bluuebunny/crossref_metadata_2025 huggingface dataset:
Bcl-2 Protein as a Marker of Neuronal Immaturity in Postnatal Primate Brain
Authors: Bernier Patrick J. , Parent André
Published: April 2018

The distribution of neurons expressing immunoreactivity for the protein Bcl-2 was studied in the brain of squirrel monkeys (Saimiri sciureus) of various ages. Several subsets of small and intensely immunoreactive neurons displaying an immature appearance were disclosed in the amygdala and piriform cortex. The piriform cortex exhibited clusters of various forms in which Bcl-2+ neurons appeared linked to one another by their own neurites. The subventricular zone, which is known to harbor the largest population of rapidly and constitutively proliferating cells in the adult rat brain, was intensely stained, particularly at the basis of the lateral ventricle. A long and dorsoventrally oriented Bcl-2+ fiber fascicle was seen to emerge from the subventricular zone, together with numerous Bcl-2+ cells that formed a densely packed column directed at the olfactory tubercle. In adult and aged monkeys, the small and intensely labeled neurons were progressively replaced by larger and more weakly stained neurons in the amygdala and piriform cortex. In contrast, Bcl-2 immunostaining did not change with age in the subventricular zone and olfactory tubercle, the islands of Calleja of which were markedly enriched with Bcl-2. The dentate gyrus contained only a few layers of intensely labeled granule cells in juvenile monkeys, but the number of these layers increased markedly in adult and aged monkeys. These findings suggest that Bcl-2 can serve as a marker of both proliferating and differentiating neurons and indicate that such immature neurons may be much more widespread than previously thought in postnatal primate brain.
Estradiol Increases Dendritic Spine Density by Reducing GABA Neurotransmission in Hippocampal Neurons
Authors: Murphy Diane D. , Cole Nelson B. , Greenberger V. , Segal Menahem
Published: April 2018

We have previously shown that estradiol causes a twofold rise in dendritic spine density in cultured rat hippocampal neurons, as it doesin vivo. More recently, estrogen receptors have been localized to aspiny inhibitory hippocampal interneurons, indicating that their effect on spiny pyramidal neurons may be indirect. We therefore examined the possibility that estradiol affects spine density by regulating inhibition in cultured hippocampal interneurons. Immunocytochemically, estrogen receptors were found to be co-localized with glutamate decarboxylase (GAD)-positive neurons (∼21% of total neurons in the culture). Exposure of cultures to estradiol for 1 d caused a marked decrease (up to 80%) in the GAD content of the interneurons, measured both by immunohistochemistry and Western blotting. Also, the number of GAD-positive neurons in the cultures decreased to 12% of the total cell population. Moreover, GABAergic miniature IPSCs were reduced in both size and frequency by estradiol, whereas miniature EPSCs increased in frequency. We then mimicked the proposed effects of estradiol by blocking GABA synthesis with mercaptopropionic acid (MA). Cultures treated with MA expressed a dose-dependent decrease in GABA immunostaining that mimicked that seen with estradiol. MA-treated cultures displayed a significant 50% increase in dendritic spine density over controls, similar to that produced by estradiol. These results indicate that estradiol decreases GABAergic inhibition in the hippocampus, which appears to effectively increase the excitatory drive on pyramidal cells, and thus may provide a mechanism for formation of new dendritic spines.
GABA Inhibits Migration of Luteinizing Hormone-Releasing Hormone Neurons in Embryonic Olfactory Explants
Authors: Fueshko Susan M. , Key Sharon , Wray Susan
Published: April 2018

During development, a subpopulation of olfactory neurons transiently expresses GABA. The spatiotemporal pattern of GABAergic expression coincides with migration of luteinizing hormone-releasing hormone (LHRH) neurons from the olfactory pit to the CNS. In this investigation, we evaluated the role of GABAergic input on LHRH neuronal migration using olfactory explants, previously shown to exhibit outgrowth of olfactory axons, migration of LHRH neurons in association with a subset of these axons, and the presence of the olfactory-derived GABAergic neuronal population. GABAAreceptor antagonists bicuculline (10−5m) or picrotoxin (10−4m) had no effect on the length of peripherin-immunoreactive olfactory fibers or LHRH cell number. However, LHRH cell migration, as determined by the distance immunopositive cells migrated from olfactory pits, was significantly increased by these perturbations. Addition of tetrodotoxin (10−6m), to inhibit Na+-transduced electrical activity, also significantly enhanced LHRH migration. The most robust effect observed was dramatic inhibition of LHRH cell migration in explants cultured in the presence of the GABAAreceptor agonist muscimol (10−4m). This study demonstrates that GABAergic activity in nasal regions can have profound effects on migration of LHRH neurons and suggests that GABA participates in appropriate timing of LHRH neuronal migration into the developing brain.
Differential Effects of Amygdala Lesions on Early and Late Plastic Components of Auditory Cortex Spike Trains during Fear Conditioning
Authors: Armony Jorge L. , Quirk Gregory J. , LeDoux Joseph E.
Published: April 2018

