bluuebunny/crossref_metadata_2025 huggingface dataset:
EAT-4, a Homolog of a Mammalian Sodium-Dependent Inorganic Phosphate Cotransporter, Is Necessary for Glutamatergic Neurotransmission inCaenorhabditis elegans
Authors: Lee Raymond Y. N. , Sawin Elizabeth R. , Chalfie Martin , Horvitz H. Robert , Avery Leon
Published: April 2018

TheCaenorhabditis elegansgeneeat-4affects multiple glutamatergic neurotransmission pathways. We find thateat-4encodes a protein similar in sequence to a mammalian brain-specific sodium-dependent inorganic phosphate cotransporter I (BNPI). Like BNPI in the rat CNS,eat-4is expressed predominantly in a specific subset of neurons, including several proposed to be glutamatergic. Loss-of-function mutations ineat-4cause defective glutamatergic chemical transmission but appear to have little effect on other functions of neurons. Our data suggest that phosphate ions imported into glutamatergic neurons through transporters such as EAT-4 and BNPI are required specifically for glutamatergic neurotransmission.
Dendritic and Postsynaptic Protein Synthetic Machinery
Authors: Gardiol Alejandra , Racca Claudia , Triller Antoine
Published: April 2018

There is a growing body of evidence that local protein synthesis beneath synapses may provide a novel mechanism underlying plastic phenomena.In vivoandin vitrobiochemical data show that dendrites can perform translation and glycosylation. Using antibodies directed against the eukaryotic protein synthetic machinery, we sought to identify the structures implicated in nonperinuclear translation, namely dendritic and postsynaptic protein synthesis. We performed a morphological and immunocytochemical analysis of ventromedial horn rat spinal cord neurons using both light and electron microscopy.

We show at the cellular level that,in vivo, protein synthesis macrocomplexes (ribosomes and eIF-2) as well as the endomembranous system implicated in cotranslational and posttranslational modifications (endoplasmic reticulum and Golgi cisternae) penetrated some dendrites. Membrane-limited organelles of different shape and size are present close to the postsynaptic differentiations of most synapses, independently of their localization on the neuronal surface. We demonstrate (1) that some cisternae are immunoreactive for antibodies against ribosomal proteins and eIF-2, and (2) that markers of endoplasmic reticulum (BiP), intermediate compartment, and Golgi complex (rab1, CTR433, TGN38) label subsets of these subsynaptic organelles.

Therefore, these findings indicate that synapses are equipped with the essential elements required for the synthesis and insertion of a well folded and glycosylated transmembrane protein.
Absence of the p75 Neurotrophin Receptor Alters the Pattern of Sympathosensory Sprouting in the Trigeminal Ganglia of Mice Overexpressing Nerve Growth Factor
Authors: Walsh Gregory S. , Krol Karmen M. , Kawaja Michael D.
Published: April 2018

Sympathetic axons invade the trigeminal ganglia of mice overexpressing nerve growth factor (NGF) (NGF/p75+/+mice) and surround sensory neurons having intense NGF immunolabeling; the growth of these axons appears to be directional and specific (Walsh and Kawaja, 1998). In this investigation, we provide new insight into the neurochemical features and receptor requirements of this sympathosensory sprouting. Using double-antigen immunohistochemistry, we demonstrate that virtually all (98%) trigeminal neurons that exhibit a sympathetic plexus aretrktyrosine kinase receptor (trkA)-positive. In addition, the majority (86%) of those neurons enveloped by sympathetic fibers is also calcitonin gene-related peptide (CGRP)-positive; a smaller number of plexuses (14%) surrounded other somata lacking this neuropeptide. Our results show that sympathosensory interactions form primarily between noradrenergic sympathetic efferents and the trkA/CGRP-expressing sensory somata. To assess the contribution of the p75 neurotrophin receptor (p75NTR) in sympathosensory sprouting, a hybrid strain of mice was used that overexpresses NGF but lacks p75NTRexpression (NGF/p75−/−mice). The trigeminal ganglia of NGF/p75−/−mice, like those of NGF/p75+/+mice, have increased levels of NGF protein and display a concomitant ingrowth of sympathetic axons. In contrast to the precise pattern of sprouting seen in the ganglia of NGF/p75+/+mice, sympathetic axons course randomly throughout the ganglionic neuropil of NGF/p75−/−mice, forming few perineuronal plexuses. Our results indicate that p75NTRis not required to initiate or sustain the growth of sympathetic axons into the NGF-rich trigeminal ganglia but rather plays a role in regulating the directional patterns of axon growth.
Computation of Inertial Motion: Neural Strategies to Resolve Ambiguous Otolith Information
Authors: Angelaki Dora E. , McHenry M. Quinn , Dickman J. David , Newlands Shawn D. , Hess Bernhard J. M.
Published: April 2018

