bluuebunny/crossref_metadata_2025 huggingface dataset:
Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice
Authors: Feldker Dorine E. M. , Datson Nicole A. , Veenema Alexa H. , Meulmeester Erik , De Kloet E. Ronald , Vreugdenhil Erno
Published: March 2003

The genetically selected long attack latency (LAL) and short attack latency (SAL) mice differ in a wide variety of behavioural traits and display differences in the serotonergic system and the hypothalamus‐pituitary‐adrenocortical (HPA)‐axis. Serial analysis of gene expression (SAGE) was used to generate a hippocampal expression profile of almost 30 000 genes in LAL and SAL mice. Using SAGE, we found differential expression of 191 genes. Among these were genes involved in growth, signal transduction, and cell metabolism. The SAGE study was supported by GeneChip analysis (Affymetrix). Strikingly, both SAGE and GeneChips showed a higher expression of numerous cytoskeleton genes, such as cofilin and several tubulin isotypes in LAL mice. LAL mice also showed a higher expression of several calmodulin‐related genes and genes encoding components of a MAPK cascade, namely raf‐related oncogene and ERK2. The findings were confirmed by in situ hybridization. Our results of differential expression of cytoskeleton and signal transduction genes therefore suggest differential regulation of the raf/ERK pathway that may be related to structural differences in the hippocampus of LAL and SAL mice. As stress‐related disorders, such as depression, are also linked to differential regulation of the HPA‐axis and the serotonergic system and are associated with altered hippocampal morphology, differential regulation of these genes may be involved in the pathogenesis of these diseases.
Protein 4.1B associates with both Caspr/paranodin and Caspr2 at paranodes and juxtaparanodes of myelinated fibres
Authors: Denisenko‐Nehrbass Natalia , Oguievetskaia Ksénia , Goutebroze Laurence , Galvez Thierry , Yamakawa Hisashi , Ohara Osamu , Carnaud Michèle , Girault Jean‐Antoine
Published: March 2003

Caspr/paranodin, a neuronal transmembrane glycoprotein, is essential for the structure and function of septate‐like paranodal axoglial junctions at nodes of Ranvier. A closely related protein, Caspr2, is concentrated in juxtaparanodal regions where it associates indirectly with the shaker‐type potassium channels. Although ultrastructural studies indicate that paranodal complexes are linked to the cytoskeleton, the intracellular partners of Caspr/paranodin, as well as those of Caspr2, are poorly characterized. We show that the conserved intracellular juxtamembrane regions (GNP motif) of Caspr/paranodin and Caspr2 bind proteins 4.1R and 4.1B. 4.1B is known to be enriched in paranodal and juxtaparanodal regions. 4.1B immunoreactivity accumulates progressively at paranodes and juxtaparanodes during postnatal development, following the concentration of Caspr/paranodin and Caspr2, respectively, in central and peripheral myelinated axons. These two proteins coimmunoprecipitated with 4.1B in brain homogenates. Our results provide strong evidence for the association of 4.1B with Caspr/paranodin at paranodes and with Caspr2 at juxtaparanodes. We propose that 4.1B anchors these axonal proteins to the actin‐based cytoskeleton in these two regions.
Suprachiasmatic control of melatonin synthesis in rats: inhibitory and stimulatory mechanisms
Authors: Perreau‐Lenz Stéphanie , Kalsbeek Andries , Garidou Marie‐Laure , Wortel Joke , Van Der Vliet Jan , Van Heijningen Caroline , Simonneaux Valérie , Pévet Paul , Buijs Ruud M.
Published: March 2003

The suprachiasmatic nucleus (SCN) controls the circadian rhythm of melatonin synthesis in the mammalian pineal gland by a multisynaptic pathway including, successively, preautonomic neurons of the paraventricular nucleus (PVN), sympathetic preganglionic neurons in the spinal cord and noradrenergic neurons of the superior cervical ganglion (SCG). In order to clarify the role of each of these structures in the generation of the melatonin synthesis rhythm, we first investigated the day‐ and night‐time capacity of the rat pineal gland to produce melatonin after bilateral SCN lesions, PVN lesions or SCG removal, by measurements of arylalkylamine N‐acetyltransferase (AA‐NAT) gene expression and pineal melatonin content. In addition, we followed the endogenous 48 h‐pattern of melatonin secretion in SCN‐lesioned vs. intact rats, by microdialysis in the pineal gland. Corticosterone content was measured in the same dialysates to assess the SCN lesions effectiveness. All treatments completely eliminated the day/night difference in melatonin synthesis. In PVN‐lesioned and ganglionectomised rats, AA‐NAT levels and pineal melatonin content were low (i.e. 12% of night‐time control levels) for both day‐ and night‐time periods. In SCN‐lesioned rats, AA‐NAT levels were intermediate (i.e. 30% of night‐time control levels) and the 48‐h secretion of melatonin presented constant levels not exceeding 20% of night‐time control levels. The present results show that ablation of the SCN not only removes an inhibitory input but also a stimulatory input to the melatonin rhythm generating system. Combination of inhibitory and stimulatory SCN outputs could be of a great interest for the mechanism of adaptation to day‐length (i.e. adaptation to seasons).
Low dose cocaine self‐administration transiently increases but high dose cocaine persistently decreases brain reward function in rats
Authors: Kenny Paul J. , Polis Ilham , Koob George F. , Markou Athina
Published: March 2003