In auditory fear conditioning, pairing of a neutral acoustic conditioned stimulus (CS) with an aversive unconditioned stimulus (US) results in an enhancement of neural responses to the CS in the amygdala and auditory cortex. It is not clear, however, whether cortical plasticity governs neural changes in the amygdala or vice versa, or whether learning in these two structures is determined by independent processes. We examined this issue by recording single-cell activity in the auditory cortex (areas Te1, Te1v, and Te3) of freely behaving, amygdalectomized rats using a movable bundle of microwires. Amygdala damage did not affect short-latency (0–50 msec) tone responses, nor did it interfere with conditioning-induced increases of these onset responses. In contrast, lesions of the amygdala interfered with the development of late (500–1500 msec) conditioned tone responses that were not present before conditioning. Furthermore, whereas onset conditioned responses in the control group remained elevated after 30 extinction trials (presentation of CS alone), onset responses in lesioned animals returned to their preconditioning firing level after approximately 10 extinction trials. These results suggest that the amygdala enables the development of long-latency (US anticipatory) responses and prevents the extinction of short-latency onset responses to threatening stimuli. The findings further suggest that auditory cortex cells may participate differently in explicit and implicit memory networks.
Functional Organization of Rat Olfactory Bulb Glomeruli Revealed by Optical Imaging
Authors: Keller Asaf , Yagodin Sergey , Aroniadou-Anderjaska Vassiliki , Zimmer Lee A. , Ennis Matthew , Sheppard Norman F. , Shipley Michael T.
Published: April 2018

The functional organization and synaptic physiology of olfactory bulb glomeruli were studied in ratin vitroslice preparations stained with the voltage-sensitive dye RH-155. Optical signals were recorded with a 100-element photodiode array at high temporal resolution. Pharmacological and ionic manipulations were used to investigate synaptic responses to stimulation of the olfactory nerve layer (ONL). ONL stimulation evoked a sodium-mediated compound action potential that propagated across the ONL and invaded individual glomeruli. This presynaptic volley evoked calcium-dependent synaptic responses the amplitudes of which were largest within the glomerular layer (GL); smaller amplitude responses were recorded in deeper layers of the olfactory bulb. Synaptic responses in the GL were attenuated by the non-NMDA ionotropic glutamate receptor antagonist CNQX; the residual component was suppressed by the NMDA glutamate receptor antagonist AP-5. The GABAAreceptor antagonist bicuculline methiodide had little effect, whereas the GABABreceptor agonist baclofen dramatically attenuated ONL-evoked synaptic responses. The effects of baclofen were reversed by the GABABreceptor antagonist CGP35348. Paired-pulse depression of ONL-evoked synaptic responses in the GL was partially reversed by CGP35348. These findings suggest that olfactory nerve axons release glutamate to activate both NMDA and non-NMDA receptors on GL neurons, that GABAAreceptor-mediated inhibition has little effect on these responses, and that GABABreceptor-mediated inhibition may act presynaptically on olfactory nerve axons to modulate their inputs to olfactory bulb neurons.
Structure of Receptive Fields in Area 3b of Primary Somatosensory Cortex in the Alert Monkey
Authors: DiCarlo James J. , Johnson Kenneth O. , Hsiao Steven S.
Published: April 2018

We investigated the two-dimensional structure of area 3b neuronal receptive fields (RFs) in three alert monkeys. Three hundred thirty neurons with RFs on the distal fingerpads were studied with scanned, random dot stimuli. Each neuron was stimulated continuously for 14 min, yielding 20,000 response data points. Excitatory and inhibitory components of each RF were determined with a modified linear regression algorithm. Analyses assessing goodness-of-fit, repeatability, and generality of the RFs were developed. Two hundred forty-seven neurons yielded highly repeatable RF estimates, and most RFs accounted for a large fraction of the explainable response of each neuron. Although the area 3b RF structures appeared to be continuously distributed, certain structural generalities were apparent. Most RFs (94%) contained a single, central region of excitation and one or more regions of inhibition located on one, two, three, or all four sides of the excitatory center. The shape, area, and strength of excitatory and inhibitory RF regions ranged widely. Half the RFs contained almost evenly balanced excitation and inhibition. The findings indicate that area 3b neurons act as local spatiotemporal filters that are maximally excited by the presence of particular stimulus features. We believe that form and texture perception are based on high-level representations and that area 3b is an intermediate stage in the processes leading to these representations. Two possibilities are considered: (1) that these high-level representations are basically somatotopic and that area 3b neurons amplify some features and suppress others, or (2) that these representations are highly transformed and that area 3b effects a step in the transformation.
Age-Related Alteration in Processing of Temporal Sound Features in the Auditory Midbrain of the CBA Mouse
Authors: Walton Joseph P. , Frisina Robert D. , O’Neill William E.
Published: April 2018

The perception of complex sounds, such as speech and animal vocalizations, requires the central auditory system to analyze rapid, ongoing fluctuations in sound frequency and intensity. A decline in temporal acuity has been identified as one component of age-related hearing loss. The detection of short, silent gaps is thought to reflect an important fundamental dimension of temporal resolution. In this study we compared the neural response elicited by silent gaps imbedded in noise of single neurons in the inferior colliculus (IC) of young and old CBA mice. IC neurons were classified by their temporal discharge patterns. Phasic units, which accounted for the majority of response types encountered, tended to have the shortest minimal gap thresholds (MGTs), regardless of age. We report three age-related changes in neural processing of silent gaps. First, although the shortest MGTs (1–2 msec) were observed in phasic units from both young and old animals, the number of neurons exhibiting the shortest MGTs was much lower in old mice, regardless of the presentation level. Second, in the majority of phasic units, recovery of response to the stimulus after the silent gap was of a lower magnitude and much slower in units from old mice. Finally, the neuronal map representing response latency versus best frequency was found to be altered in the old IC. These results demonstrate a central auditory system correlate for age-related decline in temporal processing at the level of the auditory midbrain.
Coding of Serial Order by Neostriatal Neurons: A “Natural Action” Approach to Movement Sequence
Authors: Aldridge J. Wayne , Berridge Kent C.
Published: April 2018

