bluuebunny/crossref_metadata_2025_split huggingface dataset:
Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear
Authors: Falzone Tomás L. , Gelman Diego M. , Young Juan I. , Grandy David K. , Low Malcolm J. , Rubinstein Marcelo 
Published: March 2003

AbstractThe prefrontal cortex receives a major dopaminergic input from the ventral tegmental area, which plays an important role in the integration of neuronal signals influencing behavioural responses to stressful environmental stimuli. The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2‐like receptor localized in this brain area. To investigate the functional significance of D4Rs in dopamine‐mediated responses we have analysed a strain of mice lacking this receptor subtype (Drd4–/–). Wild‐type and Drd4–/– mice were challenged in two different approach/avoidance conflict paradigms: the elevated plus maze and the light/dark preference exploration test. By these behavioural measures Drd4–/– mice showed heightened avoidance to the more fear‐provoking areas of each maze as demonstrated by reduced exploration of the open arms of the plus maze and longer latencies to explore the illuminated compartment of the light/dark shuttle box. These exaggerated avoidance behaviours were further enhanced by an additional handling stress but completely prevented by anxiolytic agents such as the benzodiazepine midazolam and ethanol. Although Drd4–/– mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two‐bottle choice test. Learned fear responses evaluated by contextual, cued and instrumental fear‐conditioning tests showed no difference between wild‐type and Drd4–/– mice. Taken together these results indicate that the absence of D4Rs increases avoidance behaviour to unconditioned stimuli and does not impair behavioural reactions to Pavlovian fear‐conditioning, suggesting that the D4R could play a key role in the dopaminergic modulation of cortical signals triggered by environmental stimuli.
Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease
Authors: Lundblad M. , Andersson M. , Winkler C. , Kirik D. , Wierup N. , Cenci M. A. 
Published: March 2003

AbstractIn an attempt to define clinically relevant models of akinesia and dyskinesia in 6‐hydroxydopamine (6‐OHDA)‐lesioned rats, we have examined the effects of drugs with high (l‐DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6‐OHDA lesions received single daily i.p. injections of l‐DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, l‐DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than l‐DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, l‐DOPA‐treated animals showed declining levels of performance in this test because the drug‐induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. l‐DOPA‐induced axial, limb and orolingual AIM scores were significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (−91%, yohimbine 10 mg/kg; −19%, naloxone 4–8 mg/kg; −37%, 5‐methoxy 5‐N,N‐dimethyl‐tryptamine 2 mg/kg; −30%, clozapine 8 mg/kg; −50%, amantadine 40 mg/kg). l‐DOPA‐induced rotation was, however, not affected. The present results demonstrate that 6‐OHDA‐lesioned rats do exhibit motor deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.
Time‐dependent inhibition of hippocampal LTP in vitro following contextual fear conditioning in the rat
Authors: Sacchetti Benedetto , Lorenzini Carlo Ambrogi , Baldi Elisabetta , Bucherelli Corrado , Roberto Marisa , Tassoni Giovanna , Brunelli Marcello 
Published: March 2003

AbstractThe effects of contextual fear‐learning on hippocampal synaptic excitability were investigated by means of high frequency tetanic stimulation (HFS) in rat brain slices (hippocampal CA1 region), prepared at different intervals (immediately, 24 h or 7 days) after a one‐trial contextual fear conditioning paradigm session. In the latter, rats that had previously received aversive electrical footshocks in the experimental apparatus exhibited freezing (the conditioned response) when placed again in the same apparatus (retrieval test). It was shown that contextual fear‐learning affects the hippocampal synaptic response. In fact, the HFS produced a decrease in the amplitude of short‐term (STP) and long‐term potentiation (LTP) when compared to control ‘naïve’ subject values. This decrease in STP amplitude could be observed only in slices prepared immediately after the training session. A decrease in the amplitude of long‐term but not short‐term potentiation was also observed at 24 h. At 7 days, no decreases in amplitude were observed. These modifications may be thought of as specifically associated with the learning process as they were not recorded in brain preparations from ‘shock‐only’ rats (i.e. those that received the same number of aversive stimuli of equal intensity as the conditioned group but with the shocks compressed temporally so that the shocked subjects could not associate nociceptive stimulation and surroundings – no conditioned freezing during retention testing). In ‘exploration’ preparations (brain slices from rats having only freely explored the experimental apparatus without receiving any adverse stimulation) a decrease in LTP amplitude was recorded only immediately after the training session, and STP was never modified. The synaptic response modifications do not appear to be due to presynaptic events, as they are not associated with paired‐pulse facilitation curve (PPF) modifications. The present results show that contextual fear conditioning and exploration of a novel environment (i) reduce the ability to induce synaptic plasticity; (ii) differentially influence STP and LTP and that (iii) the persistence of synaptic modifications depends on an animal's prior experience.
Voltage‐gated ionic currents in an identified modulatory cell type controlling molluscan feeding
Authors: Staras Kevin , Győri János , Kemenes György 
Published: March 2003

