bluuebunny/crossref_metadata_2025 huggingface dataset:
Key role for enkephalinergic tone in cortico–striatal–thalamic function
Authors: Solbrig Marylou V. , Koob George F. , Lipkin W. Ian
Published: March 2003

Whereas the role of dopaminergic tone in the cortico‐striatal‐thalamic system is well‐established, the role of endogenous opioids in the function of this system is less understood. We show that Borna disease virus infection of adult rats results in an increase in preproenkephalin transcripts in the striatum of Borna‐infected rats, a region important for forming coordinated sequential motor actions and in developing programmes of thought and motivation. Stereotypic behaviours and dyskinesias, the clinical hallmarks of infection in adult Lewis rats (BD rats), are accompanied by a disrupted pattern of immediate early gene c‐fos activation in the motor thalamus, with significance for the breakdown in coordinated sequential motor actions. We also find increased preproenkephalin in infected cultured neuroblastoma and rat foetal glial cells. The expression pattern of enkephalin mRNA in vivo and in vitro suggest that increased enkephalin function is one of the neuropharmacological means by which Borna disease virus causes motor disease of animals and possibly cognitive and affective disease in man, and further suggest that enkephalins play a critical role in the maintenance of a balanced tone of activity in the cortico‐basal ganglia‐thalamo‐cortical loops.
Sexual dimorphism in the spontaneous recovery from spinal cord injury: a gender gap in beneficial autoimmunity?
Authors: Hauben Ehud , Mizrahi Tal , Agranov Evgenia , Schwartz Michal
Published: March 2003

Immune cells have been shown to contribute to spontaneous recovery from central nervous system (CNS) injury. Here we show that adult female rats and mice recover significantly better than their male littermates from incomplete spinal cord injury (ISCI). This sexual dimorphism is wiped out and recovery is worse in adult mice deprived of mature T cells. After spinal cord contusion in adult rats, functional recovery (measured by locomotor scores in an open field) was significantly worse in females treated with dihydrotestosterone prior to the injury than in placebo‐treated controls, and significantly better in castrated males than in their noncastrated male littermates. Post‐traumatic administration of the testosterone receptor antagonist flutamide promoted the functional recovery in adult male rats. These results, in line with the known inhibitory effect of testosterone on cell‐mediated immunity, suggest that androgen‐mediated immunosuppression plays a role in ISCI‐related immune dysfunction and can therefore partly explain the worse outcome of ISCI in males than in female. We suggest that females, which are more prone to develop autoimmune response than males, benefit from this response in cases of CNS insults.
Characterization of a novel NCAM ligand with a stimulatory effect on neurite outgrowth identified by screening a combinatorial peptide library
Authors: Rønn Lars C. B. , Olsen Marianne , Soroka Vladislav , Østergaard Søren , Dissing Steen , Poulsen Flemming M. , Holm Arne , Berezin Vladimir , Bock Elisabeth
Published: March 2003

The neural cell adhesion molecule, NCAM, plays a key role in neural development and plasticity mediating cell adhesion and signal transduction. By screening a combinatorial library of synthetic peptides with NCAM purified from postnatal day 10 rat brains, we identified a nonapeptide, termed NCAM binding peptide 10 (NBP10) and showed by nuclear magnetic resonance analysis that it bound the NCAM IgI module of NCAM. NBP10 modulated cell aggregation as well as neurite outgrowth induced specifically by homophilic NCAM binding. Moreover, both monomeric and multimeric forms of NBP10 stimulated neurite outgrowth from primary hippocampal neurons. The neurite outgrowth response to NBP10 was inhibited by a number of compounds previously shown to inhibit neurite outgrowth induced by homophilic NCAM binding, including voltage‐dependent calcium channel antagonists, suggesting that NBP10 induced neurite outgrowth by activating a signal transduction pathway similar to that activated by NCAM itself. Moreover, an inhibitor of intracellular calcium mobilization, TMB‐8, prevented NBP10‐induced neurite outgrowth suggesting that NCAM‐dependent neurite outgrowth also requires mobilization of calcium from intracellular calcium stores in addition to calcium influx from extracellular sources. By single‐cell calcium imaging we further demonstrated that NBP10 was capable of inducing an increase in intracellular calcium in PC12E2 cells. Thus, the NBP10 peptide is a new tool for the study of molecular mechanisms underlying NCAM‐dependent signal transduction and neurite outgrowth, and could prove to be a useful modulator of regenerative processes in the peripheral and central nervous system.
Reorganization of descending motor tracts in the rat spinal cord
Authors: Raineteau Olivier , Fouad Karim , Bareyre Florence M. , Schwab Martin E.
Published: March 2003

