bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo regulation of dopamine and noradrenaline release by α2A‐adrenoceptors in the mouse prefrontal cortex
Authors: Ihalainen Jouni A. , Tanila Heikki
Published: March 2003

The present study investigated the role of α2A‐adrenoceptor subtype in the regulation of noradrenaline and dopamine release in the medial prefrontal cortex. The effect of local introduction of the α2‐adrenoceptor agonist dexmedetomidine (10−9−10−8 m) on noradrenaline and dopamine release was investigated in α2A‐adrenoceptor knockout and control mice by using in vivo microdialysis. Furthermore, to reveal a possible distinction between regulation of baseline and peak release, we sampled the dialysate during both rest and handling‐induced mild stress. Baseline noradrenaline and dopamine concentrations did not differ between α2A‐adrenoceptor knockout and control mice. Dexmedetomidine decreased, in a concentration‐dependent manner, noradrenaline and dopamine levels in both genotypes. However, the effect of dexmedetomidine on noradrenaline release was attenuated in the α2A‐adrenoceptor knockout mice, whereas the effect on dopamine release did not differ between the genotypes. The first handling episode increased noradrenaline and dopamine levels to the same extent in both genotypes. However, in α2A‐adrenoceptor knockout mice the noradrenaline and dopamine levels remained elevated in the samples following the first handling whilst, in the control mice, transmitter levels returned to baseline levels. In control mice the handling‐induced peak noradrenaline and dopamine levels were lower after the administration of dexmedetomidine than during the first handling episode, but in α2A‐adrenoceptor knockout mice no drug effect on handling‐induced peak noradrenaline and dopamine levels was found. Our results suggest that the release of noradrenaline in the medial prefrontal cortex is mainly regulated via α2A‐adrenoceptors, whilst other α‐adrenoceptor subtypes play a significant role in the regulation of dopamine release.
Differential Ca2+‐dependence of transmitter release mediated by P/Q‐ and N‐type calcium channels at neonatal rat neuromuscular junctions
Authors: Rosato‐Siri Marcelo D. , Piriz Joaquin , Tropper Barbara A. Giugovaz , Uchitel Osvaldo D.
Published: March 2003

N‐ and P/Q‐type voltage dependent calcium channels (VDCCs) mediate transmitter release at neonatal rat neuromuscular junction (NMJ). Thus the neonatal NMJ allows an examination of the coupling of different subtypes of VDCCs to the release process at a single synapse. We studied calcium dependence of transmitter release mediated by each channel by blocking with ω‐conotoxin GVIA the N‐type channel or with ω‐agatoxin IVA the P/Q‐type channel while changing the extracellular calcium concentration ([Ca2+]o). Transmitter release mediated by P/Q‐type VDCCs showed steeper calcium dependence than N‐type mediated release (average slope 3.6 ± 0.09 vs. 2.6 ± 0.03, respectively). Loading the nerve terminals with 10 µm BAPTA‐AM in the extracellular solution reduced transmitter release and occluded the blocking effect of ω‐conotoxin GVIA (blockade −2 ± 9%) without affecting the action of ω‐agatoxin IVA (blockade 85 ± 4%). Both VDCC blockers were able to reduce the amount of facilitation produced by double‐pulse stimulation. In these conditions facilitation was restored by increasing [Ca2+]o. The facilitation index (fi) was also reduced by loading nerve terminals with 10 µm BAPTA‐AM (fi = 1.2 ± 0.1). The control fi was 2.5 ± 0.1. These results show that P/Q‐type VDCCs were more efficiently coupled to neurotransmitter release than were N‐type VDCCs at the neonatal neuromuscular junction. This difference could be accounted for by a differential location of these channels at the release site. In addition, our results indicate that space–time overlapping of calcium domains was required for facilitation.
Effects of nursing mothers on rPer1 and rPer2 circadian expressions in the neonatal rat suprachiasmatic nuclei vary with developmental stage
Authors: Ohta Hidenobu , Honma Sato , Abe Hiroshi , Honma Ken‐ichi
Published: March 2003

The ability of nursing mothers to entrain the circadian pacemaker of rat pups was examined by measuring the rat Per1 (rPer1) and rPer2 expression levels in the suprachiasmatic nuclei (SCN). Newborn rats from mothers under a light–dark cycle (LD) were blinded immediately after birth and reared by foster mothers under either LD (LD blind pups) or reversed light–dark cycle (DL; DL blind pups). At postnatal day (P)6, small but significant phase differences were observed in the circadian gene expression rhythms of the SCN not only between the blind and sighted pups, but also between the two groups of blind pups, indicating the involvement of both free‐running and maternal influence in phase‐resetting the circadian rhythms of blind pups. However, from P6 to P13 the circadian rhythms of both LD and DL blind pups showed phase delays of similar extent, which suggests that the influence of nursing mothers was lost. From P13 to P20 (the day of weaning), the rPer1 and rPer2 rhythms phase‐shifted in a different manner, the rPer2 rhythm being related more closely to the behavioural rhythm than was the rPer1. This finding suggests a differential influence of mothers on the rPer1 and rPer2 rhythms in the third week of life. It is concluded that the ability of nursing mothers to entrain pup circadian oscillation depends on the developmental stage.
Synaptic localization of GABAA receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum
Authors: Fujiyama Fumino , Stephenson F. Anne , Bolam J. Paul
Published: March 2003