AbstractAn important modulatory cell type, found in all molluscan feeding networks, was investigated using two‐electrode voltage‐ and current‐clamp methods. In the cerebral giant cells of Lymnaea, a transient inward Na+ current was identified with activation at −58 ± 2 mV. It was sensitive to tetrodotoxin only in high concentrations (≈ 50% block at 100 µm), a characteristic of Na+ channels in many molluscan neurons. A much smaller low‐threshold persistent Na+ current (activation at < −90 mV) was also identified. Two purely voltage‐sensitive outward K+ currents were also found: (i) a transient A‐current type which was activated at −59 ± 4 mV and blocked by 4‐aminopyridine; (ii) a sustained tetraethylammonium‐sensitive delayed rectifier current which was activated at −47 ± 2 mV. There was also evidence that a third, Ca2+‐activated, K+ channel made a contribution to the total outward current. No inwardly rectifying currents were found. Two Ca2+ currents were characterized: (i) a transient low‐voltage (−65 ± 2 mV) activated T‐type current, which was blocked in NiCl2 (2 mm) and was completely inactivated at ≈ −50 mV; (ii) A sustained high voltage (−40 ± 1 mV) activated current, which was blocked in CdCl2 (100 µm) but not in ω‐conotoxin GVIA (10 µm), ω‐agatoxin IVA (500 nm) or nifedipine (10 µm). This current was enhanced in Ba2+ saline. Current‐clamp experiments revealed how these different current types could define the membrane potential and firing properties of the cerebral giant cells, which are important in shaping the wide‐acting modulatory influence of this neuron on the rest of the feeding network.
Neuronal expression and regulation of rat inhibitor of apoptosis protein‐2 by kainic acid in the rat brain
Authors: Belluardo Natale , Korhonen Laura , Mudo Giuseppa , Lindholm Dan 
Published: March 2003

AbstractInhibitors of apoptosis proteins (IAPs) define a protein family with the ability to counteract cell death by the inhibition of different caspases activated during apoptosis. These proteins are present in different cells, however, the function and roles of IAPs in brain tissue are not fully understood. We report here that RIAP‐2, the rat homologue of human cIAP‐1/HIAP‐2, is expressed in different areas of rat brain as shown by in situ hybridization and immunohistochemistry. Brain regions with relatively high expression of RIAP‐2 mRNA included cortex, cerebellum and different subregions of rat hippocampus. Double labelling using a specific anti‐RIAP antibody and markers for neurons and glial cells, showed that RIAP‐2 is predominantly expressed by nerve cells. Kainic acid treatment, which induces seizures, transiently up‐regulated RIAP‐2 mRNA levels in cerebral cortex, in the CA1 and dentate gyrus regions of hippocampus, which returned to normal levels at 24 h. However in the CA3 region, RIAP‐2 mRNA was decreased at 6 h following an early up‐regulation. This region contains neurons particularly vulnerable to kainic acid induced cell degeneration. The decrease in RIAP‐2 following kainic acid was also observed using immunohistochemistry. RIAP‐2 protein did not colocalize with TUNEL labelling present in cells undergoing cell death. The results show that in the adult rat brain RIAP‐2 is expressed mainly by neurons, and that the levels are regulated by kainic acid, which activates glutamate receptors. The decrease in RIAP‐2 in specific neuronal populations may contribute to cell degeneration in vulnerable brain regions observed after kainic acid treatment.
Dopaminergic signalling in the rodent neonatal suprachiasmatic nucleus identifies a role for protein kinase A and mitogen‐activated protein kinase in circadian entrainment
Authors: Schurov Irina L. , Hepworth Tracie J. , Hastings Michael H. 
Published: March 2003