According to Einstein’s equivalence principle, inertial accelerations during translational motion are physically indistinguishable from gravitational accelerations experienced during tilting movements. Nevertheless, despite ambiguous sensory representation of motion in primary otolith afferents, primate oculomotor responses are appropriately compensatory for the correct translational component of the head movement. The neural computational strategies used by the brain to discriminate the two and to reliably detect translational motion were investigated in the primate vestibulo-ocular system. The experimental protocols consisted of either lateral translations, roll tilts, or combined translation–tilt paradigms. Results using both steady-state sinusoidal and transient motion profiles in darkness or near target viewing demonstrated that semicircular canal signals are necessary sensory cues for the discrimination between different sources of linear acceleration. When the semicircular canals were inactivated, horizontal eye movements (appropriate for translational motion) could no longer be correlated with head translation. Instead, translational eye movements totally reflected the erroneous primary otolith afferent signals and were correlated with the resultant acceleration, regardless of whether it resulted from translation or tilt. Therefore, at least for frequencies in which the vestibulo-ocular reflex is important for gaze stabilization (>0.1 Hz), the oculomotor system discriminates between head translation and tilt primarily by sensory integration mechanisms rather than frequency segregation of otolith afferent information. Nonlinear neural computational schemes are proposed in which not only linear acceleration information from the otolith receptors but also angular velocity signals from the semicircular canals are simultaneously used by the brain to correctly estimate the source of linear acceleration and to elicit appropriate oculomotor responses.
A Nonphotic Stimulus Inverts the Diurnal–Nocturnal Phase Preference inOctodon degus
Authors: Kas Martien J. H. , Edgar Dale M.
Published: April 2018

Mechanisms differentiating diurnal from nocturnal species are thought to be innate components of the circadian timekeeping system and may be located downstream from the circadian pacemaker within the suprachiasmatic nucleus (SCN) of the hypothalamus. In the present study, we found that the dominant phase of behavioral activity and body temperature (Tb) is susceptible to modification by a specific modality of behavioral activity (wheel-running activity) inOctodon degus, a mammal that exhibits multiple chronotypes. SevenOctodon degusexhibited diurnal Tb and locomotor activity (LMA) circadian rhythms while entrained to a 24 h light/dark cycle (LD 12:12). When the diurnal animals were provided unrestricted access to a running wheel, the overt daily rhythms in these animals inverted to nocturnal. This nocturnal pattern was sustained in constant darkness and returned to diurnal after removal of the running wheel. Six additional animals exhibited nocturnal chronotypes in LD 12:12 regardless of access to running wheels. Wheel-running activity inverted the phase preference in the diurnal animals without changing the 24 hr mean LMA or Tb levels. Because wheel running did not increase the amplitude of the pre-existing diurnal pattern, simple masking effects on LMA and Tb cannot explain the rhythm inversion. The diurnal–nocturnal inversion occurred without reversing crepuscular-timed episodes of activity, suggesting that diurnal or nocturnal phase preference is controlled separately from the intrinsic timing mechanisms within the SCN and can be dependent on behavioral or environmental factors.
Estrogen-Induced Activation of Mitogen-Activated Protein Kinase in Cerebral Cortical Explants: Convergence of Estrogen and Neurotrophin Signaling Pathways
Authors: Singh Meharvan , Sétáló György , Guan Xiaoping , Warren Matthew , Toran-Allerand C. Dominique
Published: April 2018

We have shown that estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing CNS. We subsequently demonstrated widespread colocalization of estrogen and neurotrophin receptors (trk) within developing forebrain neurons and reciprocal transcriptional regulation of these receptors by their ligands. Using organotypic explants of the cerebral cortex, we tested the hypothesis that estrogen/neurotrophin receptor coexpression also may result in convergence or cross-coupling of their signaling pathways. Estradiol elicited rapid (within 5–15 min) tyrosine phosphorylation/activation of the mitogen-activated protein (MAP) kinases, ERK1 and ERK2, that persisted for at least 2 hr. This extracellular signal-regulated protein kinase (ERK) activation was inhibited successfully by the MEK1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780, and did not appear to result from estradiol-induced activation oftrk. Furthermore, we also found that estradiol elicited an increase in B-Raf kinase activity. The latter and subsequent downstream events leading to ERK activation may be a consequence of our documentation of a multimeric complex consisting of, at least, the ER, hsp90, and B-Raf. These novel findings provide an alternative mechanism for some of the estrogen actions in the developing CNS and could explain not only some of the very rapid effects of estrogen but also the ability of estrogen and neurotrophins to regulate the same broad array of cytoskeletal and growth-associated genes involved in neurite growth and differentiation.
Distinct Mechanisms Underlie Neurotoxin-Mediated Cell Death in Cultured Dopaminergic Neurons
Authors: Lotharius Julie , Dugan Laura L. , O’Malley Karen L.
Published: April 2018

Oxidative stress is thought to contribute to dopaminergic cell death in Parkinson’s disease (PD). The neurotoxin 6-hydroxydopamine (6-OHDA), which is easily oxidized to reactive oxygen species (ROS), appears to induce neuronal death by a free radical-mediated mechanism, whereas the involvement of free radicals inN-methyl-4-phenylpyridinium (MPP+) toxicity is less clear. Using free radical-sensitive fluorophores and vital dyes withpost hocidentification of tyrosine hydroxylase-positive neurons, we monitored markers of apoptosis and the production of ROS in dopaminergic neurons treated with either 6-OHDA or MPP+. Annexin-V staining suggested that 6-OHDA but not MPP+-mediated cell death was apoptotic. In accordance with this assignment, the general caspase inhibitor Boc-(Asp)-fluoromethylketone only blocked 6-OHDA neurotoxicity. Both toxins exhibited an early, sustained rise in ROS, although only 6-OHDA induced a collapse in mitochondrial membrane potential temporally related to the increase in ROS. Recently, derivatives of buckminsterfullerene (C60) molecules have been shown to act as potent antioxidants in several models of oxidative stress (Dugan et al., 1997). Significant, dose-dependent levels of protection were also seen in thesein vitromodels of PD using the C3carboxyfullerene derivative. Specifically, C3was fully protective in the 6-OHDA paradigm, whereas it only partially rescued dopaminergic neurons from MPP+-induced cell death. In either model, it was more effective than glial-derived neurotrophic factor. These data suggest that cell death in response to 6-OHDA and MPP+may progress through different mechanisms, which can be partially or entirely saved by carboxyfullerenes.
Reelin Regulates the Development and Synaptogenesis of the Layer-Specific Entorhino-Hippocampal Connections
Authors: Borrell Vı́ctor , Del Rı́o José A. , Alcántara Soledad , Derer Michèle , Martı́nez Albert , D’Arcangelo Gabriella , Nakajima Kazunori , Mikoshiba Katsuhiko , Derer Paul , Curran Tom , Soriano Eduardo
Published: April 2018