Following lesion of the central nervous system (CNS), reinnervation of denervated areas may occur via two distinct processes: regeneration of the lesioned fibres or/and sprouting from adjacent intact fibres into the deafferented zone. Both regeneration and axonal sprouting are very limited in the fully mature CNS of higher vertebrates, but can be enhanced by neutralizing the neurite outgrowth inhibitory protein Nogo‐A. This study takes advantage of the distinct spinal projection pattern of two descending tracts, the corticospinal tract (CST) and the rubrospinal tract (RST), to investigate if re‐innervation of denervated targets can occur by sprouting of anatomically separate, undamaged tracts in the adult rat spinal cord. The CST was transected bilaterally at its entry into the pyramidal decussation. Anatomical studies of the RST in IN‐1 antibody‐treated rats showed a reorganization of the RST projection pattern after neutralization of the myelin associated neurite growth inhibitor Nogo‐A. The terminal arborizations of the rubrospinal fibres, which are normally restricted to the intermediate layers of the spinal cord, invaded the ventral horn but not the dorsal horn of the cervical spinal cord. Moreover, new close appositions were observed, in the ventral horn, onto motoneurons normally receiving CST projections. Red nucleus microstimulation experiments confirmed the reorganization of the RST system. These observations indicate that mature descending motor tracts are capable of significant intraspinal reorganization following lesion and suggests the expression of cues guiding and/or stabilizing newly formed sprouts in the adult, denervated spinal cord.
Overexpression of corticotropin‐releasing hormone in transgenic mice and chronic stress‐like autonomic and physiological alterations
Authors: Dirks Anneloes , Groenink Lucianne , Bouwknecht J. Adriaan , Hijzen Theo H. , Van Der Gugten Jan , Ronken Eric , Verbeek J. Sjef , Veening Jan G. , Dederen Pieter J. W. C. , Korosi Aniko , Schoolderman Louise F. , Roubos Eric W. , Olivier Berend
Published: March 2003

To gain a greater insight into the relationship between hyperactivity of the corticotropin‐releasing hormone (CRH) system and autonomic and physiological changes associated with chronic stress, we developed a transgenic mouse model of central CRH overproduction. The extent of central and peripheral CRH overexpression, and the amount of bioactive CRH in the hypothalamus were determined in two lines of CRH‐overexpressing (CRH‐OE) mice. Furthermore, 24 h patterns of body temperature, heart rate, and activity were assessed using radiotelemetry, as well as cumulative water and food consumption and body weight gain over a 7‐day period. CRH‐OE mice showed increased amounts of CRH peptide and mRNA only in the central nervous system. Despite the presence of the same CRH transgene in their genome, only in one of the two established lines of CRH‐OE mice (line 2122, but not 2123) was overexpression of CRH associated with increased levels of bioactive CRH in the hypothalamus, increased body temperature and heart rate (predominantly during the light (inactive) phase of the diurnal cycle), decreased heart rate variability during the dark (active) phase, and increased food and water consumption, when compared with littermate wildtype mice. Because line 2122 of the CRH transgenic mice showed chronic stress‐like neuroendocrine and autonomic changes, these mice appear to represent a valid animal model for chronic stress and might be valuable in the research on the consequences of CRH excess in situations of chronic stress.
Retinofugal projections following early lesions of the visual cortex in the ferret
Authors: Restrepo C. Ernesto , Manger Paul R. , Innocenti Giorgio M.
Published: March 2003

Extensive lesions of the occipital cortex comprising the developing occipital visual areas and beyond in young ferrets (postnatal day 5) are followed by massive, but incomplete, degeneration of the lateral geniculate (LGN) and lateralis posterior (LP) nuclei of the thalamus, and minor volumetric reduction of the superior colliculus. Retinal projections (revealed by intraocular tracer injections), while reduced, remain confined to their territories of normal termination, both in the adult and throughout development. Comparisons with other mammalian species point to several common features in the developmental plasticity of retinofugal pathway.
Cellular imaging with zif268 expression in the rat nucleus accumbens and frontal cortex further dissociates the neural pathways activated following the retrieval of contextual and cued fear memory
Authors: Thomas Kerrie L. , Hall Jeremy , Everitt Barry J.
Published: March 2003

Quantitative in situ hybridization revealed that the expression of the plasticity‐associated gene zif268 was increased in specific regions of the rat frontal cortex and nucleus accumbens following fear memory retrieval. Increased expression of zif268 was observed in neurons in the core of the nucleus accumbens during the retrieval of contextual and discrete cued fear associations. In contrast, zif268 expression was additionally induced in neurons of the nucleus accumbens shell and the anterior cingulate cortex during the retrieval of contextual but not cued fear memories. No changes in the expression of this gene were seen in the ventral medial prefrontal cortex or ventral and lateral regions of the orbitofrontal cortex that were correlated specifically with the retrieval of fear memory. These experiments demonstrate the specific and dissociable activation of limbic cortical–ventral striatal regions that accompanies cued and contextual fear. These data, together with those previously published by our laboratory (Hall, J., Thomas, K.L. & Everitt, B.J. (2001) J. Neurosci., 21, 2186–2193), suggest that retrieval of contextual fear memories activates a wider limbic cortical–ventral striatal neural circuitry than does retrieval of cued fear memories. Moreover, the expression of zif268 may contribute to plasticity and reconsolidation of fear memory in these dissociable pathways.
EphB receptors influence growth of ephrin‐B1‐positive statoacoustic nerve fibers
Authors: Bianchi Lynne M. , Gray Neil A.
Published: March 2003

The Eph family of receptors and ligands has been implicated in a variety of developmental processes, including the provision of inhibitory guidance cues to developing nerve fibers. A unique property of the B class of receptors is that they are able to phosphorylate ephrin‐B ligands, allowing for bi‐directional, or reverse signalling. While most of the studies to date have focused on central nerve fibers, little is known about the role of Eph molecules in guiding nerve fibers of the peripheral nervous system. In the present study, ephrin‐B1 was found to be highly expressed on developing peripheral nerve fibers including auditory and vestibular (statoacoustic) and dorsal root ganglion nerve fibers. In vitro assays revealed that EphB‐Fc receptors inhibited further growth of statoacoustic nerve fibers. In contrast, EphA7‐Fc and ephrin‐B2‐Fc did not prevent further growth of SAG. Together, these results suggest a role for EphB receptors in providing guidance signals to ephrin‐B1‐positive SAG nerve fibers.
Conditioned appetitive stimulus increases extracellular dopamine in the nucleus accumbens of the rat
Authors: Datla K. P. , Ahier R. G. , Young A. M. J. , Gray J. A. , Joseph M. H.
Published: March 2003