AbstractThe circadian clock of the suprachiasmatic nuclei (SCN) of perinatal rodents is entrained by maternally derived cues. The SCN of neonatal Syrian hamsters express high‐affinity D1 dopamine receptors, and the circadian activity–rest cycle of pups can be entrained by maternal injection of dopaminergic agonists. The present study sought to characterize the intracellular pathways mediating dopaminergic signalling in neonatal rodent SCN. Both dopamine and the D1 agonist SKF81297 caused a dose‐dependent increase in phosphorylation of the transcriptional regulator Ca2+/cyclic AMP response element (CRE) binding protein (CREB) in suprachiasmatic GABA‐immunoreactive (‐IR) neurons held in primary culture. The D1 antagonist SCH23390 blocked this effect. Dopaminergic induction of pCREB‐IR in GABA‐IR neurons was also blocked by a protein kinase A (PKA) inhibitor, 5–24, and by the MAPK inhibitor, PD98059, whereas KN‐62, an inhibitor of Ca2+/calmodulin‐dependent (CAM) kinase II/IV was ineffective. Treatment with NMDA increased the level of intracellular Ca2+ in the cultured primary SCN neurons in Mg2+‐free medium, but SKF81297 did not. Blockade of CaM kinase II/IV with KN‐62 inhibited glutamatergic induction of pCREB‐IR in GABA‐IR neurons, whereas 5–24 was ineffective, confirming the independent action of Ca2+‐ and cAMP‐mediated inputs on pCREB. SKF81297 caused an increase in pERK‐IR in SCN cells, and this was blocked by 5–24, indicative of activation of MAPK via D1/cAMP. These results demonstrate that dopaminergic signalling in the neonatal SCN is mediated via the D1‐dependent activation of PKA and MAPK, and that this is independent of the glutamatergic regulation via Ca2+ and CaM kinase II/IV responsible for entrainment to the light/dark cycle.
The expression of Fos following kainic acid‐induced seizures is age‐dependent
Authors: Silveira Diosely C. , Sogawa Yoshimi , Holmes Gregory L. 
Published: March 2003

AbstractThe expression of limbic seizures following kainic acid (KA) administration starts at approximately postnatal day (P) 19 in rats. In this study we investigated whether the expression of Fos‐like immunoreactivity (Fos‐IR) in limbic regions occurs concomitantly with the behavioural expression of limbic seizures. Immunohistochemistry for c‐Fos protein was examined 1, 2, 4, 12 and 24 h following seizure onset (KA‐treated rats) or saline injections (controls) in immature and adult rats at P7, P13, P20 and P60. The expression of Fos‐IR in limbic structures following KA‐induced seizures is age‐dependent. There is a strong and selective induction of Fos‐IR in the CA3 region of the hippocampus following KA‐induced seizures in rats at P7. However, the expression of Fos‐IR in KA‐treated rats at P13, P20 and P60 involved other hippocampal structures in addition to CA3. Abundant induction of Fos‐IR was found in the CA1, CA3 and dentate gyrus (DG) in KA‐treated rats at P13, P20 and P60. While immature rats at P7 and P13 showed very few or no Fos‐IR neurons in most amygdala nuclei, rat pups at P20 showed strong induction of Fos‐IR in the amygdala. Our results demonstrated that the induction of Fos‐IR in most amygdala nuclei and the full expression of behavioural limbic seizures occur at the same developmental age, which is consistent with the idea that the amygdala may play a role in the modulation of limbic seizures.
The organization of visual object representations: a connectionist model of effects of lesions in perirhinal cortex
Authors: Bussey Timothy J. , Saksida Lisa M. 
Published: March 2003