The inhibitory amino acid, γ‐aminobutyric acid (GABA), plays a critical role in the substantia nigra (SN) in health and disease. GABA transmission is controlled in part by the type(s) of GABA receptor expressed, their subunit composition and their location in relation to GABA release sites. In order to define the subcellular localization of GABAA receptors in the SN in normal and pathological conditions, sections of SN from control rats and rats that had received quinolinic acid lesions of the striatum were immunolabelled using the postembedding immunogold technique with antibodies against subunits of the GABAA receptor. Immunolabelling for α1, β2/3 and γ2 subunits was primarily located at symmetrical synapses. Double‐labelling revealed that β2/3 subunit‐positive synapses were formed by terminals that were enriched in GABA. Colocalization of α1, β2/3 and γ2 subunits occurred at individual symmetrical synapses, some of which were identified as degenerating terminals derived from the striatum. In the SN ipsilateral to the striatal lesion there was a significant elevation of immunolabelling for β2/3 subunits of the GABAA receptor at symmetrical synapses, but not of GluR2/3 subunits of the AMPA receptor at asymmetrical synapses. It was concluded that fast GABAA‐mediated transmission occurs primarily at symmetrical synapses within the SN, that different receptor subunits coexist at individual synapses and that the upregulation of GABAA receptors following striatal lesions is expressed as increased receptor density at synapses. The upregulation of GABAA receptors in Huntington's disease and its models is thus likely to lead to an increased efficiency of transmission at intact GABAergic synapses in the SN and may partly underlie the motor abnormalities of this disorder.
Donepezil reverses a mnemonic deficit produced by scopolamine but not by perforant path lesion or transient cerebral ischaemia
Authors: Higgins G.A. , Enderlin M. , Fimbel R. , Haman M. , Grottick A.J. , Soriano M. , Richards J.G. , Kemp J.A. , Gill R.
Published: March 2003

The purpose of these studies were threefold. Firstly, to further characterize the effect of perforant path transection on a test of short‐term memory: delayed matching (or nonmatching)‐to‐position [D(N)MTP]. Secondly, to evaluate the effect of a transient cerebral ischaemia in the same task. Both surgical procedures were chosen as they produce a CNS lesion similar to that described in Alzheimer's Disease (AD). Thirdly, the effect of the acetylcholinesterase inhibitor, donepezil (Aricept®, E2020), on the resulting cognitive impairment was studied. Perforant path transection produced a robust, delay‐dependent impairment of choice accuracy in rats performing either a delayed matching‐ or nonmatching‐to‐position task. Sample latency was also reduced following lesion, yet the lesion‐induced impairment was not affected by increasing the response requirement at the sample stage. An 11‐min period of transient ischaemia (two‐vessel occlusion model) resulted in almost complete loss of hippocampal CA1 pyramidal cells and a delay‐dependent impairment in DMTP performance. However, unlike perforant path lesions, this deficit was unstable and declined in magnitude over the experimental period. Increasing the delay interval restored this deficit. Donepezil, at doses that robustly attenuated a scopolamine (0.06 mg/kg s.c.)‐induced DMTP accuracy impairment in naïve, unoperated rats, had no effect against either lesion‐induced impairment. The results are considered in terms of the effectiveness of acetylcholinesterase inhibitors in noncholinergic‐based preclinical cognitive models.
Cannabinoids inhibit excitatory inputs to neurons in the shell of the nucleus accumbens: an in vivo electrophysiological study
Authors: Pistis Marco , Muntoni Anna Lisa , Pillolla Giuliano , Gessa Gian Luigi
Published: March 2003

The nucleus accumbens (NAc) represents a critical site for the rewarding properties of diverse classes of drugs of abuse. Glutamatergic afferents to the NAc are involved in the actions of psychostimulants and opioids, while the potentiation of dopaminergic neurotransmission in the NAc is a common feature of abused drugs, including cannabinoids. Cannabinoid receptors (CB1) are densely expressed in regions that provide excitatory innervation to the NAc, such as the amygdala, the cortex and the hippocampus. Recent in vitro evidence suggests that indeed cannabinoids modulate glutamatergic synapses in the NAc. In this study we recorded extracellularly from neurons in the shell of the NAc which responded to the stimulation of the baso‐lateral amygdala (BLA) or the medial prefrontal cortex (PFC) in urethane anaesthetized rats. BLA or PFC stimulation induced generation of action potentials in NAc neurons. This excitatory effect was strongly inhibited by the synthetic cannabinoid agonists WIN 55212,2 (0.062–0.25 mg/kg, i.v.) and HU‐210 (0.125–0.25 mg/kg, i.v.) or the psychoactive principle of Cannabis delta(9)‐tetrahydrocannabinol (1.0 mg/kg, i.v.). Neither the D1 or D2 dopamine receptor antagonists (SCH23390 0.5–1.0 mg/kg, sulpiride 5–10 mg/kg, i.v.) or the opioid antagonist naloxone (1.0 mg/kg, i.v.) were able to reverse the action of cannabinoids, while the selective CB1 receptor antagonist/reverse agonist SR141716A (0.5 mg/kg, i.v.) fully suppressed the action of cannabinoid agonists, whereas per se had no significant effect. These results provide evidence that cannabinoids, in common with other drugs of abuse, in vivo strongly inhibit the excitability of neurons in the shell of the NAc.
Modulation by adenosine of both muscarinic M1‐facilitation and M2‐inhibition of [3H]‐acetylcholine release from the rat motor nerve terminals
Authors: Oliveira Laura , Timóteo M. Alexandrina , Correia‐de‐Sá Paulo
Published: March 2003