Here we examine the role of Reelin, an extracellular protein involved in neuronal migration, in the formation of hippocampal connections. Both at prenatal and postnatal stages, the general laminar and topographic distribution of entorhinal projections is preserved in the hippocampus of reeler mutant mice, in the absence of Reelin. However, developing and adult entorhinal afferents show severe alterations, including increased numbers of misrouted fibers and the formation of abnormal patches of termination from the medial and lateral entorhinal cortices. At perinatal stages, single entorhinal axons in reeler mice are grouped into thick bundles, and they have decreased axonal branching and decreased extension of axon collaterals. We also show that the number of entorhino-hippocampal synapses is lower in reeler mice than in control animals during development. Studies performed in mixed entorhino-hippocampal co-cultures combining slices from reeler and wild-type mice indicate that these abnormalities are caused by the lack of Reelin in the target hippocampus. These findings imply that Reelin fulfills a modulatory role during the formation of layer-specific and topographic connections in the hippocampus. They also suggest that Reelin promotes maturation of single fibers and synaptogenesis by entorhinal afferents.
GDNF Protection against 6-OHDA–Induced Reductions in Potassium-Evoked Overflow of Striatal Dopamine
Authors: Cass Wayne A. , Manning Michael W.
Published: April 2018

Glial cell line–derived neurotrophic factor (GDNF), when administered before 6-hydroxydopamine (6-OHDA), has been shown to prevent the reduction in nigral dopamine (DA) levels and tyrosine hydroxylase–positive neurons normally observed after 6-OHDA lesions. The present study examined the ability of GDNF to prevent 6-OHDA–induced reductions in striatal DA release and reductions in striatal and nigral DA levels. GDNF (10 μg), or vehicle, was injected into the right nigra of anesthetized male Fischer-344 rats and was followed 6 hr later by intranigral 6-OHDA or saline. Three to four weeks later the animals were anesthetized with urethane and prepared forin vivoelectrochemistry. Potassium-evoked overflow of DA was dramatically decreased in the right striatum of the vehicle + 6-OHDA–treated animals. GDNF appeared to prevent the reduction in evoked overflow of DA in the right striatum of the 6-OHDA–treated animals. However, in comparison with that in animals that received GDNF + saline, the overflow of DA was significantly reduced in the GDNF + 6-OHDA animals. Similarly, although nigral levels of DA were above normal in the GDNF + 6-OHDA–treated animals, they were below DA levels found in GDNF + saline–treated rats. Striatal DA levels were partially protected by GDNF. In animals examined 10–12 weeks after the GDNF and 6-OHDA treatments, the apparent protective ability of GDNF on the evoked overflow of DA in the striatum was diminished. Thus, although intranigral GDNF can prevent 6-OHDA–induced reductions in nigral DA levels, long-term protection of the evoked overflow of DA in the striatum is minimal.
Role of Phosphatidylinositol 3-Kinase in Angiotensin II Regulation of Norepinephrine Neuromodulation in Brain Neurons of the Spontaneously Hypertensive Rat
Authors: Yang Hong , Raizada Mohan K.
Published: April 2018

Chronic stimulation of norepinephrine (NE) neuromodulation by angiotensin II (Ang II) involves activation of the Ras—Raf—MAP kinase signal transduction pathway in Wistar Kyoto (WKY) rat brain neurons. This pathway is only partially responsible for this heightened action of Ang II in the spontaneously hypertensive rat (SHR) brain neurons. In this study, we demonstrate that the MAP kinase-independent signaling pathway in the SHR neuron involves activation of PI3-kinase and protein kinase B (PKB/Akt). Ang II stimulated PI3-kinase activity in both WKY and SHR brain neurons and was accompanied by its translocation from the cytoplasmic to the nuclear compartment. Although the magnitude of stimulation by Ang II was comparable, the stimulation was more persistent in the SHR neuron compared with the WKY rat neuron. Inhibition of PI3-kinase had no significant effect in the WKY rat neuron. However, it caused a 40–50% attenuation of the Ang II-induced increase in norepinephrine transporter (NET) and tyrosine hydroxylase (TH) mRNAs and [3H]-NE uptake in the SHR neuron. In contrast, inhibition of MAP kinase completely attenuated Ang II stimulation of NET and TH mRNA levels in the WKY rat neuron, whereas it caused only a 45% decrease in the SHR neuron. However, an additive attenuation was observed when both kinases of the SHR neurons were inhibited. Ang II also stimulated PKB/Akt activity in both WKY and SHR neurons. This stimulation was 30% higher and lasted longer in the SHR neuron compared with the WKY rat neuron. In conclusion, these observations demonstrate an exclusive involvement of PI3-kinase–PKB-dependent signaling pathway in a heightened NE neuromodulatory action of Ang II in the SHR neuron. Thus, this study offers an excellent potential for the development of new therapies for the treatment of centrally mediated hypertension.
The Mitogen-Activated Protein Kinase Pathway Mediates Estrogen Neuroprotection after Glutamate Toxicity in Primary Cortical Neurons
Authors: Singer Cherie A. , Figueroa-Masot Xavier A. , Batchelor Robert H. , Dorsa Daniel M.
Published: April 2018