This study used in vivo microdialysis to examine the release of dopamine (DA) in the nucleus accumbens (nAc) during the performance of a previously learned, signalled sucrose reward task, and during conditioning of a neutral tone stimulus to this reward. Behavioural measures (magazine entries) confirmed that stimuli associated with sucrose presentation became secondary rewarding stimuli, and DA release was also monitored during subsequent presentation of these stimuli alone. Perhaps surprisingly, during magazine entry for consumption of sucrose, i.e. in conditions similar to routine training, dialysate DA levels in the nAc did not increase. In contrast, during conditioning of the tone with light‐sucrose, dopamine levels increased consistently and significantly. Interestingly, DA levels were somewhat, but significantly, increased when tone alone was presented in a test session, i.e. two hours after conditioning, and even more so when tone was combined with the light previously associated with sucrose. In this latter case the number of magazine entries increased to a level similar to that seen during conditioning. Presentation of light alone resulted in a similar level of magazine entries to tone alone, but no significant increase in DA. In summary, these studies confirm that a neutral stimulus can acquire the behavioural properties of reward when conditioned. The neurochemical data, on the other hand, suggest that increases of DA in nAc are more likely to be related to new associative learning than to established incentive or consumatory processes. The increase in DA release in the test session may be related either to the secondary reinforcing properties acquired by the stimulus, or to the change in contingencies, or to the aversive effects of the omission of reward.
Plantar flexor stretch reflex responses to whole body loading/unloading during human walking
Authors: Grey Michael J. , Van Doornik Johan , Sinkjær Thomas
Published: March 2003

Numerous animal and human studies have shown that afferent information from the periphery contributes to the control of walking. In particular, recent studies have consistently shown that load receptor input is an important element of the locomotion control mechanism. The objective of this study was to investigate the contribution of load receptor feedback to the compensatory stretch reflex response. We examined the contribution of load receptor feedback to the magnitude of the short and medium latency components of the ankle plantar flexor stretch reflex responses following an unexpected dorsiflexion perturbation during human walking. Three body load conditions were investigated: normal body load, a 30% increase in body load, and a 30% decrease in body load. Healthy subjects walked on a treadmill at ∼ 3.6 km/h with the left ankle attached to a portable stretching device. Dorsiflexion perturbations (8°; 350–425 °/s) were generated during the late stance phase of gate (∼ 400 ms following heel contact). Electromyographic activity was recorded from the soleus, tibialis anterior, medial gastrocnemius, rectus femoris, and biceps femoris muscles using bipolar surface electrodes. Stretch reflex responses were observed in the soleus and gastrocnemius muscles for all of the body load conditions; however, increasing or decreasing the body load did not affect the timing and magnitude of the responses. This study provides evidence that load receptor input does not contribute strongly to the corrective response of the stretch reflex in the plantar flexor muscles during walking.
Interaction of linear vestibular and visual stimulation in the macaque ventral intraparietal area (VIP)
Authors: Schlack Anja , Hoffmann Klaus‐Peter , Bremmer Frank
Published: March 2003

Navigation in space requires the brain to combine information arising from different sensory modalities with the appropriate motor commands. Sensory information about self‐motion in particular is provided by the visual and the vestibular system. The macaque ventral intraparietal area (VIP) has recently been shown to be involved in the processing of self‐motion information provided by optical flow, to contain multimodal neurons and to receive input from areas involved in the analysis of vestibular information. By studying responses to linear vestibular, visual and bimodal stimulation we aimed at gaining more insight into the mechanisms involved in multimodal integration and self‐motion processing. A large proportion of cells (77%) revealed a significant response to passive linear translation of the monkey. Of these cells, 59% encoded information about the direction of self‐motion. The phase relationship between vestibular stimulation and neuronal responses covered a broad spectrum, demonstrating the complexity of the spatio‐temporal pattern of vestibular information encoded by neurons in area VIP. For 53% of the direction‐selective neurons the preferred directions for stimuli of both modalities were the same; they were opposite for the remaining 47% of the neurons. During bimodal stimulation the responses of neurons with opposite direction selectivity in the two modalities were determined either by the visual (53%) or the vestibular (47%) modality. These heterogeneous responses to unimodal and bimodal stimulation might be used to prevent misjudgements about self‐ and/or object‐motion, which could be caused by relying on information of one sensory modality alone.
Time‐dependent hierarchical organization of spatial working memory: a transcranial magnetic stimulation study
Authors: Nyffeler Thomas , Pierrot‐Deseilligny Charles , Felblinger Jaques , Mosimann Urs P. , Hess Christian W. , Müri René M.
Published: March 2003

The performance of memory‐guided saccades with two different delays (3 and 30 s of memorization) was studied in seven healthy subjects. Double‐pulse transcranial magnetic stimulation (dTMS) with an interstimulus interval of 100 ms was applied over the right dorsolateral prefrontal cortex (DLPFC) early (1 s after target presentation) and late (28 s after target presentation). Early stimulation significantly increased in both delays the percentage of error in amplitude (PEA) of contralateral memory‐guided saccades compared to the control experiment without stimulation. dTMS applied late in the delay had no significant effect on PEA. Furthermore, we found a significantly smaller effect of early stimulation in the long‐delay paradigm.