This study investigated the effects of self‐administered cocaine on brain reward function, measured by intracranial self‐stimulation (ICSS) reward thresholds in rats. Self‐administration of 10 and 20 cocaine injections (0.25 mg per injection, equivalent to 4.94 ± 0.23 and 9.88 ± 0.46 mg/kg, self‐administered over 40 ± 6.9 and 99 ± 11.9 min, respectively) lowered reward thresholds 15 min later, indicating a facilitation of rewarding ICSS, but had no effect at 2, 24 or 48 h after administration. Thus, self‐administration of low cocaine doses did not cause persistent changes in brain reward function. Forty cocaine injections (19.64 ± 0.94 mg/kg; self‐administered over 185 ± 10.9 min) also transiently lowered reward thresholds 15 min later, while significant threshold current elevations were observed at 2 and 24 h after administration, indicating persistent withdrawal‐like reward deficits. Finally, 80 cocaine injections (39.53 ± 1.84 mg/kg, self‐administered over 376 ± 19.9 min) significantly elevated thresholds 2 and 48 h after self‐administration, but not at 24 h. Threshold currents also tended to be elevated 15 min after self‐administration. Overall, these data suggest that as the amount of self‐administered cocaine increases the motivation to consume further cocaine may be shifted, from obtaining the rewarding actions of cocaine to avoidance and alleviation of a cocaine‐induced negative affective state.
Age‐dependent cognitive decline in the APP23 model precedes amyloid deposition
Authors: Van Dam Debby , D'Hooge Rudi , Staufenbiel Matthias , Van Ginneken Chris , Van Meir Frans , De Deyn Peter P.
Published: March 2003

Heterozygous APP23 mice, expressing human amyloid‐precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6–8 weeks, 3 and 6 months. A hidden‐platform Morris‐type water maze showed an age‐dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage‐activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2‐h recording during dusk phase demonstrated lower activity levels in 6‐month‐old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open‐field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque‐associated human amyloid‐β1–42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque‐associated amyloid‐β1–42 peptides, but probe trial performance did correlate negatively with soluble amyloid‐β brain concentration in 3‐month‐old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model.
Olfactory learning modifies the expression of odour‐induced oscillatory responses in the gamma (60–90 Hz) and beta (15–40 Hz) bands in the rat olfactory bulb
Authors: Ravel Nadine , Chabaud Pascal , Martin Claire , Gaveau Valérie , Hugues Etienne , Tallon‐Baudry Catherine , Bertrand Olivier , Gervais Rémi
Published: March 2003

This study addressed the question of the possible functional relevance of two different oscillatory activities, beta and gamma (15–40 and 60–90 Hz, respectively) for perception and memory processes in olfactory areas of mammals. Local field potentials were recorded near relay olfactory bulb neurons while rats performed an olfactory discrimination task. Signals reflected the mass activity from this region and characteristics of oscillatory activities were used as an index of local synchrony. Beta and gamma oscillatory activities were quantified by time‐frequency methods before during and after odour sampling. In rats early in their training, olfactory sampling was associated with a significant decrease in power in the gamma band in parallel with a weak but significant increase in the beta band (centred on 27 Hz). Several days later, in well‐trained rats, the gamma oscillatory depression was significantly enhanced both in duration and amplitude. It appeared within the 500 ms time period preceding odour onset and was further reduced during the odour period. Concurrently the beta oscillatory response (now centred on 24 Hz) during odour sampling was amplified by a twofold factor. The beta band response was modulated according to the chemical nature of the stimuli and rat's behavioural response. This study showed for the first time that odour sampling in behaving animals is associated with a clear shift in the olfactory bulb neuronal activity from a gamma to a beta oscillatory regime. Moreover, the data stress the importance of studying the odour‐induced beta activity and its relation to perception and memory.
The serotonin transporter intronic VNTR enhancer correlated with a predisposition to affective disorders has distinct regulatory elements within the domain based on the primary DNA sequence of the repeat unit
Authors: Lovejoy E. A. , Scott A. C. , Fiskerstrand C. E. , Bubb V. J. , Quinn J. P.
Published: March 2003

We have demonstrated that a variable number tandem repeat domain (VNTR) within intron 2 of the serotonin transporter gene is a transcriptional regulatory domain which is potentially correlated with a predisposition to affective disorders and other behavioural conditions. This correlation based on copy number of the VNTR alone (nine, 10 or 12 copies of 16/17 base‐pair element) has been controversial and not reproduced in all studies. We demonstrate that individual repeat elements within the VNTR domain differ in their enhancer activity in an embryonic stem cell model. This has implications for both the mechanism by which these VNTRs are correlated with the progression of the disease and suggests that clinical analysis should now be extended to correlate sequence variation within the VNTR with the disorder. The latter may resolve some of the conflicting data published to date.
Accumbal dopamine and serotonin in anticipation of the next aggressive episode in rats
Authors: Ferrari P. F. , Van Erp A. M. M. , Tornatzky W. , Miczek K. A.
Published: March 2003