Pharmacological and biochemical approaches were used to elucidate the involvement of growth factor signaling pathways mediating estrogen neuroprotection in primary cortical neurons after glutamate excitotoxicity. We addressed the activation of mitogen-activated protein kinase (MAPK) signaling pathways, which are activated by growth factors such as nerve growth factor (NGF). Inhibition of MAPK signaling with the MAPK kinase inhibitor PD98059 blocks both NGF and estrogen neuroprotection in these neurons. These results correlate with a rapid and sustained increase in MAPK activity within 30 min of estrogen exposure. The involvement of signaling molecules upstream from MAPK was also examined to determine whether activation of MAPK by estrogen is mediated by tyrosine kinase activity. Estrogen produces a rapid, transient activation of src-family tyrosine kinases and tyrosine phosphorylation of p21ras-guanine nucleotide activating protein. Effects of estrogen on neuroprotection, as well as rapid activation of tyrosine kinase and MAPK activity, are blocked by the anti-estrogen ICI 182,780. This provides evidence that activation of the MAPK pathway by estrogen participates in mediating neuroprotection via an estrogen receptor. These results describe a novel mechanism by which cytoplasmic actions of the estrogen receptor may activate the MAPK pathway, thus broadening the understanding of effects of estrogen in neurons.
Synaptic Vesicle Dynamics in Rat Fast and Slow Motor Nerve Terminals
Authors: Reid Brian , Slater Clarke R. , Bewick Guy S.
Published: April 2018

We have investigated whether rat motor nerve terminals with differentin vivoactivity patterns also have different vesicle trafficking characteristics. To do this, we monitored, using combined optical and electrical techniques, the rate of exocytosis (during different frequencies and patterns of activity), the releasable pool size, and the recycle time of synaptic vesicles in terminals on soleus (slow-twitch) and extensor digitorum longus [(EDL); fast-twitch] muscle fibers. EDL terminals had a higher initial quantal content (QC) than soleus, but during tonic or phasic stimulation at 20–80 Hz, EDL QC ran down to a greater extent than soleus QC. By recording loss of fluorescence from exocytosing vesicles labeled with the dye FM1–43, EDL terminals were found to destain faster than those in soleus. Simultaneous intracellular recording of end plate potentials, to count the number of vesicles released, permitted estimation of the total vesicle pool (VP) size and the recycle time by combining the optical and electrophysiological data. Soleus vesicle pool was larger than EDL, but recycle time was not significantly different. These terminals, therefore, are adapted to theirin vivoactivity patterns by alterations in QC and VP size but not recycle time.
Immunohistological Studies of Metabotropic Glutamate Receptor Subtype 6-Deficient Mice Show No Abnormality of Retinal Cell Organization and Ganglion Cell Maturation
Authors: Tagawa Yoshiaki , Sawai Hajime , Ueda Yoshiki , Tauchi Masaki , Nakanishi Shigetada
Published: April 2018

Immature retinal ganglion cells (RGCs) initially show a multistratified dendritic pattern, and, during the postnatal period, these dendrites gradually monostratify into ON and OFF sublaminae. The selective agonist of group III metabotropic glutamate receptors (mGluR),l-2-amino-4-phosphonobutyrate (l-AP-4), hyperpolarizes ON bipolar cells and reduces glutamate release. On the basis ofl-AP-4-evoked inhibitory effects on ON–OFF segregation of developing RGCs, it has been hypothesized that glutamate-mediated synaptic activity is crucial for formation of the ON–OFF network. Gene-targeted ablation of mGluR6 specifically expressed in ON bipolar cells blocks normal ON responses but has been predicted to enhance glutamate release from ON bipolar cells. The mGluR6 knock-out mouse therefore provides a unique opportunity to investigate whether glutamate release and ON responses are important factors in the development of ON–OFF segregation. The combination of several different morphological analyses indicates that ON bipolar cells, as well as several distinct amacrine cells, in mGluR6 knock-out mice are normally distributed and correctly extend their terminals to defined retinal laminae. Importantly, both α and δ RGCs in adult mGluR6 knock-out mice are found monostratified into cell type-specific layers. Furthermore, no difference between wild-type and mGluR6 knock-out mice is observed in the maturation and dendritic stratification of developing RGCs. Hence, despite a deficit in normal ON responses, mGluR6 deficiency causes no abnormality in the retinal cellular organization nor in the stratifications of both ON bipolar cells and developing and mature RGCs. Based on these findings, we discuss several possible mechanisms that may underlie ON–OFF segregation of RGCs.
Differential Effects of Apamin- and Charybdotoxin-Sensitive K+Conductances on Spontaneous Discharge Patterns of Developing Retinal Ganglion Cells
Authors: Wang Guo-Yong , Olshausen Bruno A. , Chalupa Leo M.
Published: April 2018

