. , Williams M. T. , Vorhees C. V.
Published: March 2003

d‐Fenfluramine, a serotonin releaser, was administered to neonatal rats on postnatal days 11–20 (a stage of hippocampal development analogous to third trimester human ontogeny). As adults, the d‐fenfluramine‐treated offspring exhibited dose‐related impairments of sequential and spatial learning and reference memory in the absence of sensorimotor impairments. Procedures to minimize stress and to control for other performance effects prior to testing for spatial learning demonstrated that nonspecific factors did not account for the selective effects of d‐fenfluramine on learning and memory. Developmental d‐fenfluramine‐induced spatial and sequential learning deficits are similar to previous findings with developmental MDMA treatment. By contrast, recent findings with developmental d‐methamphetamine treatment showed spatial learning deficits while sparing sequential learning. The spatial learning effects common to all three drugs suggest that they may share a common mechanism of action, however, the effects are not related to long‐lasting changes in hippocampal 5‐HT levels as no differences were found in adulthood. Whether the cognitive deficits are related to the effects of substituted amphetamines on corticosteroids, other aspects of the 5‐HT system, or some unidentified neuronal substrates is not known, but the data demonstrate that these drugs are all capable of inducing long‐term adverse effects on learning.
Vasopressin from hypothalamic magnocellular neurons has opposite actions at the adenohypophysis and in the supraoptic nucleus on ACTH secretion
Authors: Wotjak Carsten T. , Ludwig Mike , Ebner Karl , Russell John A. , Singewald Nicolas , Landgraf Rainer , Engelmann Mario
Published: March 2003

Magnocellular vasopressinergic and oxytocinergic neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei comprise the hypothalamic–neurohypophysial system, which is crucially involved in the regulation of body fluid and electrolyte homeostasis. However, still controversial is to what extent the same system influences the secretion of adrenocorticotropic hormone (ACTH) from the adenohypophysis. Therefore, we selectively stimulated magnocellular neurons of the SON of conscious male Wistar rats via retrodialysis. As expected, dialysis of the SON with hypertonic medium increased both the release of vasopressin within the SON and the secretion of vasopressin and oxytocin into the systemic blood circulation. This activation of the hypothalamic–neurohypophysial system was accompanied by a fivefold increase in plasma ACTH concentration. This effect was observed only if the tip of the microdialysis probe was within the SON. Intravenous infusion of the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP significantly attenuated the effects of local osmotic stimulation of the SON on ACTH secretion. In contrast, administration of the same antagonist directly into the SON significantly enhanced the osmotically stimulated secretion of ACTH and corticosterone, primarily by delaying the restoration of the hormone secretion to prestimulation levels. We conclude from these findings that vasopressin from the hypothalamic–neurohypophysial system participates in the regulation of the hormonal stress response in a counterbalanced manner at the level of the SON and the adenohypophysis.
Spatial and temporal variation of passer Per2 gene expression in two distinct cell groups of the suprachiasmatic hypothalamus in the house sparrow (Passer domesticus)
Authors: Abraham Ute , Albrecht Urs , Gwinner Eberhard , Brandstätter Roland
Published: March 2003

In mammals, the major pacemaker controlling circadian rhythmicity is located in the hypothalamic suprachiasmatic nuclei. Although there is evidence for the presence of a hypothalamic circadian oscillator in birds from lesioning studies, neuroanatomical, neurochemical and functional investigations have failed to identify its exact location. Two cell groups in the avian hypothalamus have been shown to bear characteristics of the mammalian suprachiasmatic nucleus: the suprachiasmatic nucleus and the lateral hypothalamic retinorecipient nucleus. We cloned an avian period homologue (pPer2) and investigated the temporal and spatial expression pattern of this gene in the house sparrow hypothalamus using in situ hybridization. Applying quantitative morphometry, we found rhythmic expression of pPer2 during light–dark as well as in constant conditions in the suprachiasmatic nucleus and in the lateral hypothalamus. The temporal and spatial distribution of pPer2 expression in the suprachiasmatic nucleus suggest a longitudinal compartmentalization of the nucleus with period gene expression being initiated in the most rostral portion of the suprachiasmatic nucleus before lights on. In the lateral hypothalamus, phasing of pPer2‐rhythmicity appeared different from the suprachiasmatic nucleus. The major difference between light–dark and constant conditions was a decrease in the amplitude of pPer2 rhythmicity in the suprachiasmatic nucleus. Our data demonstrate that, unlike in mammals, Per gene expression in the suprachiasmatic hypothalamus of the house sparrow is not confined to a single cell group, indicating a more complex organization of the circadian oscillator in the hypothalamus of birds.
Memory impairment following status epilepticus in immature rats: time‐course and environmental effects
Authors: Rutten Annemarieke , Van Albada Mirjam , Silveira Diosely C. , Cha Byung Ho , Liu Xianzeng , Hu Yingchu N. , Cilio Maria Roberta , Holmes Gregory L.
Published: March 2003