The crosstalk between adenosine and muscarinic autoreceptors regulating evoked [3H]‐acetylcholine ([3H]‐ACh) release was investigated on rat phrenic nerve‐hemidiaphragm preparations. Motor nerve terminals possess facilitatory M1 and inhibitory M2 autoreceptors that can be activated by McN‐A‐343 (1–30 µm) and oxotremorine (0.3–100 µm), respectively. The muscarinic receptor antagonist, dicyclomine (3 nm−10 µm), caused a biphasic (inhibitory/facilitatory) effect, indicating that M1‐facilitation prevails during 5 Hz stimulation trains. Concomitant activation of AF–DX 116‐sensitive M2 receptors was partially attenuated, as pretreatment with M1 antagonists, muscarinic toxin 7 (MT‐7, 0.1 nm) and pirenzepine (1 nm), significantly enhanced inhibition by oxotremorine. Activation of A2A‐adenosine receptors with CGS 21680C (2 nm) (i) potentiated oxotremorine inhibition, and (ii) shifted McN‐A‐343‐induced facilitation into a small inhibitory effect. Conversely, the A1‐receptor agonist, R‐N6‐phenylisopropyl adenosine (R‐PIA, 100 nm), attenuated the inhibitory effect of oxotremorine, without changing facilitation by McN‐A‐343. Synergism between A2A and M2 receptors is regulated by a reciprocal interaction with facilitatory M1 receptors, which may be prevented by pirenzepine (1 nm). During 50 Hz‐bursts, facilitation (M1) of [3H]‐ACh release by McN‐A‐343 disappeared, while the inhibitory (M2) effect of oxotremorine became predominant. This muscarinic shift results from the interplay with A2A receptors, as it was precluded by the selective A2A receptor antagonist, ZM 241385 (10 nm). In conclusion, when the muscarinic M1 positive feedback loop is fully operative, negative regulation of ACh release is mediated by adenosine A1 receptors. During high frequency bursts, tonic activation of A2A receptors promotes M2 autoinhibition by braking the M1 receptor operated counteraction.
Posterior parietal cortex control of reach‐to‐grasp movements in humans
Authors: Chapman Heidi , Gavrilescu Maria , Wang Hong , Kean Michael , Egan Gary , Castiello Umberto
Published: March 2003

The aim of the present study was to ascertain the neural correlates for the integration of visual information with the control of the reach‐to‐grasp action in the healthy human brain. Nine adult subjects (18–38 years; four females and five males) were scanned using functional magnetic resonance imaging while reaching‐to‐grasp a three‐dimensional target. Results demonstrated differential activation of the parietal cortices according to the number of potential targets to be taken into account before movement initiation and the variability of target location. Comparing conditions where a target object that can appear at an unpredictable location with conditions where the target object appears at a predictable location revealed activations in the left superior parietal lobule, the left parieto‐occipital sulcus and the right intraparietal sulcus. Results are discussed in terms of visual selective attention and action planning.
Variations in cell density in the ganglion cell layer of the retina as a function of ocular pigmentation
Authors: Donatien Philippe , Aigner Bernhard , Jeffery Glen
Published: March 2003

Ocular melanin regulates retinal development, including cell density gradients in the central retina, a region essential for normal visual acuity. In albinos this region is underdeveloped and peak cell numbers are reduced. It is not known whether there is a dosage relationship between pigmentation and the degree of this underdevelopment, as studies of the retinal effects of albinism have commonly used rodents. These have poorly developed central regions even in the wild type. Rabbits, however, have a unique, highly specialized, visual streak in the central retina where cell density gradients are very steep and these are reduced in albinos. Here, cell densities in the ganglion cell layer of separate groups of rabbits, with different levels of ocular pigmentation and known mutations of the tyrosinase gene coding sequence, were examined. These revealed reductions in peak cell densities and/or in the regions over which high cell densities were maintained in all hypopigmented phenotypes. There was no dosage relationship between levels of pigmentation and deficits in the ganglion cell layer as animals with relatively small reductions in retinal pigment had deficits comparable to those found in albinos. The greatest variability between pigmentation phenotypes was between the two completely unpigmented strains. Consequently, although pigment may regulate the development of the central retina, this study failed to show that it does so in a dose‐dependent manner.
Reminder effects – reconsolidation or retrieval deficit? Pharmacological dissection with protein synthesis inhibitors following reminder for a passive‐avoidance task in young chicks
Authors: Anokhin Konstantin V. , Tiunova Anna A. , Rose Steven P. R.
Published: March 2003

It is generally accepted that memory formation involves an irreversible passage via labile phases to the stable form of ‘long‐term memory’ impervious to amnestic agents such as protein synthesis inhibitors. However, recent experiments demonstrate that reactivation of memory by way of a reminder renders it labile to such inhibitors, suggesting that such retrieval is followed by a so‐called reconsolidation process similar or identical in its cellular and molecular correlates to that occurring during the initial consolidation. We compared the effects of the protein synthesis inhibitor anisomycin and the glycoprotein synthesis inhibitor 2‐deoxygalactose on the temporal dynamics and pharmacological sensitivity of initial consolidation and memory expression following a reminder in a one‐trial passive‐avoidance task in day‐old chicks. This comparison revealed three differences between the action of the inhibitors on newly formed compared with reactivated memory. First, the recall deficit after the reminder was temporary, whilst the amnesia following inhibitor treatment during training was stable. Second, the sensitive period for the effect of anisomycin was shorter in the reminder than in the training situation. Third, the effective dose for either inhibitor for reminder‐associated amnesia was several times lower than for amnesia developing after training. Thus though like initial consolidation, memory expression at delayed periods following reminder depends on protein and glycoprotein synthesis, the differences between the temporal and pharmacological dynamics in the two situations point to the distinct character of the molecular processes involved in postreminder effects.
The contribution of the intrinsic excitability of vestibular nucleus neurons to recovery from vestibular damage
Authors: Darlington Cynthia L. , Dutia Mayank B. , Smith Paul F.
Published: March 2003