The neostriatum controls behavioral sequencing, or action syntax, as well as simpler aspects of movement. Yet the precise nature of the neostriatums role in sequencing remains unclear. Here we used a “natural action” approach that combined electrophysiological and neuroethological techniques. We identified neostriatal neurons that code theserial orderof natural movement sequences of rats. During grooming behavior, rats emit complex but highly predictable species-specific sequences of movements, termed “syntactic chains.” Neuronal activity of 41% of cells in the dorsolateral and ventromedial neostriatum coded the sequential pattern of syntactic chains. Only 14% coded simple motor properties of grooming movements. Neurons fired preferentially during syntactic chains compared with similar grooming movements made in different sequential order or to behavioral resting. Sequential coding differed between the dorsolateral and ventromedial neostriatum. Neurons in the dorsolateral site increased firing by 116% during syntactic chains, compared with only a 30% increase by neurons in the ventromedial site, and dorsolateral neurons showed strongest coding of grooming syntax by several additional criteria. These data demonstrate that neostriatal neurons code abstract properties of serial order for natural movement and support the hypothesis that the dorsolateral neostriatum plays a special role in implementing action syntax.
In VivoModulation of Interacting Central Pattern Generators in Lobster Stomatogastric Ganglion: Influence of Feeding and Partial Pressure of Oxygen
Authors: Clemens Stefan , Massabuau Jean-Charles , Legeay Alexia , Meyrand Pierre , Simmers John
Published: April 2018

The stomatogastric ganglion (STG) of the European lobsterHomarus gammaruscontains two rhythm-generating networks (the gastric and pyloric circuits) that in resting, unfed animals produce two distinct, yet strongly interacting, motor patterns. By using simultaneous EMG recordings from the gastric and pyloric musclesin vivo, we found that after feeding, the gastropyloric interaction disappears as the two networks express accelerated motor rhythms. The return to control levels of network activity occurs progressively over the following 1–2 d and is associated with a gradual reappearance of the gastropyloric interaction. In parallel with this change in network activity is an alteration of oxygen levels in the blood. In resting, unfed animals, arterial partial pressure of oxygen (Po2) is most often between 1 and 2 kPa and then doubles within 1 hr after feeding, before returning to control values some 24 hr later.In vivo, experimental prevention of the arterial Po2increase after feeding leads to a slowing of pyloric rhythmicity toward control values and a reappearance of the gastropyloric interaction, without apparent effect on gastric network operation. Usingin vitropreparations of the stomatogastric nervous system and by changing oxygen levels uniquely at the level of the STG within the range observed in the intact animal, we were able to mimic most of the effects observedin vivo. Our data indicate that the gastropyloric interaction appears only during a “free run” mode of foregut activity and that the coordinated operation of multiple neural networks may be modulated by local changes in oxygenation.
Cannabinoids Enhance NMDA-Elicited Ca2+Signals in Cerebellar Granule Neurons in Culture
Authors: Netzeband Jeffrey G. , Conroy Shannon M. , Parsons Kathy L. , Gruol Donna L.
Published: April 2018

A physiological role for cannabinoids in the CNS is indicated by the presence of endogenous cannabinoids and cannabinoid receptors. However, the cellular mechanisms of cannabinoid actions in the CNS have yet to be fully defined. In the current study, we identified a novel action of cannabinoids to enhance intracellular Ca2+responses in CNS neurons. Acute application of the cannabinoid receptor agonistsR(+)-methanandamide,R(+)-WIN, and HU-210 (1–50 nm) dose-dependently enhanced the peak amplitude of the Ca2+response elicited by stimulation of the NMDA subtype of glutamate receptors (NMDARs) in cerebellar granule neurons. The cannabinoid effect was blocked by the cannabinoid receptor antagonist SR141716A and the Gi/Goprotein inhibitor pertussis toxin but was not mimicked by the inactive cannabinoid analogS(−)-WIN, indicating the involvement of cannabinoid receptors. In current-clamp studies neitherR(+)-WIN norR(+)-methanandamide altered the membrane response to NMDA or passive membrane properties of granule neurons, suggesting that NMDARs are not the primary sites of cannabinoid action. Additional Ca2+imaging studies showed that cannabinoid enhancement of the Ca2+signal to NMDA did not involve N-, P-, or L-type Ca2+channels but was dependent on Ca2+release from intracellular stores. Moreover, the phospholipase C inhibitor U-73122 and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist xestospongin C blocked the cannabinoid effect, suggesting that the cannabinoid enhancement of NMDA-evoked Ca2+signals results from enhanced release from IP3-sensitive Ca2+stores. These data suggest that the CNS cannabinoid system could serve a critical modulatory role in CNS neurons through the regulation of intracellular Ca2+signaling.
Comparing Astrocytic Cell Lines that Are Inhibitory or Permissive for Axon Growth: the Major Axon-Inhibitory Proteoglycan Is NG2
Authors: Fidler Penny S. , Schuette Katrin , Asher Richard A. , Dobbertin Alexandre , Thornton Suzanne R. , Calle-Patino Yolanda , Muir Elizabeth , Levine Joel M. , Geller Herbert M. , Rogers John H. , Faissner Andreas , Fawcett James W.
Published: April 2018