Status epilepticus (SE) has a high mortality and morbidity rate in children. Disturbances in learning and memory are frequently associated with SE although it is not clear when the cognitive deficits occur. If cognitive dysfunction occurs immediately following the seizure, the window of opportunity for therapeutic intervention is limited. The first goal of this study was to determine the timing of cognitive dysfunction following SE in weanling rats. As there is evidence that enriching the environment can improve cognitive and motor deficits following brain injury, our second goal was to determine whether environmental enrichment improves cognitive function following SE. Rats underwent lithium‐pilocarpine‐induced SE at postnatal (P) day 20 and were then tested for visual‐spatial memory in the water maze at P22, P25, P30, or P50. Rats with SE performed significantly worse in the water maze than control rats at all time points. Once the time‐courses of visual‐spatial memory deficits were determined, a second group of P20 rats were subjected to SE and were then placed in an enriched environment (enriched group) or remained in standard cages in the vivarium (nonenriched group) for 28 days. Following environmental manipulation, the animals were tested in the water maze. Rats housed in an enriched environment following the SE performed substantially better in the water maze than rats housed in standard cages. However, no differences were found between the enriched and nonenriched groups in EEG or histological evaluation. Although SE results in cognitive impairment within days of the seizure, housing in an enriched environment after SE has a beneficial effect on cognitive performance in rats.
Intravenous cocaine induced‐activity and behavioural sensitization in norepinephrine‐, but not dopamine‐transporter knockout mice
Authors: Mead Andy N. , Rocha Beatriz A. , Donovan David M. , Katz Jonathan L.
Published: March 2003

Previously, it was reported that both norepinephrine transporter (NET) and dopamine transporter (DAT) knockout (KO) mice were sensitive to the reinforcing effects of cocaine. However, assessing the locomotor‐stimulant effects of cocaine in these subjects has proven difficult due to significant differences in their baseline activity compared to wild‐type controls. The present studies were designed to clarify the role of NET and DAT in the stimulant effects of acute and repeated cocaine utilizing these knockout mice, and thereby assess the role of these substrates in the locomotor stimulant effects of cocaine. Mice were habituated to the test environment for sufficient time to ensure equal baselines at the time of cocaine administration. Mice then received cocaine (3–25 mg/kg) intravenously according to a within‐session cumulative dose–response design. Cocaine dosing was repeated at 48‐h intervals for four sessions to assess behavioural sensitization. NET‐KO mice exhibited a reduced response to acute cocaine administration compared to wild‐type (WT) controls. However, comparable sensitization developed in NET‐KO and WT mice. The DAT‐KO and DAT‐heterozygote (HT) mice displayed no locomotor activation following either acute or repeated cocaine administration. These data suggest a role for the NET in the acute response to cocaine, but no involvement in sensitization to cocaine. In contrast, DAT appears to be necessary for both the acute locomotor response to cocaine and the subsequent development of sensitization. In addition to existing data concerning the reinforcing effects of cocaine in DAT‐KO mice, these data suggest a dissociation between the reinforcing and locomotor stimulant effects of cocaine.
Genes controlling hypothalamic development and sexual differentiation*
Authors: Tobet Stuart A.
Published: March 2003

Steroid hormones dramatically influence the development of numerous sites in the nervous system. Basic mechanisms in neural development provide foci for understanding how factors related to sex can alter the ontogeny of these regions. Sex differences in neurogenesis, cell migration, cell differentiation, cell death, and synaptogenesis are being addressed. Any and all of these events serve as likely targets for genetic or gonadal steroid‐dependent mechanisms throughout development. Although the majority of sexually dimorphic characteristics in brain have been described in older animals, many hormonal mechanisms that determine sexually differentiated brain characteristics occur during critical perinatal periods. Genes suggested to contribute to the development of specific hypothalamic nuclear groups have rarely been examined in the context of sex. The identification of sex differences in the expression of some of these genes may suggest early and likely transient molecular events that set the stage for later amplification by hormone actions. Sex differences in the positioning of cells in the developing hypothalamus further suggest that cell migration may be one key target for early gene actions that impact long‐term susceptibility to brain sexual differentiation.
Tissue plasminogen activator is required for corticostriatal long‐term potentiation
Authors: Centonze Diego , Napolitano Maddalena , Saulle Emilia , Gubellini Paolo , Picconi Barbara , Martorana Alessandro , Pisani Antonio , Gulino Alberto , Bernardi Giorgio , Calabresi Paolo
Published: March 2003

Several experimental data indicate that tissue plasminogen activator (tPA) is involved in memory formation and synaptic plasticity in different brain areas. In the attempt to highlight the role of this serine protease in striatal neuron activity, mice lacking tPA have been used for electrophysiological, immunohistochemical and Western blot experiments. Disruption of tPA gene prevented corticostriatal long‐term potentiation, an NMDA‐dependent form of synaptic plasticity requiring the stimulation of both dopamine and acetylcholine receptors. Spontaneous and evoked glutamatergic transmission was intact in the striatum of tPA‐deficient mice, as was the nigrostriatal dopamine innervation and the expression of dopamine D1 receptors. Conversely, the sensitivity of striatal cholinergic interneurons to dopamine D1 receptor stimulation was lost in these mutants, suggesting that tPA facilitates long‐term potentiation (LTP) induction in the striatum by favouring the D1 receptor‐mediated excitation of acetylcholine‐producing interneurons. The demonstration that tPA ablation interferes with the induction of corticostriatal LTP and with the dopamine receptor‐mediated control of cholinergic interneurons might help to explain the altered striatum‐dependent learning deficits observed in tPA‐deficient mice and provides new insights into the molecular mechanisms underlying synaptic plasticity in the striatum.
Serotonin differentially modulates the electrical properties of different subsets of taste receptor cells in bullfrog
Authors: Imendra Kotapola G. , Miyamoto Takenori , Okada Yukio , Toda Kazuo
Published: March 2003