Damage to the peripheral vestibular system results in a syndrome of ocular motor and postural abnormalities that partially and gradually abate over time in a process known as ‘vestibular compensation’. The first, rapid, phase of compensation has been associated with a recovery of spontaneous resting activity in the ipsilateral vestibular nucleus complex (VNC), as a consequence of neuronal and synaptic plasticity. Increasing evidence suggests that normal VNC neurons in labyrinthine‐intact animals, as well as ipsilateral VNC neurons following unilateral vestibular deafferentation (UVD), rely to some extent on intrinsic pacemaker activity provided by voltage‐dependent conductances for their resting activity. Modification of this intrinsic pacemaker activity may underlie the recovery of resting activity that occurs in ipsilateral VNC neurons following UVD. This review summarizes and critically evaluates the ‘intrinsic mechanism hypothesis’, identifying discrepancies amongst the current evidence and suggesting experiments that may test it further.
Specific expression of the cell cycle regulation proteins, GADD34 and PCNA, in the peri‐infarct zone after focal cerebral ischaemia in the rat
Authors: Imai H. , Harland J. , McCulloch J. , Graham D.I. , Brown S.M. , Macrae I.M.
Published: March 2003

Cell cycle proteins play key roles in cell survival or death under pathological conditions. Expression of growth arrest and DNA damage‐inducible protein, GADD34 and proliferating cell nuclear antigen (PCNA) have been investigated in the core and peri‐infarct zone at 2 and 24 h after middle cerebral artery occlusion (MCAO). At these times after MCAO, numerous GADD34‐positive cells were present, particularly in the peri‐infarct zone (e.g. 24 ± 4 and 52 ± 6 immunopositive cells/0.25 mm2 at 2 and 24 h, respectively, in cortex). PCNA‐immunopositive cells were barely detectable in the peri‐infarct zone at 2 h; however, numerous PCNA‐immunopositive cells were present in this zone by 24 h (0.7 ± 0.3 and 10.6 ± 1.5 immunopositive cells/0.25 mm2, respectively) as well as in the adjacent cortex and in the contralateral cingulate cortex. Most GADD34‐immunopositive cells coexpressed the neuronal marker Neu‐N with a smaller number coexpressing the microglial marker, Mrf‐1. Evidence of morphologically ‘abnormal’ and ‘normal’ GADD34 immunopositive neurons was found within the peri‐infarct zone. The majority of PCNA immunopositive cells were Mrf‐1 positive with a smaller number Neu‐N positive. Double‐labelling revealed colocalization of GADD34 and PCNA in some cells within the peri‐infarct zone and in the ependymal cells lining the ventricles. The presence of GADD34 and PCNA in a key anatomical location pertinent to the evolving ischaemic lesion indicates that GADD34, either alone or in combination with PCNA, has the potential to influence cell survival in ischaemically compromised tissue.
A point mutant of GAP‐43 induces enhanced short‐term and long‐term hippocampal plasticity
Authors: Hulo S. , Alberi S. , Laux T. , Muller D. , Caroni P.
Published: March 2003

The growth‐associated protein GAP‐43 (or neuromodulin or B‐50) plays a critical role during development in mechanisms of axonal growth and formation of synaptic networks. At later times, GAP‐43 has also been implicated in the regulation of synaptic transmission and properties of plasticity such as long‐term potentiation. In a molecular approach, we have analyzed transgenic mice overexpressing different mutated forms of GAP‐43 or deficient in GAP‐43 to investigate the role of the molecule in short‐term and long‐term plasticity. We report that overexpression of a mutated form of GAP‐43 that mimics constitutively phosphorylated GAP‐43 results in an enhancement of long‐term potentiation in CA1 hippocampal slices. This effect is specific, because LTP was affected neither in transgenic mice overexpressing mutated forms of non‐phosphorylatable GAP‐43 nor in GAP‐43 deficient mice. The increased LTP observed in transgenic mice expressing a constitutively phosphorylated GAP‐43 was associated with an increased paired‐pulse facilitation as well as an increased summation of responses during high frequency bursts. These results indicate that, while GAP‐43 is not necessary for LTP induction, its phosphorylation may regulate presynaptic properties, thereby affecting synaptic plasticity and the induction of LTP.
Involvement of Cajal–Retzius cells in robust and layer‐specific regeneration of the entorhino‐hippocampal pathways
Authors: Del Río José A. , Solé Marta , Borrell Víctor , Martínez Albert , Soriano Eduardo
Published: March 2003

