bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilateral choanal atresia in an adult: is it compatible with life?
Authors: Panda Naresh K. , Simhadri Sridhar , Ghosh Shakuntala
Published: March 2004

Bilateral choanal atresia is potentially life-threatening. The condition almost always presents in the new born, with alternating phases of respiratory distress and apnoea relieved by crying. We report a rare case of bilateral choanal atresia presenting for the first time at 22 years of age. The patient had no features of cyanosis or apnoea, presenting only with bilateral nasal obstruction, rhinorrhoea and anosmia. His neonatal history was unremarkable. No syndromic association was noted excepting for telecanthus. The presence of bony atresia was confirmed on computed tomography (CT) scan and transnasal endoscopic surgery was used to obtain a patent airway. This case is a rare report of bilateral choanal atresia presenting for the first time in adult life.
Action Potential-Independent Release of Glutamate by Ca2+Entry through Presynaptic P2X Receptors Elicits Postsynaptic Firing in the Brainstem Autonomic Network
Authors: Shigetomi Eiji , Kato Fusao
Published: March 2004

P2X receptors are ATP-gated channels permeable to cations including Ca2+. In acute slices containing the nucleus of the solitary tract, in which neuronal ATP release and ATP-elicited physiological responses are demonstratedin vivo, we recorded spontaneous action potential-independent EPSCs [miniature EPSCs (mEPSCs)]. Activation of presynaptic P2X receptors with α,β-methylene ATP (αβmATP) triggered Ca2+-dependent glutamate release that was resistant to blockade of voltage-dependent calcium channels but abolished by P2X receptor antagonists. mEPSCs elicited with αβmATP were of larger amplitude than basal mEPSCs and resulted in postsynaptic firing caused by temporal summation of miniature events. The large-amplitude mEPSCs provoked by αβmATP were likely to result from highly synchronized multivesicular release of glutamate at single release sites. Neither αβmATP nor ATP facilitated GABA release. We conclude that this facilitated release and consequent postsynaptic firing underlie the profound autonomic responses to activation of P2X receptors observedin vivo.
Insulinoma-Associated Protein IA-2, a Vesicle Transmembrane Protein, Genetically Interacts with UNC-31/CAPS and Affects Neurosecretion inCaenorhabditis elegans
Authors: Cai Tao , Fukushige Tetsunari , Notkins Abner L. , Krause Michael
Published: March 2004

IA-2 (insulinoma-associated protein 2), a major autoantigen in type 1 diabetes, is a receptor-tyrosine phosphatase-like protein associated with the membrane of secretory granules of neural and endocrine-specific cells. Loss of IA-2 activity in the mouse results in reduced insulin release and additional phenotypes, consistent with a general effect on neurosecretion and hormone release. To gain further insight into the cellular mechanisms of IA-2 function, we have studied theCaenorhabditis eleganshomolog, CeIA-2 encoded by theida-1gene. Using two independent putative null alleles ofida-1, we demonstrate that animals lacking CeIA-2 activity are viable and exhibit subtle defects. Genetic studies of mutants inida-1and several genes involved in neurosecretory vesicle cargo release and signaling highlight two roles for CeIA-2. First, CeIA-2 has a specific and novel genetic interaction with UNC-31/CAPS, a protein that has been shown in other systems to regulate dense-core vesicle cargo release. Second, loss of CeIA-2 activity enhances weak alleles in the insulin-like signaling pathway. These results suggest that CeIA-2 may be an important factor in dense-core vesicle cargo release with parallels to insulin signaling in mammals.
Representation in the Human Brain of Food Texture and Oral Fat
Authors: de Araujo Ivan E. , Rolls Edmund T.
Published: March 2004

Important factors that influence food palatability are its texture and fat content. We investigated their representation in the human brain using event-related functional magnetic resonance imaging. It was shown that the viscosity of oral stimuli is represented in the (primary) taste cortex in the anterior insula, in which activation was proportional to the log of the viscosity of a cellulose stimulus (carboxymethyl cellulose), and was also produced by sucrose. Oral viscosity was also represented in a mid-insular region that was posterior to the taste cortex. Third, it was found that oral delivery of fatty vegetable oil activates both of these insular cortex regions, the hypothalamus, and the dorsal midanterior cingulate cortex. Fourth, it was found that the ventral anterior cingulate cortex, where it borders the medial orbitofrontal cortex, was activated by oral fat independently of its viscosity and was also activated by sucrose taste. This ventral anterior cingulate region thus represents two indicators of the energy content and palatability of foods. These are the first investigations of the oral sensory representation of food texture and fat in the human brain, and they start to reveal brain mechanisms that may be important in texture-related sensory properties of foods that make them palatable and that may accordingly play a role in the hedonic responses to foods, the control of food intake, and obesity.
Spatial Distribution of Calcium Entry Evoked by Single Action Potentials within the Presynaptic Active Zone
Authors: Wachman Elliot S. , Poage Robert E. , Stiles Joel R. , Farkas Daniel L. , Meriney Stephen D.
Published: March 2004