The spontaneous discharge patterns of developing retinal ganglion cells are thought to play a crucial role in the refinement of early retinofugal projections. To investigate the contributions of intrinsic membrane properties to the spontaneous activity of developing ganglion cells, we assessed the effects of blocking large and small calcium-activated potassium conductances on the temporal pattern of such discharges by means of patch-clamp recordings from the intact retina of developing ferrets. Application of apamin and charybdotoxin (CTX), which selectively block the small and large calcium-activated potassium channels, respectively, resulted in significant changes in spontaneous firings. In cells recorded from the oldest animals [postnatal day 30 (P30)–P45], which manifested relatively sustained discharge patterns, application of either blocker induced bursting activity. With CTX the bursts were highly periodic, short in duration, and of high frequency. In contrast, with apamin the interburst intervals were longer, less regular, and lower in overall spike frequency. These differences between the effects of the two blockers on spontaneous activity were documented by spectral analysis of discharge patterns. Filling cells from which recordings were made with Lucifer yellow revealed that these effects were obtained in all three morphological classes of cells: α, β, and γ. These findings provide the first evidence that apamin- and CTX-sensitive K+conductances can have differential effects on the spontaneous discharge patterns of retinal ganglion cells. Remarkably, the bursts of activity obtained after apamin application in more mature neurons appeared very similar to the spontaneous bursting patterns observed in developing neurons. These findings suggest that the maturation of calcium-activated potassium channels, particularly the apamin-sensitive conductance, may contribute to the changes in spontaneous firings exhibited by retinal ganglion cells during the course of normal development.
GABAergic Neurons that Contain Neuropeptide Y Selectively Target Cells with the Neurokinin 1 Receptor in Laminae III and IV of the Rat Spinal Cord
Authors: Polgár Erika , Shehab Safa A. S. , Watt Christine , Todd Andrew J.
Published: April 2018

Neuropeptide Y (NPY) is contained in a population of GABAergic interneurons in the spinal dorsal horn and, when administered intrathecally, can produce analgesia. We previously identified a strong monosynaptic link between substance P-containing primary afferents and cells in lamina III or IV with the neurokinin 1 (NK1) receptor. Because some of these cells belong to the spinothalamic tract, they are likely to have an important role in pain mechanisms.

In this study, we used confocal microscopy to examine the input to lamina III/IV NK1 receptor-immunoreactive neurons from NPY-containing axons. All of the cells studied received a dense innervation from NPY-immunoreactive axons, and electron microscopy revealed that synapses were often present at points of contact. Most NPY-immunoreactive boutons were also GABAergic, which supports the suggestion that they are derived from local neurons. The association between NPY-containing axons and NK1 receptor-immunoreactive neurons was specific, because postsynaptic dorsal column neurons (which were located in laminae III–V but did not possess NK1 receptors) and lamina I neurons with the NK1 receptor received significantly fewer contacts from NPY-immunoreactive axons. In addition, the NK1 receptor-immunoreactive lamina III/IV cells received few contacts from nitric oxide synthase-containing axons (which belong to a different population of GABAergic dorsal horn neurons). The NPY-containing axons appeared to be targeted to the NK1 receptor-immunoreactive neurons themselves rather than to their associated substance P-immunoreactive inputs.

The dense innervation of these cells by NPY-containing axons suggests that they may possess receptors for NPY and that activation of these receptors may contribute to NPY-mediated analgesia.
Optic Flow Selectivity in the Anterior Superior Temporal Polysensory Area, STPa, of the Behaving Monkey
Authors: Anderson Kathleen C. , Siegel Ralph M.
Published: April 2018

Earlier studies of neurons in the anterior region of the superior temporal polysensory area (STPa) have demonstrated selectivity for visual motion using stimuli contaminated by nonmotion cues, including texture, luminance, and form. The present experiments investigated the motion selectivity of neurons in STPa in the absence of form cues using random dot optic flow displays. The responses of neurons were tested with translation, rotation, radial, and spiral optic flow displays designed to mimic the types of motion that occur during locomotion. Over half of the neurons tested responded significantly to at least one of these displays. On a cell by cell basis, 60% of the neurons tested responded selectively to rotation, radial, and spiral motion, whereas 20% responded selectively to translation motion. The majority of neurons responded maximally to single-component optic flow displays but was also significantly activated by the spiral displays that contained their preferred component. Moreover, there was a bias in the selectivity of the neurons for radial expansion motion. These results suggest that neurons within STPa are contributing to the analysis of optic flow. Furthermore, the preponderance of cells selective for radial expansion provides evidence that this area may be specifically involved in the processing of forward locomotion and/or looming stimuli. Finally, these results provide carefully controlled physiological evidence for an extension and specialization of the motion-processing pathway into the anterior temporal lobe.
The Magnitude and Phase of Temporal Modulation Transfer Functions in Cat Auditory Cortex
Authors: Eggermont Jos J.
Published: April 2018

Temporal modulation transfer functions (tMTFs) in response to periodic click trains are presented for simultaneous recordings from primary auditory cortex, anterior auditory field, and secondary auditory cortex in 21 cats. The multiunit records could be separated in to 215 single-unit spike trains that allowed a reliable estimate of a group delay, which represents the cumulative delay for responses to repetitive stimuli. For approximately two-thirds of the 215 single units the group delay was within 7.5 msec of the response latency to the first clicks in the trains. For the remaining units, the group delay was on average ∼14 msec higher, and this may result from differences in synaptic properties. These findings were similar in the three cortical areas studied. The findings are modeled based on presynaptic facilitation and depression and pyramidal cell calcium kinetics, and a quantitative description of the magnitude of the tMTF was obtained that resulted in substantially shorter depression time constants (20 msec) than reported for visual cortex (300 msec). A small amount (0–5.5%) of facilitation that decayed with a time constant of 60 msec was obtained. Auditory cortical cells apparently have much faster recovery mechanisms than visual cortical cells. This allows for the ability of the auditory cortex to reliably track the rhythms that occur in natural sounds.
Interleukin-1β in Immune Cells of the Abdominal Vagus Nerve: a Link between the Immune and Nervous Systems?
Authors: Goehler Lisa E. , Gaykema Ron P. A. , Nguyen Kien T. , Lee Jacqueline E. , Tilders Fred J. H. , Maier Steven F. , Watkins Linda R.
Published: April 2018