Serotonin (5‐hydroxytryptamin, 5‐HT) is localized in taste bud cells of vertebrates. Effects of the external application of 5‐HT on the membrane currents of frog taste receptor cells (TRCs) were investigated using patch‐clamp technique in whole‐cell configuration. The 5‐HT (0.1–1 µm) and 5‐HT1A receptor agonist (+/–)‐8‐OH‐2‐(D1‐n‐propyl‐amino)tetralin (8‐OH‐DPAT) (1–20 µm) inhibited both voltage‐gated sodium current (INa) and voltage‐gated potassium current (IK) in 50% of TRCs, but potentiated IK without any significant effect on INa in another subset of 18% of TRCs. Voltage‐gated currents in the residual TRCs were not affected by 5‐HT or 8‐OH‐DPAT. External application of 10 µm forskolin and 300 µm 8‐cpt cAMP [8‐(4‐chlorophenylthio)adenosine 3′:5′‐cyclic monophosphate] mimicked the inhibitory effect of 5‐HT and 8‐OH‐DPAT on IK and INa while internal dialysis with 50 µm protein kinase A inhibitor prevented the 5‐HT‐mediated inhibitory effects on IK and INa in TRCs. Internal dialysis of TRCs with high Ca2+‐pipette solution (1 µm) increased the IK in 58% of TRCs. The 5‐HT reversibly increased the [Ca2+]i in 17% of TRCs when measured by Ca2+‐imaging using a Ca2+‐sensitive dye (fura‐2 AM). These results suggest that 5‐HT differentially modulates the voltage‐gated membrane currents in different subsets of TRCs.
Differential and long‐lasting alterations of high‐voltage activated calcium currents in CA1 and dentate granule neurons after status epilepticus
Authors: Gorter Jan A. , Borgdorff Aren J. , Van Vliet Erwin A. , Da Silva Fernando H. Lopes , Wadman Wytse J.
Published: March 2003

The effects on high‐voltage activated (HVA) calcium currents were examined in hippocampal CA1 cells and dentate gyrus (DG) granule neurons, 2 days (short‐term; ST) and 2–3 months (long‐term; LT) after electrically induced, limbic electrographic and behavioural seizures in rats. Whole‐cell voltage‐clamp recordings in dissociated CA1 neurons of LT rats showed a decrease in the sustained HVA calcium current amplitude and a faster inactivation of the current both in rats that had experienced a status epilepticus (post‐SE rats) and those in which the stimulation did not lead to SE (non‐SE rats). In CA1 neurons of LT–SE rats this resulted in a reduced Ca2+ entry through the HVA channels. Perforated‐patch voltage‐clamp recordings in dissociated DG granule neurons of LT–SE rats showed an increased sustained HVA current amplitude compared to controls and non‐SE rats, leading to an increased Ca2+ entry via HVA calcium channels. Two days after SE, we observed an increased Ca2+ entry for a defined depolarization, although the change in HVA current amplitude and inactivation rate did not reach significance. We also observed a decrease in calbindin‐D28k staining in DG post‐SE neurons, but this change was not associated with a change in HVA current inactivation. The opposite changes in neuronal Ca2+ entry through HVA channels in CA1 vs. DG cells depended strongly on whether rats had experienced SE and later spontaneous seizure activity. These changes are likely to contribute to regionally different effects on local network excitability.
A divergent gene family encoding candidate olfactory receptors of the moth Heliothis virescens
Authors: Krieger Jürgen , Raming Klaus , Dewer Youssef M. E. , Bette Stefanie , Conzelmann Sidonie , Breer Heinz
Published: March 2003

The antennae of moths have been an invaluable model for studying the principles of odour perception. In spite of the enormous progress in understanding olfaction on the molecular level, for the moth one of the key elements in olfactory signalling, the odourant receptors, are still elusive. We have assessed a genome database of a heliothine moth (Heliothis virescens, Noctuidae) and employed exon‐specific probes to screen an antennal cDNA library of this species. Analysis of isolated cDNA‐clones led to the discovery of a divergent gene family encoding putative seven‐transmembrane domain proteins. The notion that they may encode candidate olfactory receptors of the moth, was supported by a tissue‐specific expression; several of the subtypes were exclusively expressed in antennae. By means of double‐labelling in situ hybridization studies it was demonstrated that the receptors are indeed expressed in antennal sensory neurons; moreover, each receptor subtype appears to be expressed in a distinct population of sensory cells. The results strongly suggest that the newly discovered gene family indeed encodes olfactory receptors of moth.
Influences of the corticotropic axis and sympathetic activity on neurochemical consequences of 3,4‐methylenedioxymethamphetamine (MDMA) administration in Fischer 344 rats
Authors: Fernandez Francesca , Aguerre Sylvie , Mormède Pierre , Chaouloff Francis
Published: March 2003