Severed adult CNS axons can extend over long distances when a permissive ‘milieu’, such as grafted Schwann cells or ensheathing cells, is provided. Moreover, functional blocking of endogenous inhibitory factors, such as Nogo‐A or proteoglycans, enhances the regeneration of axotomized neurons. Here we examine whether guidance cues available during the development of axonal pathways could also potentiate the regeneration of lesioned adult circuits. The Cajal–Retzius cells in the hippocampus are transient pioneer neurons that guide entorhino‐hippocampal afferents to their target layers. By using an in vitro model of axotomy of the entorhino‐hippocampal pathway we show that Cajal–Retzius cells triggered the regeneration of the axotomized entorhino‐hippocampal pathway. Furthermore, the regrowth induced by Cajal–Retzius cells was robust and its pattern was indistinguishable from that of the unlesioned entorhino‐hippocampal pathway. Thus, regenerating axons regrew in a layer‐specific fashion towards the appropriate target layers, making synaptic contacts with target pyramidal neurons. Interestingly, the ability of lesioned entorhinal axons to regrow was maintained for at least 9 days after axotomy. These results show that the growth‐promoting cells controlling the development of neural circuits will be a relevant approach to promoting the regeneration of lesioned adult CNS pathways.
The influence of selective lesions to components of the hippocampal system on the orientating response, habituation and latent inhibition
Authors: Oswald C. J. P. , Yee B. K. , Rawlins J. N. P. , Bannerman D. B. , Good M. , Honey R. C.
Published: March 2003

The contribution that components of the hippocampal system in the rat make to the modulation of attention or stimulus processing was assessed using several simple behavioural assays: the orienting response (OR) to a novel stimulus, the subsequent habituation and dishabituation of this OR, and the latent inhibition effect that typically results from repeated exposure to a stimulus. Excitotoxic lesions of components of the hippocampal system produce dissociable effects on the OR, habituation and latent inhibition: lesions of the entorhinal cortex have no effect on the OR or changes in the OR during exposure to a stimulus, but disrupt latent inhibition; lesions of the subiculum disrupt the OR but not latent inhibition; and lesions of the hippocampus disrupt the OR and latent inhibition. These effects have important implications for our understanding of habituation and latent inhibition, and the neural mechanisms involved in attentional modulation.
Multiple zonal projections of the nucleus reticularis tegmenti pontis to the cerebellar cortex of the rat
Authors: Serapide M. F. , Parenti R. , Pantò M. R. , Zappalà A. , Cicirata F.
Published: March 2003

Compartmentalization (alternating labelled and unlabelled stripes) of mossy fibre terminals was found in the cerebellar cortex after iontophoretic injections of biotinylated dextran amine into discrete regions of the nucleus reticularis tegmenti pontis (NRTP). The zonal pattern was only observed when volumes of nuclear tissue ranging from 4.5 × 106 to 17.66 × 106 µm3 were impregnated. Up to nine compartments (i.e. up to five stripes separated by four interstripes) were found in crus I and in vermal lobule VI. Up to seven compartments (four stripes and three interstripes) were found in crus II; up to five compartments (three stripes and two interstripes) were identified in the lobulus simplex, the paraflocculus and vermal lobules IV, V and VII; up to three compartments (two stripes and one interstripe) were identified in the paramedian lobule and, finally, up to two compartments (one stripe and one interstripe) were identified in the copula pyramidis, in the flocculus and in vermal lobules II, III, VIII and IX. The projections of the NRTP are arranged according to a divergent/convergent projection pattern. From single injections in the NRTP, projections were traced to a set of cortical stripes widely distributed over the cerebellar cortex. The set of stripes labelled from different regions of the NRTP partially overlapped but complete overlap was never found. This finding revealed that the topographic combination of the projections of the NRTP to the cerebellar cortex is specific for each region of the NRTP. Finally, the projections to single cortical areas were arranged according to a pattern of compartmentalization that is specific for each cortical area, independent of the site of injection in the NRTP and of the number of stripes evident in the cortex.
Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia
Authors: Tang Yang , Lu Aigang , Aronow Bruce J. , Wagner Kenneth R. , Sharp Frank R.
Published: March 2003

RNA expression profiles in rat brain were examined 24 h after ischemic stroke, intracerebral haemorrhage, kainate‐induced seizures, insulin‐induced hypoglycemia, and hypoxia and compared to sham‐ or untouched controls. Rat oligonucleotide microarrays were used to compare expression of over 8000 transcripts from three subjects in each group (n = 27). Of the somewhat less than 4000 transcripts called ‘present’ in normal or treated cortex, 5–10% of these were up‐regulated 24 h after ischemia (415), haemorrhage (205), kainate (187), and hypoglycemia (302) with relatively few genes induced by 6 h of moderate (8% oxygen) hypoxia (15). Of the genes induced 24 h after ischemia, haemorrhage, and hypoglycemia, approximately half were unique for each condition suggesting unique components of the responses to each of the injuries. A significant component of the responses involved immune‐process related genes likely to represent responses to dying neurons, glia and vessels in ischemia; to blood elements in haemorrhage; and to the selectively vulnerable neurons that die after hypoglycemia. All of the genes induced by kainate were also induced either by ischemia, haemorrhage or hypoglycemia. This strongly supports the concept that excitotoxicity not only plays an important role in ischemia, but is an important mechanism of brain injury after intracerebral haemorrhage and hypoglycemia. In contrast, there was only a single gene that was down‐regulated by all of the injury conditions suggesting there is not a common gene down‐regulation response to injury.
Effect of systemic nitroglycerin on CGRP and 5‐HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen
Authors: Pardutz A. , Multon S. , Malgrange B. , Parducz A. , Vecsei L. , Schoenen J.
Published: March 2003