The nature of presynaptic calcium (Ca2+) signals that initiate neurotransmitter release makes these signals difficult to study, in part because of the small size of specialized active zones within most nerve terminals. Using the frog motor nerve terminal, which contains especially large active zones, we show that increases in intracellular Ca2+concentration within 1 msec of action potential invasion are attributable to Ca2+entry through N-type Ca2+channels and are not uniformly distributed throughout active zone regions. Furthermore, changes in the location and magnitude of Ca2+signals recorded before and after experimental manipulations (ω-conotoxin GVIA, diaminopyridine, and lowered extracellular Ca2+) support the hypothesis that there is a remarkably low probability of a single Ca2+channel opening within an active zone after an action potential. The trial-to-trial variability observed in the spatial distribution of presynaptic Ca2+entry also supports this conclusion, which differs from the conclusions of previous work in other synapses.
Oxytocin Attenuates Stress-Induced c-fosmRNA Expression in Specific Forebrain Regions Associated with Modulation of Hypothalamo–Pituitary–Adrenal Activity
Authors: Windle Richard J. , Kershaw Yvonne M. , Shanks Nola , Wood Susan A. , Lightman Stafford L. , Ingram Colin D.
Published: March 2004

We reported previously that the neuropeptide oxytocin attenuates stress-induced hypothalamo–pituitary–adrenal (HPA) activity and anxiety behavior. This study sought to identify forebrain target sites through which oxytocin may mediate its anti-stress effects. Ovariectomized, estradiol-treated rats received intracerebroventricular infusions of oxytocin (1 or 10 ng/hr) or vasopressin (10 ng/hr), and the patterns of neuronal activation after restraint stress were determined by semiquantitative mapping of c-fosmRNA expression. Oxytocin administration significantly attenuated the release of ACTH and corticosterone and the increase in corticotropin-releasing factor mRNA expression in the hypothalamic paraventricular nucleus (PVN) in response to 30 min restraint. Restraint also induced the expression of c-fosmRNA in selective regions of the forebrain, including the PVN, paraventricular thalamic nucleus, habenula, medial amygdala, ventrolateral septum (LSV), most subfields of the dorsal and ventral hippocampus, and piriform and endopiriform cortices. In most cases, this level of gene expression was unaffected by concomitant administration of oxytocin. However, in the PVN, LSV, and throughout all subfields of the dorsal hippocampus, restraint evoked no detectable increase in c-fosmRNA in animals treated with either dose of oxytocin. Vasopressin had no effects on either HPA axis responses or neuronal activation in response to restraint, indicating that the effects were highly peptide selective. These data show that central oxytocin attenuates both the stress-induced neuroendocrine and molecular responses of the HPA axis and that the dorsal hippocampus, LSV, and PVN constitute an oxytocin-sensitive forebrain stress circuit.
Anticonvulsant and Antiepileptogenic Effects Mediated by Adeno-Associated Virus Vector Neuropeptide Y Expression in the Rat Hippocampus
Authors: Richichi Cristina , Lin En-Ju D. , Stefanin Daniela , Colella Daniele , Ravizza Teresa , Grignaschi Giuliano , Veglianese Pietro , Sperk Günther , During Matthew J. , Vezzani Annamaria
Published: March 2004

Neuropeptide Y (NPY) inhibits seizures in experimental models and reduces excitability in human epileptic tissue. We studied the effect of long-lasting NPY overexpression in the rat hippocampus with local application of recombinant adeno-associated viral (AAV) vectors on acute kainate seizures and kindling epileptogenesis.

Transgene expression was significantly increased by 7 d, reached maximal expression by 2 weeks, and persisted for at least 3 months. Serotype 2 AAV vector increased NPY expression in hilar interneurons, whereas the chimeric serotype 1/2 vector caused far more widespread expression, also including mossy fibers, pyramidal cells, and the subiculum. EEG seizures induced by intrahippocampal kainate were reduced by 50–75%, depending on the vector serotype, and seizure onset was markedly delayed.

In rats injected with the chimeric serotype 1/2 vector, status epilepticus was abolished, and kindling acquisition was significantly delayed. Thus, targeted NPY gene transfer provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.
Novel Neuronal Phenotypes from Neural Progenitor Cells
Authors: Markakis Eleni A. , Palmer Theo D. , Randolph-Moore Lynne , Rakic Pasko , Gage Fred H.
Published: March 2004

We report the first isolation of progenitor cells from the hypothalamus, a derivative of the embryonic basal plate that does not exhibit neurogenesis postnatally. Neurons derived from hypothalamic progenitor cells were compared with those derived from progenitor cultures of hippocampus, an embryonic alar plate derivative that continues to support neurogenesisin vivointo adulthood. Aside from their different embryonic origins and their different neurogenic potentialin vivo, these brain regions were chosen because they are populated with cells of three different categories: Category I cells are generated in both hippocampus and hypothalamus, Category II cells are generated in the hypothalamus but are absent from the hippocampus, and Category III is a cell type generated in the olfactory placode that migrates into the hypothalamus during development. Stem-like cells isolated from other brain regions, with the ability to generate neurons and glia, produce neurons of several phenotypes including gabaergic, dopaminergic, and cholinergic lineages. In the present study, we extended our observations into neuroendocrine phenotypes. The cultured neural precursors from 7-week-old rat hypothalamus readily generated neuropeptide-expressing neurons. Hippocampal and hypothalamic progenitor cultures converged to indistinguishable populations and produced neurons of all three categories, confirming that even short-term culture confers or selects for immature progenitors with enough plasticity to elaborate neuronal phenotypes usually inhibitedin vivoby the local microenvironment. The range of phenotypes generated from neuronal precursorsin vitronow includes the peptides found in the neuroendocrine system: corticotropin-releasing hormone, growth hormone-releasing hormone, gonadotropin-releasing hormone, oxytocin, somatostatin, thyrotropin-releasing hormone, and vasopressin.
Barhl1Regulates Migration and Survival of Cerebellar Granule Cells by Controlling Expression of the Neurotrophin-3 Gene
Authors: Li Shengguo , Qiu Feng , Xu Anlong , Price Sandy M. , Xiang Mengqing
Published: March 2004