The respective influences of the corticotropic axis and sympathetic activity on 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) immediate effects on body temperature and long‐term neurotoxicity, as assessed by decreases in hippocampal and striatal [3H]5‐hydroxytryptamine ([3H]5‐HT) reuptake, [3H]paroxetine binding at 5‐HT transporters (5‐HTT), and 5‐HT and 5‐hydroxyindoleacetic acid (5‐HIAA) levels, were examined in Fischer 344 rats. On each of the two injections of MDMA (5 or 10 mg/kg s.c. once a day for 2 consecutive days) body temperature rapidly increased in a dose‐dependent manner. Six days after the last injection of 10 mg/kg MDMA, [3H]5‐HT reuptake, [3H]paroxetine binding and 5‐HT and 5‐HIAA levels were decreased in the hippocampus and, to a lower extent, in striatum. Prior adrenalectomy (1 week beforehand), which weakened the immediate hyperthermic effect of MDMA, prevented the long‐term MDMA‐elicited reduction in hippocampal and striatal [3H]paroxetine binding. Supplementation of adrenalectomised Fischer 344 rats with corticosterone almost reinstated the immediate hyperthermic effect of MDMA and restored MDMA‐elicited reduction in hippocampal and striatal [3H]paroxetine binding. In a final set of experiments, Fischer 344 rats were pretreated (30 min before each of the two injections of 10 mg/kg MDMA) with the ganglionic blocker chlorisondamine (2.5 mg/kg). This pretreatment markedly reduced the amplitudes of the immediate hyperthermia and long‐term declines in hippocampal [3H]5‐HT reuptake and [3H]paroxetine binding at 5‐HTT, and in hippocampal and striatal 5‐HT and 5‐HIAA levels. These results suggest that sympathetic activity (possibly through its control of body temperature), but not corticotropic activity, plays a key role in MDMA‐elicited neurotoxicity in Fischer 344 rats.
Degeneration of pontine mossy fibres during cerebellar development in weaver mutant mice
Authors: Ozaki Miwako , Hashikawa Tsutomu , Ikeda Kazutaka , Miyakawa Yukie , Ichikawa Tomio , Ishihara Yoshihiro , Kumanishi Toshiro , Yano Ryoji
Published: March 2003

In weaver mutant mice, substitution of an amino acid residue in the pore region of GIRK2, a subtype of the G‐protein‐coupled inwardly rectifying K+ channel, changes the properties of the homomeric channel to produce a lethal depolarized state in cerebellar granule cells and dopaminergic neurons in substantia nigra. Degeneration of these types of neurons causes strong ataxia and Parkinsonian phenomena in the mutant mice, respectively. On the other hand, the mutant gene is also expressed in various other brain regions, in which the mutant may have effects on neuronal survival. Among these regions, we focused on the pontine nuclei, the origin of the pontocerebellar mossy fibres, projecting mainly into the central region of the cerebellar cortex. The results of histological analysis showed that by P9 the number of neurons in the nuclei was reduced in the mutant to about one half and by P18 to one third of those in the wild type, whereas until P7 the number were about the same in wild‐type and weaver mutant mice. Three‐dimensional reconstruction of the nuclei showed a marked reduction in volume and shape of the mutant nuclei, correlating well with the decrease in neuronal number. In addition, DiI (a lipophilic tracer dye) tracing experiments revealed retraction of pontocerebellar mossy fibres from the cerebellar cortex after P5. From these results, we conclude that projecting neurons in the pontine nuclei, as well as cerebellar granule cells and dopaminergic neurons in substantia nigra, strongly degenerate in weaver mutant mice, resulting in elimination of pontocerebellar mossy fibres during cerebellar development.
Spontaneous network activity of cerebellar granule neurons: impairment by in vivo chronic cannabinoid administration
Authors: Ghozland Sandy , Aguado Fernando , Espinosa‐Parrilla Juan F. , Soriano Eduardo , Maldonado Rafael
Published: March 2003

Synchronized activity of neuronal networks has been proposed to be essential for cerebellar function. To examine the occurrence and organization of spontaneous neuronal activity in the cerebellum in vivo, we imaged mouse cerebellar slices loaded with the intracellular Ca2+ concentration indicator, fura‐2. Recordings were then analysed statistically to identify correlated network activity. Ca2+ imaging revealed consistent spontaneous correlated network activity of granule cells (GC), which often occurred in clusters of coactivated GC. The number of spontaneously active GC, their activation frequency and correlation, were controlled by glutamate and GABA ionotropic receptors. These findings indicate that distinctive patterns of correlated activity between GC networks may be relevant for cerebellar circuit function. Cannabinoid antagonist‐precipitated Δ9‐tetrahydrocannabinol (THC) withdrawal impaired motor coordination. Given that the cerebellum has been suggested recently to be a main substrate for cannabinoid withdrawal, we used imaging of spontaneous network activity to examine whether GC, which contain CB1 cannabinoid receptors, respond to chronic THC treatment and withdrawal. Acute administration of THC had no effect on patterns of spontaneous GC network activity. In contrast, chronic THC administration severely impaired GC activity and network coordination. Incubation of cerebellar slices, from chronically THC‐treated mice, with the cannabinoid antagonist, SR141716A increased the number and network correlation of active GC. These data provide physiological evidence of the involvement of cerebellar circuits in the adaptive changes occurring during chronic THC exposure and withdrawal.
Neuronal nitric oxide synthase expression in the mouse vomeronasal organ during prenatal development
Authors: Zancanaro Carlo , Merigo Flavia , Mucignat‐Caretta Carla , Cavaggioni Andrea
Published: March 2003

The presence and distribution of immunoreactivity for nitric oxide synthase type I and a panel of regulatory neuropeptides was investigated in the vomeronasal organ (VNO) of mouse embryos. Results show that nitric oxide synthase type I is first expressed in putative extrinsic nerve fibers reaching areas of vascular development at embryonic day 16 and in the vomeronasal nerve at embryonic day 15. Immunoreactivity for vasoactive intestinal peptide appears around developing vessels of the VNO during embryonic day 18. No immunoreactivity for atrial natriuretic peptide, substance P and calcitonin gene‐related peptide is present in the VNO. It is concluded that, in the mouse, nitric oxide synthesis is a precocious event in the development of peripheral and central neural vomeronasal structures, representing a very early step in the neurochemical maturation of the VNO.
Analysis of a slow desensitized state of recombinant adult‐type nicotinic acetylcholine receptor channels
Authors: Krampfl K. , Jahn K. , Cordes A.‐L. , Dengler R. , Bufler J.
Published: March 2003