Systemic administration of nitroglycerin, a nitric oxide donor, triggers in migraine patients a delayed attack of unknown mechanism. After puberty migraine is more prevalent in women. Attacks can be triggered by abrupt falls in plasma estrogen levels, which accounts in part for sexual dimorphism, but lacks an established neurobiological explanation. We studied the effect of nitroglycerin on the innervated area of calcitonin gene‐related peptide (CGRP) and serotonin‐immunoreactive afferents to the superficial laminae of the spinal portion of trigeminal nucleus caudalis, and its modulation by estrogen. In male rats, nitroglycerin produced after 4 h a significant decrease of the area innervated by CGRP‐immunoreactive afferents and an increase of that covered by serotonin‐immunoreactive fibres. These effects were not observed in the superficial laminae of thoracic dorsal horns. The effect of nitroglycerin was similar in ovariectomized females. In estradiol‐treated ovariectomized females the area in the spinal portion of trigeminal nucleus caudalis laminae I–II covered by CGRP‐immunoreactive fibres was lower and that of serotonin‐immunoreactive fibres was higher than in males and for both transmitters not significantly changed after nitroglycerin. The bouton size of CGRP profiles was smaller in estradiol‐treated ovariectomized females, whereas after nitroglycerin it decreased significantly but only in males and ovariectomized females. Nitroglycerin, i.e. nitric oxide, is thus able to differentially influence afferent fibres in the superficial laminae of rat spinal trigeminal nucleus caudalis. Estradiol modulates the basal expression of these transmitters and blocks the nitroglycerin effect. These data may contribute to understanding the mechanisms by which estrogens influence migraine severity and the triggering of attacks by nitric oxide.
Expression and distribution of metabotropic GABA receptor subtypes GABABR1 and GABABR2 during rat neocortical development
Authors: López‐Bendito G. , Shigemoto R. , Kulik A. , Paulsen O. , Fairén A. , Luján R.
Published: March 2003

To understand the possible contribution of metabotropic γ‐aminobutyric acid receptors (GABABR) in cortical development, we investigated the expression pattern and the cellular and subcellular localization of the GABABR1 and GABABR2 subtypes in the rat neocortex from embryonic day 14 (E14) to adulthood. At the light microscopic level, both GABABR1 and GABABR2 were detected as early as E14. During prenatal development, both subtypes were expressed highly in the cortical plate. Using double immunofluorescence, GABABR1 colocalized with GABABR2 in neurons of the marginal zone and subplate, indicating that these proteins are coexpressed and could be forming functional GABABRs during prenatal development in vivo. In contrast, only GABABR1 but not GABABR2 was detected in the tangentially migratory cells in the lower intermediate zone. During postnatal development, immunoreactivity for GABABR1 and GABABR2 was distributed mainly in pyramidal cells. Discrete GABABR1‐immunopositive cell bodies of interneurons were present throughout the neocortex. In addition, GABABR1 but not GABABR2 was found in identified Cajal‐Retzius cells in layer I. At the electron microscopic level, immunoreactivity for GABABR1 and GABABR2 was found in dendritic spines and dendritic shafts at extrasynaptic and perisynaptic sites throughout postnatal development. We further demonstrated the presynaptic localization of GABABR1 and GABABR2, as well as the association of the receptors with asymmetrical synaptic junctions. These results indicate potentially important roles for the GABABRs in the regulation of migratory processes during corticogenesis and in the modulation of synaptic transmission during early development of cortical circuitry.
Direct measurement of local raised subplasmalemmal calcium concentrations in growth cones advancing on an N‐cadherin substrate
Authors: Chadborn Neil , Eickholt Britta , Doherty Patrick , Bolsover Stephen
Published: March 2003

We have used the membrane‐localized calcium probe fura‐piperazine‐C12H25 (FFP‐18) to examine cytosolic calcium concentrations in a volume close to the plasmalemma. Although promotion of axon outgrowth by cell adhesion molecules requires extracellular calcium and is correlated with an opening of plasmalemmal channels, conventional indicators cannot detect a change in the calcium concentration in such stimulated growth cones. We have examined calcium signalling in chick retinal ganglion cell growth cones extending along stripes of N‐cadherin. Subplasmalemmal calcium concentrations, reported by FFP‐18, were significantly higher in these growth cones than in neighbouring growth cones on either fibronectin or polylysine. In contrast, the bulk cytosolic calcium concentration throughout the growth cone, as measured by Fura‐2, was identical in growth cones on and off the N‐cadherin stripes. Our results suggest that guidance cues can use extremely local calcium signals to control pathfinding decisions.
Pineal arylalkylamine N‐acetyltransferase gene expression is highly stimulated at night in the diurnal rodent, Arvicanthis ansorgei
Authors: Garidou Marie‐Laure , Gauer François , Vivien‐Roels Berthe , Sicard Bruno , Pévet Paul , Simonneaux Valérie
Published: March 2003