Intraperitoneal administration of the cytokine interleukin-1β (IL-1β) induces brain-mediated sickness symptoms that can be blocked by subdiaphragmatic vagotomy. Intraperitoneal IL-1β also induces expression of the activation marker c-fos in vagal primary afferent neurons, suggesting that IL-1β is a key component of vagally mediated immune-to-brain communication. The cellular sources of IL-1β activating the vagus are unknown, but may reside in either blood or in the vagus nerve itself. We assayed IL-1β protein after intraperitoneal endotoxin [lipopolysaccharide (LPS)] injection in abdominal vagus nerve, using both an ELISA and immunohistochemistry, and in blood plasma using ELISA. IL-1β levels in abdominal vagus nerve increased by 45 min after LPS administration and were robust by 60 min. Plasma IL-1β levels increased by 60 min, whereas little IL-1β was detected in cervical vagus or sciatic nerve. IL-1β-immunoreactivity (IR) was expressed in dendritic cells and macrophages within connective tissues associated with the abdominal vagus by 45 min after intraperitoneal LPS injection. By 60 min, some immune cells located within the nerve and vagal paraganglia also expressed IL-1β-IR. Thus, intraperitoneal LPS induced IL-1β protein within the vagus in a time-frame consistent with signaling of immune activation. These results suggest a novel mechanism by which IL-1β may serve as a molecular link between the immune system and vagus nerve, and thus the CNS.
Altered Formation of Hemichannels and Gap Junction Channels Caused by C-Terminal Connexin-32 Mutations
Authors: Castro Carmen , Gómez-Hernandez Juan M. , Silander Kaisa , Barrio Luis C.
Published: April 2018

Hexamers of connexins (Cxs) form hemichannels that dock tightly in series via their extracellular domains to give rise to gap junction channels. Here we examined the ability of a variety of C-terminal Cx32 mutations, most of which have been identified in X-linked Charcot–Marie–Tooth disease, to form hemichannels and to complete gap junction channels using theXenopusoocyte system. First, we show that undocked wild-type Cx32 hemichannels at the plasma membrane can be detected as opening channels activated by depolarization. We have been able to estimate the efficiency of assembly of complete channels by measuring the time-dependent incorporation of preformed hemichannels into gap junction channels after cell-to-cell contact. These data offer strong evidence that hemichannels are the direct precursors of gap junction channels. Of 11 Cx32 mutants tested, a group of 5 mutations prevented the formation of functional hemichannels at the cell surface, whereas 4 mutations were fully able to form precursors but reduced the ability of hemichannels to assemble into complete channels, and 2 mutants formed channels normally. The data revealed that a minimum length of human Cx32 including the residue Arg-215 is required for the expression of hemichannels at the cell surface and that the efficiency of hemichannel incorporation into complete channels decreased gradually with the progressive shortening of the cytoplasmic C-terminal domain.
Segmentation by Color Influences Responses of Motion-Sensitive Neurons in the Cortical Middle Temporal Visual Area
Authors: Croner Lisa J. , Albright Thomas D.
Published: April 2018

We previously showed that human subjects are better able to discriminate the direction of a motion signal in dynamic noise when the signal is distinguished (segmented) from the noise by color. This finding suggested a hitherto unexplored avenue of interaction between motion and color pathways in the primate visual system. To examine whether chromatic segmentation exerts a similar influence on cortical neurons that contribute to motion direction discrimination, we have now compared the discriminative capacity of single MT neurons and psychophysical observers viewing motion signals with and without chromatic segmentation. All data were obtained from rhesus monkeys trained to discriminate motion direction in dynamic stimuli containing varying proportions of coherently moving (signal) and randomly moving (noise) dots. We obtained psychophysical and neurophysiological data in the same animals, on the same trials, and using the same visual display. Chromatic segmentation of the signal from the noise enhanced both neuronal and psychophysical sensitivity to the motion signal but had a smaller influence on neuronal than on psychophysical sensitivity. Hence the ratio of neuronal to psychophysical thresholds, one measure of the relation between neuronal and psychophysical performance, depended on chromatic segmentation. Increased neuronal sensitivity to chromatically segmented displays stemmed from larger and less noisy responses to motion in the preferred directions of the neurons, suggesting that specialized mechanisms influence responses in the motion pathway when color segments motion signal in visual scenes. These findings lead us to reevaluate potential mechanisms for pooling of MT responses and the role of MT in motion perception.
Dopamine Mediates Circadian Rhythms of Rod–Cone Dominance in the Japanese Quail Retina
Authors: Manglapus Mary K. , Iuvone P. Michael , Underwood Herbert , Pierce Mary E. , Barlow Robert B.
Published: April 2018