A characteristic feature of the kinetics of nicotinic acetylcholine receptor (nAChR) channels is fast and nearly complete desensitization with a time course between 10 and 100 ms and recovery from desensitization in the range of some hundred ms. In the present study we used a piezo‐driven system for ultra‐fast solution exchange, analysed the recovery from the fast desensitized state of mouse recombinant adult‐type nAChR channels and found no difference to that of embryonic‐type channels. By double pulse experiments with application of pulses with a saturating concentration of 1 mm acetylcholine (ACh) with increasing duration of the first pulse and a constant interval between pulses we detected a second slow desensitized state which was entered with a time constant of 2835 ms. Recovery from the slow desensitized state proceeded with a single exponential with a time constant of 16134 ms. The experimental data were interpreted by the addition of a transition from the desensitized state with two bound ACh molecules to a slow desensitized state to the well known circular kinetic scheme of activation and desensitization of nAChR channels. This slow desensitized state might play a role in muscle fatigue or in pathological states like myasthenic syndromes.
Comparative distribution of the mammalian mediator subunit thyroid hormone receptor‐associated protein (TRAP220) mRNA in developing and adult rodent brain
Authors: Galeeva Anastasia , Treuter Eckardt , Tuohimaa Pentti , Pelto‐Huikko Markku
Published: March 2003

TRAP220 (thyroid hormone receptor‐associated protein) is a recently cloned nuclear receptor coactivator, which interacts with several nuclear receptors in a ligand‐dependent manner and stimulates transcription by recruiting the TRAP mediator complex to hormone responsive promoter regions. TRAP220 has been shown to interact with thyroid hormone receptors, vitamin D receptors, peroxisome proliferator‐activated receptors, retinoic acid receptors and oestrogen receptors. Thyroid hormone and retinoic acid play very important roles in brain development and they also influence adult brain. Using in situ hybridization we have examined expression of TRAP220 mRNA in the central nervous system during development and in adult rat and mouse brain. Expression of TRAP220 was seen already during early embryonic development in the epithelium of neural tube at E9 in mouse and at E12 in rat. At later stages of development the strongest signal was seen in different layers of cerebral neocortex, external germinal layer of cerebellum, differentiating fields of hippocampus and neuroepithelium, and a moderate signal was detected in basal ganglia, different areas of diencephalon and midbrain. In adult rat brain the signal was more restricted than during development. TRAP220 expression occurred mostly in the granular layer of cerebellar cortex, piriform cortex and hippocampal formation. The signal was found predominantly in neurons. Our work supports the assumption that TRAP220 plays an important role in growth and differentiation of central nervous system and may have a function in certain areas of adult brain.
Migration of LHRH neurons into the spinal cord: evidence for axon‐dependent migration from the transplanted chick olfactory placode
Authors: Murakami Shizuko , Arai Yasumasa
Published: March 2003

In the chick embryo, luteinizing hormone‐releasing hormone (LHRH) neurons originate in the olfactory placode and migrate along the olfactory nerve to the forebrain. In previous studies, we demonstrated that LHRH neurons followed the trigeminal nerve when the olfactory nerve was physically interrupted. To examine whether LHRH neurons posses the capacity to migrate along the different type of axons, the olfactory placode was transplanted into the base of the forelimb. Three to five days after the transplantation, LHRH neurons were detectable in the spinal nerve, the dorsal root ganglion, the sympathetic ganglion and the spinal cord. Double or triple labelling studies for LHRH, somatostatin and/or axonin‐1 showed that LHRH neurons entered the spinal nerve in contact with the olfactory axons, which are specifically immunoreactive to somatostatin. Migrating LHRH neurons continued to associate closely with the olfactory axons in the spinal nerve. However, some LHRH neurons often migrated along with the axonin‐1 positive spinal sensory axons, maintaining a distance from the olfactory axons. Furthermore, a few LHRH neurons were observed in the ventral root and the ventral funiculus independent of olfactory axons. As LHRH neurons were observed in the motor component of the spinal nerve, it is probable that LHRH neurons also invaded the spinal cord using the motor axons as a guiding substrate for their migration. These results suggest that the migration mode of LHRH neurons is axon dependent in the peripheral region, however, chemical identity with regard to axonal substrate choice for migration was not specified in the present study.
The effect of whole‐body tilt on sound lateralization
Authors: Lewald Jörg , Karnath Hans‐Otto
Published: March 2003