The different mechanisms underlying the control of diurnal vs. nocturnal activity are still unknown. Regarding the nocturnal synthesis of the pineal hormone, melatonin, experiments performed on diurnal sheep or bovine and on nocturnal rat or hamster revealed important differences in the regulation of the melatonin rate‐limiting enzyme, arylalkylamine N‐acetyltransferase (AA‐NAT). These observations raised the hypothesis that melatonin synthesis may be different in nocturnal vs. diurnal animals. In this study, we cloned the cDNA coding for Aa‐nat and analysed the mechanisms of AA‐NAT enzyme activation in the pineal gland of the diurnal grass rat, Arvicanthis ansorgei, and compared them to those of the nocturnal Wistar rat, Rattus norvegicus. Aa‐nat gene sequences of both species are 86.6% identical. In Arvicanthis, Aa‐nat gene expression is markedly increased at the beginning of the night and is followed by a large increase in AA‐NAT activity and melatonin content. In contrast, at the end of the night, the decrease in AA‐NAT activity and melatonin content precedes that of Aa‐nat mRNA. A β‐adrenergic agonist given at daytime reproduces the nocturnal activation of melatonin synthesis, whereas, a β‐adrenergic antagonist given at night‐time inhibits AA‐NAT activity and melatonin synthesis independently of Aa‐nat mRNA. The day–night regulation of melatonin synthesis in the pineal of the diurnal Arvicanthis, involving a transcriptional activation in early night and a post‐translational inhibition at late night, is very similar to that of the nocturnal Wistar rat. In conclusion, the fundamental differences underlying melatonin synthesis among species rely upon phylogenetic rather than behavioural differences.
Rapid regrowth of hippocampal mossy fibres and preceding maturation of NMDA receptor‐mediated neurotransmission
Authors: Ikegaya Yuji , Koyama Ryuta , Yamada Maki K. , Nishiyama Nobuyoshi , Matsuki Norio
Published: March 2003

Early in postnatal development, glutamatergic synapses contain primarily NMDA receptors and progressively acquire AMPA receptor function. To determine whether this transformation occurs in a process of regenerative synaptogenesis following axotomy, we investigated the recovery of AMPA and NMDA receptor‐mediated neurotransmission after the transection of mossy fibres (MF) in organotypic hippocampal cultures. An NMDA component could already be elicited 1 day after the lesion and reached a saturated level after 3 days. Thereafter, an AMPA component appeared and slowly matured after 10 days. The preceding establishment of NMDA receptor function implies that immature MF synapses are functionally silent at least for the first several days of recovery. The appearance of AMPA receptor‐mediated neurotransmission was unchanged in the presence of an NMDA‐receptor antagonist or tetrodotoxin, which suggests that the AMPA receptor maturation is virtually independent of neuronal activity. Thus, the conversion of silent to functional synapses is not unique to synaptic plasticity or developmental processes but also occurs in recovery after brain damage, but its mechanism is likely to differ from NMDA receptor‐dependent recruitment of AMPA receptors in synaptic plasticity.
Amphetamine and cocaine do not increase Narp expression in rat ventral tegmental area, nucleus accumbens or prefrontal cortex, but Narp may contribute to individual differences in responding to a novel environment
Authors: Lu W. , Marinelli M. , Xu D. , Worley P. F. , Wolf M. E.
Published: March 2003

Narp is an immediate early gene product that acts extracellularly to cluster AMPA receptors at excitatory synapses. The present study tested the hypothesis that drugs of abuse alter Narp expression and thereby influence AMPA receptor transmission in addiction‐related circuits. Immunohistochemical studies demonstrated the existence of Narp‐positive cells in hippocampus, prefrontal cortex (PFC) and nucleus accumbens (NAc), with lower levels of staining in the ventral tegmental area (VTA). To study the effects of psychomotor stimulants, Narp levels were quantified by Western blotting and normalized to actin. There were no differences in Narp levels in any brain region between rats treated with repeated saline injections, a single amphetamine injection (5 mg/kg), repeated amphetamine injections (5 mg/kg × 5 days), or repeated cocaine injections (20 mg/kg twice daily × 7 days). We also examined the possible role of Narp in individual differences in responding to a novel environment, a predictor of behavioural responses to psychomotor stimulant drugs including the propensity to acquire drug self‐administration. Narp levels in the PFC, but not other regions, were significantly correlated with locomotor activity in a novel environment. These findings suggest that differential Narp expression in the PFC may be involved in determining individual vulnerability to drugs of abuse, perhaps by influencing the activity of its excitatory projections.
5,7‐DHT‐induced hippocampal 5‐HT depletion attenuates behavioural deficits produced by 192 IgG‐saporin lesions of septal cholinergic neurons in the rat
Authors: Lehmann Olivia , Bertrand Fabrice , Jeltsch Hélène , Morer Martine , Lazarus Christine , Will Bruno , Cassel Jean‐Christophe
Published: March 2003

Adult Long–Evans male rats sustained injections of 5,7‐dihydroxytryptamine into the fimbria–fornix (2.5 µg/side) and the cingular bundle (1.5 µg/side) and/or to intraseptal injections of 192 IgG‐saporin (0.4 µg/side) in order to deprive the hippocampus of its serotonergic and cholinergic innervations, respectively. Sham‐operated rats were used as controls. The rats were tested for locomotor activity (postoperative days 18, 42 and 65), spontaneous T‐maze alternation (days 20–29), beam‐walking sensorimotor (days 34–38), water maze (days 53–64) and radial maze (days 80–133) performances. The cholinergic lesions, which decreased the hippocampal concentration of ACh by about 65%, induced nocturnal hyperlocomotion, reduced T‐maze alternation, impaired reference‐memory in the water maze and working‐memory in the radial maze, but had no effect on beam‐walking scores and working‐memory in the water maze. The serotonergic lesions, which decreased the serotonergic innervation of the hippocampus by about 55%, failed to induce any behavioural deficit. In the group of rats given combined lesions, all deficits produced by the cholinergic lesions were observed, but the nocturnal hyperlocomotion and the working‐memory deficits in the radial maze were attenuated significantly. These results suggest that attenuation of the serotonergic tone in the hippocampus may compensate for some dysfunctions subsequent to the loss of cholinergic hippocampal inputs. This observation is in close concordance with data showing that a reduction of the serotonergic tone, by pharmacological activation of somatodendritic 5‐HT1A receptors on raphe neurons, attenuates the cognitive disturbances produced by the intrahippocampal infusion of the antimuscarinic drug, scopolamine. This work has been presented previously [Serotonin Club/Brain Research Bulletin conference, Serotonin: From Molecule to the Clinic (satellite to the Society for Neuroscience Meeting, New Orleans, USA, November 2–3, 2000)].
Direction‐specific motion blindness induced by focal stimulation of human extrastriate cortex
Authors: Blanke O. , Landis T. , Safran A. B. , Seeck M.
Published: March 2003