    These results suggest a time‐dependent hierarchical organization of the spatial working memory with a functional dominance of DLPFC during the early memorization, independent from the memorization delay. For a long memorization delay, however, working memory seems to have an additional, DLPFC‐independent component.
ATP and UTP excite sensory neurons and induce CREB phosphorylation through the metabotropic receptor, P2Y2
Authors: Molliver Derek C. , Cook Sean P. , Carlsten Julie A. , Wright Douglas E. , McCleskey Edwin W.
Published: March 2003

Extracellular ATP rapidly excites nociceptive sensory neurons by opening ATP‐gated ion channels (P2X receptors). Here, we describe two actions of both ATP and UTP on rat sensory neurons that are relatively slow and sustained: phosphorylation of the transcription factor CREB and delayed action potential firing that persists for tens of seconds after removal of the ligand. The pharmacology of these responses indicates that they are mediated by the metabotropic receptor P2Y2, and not by P2X receptors. CREB phosphorylation occurred in a subset of small peripherin‐positive neurons likely to be unmyelinated nociceptors. In situ hybridization analysis revealed widespread expression of P2Y2 mRNA in sensory neurons. CREB phosphorylation is mediated by both action‐potential‐evoked calcium influx and calcium release from intracellular stores. These findings suggest that P2Y2 contributes to the transduction of ATP‐mediated sensory signalling, and may be involved in the activity‐dependent regulation of nociceptor phenotype.
5,7‐dihydroxytryptamine lesions enhance and serotonergic grafts normalize the evoked overflow of acetylcholine in rat hippocampal slices
Authors: Birthelmer Anja , Schweizer Theresa , Jeltsch Hélène , Jackisch Rolf , Cassel Jean‐Christophe
Published: March 2003

Adult rats were subjected to intracerebroventricular injections of 5,7‐dihydroxytryptamine (5,7‐DHT; 150 µg) and, 15 days later, to intrahippocampal grafts of fetal raphe cell suspensions. About 11 months later, we assessed baseline and electrically evoked release of tritium ([3H]) in hippocampal slices, preloaded with tritiated ([3H])choline or [3H]serotonin (5‐HT), in the presence or absence of the 5‐HT1B receptor agonist CP‐93,129 and the 5‐HT receptor antagonist methiothepine. HPLC determinations of monoamine concentrations were also performed. The lesions reduced the concentration of 5‐HT (−90%) and the accumulation (−80%) as well as the evoked release (−90%) of [3H]5‐HT. They also decreased the inhibitory effects of CP‐93,129 on the evoked release of [3H]5‐HT. Most interestingly, they facilitated the evoked release of [3H]acetylcholine (+20%). In slices from rats subjected to lesions and grafts, the responsiveness of the serotonergic autoreceptors (presumably located on the terminals of the grafted neurons) and the release of acetylcholine were close to normal. These results confirm that grafts rich in serotonergic neurons may partially compensate for the dramatic effects of 5,7‐DHT lesions on serotonergic hippocampal functions. The lesion‐induced reduction of the 5‐HT1B autoreceptor‐mediated inhibition of evoked 5‐HT release may be an adaptation enhancing serotonergic transmission in the (few) remaining terminals. The facilitated release of acetylcholine is probably caused by a reduced serotonergic tone on the inhibitory 5‐HT1B heteroreceptors of the cholinergic terminals. When related to data in the literature, this facilitation may be of particular interest in terms of transmitter‐based strategies developed to tackle cognitive symptoms related to neurodegenerative diseases.
Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons
Authors: Chung Sangmi , Sonntag Kai‐C. , Andersson Therese , Bjorklund Lars M. , Park Jae‐Joon , Kim Dong‐Wook , Kang Un Jung , Isacson Ole , Kim Kwang‐Soo
Published: March 2003

Nurr1 is a transcription factor critical for the development of midbrain dopaminergic (DA) neurons. This study modified mouse embryonic stem (ES) cells to constitutively express Nurr1 under the elongation factor‐1α promoter. The Nurr1‐expression in ES cells lead to up‐regulation of all DA neuronal markers tested, resulting in about a 4‐ to 5‐fold increase in the proportion of DA neurons. In contrast, other neuronal and glial markers were not significantly changed by Nurr1 expression. It was also observed that there was an additional 4‐fold increase in the number of DA neurons in Nurr1‐expressing clones following treatment with Shh, FGF8 and ascorbic acid. Several lines of evidence suggest that these neurons may represent midbrain DA neuronal phenotypes; firstly, they coexpress midbrain DA markers such as aromatic l‐amino acid decarboxylase, calretinin, and dopamine transporter, in addition to tyrosine hydroxylase and secondly, they do not coexpress other neurotransmitters such as GABA or serotonin. Finally, consistent with an increased number of DA neurons, the Nurr1 transduction enhanced the ability of these neurons to produce and release DA in response to membrane depolarization. This study demonstrates an efficient genetic manipulation of ES cells that facilitates differentiation to midbrain DA neurons, and it will serve as a framework of genetic engineering of ES cells by key transcription factor to regulate their cell fate.
Apomorphine induces trophic factors that support fetal rat mesencephalic dopaminergic neurons in cultures
Authors: Guo Hong , Tang Zhongshu , Yu Yi , Xu Lei , Jin Guozhang , Zhou Jiawei
Published: March 2003

