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Sample records for 3a neuron response

  1. CHOP Potentially Co-Operates with FOXO3a in Neuronal Cells to Regulate PUMA and BIM Expression in Response to ER Stress

    PubMed Central

    Ghosh, Arindam P.; Klocke, Barbara J.; Ballestas, Mary E.; Roth, Kevin A.

    2012-01-01

    Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in various neurodegenerative diseases including Parkinson Disease, Alzheimer Disease and Huntington Disease. PUMA (p53 upregulated modulator of apoptosis) and BIM (BCL2 interacting mediator of cell death), pro-apoptotic BH3 domain-only, BCL2 family members, have previously been shown to regulate ER stress-induced cell death, but the upstream signaling pathways that regulate this response in neuronal cells are incompletely defined. Consistent with previous studies, we show that both PUMA and BIM are induced in response to ER stress in neuronal cells and that transcriptional induction of PUMA regulates ER stress-induced cell death, independent of p53. CHOP (C/EBP homologous protein also known as GADD153; gene name Ddit3), a critical initiator of ER stress-induced apoptosis, was found to regulate both PUMA and BIM expression in response to ER stress. We further show that CHOP knockdown prevents perturbations in the AKT (protein kinase B)/FOXO3a (forkhead box, class O, 3a) pathway in response to ER stress. CHOP co-immunoprecipitated with FOXO3a in tunicamycin treated cells, suggesting that CHOP may also regulate other pro-apoptotic signaling cascades culminating in PUMA and BIM activation and cell death. In summary, CHOP regulates the expression of multiple pro-apoptotic BH3-only molecules through multiple mechanisms, making CHOP an important therapeutic target relevant to a number of neurodegenerative conditions. PMID:22761832

  2. Neuronal Responses to Physiological Stress

    PubMed Central

    Kagias, Konstantinos; Nehammer, Camilla; Pocock, Roger

    2012-01-01

    Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. It can be divided into three different aspects: environmental stress, intrinsic developmental stress, and aging. Throughout life all living organisms are challenged by changes in the environment. Fluctuations in oxygen levels, temperature, and redox state for example, trigger molecular events that enable an organism to adapt, survive, and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner chemistry during normal development. For example, conditions such as intrinsic hypoxia and oxidative stress, due to an increase in tissue mass, have to be confronted by developing embryos in order to complete their development. Finally, organisms face the challenge of stochastic accumulation of molecular damage during aging that results in decline and eventual death. Studies have shown that the nervous system plays a pivotal role in responding to stress. Neurons not only receive and process information from the environment but also actively respond to various stresses to promote survival. These responses include changes in the expression of molecules such as transcription factors and microRNAs that regulate stress resistance and adaptation. Moreover, both intrinsic and extrinsic stresses have a tremendous impact on neuronal development and maintenance with implications in many diseases. Here, we review the responses of neurons to various physiological stressors at the molecular and cellular level. PMID:23112806

  3. Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A

    PubMed Central

    Joyal, Jean-Sébastien; Sitaras, Nicholas; Binet, François; Rivera, Jose Carlos; Stahl, Andreas; Zaniolo, Karine; Shao, Zhuo; Polosa, Anna; Zhu, Tang; Hamel, David; Djavari, Mikheil; Kunik, Dario; Honoré, Jean-Claude; Picard, Emilie; Zabeida, Alexandra; Varma, Daya R.; Hickson, Gilles; Mancini, Joseph; Klagsbrun, Michael; Costantino, Santiago; Beauséjour, Christian; Lachapelle, Pierre; Smith, Lois E. H.

    2011-01-01

    The failure of blood vessels to revascularize ischemic neural tissue represents a significant challenge for vascular biology. Examples include proliferative retinopathies (PRs) such as retinopathy of prematurity and proliferative diabetic retinopathy, which are the leading causes of blindness in children and working-age adults. PRs are characterized by initial microvascular degeneration, followed by a compensatory albeit pathologic hypervascularization mounted by the hypoxic retina attempting to reinstate metabolic equilibrium. Paradoxically, this secondary revascularization fails to grow into the most ischemic regions of the retina. Instead, the new vessels are misdirected toward the vitreous, suggesting that vasorepulsive forces operate in the avascular hypoxic retina. In the present study, we demonstrate that the neuronal guidance cue semaphorin 3A (Sema3A) is secreted by hypoxic neurons in the avascular retina in response to the proinflammatory cytokine IL-1β. Sema3A contributes to vascular decay and later forms a chemical barrier that repels neo-vessels toward the vitreous. Conversely, silencing Sema3A expression enhances normal vascular regeneration within the ischemic retina, thereby diminishing aberrant neovascularization and preserving neuroretinal function. Overcoming the chemical barrier (Sema3A) released by ischemic neurons accelerates the vascular regeneration of neural tissues, which restores metabolic supply and improves retinal function. Our findings may be applicable to other neurovascular ischemic conditions such as stroke. PMID:21355092

  4. Siah regulation of Pard3A controls neuronal cell adhesion during germinal zone exit.

    PubMed

    Famulski, Jakub K; Trivedi, Niraj; Howell, Danielle; Yang, Yuan; Tong, Yiai; Gilbertson, Richard; Solecki, David J

    2010-12-24

    The brain's circuitry is established by directed migration and synaptogenesis of neurons during development. Although neurons mature and migrate in specific patterns, little is known about how neurons exit their germinal zone niche. We found that cerebellar granule neuron germinal zone exit is regulated by proteasomal degradation of Pard3A by the Seven in Absentia homolog (Siah) E3 ubiquitin ligase. Pard3A gain of function and Siah loss of function induce precocious radial migration. Time-lapse imaging using a probe to measure neuronal cell contact reveals that Pard3A promotes adhesive interactions needed for germinal zone exit by recruiting the epithelial tight junction adhesion molecule C to the neuronal cell surface. Our findings define a Siah-Pard3A signaling pathway that controls adhesion-dependent exit of neuronal progenitors or immature neurons from a germinal zone niche.

  5. Response variability of marmoset parvocellular neurons.

    PubMed

    Victor, J D; Blessing, E M; Forte, J D; Buzás, P; Martin, P R

    2007-02-15

    This study concerns the properties of neurons carrying signals for colour vision in primates. We investigated the variability of responses of individual parvocellular lateral geniculate neurons of dichromatic and trichromatic marmosets to drifting sinusoidal luminance and chromatic gratings. Response variability was quantified by the cycle-to-cycle variation in Fourier components of the response. Averaged across the population, the variability at low contrasts was greater than predicted by a Poisson process, and at high contrasts the responses were approximately 40% more variable than responses at low contrasts. The contrast-dependent increase in variability was nevertheless below that expected from the increase in firing rate. Variability falls below the Poisson prediction at high contrast, and intrinsic variability of the spike train decreases as contrast increases. Thus, while deeply modulated responses in parvocellular cells have a larger absolute variability than weakly modulated ones, they have a more favourable signal: noise ratio than predicted by a Poisson process. Similar results were obtained from a small sample of magnocellular and koniocellular ('blue-on') neurons. For parvocellular neurons with pronounced colour opponency, chromatic responses were, on average, less variable (10-15%, p<0.01) than luminance responses of equal magnitude. Conversely, non-opponent parvocellular neurons showed the opposite tendency. This is consistent with a supra-additive noise source prior to combination of cone signals. In summary, though variability of parvocellular neurons is largely independent of the way in which they combine cone signals, the noise characteristics of retinal circuitry may augment specialization of parvocellular neurons to signal luminance or chromatic contrast. PMID:17124265

  6. Impaired Neurite Contact Guidance in Ubiquitin Ligase E3a (Ube3a)-Deficient Hippocampal Neurons on Nanostructured Substrates.

    PubMed

    Tonazzini, I; Meucci, S; Van Woerden, G M; Elgersma, Y; Cecchini, M

    2016-04-01

    Recent discoveries indicate that during neuronal development the signaling processes that regulate extracellular sensing (e.g., adhesion, cytoskeletal dynamics) are important targets for ubiquitination-dependent regulation, in particular through E3 ubiquitin ligases. Among these, Ubiquitin E3a ligase (UBE3A) has a key role in brain functioning, but its function and how its deficiency results in the neurodevelopmental disorder Angelman syndrome is still unclear. Here, the role of UBE3A is investigated in neurite contact guidance during neuronal development, in vitro. The microtopography sensing of wild-type and Ube3a-deficient hippocampal neurons is studied by exploiting gratings with different topographical characteristics, with the aim to compare their capabilities to read and follow physical directional stimuli. It is shown that neuronal contact guidance is defective in Ube3a-deficient neurons, and this behavior is linked to an impaired activation of the focal adhesion signaling pathway. Taken together, the results suggest that the neuronal contact sensing machinery might be affected in Angelman syndrome. PMID:26845073

  7. Searching for optimal stimuli: ascending a neuron's response function.

    PubMed

    Koelling, Melinda Evrithiki; Nykamp, Duane Q

    2012-12-01

    Many methods used to analyze neuronal response assume that neuronal activity has a fundamentally linear relationship to the stimulus. However, some neurons are strongly sensitive to multiple directions in stimulus space and have a highly nonlinear response. It can be difficult to find optimal stimuli for these neurons. We demonstrate how successive linear approximations of neuronal response can effectively carry out gradient ascent and move through stimulus space towards local maxima of the response. We demonstrate search results for a simple model neuron and two models of a highly selective neuron. PMID:22580579

  8. Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice.

    PubMed

    Jones, Kelly A; Han, Ji Eun; DeBruyne, Jason P; Philpot, Benjamin D

    2016-01-01

    Mutations or deletions of the maternal allele of the UBE3A gene cause Angelman syndrome (AS), a severe neurodevelopmental disorder. The paternal UBE3A/Ube3a allele becomes epigenetically silenced in most neurons during postnatal development in humans and mice; hence, loss of the maternal allele largely eliminates neuronal expression of UBE3A protein. However, recent studies suggest that paternal Ube3a may escape silencing in certain neuron populations, allowing for persistent expression of paternal UBE3A protein. Here we extend evidence in AS model mice (Ube3a(m-/p+)) of paternal UBE3A expression within the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Paternal UBE3A-positive cells in the SCN show partial colocalization with the neuropeptide arginine vasopressin (AVP) and clock proteins (PER2 and BMAL1), supporting that paternal UBE3A expression in the SCN is often of neuronal origin. Paternal UBE3A also partially colocalizes with a marker of neural progenitors, SOX2, implying that relaxed or incomplete imprinting of paternal Ube3a reflects an overall immature molecular phenotype. Our findings highlight the complexity of Ube3a imprinting in the brain and illuminate a subpopulation of SCN neurons as a focal point for future studies aimed at understanding the mechanisms of Ube3a imprinting. PMID:27306933

  9. Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice

    PubMed Central

    Jones, Kelly A.; Han, Ji Eun; DeBruyne, Jason P.; Philpot, Benjamin D.

    2016-01-01

    Mutations or deletions of the maternal allele of the UBE3A gene cause Angelman syndrome (AS), a severe neurodevelopmental disorder. The paternal UBE3A/Ube3a allele becomes epigenetically silenced in most neurons during postnatal development in humans and mice; hence, loss of the maternal allele largely eliminates neuronal expression of UBE3A protein. However, recent studies suggest that paternal Ube3a may escape silencing in certain neuron populations, allowing for persistent expression of paternal UBE3A protein. Here we extend evidence in AS model mice (Ube3am–/p+) of paternal UBE3A expression within the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Paternal UBE3A-positive cells in the SCN show partial colocalization with the neuropeptide arginine vasopressin (AVP) and clock proteins (PER2 and BMAL1), supporting that paternal UBE3A expression in the SCN is often of neuronal origin. Paternal UBE3A also partially colocalizes with a marker of neural progenitors, SOX2, implying that relaxed or incomplete imprinting of paternal Ube3a reflects an overall immature molecular phenotype. Our findings highlight the complexity of Ube3a imprinting in the brain and illuminate a subpopulation of SCN neurons as a focal point for future studies aimed at understanding the mechanisms of Ube3a imprinting. PMID:27306933

  10. Prefrontal Neuronal Responses during Audiovisual Mnemonic Processing

    PubMed Central

    Hwang, Jaewon

    2015-01-01

    During communication we combine auditory and visual information. Neurophysiological research in nonhuman primates has shown that single neurons in ventrolateral prefrontal cortex (VLPFC) exhibit multisensory responses to faces and vocalizations presented simultaneously. However, whether VLPFC is also involved in maintaining those communication stimuli in working memory or combining stored information across different modalities is unknown, although its human homolog, the inferior frontal gyrus, is known to be important in integrating verbal information from auditory and visual working memory. To address this question, we recorded from VLPFC while rhesus macaques (Macaca mulatta) performed an audiovisual working memory task. Unlike traditional match-to-sample/nonmatch-to-sample paradigms, which use unimodal memoranda, our nonmatch-to-sample task used dynamic movies consisting of both facial gestures and the accompanying vocalizations. For the nonmatch conditions, a change in the auditory component (vocalization), the visual component (face), or both components was detected. Our results show that VLPFC neurons are activated by stimulus and task factors: while some neurons simply responded to a particular face or a vocalization regardless of the task period, others exhibited activity patterns typically related to working memory such as sustained delay activity and match enhancement/suppression. In addition, we found neurons that detected the component change during the nonmatch period. Interestingly, some of these neurons were sensitive to the change of both components and therefore combined information from auditory and visual working memory. These results suggest that VLPFC is not only involved in the perceptual processing of faces and vocalizations but also in their mnemonic processing. PMID:25609614

  11. Dopamine neurons share common response function for reward prediction error

    PubMed Central

    Eshel, Neir; Tian, Ju; Bukwich, Michael; Uchida, Naoshige

    2016-01-01

    Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically-identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found striking homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we could describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal. PMID:26854803

  12. Dopamine neurons share common response function for reward prediction error.

    PubMed

    Eshel, Neir; Tian, Ju; Bukwich, Michael; Uchida, Naoshige

    2016-03-01

    Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found marked homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we were able to describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal. PMID:26854803

  13. Dopamine neurons share common response function for reward prediction error.

    PubMed

    Eshel, Neir; Tian, Ju; Bukwich, Michael; Uchida, Naoshige

    2016-03-01

    Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found marked homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we were able to describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal.