Astrocytes, oligodendrocytes, and oligodendrocyte/type 2 astrocyte progenitors (O2A cells) can all produce molecules that inhibit axon regeneration. We have shown previously that inhibition of axon growth by astrocytes involves proteoglycans. To identify inhibitory mechanisms, we created astrocyte cell lines that are permissive or nonpermissive and showed that nonpermissive cells produce inhibitory chondroitin sulfate proteoglycans (CS-PGs). We have now tested these cell lines for the production and inhibitory function of known large CS-PGs. The most inhibitory line, Neu7, produces three CS-PGs in much greater amounts than the other cell lines: NG2, versican, and the CS-56 antigen. The contribution of NG2 to inhibition by the cells was tested using a function-blocking antibody. This allowed increased growth of dorsal root ganglion (DRG) axons over Neu7 cells and matrix and greatly increased the proportion of cortical axons able to cross from permissive A7 cells onto inhibitory Neu7 cells; CS-56 antibody had a similar effect. Inhibitory fractions of conditioned medium contained NG2 coupled to CS glycosaminoglycan chains, whereas noninhibitory fractions contained NG2 without CS chains. Enzyme preparations that facilitated axon growth in Neu7 cultures were shown to either degrade the NG2 core protein or remove CS chains. Versican is present as patches on Neu7 monolayers, but DRG axons do not avoid these patches. Therefore, NG2 appears to be the major axon-inhibitory factor made by Neu7 astrocytes. In the CNS, NG2 is expressed by O2A cells, which react rapidly after injury to produce a dense NG2-rich network, and by some reactive astrocytes. Our results suggest that NG2 may be a major obstacle to axon regeneration.
Neuroprotective Effect of High Glucose Against NMDA, Free Radical, and Oxygen–Glucose Deprivation through Enhanced Mitochondrial Potentials
Authors: Seo So Y. , Kim Eun Y. , Kim Harriet , Gwag Byoung J.
Published: April 2018

Cultured cortical neurons maintained in 25 mmglucose underwent a widespread neuronal death after exposure to NMDA, AMPA, and kainate. Among these, NMDA toxicity was substantially reduced in neurons maintained in 100 mmglucose. NMDA-induced increase in [Ca2+]iand reactive oxygen species was attenuated in neurons maintained in high glucose that revealed increased mitochondrial membrane and redox potentials as determined using rhodamine 123 and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide.p-trifluoromethoxy-phenylhydrazone, KCN, and rotenone, the selective inhibitors of mitochondrial potential, abrogated neuroprotective effect of high glucose against NMDA. The neuroprotective action of high glucose was extended against oxygen or combined oxygen–glucose deprivation. The present study provides evidence that prolonged exposure of cortical cells to high glucose attenuates NMDA- and free radical-mediated neuronal death via enhanced mitochondrial function.
Lack of the p50 Subunit of Nuclear Factor-κB Increases the Vulnerability of Hippocampal Neurons to Excitotoxic Injury
Authors: Yu ZaiFang , Zhou Daohong , Bruce-Keller Annadora J. , Kindy Mark S. , Mattson Mark P.
Published: April 2018

Nuclear factor-κB (NF-κB) is activated in brain cells after various insults, including cerebral ischemia and epileptic seizures. Although cell culture studies have suggested that the activation of NF-κB can prevent neuronal apoptosis, the role of this transcription factor in neuronal injuryin vivois unclear, and the specific κB subunits involved are unknown. We now report that mice lacking the p50 subunit of NF-κB exhibit increased damage to hippocampal pyramidal neurons after administration of the excitotoxin kainate. Gel-shift analyses showed that p50 is required for the majority of κB DNA-binding activity in hippocampus. Intraventricular administration of κB decoy DNA before kainate administration in wild-type mice resulted in an enhancement of damage to hippocampal pyramidal neurons, indicating that reduced NF-κB activity was sufficient to account for the enhanced excitotoxic neuronal injury in p50−/−mice. Cultured hippocampal neurons from p50−/−mice exhibited enhanced elevations of intracellular calcium levels and increased levels of oxidative stress after exposure to glutamate and were more vulnerable to excitotoxicity than were neurons from p50+/+and p50+/−mice. Collectively, our data demonstrate an important role for the p50 subunit of NF-κB in protecting neurons against excitotoxic cell death.
A Role for the Eph Ligand Ephrin-A3 in Entorhino-Hippocampal Axon Targeting
Authors: Stein Eckart , Savaskan Nicolai E. , Ninnemann Olaf , Nitsch Robert , Zhou Renping , Skutella Thomas
Published: April 2018

Neurons of layers II and III of the entorhinal cortex constitute the major afferent connection of the hippocampus. The molecular mechanisms that target the entorhinal axons to specific layers in the hippocampus are not known. EphA5, a member of the Eph receptor family, which has been shown to play critical roles in axon guidance, is expressed in the entorhinal cortex, the origin of the perforant pathway. In addition, ligands that interact with EphA5 are expressed in distinct hippocampal regions during development of the entorhino-hippocampal projection. Of these ligands, ephrin-A3 mRNA is localized both in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the cornu ammonis, whereas ephrin-A5 mRNA is only expressed in the pyramidal cell layer of the cornu ammonis. In the dentate gyrus, the ligand protein is not present in the termination zone of the entorhinal efferents (the outer molecular layer of the dentate gyrus) but is concentrated in the inner molecular layer into which entorhinal efferents do not grow. We used outgrowth and stripe assays to test the effects of ephrin-A3 and ephrin-A5 on the outgrowth behavior of entorhinal axons. This functional analysis revealed that entorhinal neurites were repelled by ephrin-A3 but not by ephrin-A5. These observations suggest that ephrin-A3 plays an important role in the layer-specific termination of the perforant pathway and that this ligand may interact with the EphA5 receptor to restrict entorhinal axon terminals in the outer molecular layer of the dentate gyrus.
Role of Neurotrophin Receptor TrkB in the Maturation of Rod Photoreceptors and Establishment of Synaptic Transmission to the Inner Retina
Authors: Rohrer Baerbel , Korenbrot Juan I. , LaVail Matthew M. , Reichardt Louis F. , Xu Baoji
Published: April 2018