Apomorphine, the catechol‐derived dopamine D1/D2 receptor agonist, is currently in use as an antiparkinsonian drug. It has previously been reported that apomorphine was able to elicit expression of the enzyme tyrosine hydroxylase, a marker for DA neurons, in the fetal rat cerebrocortical cultures whilst in the presence of brain‐derived neurotrophic factor. The present study demonstrated that treatment of fetal rat ventral mesencephalic cultures with apomorphine caused a marked increase in the number of dopaminergic neurons. The action of apomorphine can be mimicked by dopamine receptor (D1 and D2) agonists or blocked by preincubation with D1/D2 receptor antagonists. Incubation of recipient mesencephalic cultures with the conditioned medium derived from apomorphine‐stimulated donor mesencephalic cultures elicited a 3.72‐fold increase in the number of TH‐positive neurons. Increased mRNA expression levels of brain‐derived neurotrophic factor and glial cell line‐derived neurotrophic factor were also found in the apomorphine‐treated mesencephalic cells along with concomitant protein expression increases in the conditioned medium. Moreover, the trophic activity observed could be partially neutralized by antibodies against either brain‐derived neurotrophic factor or glial cell line‐derived neurotrophic factor. Cultured fetal striatal cells, but not hippocampal cells, also responded to apomorphine treatment. The membrane filtration studies revealed that both <30 kDa and >50 kDa fractions contained trophic activities. The latter characterization distinguishes them from most known neurotrophic factors. These results suggest that the apomorphine‐modulated development of dopaminergic neurons may be mediated by activation of the dopamine receptor subtypes D1and D2 thereby increasing the production of multiple growth factors.
The rat ponto‐medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study
Authors: Boissard Romuald , Gervasoni Damien , Schmidt Markus H , Barbagli Bruno , Fort Patrice , Luppi Pierre‐Hervé
Published: March 2003

The neuronal network responsible for paradoxical sleep (PS) onset and maintenance has not previously been identified in the rat, unlike the cat. To fill this gap, this study has developed a new technique involving the recording of sleep–wake states in unanaesthetized head‐restrained rats whilst locally administering pharmacological agents by microiontophoresis from glass multibarrel micropipettes, into the dorsal pontine tegmentum and combining this with functional neuroanatomy. Pharmacological agents used for iontophoretic administration included carbachol, kainic acid, bicuculline and gabazine. The injection sites and their efferents were then identified by injections of anterograde (phaseolus vulgaris leucoagglutinin) or retrograde (cholera toxin B subunit) tracers through an adjacent barrel of the micropipette assembly and by C‐Fos immunostaining. Bicuculline, gabazine and kainic acid ejections specifically into the pontine sublaterodorsal nucleus (SLD) induced within a few minutes a PS‐like state characterized by a continuous muscle atonia, low voltage EEG and a lack of reaction to stimuli. In contrast, carbachol ejections into the SLD induced wakefulness. In PHA‐L, glycine and C‐Fos multiple double‐labelling experiments, anterogradely labelled fibres originating from the SLD were seen apposed on glycine and C‐Fos positive neurons (labelled after 90 min of pharmacologically induced PS‐like state) from the ventral gigantocellular and parvicellular reticular nuclei. Altogether, these data indicate that the SLD nuclei contain a population of neurons playing a crucial role in PS onset and maintenance. Furthermore, they suggest that GABAergic disinhibition and glutamate excitation of these neurons might also play a crucial role in the onset of PS.
Ionic currents determining the membrane characteristics of type I spiral ganglion neurons of the guinea pig
Authors: Szabó ZS. , Harasztosi CS. , Sziklai I. , Szûcs G. , Rusznák Z.
Published: March 2003

Enzymatically isolated type I spiral ganglion neurons of the guinea pig have been investigated in the present study. The identity of the cells was confirmed by using anti‐neuron‐specific enolase immunostaining. The presence and shredding of the myelin sheath was also documented by employing anti‐S100 immunoreaction. The membrane characteristics of the cells were studied by using the whole‐cell patch‐clamp technique. The whole‐cell capacitance of the cells was 9 ± 2 pF (n = 51), while the resting membrane potential of the cells was −62 ± 9 mV (n = 19). When suprathreshold depolarizing stimuli were applied, the neurons fired a single action potential at the beginning of the stimulation. It was confirmed in this study that type I spiral ganglion cells possess a hyperpolarization‐activated nonspecific cationic current (Ih). The major characteristics of this current component were unaffected by the enzyme treatment. Type I spiral ganglion cells also expressed various depolarization‐activated K+ current components. A high‐threshold outward current was sensitive to 1–10 mm TEA+ application. The ganglion cells also expressed a relatively small, but nevertheless present, transient outward current component which was less sensitive to TEA+ but could be inhibited by 100 µm 4‐aminopyridine. A DTX‐I‐sensitive current was responsible for some 30% of the total outward current (at 0 mV), showed rapid activation at membrane potentials positive to −50 mV and demonstrated very little inactivation. However, inhibition of the highly 4‐AP‐ or DTX‐I‐sensitive component did not alter the rapidly inactivating nature of the firing pattern of the cells.
Physiological and morphological plasticity induced by chronic treatment with NT‐3 or NT‐4/5 in hippocampal slice cultures
Authors: Schwyzer Lucia , Mateos José María , Abegg Mathias , Rietschin Lotty , Heeb Lucette , Thompson Scott M. , Lüthi Andreas , Gähwiler Beat H. , McKinney R. Anne
Published: March 2003