The neurons generated at the germinal rhombic lip undergo long distance migration along divergent pathways to settle in widely dispersed locations within the hindbrain, giving rise to cerebellar granule cells and precerebellar nuclei. Neurotrophin-3 (NT-3) signaling has been shown to be required for proper migration and survival of cerebellar granule cells. The molecular bases that governNT-3expression within the cerebellum, however, remain unknown at present. Here we report that, during early mouse neurogenesis, theBarhl1homeobox gene is highly expressed by the rhombic lip and rhombic lip-derived migratory neurons. Its expression is later restricted to cerebellar granule cells and precerebellar neurons extending mossy fibers, two groups of neurons that synaptically connect in the adult cerebellar system. Loss ofBarhl1function causes cerebellar phenotypes with a striking similarity to those ofNT-3conditional null mice, which include attenuated cerebellar foliation as well as defective radial migration and increased apoptotic death of granule cells. Correlating with these defects, we find thatNT-3expression is dramatically downregulated in granule cells of the posterior lobe ofBarhl1–/– cerebella. Moreover, in the precerebellar system ofBarhl1–/–mice, all five nuclei that project mossy fibers fail to form correctly because of aberrant neuronal migration and elevated apoptosis. These results suggest thatBarhl1plays an essential role in the migration and survival of cerebellar granule cells and precerebellar neurons and functionally linkBarhl1to the NT-3 signaling pathway during cerebellar development.
Activation of Adenosine A2AReceptor Facilitates Brain-Derived Neurotrophic Factor Modulation of Synaptic Transmission in Hippocampal Slices
Authors: Diógenes Maria José , Fernandes Catarina Cunha , Sebastião Ana Maria , Ribeiro Joaquim Alexandre
Published: March 2004

Both brain-derived neurotrophic factor (BDNF) and adenosine influence neuronal plasticity. We now investigated how adenosine influences the action of BDNF on synaptic transmission in the CA1 area of the rat hippocampal slices. Alone, BDNF (20–100 ng/ml) did not significantly affect field EPSPs (fEPSPs). However, a 2 min pulse of high-K+(10 mm) 46 min before the application of BDNF (20 ng/ml) triggered an excitatory action, an effect blocked by the TrkB receptor inhibitor K252a (200 nm), by the adenosine A2Areceptor antagonist ZM 241385 (50 nm), and by the protein kinase A inhibitor H-89 (1 μm). Presynaptic, rather than postsynaptic depolarization was required to trigger the BDNF action because after K+depolarization BDNF also increased EPSCs recorded from pyramidal neurons voltage-clamped at –60 mV, and transient postsynaptic depolarization was unable to unmask the BDNF action. A weak theta burst stimulation of the afferents could elicit potentiation of synaptic transmission only when applied in the presence of BDNF. Activation of adenosine A2Areceptors with CGS 21680 (10 nm), or the increase in extracellular adenosine levels induced by 5-iodotubercidin (100 nm) triggered the excitatory action of BDNF, a process prevented by ZM 241385 and by H-89. In the presence of dibutyryl-cAMP (0.5 mm), BDNF also increased fEPSPs but postsynaptic cAMP (0.5 mm) was unable to trigger the BDNF action.

It is concluded that presynaptic activity-dependent release of adenosine, through activation of A2Areceptors, facilitates BDNF modulation of synaptic transmission at hippocampal synapses.
Opioids Inhibit Lateral Amygdala Pyramidal Neurons by Enhancing a Dendritic Potassium Current
Authors: Faber E. S. Louise , Sah Pankaj
Published: March 2004

Pyramidal neurons in the lateral amygdala discharge trains of action potentials that show marked spike frequency adaptation, which is primarily mediated by activation of a slow calcium-activated potassium current. We show here that these neurons also express an α-dendrotoxin- and tityustoxin-Kα-sensitive voltage-dependent potassium current that plays a key role in the control of spike discharge frequency. This current is selectively targeted to the primary apical dendrite of these neurons. Activation of μ-opioid receptors by application of morphine ord-Ala2-N-Me-Phe4-Glycol5-enkephalin (DAMGO) potentiates spike frequency adaptation by enhancing the α-dendrotoxin-sensitive potassium current. The effects of μ-opioid agonists on spike frequency adaptation were blocked by inhibiting G-proteins withN-ethylmaleimide (NEM) and by blocking phospholipase A2. Application of arachidonic acid mimicked the actions of DAMGO or morphine. These results show that μ-opioid receptor activation enhances spike frequency adaptation in lateral amygdala neurons by modulating a voltage-dependent potassium channel containing Kv1.2 subunits, through activation of the phospholipase A2–arachidonic acid–lipoxygenases cascade.
Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets
Authors: Kholodilov Nikolai , Yarygina Olga , Oo Tinmarla Frances , Zhang Hui , Sulzer David , Dauer William , Burke Robert E.
Published: March 2004

Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine (DA) neurons in injury models and is being evaluated for the treatment of Parkinson's disease. Nevertheless, little is known of its physiological role. We have shown that GDNF suppresses apoptosis in DA neurons of the substantia nigra (SN) postnatally bothin vitroand during their first phase of natural cell deathin vivo. Furthermore, intrastriatal injection of neutralizing antibodies augments cell death, suggesting that endogenous GDNF plays a role as a target-derived factor. Such a role would predict that overexpression of GDNF in striatum would increase the surviving number of SN DA neurons. To test this hypothesis, we used the tetracycline-dependent transcription activator (tTA)/tTA-responsive promoter system to create mice that overexpress GDNF selectively in the striatum, cortex, and hippocampus. These mice demonstrate an increased number of SN DA neurons after the first phase of natural cell death. However, this increase does not persist into adulthood. As adults, these mice also do not have increased dopaminergic innervation of the striatum. They do, however, demonstrate increased numbers of ventral tegmental area (VTA) neurons and increased innervation of the cortex. This morphologic phenotype is associated with an increased locomotor response to amphetamine. We conclude that striatal GDNF is necessary and sufficient to regulate the number of SN DA neurons surviving the first phase of natural cell death, but it is not sufficient to increase their final adult number. GDNF in VTA targets, however, is sufficient to regulate the adult number of DA neurons.
Discovering Spike Patterns in Neuronal Responses
Authors: Fellous Jean-Marc , Tiesinga Paul H. E. , Thomas Peter J. , Sejnowski Terrence J.
Published: March 2004

When a cortical neuron is repeatedly injected with the same fluctuating current stimulus (frozen noise) the timing of the spikes is highly precise from trial to trial and the spike pattern appears to be unique. We show here that the same repeated stimulus can produce more than one reliable temporal pattern of spikes. A new method is introduced to find these patterns in raw multitrial data and is tested on surrogate data sets. Using it, multiple coexisting spike patterns were discovered in pyramidal cells recorded from rat prefrontal cortexin vitro, in data obtainedin vivofrom the middle temporal area of the monkey (Buracas et al., 1998) and from the cat lateral geniculate nucleus (Reinagel and Reid, 2002). The spike patterns lasted from a few tens of millisecondsin vitroto several secondsin vivo. We conclude that the prestimulus history of a neuron may influence the precise timing of the spikes in response to a stimulus over a wide range of time scales.
Dopamine Modulates Inwardly Rectifying Potassium Currents in Medial Prefrontal Cortex Pyramidal Neurons
Authors: Dong Yan , Cooper Donald , Nasif Fernando , Hu Xiu-Ti , White Francis J.
Published: March 2004

Dopamine (DA) modulation of excitability in medial prefrontal cortex (mPFC) pyramidal neurons has attracted considerable attention because of the involvement of mPFC DA in several neuronal disorders. Here, we focused on DA modulation of inwardly rectifying K+current (IRKC) in pyramidal neurons acutely dissociated from rat mPFC. A Cs+-sensitive whole-cell IRKC was elicited by hyperpolarizing voltage steps from a holding potential of –50 mV. DA (20 μm) reduced IRKC amplitude, as did selective stimulation of DA D1or D2class receptors (D1Rs and D2Rs). D1Rs activate, whereas D2Rs inhibit, the adenylyl cyclase–cAMP–protein kinase A (PKA) signaling pathway. Suppression of IRKC by D2R stimulation was attributable to decreased PKA activity because similar inhibition was observed with PKA inhibitors, whereas enhancing PKA activity increased IRKC. This suggests that the DA D1R suppression of IRKC occurred through a PKA phosphorylation-independent process. Using outside-out patches of mPFC pyramidal neurons, which preclude involvement of cytosolic signaling molecules, we observed a Cs+-sensitive macroscopic IRKC that was suppressed by the membrane-permeable cyclic nucleotide Sp-cAMP but was unaffected by non-nucleotide modulators of PKA, suggesting direct interactions of the cyclic nucleotides with IRK channels. Our results indicate that DA suppresses IRKC through two mechanisms: D1R activation of cAMP and direct interactions of the nucleotide with IRK channels and D2R-mediated dephosphorylation of IRK channels. The DA modulation of IRKC indicates that ambient DA would tend to increase responsiveness to excitatory inputs when PFC neurons are near the resting membrane potential and may provide a mechanism by which DA impacts higher cognitive function.
Netrin-1 and Semaphorin 3A Promote or Inhibit Cortical Axon Branching, Respectively, by Reorganization of the Cytoskeleton
Authors: Dent Erik W. , Barnes Aileen M. , Tang Fangjun , Kalil Katherine
Published: March 2004