Autonomic and limbic neural activities are linked to aggressive behavior, and it is hypothesized that activities in the cardiovascular and monoaminergic systems play a role in preparing for an aggressive challenge. The objective was to learn about the emergence of monoamine activity in nucleus accumbens before an aggressive confrontation that was omitted at the regular time of occurrence, dissociating the motoric from the aminergic activity. Dopamine, serotonin, heart rate and behavioral activity were monitored before, during and after a single 10‐min confrontation in resident male Long‐Evans rats fitted with a microdialysis probe in the n. accumbens and with a telemetry sender (experiment 1). DA, but not 5‐HT efflux, was confirmed to increase in n. accumbens during and after a single aggressive episode. In aggressive males that confronted an opponent daily for 10 days (experiment 2) heart rate rose 1 h before the regularly scheduled encounter relative to control rats, as measured on day 11 in the absence of any aggression. Concurrently, DA levels increased by 60–70% over baseline levels and 5‐HT levels decreased by 30–35% compared to baseline levels. These changes were sustained over 1 h, and contrasted with no significant changes in DA, 5‐HT, heart rate or behavioral activity in control rats. The rise in mesolimbic DA appears to be significant in anticipating the physiological and behavioral demands of an aggressive episode, and the fall in 5‐HT in its termination, dissociated from the actual execution of the behavior.
Neuronal representation of odourants in the olfactory bulb of Xenopus laevis tadpoles
Authors: Czesnik Dirk , Rössler Wolfgang , Kirchner Friedrich , Gennerich Arne , Schild Detlev
Published: March 2003

When an odourant enters the nose, olfactory receptor neurons (ORNs) convey information about it to the olfactory bulb (OB), where this information is processed and where the first central representations of the odourant are generated. In this paper we show how odourants are represented by ensembles of OB neurons, in particular mitral cells (MCs) which are the output neurons of the OB. We were able to demonstrate for the first time that the intracellular calcium concentrations ([Ca2+]i) in the somata of these neurons undergo specific changes and that different stimuli are represented by different neuronal [Ca2+]i patterns. The similarity of patterns was assessed by cross‐correlation analysis. We further show that noradrenaline (NA), which is reported to be involved in olfactory memory formation and to modulate synaptic transmission at dendrodendritic synapses in the OB, profoundly changes the representation of odourants at the level of MCs.
Imaging of calcineurin activated by long‐term depression‐inducing synaptic inputs in living neurons of rat visual cortex
Authors: Yasuda Hiroki , Higashi Hideyoshi , Kudo Yoshihisa , Inoue Takafumi , Hata Yoshio , Mikoshiba Katsuhiko , Tsumoto Tadaharu
Published: March 2003

Long‐term depression (LTD) of synaptic transmission is induced by low‐frequency stimulation (LFS) of afferents lasting for a long time, typically for 10–15 min, in neocortical and hippocampal slices. It is suggested that calcineurin, Ca2+/calmodulin‐dependent protein phosphatase, plays a role in the induction of LTD, based on the results that pharmacological or genetic manipulation of calcineurin activity interfered in its induction. However, questions as to why it takes so long to induce LTD and in which compartment of neurons calcineurin is activated remain unanswered. With a fluorescent indicator for calcineurin activity, we visualized the spatiotemporal pattern of its activation in living neurons in layer II/III of visual cortical slices of rats during the LFS of layer IV that induced LTD of synaptic responses. During LFS, the fluorescence intensity gradually increased with a latency of a few minutes in dendrites and soma of neurons, and remained increased during the whole observation period (10–25 min) after LFS. The onset latency of the increase in the soma was slower than that in the distal dendritic region. The LFS‐induced rise in fluorescence was not observed in neurons which were loaded with inhibitors of calcineurin, indicating that the intensity of fluorescence reflects calcineurin activity. Control stimulation at 0.05 Hz and θ‐burst stimulation did not significantly change the intensity of fluorescence. Only LFS‐type inputs effectively activate calcineurin in postsynaptic neurons in an augmenting manner, and such a time‐consuming activation of calcineurin may be a reason why long‐lasting LFS is necessary for the induction of LTD.
Neurons of the trigeminal main sensory nucleus participate in the generation of rhythmic motor patterns
Authors: Tsuboi A. , Kolta A. , Chen C. C. , Lund J. P.
Published: March 2003

The trigeminal principal sensory nucleus (NVsnpr) contains both trigemino‐thalamic neurons and interneurons projecting to the reticular formation and brainstem motor nuclei. Here we describe the inputs and patterns of firing of NVsnpr neurons during fictive mastication in anaesthetized and paralysed rabbits to determine the role that NVsnpr may play in patterning mastication. Of the 272 neurons recorded in NVsnpr, 107 changed their firing patterns during repetitive stimulation of the left or right sensorimotor cortex to induce fictive mastication. Thirty increased their firing tonically. Seventy‐seven became rhythmically active, but only 31 fired in phase with mastication. The others discharged in bursts at more than twice the frequency of trigeminal motoneurons. Most rhythmic masticatory neurons were concentrated in the dorsal part, and those which fired during the jaw closing phase of the cycle were confined to the anterior pole of the nucleus. Most of these cells had inputs from muscle spindle afferents, whereas most of those firing during jaw opening had inputs from periodontal receptors. Non‐masticatory rhythmical neurons had receptive fields on the lips and face. The majority of rhythmical masticatory units were modulated during fictive mastication evoked by both the left and right cortices and only four changed their phase of firing when switching from one cortex to the other. When coupled with the finding that NVsnpr neurons exhibit spontaneous bursting in vitro[Sandler et al. (1998) Neuroscience, 83, 891], the results described here suggest that neurons of dorsal NVsnpr may form the core of the central pattern generator for mastication.
Muscarinic and GABAA receptors modulate acetylcholine release in feline basal forebrain
Authors: Vazquez Jacqueline , Baghdoyan Helen A.
Published: March 2003