  14. The Drosophila melanogaster homolog of UBE3A is not imprinted in neurons

    PubMed Central

    Hope, Kevin A.; LeDoux, Mark S.; Reiter, Lawrence T.

    2016-01-01

    ABSTRACT In mammals, expression of UBE3A is epigenetically regulated in neurons and expression is restricted to the maternal copy of UBE3A. A recent report claimed that Drosophila melanogaster UBE3A homolog (Dube3a) is preferentially expressed from the maternal allele in fly brain, inferring an imprinting mechanism. However, complex epigenetic regulatory features of the mammalian imprinting center are not present in Drosophila, and allele specific expression of Dube3a has not been documented. We used behavioral and electrophysiological analysis of the Dube3a loss-of-function allele (Dube3a15b) to investigate Dube3a imprinting in fly neurons. We found that motor impairment (climbing ability) and a newly-characterized defect in synaptic transmission are independent of parental inheritance of the Dube3a15b allele. Furthermore, expression analysis of coding single nucleotide polymorphisms (SNPs) in Dube3a did not reveal allele specific expression differences among reciprocal crosses. These data indicate that Dube3a is neither imprinted nor preferentially expressed from the maternal allele in fly neurons. PMID:27599063

  15. Response of Morris-Lecar neurons to various stimuli

    NASA Astrophysics Data System (ADS)

    Wang, Hengtong; Wang, Longfei; Yu, Lianchun; Chen, Yong

    2011-02-01

    We studied the responses of three classes of Morris-Lecar neurons to sinusoidal inputs and synaptic pulselike stimuli with deterministic and random interspike intervals (ISIs). It was found that the responses of the output frequency of class 1 and 2 neurons showed similar evolution properties by varying input amplitudes and frequencies, whereas class 3 neuron exhibited substantially different properties. Specifically, class 1 and 2 neurons display complicated phase locking (p : q, p>q, denoting output action potentials per input spikes) in low-frequency sinusoidal input area when the input amplitude is above their threshold, but a class 3 neuron does not fire action potentials in this area even if the amplitude is much higher. In the case of the deterministic ISI synaptic injection, all the three classes of neurons oscillate spikes with an arbitrary small frequency. When increasing the input frequency (both sinusoidal and deterministic ISI synaptic inputs), all neurons display 1 : 1 phase locking, whereas the response frequency decreases even fall to zero in the high-frequency input area. When the random ISI synaptic pulselike stimuli are injected into the neurons, one can clearly see the low-pass filter behaviors from the return map. The output ISI distribution depends on the mean ISI of input train as well as the ISI variation. Such different responses of three classes of neurons result from their distinct dynamical mechanisms of action potential initiation. It was suggested that the intrinsic dynamical cellular properties are very important to neuron information processing.

  16. Response of cat cortical neurons to position and movement of the femur.

    PubMed

    Aloisi, A M; Decchi, B; Fontani, G; Rossi, A; Carli, G

    1996-01-01

    The contribution of joint afferents to the response of cortical neurons in area 3a to mechanical stimulation of the contralateral hindlimb was evaluated in cats anesthetized with sodium pentobarbital and paralyzed with pancuronium bromide. The hindlimb projection to the pericruciate cortex was established by recording the evoked potentials to electrical stimulation of the sciatic nerve and some of its branches, the bicepssemitendinosus and the quadratus femoris. Out of 169 neurons, 63 responded exclusively to cutaneous stimuli (superficial), whereas the others could be activated by local pressure of hindlimb muscles and/or by joint rotation (deep). Deep neurons were classified as slowly adapting (SA) or rapidly adapting (RA) units. In the neurons responding exclusively to joint rotation, the site of the receptive field could not be identified with certainty. In 13 deep neurons, their firing was affected by rotation of multiple joints of the contralateral hindlimb. In an attempt to identify the source of activation of cortical neurons, partial denervations and muscle disconnections were performed in five animals to isolate and stimulate the hip capsule. In these preparations, in 14 of 15 cortical neurons the source of activation was localized in the periarticular muscles, with no response to mechanical stimulation of the joint capsule. Only one neuron (SA) could be selectively excited by punctate pressure on the hip capsule. Our results suggest that in neurons of area 3a of the cat, the information about the position of the femur relies mainly on muscle afferents.

  17. A coding-independent function of an alternative Ube3a transcript during neuronal development.

    PubMed

    Valluy, Jeremy; Bicker, Silvia; Aksoy-Aksel, Ayla; Lackinger, Martin; Sumer, Simon; Fiore, Roberto; Wüst, Tatjana; Seffer, Dominik; Metge, Franziska; Dieterich, Christoph; Wöhr, Markus; Schwarting, Rainer; Schratt, Gerhard

    2015-05-01

    The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD. PMID:25867122

  18. Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing

    PubMed Central

    Stanurova, Jana; Neureiter, Anika; Hiber, Michaela; de Oliveira Kessler, Hannah; Stolp, Kristin; Goetzke, Roman; Klein, Diana; Bankfalvi, Agnes; Klump, Hannes; Steenpass, Laura

    2016-01-01

    Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin-specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs). In these iPSCs, both parental alleles are present, distinguishable by the mutation, and express UBE3A. Detailed characterization of these iPSCs demonstrated their pluripotency and exceptional stability of the differentially methylated region regulating imprinted UBE3A expression. We observed strong induction of SNHG14 and silencing of paternal UBE3A expression only late during neuronal differentiation, in vitro. This new Angelman syndrome iPSC line allows to study imprinted gene regulation on both parental alleles and to dissect molecular pathways affected by the absence of UBE3A protein. PMID:27484051

  19. Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing

    PubMed Central

    Stanurova, Jana; Neureiter, Anika; Hiber, Michaela; de Oliveira Kessler, Hannah; Stolp, Kristin; Goetzke, Roman; Klein, Diana; Bankfalvi, Agnes; Klump, Hannes; Steenpass, Laura

    2016-01-01

    Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin-specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs). In these iPSCs, both parental alleles are present, distinguishable by the mutation, and express UBE3A. Detailed characterization of these iPSCs demonstrated their pluripotency and exceptional stability of the differentially methylated region regulating imprinted UBE3A expression. We observed strong induction of SNHG14 and silencing of paternal UBE3A expression only late during neuronal differentiation, in vitro. This new Angelman syndrome iPSC line allows to study imprinted gene regulation on both parental alleles and to dissect molecular pathways affected by the absence of UBE3A protein. PMID:27484051

  20. Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing.

    PubMed

    Stanurova, Jana; Neureiter, Anika; Hiber, Michaela; de Oliveira Kessler, Hannah; Stolp, Kristin; Goetzke, Roman; Klein, Diana; Bankfalvi, Agnes; Klump, Hannes; Steenpass, Laura

    2016-01-01

    Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin-specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs). In these iPSCs, both parental alleles are present, distinguishable by the mutation, and express UBE3A. Detailed characterization of these iPSCs demonstrated their pluripotency and exceptional stability of the differentially methylated region regulating imprinted UBE3A expression. We observed strong induction of SNHG14 and silencing of paternal UBE3A expression only late during neuronal differentiation, in vitro. This new Angelman syndrome iPSC line allows to study imprinted gene regulation on both parental alleles and to dissect molecular pathways affected by the absence of UBE3A protein. PMID:27484051

  1. Responses of neurons to extreme osmomechanical stress.

    PubMed

    Wan, X; Harris, J A; Morris, C E

    1995-05-01

    Neurons are often regarded as fragile cells, easily destroyed by mechanical and osmotic insult. The results presented here demonstrate that this perception needs revision. Using extreme osmotic swelling, we show that molluscan neurons are astonishingly robust. In distilled water, a heterogeneous population of Lymnaea stagnalis CNS neurons swelled to several times their initial volume, yet had a ST50 (survival time for 50% of cells) > 60 min. Cells that were initially bigger survived longer. On return to normal medium, survivors were able, over the next 24 hr, to rearborize. Reversible membrane capacitance changes corresponding to about 0.7 muF/cm2 of apparent surface area accompanied neuronal swelling and shrinking in hypo- and hyperosmotic solutions; reversible changes in cell surface area evidently contributed to the neurons' ability to accommodate hydrostatic pressures then recover. The reversible membrane area/capacitance changes were not dependent on extracellular Ca2+. Neurons were monitored for potassium currents during direct mechanical inflation and during osmotically driven inflation. The latter but not the former stimulus routinely elicited small potassium currents, suggesting that tension increases activate the currents only if additional disruption of the cortex has occurred. Under stress in distilled water, a third of the neurons displayed a quite unexpected behavior: prolonged writhing of peripheral regions of the soma. This suggested that a plasma membrane-linked contractile machinery (presumably actomyosin) might contribute to the neurons' mechano-osmotic robustness by restricting water influx. Consistent with this possibility, 1 mM N-ethyl-maleimide, which inhibits myosin ATPase, decreased the ST50 to 18 min, rendered the survival time independent of initial size, and abolished writhing activity. For neurons, active mechanical resistance of the submembranous cortex, along with the mechanical compliance supplied by insertion or eversion of membrane

  2. Egr2-neurons control the adult respiratory response to hypercapnia

    PubMed Central

    Ray, Russell S.; Corcoran, Andrea E.; Brust, Rachael D.; Soriano, Laura P.; Nattie, Eugene E.; Dymecki, Susan M.

    2013-01-01

    ‘The early growth response 2 transcription factor, Egr2, establishes a population of brainstem neurons essential for normal breathing at birth. Egr2-null mice die perinatally of respiratory insufficiency characterized by subnormal respiratory rate and severe apneas. Here we bypass this lethality using a noninvasive pharmacogenetic approach to inducibly perturb neuron activity postnatally, and ask if Egr2-neurons control respiration in adult mice. We found that the normal ventilatory increase in response to elevated tissue CO2 was impaired, blunted by 63.1±8.7% after neuron perturbation due to deficits in both respiratory amplitude and frequency. By contrast, room-air breathing was unaffected, suggesting that the drive for baseline breathing may not require those Egr2-neurons manipulated here. Of the multiple brainstem sites proposed to affect ventilation in response to hypercapnia, only the retrotrapezoid nucleus, a portion of the serotonergic raphé, and a portion of the A5 nucleus have a history of Egr2 expression. We recently showed that acute inhibition of serotonergic neurons en masse blunts the CO2 chemoreflex in adults, causing a difference in hypercapnic response of ~50% after neuron perturbation through effects on respiratory amplitude only. The suppressed respiratory frequency upon perturbation of Egr2-neurons thus may stem from non-serotonergic neurons within the Egr2 domain. Perturbation of Egr2-neurons did not affect body temperature, even on exposure to ambient 4 °C. These findings support a model in which Egr2-neurons are a critical component of the respiratory chemoreflex into adulthood. Methodologically, these results highlight how pharmacogenetic approaches allow neuron function to be queried in unanesthetized adult animals, reaching beyond the roadblocks of developmental lethality and compensation as well as the anatomical disturbances associated with invasive methods. PMID:23261662

  3. Authors’ response: mirror neurons: tests and testability.

    PubMed

    Catmur, Caroline; Press, Clare; Cook, Richard; Bird, Geoffrey; Heyes, Cecilia

    2014-04-01

    Commentators have tended to focus on the conceptual framework of our article, the contrast between genetic and associative accounts of mirror neurons, and to challenge it with additional possibilities rather than empirical data. This makes the empirically focused comments especially valuable. The mirror neuron debate is replete with ideas; what it needs now are system-level theories and careful experiments – tests and testability.

  4. Interhemispheric Synchronization of Oscillatory Neuronal Responses in Cat Visual Cortex

    NASA Astrophysics Data System (ADS)

    Engel, Andreas K.; Konig, Peter; Kreiter, Andreas K.; Singer, Wolf

    1991-05-01

    Neurons in area 17 of cat visual cortex display oscillatory responses that can synchronize across spatially separate columns in a stimulus-specific way. Response synchronization has now been shown to occur also between neurons in area 17 of the right and left cerebral hemispheres. This synchronization was abolished by section of the corpus callosum. Thus, the response synchronization is mediated by corticocortical connections. These data are compatible with the hypothesis that temporal synchrony of neuronal discharges serves to bind features within and between the visual hemifields.

  5. Temporal characteristics of gustatory responses in rat parabrachial neurons vary by stimulus and chemosensitive neuron type.