In many CNS pathways, target innervation occurs by axon branching rather than extension of the primary growth cone into targets. To investigate mechanisms of branch formation, we studied the effects of attractive and inhibitory guidance cues on cortical axon branching. We found that netrin-1, which attracts cortical axons, and FGF-2 increased branching by >50%, whereas semaphorin 3A (Sema3A), which repels cortical axons, inhibited branching by 50%. Importantly, none of the factors affected axon length significantly. The increase in branching by FGF-2 and the inhibition of branching by Sema3A were mediated by opposing effects on the growth cone (expansion vs collapse) and on the cytoskeleton. FGF-2 increased actin polymerization and formation of microtubule loops in growth cones over many hours, whereas Sema3A depolymerized actin filaments, attenuated microtubule dynamics, and collapsed microtubule arrays within minutes. Netrin-1 promoted rapid axon branching, often without involving the growth cone. Branches formedde novoon the axon shaft within 30 min after local application of netrin-1, which induced rapid accumulation of actin filaments in filopodia. Importantly, increased actin polymerization and microtubule dynamics were necessary for axon branching to occur. Taken together, these results show that guidance factors influence the organization and dynamics of the cytoskeleton at the growth cone and the axon shaft to promote or inhibit axon branching. Independent of axon outgrowth, axon branching in response to guidance cues can occur over different time courses by different cellular mechanisms.
Amygdala Responses to Fearful and Happy Facial Expressions under Conditions of Binocular Suppression
Authors: Williams Mark A. , Morris Adam P. , McGlone Francis , Abbott David F. , Mattingley Jason B.
Published: March 2004

The human amygdala plays a crucial role in processing affective information conveyed by sensory stimuli. Facial expressions of fear and anger, which both signal potential threat to an observer, result in significant increases in amygdala activity, even when the faces are unattended or presented briefly and masked. It has been suggested that afferent signals from the retina travel to the amygdala via separate cortical and subcortical pathways, with the subcortical pathway underlying unconscious processing. Here we exploited the phenomenon of binocular rivalry to induce complete suppression of affective face stimuli presented to one eye. Twelve participants viewed brief, rivalrous visual displays in which a fearful, happy, or neutral face was presented to one eye while a house was presented simultaneously to the other. We used functional magnetic resonance imaging to study activation in the amygdala and extrastriate visual areas for consciously perceived versus suppressed face and house stimuli. Activation within the fusiform and parahippocampal gyri increased significantly for perceived versus suppressed faces and houses, respectively. Amygdala activation increased bilaterally in response to fearful versus neutral faces, regardless of whether the face was perceived consciously or suppressed because of binocular rivalry. Amygdala activity also increased significantly for happy versus neutral faces, but only when the face was suppressed. This activation pattern suggests that the amygdala has a limited capacity to differentiate between specific facial expressions when it must rely on information received via a subcortical route. We suggest that this limited capacity reflects a tradeoff between specificity and speed of processing.
Neuron-Specific mRNA Complexity Responses during Hippocampal Apoptosis after Traumatic Brain Injury
Authors: Marciano Paolo G. , Brettschneider Julia , Manduchi Elisabetta , Davis Jason E. , Eastman Scott , Raghupathi Ramesh , Saatman Kathryn E. , Speed Terence P. , Stoeckert Christian J. , Eberwine James H. , McIntosh Tracy K.
Published: March 2004

In an effort to understand the complexity of genomic responses within selectively vulnerable regions after experimental brain injury, we examined whether single apoptotic neurons from both the CA3 and dentate differed from those in an uninjured brain. The mRNA from individual active caspase 3(+)/terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling [TUNEL(–)] and active caspase 3(+)/TUNEL(+) pyramidal and granule neurons in brain-injured mice were amplified and compared with those from nonlabeled neurons in uninjured brains. Gene analysis revealed that overall expression of mRNAs increased with activation of caspase 3 and decreased to below uninjured levels with TUNEL reactivity. Cell type specificity of the apoptotic response was observed with both regionally distinct expression of mRNAs and differences in those mRNAs that were maximally regulated. Immunohistochemical analysis for two of the most highly differentially expressed genes (prionandSos2) demonstrated a correlation between the observed differential gene expression after traumatic brain injury and corresponding protein translation.
Glutamic Acid Decarboxylase 67 mRNA Regulation in Two Globus Pallidus Neuron Populations by Dopamine and the Subthalamic Nucleus
Authors: Billings Lauren M. , Marshall John F.
Published: March 2004

The globus pallidus (GP) consists of two neuron populations, distinguished according to their immunoreactivity for parvalbumin (PV). The PV-immunoreactive (PV+) neurons project preferentially to “downstream” targets such as the subthalamic and entopeduncular nuclei, whereas neurons lacking PV (PV– neurons) project preferentially to the striatum, suggesting a role for PV– cells in feedback to striatal neurons. Although dopamine D2 antagonist administration induces immediate early gene expression preferentially in PV– GP neurons, little is known about long-term regulation of PV– versus PV+ GP neurons. Nigral 6-hydroxydopamine (6-OHDA) lesions or repeated D2-class antagonist injections have been shown to increase pallidal expression of glutamate decarboxylase (GAD67isoform) mRNA. This increase in GAD67is believed to be secondary to activation of excitatory subthalamopallidal projections. The current study examined the effects of subthalamic nucleus (STN) lesion on 6-OHDA- or repeated D2 antagonist-induced changes in GP GAD67mRNA expression in PV+ and PV– neurons. Five or 21 d after nigral 6-OHDA injections or after 3, 7, or 21 d of D2 antagonist administration, GAD67mRNA increased in both the PV– and PV+ GP neurons, but the magnitude of the increase was significantly greater in PV– neurons. By contrast, STN lesion resulted in declines in GAD67mRNA in both cell populations, with the decreases in PV+ neurons exceeding those in PV– neurons. Furthermore, STN lesion completely blocked 6-OHDA- or D2 antagonist-induced GAD67mRNA increases in PV+ cells but only partly offset the GAD67mRNA increase in PV– pallidal neurons. Thus, the PV+ and PV– neurons are influenced in qualitatively similar ways by dopamine and the STN, but these cell types exhibit contrasting degrees of regulation by the dopaminergic and STN perturbations. This pattern of results has implications for pallidal control of striatal versus downstream basal ganglia nuclei.
The Ventral Tegmental Area Is Required for the Behavioral and Nucleus Accumbens Neuronal Firing Responses to Incentive Cues
Authors: Yun Irene A. , Wakabayashi Ken T. , Fields Howard L. , Nicola Saleem M.
Published: March 2004