Acetylcholine (ACh) release within the basal forebrain changes significantly as a function of sleep and wakefulness, hence identifying the neurochemical modulators of basal forebrain ACh release will contribute to a mechanistic understanding of sleep cycle regulation. This study tested the hypothesis that muscarinic and gamma aminobutyric acidA (GABAA) receptors modulate basal forebrain ACh release. Cats were anaesthetized with halothane to hold arousal state constant and a microdialysis probe was aimed stereotaxically for the substantia innominata region of the basal forebrain. Four concentrations of the muscarinic antagonist scopolamine (0.1, 0.3, 1.0, and 10 nm) and five concentrations of the GABAA antagonist bicuculline (3, 10, 30, 100, and 300 µm) were delivered by reverse dialysis from the same probes used to collect ACh. These results are based on 27 experiments in nine animals. Scopolamine and bicuculline each caused a concentration dependent enhancement of ACh release. Scopolamine increased ACh by 118% above control levels whereas bicuculline was more effective, causing a 287% increase in ACh release. Scopolamine was more potent (EC50 = 0.16 nm) than bicuculline (EC50 ≥ 90 µm) for increasing ACh release. The results support the hypothesis that substantia innominata ACh release is modulated by muscarinic autoreceptors and inhibited by GABAA receptors. These findings are consistent with the interpretation that inhibition of basal forebrain cholinergic neurotransmission by GABA contributes to the generation of sleep.
Cellular mechanisms of Δ9‐tetrahydrocannabinol behavioural sensitization
Authors: Rubino T. , Viganò D. , Massi P. , Parolaro D.
Published: March 2003

We investigated the cellular events linked to the induction of cannabinoid behavioural sensitization. In sensitized rats, autoradiographic binding studies with [3H]CP‐55,940 showed a significant increase in cannabinoid receptor binding, specifically in the cerebellum, with no changes in the other brain areas where basal CB1‐receptor expression is observed. In vitro autoradiography of CP‐55,940‐stimulated [35S]GTPγS binding provided a picture of cannabinoid receptor‐mediated G protein activation. Basal [35S]GTPγS binding was not affected, whereas sensitized rats showed a significant increase of net [35S]GTPγS binding in the caudate putamen and cerebellum. Autoradiographic studies suggested that only these two areas had altered receptor functionality. We therefore focused our intracellular investigations only there, first surveying the responsiveness of the cAMP system to cannabinoids. CP‐55,940 was unable to inhibit forskolin‐induced cAMP accumulation in the cerebellum of sensitized animals, but no difference was observed between groups in the caudate putamen. Finally, we surveyed the levels of CREB and AP‐1 binding activity, in the same two areas and found no difference in sensitized rats. The intracellular picture in sensitized rats suggests that besides the cAMP cascade, other signalling pathways may participate in the development of cannabinoid sensitization.
Substance induced plasticity in noradrenergic innervation of the paraventricular hypothalamic nucleus
Authors: Jansen Arthur S. P. , Schmidt E. Donné , Voorn Pieter , Tilders Fred J. H.
Published: March 2003

Single administration of the cytokine interleukin‐1α (IL‐1), or the psychostimulant amphetamine, enhanced adrenocorticotropin hormone and corticosterone responses to a stress challenge weeks later. This long‐lasting hypothalamic‐pituitary‐adrenal (HPA)‐sensitization is paralleled by an increase in electrically evoked release of noradrenaline in the paraventricular hypothalamic nucleus (PVN). We hypothesized that these functional changes may be associated with morphological plasticity of noradrenergic projections to the PVN, a parameter that shows high reproducibility. Specific alterations in relative (nor)adrenergic innervation density were studied by using dopamine‐α‐hydroxylase (DBH) as a marker. An image analysis system was used to detect changes in the relative DBH innervation density of the PVN. Groups of adult male rats were given IL‐1 (10 µg/kg i.p.), amphetamine (5 mg/kg i.p.), or saline. Three weeks later, IL‐1 and amphetamine primed rats showed enhanced adrenocorticotropin hormone and corticosterone responses to an amphetamine challenge. In another set of experiments, the relative DBH innervation density was measured in different PVN subnuclei at four rostro‐caudal levels. Single administration of either IL‐1 or amphetamine causes three weeks later a selective decrease in relative DBH innervation density in those subnuclei of the PVN that contain high numbers of corticotrophin‐releasing hormone (CRH) producing neurons: the dorsal parvocellular and medial parvocellular PVN. We conclude that (1) long‐lasting sensitization induced by single exposure to IL‐1 and amphetamine induces specific pattern of neuroplastic changes in (nor)adrenergic innervation in the PVN and (2) reduction of relative DBH innervation density in CRH‐rich areas is associated with paradoxical increase of electrically evoked release of (nor)adrenaline.
Attention‐dependent coupling between beta activities recorded in the cat's thalamic and cortical representations of the central visual field
Authors: Bekisz Marek , Wróbel Andrzej
Published: March 2003