    PubMed

    Geran, Laura; Travers, Susan

    2013-01-01

    It has been demonstrated that temporal features of spike trains can increase the amount of information available for gustatory processing. However, the nature of these temporal characteristics and their relationship to different taste qualities and neuron types are not well-defined. The present study analyzed the time course of taste responses from parabrachial (PBN) neurons elicited by multiple applications of "sweet" (sucrose), "salty" (NaCl), "sour" (citric acid), and "bitter" (quinine and cycloheximide) stimuli in an acute preparation. Time course varied significantly by taste stimulus and best-stimulus classification. Across neurons, the ensemble code for the three electrolytes was similar initially but quinine diverged from NaCl and acid during the second 500 ms of stimulation and all four qualities became distinct just after 1s. This temporal evolution was reflected in significantly broader tuning during the initial response. Metric space analyses of quality discrimination by individual neurons showed that increases in information (H) afforded by temporal factors was usually explained by differences in rate envelope, which had a greater impact during the initial 2s (22.5% increase in H) compared to the later response (9.5%). Moreover, timing had a differential impact according to cell type, with between-quality discrimination in neurons activated maximally by NaCl or citric acid most affected. Timing was also found to dramatically improve within-quality discrimination (80% increase in H) in neurons that responded optimally to bitter stimuli (B-best). Spikes from B-best neurons were also more likely to occur in bursts. These findings suggest that among PBN taste neurons, time-dependent increases in mutual information can arise from stimulus- and neuron-specific differences in response envelope during the initial dynamic period. A stable rate code predominates in later epochs.

  6. A simple white noise analysis of neuronal light responses.

    PubMed

    Chichilnisky, E J

    2001-05-01

    A white noise technique is presented for estimating the response properties of spiking visual system neurons. The technique is simple, robust, efficient and well suited to simultaneous recordings from multiple neurons. It provides a complete and easily interpretable model of light responses even for neurons that display a common form of response nonlinearity that precludes classical linear systems analysis. A theoretical justification of the technique is presented that relies only on elementary linear algebra and statistics. Implementation is described with examples. The technique and the underlying model of neural responses are validated using recordings from retinal ganglion cells, and in principle are applicable to other neurons. Advantages and disadvantages of the technique relative to classical approaches are discussed. PMID:11405422

  7. Asynchronous response of coupled pacemaker neurons

    PubMed Central

    Dodla, Ramana; Wilson, Charles J.

    2009-01-01

    We study a network model of two conductance-based pacemaker neurons of differing natural frequency, coupled with either mutual excitation or inhibition, and receiving shared random inhibitory synaptic input. The networks may phase-lock spike-to-spike for strong mutual coupling. But the shared input can desynchronize the locked spike-pairs by selectively eliminating the lagging spike or modulating its timing with respect to the leading spike depending on their separation time window. Such loss of synchrony is also found in a large network of sparsely coupled heterogeneous spiking neurons receiving shared input. PMID:19257636

  8. Flotillin-mediated endocytic events dictate cell-type specific responses to Semaphorin 3A

    PubMed Central

    Carcea, Ioana; Ma'ayan, Avi; Mesias, Roxana; Sepulveda, Bryan; Salton, Stephen R.; Benson, Deanna L.

    2010-01-01

    Cortical efferents growing in the same environment diverge early in development. The expression of particular transcription factors dictates the trajectories taken presumably by regulating responsiveness to guidance cues via cellular mechanisms that are not yet known. Here we show that cortical neurons that are dissociated and grown in culture maintain their cell-type specific identities defined by the expression of transcription factors. Using this model system we sought to identify and characterize mechanisms that are recruited to produce cell-type specific responses to Semaphorin 3A (Sema3A), a guidance cue that would be presented similarly to cortical axons in vivo. Axons from presumptive corticofugal neurons lacking the transcription factor Satb2 and expressing Ctip2 or Tbr1 respond far more robustly to Sema3A than those from presumptive callosal neurons expressing Satb2. Both populations of axons express similar levels of Sema3A receptors (Neuropilin-1, L1CAM and PlexinA4), but significantly, axons from neurons lacking Satb2 internalize more Sema3A and they do so via a raft-mediated endocytic pathway. We used an in silico approach to identify the endocytosis effector Flotillin-1 as a Sema3A signaling candidate. We tested the contributions of Flotillin-1 to Sema3A endocytosis and signaling, and show that raft-mediated Sema3A endocytosis is defined by and depends on the recruitment of Flotillin-1, which mediates LIMK activation, and regulates axon responsiveness to Sema3A in presumptive corticofugal axons. PMID:21068336

  9. Sexually dimorphic neuronal responses to social isolation

    PubMed Central

    Senst, Laura; Baimoukhametova, Dinara; Sterley, Toni-Lee; Bains, Jaideep Singh

    2016-01-01

    Many species use social networks to buffer the effects of stress. The mere absence of a social network, however, may also be stressful. We examined neuroendocrine, PVN CRH neurons and report that social isolation alters the intrinsic properties of these cells in sexually dimorphic fashion. Specifically, isolating preadolescent female mice from littermates for <24 hr increased first spike latency (FSL) and decreased excitability of CRH neurons. These changes were not evident in age-matched males. By contrast, subjecting either males (isolated or grouped) or group housed females to acute physical stress (swim), increased FSL. The increase in FSL following either social isolation or acute physical stress was blocked by the glucocorticoid synthesis inhibitor, metyrapone and mimicked by exogenous corticosterone. The increase in FSL results in a decrease in the excitability of CRH neurons. Our observations demonstrate that social isolation, but not acute physical stress has sex-specific effects on PVN CRH neurons. DOI: http://dx.doi.org/10.7554/eLife.18726.001 PMID:27725087

  10. Visual attention model based on statistical properties of neuron responses.

    PubMed

    Duan, Haibin; Wang, Xiaohua

    2015-01-01

    Visual attention is a mechanism of the visual system that can select relevant objects from a specific scene. Interactions among neurons in multiple cortical areas are considered to be involved in attentional allocation. However, the characteristics of the encoded features and neuron responses in those attention related cortices are indefinite. Therefore, further investigations carried out in this study aim at demonstrating that unusual regions arousing more attention generally cause particular neuron responses. We suppose that visual saliency is obtained on the basis of neuron responses to contexts in natural scenes. A bottom-up visual attention model is proposed based on the self-information of neuron responses to test and verify the hypothesis. Four different color spaces are adopted and a novel entropy-based combination scheme is designed to make full use of color information. Valuable regions are highlighted while redundant backgrounds are suppressed in the saliency maps obtained by the proposed model. Comparative results reveal that the proposed model outperforms several state-of-the-art models. This study provides insights into the neuron responses based saliency detection and may underlie the neural mechanism of early visual cortices for bottom-up visual attention. PMID:25747859

  11. A novel rotate-and-fire digital spiking neuron and its neuron-like bifurcations and responses.

    PubMed

    Hishiki, Tetsuya; Torikai, Hiroyuki

    2011-05-01

    A novel rotate-and-fire digital spiking neuron is presented. The digital neuron is a wired system of shift registers and thus it is suited to on-chip learning unlike many other analog spiking neuron models. By adjusting the wiring pattern among the registers, the digital neuron can generate spike trains with various spike patterns and can exhibit related bifurcations. A discrete-continuous hybrid map, which describes the neuron dynamics without any approximation, is derived analytically. Using the hybrid map, it is shown that the digital spiking neuron can mimic typical bifurcation phenomena and various nonlinear responses of biological neurons.

  12. Finding and Not Finding Rat Perirhinal Neuronal Responses to Novelty

    PubMed Central

    Muller, Robert U.; Brown, Malcolm W.

    2016-01-01

    ABSTRACT There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in “paired viewing” experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had “object fields”); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition‐related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used.

  13. Finding and Not Finding Rat Perirhinal Neuronal Responses to Novelty.

    PubMed

    von Linstow Roloff, Eva; Muller, Robert U; Brown, Malcolm W

    2016-08-01

    There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in "paired viewing" experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had "object fields"); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition-related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used. © 2016 The Authors

  14. Responses of neurons in the auditory pathway of the barn owl to partially correlated binaural signals.

    PubMed

    Albeck, Y; Konishi, M

    1995-10-01

    1. Extracellular single-unit recording in anesthetized barn owls was used to study neuronal response to dichotic stimuli of variable binaural correlation (BC). Recordings were made in the output fibers of nucleus laminaris (NL), the anterior division of the ventral lateral lemniscal nucleus (VLVa), the core of the central nucleus of the inferior colliculus (ICcC), the lateral shell of the central nucleus of the inferior colliculus (ICcLS), and the external nucleus of the inferior colliculus (ICx). 2. The response of all neurons sensitive to interaural time difference (ITD) varied with BC. The relationship between BC and impulse number fits a linear, a parabolic, or a ramp model. A linear or parabolic model fits most neurons in low-level nuclei. Higher order neurons in ICx did not respond to noise bursts with strong negative binaural correlation, creating a ramp-like response to BC. 3. A neuron's ability to detect ITD varied as a function of BC. Conversely, a neuron's response to BC changed with ITD. Neurons in NL, VLVa, and ICcC show almost periodic ITD response curves. In these neurons peaks and troughs of ITD response curves diminished as BC decreased, creating a flat ITD response when BC = 0. When BC was set to -1, the most favorable ITD became the least favorable one and vice versa. The ITD response curve of ICx neurons usually has a single dominant peak. The response of those neurons to a negatively correlated noise pair (BC = -1) showed two ITD peaks, flanking the position of the primary peak. 4. The parabolic BC response of NL neurons fits the prediction of the cross-correlation model, assuming half-wave rectification of the sound by the cochlea. Linear response is not predicted by the model. However, the parabolic and the linear neurons probably do not belong to two distinct groups as the difference between them is not statistically significant. Thus, the cross-correlation model provides a good description of the binaural response not only in NL but also in

  15. VTA neurons show a potentially protective transcriptional response to MPTP.

    PubMed

    Phani, Sudarshan; Gonye, Gregory; Iacovitti, Lorraine

    2010-07-01

    Parkinson's disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a dynamic transcriptional response within the cells of the VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation (Phf6) and ion/metal regulation (PANK2 and Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge.

  16. Loss of Npn1 from motor neurons causes postnatal deficits independent from Sema3A signaling.

    PubMed

    Helmbrecht, Michaela S; Soellner, Heidi; Truckenbrodt, Anna M L; Sundermeier, Julia; Cohrs, Christian; Hans, Wolfgang; de Angelis, Martin Hrabě; Feuchtinger, Annette; Aichler, Michaela; Fouad, Karim; Huber, Andrea B

    2015-03-01

    The correct wiring of neuronal circuits is of crucial importance for the function of the vertebrate nervous system. Guidance cues like the neuropilin receptors (Npn) and their ligands, the semaphorins (Sema) provide a tight spatiotemporal control of sensory and motor axon growth and guidance. Among this family of guidance partners the Sema3A-Npn1 interaction has been shown to be of great importance, since defective signaling leads to wiring deficits and defasciculation. For the embryonic stage these defects have been well described, however, also after birth the organism can adapt to new challenges by compensational mechanisms. Therefore, we used the mouse lines Olig2-Cre;Npn1(cond) and Npn1(Sema-) to investigate how postnatal organisms cope with the loss of Npn1 selectively from motor neurons or a systemic dysfunctional Sema3A-Npn1 signaling in the entire organism, respectively. While in Olig2-Cre(+);Npn1(cond-/-) mice clear anatomical deficits in paw posturing, bone structure, as well as muscle and nerve composition became evident, Npn1(Sema-) mutants appeared anatomically normal. Furthermore, Olig2-Cre(+);Npn1(cond) mutants revealed a dysfunctional extensor muscle innervation after single-train stimulation of the N.radial. Interestingly, these mice did not show obvious deficits in voluntary locomotion, however, skilled motor function was affected. In contrast, Npn1(Sema-) mutants were less affected in all behavioral tests and able to improve their performance over time. Our data suggest that loss of Sema3A-Npn1 signaling is not the only cause for the observed deficits in Olig2-Cre(+);Npn1(cond-/-) mice and that additional, yet unknown binding partners for Npn1 may be involved that allow Npn1(Sema-) mutants to compensate for their developmental deficits.