Brain-derived neurotrophic factor (BDNF) acts through TrkB, a receptor with kinase activity, and mitigates light-induced apoptosis in adult mouse rod photoreceptors. To determine whether TrkB signaling is necessary for rod development and function, we examined the retinas of mice lacking all isoforms of the TrkB receptor. Rod migration and differentiation occur in the mutant retina, but proceed at slower rates than in wild-type mice. In postnatal day 16 (P16) mutants, rod outer segment dimensions and rhodopsin content are comparable with those of photoreceptors in P12 wild type (WT). Quantitative analyses of the photoreceptor component in the electroretinogram (ERG) indicate that the gain and kinetics of the rod phototransduction signal in dark-adapted P16 mutant and P12 WT retinas are similar. In contrast to P12 WT, however, the ERG in mutant mice entirely lacks a b-wave, indicating a failure of signal transmission in the retinal rod pathway. In the inner retina of mutant mice, although cells appear anatomically and immunohistochemically normal, they fail to respond to prolonged stroboscopic illumination with the normal expression of c-fos. Absence of the b-wave and failure of c-fos expression, in view of anatomically normal inner retinal cells, suggest that lack of TrkB signaling causes a defect in synaptic signaling between rods and inner retinal cells. Retinal pigment epithelial cells and cells in the inner retina, including Müller, amacrine, and retinal ganglion cells, express the TrkB receptor, but rod photoreceptors do not. Moreover, inner retinal cells respond to exogenous BDNF with c-fos expression and extracellular signal-regulated kinase phosphorylation. Thus, interactions of rods with TrkB-expressing cells must be required for normal rod development.
Dopamine Affects Parvalbumin Expression during Cortical DevelopmentIn Vitro
Authors: Porter Linda L. , Rizzo Elena , Hornung Jean-Pierre
Published: April 2018

This study was undertaken to determine how dopamine influences cortical development. It focused on morphogenesis of GABAergic neurons that contained the calcium-binding protein parvalbumin (PV). Organotypic slices of frontoparietal cortex were taken from neonatal rats, cultured with or without dopamine, harvested daily (4–30 d), and immunostained for parvalbumin. Expression of parvalbumin occurred in the same regional and laminar sequence asin vivo. Expression in cingulate and entorhinal preceded that in lateral frontoparietal cortices. Laminar expression progressed from layer V to VI and finally II-IV. Somal labeling preceded fiber labeling by 2 d.

Dopamine accelerated PV expression. In treated slices, a dense band of PV-immunoreactive neurons appeared in layer V at 7 din vitro(DIV), and in all layers of frontoparietal cortex at 14 DIV, whereas in control slices such labeling did not appear until 14 and 21 DIV, respectively. The laminar distribution and dendritic branching of PV-immunoreactive neurons were quantified. More labeled neurons were in the superficial layers, and their dendritic arborizations were significantly increased by dopamine. Treatment with a D1 receptor agonist had little effect, whereas a D2 agonist mimicked dopamine’s effects. Likewise, the D2 but not the D1 antagonist blocked dopamine-induced changes, indicating that they were mediated primarily by D2 receptors.

Parvalbumin expression was accelerated by dopaminergic reinnervation of cortical slices that were cocultured with mesencephalic slices.

Coapplication of the glutamate NMDA receptor antagonist MK801 or AP5 blocked dopamine-induced increases in dendritic branching, suggesting that changes were mediated partly by interaction with glutamate to alter cortical excitability.
Astroglial Differentiation of Cortical Precursor Cells Triggered by Activation of the cAMP-Dependent Signaling Pathway
Authors: McManus Matthew F. , Chen Li-Chun , Vallejo Inmaculada , Vallejo Mario
Published: April 2018

In the developing brain, differentiation of neural precursors into neurons or glial cells occurs in response to neurotrophic factors acting on the cell surface. Intracellular signaling mechanisms that relay information to initiate differentiative responses of neural precursor cells are poorly understood. To investigate whether stimulation of the cAMP-dependent signaling pathway participates in differentiative responses of cells in the developing CNS, we performed experiments using both conditionally immortalized neural precursor cells (RC2.E10 cells) and primary cultures of cells from developing rat cortex. Initially, we determined that RC2.E10 cells retain phenotypic features of neural precursors after inactivation of the immortalizing oncogene, a temperature-sensitive mutant of the simian virus 40 large-T antigen (SV40T). We found that, once SV40T is inactivated, RC2.E10 cells cease to divide and die. However, RC2.E10 cells can proliferate in the presence of basic fibroblast growth factor. In addition, they express nestin, a marker of neural precursor cells. Both RC2.E10 cells and primary cortical precursor cells undergo astroglial differentiation in response to cAMP stimulation by treatment with 8-bromo-cAMP. In both cases, cAMP-induced astrocyte differentiation is characterized by morphological changes, stimulation of glial fibrillary acidic protein expression, downregulation of nestin expression, and decreased proliferation. No increases in the expression of neuronal or oligodendrocytic markers were observed. Our results support the notion that the developing CNS contains neural precursor cells with the capacity of undergoing astrocyte differentiation in response to increased intracellular cAMP concentrations.
Muscimol Inactivation of the Dorsal Hippocampus Impairs Contextual Retrieval of Fear Memory
Authors: Holt William , Maren Stephen
Published: April 2018