We have previously proposed that enhanced 16–24 Hz (beta) local field potential activity in the primary visual cortex and lateral geniculate nucleus may be an electrophysiological correlate of the attentional mechanism that increases the gain of afferent visual information flow to the cortex. In this study, we measured coupling between beta signals recorded in the thalamic (i.e. lateral geniculate or perigeniculate) and cortical representations of the central visual field (within 5° fromarea centralis), during visual and auditory attentive situations. Signal coupling was calculated in two ways: (i) by means of crosscorrelation between raw beta activities, which depends primarily on phase coherence, and (ii) by phase‐independent crosscorrelation between amplitude envelopes of beta activities. Mean amplitudes of raw signal crosscorrelations obtained for thalamo‐cortical recording pairs were not significantly different when calculated during behavioural demands for either visual or auditory attention. In contrast, amplitudes of envelope crosscorrelations obtained during behaviour requiring visual attention were, on average, two times higher than those calculated during the auditory task. This attention‐related coupling emerged from synchronized amplitude modulation of beta oscillatory activity that occurs within the cortico‐thalamic circuit involved in central vision.
Localization of a FMRFamide‐related peptide in efferent neurons and analysis of neuromuscular effects of DRNFLRFamide (DF2) in the crustacean Idotea emarginata.
Authors: Weiss Torsten , Kreissl Sabine , Rathmayer Werner
Published: March 2003

In the ventral nerve cord of the isopod Idotea emarginata, FMRFamide‐immunoreactive efferent neurons are confined to pereion ganglion 5 where a single pair of these neurons was identified. Each neuron projects an axon into the ipsilateral ventral and dorsal lateral nerves, which run through the entire animal. The immunoreactive axons form numerous varicosities on the ventral flexor and dorsal extensor muscle fibres, and in the pericardial organs. To analyse the neuromuscular effects of a FMRFamide, we used the DRNFLRFamide (DF2). DF2 acted both pre‐ and postsynaptically. On the presynaptic side, DF2 increased transmitter release from neuromuscular endings. Postsynaptically, DF2 depolarized muscle fibres by approximately 10 mV. This effect was not observed in leg muscles of a crab. The depolarization required Ca2+, was blocked by substituting Ca2+ with Co2+, but not affected by nifedipine or amiloride. In Idotea, DF2 also potentiated evoked extensor muscle contractions. The amplitude of high K+ contractures was increased in a dose dependent manner with an EC50 value of 40 nm. In current‐clamped fibres, DF2 strongly potentiated contractions evoked by current pulses exceeding excitation‐contraction threshold. In voltage‐clamped fibres, the inward current through l‐type Ca2+ channels was increased by the peptide. The observed physiological effects together with the localization of FMRFamide‐immunoreactive efferent neurons suggest a role for this type of peptidergic modulation for the neuromuscular performance in Idotea. The pre‐ and postsynaptic effects of DF2 act synergistically and, in vivo, all should increase the efficacy of motor input to muscles resulting in potentiation of contractions.
Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system
Authors: Rosenblad Carl , Georgievska Biljana , Kirik Deniz
Published: March 2003

Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long‐term glial cell line‐derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25–100‐fold increase above control vector‐ or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39–72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase‐immunoreactive innervation in the striatum was reduced by 25–52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2‐immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. Taken together our findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur.
Odorant specificity of three oscillations and the DC signal in the turtle olfactory bulb
Authors: Lam Ying‐Wan , Cohen Lawrence B. , Zochowski Michal R.
Published: March 2003

The odour‐induced population response in the in vivo turtle (Terepene sp.) olfactory bulb consists of three oscillatory components (rostral, middle and caudal) that ride on top of a DC signal. In an initial step to determine the functional role of these four signals, we compared the signals elicited by different odorants. Most experiments compared isoamyl acetate and cineole, odorants which have very different maps of input to olfactory bulb glomeruli in the turtle and a different perceptual quality for humans. We found substantial differences in the response to the two odours in the rise‐time of the DC signal and in the latency of the middle oscillation. The rate of rise for cineole was twice as fast as that for isoamyl acetate. Similarly, the latency for the middle oscillation was about twice as long for isoamyl acetate as it was for cineole. On the other hand, a number of characteristics of the signals were not substantially different for the two odorants. These included the latency of the rostral and caudal oscillation, the frequency and envelope of all three oscillations and their locations and spatial extents. A smaller number of experiments were carried out with hexanone and hexanal; the oscillations elicited by these odorants did not appear to be different from those elicited by isoamyl acetate and cineole. Qualitative differences between the oscillations in the turtle and those in two invertebrate phyla suggest that different odour processing strategies may be used.
Long‐term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning
Authors: Okada Takashi , Yamada Nobuaki , Tsuzuki Keisuke , Horikawa Hiroshi P. M. , Tanaka Kohichi , Ozawa Seiji
Published: March 2003