  17. Phasic activation of ventral tegmental neurons increases response and pattern similarity in prefrontal cortex neurons

    PubMed Central

    Iwashita, Motoko

    2014-01-01

    Dopamine is critical for higher neural processes and modifying the activity of the prefrontal cortex (PFC). However, the mechanism of dopamine contribution to the modification of neural representation is unclear. Using in vivo two-photon population Ca2+ imaging in awake mice, this study investigated how neural representation of visual input to PFC neurons is regulated by dopamine. Phasic stimulation of dopaminergic neurons in the ventral tegmental area (VTA) evoked prolonged Ca2+ transients, lasting ∼30 s in layer 2/3 neurons of the PFC, which are regulated by a dopamine D1 receptor-dependent pathway. Furthermore, only a conditioning protocol with visual sensory input applied 0.5 s before the VTA dopaminergic input could evoke enhanced Ca2+ transients and increased pattern similarity (or establish a neural representation) of PFC neurons to the same sensory input. By increasing both the level of neuronal response and pattern similarity, dopaminergic input may establish robust and reliable cortical representation. DOI: http://dx.doi.org/10.7554/eLife.02726.001 PMID:25269147

  18. Modeling of Auditory Neuron Response Thresholds with Cochlear Implants

    PubMed Central

    Venail, Frederic; Mura, Thibault; Akkari, Mohamed; Mathiolon, Caroline; Menjot de Champfleur, Sophie; Piron, Jean Pierre; Sicard, Marielle; Sterkers-Artieres, Françoise; Mondain, Michel; Uziel, Alain

    2015-01-01

    The quality of the prosthetic-neural interface is a critical point for cochlear implant efficiency. It depends not only on technical and anatomical factors such as electrode position into the cochlea (depth and scalar placement), electrode impedance, and distance between the electrode and the stimulated auditory neurons, but also on the number of functional auditory neurons. The efficiency of electrical stimulation can be assessed by the measurement of e-CAP in cochlear implant users. In the present study, we modeled the activation of auditory neurons in cochlear implant recipients (nucleus device). The electrical response, measured using auto-NRT (neural responses telemetry) algorithm, has been analyzed using multivariate regression with cubic splines in order to take into account the variations of insertion depth of electrodes amongst subjects as well as the other technical and anatomical factors listed above. NRT thresholds depend on the electrode squared impedance (β = −0.11 ± 0.02, P < 0.01), the scalar placement of the electrodes (β = −8.50 ± 1.97, P < 0.01), and the depth of insertion calculated as the characteristic frequency of auditory neurons (CNF). Distribution of NRT residues according to CNF could provide a proxy of auditory neurons functioning in implanted cochleas. PMID:26236725

  19. Role of spinal bombesin-responsive neurons in nonhistaminergic itch.

    PubMed

    Akiyama, Tasuku; Tominaga, Mitsutoshi; Takamori, Kenji; Carstens, Mirela Iodi; Carstens, E

    2014-11-01

    Intrathecal administration of the neurotoxin bombesin-saporin reduces or abolishes pruritogen-evoked scratching behavior. We investigated whether spinal neurons that respond to intradermal (ID) injection of pruritogens also respond to spinal superfusion of bombesin and vice versa. Single-unit recordings were made from superficial lumbar spinal dorsal horn neurons in anesthetized mice. We identified neurons with three search strategies: 1) ID injection of the nonhistaminergic itch mediator chloroquine, 2) spinal superfusion of bombesin, and 3) noxious pinch. All units were tested with an array of itch mediators (chloroquine, histamine, SLIGRL, BAM8-22), algogens [capsaicin, allyl isothiocyanate (AITC)], and physical stimuli (brush, pinch, noxious heat, cooling) applied to the hindlimb receptive field. The vast majority of chloroquine-responsive units also responded to bombesin. Of 26 chloroquine-sensitive units tested, most responded to SLIGRL, half responded to histamine and/or BAM8-22, and most responded to capsaicin and/or AITC as well as noxious thermal and mechanical stimuli. Of 29 bombesin-responsive units, a large majority also responded to other itch mediators as well as AITC, capsaicin, and noxious thermal and mechanical stimuli. Responses to successive applications of bombesin exhibited tachyphylaxis. In contrast, of 36 units responsive to noxious pinch, the majority (67%) did not respond to ID chloroquine or spinal bombesin. It is suggested that chloroquine- and bombesin-sensitive spinal neurons signal itch from the skin.

  20. Neuronal modelling of baroreflex response to orthostatic stress

    NASA Astrophysics Data System (ADS)

    Samin, Azfar

    The accelerations experienced in aerial combat can cause pilot loss of consciousness (GLOC) due to a critical reduction in cerebral blood circulation. The development of smart protective equipment requires understanding of how the brain processes blood pressure (BP) information in response to acceleration. We present a biologically plausible model of the Baroreflex to investigate the neural correlates of short-term BP control under acceleration or orthostatic stress. The neuronal network model, which employs an integrate-and-fire representation of a biological neuron, comprises the sensory, motor, and the central neural processing areas that form the Baroreflex. Our modelling strategy is to test hypotheses relating to the encoding mechanisms of multiple sensory inputs to the nucleus tractus solitarius (NTS), the site of central neural processing. The goal is to run simulations and reproduce model responses that are consistent with the variety of available experimental data. Model construction and connectivity are inspired by the available anatomical and neurophysiological evidence that points to a barotopic organization in the NTS, and the presence of frequency-dependent synaptic depression, which provides a mechanism for generating non-linear local responses in NTS neurons that result in quantifiable dynamic global baroreflex responses. The entire physiological range of BP and rate of change of BP variables is encoded in a palisade of NTS neurons in that the spike responses approximate Gaussian 'tuning' curves. An adapting weighted-average decoding scheme computes the motor responses and a compensatory signal regulates the heart rate (HR). Model simulations suggest that: (1) the NTS neurons can encode the hydrostatic pressure difference between two vertically separated sensory receptor regions at +Gz, and use changes in that difference for the regulation of HR; (2) even though NTS neurons do not fire with a cardiac rhythm seen in the afferents, pulse

  1. 18 CFR 3a.13 - Classification responsibility and procedure.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Classification responsibility and procedure. 3a.13 Section 3a.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION Classification §...

  2. 18 CFR 3a.13 - Classification responsibility and procedure.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Classification responsibility and procedure. 3a.13 Section 3a.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION Classification §...

  3. 18 CFR 3a.13 - Classification responsibility and procedure.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Classification responsibility and procedure. 3a.13 Section 3a.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION Classification §...

  4. 18 CFR 3a.13 - Classification responsibility and procedure.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Classification responsibility and procedure. 3a.13 Section 3a.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION Classification §...

  5. 18 CFR 3a.13 - Classification responsibility and procedure.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Classification responsibility and procedure. 3a.13 Section 3a.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION Classification §...

  6. Broadband macroscopic cortical oscillations emerge from intrinsic neuronal response failures.

    PubMed

    Goldental, Amir; Vardi, Roni; Sardi, Shira; Sabo, Pinhas; Kanter, Ido

    2015-01-01

    Broadband spontaneous macroscopic neural oscillations are rhythmic cortical firing which were extensively examined during the last century, however, their possible origination is still controversial. In this work we show how macroscopic oscillations emerge in solely excitatory random networks and without topological constraints. We experimentally and theoretically show that these oscillations stem from the counterintuitive underlying mechanism-the intrinsic stochastic neuronal response failures (NRFs). These NRFs, which are characterized by short-term memory, lead to cooperation among neurons, resulting in sub- or several- Hertz macroscopic oscillations which coexist with high frequency gamma oscillations. A quantitative interplay between the statistical network properties and the emerging oscillations is supported by simulations of large networks based on single-neuron in-vitro experiments and a Langevin equation describing the network dynamics. Results call for the examination of these oscillations in the presence of inhibition and external drives. PMID:26578893

  7. Broadband macroscopic cortical oscillations emerge from intrinsic neuronal response failures

    PubMed Central

    Goldental, Amir; Vardi, Roni; Sardi, Shira; Sabo, Pinhas; Kanter, Ido

    2015-01-01

    Broadband spontaneous macroscopic neural oscillations are rhythmic cortical firing which were extensively examined during the last century, however, their possible origination is still controversial. In this work we show how macroscopic oscillations emerge in solely excitatory random networks and without topological constraints. We experimentally and theoretically show that these oscillations stem from the counterintuitive underlying mechanism—the intrinsic stochastic neuronal response failures (NRFs). These NRFs, which are characterized by short-term memory, lead to cooperation among neurons, resulting in sub- or several- Hertz macroscopic oscillations which coexist with high frequency gamma oscillations. A quantitative interplay between the statistical network properties and the emerging oscillations is supported by simulations of large networks based on single-neuron in-vitro experiments and a Langevin equation describing the network dynamics. Results call for the examination of these oscillations in the presence of inhibition and external drives. PMID:26578893

  8. Estradiol modulates Kiss1 neuronal response to ghrelin

    PubMed Central

    Frazao, Renata; Lemko, Heather M. Dungan; da Silva, Regina P.; Ratra, Dhirender V.; Lee, Charlotte E.; Williams, Kevin W.; Zigman, Jeffrey M.

    2014-01-01

    Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administration suppresses gonadotropin secretion and inhibits the neuroendocrine reproductive axis. Interestingly, ghrelin's effect in female metabolism varies according to the estrogen milieu predicting an interaction between ghrelin and estrogens, likely at the hypothalamic level. Here, we show that ghrelin receptor (GHSR) and estrogen receptor-α (ERα) are coexpressed in several hypothalamic sites. Higher levels of circulating estradiol increased the expression of GHSR mRNA and the co-xpression of GHSR mRNA and ERα selectively in the arcuate nucleus (ARC). Subsets of preoptic and ARC Kiss1 neurons coexpressed GHSR. Increased colocalization was observed in ARC Kiss1 neurons of ovariectomized estradiol-treated (OVX + E2; 80%) compared with ovariectomized oil-treated (OVX; 25%) mice. Acute actions of ghrelin on ARC Kiss1 neurons were also modulated by estradiol; 75 and 22% of Kiss1 neurons of OVX + E2 and OVX mice, respectively, depolarized in response to ghrelin. Our findings indicate that ghrelin and estradiol may interact in several hypothalamic sites. In the ARC, high levels of E2 increase GHSR mRNA expression, modifying the colocalization rate with ERα and Kiss1 and the proportion of Kiss1 neurons acutely responding to ghrelin. Our findings indicate that E2 alters the responsiveness of kisspeptin neurons to metabolic signals, potentially acting as a critical player in the metabolic control of the reproductive physiology. PMID:24473434

  9. Spinal nerve injury increases the percentage of cold-responsive DRG neurons.

    PubMed

    Djouhri, L; Wrigley, D; Thut, P D; Gold, M S

    2004-03-01

    We tested the hypothesis that cold allodynia, observed following nerve injury reflects change(s) in the cold responsiveness of sensory neurons. To test this hypothesis we assessed the impact of the spinal nerve ligation (SNL) model of nerve injury on the responses of cutaneous sensory neurons to cooling in vitro. Nerve injury induced a significant increase in the incidence of cold responsive cutaneous neurons in uninjured but not injured ganglia. Because an increase in the percentage of cold responsive neurons in uninjured ganglia should increase the total neuronal response to cooling of peripheral tissue, these findings suggest that cold allodynia reflects, at least in part, a change in sensory neurons. PMID:15094503

  10. Finite Post Synaptic Potentials Cause a Fast Neuronal Response

    PubMed Central

    Helias, Moritz; Deger, Moritz; Rotter, Stefan; Diesmann, Markus

    2011-01-01

    A generic property of the communication between neurons is the exchange of pulses at discrete time points, the action potentials. However, the prevalent theory of spiking neuronal networks of integrate-and-fire model neurons relies on two assumptions: the superposition of many afferent synaptic impulses is approximated by Gaussian white noise, equivalent to a vanishing magnitude of the synaptic impulses, and the transfer of time varying signals by neurons is assessable by linearization. Going beyond both approximations, we find that in the presence of synaptic impulses the response to transient inputs differs qualitatively from previous predictions. It is instantaneous rather than exhibiting low-pass characteristics, depends non-linearly on the amplitude of the impulse, is asymmetric for excitation and inhibition and is promoted by a characteristic level of synaptic background noise. These findings resolve contradictions between the earlier theory and experimental observations. Here we review the recent theoretical progress that enabled these insights. We explain why the membrane potential near threshold is sensitive to properties of the afferent noise and show how this shapes the neural response. A further extension of the theory to time evolution in discrete steps quantifies simulation artifacts and yields improved methods to cross check results. PMID:21427776

  11. HDAC2 selectively regulates FOXO3a-mediated gene transcription during oxidative stress-induced neuronal cell death.

    PubMed

    Peng, Shengyi; Zhao, Siqi; Yan, Feng; Cheng, Jinbo; Huang, Li; Chen, Hong; Liu, Qingsong; Ji, Xunming; Yuan, Zengqiang

    2015-01-21

    All neurodegenerative diseases are associated with oxidative stress-induced neuronal death. Forkhead box O3a (FOXO3a) is a key transcription factor involved in neuronal apoptosis. However, how FOXO3a forms complexes and functions in oxidative stress processing remains largely unknown. In the present study, we show that histone deacetylase 2 (HDAC2) forms a physical complex with FOXO3a, which plays an important role in FOXO3a-dependent gene transcription and oxidative stress-induced mouse cerebellar granule neuron (CGN) apoptosis. Interestingly, we also found that HDAC2 became selectively enriched in the promoter region of the p21 gene, but not those of other target genes, and inhibited FOXO3a-mediated p21 transcription. Furthermore, we found that oxidative stress reduced the interaction between FOXO3a and HDAC2, leading to an increased histone H4K16 acetylation level in the p21 promoter region and upregulated p21 expression in a manner independent of p53 or E2F1. Phosphorylation of HDAC2 at Ser 394 is important for the HDAC2-FOXO3a interaction, and we found that cerebral ischemia/reperfusion reduced phosphorylation of HDAC2 at Ser 394 and mitigated the HDAC2-FOXO3a interaction in mouse brain tissue. Our study reveals the novel regulation of FOXO3a-mediated selective gene transcription via epigenetic modification in the process of oxidative stress-induced cell death, which could be exploited therapeutically.

  12. Spontaneous olfactory receptor neuron activity determines follower cell response properties

    PubMed Central

    Joseph, Joby; Dunn, Felice A.; Stopfer, Mark

    2012-01-01

    Noisy or spontaneous activity is common in neural systems and poses a challenge to detecting and discriminating signals. Here we use the locust to answer fundamental questions about noise in the olfactory system: Where does spontaneous activity originate? How is this activity propagated or reduced throughout multiple stages of neural processing? What mechanisms favor the detection of signals despite the presence of spontaneous activity? We found that spontaneous activity long observed in the secondary projection neurons (PNs) originates almost entirely from the primary olfactory receptor neurons (ORNs) rather than from spontaneous circuit interactions in the antennal lobe, and that spontaneous activity in ORNs tonically depolarizes the resting membrane potentials of their target PNs and local neurons (LNs), and indirectly tonically depolarizes tertiary Kenyon cells (KCs). However, because these neurons have different response thresholds, in the absence of odor stimulation, ORNs and PNs display a high spontaneous firing rate but KCs are nearly silent. Finally, we used a simulation of the olfactory network to show that discrimination of signal and noise in the KCs is best when threshold levels are set so that baseline activity in PNs persists. Our results show how the olfactory system benefits from making a signal detection decision after a point of maximal information convergence, e.g., after KCs pool inputs from many PNs. PMID:22357872

  13. GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility.

    PubMed

    Judson, Matthew C; Wallace, Michael L; Sidorov, Michael S; Burette, Alain C; Gu, Bin; van Woerden, Geeske M; King, Ian F; Han, Ji Eun; Zylka, Mark J; Elgersma, Ype; Weinberg, Richard J; Philpot, Benjamin D

    2016-04-01

    Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS.