A circadian clock modulates the functional organization of the Japanese quail retina. Under conditions of constant darkness, rods dominate electroretinogram (ERG) b-wave responses at night, and cones dominate them during the day, yielding a circadian rhythm in retinal sensitivity and rod–cone dominance. The activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, also exhibits a circadian rhythm in the retina with approximately threefold higher levels during the day than at night. The rhythm of tyrosine hydroxylase activity is opposite in phase to the circadian activity of tryptophan hydroxylase, the first enzyme in the melatonin biosynthetic pathway. We tested whether dopamine may be related to the physiological rhythms of the retina by examining the actions of pharmacological agents that effect dopamine receptors. We found that blocking dopamine D2 receptors in the retina during the day mimics the nighttime state by increasing the amplitude of the b-wave and shifting the retina to rod dominance. Conversely, activating D2 receptors at night mimics the daytime state by decreasing the amplitude of the b-wave and shifting the retina to cone dominance. A selective antagonist for D1 dopamine receptors has no effect on retinal sensitivity or rod–cone dominance. Reducing retinal dopamine partially abolishes rhythms in sensitivity and yields a rod-dominated retina regardless of the time of day. These results suggest that dopamine, under the control of a circadian oscillator, has a key role in modulating sensitivity and rod–cone dominance in the Japanese quail retina.
Adenosine: a Mediator of Interleukin-1β-Induced Hippocampal Synaptic Inhibition
Authors: Luk Wah Ping , Zhang Yu , White Thomas D. , Lue Franklin A. , Wu Chiping , Jiang Cheng-Gan , Zhang Liang , Moldofsky Harvey
Published: April 2018

Interleukin-1 (IL-1) is a pleotrophic cytokine implicated in a variety of central activities, including fever, sleep, ischemic injury, and neuromodulatory responses, such as neuroimmune, and neuroendocrine interactions. Although accumulating evidence is available regarding the expression pattern of this cytokine, its receptors in the CNS, and its mechanistic profile under pathological levels, it is unclear whether this substance modulates central neurons under physiological concentrations. Further, in light of the functional and spatial overlap between the adenosine and IL-1 systems, it is not known whether these two systems are coupled. We report here that, in rat brain slices, brief application of sub-femtomolar IL-1β causes a profound decrease of glutamate transmission, but not GABAergic inhibition, in hippocampal CA1 pyramidal neurons. This decrease by IL-1β is prevented by pharmacological blockade of adenosine A1receptors. In addition, we show that IL-1β failed to suppress glutamate transmission at room temperature. Because the production and release of adenosine in the CNS is thought to be metabolically dependent, this observation suggests that one of the functions of IL-1β is to increase the endogenous production of adenosine. Together, these data suggest for the first time that sub-femtomolar levels of IL-1 can effectively modulate glutamate excitation in hippocampal neurons via an adenosine-dependent mechanism.
Sensory Impairments and Delayed Regeneration of Sensory Axons in Interleukin-6-Deficient Mice
Authors: Zhong Jian , Dietzel Irmgard D. , Wahle Petra , Kopf Manfred , Heumann Rolf
Published: April 2018

Interleukin-6 (IL-6) is a multifunctional cytokine mediating inflammatory or immune reactions. Here we investigated the possible role of IL-6 in the intact or lesioned peripheral nervous system using adult IL-6 gene knockout (IL-6−/−) mice. Various sensory functions were tested by applying electrophysiological, morphological, biochemical, and behavioral methods. There was a 60% reduction of the compound action potential of the sensory branch of IL-6−/−mice as compared with the motor branch in the intact sciatic nerve. Cross sections of L5 DRG of IL-6−/−mice showed a shift in the relative size distribution of the neurons. The temperature sensitivity of IL-6−/−mice was also significantly reduced.

After crush lesion of the sciatic nerve, its functional recovery was delayed in IL-6−/−mice as analyzed from a behavioral footprint assay. Measurements of compound action potentials 20 d after crush lesion showed that there was a very low level of recovery of the sensory but not of the motor branch of IL-6−/−mice. Similar results of sensory impairments were obtained with mice showing slow Wallerian degeneration (Wlds) and a delayed lesion-induced recruitment of macrophages. However, in contrast to WldSmice, in IL-6−/−mice we observed the characteristic lesion-induced invasion of macrophages and the upregulation of low-affinity neurotrophin receptor p75 (p75LNTR) mRNA levels identical to those of IL-6+/+mice. Thus, the mechanisms leading to the common sensory deficiencies were different between IL-6−/−and WldSmice. Altogether, the results suggest that interleukin-6 is essential to modulate sensory functionsin vivo.
Chemoattraction and Chemorepulsion of Olfactory Bulb Axons by Different Secreted Semaphorins
Authors: Castro Fernando de , Hu Lingjia , Drabkin Harry , Sotelo Constantino , Chédotal Alain
Published: April 2018

During development, growth cones can be guided at a distance by diffusible factors, which are attractants and/or repellents. The semaphorins are the largest family of repulsive axon guidance molecules. Secreted semaphorins bind neuropilin receptors and repel sensory, sympathetic, motor, and forebrain axons. We found that in rat embryos, the olfactory epithelium releases a diffusible factor that repels olfactory bulb axons. In addition, Sema A and Sema IV, but not Sema III, Sema E, or Sema H, are able to orientin vitrothe growth of olfactory bulb axons; Sema IV has a strong repulsive action, whereas Sema A appears to attract those axons. The expression patterns ofsema Aandsema IVin the developing olfactory system confirm that they may play a cooperative role in the formation of the lateral olfactory tract. This also represents a further evidence for a chemoattractive function of secreted semaphorins.
Glutamate Acting at NMDA Receptors Stimulates Embryonic Cortical Neuronal Migration
Authors: Behar Toby N. , Scott Catherine A. , Greene Carolyn L. , Wen Xiling , Smith Susan V. , Maric Dragan , Liu Qi-Ying , Colton Carol A. , Barker Jeffery L.
Published: April 2018