The effect of passive whole‐body tilt in the frontal plane on the lateralization of dichotic sound was investigated in human subjects. Pure‐tone pulses (1 kHz, 100 ms duration) with various interaural time differences were presented via headphones while the subject was in an upright position or tilted 45° or 90° to the left or right. Subjects made two‐alternative forced‐choice (left/right) judgements on the intracranial sound image. During body tilt, the auditory median plane of the head, computed from the resulting psychometric functions, was always shifted to the upward ear, indicating a shift of the auditory percept to the downward ear, that is, in the direction of gravitational linear acceleration. The mean maximum magnitude of the auditory shift obtained with 90° body tilt was 25 µs. On the one hand, these findings suggest a certain influence of the otolith information about body position relative to the direction of gravity on the representation of auditory space. However, in partial contradiction to previous work, which had assumed existence of a significant ‘audiogravic illusion’, the very slight magnitude of the present effect rather reflects the excellent stability in the neural processing of auditory spatial cues in humans. Thus, it might be misleading to use the term ‘illusion’ for this quite marginal effect.
Metabolic signals, hormones and neuropeptides involved in control of energy balance and reproductive success in hamsters*
Authors: Schneider J. E. , Buckley C. A. , Blum R. M. , Zhou D. , Szymanski L. , Day D. E. , Bartness T. J.
Published: March 2003

In the ‘postgenome era’, most research on the neuroendocrine control of energy homeostasis has focused on hormonal and neuropeptide control of food intake (i.e. the amount of food eaten) in rats and mice. The amount of food consumed is influenced by both the motivation to procure food and the consummatory act of ingestion. In some species, the rate of food intake remains relatively constant, while survival is maintained via changes in food procurement, external storage and internal expenditure. For example, in hamsters, metabolic signals, peripheral hormones and central neuropeptides influence hunger motivation, food hoarding and changes in energy expenditure without necessarily influencing the amount of food ingested. A similar suite of metabolic signals, hormones and neuropeptides is involved in optimizing reproductive success under fluctuating energetic conditions. Reproductive processes are inhibited or delayed when energy expenditure outstrips energy intake and mobilization from storage. Estrous cyclicity in Syrian hamsters is sensitive to the availability of oxidizable glucose, but the presence of central glucose alone is not sufficient for normal estrous cycles. Food deprivation‐induced anestrus does not depend upon food deprivation‐induced increases in concentrations of adrenal hormones such as glucocorticoids. If hormones such as insulin and leptin play a role, they might do so by modulating the availability of glucose detected at extra‐hypothalamic sites, instead of or in addition to direct effects on the mechanisms that control gonadotropin releasing hormone secretion. Despite our ability to measure and manipulate gene transcription, understanding of fuel homeostasis requires examination of indirect effects of hormones and neuropeptides on peripheral metabolism, attention to the motivational as well as consummatory aspects of ingestion, and the study of behaviour in a natural or seminatural context.
Multiple maps and activity‐dependent representational plasticity in the anterior Wulst of the adult barn owl (Tyto alba)
Authors: Manger Paul R. , Elston Guy N. , Pettigrew John D.
Published: March 2003

In the present study we addressed the issue of somatosensory representation and plasticity in a nonmammalian species, the barn owl. Multiunit mapping techniques were used to examine the representation of the specialized receptor surface of the claw in the anterior Wulst. We found dual somatotopic mirror image representations of the skin surface of the contralateral claw. In addition, we examined both representations 2 weeks after denervation of the distal skin surface of a single digit. In both representations, the denervated digital representation became responsive to stimulation of the adjacent, mutually functional, digit. The mutability and multiple representations indicates that the Wulst provides the owl with sensory processing capabilities analogous to those in mammals.
Evidence that metyrapone can act as a stressor: effect on pituitary‐adrenal hormones, plasma glucose and brain c‐fos induction
Authors: Rotllant David , Ons Sheila , Carrasco Javier , Armario Antonio
Published: March 2003

Metyrapone, a 11‐β steroid hydroxylase inhibitor that blocks stress‐induced glucocorticoid release, is extensively used to study the physiological and behavioural roles of glucocorticoids. However, there is circumstancial evidence suggesting that metyrapone could act as a pharmacological stressor. Thus, the effects of various doses of metyrapone on two well‐characterized stress markers (ACTH and glucose) were studied in male rats. Metyrapone administration, while exerting a modest effect on plasma corticosterone levels, dose‐dependently increased plasma ACTH and glucose levels. Using the highest doses previously tested (200 mg/kg) we further observed, as evaluated by fos‐like immunoreactivity (FLI), a strong activation of a wide range of brain areas, including the parvocellular region of the hypothalamic paraventricular nucleus (PVNp), the origin of the main ACTH secretagogues. Metyrapone‐induced FLI was observed in neocortical and allocortical areas, in several limbic, thalamic and hypothalamic nuclei and, to a lesser extent, in the brainstem. In a final experiment, a dose–response study of metyrapone‐induced FLI was carried out focusing on selected brain areas. The study revealed that the paraventricular thalamic nucleus and central amygdala were the areas most sensitive to metyrapone as they responded even to the lowest dose of the drug. Most areas, among them the PVNp, only showed enhanced FLI with the two highest doses, i.e. when it was associated with ACTH and glucose responses. These data suggest that some of the effects of metyrapone could be due to its stressful properties rather than its ability to inhibit glucocorticoid synthesis. The exact mechanisms involved remain to be established.
Neither ibotenic acid nor volkensin lesions of the nucleus accumbens shell affect the expression of cocaine sensitization
Authors: Todtenkopf M. S. , Stellar J. R. , Melloni R. H.
Published: March 2003