AbstractWe have developed a simple connectionist model based on the idea that perirhinal cortex has properties similar to other regions in the ventral visual stream, or ‘what’ pathway. The model is based on the assumption that representations in the ventral visual stream are organized hierarchically, such that representations of simple features of objects are stored in caudal regions of the ventral visual stream, and representations of the conjunctions of these features are stored in more rostral regions. We propose that a function of these feature conjunction representations is to help to resolve ‘feature ambiguity’, a property of visual discrimination problems that can emerge when features of an object predict a given outcome (e.g. reward) when part of one object, but predict a different outcome when part of another object. Several recently reported effects of lesions of perirhinal cortex in monkeys have provided key insights into the functions of this region. In the present study these effects were simulated by comparing the performance of connectionist networks before and after removal of a layer of units corresponding to perirhinal cortex. The results of these simulations suggest that effects of lesions in perirhinal cortex on visual discrimination may be due not to the impairment of a specific type of learning or memory, such as declarative or procedural, but to compromising the representations of visual stimuli. Furthermore, we propose that attempting to classify perirhinal cortex function as either ‘perceptual’ or ‘mnemonic’ may be misguided, as it seems unlikely that these broad constructs will map neatly onto anatomically defined regions of the brain.
Perirhinal cortex resolves feature ambiguity in complex visual discriminations
Authors: Bussey, Timothy J. , Saksida Lisa M. , Murray Elisabeth A. 
Published: March 2003

AbstractThe present experiment tested predictions of a ‘perceptual–mnemonic/feature conjunction’ (PMFC) model of perirhinal cortex function. The model predicts that lesions of perirhinal cortex should disrupt complex visual discriminations with a high degree of ‘feature ambiguity’, a property of visual discrimination problems that can emerge when features of an object are rewarded when they are part of one object, but not when part of another. As feature ambiguity is thought to be the critical factor, such effects should be independent of the number of objects to be discriminated. This was tested directly, by assessing performance of control monkeys and monkeys with aspiration lesions of perirhinal cortex on a series of concurrent discriminations in which the number of object pairs was held constant, but the degree of feature ambiguity was varied systematically. Monkeys were tested in three conditions: Maximum Feature Ambiguity, in which all features were explicitly ambiguous (AB+, CD+, BC–, AD–; the biconditional problem); Minimum Feature Ambiguity, in which no features were explicitly ambiguous (AB+, CD+, EF–, GH–); and Intermediate Feature Ambiguity, in which half the features were explicitly ambiguous (AB+, CD+, CE–, AF–). The pattern of results closely matched that predicted by simulations using a connectionist network: monkeys with perirhinal cortex lesions were unimpaired in the Minimum Feature Ambiguity condition, mildly impaired in the Intermediate Feature Ambiguity condition and severely impaired in the Maximum Feature Ambiguity condition. These results confirm the predictions of the PMFC model, and force a reconsideration of prevailing views regarding perirhinal cortex function.
Opposing actions of neuropeptide Y and light on the expression of circadian clock genes in the mouse suprachiasmatic nuclei
Authors: Maywood Elizabeth S. , Okamura Hitoshi , Hastings Michael H. 
Published: March 2003

AbstractThe circadian clockwork of the hypothalamic suprachiasmatic nuclei (SCN) is synchronized by light and by nonphotic cues. The core timing mechanism is cell‐autonomous, based on an autoregulatory transcriptional/translational feedback loop of circadian genes and their products. This study investigated the effects of neuropeptide Y (NPY), a potent nonphotic resetting cue, and its interaction with light in regulating clock gene expression in the SCN in vivo. Injection of NPY adjacent to the SCN and transfer to darkness 7 h before scheduled lights out, shifted the circadian activity–rest cycle. Exposure to light for 1 h immediately after NPY infusion blocked this behavioural response. NPY‐induced shifts were accompanied by suppression of both mPer1 and mPer2 mRNA in the SCN, assessed 3 h after infusion. mPer mRNAs were not altered 1 h after infusion. Levels of mClock mRNA or mCLOCK immunoreactivity in the SCN were not affected by NPY at either time point. In parallel to the behavioural response, the NPY‐induced suppression of mPer genes in the SCN was attenuated when a light pulse was delivered immediately after the infusion. These results identify mPer1 and mPer2 as molecular targets for both photic and nonphotic (NPY‐induced) resetting of the clockwork, and support a synthetic model of circadian entrainment based upon convergent up‐ and downregulation of mPer expression.
Expression of CRABP I mRNA in fastigial cells of the developing cerebellum
Authors: Parenti Rosalba , Wassef Marion , Cicirata Federico 
Published: March 2003