NMDA receptor‐dependent long‐term potentiation (LTP) at hippocampal synapses has been considered a crucial component of the cellular basis for learning and memory. This form of LTP occurs in excitatory synapses in both the CA1 area and the dentate gyrus in the hippocampus. However, differential roles of LTP in these areas have not yet been identified. To address this issue, we enhanced the degree of LTP by expressing Ca2+‐permeable AMPA receptors at either hippocampal CA1 or dentate gyrus synapses using Sindbis viral vectors (SINs) encoding both green fluorescent proteins and unedited GluR2 (GluR2Q) subunits, and examined their effects on rat spatial learning. The viral vectors were locally injected into the 8‐week‐old‐rat brain in vivo bilaterally. The postsynaptic expression of Ca2+‐permeable AMPA receptors enhanced the degree of LTP, and induced NMDA receptor‐independent LTP in the presence of the NMDA receptor antagonist in SIN‐infected regions in both CA1 and dentate gyrus in hippocampal slice preparations. However, the regional expression of Ca2+‐permeable AMPA receptors caused opposite behavioural consequences on the Morris water maze task: rats with SIN‐infected CA1 pyramidal cells showed shorter escape latency and better probe test performance, whereas those with SIN‐infected dentate gyrus granule cells showed impaired performance. Thus, it was demonstrated that CA1 and dentate gyrus synapses play different functional roles in spatial learning despite their similar mechanism for LTP induction.
Induction of bilateral plasticity in sensory cortical maps by small unilateral cortical infarcts in rats
Authors: Reinecke S. , Dinse H. R. , Reinke H. , Witte O. W.
Published: March 2003

Behavioural impairments caused by brain lesions show a considerable, though often incomplete, recovery. It is hypothesized that cortical and subcortical plasticity of sensory representations contribute to this recovery. In the hindpaw representation of somatosensory cortex of adult rats we investigated the effects of focal unilateral cortical lesions on remote areas. Cortical lesions with a diameter of ≈ 2 mm were induced in the parietal cortex by photothrombosis with the photosensitive dye Rose Bengal. Subsequently, animals were kept in standard cages for 7 days. On day seven, animals were anaesthetized and cutaneous receptive fields in the cortical hindpaw representations ipsi‐ and contralateral to the lesion were constructed from extracellular recordings of neurons in layer IV using glass microelectrodes. Receptive fields in the lesioned animals were compared to receptive fields measured in nonlesioned animals serving as controls. Quantitative analysis of receptive fields revealed a significant increase in size in the lesioned animals. This doubling in receptive field size was observed equally in the hemispheres ipsi‐ and contralateral to the lesion. The results indicate that the functional consequences of restricted cortical lesions are not limited to the area surrounding the lesion, but affect the cortical maps on the contralateral, nonlesioned hemisphere.
Activation of the phasic pontine‐wave generator enhances improvement of learning performance: a mechanism for sleep‐dependent plasticity
Authors: Mavanji Vijayakumar , Datta Subimal
Published: March 2003

The aim of this study was to test the hypothesis that supplementary activation of the phasic pontine wave (P‐wave) generator during rapid eye movement (REM) sleep enhances consolidation and integration of memories, resulting in improved learning. To test this hypothesis, two groups of rats were trained on a two‐way active avoidance learning task in the morning. Immediately after training, one group of rats received a carbachol microinjection into the P‐wave generator and the other group was microinjected with control saline into the same target area. After training trials and microinjections, rats were allowed a 6‐h period of undisturbed sleep in the polygraphic recording chamber. At the end of 6 h of undisturbed sleep–wake recordings, rats were retested in a session of avoidance learning trials. After learning trials, the total percentage of time spent in REM sleep was significantly increased in both saline (15.36%)‐ and carbachol (17.70%)‐microinjected rats. After learning trials, REM sleep P‐wave density was significantly greater throughout the 6‐h period of recordings in carbachol treated rats than in the saline treated rats. In the retrial session, the improvement in learning task performance was 22.75% higher in the carbachol‐microinjected rats than in the saline‐microinjected rats. These findings show that the consolidation and integration of memories create a homeostatic demand for P‐waves. In addition, these findings provide experimental evidence, for the first time, that activation of the P‐wave generator may enhance consolidation and integration of memories, resulting in improved performance on a recently learned task.
cDNA profiling of epileptogenesis in the rat brain
Authors: Lukasiuk Katarzyna , Kontula Laura , Pitkänen Asla
Published: March 2003