Some models of hippocampal function have suggested a role of the hippocampus in contextual memory retrieval. We have examined this hypothesis by assessing the impact of reversible inactivation of the dorsal hippocampus (DH) on the context-specific expression of latent inhibition, a decrement in conditional responding produced by preexposure to a to-be-conditional stimulus. In Experiment 1, rats received tone preexposure either in the context that would later be used for extinction testing (context A) or in a different context (context C); a third group of rats did not receive tone preexposure. All rats then received fear conditioning, which consisted of tone–footshock pairings, in a third distinct context (context B). The following day conditional fear to the tone was assessed in one of the preexposure contexts (context A) by measuring freezing during a tone extinction test. Rats preexposed and tested in the same context exhibited less freezing to the tone than either rats preexposed and tested in different contexts or nonpreexposed rats. These results indicate that the expression of latent inhibition is context specific. In Experiment 2, DH inactivation eliminated the context-specific expression of latent inhibition. Compared with saline-infused rats, rats infused with muscimol into the DH exhibited low levels of tone freezing independent of whether they had received tone preexposure in the test context or in a different context. Experiment 3 revealed normal contextual discrimination in rats after DH inactivation. These results suggest the DH is required for contextual memory retrieval in a latent inhibition paradigm.
Presynaptic Long-Term Potentiation in Corticothalamic Synapses
Authors: Castro-Alamancos Manuel A. , Calcagnotto Maria E.
Published: April 2018

The thalamus and neocortex are two highly organized and complex brain structures that work in concert with each other. The largest synaptic input to the thalamus arrives from the neocortex via corticothalamic fibers. Using brain slices, we describe long-term potentiation (LTP) in corticothalamic fibers contacting the ventrobasal thalamus. Corticothalamic LTP is input-specific, NMDA receptor-independent, and reversible. The induction of corticothalamic LTP is entirely presynaptic and Ca2+-dependent. The expression of corticothalamic LTP is associated with a decrease in paired-pulse facilitation (PPF) and blocked by an inhibitor of the cAMP-dependent protein kinase A (PKA). Consistent with an involvement of cAMP and PKA, activation of adenylyl cyclase induced a synaptic enhancement that was associated with a decrease in PPF and occluded LTP. Corticothalamic LTP may serve to enhance the efficacy of cortico-cortical communication via the thalamus and/or to mediate experience-dependent long-term modifications of thalamocortical receptive fields.
Mauthner Cell-Initiated Electromotor Behavior Is Mediated via NMDA and Metabotropic Glutamatergic Receptors on Medullary Pacemaker Neurons in a Gymnotid Fish
Authors: Curti Sebastián , Falconi Atilio , Morales Francisco R. , Borde Michel
Published: April 2018

Weakly electric fish generate meaningful electromotor behaviors by specific modulations of the discharge of their medullary pacemaker nucleus from which the rhythmic command for each electric organ discharge (EOD) arises. Certain electromotor behaviors seem to involve the activation of specific neurotransmitter receptors on particular target cells within the nucleus, i.e., on pacemaker or on relay cells. This paper deals with the neural basis of the electromotor behavior elicited by activation of Mauthner cells inGymnotus carapo. This behavior consists of an abrupt and prolonged increase in the rate of the EOD. The effects of specific glutamate agonists and antagonists on basal EOD frequency and on EOD accelerations induced by Mauthner cell activation were assessed. Injections of both ionotropic (AMPA, kainate, and NMDA) and metabotropic (trans-(±)-1-amino-1,3-cyclopentanedicarboxylic acid) glutamate agonists induced increases in EOD rate that were maximal when performed close to the soma of pacemaker cells. In contrast, injections in the proximity of relay cells were ineffective. Therefore, pacemaker neurons are probably endowed with diverse glutamate receptor subtypes, whereas relay cells are probably not. The Mauthner cell-evoked electromotor behavior was suppressed by injections of AP-5 and (±)-amino-4-carboxy-methyl-phenylacetic acid, NMDA receptor and metabotropic glutamate receptor antagonists, respectively. Thus, this electromotor behavior relies on the activation of the NMDA and metabotropic glutamate receptor subtypes of pacemaker cells. Our study gives evidence for the synergistic effects of NMDA and metabotropic receptor activation and shows how a simple circuit can produce specific electromotor outputs.
GABA Receptors Inhibited by Benzodiazepines Mediate Fast Inhibitory Transmission in the Central Amygdala
Authors: Delaney Andrew J. , Sah Pankaj
Published: April 2018