Expression of neurotrophins (NTs) and their receptors is elevated in the adult CNS under several neuropathological conditions. We have investigated the anatomical and electrophysiological consequences of chronic NT‐3 or NT‐4/5 treatment on established organotypic hippocampal slice cultures maintained in vitro for > 14 days. Both NT‐3 and NT‐4/5 increased spontaneous, action potential‐dependent excitatory synaptic activity (sEPSCs), but only NT‐3 increased inhibitory synaptic activity (sIPSCs) in CA3 pyramidal cells. Both NTs strongly promoted spontaneous synaptic bursting activity. Spontaneous bursts of EPSCs were observed after either NT treatment but only NT‐3‐treated cultures exhibited an increase in spontaneous bursts of IPSCs. In addition, sIPSC bursts were eliminated by blocking glutamatergic excitation. The frequency of miniature inhibitory postsynaptic currents, but not miniature excitatory postsynaptic currents, was also increased by both NT‐3 and NT‐4/5. Furthermore, NT‐3 and NT‐4/5 induced an up‐regulation of the growth‐associated protein GAP‐43, suggesting that neurotrophins may be able to induce axonal reorganization in established neuronal networks. CA1 pyramidal cells exhibited slight alterations in dendritic branching after NT‐4/5, but not NT‐3 treatment. We conclude that chronic treatment with NT‐3 or NT‐4/5 can affect an established hippocampal network by elevating spontaneous inhibitory and excitatory synaptic activity and inducing coordinated pre‐ and postsynaptic structural changes.
Genetic and pharmacological demonstration of a role for cyclic AMP‐dependent protein kinase‐mediated suppression of protein phosphatases in gating the expression of late LTP
Authors: Woo Newton H. , Abel Ted , Nguyen Peter V.
Published: March 2003

Protein kinases and phosphatases play antagonistic roles in regulating hippocampal long‐term potentiation (LTP), with kinase inhibition and phosphatase activation both impairing LTP. The late phase of LTP (L‐LTP) requires activation of cAMP‐dependent protein kinase (PKA) for its full expression. One way in which PKA may critically modulate L‐LTP is by relieving an inhibitory constraint imposed by protein phosphatases. Using mutant PKA mice [R(AB) transgenic mice] that have genetically reduced hippocampal PKA activity, we show that deficient L‐LTP in area CA1 of mutant hippocampal slices is rescued by acute application of two inhibitors of protein phosphatase‐1 and protein phosphatase‐2A (PP1/2A) (okadaic acid and calyculin A). Furthermore, synaptic facilitation induced by forskolin, an adenylyl cyclase activator, was impaired in R(AB) transgenics and was also rescued by a PP1/2A inhibitor in mutant slices. Inhibition of PP1/2A did not affect early LTP (E‐LTP) or basal synaptic transmission in mutant and wildtype slices. Our data show that genetic inhibition of PKA impairs L‐LTP by reducing PKA‐mediated suppression of PP1/2A.
Periaqueductal gray and the region of the paralemniscal area have different functions in the control of vocalization in the neotropical bat, Phyllostomus discolor
Authors: Fenzl T. , Schuller G.
Published: March 2003

The periaqueductal gray matter and the region of the paralemniscal area were neuroanatomically delineated in the brain of the neotropical bat Phyllostomus discolor[Wagner (1843) Arch. Naturgesch., 9, 365–368] and were probed with electrical microstimulation for eliciting vocalizations. In a well‐delimited rostral portion of the periaqueductal gray exclusively, communication calls could be triggered at low stimulation currents. Communication calls as well as echolocation calls could be elicited at the dorsal and ventral edges of this area. Pharmacological stimulation with microdialysed kainic acid in this particular periaqueductal gray area demonstrated that neurons and not fibres of passage are activated for triggering vocalization. Solely echolocation calls were emitted upon electrical microstimulation or with microdialysed kainic acid in the region of the paralemniscal area. The periaqueductal gray appears to be involved in vocal pathways that control both communication calls and echolocation calls, while the region of the paralemniscal area seems to be specialized for control of echolocation calls only. Respiration is similarly influenced by stimulation in the periaqueductal gray and the region of the paralemniscal area. Periaqueductal gray and paralemniscal area interact differently with the final common pathway for vocalization, and may represent different functional organization in the vocal controlling pathways for communication calls and echolocation calls.
Tonically active neurons in the primate striatum and their role in the processing of information about motivationally relevant events
Authors: Apicella Paul
Published: March 2003