  14. GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility.

    PubMed

    Judson, Matthew C; Wallace, Michael L; Sidorov, Michael S; Burette, Alain C; Gu, Bin; van Woerden, Geeske M; King, Ian F; Han, Ji Eun; Zylka, Mark J; Elgersma, Ype; Weinberg, Richard J; Philpot, Benjamin D

    2016-04-01

    Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS. PMID:27021170

  15. Aerobic exercise reduces neuronal responses in food reward brain regions.

    PubMed

    Evero, Nero; Hackett, Laura C; Clark, Robert D; Phelan, Suzanne; Hagobian, Todd A

    2012-05-01

    Acute exercise suppresses ad libitum energy intake, but little is known about the effects of exercise on food reward brain regions. After an overnight fast, 30 (17 men, 13 women), healthy, habitually active (age = 22.2 ± 0.7 yr, body mass index = 23.6 ± 0.4 kg/m(2), Vo(2peak) = 44.2 ± 1.5 ml·kg(-1)·min(-1)) individuals completed 60 min of exercise on a cycle ergometer or 60 min of rest (no-exercise) in a counterbalanced, crossover fashion. After each condition, blood oxygen level-dependent responses to high-energy food, low-energy food, and control visual cues, were measured by functional magnetic resonance imaging. Exercise, compared with no-exercise, significantly (P < 0.005) reduced the neuronal response to food (high and low food) cues vs. control cues in the insula (-0.37 ± 0.13 vs. +0.07 ± 0.18%), putamen (-0.39 ± 0.10 vs. -0.10 ± 0.09%), and rolandic operculum (-0.37 ± 0.17 vs. 0.17 ± 0.12%). Exercise alone significantly (P < 0.005) reduced the neuronal response to high food vs. control and low food vs. control cues in the inferior orbitofrontal cortex (-0.94 ± 0.33%), insula (-0.37 ± 0.13%), and putamen (-0.41 ± 0.10%). No-exercise alone significantly (P < 0.005) reduced the neuronal response to high vs. control and low vs. control cues in the middle (-0.47 ± 0.15%) and inferior occipital gyrus (-1.00 ± 0.23%). Exercise reduced neuronal responses in brain regions consistent with reduced pleasure of food, reduced incentive motivation to eat, and reduced anticipation and consumption of food. Reduced neuronal response in these food reward brain regions after exercise is in line with the paradigm that acute exercise suppresses subsequent energy intake.

  16. Potentiation by desipramine of neuronal responses to mescaline.

    PubMed

    Bevan, P; Bradshaw, C M; Szabadi, E

    1976-05-01

    The effect of desipramine on responses of single cortical neurones to mescaline was studied by the microelectrophoretic technique. Both potentiation and antagonism of responses to mescaline by desipramine were observed. The antagonism may be related to the alpha-adrenolytic action of desipramine. The potentiation is unlikely to reflect the uptake blocking action of desipramine, since desipramine does not block the uptake of mescaline in the cerebral cortex. It is suggested that the potentiation may be due to a post-synaptic action of desipramine.

  17. ERM proteins regulate growth cone responses to Sema3A

    PubMed Central

    Mintz, C. David; Carcea, Ioana; McNickle, Daniel G.; Dickson, Tracey C.; Ge, Yongchao; Salton, Stephen R.J.; Benson, Deanna L.

    2008-01-01

    Axonal growth cones initiate and sustain directed growth in response to cues in their environment. A variety of events such as receptor internalization, kinase activation, and actin rearrangement can be stimulated by guidance cues and are essential for mediating targeted growth cone behavior. Surprisingly little is known about how such disparate actions are coordinated. Our data suggest that ezrin, radixin, and moesin (ERMs), a family of highly homologous, multifunctional proteins may be able to coordinate growth cone responses to the guidance cue, Sema3A. We show that active ERMs concentrate asymmetrically in neocortical growth cones, are rapidly and transiently inactivated by Sema3A, and are required for Sema3A-mediated growth cone collapse and guidance. The FERM domain of active ERMs regulates internalization of the Sema3A receptor, Npn1 and its co-receptor, L1CAM, while the ERM C-terminal domain binds and caps F-actin. Our data support a model in which ERMs can coordinate membrane and actin dynamics in response to Sema3A. PMID:18651636

  18. Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration.

    PubMed

    Louvi, Angeliki; Nishimura, Sayoko; Günel, Murat

    2014-03-01

    Loss of function of cerebral cavernous malformation 3 (CCM3) results in an autosomal dominant cerebrovascular disorder. Here, we uncover a developmental role for CCM3 in regulating neuronal migration in the neocortex. Using cell type-specific gene inactivation in mice, we show that CCM3 has both cell autonomous and cell non-autonomous functions in neural progenitors and is specifically required in radial glia and newly born pyramidal neurons migrating through the subventricular zone, but not in those migrating through the cortical plate. Loss of CCM3 function leads to RhoA activation, alterations in the actin and microtubule cytoskeleton affecting neuronal morphology, and abnormalities in laminar positioning of primarily late-born neurons, indicating CCM3 involvement in radial glia-dependent locomotion and possible interaction with the Cdk5/RhoA pathway. Thus, we identify a novel cytoplasmic regulator of neuronal migration and demonstrate that its inactivation in radial glia progenitors and nascent neurons produces severe malformations of cortical development. PMID:24595293

  19. Response characteristics of a low-dimensional model neuron.

    PubMed

    Cartling, B

    1996-11-15

    It is shown that a low-dimensional model neuron with a response time constant smaller than the membrane time constant closely reproduces the activity and excitability behavior of a detailed conductance-based model of Hodgkin-Huxley type. The fast response of the activity variable also makes it possible to reduce the model to a one-dimensional model, in particular for typical conditions. As an example, the reduction to a single-variable model from a multivariable conductance-based model of a neocortical pyramidal cell with somatic input is demonstrated. The conditions for avoiding a spurious damped oscillatory response to a constant input are derived, and it is shown that a limit-cycle response cannot occur. The capability of the low-dimensional model to approximate higher-dimensional models accurately makes it useful for describing complex dynamics of nets of interconnected neurons. The simplicity of the model facilitates analytic studies, elucidations of neurocomputational mechanisms, and applications to large-scale systems.

  20. Responses of Inferior Colliculus Neurons to Double Harmonic Tones

    PubMed Central

    Li, Hongzhe

    2008-01-01

    The auditory system can segregate sounds that overlap in time and frequency, if the sounds differ in acoustic properties such as fundamental frequency (f0). However, the neural mechanisms that underlie this ability are poorly understood. Responses of neurons in the inferior colliculus (IC) of the anesthetized chinchilla were measured. The stimuli were harmonic tones, presented alone (single harmonic tones) and in the presence of a second harmonic tone with a different f0 (double harmonic tones). Responses to single harmonic tones exhibited no stimulus-related temporal pattern, or in some cases, a simple envelope modulated at f0. Responses to double harmonic tones exhibited complex slowly modulated discharge patterns. The discharge pattern varied with the difference in f0 and with characteristic frequency. The discharge pattern also varied with the relative levels of the two tones; complex temporal patterns were observed when levels were equal, but as the level difference increased, the discharge pattern reverted to that associated with single harmonic tones. The results indicated that IC neurons convey information about simultaneous sounds in their temporal discharge patterns and that the patterns are produced by interactions between adjacent components in the spectrum. The representation is “low-resolution,” in that it does not convey information about single resolved components from either individual sound. PMID:17913991

  1. Neuronal response impedance mechanism implementing cooperative networks with low firing rates and μs precision.

    PubMed

    Vardi, Roni; Goldental, Amir; Marmari, Hagar; Brama, Haya; Stern, Edward A; Sardi, Shira; Sabo, Pinhas; Kanter, Ido

    2015-01-01

    Realizations of low firing rates in neural networks usually require globally balanced distributions among excitatory and inhibitory links, while feasibility of temporal coding is limited by neuronal millisecond precision. We show that cooperation, governing global network features, emerges through nodal properties, as opposed to link distributions. Using in vitro and in vivo experiments we demonstrate microsecond precision of neuronal response timings under low stimulation frequencies, whereas moderate frequencies result in a chaotic neuronal phase characterized by degraded precision. Above a critical stimulation frequency, which varies among neurons, response failures were found to emerge stochastically such that the neuron functions as a low pass filter, saturating the average inter-spike-interval. This intrinsic neuronal response impedance mechanism leads to cooperation on a network level, such that firing rates are suppressed toward the lowest neuronal critical frequency simultaneously with neuronal microsecond precision. Our findings open up opportunities of controlling global features of network dynamics through few nodes with extreme properties.

  2. Neuronal response impedance mechanism implementing cooperative networks with low firing rates and μs precision

    PubMed Central

    Vardi, Roni; Goldental, Amir; Marmari, Hagar; Brama, Haya; Stern, Edward A.; Sardi, Shira; Sabo, Pinhas; Kanter, Ido

    2015-01-01

    Realizations of low firing rates in neural networks usually require globally balanced distributions among excitatory and inhibitory links, while feasibility of temporal coding is limited by neuronal millisecond precision. We show that cooperation, governing global network features, emerges through nodal properties, as opposed to link distributions. Using in vitro and in vivo experiments we demonstrate microsecond precision of neuronal response timings under low stimulation frequencies, whereas moderate frequencies result in a chaotic neuronal phase characterized by degraded precision. Above a critical stimulation frequency, which varies among neurons, response failures were found to emerge stochastically such that the neuron functions as a low pass filter, saturating the average inter-spike-interval. This intrinsic neuronal response impedance mechanism leads to cooperation on a network level, such that firing rates are suppressed toward the lowest neuronal critical frequency simultaneously with neuronal microsecond precision. Our findings open up opportunities of controlling global features of network dynamics through few nodes with extreme properties. PMID:26124707

  3. Stimulus-induced response patterns of medium-embedded neurons

    NASA Astrophysics Data System (ADS)

    Postnov, D. E.; Chetverikov, A. P.; Postnov, D. D.

    2010-09-01

    Neuronal ensembles in living organisms are often embedded in a media that provides additional interaction pathways and autoregulation. The underlying mechanisms include but are not limited to modulatory activity of some distantly propagated neuromediators like serotonin, variation of extracellular potassium concentration in brain tissue, and calcium waves propagation in networks of astrocytes. Interaction of these diverse processes can lead to formation of complex spatiotemporal patterns, both self-sustained or triggered by external signal. Besides network effects, many dynamical features of such systems originate from reciprocal interaction between single neuron and surrounding medium. In the present paper we study the response of such systems to the application of a single stimulus pulse. We use a minimal mathematical model representing a forced excitable unit that is embedded in a diffusive or (spatially inhomogeneous) excitable medium. We illustrate three different mechanisms for the formation of response patterns: (i) self-sustained depolarization, (ii) propagation of depolarization due to “nearest-neighbor” networks, and (iii) re-entrant waves.

  4. 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice.

    PubMed

    Wang, Yaoming; Zhao, Zhen; Rege, Sanket V; Wang, Min; Si, Gabriel; Zhou, Yi; Wang, Su; Griffin, John H; Goldman, Steven A; Zlokovic, Berislav V

    2016-09-01

    Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation. On the basis of proof-of-concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate-receptor 1-Akt pathway, which suggests the potential for APC-based treatment as a strategy for structural repair in the human central nervous (CNS) system. Here we report that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs might offer a new approach to the treatment of stroke and related neurological disorders. PMID:27548576

  5. Aequorin response facilitation and intracellular calcium accumulation in molluscan neurones

    PubMed Central

    Smith, Stephen J.; Zucker, Robert S.

    1980-01-01

    1. When molluscan neural somata are filled with the calcium-indicating photo-protein aequorin and subjected to a 1 Hz train of depolarizing pulses (0·3 sec duration to + 15 mV) under voltage clamp, the successive photo-emissions due to calcium influx facilitate. The origin of this phenomenon was investigated in identified neurones from the abdominal ganglion of Aplysia californica. 2. Since outward currents inactivate cumulatively in successive pulses, the effective depolarization increases due to a series resistance error. Elimination of this error by electronic compensation or pharmacological block of outward current reduced aequorin response facilitation by only about 30%, on the average. 3. When voltage-dependent sodium and potassium currents are blocked in tetraethylammonium (TEA)-substituted zero-sodium sea water, the remaining inward calcium currents display no facilitation. On the contrary, a slow decline during a pulse and a slight progressive depression in successive pulses are observed. Barium-substitution for calcium in the same medium eliminates a small residual potassium current insensitive to external TEA. The remaining inward barium currents also display depression instead of facilitation. 4. A non-pharmacological separation of calcium current was accomplished by measuring tail currents at the potassium equilibrium potential following depolarizing pulses. Calcium tail currents activate rapidly and then decline gradually and incompletely as depolarizing pulse duration is lengthened. Tail currents also show no evidence of facilitation; there is instead a slight depression of currents after successive pulses. 5. Increments of optical absorbance in neurones filled with the calcium-sensitive dye arsenazo III show a depression rather than facilitation to successive depolarizations in a train. The time course of these absorbance signals is consistent with the time-dependent depression of calcium current. 6. Calibration of arsenazo III response amplitude

  6. Encoding of head acceleration in vestibular neurons. I. Spatiotemporal response properties to linear acceleration

    NASA Technical Reports Server (NTRS)

    Bush, G. A.; Perachio, A. A.; Angelaki, D. E.