Reward-predictive cues exert powerful control over behavioral choice and may be a critical factor in drug addiction. Reward-seeking elicited by predictive cues is facilitated by the release of dopamine in the nucleus accumbens (NAc), yet the contribution of dopamine to the specific NAc firing patterns that underlie goal-directed behavior has remained elusive. We present evidence that subpopulations of NAc neurons that respond to predictive cues require the dopaminergic projection from the ventral tegmental area (VTA) to promote reward-seeking behavior. Rats trained to perform an operant response to a cue to obtain a sucrose reward were implanted with both multiunit recording electrodes in the NAc and microinjection cannulas in the VTA. Both the behavioral response to cues and the cue-evoked firing of NAc neurons were blocked by injection of the GABABagonist baclofen into the VTA. An additional group of rats was trained on the same task and then implanted with microinjection cannulas in the NAc. Like VTA baclofen injection, injection of dopamine receptor antagonists into the NAc profoundly reduced cue-elicited reward seeking. Together, these results support the conclusion that both the behavioral response to the cue and the specific NAc neuronal firing that promotes the response depend on dopamine release within the NAc. Our findings suggest a neural mechanism by which the dopamine-dependent firing of NAc neurons mediates goal-directed behavior.
Group III Metabotropic Glutamate Receptors Maintain Tonic Inhibition of Excitatory Synaptic Input to Hypocretin/Orexin Neurons
Authors: Acuna-Goycolea Claudio , Li Ying , van den Pol Anthony N.
Published: March 2004

Hypocretin/orexin neurons play an important role in hypothalamic arousal. Synaptic glutamate input to hypocretin neurons regulates cell firing. We studied the actions of group III metabotropic glutamate receptors (mGluRs) in modulating the activity of hypocretin neurons using whole-cell voltage- and current-clamp recording in mouse whole hypothalamic slices or minislices consisting only of the lateral hypothalamus. Selective green fluorescent protein expression was used to detect live hypocretin neurons. The mGluR agonistl-(+)-2-amino-4-phosphonobutyric acid (l-AP-4) inhibited synaptic input to hypocretin neurons in a dose-dependent manner; both spontaneous glutamate and GABA-mediated synaptic currents were reduced in frequency.l-AP-4 also reduced the amplitude of postsynaptic potentials evoked by a stimulating electrode placed medial or lateral to the recorded cell. No postsynaptic effect ofl-AP-4 was found relative to membrane potential, input resistance, or AMPA-evoked currents.l-AP-4 appeared to act by a presynaptic mechanism and reduced the frequency of both glutamate- and GABA-mediated miniature events recorded in the presence of tetrodotoxin, with no change in amplitude. (RS)-phosphonopentanoic acid (CPPG), a group III mGluR antagonist, suppressed the actions ofl-AP-4. Of substantial interest, CPPG by itself increased synaptic activity recorded in hypocretin neurons, suggesting an ongoing inhibitory tone attributable to activation of group III mGluRs. Glutamatergic interneurons have been suggested to play a role in a positive feedback recruitment of hypocretin on hypocretin neurons.l-AP-4 blocked hypocretin-mediated increases in EPSCs and attenuated the hypocretin-mediated increase in spike frequency. Together, these data suggest that tonically active inhibitory mGluRs are expressed on local hypocretin-sensitive glutamate neurons within the lateral hypothalamus that modulate the output of the hypocretin arousal system.
Temporal Properties of Cerebellar-Dependent Memory Consolidation
Authors: Cooke Samuel F. , Attwell Phillip J. E. , Yeo Christopher H.
Published: March 2004

Classical conditioning of the nictitating membrane response in rabbits is a well defined model of cerebellar-dependent motor memory. This memory undergoes a period of consolidation after the training session, when it is sensitive to reversible inactivations of the cerebellar cortex, but not of the cerebellar nuclei, with the GABAAreceptor agonist muscimol. Here, the temporal properties of this cerebellar cortex-dependent consolidation were examined using delayed infusions of muscimol in cortical lobule HVI. Cortical infusions delayed by 5 or 45 min after a conditioning session produced significant and very similar impairments of consolidation, but infusions delayed by 90 min produced little or no impairment. Behavioral measures indicate that the muscimol infusions produced significant effects after ∼30 min and they lasted for a few hours. So, over a time window beginning ∼1 hr after the end of the training session and closing 1 hr after that, intracortical activity is critical for consolidation of this motor memory.
HoxGene Misexpression and Cell-Specific Lesions Reveal Functionality of Homeotically Transformed Neurons
Authors: Hale Melina E. , Kheirbek Mazen A. , Schriefer Julie E. , Prince Victoria E.
Published: March 2004