Analysis of recordings of single neuronal activity in the striatum of monkeys engaged in behavioural tasks has shown that tonically active neurons (TANs) can be distinguished by their distinct spontaneous firing and functional properties. As TANs are assumed to be cholinergic interneurons, the study of their physiological characteristics allows us to gain an insight into the role of a particular type of local‐circuit neuron in the processing of information at the striatal level. In monkeys performing various behavioural tasks, the change in the activity of TANs, unlike the diversity of task‐related activations exhibited by the phasically active population of striatal neurons, involves a transient depression of the tonic firing related to environmental events of motivational significance. Such events include primary rewards and stimuli that have acquired a reward value during associative learning. These neurons also respond to an aversive air puff, indicating that their responsiveness is not restricted to appetitive conditions. Another striking feature of the TANs is that their responses can be modulated by predictions about stimulus timing. Temporal variations in event occurrence have been found to favour the responses of TANs, whereas the responses are diminished or abolished in the presence of external cues that predict the time at which events will occur. These data suggest that the TANs respond as do detectors of motivationally relevant events, but they also demonstrate that these neurons are influenced by predictive information based on past experience with a given temporal context. TANs represent a unique subset of striatal neurons that might serve a modulatory function, monitoring for temporal relationships between environmental events.
The rostral migratory stream in adult squirrel monkeys: contribution of new neurons to the olfactory tubercle and involvement of the antiapoptotic protein Bcl‐2
Authors: Bédard Andréanne , Lévesque Martin , Bernier Patrick J. , Parent André
Published: March 2003

The subventricular zone (SVZ) lying along the ependymal layer of lateral ventricle is known to generate neural progenitor cells throughout adulthood in specific areas of the mammalian brain. In rodents, the anterior region of the SVZ produces neuroblasts that migrate in chain toward the olfactory bulb along the so‐called rostral migratory stream (RMS). In the present study, the organization of the RMS in a representative of New World primates – the squirrel monkey (Saimiri sciureus) – was studied by using bromodeoxyuridine (BrdU), a thymidine analogue that incorporates itself into the DNA of cells undergoing mitotic division. Double and triple immunofluorescence labelling with a confocal microscope served to visualize cells that expressed BrdU as well as molecular markers of neurogenesis. Numerous newborn (BrdU+) cells, many ensheated in glial (GFAP+) tubes, were scattered along the entire RMS in squirrel monkeys. Some of these BrdU+ cells expressed molecular markers for early committed neurons (TuJ1), postmitotic granular neuroblasts (TUC‐4) or mature neurons (MAP‐2, NeuN), and virtually all of them expressed the antiapoptotic protein Bcl‐2. A significant number of BrdU+ cells were found to deviate from the main stream of the RMS. Instead of reaching the olfactory bulb, these cells migrated ventrally into the olfactory tubercle, where they expressed a mature neuronal phenotype (MAP‐2). These findings reveal that the RMS in New World monkeys is mitotically robust and markedly extended and suggest that Bcl‐2 might play a role in the survival and/or differentiation of newborn neurons destined to olfactory bulb and olfactory tubercle in primates.
In vivo blockade of neural activity alters dendritic development of neonatal CA1 pyramidal cells
Authors: Groc Laurent , Petanjek Zdravko , Gustafsson Bengt , Ben‐Ari Yehezkel , Hanse Eric , Khazipov Roustem
Published: March 2003

During development, neural activity has been proposed to promote neuronal growth. During the first postnatal week, the hippocampus is characterized by an oscillating neural network activity and a rapid neuronal growth. In the present study we tested in vivo, by injecting tetanus toxin into the hippocampus of P1 rats, whether this neural activity indeed promotes growth of pyramidal cells. We have previously shown that tetanus toxin injection leads to a strong reduction in the frequency of spontaneous GABA and glutamatergic synaptic currents, and to a complete blockade of the early neural network activity during the first postnatal week. Morphology of neurobiotin‐filled CA1 pyramidal cells was analyzed at the end of the first postnatal week (P6–10). In activity‐reduced neurons, the total length of basal dendritic tree was three times less than control. The number, but not the length, of basal dendritic branches was affected. The growth impairment was restricted to the basal dendrites. The apical dendrite, the axons, or the soma grew normally during activity deprivation. Thus, the in vivo neural activity in the neonate hippocampus seems to promote neuronal growth by initiating novel branches.
Kindling‐induced overexpression of Homer 1A and its functional implications for epileptogenesis
Authors: Potschka H. , Krupp E. , Ebert U. , Gümbel C. , Leichtlein C. , Lorch B. , Pickert A. , Kramps S. , Young K. , Grüne U. , Keller A. , Welschof M. , Vogt G. , Xiao B. , Worley P. F. , Löscher W. , Hiemisch H.
Published: March 2003

Despite an extensive research on the molecular basis of epilepsy, the essential players in the epileptogenic process leading to epilepsy are not known. Gene expression analysis is one strategy to enhance our understanding of the genes contributing to the functional neuronal changes underlying epileptogenesis. In the present study, we used the novel MPSS (massively parallel signature sequencing) method for analysis of gene expression in the rat kindling model of temporal lobe epilepsy. Kindling by repeated electrical stimulation of the amygdala resulted in the differential expression of 264 genes in the hippocampus compared to sham controls. The most strongly induced gene was Homer 1A, an immediate early gene involved in the modulation of glutamate receptor function. The overexpression of Homer 1A in the hippocampus of kindled rats was confirmed by RT‐PCR. In order to evaluate the functional implications of Homer 1A overexpression for kindling, we used transgenic mice that permanently overexpress Homer 1A. Immunohistochemical characterization of these mice showed a marked Homer 1A overexpression in glutamatergic neurons of the hippocampus. Kindling of Homer 1A overexpressing mice resulted in a retardation of seizure generalization compared to wild‐type controls. The data demonstrate that kindling‐induced epileptogenesis leads to a striking overexpression of Homer 1A in the hippocampus, which may represent an intrinsic antiepileptogenic and anticonvulsant mechanism in the course of epileptogenesis that counteracts progression of the disease.
Neurokinin‐receptor‐mediated depolarization of cortical neurons elicits an increase in glutamate release at excitatory synapses
Authors: Stacey Anne E. , Woodhall Gavin L. , Jones Roland S. G.
Published: March 2003