    1993-01-01

    1. Extracellular recordings were made in and around the medial vestibular nuclei in decerebrated rats. Neurons were functionally identified according to their semicircular canal input on the basis of their responses to angular head rotations around the yaw, pitch, and roll head axes. Those cells responding to angular acceleration were classified as either horizontal semicircular canal-related (HC) or vertical semicircular canal-related (VC) neurons. The HC neurons were further characterized as either type I or type II, depending on the direction of rotation producing excitation. Cells that lacked a response to angular head acceleration, but exhibited sensitivity to a change in head position, were classified as purely otolith organ-related (OTO) neurons. All vestibular neurons were then tested for their response to sinusoidal linear translation in the horizontal head plane. 2. Convergence of macular and canal inputs onto central vestibular nuclei neurons occurred in 73% of the type I HC, 79% of the type II HC, and 86% of the VC neurons. Out of the 223 neurons identified as receiving macular input, 94 neurons were further studied, and their spatiotemporal response properties to sinusoidal stimulation with pure linear acceleration were quantified. Data were obtained from 33 type I HC, 22 type II HC, 22 VC, and 17 OTO neurons. 3. For each neuron the angle of the translational stimulus vector was varied by 15, 30, or 45 degrees increments in the horizontal head plane. In all tested neurons, a direction of maximum sensitivity was identified. An interesting difference among neurons was their response to translation along the direction perpendicular to that that produced the maximum response ("null" direction). For the majority of neurons tested, it was possible to evoke a nonzero response during stimulation along the null direction always had response phases that varied as a function of stimulus direction. 4. These spatiotemporal response properties were quantified in two

  7. Response of serotonergic caudal raphe neurons in relation to specific motor activities in freely moving cats.

    PubMed

    Veasey, S C; Fornal, C A; Metzler, C W; Jacobs, B L

    1995-07-01

    Serotonergic neuronal responses during three specific motor activities were studied in nuclei raphe obscurus (NRO) and raphe pallidus (NRP) of freely moving cats by means of extracellular single-unit recordings. Responses to treadmill-induced locomotion were primarily excitatory, with 21 of 24 neurons displaying increased firing rates, directly related to treadmill speed. Individual regression analyses determined three response patterns: maximal activation at low speed (0.25 m/sec), augmentation of neuronal activity only at high treadmill speed (0.77 m/sec), and a linear increase. A smaller fraction of NRO and NRP serotonergic neurons (6 of 27) also responded to hypercarbic ventilatory challenge with increased firing rates. The magnitude of neuronal response was dependent upon the fraction of inspired CO2 and was related to ventilatory motor output, specifically, inspiratory amplitude. A subgroup of neurons responsive to hypercarbia in wakefulness demonstrated significant reductions in neuronal response to hypercarbia in slow-wave sleep. Finally, unit activity for 12 of 29 cells increased in response to spontaneous feeding, displaying two distinct patterns of neuronal response in relation to onset and termination of feeding: rapid activation and deactivation versus a gradual increase and decrease. More than half of the cells studied under all three conditions were responsive to more than one motor task. These results indicate that serotonergic caudal raphe neurons are responsive to specific motor system challenges, with many neurons responsive to multiple motor tasks, and that the responsiveness of serotonergic neurons to at least one motor task, hypercarbic ventilatory challenge, is state dependent.

  8. Role of protein kinase C in the response of an isolated neuron to photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Bragin, D. E.; Kolosov, M. S.; Uzdensky, Anatoly B.

    2002-07-01

    The role of protein kinase C (PKC) in response of neuronal and glial cells to photosensitization with low concentration of sulphonated aluminium phthalocianine Photosens was investigated. Changes in neuron firing and in the structure of chromatin morphology of neuron and glial nuclei were studied using PKC activator 12-0-Tetradecanoylphorbol 13- acetate (TPA) or PKC inhibitors staurosporine, hypercinin or cheleythrine. Protein kinase C is shown to be involved in the neuronal and glial cell responses. Its activation by TPA decreased neuron lifetime, caused nucleus swelling characteristic for necrosis, strongly suppressed apoptotic death of glial cells, and induced gliosis. These effects were probably associated with PKC-induced Ca2+ entry into cytosol. The possible cell death mechanism in this case was nectosis. Inhibition of PK, oppositely, increased neuron lifetime and caused a moderate nucleus swelling. Cheleythrine exerted pro-apoptotic effect on the glial cells surrounding the neuron, whereas other PKC inhibitors, staurosporine and hypercini, suppressed apoptosis.

  9. Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges.

    PubMed

    Cheng, Aiwu; Yang, Ying; Zhou, Ye; Maharana, Chinmoyee; Lu, Daoyuan; Peng, Wei; Liu, Yong; Wan, Ruiqian; Marosi, Krisztina; Misiak, Magdalena; Bohr, Vilhelm A; Mattson, Mark P

    2016-01-12

    The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance. In models relevant to Huntington's disease and epilepsy, Sirt3(-/-) mice exhibit increased vulnerability of striatal and hippocampal neurons, respectively. SIRT3 deficiency results in hyperacetylation of several mitochondrial proteins, including superoxide dismutase 2 and cyclophilin D. Running wheel exercise increases the expression of Sirt3 in hippocampal neurons, which is mediated by excitatory glutamatergic neurotransmission and is essential for mitochondrial protein acetylation homeostasis and the neuroprotective effects of running. Our findings suggest that SIRT3 plays pivotal roles in adaptive responses of neurons to physiological challenges and resistance to degeneration. PMID:26698917

  10. Action of ethanol on responses to nicotine from cerebellar Purkinje neurons: relationship to methyllycaconitine (MLA) inhibition of nicotine responses.

    PubMed

    Yang, X; Criswell, H E; Breese, G R

    1999-08-01

    The effect of ethanol on responses to nicotine from rat cerebellar Purkinje neurons was investigated using extracellular single-unit recording. Systemic administration of ethanol initially enhanced the nicotine-induced inhibition from 50% of the Purkinje neurons. However, irrespective of whether there was an initial enhancement, systemic administration of ethanol antagonized the response to nicotine from the majority of Purkinje neurons. When varying ethanol concentrations were electro-osmotically applied to this neuronal cell type, the responses to nicotine (6/8) were enhanced when a low concentration of ethanol (40 mM) was in the pipette, whereas the majority of nicotine responses (10/11) were antagonized when a higher concentration of ethanol (160 mM) was applied to Purkinje neurons. Thus, the concentration of ethanol presented to the neuron seemed to explain the biphasic consequence of systemically administered ethanol on responses to nicotine. In order to determine whether ethanol affected a specific nACh receptor subtype containing the alpha-7 subunit, it was initially established that the nicotinic antagonists, alpha-bungarotoxin (alpha-BTX) and methyllycaconitine (MLA), which are associated with this subunit, had identical actions on responses to nicotine from Purkinje neurons. When MLA was tested against responses to nicotine from this cell type, MLA antagonized the response to nicotine from 45% (9/20) of the neurons tested. In a direct comparison of the action of ethanol to inhibit responses to nicotine with the action of MLA on the same Purkinje neuron, ethanol inhibited responses to nicotine on all neurons sensitive to MLA. However, ethanol also affected nicotine-induced neural changes from some Purkinje neurons not sensitive to MLA antagonism of nicotine. These data support the supposition that ethanol affects a nACh receptor subtype which has an alpha-7 subunit as well as other nACh receptor subtypes without this specific subunit.

  11. Responses of pigeon vestibulocerebellar neurons to optokinetic stimulation. I. Functional organization of neurons discriminating between translational and rotational visual flow.

    PubMed

    Wylie, D R; Kripalani, T; Frost, B J

    1993-12-01

    1. Extracellular recordings were made from 235 neurons in the vestibulocerebellum (VbC), including the flocculus (lateral VbC), nodulus (folium X), and ventral uvula (ventral folium IXc,d), of the anesthetized pigeon, in response to an optokinetic stimulus. 2. The optokinetic stimuli consisted of two black and white random-dot patterns that were back-projected onto two large tangent screens. The screens were oriented parallel to each other and placed on either side of the bird's head. The resultant stimulus covered the central 100 degrees x 100 degrees of each hemifield. The directional tuning characteristics of each unit were assessed by moving the largefield stimulus in 12 different directions, 30 degrees apart. The directional tuning curves were performed monocularly or binocularly. The binocular directional tuning curves were performed with the direction of motion the same in both eyes (in-phase; e.g., ipsi = upward, contra = upward) or with the direction of motion opposite in either eye (antiphase; e.g., ipsi = upward, contra = downward). 3. Mossy fiber units (n = 17) found throughout folia IXa,b and IXc,d had monocular receptive fields and exhibited direction selectivity in response to stimulation of either the ipsilateral (n = 12) or contralateral (n = 5) eye. None had binocular receptive fields. 4. The complex spike (CS) activity of 218 Purkinje cells in folia IXc,d and X exhibited direction selectivity in response to the large-field visual stimulus moving in one or both visual fields. Ninety-one percent of the cells had binocular receptive fields that could be classified into four groups: descent neurons (n = 112) preferred upward motion in both eyes; ascent neurons (n = 14) preferred downward motion in both eyes; roll neurons (n = 33) preferred upward and downward motion in the ipsilateral and contralateral eyes, respectively; and yaw neurons (n = 40) preferred forward and backward motion in the ipsilateral and contralateral eyes, respectively. Within all

  12. Wingless-type family member 3A triggers neuronal polarization via cross-activation of the insulin-like growth factor-1 receptor pathway

    PubMed Central

    Bernis, María E.; Oksdath, Mariana; Dupraz, Sebastián; Nieto Guil, Alvaro; Fernández, Marisa M.; Malchiodi, Emilio L.; Rosso, Silvana B.; Quiroga, Santiago

    2013-01-01

    Initial axonal elongation is essential for neuronal polarization and requires polarized activation of IGF-1 receptors (IGF-1r) and the phosphatidylinositol 3 kinase (PI3k) pathway. Wingless-type family growth factors (Wnts) have also been implied in the regulation of axonal development. It is not known, however, if Wnts have any participation in the regulation of initial axonal outgrowth and the establishment of neuronal polarity. We used cultured hippocampal neurons and growth cone particles (GCPs) isolated from fetal rat brain to show that stimulation with the wingless family factor 3A (Wnt3a) was sufficient to promote neuronal polarization in the absence of IGF-1 or high insulin. We also show that Wnt3a triggered a strong activation of IGF-1r, PI3k, and Akt in developmental Stage 2 neurons and that the presence of activatable IGF-1r and PI3k activation were necessary for Wnt3a polarizing effects. Surface plasmon resonance (SPR) experiments show that Wnt3a did not bind specifically to the IGF-1r. Using crosslinking and immuno-precipitation experiments, we show that stimulation with Wnt3a triggered the formation of a complex including IGF-1r-Wnt3a-Frizzled-7. We conclude that Wnt3a triggers polarization of neurons via cross-activation of the IGF-1r/PI3k pathway upon binding to Fz7. PMID:24298236

  13. A neuron-benign microfluidic gradient generator for studying the response of mammalian neurons towards axon guidance factors.

    PubMed

    Bhattacharjee, Nirveek; Li, Nianzhen; Keenan, Thomas M; Folch, Albert

    2010-11-01

    Investigation of biochemical cues in isolation or in combinations in cell culture systems is crucial for unraveling the mechanisms that govern neural development and repair. The most widely used experimental paradigms that elicit axon guidance in vitro utilize as the source of the gradient a pulsatile pipette, transfected cells, or a loaded gel, producing time-varying gradients of poor reproducibility which are not well suited for studying slow-growing mammalian cells. Although microfluidic device design have allowed for generating stable, complex gradients of diffusible molecules, the flow-induced shear forces in a microchannel has made it impossible to maintain viable mammalian neuronal cultures for sufficiently long times. In this paper, we describe axonal responses of mouse cortical neurons in a "neuron-benign" gradient-generator device based on an open chamber that can establish highly stable gradients of diffusible molecules for at least 6 h with negligible shear stress, and also allows the neurons to thrive for at least 2 weeks. Except for the period when the gradient is on, the cells in the gradient are under the same conditions as the cells on the control surfaces, which ensure a consistent set of micro-environmental variables. The gradient stability and uniformity over the cell culture surface achieved by the device, together with our software platform for acquiring, post-processing and quantitatively analyzing the large number of images allowed us to extract valuable information even from small datasets. We report a directed response of primary mammalian neurons (from E14 embryonic mice cortex) to a diffusible gradient of netrin in vitro. We infer from our studies that a large majority (∼73%) of the neurons that extend axons during the gradient application grow towards the netrin source, and our data analysis also indicates that netrin acts as a growth factor for this same population of neurons.

  14. Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response.