During cortical development, embryonic neurons migrate from germinal zones near the ventricle into the cortical plate, where they organize into layers. Mechanisms that direct neuronal migration may include molecules that act as chemoattractants. In rats, GABA, which localizes near the target destination for migrating cortical neurons, stimulates embryonic neuronal migrationin vitro. In mice, glutamate is highly localized near the target destinations for migrating cortical neurons. Glutamate-induced migration of murine embryonic cortical cells was evaluated in cell dissociates and cortical slice cultures. In dissociates, the chemotropic effects of glutamate were 10-fold greater than the effects of GABA, demonstrating that for murine cortical cells, glutamate is a more potent chemoattractant than GABA. Thus, cortical chemoattractants appear to differ between species. Micromolar glutamate stimulated neuronal chemotaxis that was mimicked by μmNMDA but not by other ionotropic glutamate receptor agonists (AMPA, kainate, quisqualate). Responding cells were primarily derived from immature cortical regions [ventricular zone (vz)/subventricular zone (svz)]. Bromodeoxyuridine (BrdU) pulse labeling of cortical slices cultured in NMDA antagonists (μmMK801 or APV) revealed that antagonist exposure blocked the migration of BrdU-positive cells from the vz/svz into the cortical plate. PCR confirmed the presence of NMDA receptor expression in vz/svz cells, whereas electrophysiology and Ca2+imaging demonstrated that vz/svz cells exhibited physiological responses to NMDA. These studies indicate that, in mice, glutamate may serve as a chemoattractant for neurons in the developing cortex, signaling cells to migrate into the cortical plate via NMDA receptor activation.
Supporting Cells Contribute to Control of Hearing Sensitivity
Authors: Flock Åke , Flock Britta , Fridberger Anders , Scarfone Eric , Ulfendahl Mats
Published: April 2018

The mammalian hearing organ, the organ of Corti, was studied in anin vitropreparation of the guinea pig temporal bone. Asin vivo, the hearing organ responded with an electrical potential, the cochlear microphonic potential, when stimulated with a test tone. After exposure to intense sound, the response to the test tone was reduced. The electrical response either recovered within 10–20 min or remained permanently reduced, thus corresponding to a temporary or sustained loss of sensitivity.

Using laser scanning confocal microscopy, stimulus-induced changes of the cellular structure of the hearing organ were simultaneously studied. The cells in the organ were labeled with two fluorescent probes, a membrane dye and a cytoplasm dye, showing enzymatic activity in living cells. Confocal microscopy images were collected and compared before and after intense sound exposure. The results were as follows. (1) The organ of Corti could be divided into two different structural entities in terms of their susceptibility to damage: an inner, structurally stable region comprised of the inner hair cell with its supporting cells and the inner and outer pillar cells; and an outer region that exhibited dynamic structural changes and consisted of the outer hair cells and the third Deiters’ cell with its attached Hensen’s cells. (2) Exposure to intense sound caused the Deiters’ cells and Hensen’s cells to move in toward the center of the cochlear turn. (3) This event coincided with a reduced sensitivity to the test tone (i.e., reduced cochlear microphonic potential). (4) The displacement and sensitivity loss could be reversible. It is concluded that these observations have relevance for understanding the mechanisms behind hearing loss after noise exposure and that the supporting cells take an active part in protection against trauma during high-intensity sound exposure.
T-Lymphocyte Activation Increases Hypothalamic and Amygdaloid Expression of CRH mRNA and Emotional Reactivity to Novelty
Authors: Kusnecov Alexander W. , Liang Rumei , Shurin Galina
Published: April 2018

Stimulation of T-cells with staphylococcal enterotoxin B (SEB) significantly elevates interleukin-2 (IL-2) and contemporaneous activation of the hypothalamic–pituitary–adrenal (HPA) axis andc-fosin the paraventricular nucleus (PVN) of BALB/cByJ mice. Such neural signaling may promote cognitive and emotional adaptation before or during infectious illness. Because corticotropin-releasing hormone (CRH) is an anxiogenic neuropeptide that may mediate the stressor-like effects of immunological stimuli, we measured neuronal CRH mRNA alterations in mice challenged with SEB. Increased CRH mRNA levels were observed in the PVN and central nucleus of the amygdala (ceA) 4–6 hr after SEB administration. This was associated with plasma ACTH increases, which could be abrogated by the systemic administration of anti-CRH antiserum. Additional experiments did not support a role for IL-2 or prostaglandin synthesis in activating the HPA axis. Behavioral experiments testing for conditioned taste aversion did not confirm that SEB challenge promotes malaise. However, consistent with the notion that central CRH alterations induced by SEB may affect emotionality (e.g., fear), SEB challenge augmented appetitive neophobia in a context-dependent manner, being marked in a novel and stressful environment. It is hypothesized that immunological stimuli generate a cascade of events that solicit integrative neural processes involved in emotional behavior. As such, these data support the contention that affective illness may be influenced by immunological processes and the production of cytokines and are consistent with other evidence demonstrating that autoimmune reactivity is associated with enhanced emotionality.