Symptomatic temporal lobe epilepsy typically develops in three phases: brain insult → latency period (epileptogenesis) → recurrent seizures (epilepsy). We hypothesized that remodeling of neuronal circuits underlying epilepsy is associated with altered gene expression during epileptogenesis. Epileptogenesis was induced by electrically triggered status epilepticus (SE) in rats. Animals were continuously monitored with video‐EEG, and the hippocampus and temporal lobe were collected either during epileptogenesis (1, 4 and 14 days) or after the first spontaneous seizures (14 days) for cDNA array analysis. Altogether, 282 genes had altered expression, from which 87 were in the hippocampus and 208 in the temporal lobe (overlap in 13). Assessment of hippocampal gene expression during epileptogenesis indicated that 37 genes were altered in the 1‐day group, 12 in the 4‐day group and 14 in the 14‐day epileptogenesis group. There were 42 genes with altered expression in the 14‐day epilepsy group. In the temporal lobe, the number of genes with altered expression was 29 in the 1‐day group, 155 in the 4‐day group, 32 in the 14‐day epileptogenesis group and 62 in the 14‐day epilepsy group. Products of the altered genes are involved in neuronal plasticity, gliosis, organization of the cytoskeleton or extracellular matrix, cell adhesion, signal transduction, regulation of cell cycle, and metabolism. As most of these genes have not previously been implicated in epileptogenesis or epilepsy, these data open new avenues for understanding the molecular basis of epileptogenesis and provide new targets for rational development of antiepileptogenic treatments for patients with an elevated risk of epileptogenesis after brain injury.
LTP but not seizure is associated with up‐regulation of AKAP‐150
Authors: Génin A. , French P. , Doyère V. , Davis S. , Errington M. L. , Maroun M. , Stean T. , Truchet B. , Webber M. , Wills T. , Richter‐Levin G. , Sanger G. , Hunt S. P. , Mallet J. , Laroche S. , Bliss T. V. P. , O'Connor V.
Published: March 2003

We have used differential display to profile and compare the mRNAs expressed in the hippocampus of freely moving animals after the induction of long‐term potentiation (LTP) at the perforant path–dentate gyrus synapse with control rats receiving low‐frequency stimulation. We have combined this with in situ hybridization and have identified A‐kinase anchoring protein of 150 kDa (AKAP‐150) as a gene selectively up‐regulated during the maintenance phase of LTP. AKAP‐150 mRNA has a biphasic modulation in the dentate gyrus following the induction of LTP. The expression of AKAP‐150 was 29% lower than stimulated controls 1 h after the induction of LTP. Its expression was enhanced 3 (50%), 6 (239%) and 12 h (210%) after induction, returning to control levels by 24 h postinduction. The NMDA receptor antagonist CPP blocked the tetanus‐induced modulation of AKAP‐150 expression. Interestingly, strong generalized stimulation produced by electroconvulsive shock did not increase the expression of AKAP‐150. This implies that the AKAP‐150 harbours a novel property of selective responsiveness to the stimulation patterns that trigger NMDA‐dependent LTP in vivo. Its selective up‐regulation during LTP and its identified functions as a scaffold for protein kinase A, protein kinase C, calmodulin, calcineurin and ionotropic glutamate receptors suggest that AKAP‐150 encodes is an important effector protein in the expression of late LTP.
Dopamine gating of forebrain neural ensembles
Authors: O'Donnell Patricio
Published: March 2003

Dopamine may exert different actions depending on a number of factors. A common view is that D1 receptors may be responsible for excitatory actions whereas D2 receptors are involved in inhibitory actions. However, this position cannot be reconciled with several findings indicating otherwise. The role of dopamine on forebrain neural ensembles may be better understood in the light of functional states of the system. Pyramidal cortical neurons and striatal medium spiny neurons alternate between two membrane potential states (‘up’ and ‘down’) that could shape dopamine actions. It is proposed that D1 receptors can act as state‐stabilizers by sustaining up states and thereby facilitating plasticity mechanisms by providing postsynaptic depolarization and increasing NMDA function. In this way, dopamine can sustain activity in depolarized units. This action is accompanied by a decrease in cell firing (perhaps mediated by D2 receptors), which renders the cells responsive only to strong stimuli. The result would be a net increase in signal‐to‐noise ratio in a selected assembly of neurons.
Fos imaging reveals ageing‐related changes in hippocampal response to radial maze discrimination testing in mice
Authors: Touzani Khalid , Marighetto Aline , Jaffard Robert
Published: March 2003

A two‐stage radial arm maze (RAM) task has been designed recently to demonstrate a specific age‐related memory deficit in mice. It highlights the contrast between normal and deficient memory expression in a spatial discrimination problem depending on how to‐be discriminated arms were presented to the animal. This specific deficit has been interpreted as a preferential loss in a relational/declarative form of memory, thereby implying an underlying hippocampal dysfunction. To test this hypothesis, neuronal activation measured by Fos immunostaining was compared in aged (21–23 months) and adult (4–6 months) mice trained in the aforementioned task and killed after a retention session consisting in age‐insensitive probe trials, performed 6 days later (6‐day RAM). Two comparison conditions were included: (i) repeated locomotor training on a treadmill (TM); (ii) the same RAM training, except for the use of a longer (30 days instead of six) retention interval (30‐day RAM). Although all RAM groups displayed similar levels of performance at the end of the experiment, immediately before the mice were killed, significant between‐group differences in brain activation were observed. In adult mice, 6‐day RAM testing was associated with greater septal and hippocampal (CA1, CA3, DG) Fos expression than the TM condition. Lengthening the retention interval from 6 days to 30 days resulted in a significant decrease in RAM testing‐induced Fos expression in most of the septo‐hippocampal regions. With respect to adult mice, aged mice displayed reduced Fos expression (except for DG) and a lack of interrelationships between levels of Fos produced in each of the SH regions, in the 6‐day RAM testing condition. Conversely, there was no effect of ageing on Fos expression associated with either TM training or 30‐day RAM testing. These results are interpreted as reflecting age‐ (or time‐) related alterations in recruiting of brain structures that underlie a relational/declarative form of memory expression.
Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus
Authors: Varga V. , Kocsis B. , Sharp T.
Published: March 2003