    PubMed

    Jansen, A S; Nguyen, X V; Karpitskiy, V; Mettenleiter, T C; Loewy, A D

    1995-10-27

    During stress, the activity of the sympathetic nervous system is changed in a global fashion, leading to an increase in cardiovascular function and a release of adrenal catecholamines. This response is thought to be regulated by a common set of brain neurons that provide a dual input to the sympathetic preganglionic neurons regulating cardiac and adrenal medullary functions. By using a double-virus transneuronal labeling technique, the existence of such a set of central autonomic neurons in the hypothalamus and brainstem was demonstrated. These neurons innervate both of the sympathetic outflow systems and likely function in circumstances where parallel sympathetic processing occurs, such as in the fight-or-flight response.

  15. Manipulation of an Innate Escape Response in Drosophila: Photoexcitation of acj6 Neurons Induces the Escape Response

    PubMed Central

    Manoli, Devanand S.; Zhang, Feng; Deisseroth, Karl; Baker, Bruce S.; Scott, Matthew P.

    2009-01-01

    Background The genetic analysis of behavior in Drosophila melanogaster has linked genes controlling neuronal connectivity and physiology to specific neuronal circuits underlying a variety of innate behaviors. We investigated the circuitry underlying the adult startle response, using photoexcitation of neurons that produce the abnormal chemosensory jump 6 (acj6) transcription factor. This transcription factor has previously been shown to play a role in neuronal pathfinding and neurotransmitter modality, but the role of acj6 neurons in the adult startle response was largely unknown. Principal Findings We show that the activity of these neurons is necessary for a wild-type startle response and that excitation is sufficient to generate a synthetic escape response. Further, we show that this synthetic response is still sensitive to the dose of acj6 suggesting that that acj6 mutation alters neuronal activity as well as connectivity and neurotransmitter production. Results/Significance These results extend the understanding of the role of acj6 and of the adult startle response in general. They also demonstrate the usefulness of activity-dependent characterization of neuronal circuits underlying innate behaviors in Drosophila, and the utility of integrating genetic analysis into modern circuit analysis techniques. PMID:19340304

  16. KIF3C and KIF3A Form a Novel Neuronal Heteromeric Kinesin That Associates with Membrane Vesicles

    PubMed Central

    Muresan, Virgil; Abramson, Tatiana; Lyass, Asya; Winter, Dirk; Porro, Elena; Hong, Filbert; Chamberlin, Nancy L.; Schnapp, Bruce J.

    1998-01-01

    We have cloned from rat brain the cDNA encoding an 89,828-Da kinesin-related polypeptide KIF3C that is enriched in brain, retina, and lung. Immunocytochemistry of hippocampal neurons in culture shows that KIF3C is localized to cell bodies, dendrites, and, in lesser amounts, to axons. In subcellular fractionation experiments, KIF3C cofractionates with a distinct population of membrane vesicles. Native KIF3C binds to microtubules in a kinesin-like, nucleotide-dependent manner. KIF3C is most similar to mouse KIF3B and KIF3A, two closely related kinesins that are normally present as a heteromer. In sucrose density gradients, KIF3C sediments at two distinct densities, suggesting that it may be part of two different multimolecular complexes. Immunoprecipitation experiments show that KIF3C is in part associated with KIF3A, but not with KIF3B. Unlike KIF3B, a significant portion of KIF3C is not associated with KIF3A. Consistent with these biochemical properties, the distribution of KIF3C in the CNS has both similarities and differences compared with KIF3A and KIF3B. These results suggest that KIF3C is a vesicle-associated motor that functions both independently and in association with KIF3A. PMID:9487132

  17. The role of action potentials in determining neuron-type-specific responses to nitric oxide.

    PubMed

    Estes, Stephen; Zhong, Lei Ray; Artinian, Liana; Tornieri, Karine; Rehder, Vincent

    2015-05-01

    The electrical activity in developing and mature neurons determines the intracellular calcium concentration ([Ca(2+)]i), which in turn is translated into biochemical activities through various signaling cascades. Electrical activity is under control of neuromodulators, which can alter neuronal responses to incoming signals and increase the fidelity of neuronal communication. Conversely, the effects of neuromodulators can depend on the ongoing electrical activity within target neurons; however, these activity-dependent effects of neuromodulators are less well understood. Here, we present evidence that the neuronal firing frequency and intrinsic properties of the action potential (AP) waveform set the [Ca(2+)]i in growth cones and determine how neurons respond to the neuromodulator nitric oxide (NO). We used two well-characterized neurons from the freshwater snail Helisoma trivolvis that show different growth cone morphological responses to NO: B5 neurons elongate filopodia, while those of B19 neurons do not. Combining whole-cell patch clamp recordings with simultaneous calcium imaging, we show that the duration of an AP contributes to neuron-specific differences in [Ca(2+)]i, with shorter APs in B19 neurons yielding lower growth cone [Ca(2+)]i. Through the partial inhibition of voltage-gated K(+) channels, we increased the B19 AP duration resulting in a significant increase in [Ca(2+)]i that was then sufficient to cause filopodial elongation following NO treatment. Our results demonstrate a neuron-type specific correlation between AP shape, [Ca(2+)]i, and growth cone motility, providing an explanation to how growth cone responses to guidance cues depend on intrinsic electrical properties and helping explain the diverse effects of NO across neuronal populations.

  18. Biophysical properties and responses to glutamate receptor agonists of identified subpopulations of rat geniculate ganglion neurons.

    PubMed

    King, M S; Bradley, R M

    2000-06-01

    The goal of the current study was to evaluate the electrophysiological properties and responses to glutamate receptor agonists of rat geniculate ganglion (GG) neurons innervating the tongue. Subpopulations of GG neurons were labeled by injecting Fluoro-Gold (FG) or True Blue chloride into the anterior tongue and soft palate (AT and SP neurons) and applying FG crystals to the posterior auricular branch of the facial nerve (PA neurons). Three to 12 days later, the GG neurons were acutely isolated and patch clamped. Although many biophysical properties of the AT, SP and PA neurons were similar, significant differences were found among these groups in properties related to cell excitability. For example, the average amount of current necessary to elicit an action potential was 61 pA in AT neurons (n=55), 90 pA in SP neurons (n=41) and 189 pA in PA neurons (n=35, P<0.001). In addition, AT neurons tended to fire significantly more action potentials during depolarization as well as following hyperpolarizing pulses than SP or PA neuron types. Most GG neurons responded to application of glutamate receptor agonists. The neurons responded with a depolarization accompanied by a reduction in input resistance. These results suggest that subpopulations of neurons in the geniculate ganglion have distinct biophysical properties and express functional glutamate receptors. The differing biophysical properties of GG neurons is possibly related to their functional heterogeneity and glutaminergic neurotransmission may function in the processing of gustatory, and other sensory information, within the geniculate ganglion and its projections. PMID:10825499

  19. Responses of efferent octopaminergic thoracic unpaired median neurons in the locust to visual and mechanosensory signals.

    PubMed

    Field, Laurence H; Duch, Carsten; Pflüger, Hans-Joachim

    2008-01-01

    Insect thoracic ganglia contain efferent octopaminergic unpaired median neurons (UM neurons) located in the midline, projecting bilaterally and modulating neuromuscular transmission, muscle contraction kinetics, sensory sensitivity and muscle metabolism. In locusts, these neurons are located dorsally or ventrally (DUM- or VUM-neurons) and divided into functionally different sub-populations activated during different motor tasks. This study addresses the responsiveness of locust thoracic DUM neurons to various sensory stimuli. Two classes of sense organs, cuticular exteroreceptor mechanosensilla (tactile hairs and campaniform sensilla), and photoreceptors (compound eyes and ocelli) elicited excitatory reflex responses. Chordotonal organ joint receptors caused no responses. The tympanal organ (Müller's organ) elicited weak excitatory responses most likely via generally increased network activity due to increased arousal. Vibratory stimuli to the hind leg subgenual organ never elicited responses. Whereas DUM neurons innervating wing muscles are not very responsive to sensory stimulation, those innervating leg and other muscles are very responsive to stimulation of exteroreceptors and hardly responsive to stimulation of proprioceptors. After cutting both cervical connectives all mechanosensory excitation is lost, even for sensory inputs from the abdomen. This suggests that, in contrast to motor neurons, the sensory inputs to octopaminergic efferent neuromodulatory cells are pre-processed in the suboesophageal ganglion. PMID:18021797

  20. Propensity to obesity impacts the neuronal response to energy imbalance.

    PubMed

    Cornier, Marc-Andre; McFadden, Kristina L; Thomas, Elizabeth A; Bechtell, Jamie L; Bessesen, Daniel H; Tregellas, Jason R

    2015-01-01

    The mechanisms responsible for the propensity to gain weight or remain normal weight are poorly understood. The objective of this study was to study the neuronal response to visual food cues during short-term energy imbalance in healthy adults recruited as obesity-resistant (OR) or obesity-prone (OP) based on self-identification, body mass index, and personal/family weight history. Twenty-five OR and 28 OP subjects were studied in underfed (UF) and overfed (OF) as compared to eucaloric (EU) conditions in a randomized crossover design. Each study phase included a 3-day run-in diet, 1 day of controlled feeding (basal energy needs for EU, 40% above/below basal energy needs for OF/UF), and a test day. On the test day, fMRI was performed in the acute fed stated (30 min after a test meal) while subjects viewed images of foods of high hedonic value and neutral non-food objects. Measures of appetite and hormones were also performed before and every 30 min after the test meal. UF was associated with significantly increased activation of insula, somatosensory cortex, inferior and medial prefrontal cortex (PFC), parahippocampus, precuneus, cingulate, and visual cortex in OR. However, UF had no impact in OP. As a result, UF was associated with significantly greater activation, specifically in the insula, inferior PFC, and somatosensory cortex in OR as compared to OP. While OF was overall associated with reduced activation of inferior visual cortex, no group interaction was observed with OF. In summary, these findings suggest that individuals resistant to weight gain and obesity are more sensitive to short-term energy imbalance, particularly with UF, than those prone to weight gain. The inability to sense or adapt to changes in energy balance may represent an important mechanism contributing to excess energy intake and risk for obesity. PMID:25767441

  1. Propensity to Obesity Impacts the Neuronal Response to Energy Imbalance

    PubMed Central

    Cornier, Marc-Andre; McFadden, Kristina L.; Thomas, Elizabeth A.; Bechtell, Jamie L.; Bessesen, Daniel H.; Tregellas, Jason R.

    2015-01-01

    The mechanisms responsible for the propensity to gain weight or remain normal weight are poorly understood. The objective of this study was to study the neuronal response to visual food cues during short-term energy imbalance in healthy adults recruited as obesity-resistant (OR) or obesity-prone (OP) based on self-identification, body mass index, and personal/family weight history. Twenty-five OR and 28 OP subjects were studied in underfed (UF) and overfed (OF) as compared to eucaloric (EU) conditions in a randomized crossover design. Each study phase included a 3-day run-in diet, 1 day of controlled feeding (basal energy needs for EU, 40% above/below basal energy needs for OF/UF), and a test day. On the test day, fMRI was performed in the acute fed stated (30 min after a test meal) while subjects viewed images of foods of high hedonic value and neutral non-food objects. Measures of appetite and hormones were also performed before and every 30 min after the test meal. UF was associated with significantly increased activation of insula, somatosensory cortex, inferior and medial prefrontal cortex (PFC), parahippocampus, precuneus, cingulate, and visual cortex in OR. However, UF had no impact in OP. As a result, UF was associated with significantly greater activation, specifically in the insula, inferior PFC, and somatosensory cortex in OR as compared to OP. While OF was overall associated with reduced activation of inferior visual cortex, no group interaction was observed with OF. In summary, these findings suggest that individuals resistant to weight gain and obesity are more sensitive to short-term energy imbalance, particularly with UF, than those prone to weight gain. The inability to sense or adapt to changes in energy balance may represent an important mechanism contributing to excess energy intake and risk for obesity. PMID:25767441

  2. Postnatal developmental changes in the responses of mouse primary vestibular neurons to externally applied galvanic currents.

    PubMed

    Desmadryl, G

    1991-12-17

    The ontogenesis of vestibular primary neuron sensitivity to depolarisation produced by galvanic current stimulations was studied in mouse inner ear explants maintained in vitro. Cathodal galvanic stimulations, which elicit an increase of the discharge frequencies, are assumed to act on the spike initiation site by depolarizing the neuron. The responses of neurons to galvanic currents at various developmental stages were recorded. The pattern of responses reflected the sensitivities of the neurons to depolarization. At birth, about 75% of the vestibular neurons responded weakly to high intensity galvanic currents thus indicating that they were able to generate action potentials. However, the very low gain of the response to the stimulation revealed the immaturity of the neurons at the spike generation site. Between the day of birth and the ninth postnatal day, an increase in the gain of the responses was observed, indicating the enhancement of the sensitivity of the vestibular neurons to the galvanic currents. This increase in sensitivity was more pronounced from the fourth postnatal day. The response of the neurons to galvanic stimulation increased gradually during postnatal development without reaching a plateau at postnatal day 9 indicating that a further physiological maturation occurs after this stage. These results are consistent with the morphological maturation of the vestibular primary afferents and with previous studies showing that the physiological maturation parallels myelination of the afferent fibers.

  3. Responses of inferior collicular neurones of bats to tone bursts with different rise times

    PubMed Central

    Suga, N.