Motion blindness (MB) or akinetopsia is the selective disturbance of visual motion perception while other features of the visual scene such as colour and shape are normally perceived. Chronic and transient forms of MB are characterized by a global deficit of direction discrimination (pandirectional), which is generally assumed to result from damage to, or interference with, the motion complex MT+/V5. However, the most characteristic feature of primate MT‐neurons is not their motion specificity, but their preference for one direction of motion (direction specificity). Here, we report that focal electrical stimulation in the human posterior temporal lobe selectively impaired the perception of motion in one direction while the perception of motion in other directions was completely normal (unidirectional MB). In addition, the direction of MB was found to depend on the brain area stimulated. It is argued that direction specificity for visual motion is not only represented at the single neuron level, but also in much larger cortical units.
Effects of intralaminar thalamic nuclei lesion on glutamic acid decarboxylase (GAD65 and GAD67) and cytochrome oxidase subunit I mRNA expression in the basal ganglia of the rat
Authors: Bacci Jean‐Jacques , Kerkerian‐Le Goff Lydia , Salin Pascal
Published: March 2003

This study investigated the influence of thalamic inputs on neuronal metabolic activity in the rat basal ganglia. By means of in situ hybridization histochemistry, we examined the consequences of ibotenate‐induced unilateral lesion of intralaminar thalamic nuclei on mRNA expression of cytochrome oxidase subunit‐I (CoI) in the striatum and the subthalamic nucleus (STN) and of the two isoforms of glutamate decarboxylase (GAD65 and GAD67) in the striatum, globus pallidus (GP), entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr). In the striatum, GAD67 mRNA expression decreased selectively in the rostral part of the structure at 5 and 12 days postlesion (≈−30%), whereas, GAD65 mRNA levels was downregulated only in the caudal striatum at 12 days (−29%). In both the striatum and STN, CoI mRNA expression decreased ipsilaterally at 5 and bilaterally at 12 days. In GP, GAD67 and GAD65 mRNA expression decreased ipsilaterally at 5 (−20% and −26%) and 12 days (−23% and −36%). In EP, selective bilateral decreases in GAD67 mRNA expression were found at 5 and 12 days (−50% and −40%). Conversely, in SNr, only GAD65 mRNA expression was reduced bilaterally at both time points. These data show that the thalamus exerts a widespread excitatory influence on the basal ganglia network that cannot be accounted for solely by its known direct connections. Given the recent data showing that intralaminar thalamic nuclei are a major nondopaminergic site of neurodegeneration in Parkinson's disease, these results may have a critical bearing on understanding the cellular basis of basal ganglia dysfunction in parkinsonism.
Effects of transgenic overproduction of CRH on anxiety‐like behaviour
Authors: Van Gaalen Marcel M. , Stenzel‐Poore Mary P. , Holsboer Florian , Steckler Thomas
Published: March 2003

Central administration of corticotropin‐releasing hormone increases anxiety‐like behaviour and arousal in rodents, and increased anxiety‐like behaviour has been shown in mice overproducing corticotropin‐releasing hormone on an elevated plus maze and in a dark–light emergence task. However, evidence is accumulating that measures obtained from different anxiety tasks may reflect different aspects of anxiety‐like behaviour in animals. We therefore tested mice overproducing corticotropin‐releasing hormone in a battery of paradigms, studying spontaneous behaviour after a mild stressor, tasks of innate anxiety‐like behaviour (light–dark box), lick suppression (Vogel conflict), conditioned fear, and forced swimming. Exploratory behaviour was studied in a 16‐hole board task. Furthermore, pain threshold, water intake, locomotor activity and sensorimotor learning/co‐ordination were tested to control for confounding factors. In line with previous findings, increased anxiety‐like behaviour of transgenic mice was observed in the light–dark box paradigm. However, no differences were seen in the conflict paradigm. Conditioned fear was decreased 1 h but not 24 h after conditioning in transgenic mice, and immobility was increased in forced swimming in corticotropin‐releasing hormone overexpressors. Locomotor activity in a novel open field and on the hole board was reduced in transgenics. Exploratory behaviour (hole pokes) was reduced during initial exploration of an unfamiliar hole board. Moreover, sensorimotor performance on a rotorod was impaired, and water intake was reduced in corticotropin‐releasing hormone overproducing mice, while no changes were seen in nociception. No differences in locomotor activity were seen in a second group of mice, tested in a familiar open field. When these animals were challenged with diazepam, transgenic mice were less susceptible to the sedative effects of the drug on locomotor activity. These data suggest that corticotropin‐releasing hormone overproduction leads to specific effects in a subset of anxiety paradigms, and that these transgenic mice suffer from a motor deficit in addition to altered anxiety‐like behaviour/arousal.