The amygdala is intimately involved in emotional behavior, and its role in the generation of anxiety and conditioned fear is well known. Benzodiazepines, which are commonly used for the relief of anxiety, are thought to act by enhancing the action of the inhibitory transmitter GABA. We have examined the properties of GABA-mediated inhibition in the amygdala. Whole-cell recordings were made from neurons in the lateral division of the central amygdala. Application of GABA evoked a current that reversed at the chloride equilibrium potential. Application of the GABA antagonists bicuculline or SR95531 inhibited the GABA-evoked current in a manner consistent with two binding sites. Stimulation of afferents to neurons in the central amygdala evoked an IPSC that was mediated by the release of GABA. The GABAAreceptor antagonists bicuculline and picrotoxin failed to completely block the IPSC. The bicuculline-resistant IPSC was chloride-selective and was unaffected by GABAB-receptor antagonists. Furthermore, this current was insensitive to modulation by general anesthetics or barbiturates. In contrast to their actions at GABAAreceptors, diazepam and flurazepam inhibited the bicuculline-resistant IPSC in a concentration-dependent manner. These effects were fully antagonized by the benzodiazepine site antagonist Ro15–1788. We conclude that a new type of ionotropic GABA receptor mediates fast inhibitory transmission in the central amygdala. This receptor may be a potential target for the development of new therapeutic strategies for anxiety disorders.
A Role for Extracellular Adenosine in Time-Dependent Reversal of Long-Term Potentiation by Low-Frequency Stimulation at Hippocampal CA1 Synapses
Authors: Huang Chiung-Chun , Liang Ying-Ching , Hsu Kuei-Sen
Published: April 2018

The involvement of adenosine on the development of time-dependent reversal of long-term potentiation (LTP) by low-frequency stimulation (LFS) was investigated at Schaffer collateral–CA1 synapses of rat hippocampal slices. A train of LFS (2 Hz, 10 min, 1200 pulses) had no long-term effects on synaptic transmission but produced lasting depression of previously potentiated responses. This reversal of LTP (depotentiation) was observed when the stimulus was delivered ≤3 min after induction of LTP. However, application at 10 min after induction had no detectable effect on potentiation. This time-dependent reversal of LTP by LFS appeared to be mediated by extracellular adenosine, because it was mimicked by bath-applied adenosine and was specifically inhibited by the selective A1adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nm). The effect of adenosine could be mimicked by 5-HT1Areceptor agonist buspirone, but the LFS-induced depotentiation could not be antagonized by 5-HT1Areceptor antagonist NAN-190. The source of extracellular adenosine in response to LFS appeared to be attributable to the efflux of cAMP. In addition, this LFS-induced depotentiation was blocked by bath application of adenylyl cyclase activator forskolin or injection of a cAMP analog Sp-adenosine cAMP (10 mm) into postsynaptic neurons. Moreover, the selective protein phosphatase 1 and 2A inhibitors okadaic acid and calyculin A prevented the LFS-induced depotentiation. These results thus suggest that increasing extracellular adenosine appears to underlie the LFS-induced depotentiation via acting on the A1receptor subtype to interrupt the cAMP-dependent biochemical processes leading to the LTP expression.
Functional Circuitry of the Retinal Ganglion Cell's Nonlinear Receptive Field
Authors: Demb Jonathan B. , Haarsma Loren , Freed Michael A. , Sterling Peter
Published: April 2018

A retinal ganglion cell commonly expresses two spatially overlapping receptive field mechanisms. One is the familiar “center/surround,” which sums excitation and inhibition across a region somewhat broader than the ganglion cell's dendritic field. This mechanism responds to a drifting grating by modulating firing at the drift frequency (linear response). Less familiar is the “nonlinear” mechanism, which sums the rectified output of many small subunits that extend for millimeters beyond the dendritic field. This mechanism responds to a contrast-reversing grating by modulating firing at twice the reversal frequency (nonlinear response). We investigated this nonlinear mechanism by presenting visual stimuli to the intact guinea pig retinain vitrowhile recording intracellularly from large brisk and sluggish ganglion cells. A contrast-reversing grating modulated the membrane potential (in addition to the firing rate) at twice the reversal frequency. This response was initially hyperpolarizing for some cells (either ON or OFF center) and initially depolarizing for others. Experiments in which responses to bars were summed in-phase or out-of-phase suggested that the single class of bipolar cells (either ON or OFF) that drives the center/surround response also drives the nonlinear response. Consistent with this, nonlinear responses persisted in OFF ganglion cells when ON bipolar cell responses were blocked byl-AP-4. Nonlinear responses evoked from millimeters beyond the ganglion cell were eliminated by tetrodotoxin. Thus, to relay the response from distant regions of the receptive field requires a spiking interneuron. Nonlinear responses from different regions of the receptive field added linearly.
Entorhinal Cortex Lesion in Adult Rats Induces the Expression of the Neuronal Chondroitin Sulfate Proteoglycan Neurocan in Reactive Astrocytes
Authors: Haas Carola A. , Rauch Uwe , Thon Niklas , Merten Tobias , Deller Thomas
Published: April 2018