AbstractThe expression of the cellular retinoic acid binding protein type I (CRABP I) was examined in the early phase of cerebellar development in the mouse. The CRABP I was expressed from embryonic day (E) 10.5 to E15.5 in the cerebellar plate. The expression was diffused at E10.5–E11.5 and thereafter localized in a small rostrodorsal area of the cerebellar territory of both sides. By using in situ hybridization and both immunohistochemistry and carbocyanine tracing procedures, we identified the fastigial cells as the population that expresses CRABP I in the cerebellum. The results suggest that these cells play a critical role in the early development of the cerebellum.
Postnatal maturation of Na+, K+, 2Cl– cotransporter expression and inhibitory synaptogenesis in the rat hippocampus: an immunocytochemical analysis
Authors: Marty Serge , Wehrlé Rosine , Alvarez‐Leefmans Francisco Javier , Gasnier Bruno , Sotelo Constantino 
Published: March 2003

AbstractGABA, a major inhibitory neurotransmitter, depolarizes hippocampal pyramidal neurons during the first postnatal week. These depolarizations result from an efflux of Cl– through GABAA‐gated anion channels. The outward Cl– gradient that provides the driving force for Cl– efflux might be generated and maintained by the Na+, K+, 2Cl– cotransporter (NKCC) that keeps intracellular Cl– concentration above electrochemical equilibrium. The developmental pattern of expression of the cotransporter in the hippocampus is not known. We studied the postnatal distribution pattern of NKCC in the hippocampus using a monoclonal antibody (T4) against a conserved epitope in the C‐terminus of the cotransporter molecule. We also examined the temporal relationships between the developmental pattern of NKCC expression and the formation of perisomatic GABAergic synapses. This study was aimed at determining, with antivesicular inhibitory amino acid transporter (VIAAT) antibodies, whether perisomatic GABAergic synapses are formed preferentially at the time when GABA is depolarizing. During the first postnatal week, NKCC immunolabelling was restricted to cell bodies in the pyramidal cell layer and in the strata oriens and radiatum. In contrast, at postnatal day 21 (P21) and in adult animals little or no labelling occurred in cell bodies; instead, a prominent dendritic labelling appeared in both pyramidal and nonpyramidal neurons. The ultrastructural immunogold study in P21 rat hippocampi corroborated the light‐microscopy results. In addition, this study revealed that a portion of the silver‐intensified colloidal gold particles were located on neuronal plasmalemma, as expected for a functional cotransporter. The formation of inhibitory synapses on perikarya of the pyramidal cell layer was a late process. The density of VIAAT‐immunoreactive puncta in the stratum pyramidale at P21 reached four times the P7 value in CA3, and six times the P7 value in CA1. Electron microscopy revealed that the number of synapses per neuronal perikaryal profile in the stratum pyramidale of the CA3 area at P21 was three times higher than at P7, even if a concomitant 20% increase in the area of these neuronal perikaryal profiles occurred. It is concluded that, in hippocampal pyramidal cells, there is a developmental shift in the NKCC localization from a predominantly somatic to a predominantly dendritic location. The presence of NKCC during the first postnatal week is consistent with the hypothesis that this transporter might be involved in the depolarizing effects of GABA. The depolarizing effects of GABA may not be required for the establishment of the majority of GABAergic synapses in the stratum pyramidale, because their number increases after the first postnatal week, when GABA action becomes hyperpolarizing.