Hoxgenes are critical for establishing the segmental pattern of the vertebrate hindbrain. Changes in their expression can alter neural organization of hindbrain segments and may be a mechanism for brain evolution. To test the hypothesis that neurons induced through changes inHoxgene expression can integrate into functional neural circuits, we examined the roles of ectopic Mauthner cells (M-cells) in the escape response of larval zebrafish. The activity of the paired Mauthner cells in rhombomere 4 (r4) has been shown to be critical for generating a high-performance startle behavior in response to stimulation of the tail (Liu and Fetcho, 1999). Previous studies have found that misexpression of particularHoxgenes causes ectopic M-cells to be generated in r2 in addition to the r4 cells (Alexandre et al., 1996; McClintock et al., 2001). With calcium imaging, we found that the homeotically transformed neurons respond to startle stimuli. To determine the roles of ectopic and endogenous M-cells in the behavior, we lesioned the r2, r4, or both M-cells with cell-specific laser lesion and examined the effect on startle performance. Lesion of the normal M-cells did not decrease escape performance when the ectopic cells were present. These results indicate that the homeotically transformed Mauthner cells are fully functional in the escape circuit and are functionally redundant with normal M-cells. We suggest that such functional redundancy between neurons may provide a substrate for evolution of neural circuits.
Sensory Neuron Signaling to the Brain: Properties of Transmitter Release from Olfactory Nerve Terminals
Authors: Murphy Gabe J. , Glickfeld Lindsey L. , Balsen Zev , Isaacson Jeffry S.
Published: March 2004

Olfactory receptor neurons (ORNs) convey sensory information directly to the CNS via conventional glutamatergic synaptic contacts in olfactory bulb glomeruli. To better understand the process by which information contained in the odorant-evoked firing of ORNs is transmitted to the brain, we examined the properties of glutamate release from olfactory nerve (ON) terminals in slices of the rat olfactory bulb. We show that marked paired pulse depression is the same in simultaneously recorded periglomerular and tufted neurons, and that this form of short-term plasticity is attributable to a reduction of glutamate release from ON terminals. We used the progressive blockade of NMDA receptor (NMDAR) EPSCs by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine hydrogen maleate] and stationary fluctuation analysis of AMPA receptor (AMPAR) EPSCs to determine the probability of release (Pr) of ON terminals; both approaches indicated that Pris unusually high (≥0.8). The low-affinity glutamate receptor antagonists γ-d-glutamylglycine andl-amino-5-phosphonovaleric acid blocked ON-evoked AMPAR- and NMDAR-mediated EPSCs, respectively, to the same extent under conditions of low and high Pr, suggesting that multivesicular release is not a feature of ON terminals. Although release from most synapses exhibits a highly nonlinear dependence on extracellular Ca2+, we find that the relationship between glutamate release and extracellular Ca2+at ON terminals is nearly linear. Our results suggest that ON terminals have specialized features that may contribute to the reliable transmission of sensory information from nose to brain.
The cytosolic sperm factor that triggers Ca2+ oscillations and egg activation in mammals is a novel phospholipase C: PLCζ
Authors: Swann K , Larman M G , Saunders C M , Lai F A
Published: March 2004

When sperm activate eggs at fertilization the signal for activation involves increases in the intracellular free Ca2+concentration. In mammals the Ca2+changes at fertilization consist of intracellular Ca2+oscillations that are driven by the generation of inositol 1,4,5-trisphosphate (InsP3). It is not established how sperm trigger the increases in InsP3and Ca2+at fertilization. One theory suggests that sperm initiate signals to activate the egg by introducing a specific factor into the egg cytoplasm after membrane fusion. This theory has been mainly based upon the observation that injecting a cytosolic sperm protein factor into eggs can trigger the same pattern of Ca2+oscillations induced by the sperm. We have recently shown that this soluble sperm factor protein is a novel form of phospholipase C (PLC), and it is referred to as PLCζ(zeta). We describe the evidence that led to the identification of PLCζ and discuss the issues relating to its potential role in fertilization.
Enzyme Immobilization on Porous Silicon Surfaces
Authors: Létant S. E. , Hart B. R. , Kane S. R. , Hadi M. Z. , Shields S. J. , Reynolds J. G.
Published: March 2004

β‐Glucuronidase enzymes have been attached to a porous silicon surface through a direct silicon–carbon bond based linking system (see Figure). The attached enzymes display high activity and the photoluminescent (PL) properties and surface stability of the porous silicon are retained. Quenching of the PL is observed upon enzymatic breakdown of the substrate, leading to the possibility of a new class of chemical and biological sensors.
Electrical conductivity of carbon filled nylon 6,6
Authors: Heiser Jessica A. , King Julia A. , Konell Jeremiah P. , Sutter Lawrence L.
Published: March 2004

The electrical conductivity of resins can be increased by adding electrically conductive carbon fillers. A significant amount of work has been conducted varying the amount of single conductive fillers in a composite material. Limited work has been conducted concerning the effect of combinations of different conductive fillers. In this study, three different carbon fillers were used in nylon 6,6: carbon black, synthetic graphite particles, and a surface treated polyacrylonitrile (PAN) based carbon fiber. The goal of this project was to determine the effect of each filler and combinations of different fillers on the electrical conductivity of conductive resins. A 23 factorial design was analyzed to determine the effects of the three different carbon fillers in nylon 6,6. The results showed that carbon fiber caused the largest increase in composite electrical conductivity and that all the combinations of different fillers do have a statistically significant effect on composite electrical conductivity. © 2004 Wiley Periodicals, Inc. Adv Polym Techn 23: 135–146, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/adv.20004
Altered expression of the glutamate transporter EAAT2b in neurological disease
Authors: Maragakis Nicholas J. , Dykes‐Hoberg Margaret , Rothstein Jeffrey D.
Published: March 2004