The chondroitin sulfate proteoglycan neurocan is a major component of brain extracellular matrix during development. Neurocan is primarily synthesized by neurons and has the ability to interact with cell adhesion molecules involved in the regulation of cell migration and axonal growth. Within the first weeks postnatally, neurocan expression is strongly downregulated. To test whether neurocan is reexpressed in areas of axonal growth (sprouting) after brain injury, the time course of neurocan expression was analyzed in the denervated fascia dentata of the rat after entorhinal cortex lesion (12 hr; 1, 2, 4, and 10 d; 2 and 4 weeks; and 6 months after lesion). In the denervated zone, immunohistochemistry revealed neurocan-positive astrocytes by 2 d after lesion and a diffuse labeling of the extracellular matrix at all later time points. Electron microscopy confirmed the deposition of neurocan in the extracellular matrix compartment.In situhybridization demonstrated a strong upregulation of neurocan mRNA within the denervated outer molecular layer 1 and 4 d after lesion. The combination ofin situhybridization with immunohistochemistry for glial fibrillary acidic protein demonstrated that the neurocan mRNA-expressing cells are astrocytes. These data demonstrate that neurocan is reexpressed in the injured brain. In contrast to the situation during development, astrocytes, but not neurons, express neurocan and enrich the extracellular matrix with this molecule. Similar to the situation during development, neurocan is expressed in an area of active axon growth, and it is suggested that neurocan acts to maintain the boundaries of the denervated fascia dentata after entorhinal cortex lesion.
Galectin-1 Regulates Initial Axonal Growth in Peripheral Nerves after Axotomy
Authors: Horie Hidenori , Inagaki Yoshimasa , Sohma Yoshiaki , Nozawa Risa , Okawa Katsuya , Hasegawa Mitsuhiro , Muramatsu Naoki , Kawano Hitoshi , Horie Masao , Koyama Hiromichi , Sakai Ikuko , Takeshita Kaori , Kowada Yuki , Takano Masahiko , Kadoya Toshihiko
Published: April 2018

The signals that prompt the axons to send out processes in peripheral nerves after axotomy are not well understood. Here, we report that galectin-1 can play an important role in this initial stage. We developed anin vitronerve regeneration model that allows us to monitor the initial axon and support cell outgrowth from the proximal nerve stump, which is comparable to the initial stages of nerve repair. We isolated a factor secreted from COS1 cells that enhanced axonal regeneration, and we identified the factor as galectin-1. Recombinant human galectin-1 (rhGAL-1) showed the same activity at low concentrations (50 pg/ml) that are two orders of magnitude lower than those of lectin activity. A similarly low concentration was also effective inin vivoexperiments of axonal regeneration with migrating reactive Schwann cells to a grafted silicone tube after transection of adult rat peripheral nerve. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited the regenerationin vivoas well asin vitro.The same effect of rhGAL-1 was confirmed in crush/freeze experiments of the adult mouse sciatic nerve. Because galectin-1 is expressed in the regenerating sciatic nerves as well as in both sensory neurons and motor neurons, we suggest that galectin-1 may regulate initial repair after axotomy. This high activity of the factor applied under nonreducing conditions suggests that galectin-1 may work as a cytokine, not as a lectin.
Platelet-Derived Growth Factor-Mediated Signal Transduction Underlying Astrocyte Proliferation: Site of Ethanol Action
Authors: Luo Jia , Miller Michael W.
Published: April 2018

Platelet-derived growth factor (PDGF) is a critical regulator of cell proliferation. Because ethanol inhibits cell proliferationin vivoandin vitro, we hypothesize that ethanol-induced inhibition results from differential interference with signal transduction pathways activated by PDGF. Cultured cortical astrocytes were used to examine the effects of ethanol on PDGF-mediated signal transduction, on the expression of two PDGF monomers (A- and B-chains), and on the expression of two PDGF receptor subunits (PDGFαr and PDGFβr). PDGF-B chain homodimer (PDGF-BB), and to a lesser extent PDGF-A chain homodimer (PDGF-AA), stimulated the proliferation of astrocytes raised in a serum-free medium. Ethanol attenuated these actions in a concentration-dependent manner. Ethanol inhibited both PDGF-AA- and PDGF-BB-mediated phosphorylation of PDGFαr, but it had little effect on PDGFβr autophosphorylation. Likewise, ethanol abolished the association of PDGFαr to Ras GTPase-activating protein (Ras-GAP), but it did not affect the binding of Ras-GAP to PDGFβr. PDGF stimulated the activities of mitogen-activated protein kinase (MAPK) in protein kinase C (PKC) independent and dependent manners. Ethanol inhibited the PKC-independent, acute activation of MAPK; however, it stimulated the PKC-dependent, sustained activation of MAPK. The expression of neither ligand was altered by exposure to ethanol for 3 d. Moreover, such treatment specifically upregulated PDGFαr expression in a concentration-dependent manner. It did not, however, affect the binding affinity of either receptor. Thus, the signal transduction pathways initiated by PDGF-AA and PDGF-BB were differentially affected by ethanol. This differential vulnerability resulted from the preferential effects of ethanol on PDGFαr autophosphorylation. Hence, ethanol-induced alterations are transduced through specific receptors of mitogenic growth factors.
Embryonic Neurons Adapt to the Inhibitory Proteoglycan Aggrecan by Increasing Integrin Expression
Authors: Condic Maureen L. , Snow Diane M. , Letourneau Paul C.
Published: April 2018

The primary mediators of cell migration during development, wound healing and metastasis, are receptors of the integrin family. In the developing and regenerating nervous system, chondroitin sulfate proteoglycans (CSPGs) inhibit the integrin-dependent migration of neuronal growth cones. Here we report that embryonic sensory neurons cultured on the growth-promoting molecule laminin in combination with the inhibitory CSPG aggrecan rapidly adapt to inhibition. Adaptation is associated with a two- to threefold increase in the levels of RNA and surface protein for two laminin receptors, integrin α6β1 and α3β1, indicating that integrin expression is regulated by aggrecan. Increased integrin expression is associated both with increases in neuronal cell adhesion/outgrowth and with decreases in the ability of aggrecan to inhibit cell adhesion. Directly increasing integrin expression by adenoviral infection is sufficient to eliminate the inhibitory effects of aggrecan, indicating that upregulation of integrin receptors may promote neuronal regeneration in the presence of inhibitory matrix components.