Studies have shown that the nucleus accumbens shell plays an integral role in the expression of psychostimulant‐induced behavioural sensitization. Dopaminergic regulation of excitatory amino acid inputs in this region of the brain could be a key factor in the neural influence of this phenomenon. Alterations in the dopaminergic innervation patterns in the shell have been demonstrated in rats that received repeated cocaine injections. Furthermore, lesions of brain regions that send projections to the shell alter psychostimulant‐induced locomotion, both acutely and in sensitization paradigms. A previous study from our laboratory demonstrated that lesions of the shell before repeated cocaine treatment decrease the locomotor response to cocaine during the induction phase of behavioural sensitization. To better understand the role of this brain region during the expression phase of behavioural sensitization, the present study examined the effects of two forms of cytotoxic lesions of the shell. Rats received a sensitization‐inducing regimen of cocaine (bi‐daily injections of 15 mg/kg i.p. for 5 consecutive days). Two days after the last injection, rats demonstrating behavioural sensitization received one of three bilateral microinjections into the shell: (i) 0.5 µL 0.9% saline; (ii) 2.5 µg/0.5 µL ibotenic acid (which lesions the cell bodies at the injection site); or (iii), 0.5 ng/0.2 µL of volkensin (a retrograde suicide transport lectin). Upon challenge with cocaine (15 mg/kg) 12 days after surgery, neither ibotenic acid‐ nor volkensin‐lesioned rats showed any difference in their locomotor response compared with sham controls. These data indicate that bilateral shell lesions do not affect the long‐term expression of behavioural sensitization in cocaine‐sensitized rats.
Mice lacking the adenosine A1 receptor are anxious and aggressive, but are normal learners with reduced muscle strength and survival rate
Authors: Giménez‐Llort Lydia , Fernández‐Teruel Alberto , Escorihuela Rosa Maria , Fredholm Bertil B. , Tobeña Adolf , Pekny Milos , Johansson Björn
Published: March 2003

Behavioural assessment of mice lacking adenosine A1 receptors (A1Rs) showed reduced activity in some phases of the light–dark cycle, reduced exploratory behaviour in the open‐field and in the hole‐board, increased anxiety in the plus maze and dark‐light box and increased aggressiveness in the resident‐intruder test. No differences were found in spatial reference and working memory in several Morris water maze tasks. Both mutant mice had reduced muscle strength and survival rate. These results confirm the involvement of adenosine in motor activity, exploratory behaviour, anxiety and aggressiveness. A1Rs also appear to play a critical role in ageing‐related deterioration.
Differential effects of laminar stimulation of V1 cortex on target selection by macaque monkeys
Authors: Tehovnik Edward J. , Slocum Warren M. , Schiller Peter H.
Published: March 2003

We explored the effects of microstimulation on target selection by delivering stimulation at different depths within V1 (striate cortex) of the rhesus monkey (Macaca mulatta). Stimulation evoked saccadic eye movements that terminated in the receptive‐field location of the activated neurons. The current thresholds for saccade evocation were highest (≥ 30 µA) in the superficial layers and lowest (≤ 10 µA) in the deep layers. To study target selection, one visual target was presented in the receptive‐field location of the stimulated neurons and a second visual target was presented outside this location. Microstimulation delivered in concert with the appearance of the two targets decreased the probability that a monkey would select the target placed in the receptive‐field location when the upper layers of V1 were stimulated, and it increased this probability when the lower layers were stimulated. We suggest that microstimulation of the upper layers of V1 disrupts visual signals from retina en route to higher cortical areas, whereas microstimulation of the lower layers activates V1 efferents that innervate the oculomotor system.
Akt mediates the anti‐apoptotic effect of NMDA but not that induced by potassium depolarization in cultured cerebellar granule cells
Authors: Lafon‐Cazal Mireille , Perez Virgili , Bockaert Joël , Marin Philippe
Published: March 2003

Apoptosis of cultured cerebellar granule neurons (CGNs) deprived of serum is prevented by K+ depolarization or moderate concentrations of N‐methyl‐d‐aspartate (NMDA). Here, we have examined the role of the serine/threonine kinase Akt in these protective effects. The exposure of mouse CGNs to NMDA or K+ depolarization increased the phosphorylation of Akt, compared with that measured in cells incubated in a physiological K+ concentration. Only the NMDA‐evoked response was reduced by inhibitors of phosphatidylinositol 3‐kinase (wortmannin and LY294002) and mitogen‐activated protein kinase (PD98059 and U0126). Similarly, the capacity of NMDA to inhibit apoptosis of CGNs deprived of serum was greatly reduced by these inhibitors as well as by the transfection of neurons with a catalytically inactive mutant of Akt, whereas the protective effect of K+ depolarization remained unaffected. These findings indicate that K+ depolarization and NMDA activate Akt through different signalling pathways in CGNs. Moreover, Akt mediates the anti‐apoptotic effect of NMDA, but not that evoked by K+ depolarization.
Erythropoietin exerts anti‐apoptotic effects on rat microglial cells in vitro
Authors: Vairano Mauro , Russo Cinzia Dello , Pozzoli Giacomo , Battaglia Alessandra , Scambia Giovanni , Tringali Giuseppe , Aloe‐Spiriti Maria Antonietta , Preziosi Paolo , Navarra Pierluigi
Published: March 2003