Functional studies suggest that up to 95% of all glutamate transport is handled by the glutamate transporter EAAT2. Amino and C‐terminal antibodies demonstrate that under normal conditions EAAT2 is specific to astrocytes. A truncated splice variant of EAAT2, known as EAAT2b, also has been identified in astrocytes and some neurons. In vitro studies suggest EAAT2b transports glutamate similar to EAAT2, although the contribution of EAAT2b to normal clearance of extracellular glutamate is unknown. To investigate EAAT2b biology in pathological conditions, we examined the cellular and regional distribution of EAAT2b in amyotrophic lateral sclerosis. Using epitope‐specific, affinity purified antibodies, we found that EAAT2b tissue levels were increased by more than twofold in amyotrophic lateral sclerosis motor cortex, whereas EAAT2 levels were decreased by up to 95%. EAAT2b distribution in normal human cortex was largely confined to the neuropil‐like EAAT2, with occasional faint neuronal expression. In contrast, amyotrophic lateral sclerosis motor cortex had an obvious qualitative increase in neuropil EAAT2b staining and a drastic increase in neuronal soma and dendritic EAAT2b immunostaining. Despite these increases in EAAT2b immunostaining, functional transporter studies demonstrated a large loss of EAAT2 function. These studies clearly document altered regulation and splicing of the dominant glutamate transporter EAAT2 under conditions of neurological stress. Ann Neurol 2004;55:000–000
UCHL1 is a Parkinson's disease susceptibility gene
Authors: Maraganore Demetrius M. , Lesnick Timothy G. , Elbaz Alexis , Chartier‐Harlin Marie‐Christine , Gasser Thomas , Krüger Rejko , Hattori Nobutaka , Mellick George D. , Quattrone Aldo , Satoh Jun‐Ichi , Toda Taksushi , Wang Jian , Ioannidis John P.A. , de Andrade Mariza , Rocca Walter A. ,   the UCHL1 Global Genetics Consortium
Published: March 2004

An Erratum has been published for this article in Ann Neurol 2004;55:899.

The reported inverse association between the S18Y variant of the ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual‐level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73–0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57–0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis‐generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease‐modifying therapies. Ann Neurol 2004
Delayed myelopathy induced by chronic compression in the rat spinal cord
Authors: Kim Phyo , Haisa Toshihiko , Kawamoto Toshiki , Kirino Takaaki , Wakai Susumu
Published: March 2004

Cervical myelopathy is a common cause of neurological disability among the elderly; however, the exact mechanism for the insidious and progressive deterioration remains to be elucidated. To study the pathophysiology, we developed a simple experimental model reproducing the course. In rats, a thin sheet of expanding polymer was implanted microsurgically underneath the C5‐C6 laminae. In the control group, the polymer sheet was removed immediately. Changes in motor functions were monitored for 25 weeks after the operation, with voluntary exercise activity measured by odometer attached to revolving cages, and forced running capability measured by duration of exercise on a rotating treadmill. Motor neurons were counted stereologically in continuous sections. In the compression group, the forced running capability deteriorated after a latent period of 17 weeks and progressively thereafter. In the control group, it stayed unchanged throughout 25 weeks. Course of the voluntary exercise was comparable between the groups. Motor neuron density in the compression group decreased significantly in 9 weeks (−20.3%) and 25 weeks (−35.5%), but not in 1 or 3 weeks. This practical model properly reproduces characteristic features of the clinical cervical myelopathy, with progressive motor disturbance after a latency and insidious neuronal loss preceding the symptoms. Ann Neurol 2004
Benign familial neonatal‐infantile seizures: Characterization of a new sodium channelopathy
Authors: Berkovic Samuel F. , Heron Sarah E. , Giordano Lucio , Marini Carla , Guerrini Renzo , Kaplan Robert E. , Gambardella Antonio , Steinlein Ortrud K. , Grinton Bronwyn E. , Dean Joanne T. , Bordo Laura , Hodgson Bree L. , Yamamoto Toshiyuki , Mulley John C. , Zara Federico , Scheffer Ingrid E.
Published: March 2004

We recently reported mutations in the sodium channel geneSCN2Ain two families with benign familial neonatal‐infantile seizures (BFNISs). Here, we aimed to refine the molecular‐clinical correlation ofSCN2Amutations in early childhood epilepsies.SCN2Awas analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS families, and in none of the others. Our eight families had six differentSCN2Amutations; one mutation (R1319Q) occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean, 11.2 ± 9.2 weeks) with afebrile secondarily generalized partial seizures; neonatal seizures were not seen in all families. The frequency of seizures varied; some individuals had only a few attacks without treatment and others had clusters of many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset in the posterior quadrants.SCN2Amutations appear specific for BFNIS; the disorder can now be strongly suspected clinically and the families can be given an excellent prognosis. Ann Neurol 2004