Neuronal projections to the dorsal raphe nucleus (DRN) from the medial prefontal cortex (mPFC) and lateral habenula nucleus (LHb) provide the two key routes by which information processed by mood regulatory, cortico‐limbic‐striatal circuits input into the 5‐HT system. These two projections may converge as it appears that both activate local GABAergic neurons to inhibit 5‐HT neurons in the DRN. Here we have tested this hypothesis by measuring the effect of stimulation of the mPFC and LHb on the activity of 5‐HT and non‐5‐HT, putative γ‐amino butyric acid (GABA) neurons in the DRN using extracellular recordings in anaesthetized rats. A total of 119 5‐HT neurons (regular, slow firing, broad spike width) and 21 non‐5‐HT, putative GABA neurons (fast‐firing, narrow spike width) were tested. Electrical stimulation of the mPFC or LHb caused a poststimulus inhibition (30 ms latency) of 101/119 5‐HT neurons, of which 61 (60%) were inhibited by both the mPFC and LHb. Electrical stimulation of the mPFC or LHb also caused a short latency (12–20 ms) poststimulus facilitation of 10/21 non‐5‐HT neurons, of which 5 (50%) were activated by both the mPFC and LHb. These data indicate that a significant number of 5‐HT neurons and non‐5‐HT neurons in the DRN are influenced by both the mPFC and LHb. Moreover, the data are compatible with the hypothesis and that there is a convergence of mPFC and LHb inputs on local circuit GABAergic neurons in the DRN which in turn inhibit the activity of 5‐HT neurons.
Endogenous and exogenous dopamine presynaptically inhibits glutamatergic reticulospinal transmission via an action of D2‐receptors on N‐type Ca2+ channels
Authors: Svensson Erik , Wikström Martin A. , Hill Russell H. , Grillner Sten
Published: March 2003

In this study, the effects of exogenously applied and endogenously released dopamine (DA), a powerful modulator of the lamprey locomotor network, are examined on excitatory glutamatergic synaptic transmission between reticulospinal axons and spinal neurons. Bath application of DA (1–50 µm) reduced the amplitude of monosynaptic reticulospinal‐evoked glutamatergic excitatory postsynaptic potentials (EPSPs). The effect of DA was blocked by the D2‐receptor antagonist eticlopride, and mimicked by the selective D2‐receptor agonist 2,10,11 trihydroxy‐N‐propyl‐noraporphine hydrobromide (TNPA). Bath application of the DA reuptake blocker bupropion, which increases the extracellular level of dopamine, also reduced the monosynaptic EPSP amplitude. This effect was also blocked by the D2‐receptor antagonist eticlopride. To investigate if the action of DA was exerted at the presynaptic level, the reticulospinal axon action potentials were prolonged by administering K+ channel antagonists while blocking l‐type Ca2+ channels. A remaining Ca2+ component, mainly dependent on N and P/Q channels, was depressed by DA. When DA (25–50 µm) was applied in the presence of ω‐conotoxin GVIA, a toxin specific for N‐type Ca2+ channels, it failed to affect the monosynaptic EPSP amplitude. DA did not affect the response to extracellularly ejected d‐glutamate, the postsynaptic membrane potential, or the electrical component of the EPSPs. DA thus acts at the presynaptic level to modulate reticulospinal transmission.
The effects of nitric oxide on magnocellular neurons could involve multiple indirect cyclic GMP‐dependent pathways
Authors: Vacher C. M. , Hardin‐Pouzet H. , Steinbusch H. W. M. , Calas A. , De Vente J.
Published: March 2003

Nitric oxide (NO) is known to regulate the release of arginine‐vasopressin (AVP) and oxytocin (OT) by the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). The aim of the current study was to identify in these nuclei the NO‐producing neurons and the NO‐receptive cells in mice. The determination of NO‐synthesizing neurons was performed by double immunohistochemistry for the neuronal form of NO synthase (NOS), and AVP or OT. Besides, we visualized the NO‐receptive cells by detecting cyclic GMP (cGMP), the major second messenger for NO, by immunohistochemistry on hypothalamus slices. Neuronal NOS was exclusively colocalized with OT in the PVN and the SON, suggesting that NO is mainly synthesized by oxytocinergic neurons in mice. By contrast, cGMP was not observed in magnocellular neurons, but in GABA‐, tyrosine hydroxylase‐ and glutamate‐positive fibers, as well as in GFAP‐stained cells. The cGMP‐immunostaining was abolished by incubating brain slices with a NOS inhibitor (L‐NAME). Consequently, we provide the first evidence that NO could regulate the release of AVP and OT indirectly by modulating the activity of the main afferents to magnocellular neurons rather than by acting directly on magnocellular neurons. Moreover, both the NADPH‐diaphorase activity and the mean intensity of cGMP‐immunofluorescence were increased in monoamine oxidase A knock‐out mice (Tg8) compared to control mice (C3H) in both nuclei. This suggests that monoamines could enhance the production of NO, contributing by this way to the fine regulation of AVP and OT release and synthesis.