Using whole‐cell patch‐clamp recordings of spontaneous synaptic activity, we have previously shown that activation of neurokinin‐1 (NK1) but not NK3 receptors leads to increased GABA release onto principal cells in the rat entorhinal cortex. In the present study, we examine the effect of activation of these receptors on spontaneous excitatory synaptic responses mediated by glutamate. Both neurokinin B (NKB) and the specific NK3 receptor agonist, senktide, increased the spontaneous release of glutamate, and a similar effect was also seen with substance P (SP) and other NK1 receptor agonists. The increased release induced by either SP or senktide was absent in the presence of tetrodotoxin, demonstrating that it was likely to occur via activation of presynaptic excitatory neurons. Current‐clamp recordings confirmed that principal neurons were depolarized by both NK3 and NK1 agonists. However, the response to the former but not the latter persisted in tetrodotoxin, allowing us to conclude that NK3 receptor activation provoked glutamate release via recurrent collaterals between principal neurons, whereas the NK1 receptors may be localized to excitatory interneurons. Finally, the increased release induced by senktide, but not SP, was reduced by an antagonist of group III metabotropic glutamate receptors. Thus, glutamate release from recurrent collaterals is facilitated by a presynaptic group III autoreceptor [Evans, D.I.P., Jones, R.S.G. & Woodhall, G.L. (2000) J. Neurophysiol.,83, 2519–2525], whereas the terminals of neurons responsible for the NK1‐receptor induced glutamate release may not bear these receptors. These results have implications for control of activity and epileptogenesis in cortical networks.
The role of the medial supramammillary nucleus in the control of hippocampal theta activity and behaviour in rats
Authors: Pan Wei‐Xing , McNaughton Neil
Published: March 2003

The medial supramammillary nucleus (mSUM) controls the frequency of hippocampal theta activity, completely in anaethsetized rats and partially in free‐moving rats. mSUM could therefore influence hippocampal contributions to cognition and emotion. Using chemical lesions of mSUM in rats, we tested whether mSUM is involved in controlling several hippocampal‐dependent functions: (i) defensive behaviour (open field, fear conditioning); (ii) behavioural inhibition (fixed interval schedule, differential reinforcement of low rates schedule); and (iii) spatial learning (water maze). Theta frequency was measured in all these tasks. mSUM lesions produced a pattern of changes in motivated/emotional behaviours (hyperactivity in defensive and operant tasks) similar to the pattern produced by hippocampal lesions, but had no significant effect on spatial learning. mSUM lesion decreased theta frequency modestly (by ≈ 0.4 Hz) in behaving rats if the amount of movement was unchanged. There was not always a parallel between changes in theta frequency and behaviour; behaviours changed despite unchanged theta in defensive tasks and learning changed little despite a lower frequency of theta in the water maze task. This suggests that mSUM function impacts on emotional behaviour more than cognition, and can modulate theta and behaviour independently.
Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus
Authors: Kulkarni Vaishali A. , Jha Shanker , Vaidya Vidita A.
Published: March 2003

The dentate gyrus region retains the ability to generate neurons throughout adulthood. A few studies have examined the neurotransmitter regulation of adult hippocampal neurogenesis and have shown that this process is regulated by serotonin and glutamate. Given the strong noradrenergic innervation of the adult hippocampus and the ability of norepinephrine to influence proliferation during development, we examined the influence of norepinephrine on adult hippocampal neurogenesis. Our study indicates that depletion of norepinephrine by the selective noradrenergic neurotoxin, N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromo benzylamine hydrochloride (DSP‐4), results in a 63% reduction in the proliferation of dentate gyrus progenitor cells identified through 5‐bromo‐2′‐deoxyuridine (BrdU) labelling. In contrast, the survival of BrdU‐positive cells labelled prior to treatment with DSP‐4 is not influenced by norepinephrine depletion. The differentiation of BrdU labelled progenitors into neurons or glia was also not sensitive to noradrenergic depletion. These results indicate that the proliferation, but not the survival or differentiation, of adult hippocampal granule cell progenitors is affected by norepinephrine depletion.
Translocation of apoptosis‐inducing factor in cerebellar granule cells exposed to neurotoxic agents inducing oxidative stress
Authors: Fonfría E. , Daré E. , Benelli M. , Suñol C. , Ceccatelli S.
Published: March 2003

We have previously shown that the neurotoxic compounds colchicine, methylmercury (MeHg) and hydrogen peroxide (H2O2) cause apoptosis in primary cultures of cerebellar granule cells (CGC), characterized by nuclear condensation and high‐molecular weight DNA fragmentation. However, only colchicine triggers the activation of caspases, suggesting that factors other than caspase‐activated DNase (CAD) are responsible for DNA cleavage in the other two models. Here we report that the two agents that cause oxidative stress, MeHg (1 µm) and H2O2 (50 µm), induce translocation of apoptosis‐inducing factor (AIF) from the mitochondria to the nucleus in CGC. Our data suggest that, in absence of caspase activity, AIF translocation could be a key event leading to chromatin condensation and DNA degradation in CGC exposed to MeHg and H2O2.