Erythropoietin (EPO), a renal cytokine regulating haematopoiesis, is also produced by different cell types within the central nervous system, where it acts via the activation of specific receptors. Current evidence shows that EPO exerts neurotrophic and neuroprotective activities in different in vivo and in vitro models of brain damage. In the present study we investigated the effects of EPO on primary cultures of rat cortical microglia and astrocytes. We found that: (i) EPO exerted a marked stimulatory effect on microglial cell viability, assessed through the MTS assay, whereas astrocytes were almost unaffected; (ii) the cytokine increased microglial cell population size in a concentration‐dependent manner; however, as microglia cultures undergo spontaneous apoptosis after separation from astrocytes, the apparent effect on cell proliferation could be attributed to EPO antagonism of normal apoptosis; (iii) subsequent flow cytometry analysis on microglial cells demonstrated both the trophic role of factor(s) released by astrocytes in mixed cultures, and the putative anti‐apoptotic action of EPO; (iv) the latter was further confirmed through the assessment of gene expression of anti‐ and pro‐apoptotic factors, which showed that EPO is able to shift the Bcl : Bax ratio towards a net anti‐apoptotic effect; (v) EPO did not affect the pro‐inflammatory function of microglial cells.
Phosphorylated MAP1B is induced in central sprouting of primary afferents in response to peripheral injury but not in response to rhizotomy
Authors: Soares Sylvia , Von Boxberg Ysander , Lombard Marie‐Christine , Ravaille‐Veron Michèle , Fischer Itzhak , Eyer Joel , Nothias Fatiha
Published: March 2003

A peripheral nerve lesion induces sprouting of primary afferents from dorsal root ganglion (DRG) neurons into lamina II of the dorsal horn. Modifications of the environment in consequence to the axotomy provide an extrinsic stimulus. A potential neuron‐intrinsic factor that may permit axonal sprouting is microtubule‐associated protein 1B (MAP1B) in a specific phosphorylated form (MAP1B‐P), restricted to growing or regenerating axons. We show here that both in rat and mouse, a sciatic nerve cut is rapidly followed by the appearance of MAP1B‐P expression in lamina II, increasing to a maximum between 8 and 15 days, and diminishing after three months. Evidence is provided that sprouting and induction of MAP1B‐P expression after peripheral injury are phenomena concerning essentially myelinated axons. This is in accordance with in situ hybridization data showing especially high MAP1B‐mRNA levels in large size DRG neurons that give rise to myelinated fibers. We then employed a second lesion model, multiple rhizotomy with one spared root. In this case, unmyelinated CGRP expressing fibers do indeed sprout, but coexpression of MAP1B‐P and CGRP is never observed in lamina II. Finally, because a characteristic of myelinated fibers is their high content in neurofilament protein heavy subunit (NF‐H), we used NF‐H‐LacZ transgenic mice to verify that MAP1B‐P induction and central sprouting were not affected by perturbing the axonal organization of neurofilaments. We conclude that MAP1B‐P is well suited as a rapidly expressed, axon‐intrinsic marker associated with plasticity of myelinated fibers.
Hormonal enhancement of neuronal firing is linked to structural remodelling of excitatory and inhibitory synapses
Authors: Parducz A. , Hoyk Z. , Kis Z. , Garcia‐Segura L. M.
Published: March 2003

The ovarian hormone estradiol induces morphological changes in the number of synaptic inputs in specific neuronal populations. However, the functional significance of these changes is still unclear. In this study, the effect of estradiol on the number of anatomically identified synaptic inputs has been assessed in the hypothalamic arcuate nucleus. The number of axo‐somatic, axodendritic and spine synapses was evaluted using unbiased stereological methods and a parallel electrophysiological study was performed to assess whether synaptic anatomical remodelling has a functional consequence on the activity of the affected neurons. Estradiol administration to ovariectomized rats induced a decrease in the number of inhibitory synaptic inputs, an increase in the number of excitatory synapses and an enhancement of the frequency of neuronal firing. These results indicate that oestrogen modifications in firing frequency in arcuate neurons are temporally linked to anatomical modifications in the numerical balance of inhibitory and excitatory synaptic inputs.
Early behavioural changes in mice infected with BSE and scrapie: automated home cage monitoring reveals prion strain differences
Authors: Dell'Omo Giacomo , Vannoni Elisabetta , Vyssotski Alexei L. , Di Bari Michele Angelo , Nonno Romolo , Agrimi Umberto , Lipp Hans‐Peter
Published: March 2003

Mice inoculated with transmissible spongiform encephalopathies (TSE) show behavioural abnormalities well before the appearance of clinical signs. TSE strains are obtained by serial re‐infection of infectious brain homogenates in laboratory rodents. They are characterized by strain‐typical brain lesion profiles, which implies that they might be differentiated behaviourally as well. Seventy female C57BL/6 mice were tested, 14 per group. Controls received no or sham inocula, two other groups received scrapie strains adapted to mice (139A, ME7) and one group a mouse‐adapted BSE strain (301C). From week 7 until the end of the incubation period, 8 mice per group were subjected once every 2 weeks to open‐field and hot‐plate tests. Assessment of clinical signs, and measuring of body weight, food and water consumption were carried out weekly on the remaining animals kept in single cages. In addition, locomotor activity was recorded continuously in these mice by means of infrared detectors. Monitoring of circadian activity revealed early significant TSE strain differences, most pronounced during the nocturnal active phase. Behavioural changes in open‐field tests also occurred before the appearance of clinical signs, and differences in rearing, wall rearing and sniffing were strain‐specific, however, such differences varied according to the period of testing. Hind paw lick latencies increased equally in all groups after week 19, jump latencies also increased in the two scrapie groups but not in the BSE group. It was at this time that clinical signs first appeared consisting of ataxia, lack of balance, motor dyscoordination, and lordosis. These data imply that automated assessment of circadian activity in mice is a powerful and economical tool for early behavioural typing of TSE strains.