    1971-01-01

    1. A study was made of the responses of single neurones in the inferior colliculus of bats to tone bursts with different rise times (or with different rates of amplitude increase) in order to determine whether the neurones were specialized for analysis of amplitude-modulated sound, especially the rising phase in amplitude. 2. The response patterns of neurones which showed phasic on-responses usually did not change with rise time, although the response patterns of some neurones changed from phasic on-responses to inhibitory responses. 3. The thresholds of responses to tone bursts increased when the rise time was lengthened. The amount of increase greatly differed from neurone to neurone. For the excitation of neurones which showed a large increase in threshold, the stimulus amplitude should quickly increase in amplitude. For tone bursts with a short rise time, some neurones showed an upper-threshold above which the sounds failed to excite them. The upper-threshold usually disappeared when the rise time was lengthened. For the excitation of neurones which showed an upper-threshold, the rate of amplitude increase and its extent were very important parameters. 4. Lengthening the rise time of a tone burst from 0·5 to 98 msec caused various types of change in the excitatory area. In some cases, there was a diminution of the area and, in others, there was an expansion of the area. Neurones showing these changes may be considered to be specialized for responding to tone bursts with either a rapid or slow increase in amplitude. 5. Changes with rise time occurred not only in the excitatory area, but also in the inhibitory area. The change in the inhibitory area of a given neurone, however, was not necessarily the same as that in the excitatory area. 6. The latency of response usually changed as a function of stimulus amplitude and rise time. In 26% of the neurones studied, however, the latency was relatively constant regardless of stimulus amplitude and rise time. Some of

  4. Leptin activates cytosolic calcium responses through protein kinase-C dependent mechanism in immortalized RFamide-related peptide-3 neurons.

    PubMed

    Ozcan, Mete; Saatci, Tugrul; Ayar, Ahmet; Canpolat, Sinan; Kelestimur, Haluk

    2015-03-19

    RFamide-related peptide-3 (RFRP-3), a mammalian ortholog of avian gonadotropin-inhibitory hormone (GnIH), seems to be an important regulator of the hypothalamus-pituitary-gonadal (HPG) reproductive axis. Leptin, a permissive hormonal regulator of fertility, provides energy signal to brain. According to current view, leptin does not act directly on gonadotrophin-releasing hormone (GnRH) neurons. RFRP-3 neurons have been shown to express leptin receptors. The goal of the present study was to examine whether leptin acts through RFRP-3 neurons to modulate activity of the GnRH neurons. For this aim, the effects of leptin on intracellular free Ca(2+) levels ([Ca(2+)]i) in RFRP-3 neurons were investigated by using in vitro calcium imaging system. In the present study, rHypoE-7 cell line was used as a model to explore the effects of leptin on RFRP-3 neurons. rHypoE-7 cells were placed on glass coverslip and loaded with 1 μM Fura-2 AM. [Ca(2+)]i responses were quantified by the changes in 340/380 ratio. Leptin (0.1-10 μM) caused increases in [Ca(2+)]i in a dose-dependent manner. The changes in [Ca(2+)]i were significantly attenuated by pre-treatment with protein kinase C inhibitor. These results demonstrate that leptin activates intracellular calcium signaling in RFRP-3 neurons through PKC-dependent pathway, and thus leptin may exert its effect on GnRH neurons by means of RFRP-3 cells.

  5. Prokineticin-2 upregulation during neuronal injury mediates a compensatory protective response against dopaminergic neuronal degeneration

    PubMed Central

    Gordon, Richard; Neal, Matthew L.; Luo, Jie; Langley, Monica R.; Harischandra, Dilshan S.; Panicker, Nikhil; Charli, Adhithiya; Jin, Huajun; Anantharam, Vellareddy; Woodruff, Trent M.; Zhou, Qun-Yong; Kanthasamy, Anumantha G.; Kanthasamy, Arthi

    2016-01-01

    Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson's disease (PD), including PK2 reporter mice and MitoPark mice. Functional studies demonstrate that PK2 promotes mitochondrial biogenesis and activates ERK and Akt survival signalling pathways, thereby driving neuroprotection. Importantly, PK2 overexpression is protective whereas PK2 receptor antagonism exacerbates dopaminergic degeneration in experimental PD. Furthermore, PK2 expression increased in surviving nigral dopaminergic neurons from PD brains, indicating that PK2 upregulation is clinically relevant to human PD. Collectively, our results identify a paradigm for compensatory neuroprotective PK2 signalling in nigral dopaminergic neurons that could have important therapeutic implications for PD. PMID:27703142

  6. Specific responses of human hippocampal neurons are associated with better memory

    PubMed Central

    Suthana, Nanthia A.; Parikshak, Neelroop N.; Ekstrom, Arne D.; Ison, Matias J.; Knowlton, Barbara J.; Bookheimer, Susan Y.; Fried, Itzhak

    2015-01-01

    A population of human hippocampal neurons has shown responses to individual concepts (e.g., Jennifer Aniston) that generalize to different instances of the concept. However, recordings from the rodent hippocampus suggest an important function of these neurons is their ability to discriminate overlapping representations, or pattern separate, a process that may facilitate discrimination of similar events for successful memory. In the current study, we explored whether human hippocampal neurons can also demonstrate the ability to discriminate between overlapping representations and whether this selectivity could be directly related to memory performance. We show that among medial temporal lobe (MTL) neurons, certain populations of neurons are selective for a previously studied (target) image in that they show a significant decrease in firing rate to very similar (lure) images. We found that a greater proportion of these neurons can be found in the hippocampus compared with other MTL regions, and that memory for individual items is correlated to the degree of selectivity of hippocampal neurons responsive to those items. Moreover, a greater proportion of hippocampal neurons showed selective firing for target images in good compared with poor performers, with overall memory performance correlated with hippocampal selectivity. In contrast, selectivity in other MTL regions was not associated with memory performance. These findings show that a substantial proportion of human hippocampal neurons encode specific memories that support the discrimination of overlapping representations. These results also provide previously unidentified evidence consistent with a unique role of the human hippocampus in orthogonalization of representations in declarative memory. PMID:26240357

  7. [Response characteristics of neurons to tone in dorsal nucleus of the lateral lemniscus of the mouse].

    PubMed

    Si, Wen-Juan; Cheng, Yan-Ling; Yang, Dan-Dan; Wang, Xin

    2016-02-25

    The dorsal nucleus of lateral lemniscus (DNLL) is a nucleus in the auditory ascending pathway, and casts inhibitory efferent projections to the inferior colliculus. Studies on the DNLL are less than studies on the auditory brain stem and inferior colliculus. To date, there is no information about response characteristics of neurons in DNLL of albino mouse. Under free field conditions, we used extracellular single unit recording to study the acoustic signal characteristics of DNLL neurons in Kunming mice (Mus musculus). Transient (36%) and ongoing (64%) firing patterns were found in 96 DNLL neurons. Neurons with different firing patterns have significant differences in characteristic frequency and minimal threshold. We recorded frequency tuning curves (FTCs) of 87 DNLL neurons. All of the FTCs exhibit an open "V" shape. There is no significant difference in FTCs between transient and ongoing neurons, but among the ongoing neurons, the FTCs of sustained neurons are sharper than those of onset plus sustained neurons and pauser neurons. Our results showed that the characteristic frequency of DNLL neurons of mice was not correlated with depth, supporting the view that the DNLL of mouse has no frequency topological organization through dorsal-ventral plane, which is different from cats and some other animals. Furthermore, by using rate-intensity function (RIF) analysis the mouse DNLL neurons can be classified as monotonic (60%), saturated (31%) and non-monotonic (8%) types. Each RIF type includes transient and ongoing firing patterns. Dynamic range of the transient firing pattern is smaller than that of ongoing firing ones (P < 0.01), suggesting that the inhibitory inputs may underlie the formation of transient firing pattern. Multiple firing patterns and intensity coding of DNLL neurons may derive from the projections from multiple auditory nuclei, and play different roles in auditory information processing. PMID:26915316

  8. [Response characteristics of neurons to tone in dorsal nucleus of the lateral lemniscus of the mouse].

    PubMed

    Si, Wen-Juan; Cheng, Yan-Ling; Yang, Dan-Dan; Wang, Xin

    2016-02-25

    The dorsal nucleus of lateral lemniscus (DNLL) is a nucleus in the auditory ascending pathway, and casts inhibitory efferent projections to the inferior colliculus. Studies on the DNLL are less than studies on the auditory brain stem and inferior colliculus. To date, there is no information about response characteristics of neurons in DNLL of albino mouse. Under free field conditions, we used extracellular single unit recording to study the acoustic signal characteristics of DNLL neurons in Kunming mice (Mus musculus). Transient (36%) and ongoing (64%) firing patterns were found in 96 DNLL neurons. Neurons with different firing patterns have significant differences in characteristic frequency and minimal threshold. We recorded frequency tuning curves (FTCs) of 87 DNLL neurons. All of the FTCs exhibit an open "V" shape. There is no significant difference in FTCs between transient and ongoing neurons, but among the ongoing neurons, the FTCs of sustained neurons are sharper than those of onset plus sustained neurons and pauser neurons. Our results showed that the characteristic frequency of DNLL neurons of mice was not correlated with depth, supporting the view that the DNLL of mouse has no frequency topological organization through dorsal-ventral plane, which is different from cats and some other animals. Furthermore, by using rate-intensity function (RIF) analysis the mouse DNLL neurons can be classified as monotonic (60%), saturated (31%) and non-monotonic (8%) types. Each RIF type includes transient and ongoing firing patterns. Dynamic range of the transient firing pattern is smaller than that of ongoing firing ones (P < 0.01), suggesting that the inhibitory inputs may underlie the formation of transient firing pattern. Multiple firing patterns and intensity coding of DNLL neurons may derive from the projections from multiple auditory nuclei, and play different roles in auditory information processing.

  9. Immature Responses to GABA in Fragile X Neurons Derived from Human Embryonic Stem Cells

    PubMed Central

    Telias, Michael; Segal, Menahem; Ben-Yosef, Dalit

    2016-01-01

    Fragile X Syndrome (FXS) is the most common form of inherited cognitive disability. However, functional deficiencies in FX neurons have been described so far almost exclusively in animal models. In a recent study we found several functional deficits in FX neurons differentiated in-vitro from human embryonic stem cells (hESCs), including their inability to fire repetitive action potentials, and their lack of synaptic activity. Here, we investigated the responses of such neurons to pulse application of the neurotransmitter GABA. We found two distinct types of responses to GABA and sensitivity to the GABA-A receptor antagonist bicuculline; type 1 (mature) characterized by non-desensitized responses to GABA as well as a high sensitivity to bicuculline, and type 2 (immature) which are desensitized to GABA and insensitive to bicuculline. Type 1 responses were age-dependent and dominant in mature WT neurons. In contrast, FX neurons expressed primarily type 2 phenotype. Expression analysis of GABA-A receptor subunits demonstrated that this bias in human FX neurons was associated with a significant alteration in the expression pattern of the GABA-A receptor subunits α2 and β2. Our results indicate that FMRP may play a role in the development of the GABAergic synapse during neurogenesis. This is the first demonstration of the lack of a mature response to GABA in human FX neurons and may explain the inappropriate synaptic functions in FXS. PMID:27242433

  10. Responses of descending neurons to looming stimuli in the praying mantis Tenodera aridifolia.

    PubMed

    Yamawaki, Yoshifumi; Toh, Yoshihiro

    2009-03-01

    Responses to visual stimuli of some neurons that descend the nerve cord from the brain were recorded extracellularly in the mantis Tenodera aridifolia. Most of the recorded neurons showed their largest responses to looming stimuli that simulated a black circle approaching towards the mantis. The neurons showed a transient excitatory response to a gradually darkening or receding circle. The neurons showed sustained excitation to the linearly expanding stimuli, but the spike frequency decreased rapidly. The responses of the neurons were affected by both the diameter and the speed of looming stimuli. Faster or smaller looming stimuli elicited a higher peak frequency. These responses were observed in both recordings from the connective between suboesophageal and prothoracic ganglia and the connective between prothoracic and mesothoracic ganglia. There was a one-to-one correspondence of spike firing between these two recordings with a fixed delay. The neurons had the receptive field on ipsilateral side to its axon at the cervical connective. These results suggest that there is a looming-sensitive descending neuron, with an axon projecting over prothoracic ganglion, in the mantis nervous system. PMID:19093123

  11. Descending brain neurons in the cricket Gryllus bimaculatus (de Geer): auditory responses and impact on walking.

    PubMed

    Zorović, Maja; Hedwig, Berthold

    2013-01-01

    The activity of four types of sound-sensitive descending brain neurons in the cricket Gryllus bimaculatus was recorded intracellularly while animals were standing or walking on an open-loop trackball system. In a neuron with a contralaterally descending axon, the male calling song elicited responses that copied the pulse pattern of the song during standing and walking. The accuracy of pulse copying increased during walking. Neurons with ipsilaterally descending axons responded weakly to sound only during standing. The responses were mainly to the first pulse of each chirp, whereas the complete pulse pattern of a chirp was not copied. During walking the auditory responses were suppressed in these neurons. The spiking activity of all four neuron types was significantly correlated to forward walking velocity, indicating their relevance for walking. Additionally, injection of depolarizing current elicited walking and/or steering in three of four neuron types described. In none of the neurons was the spiking activity both sufficient and necessary to elicit and maintain walking behaviour. Some neurons showed arborisations in the lateral accessory lobes, pointing to the relevance of this brain region for cricket audition and descending motor control.

  12. Concentration dependent requirement for local protein synthesis in motor neuron subtype specific response to axon guidance cues

    PubMed Central

    Nedelec, Stephane; Peljto, Mirza; Shi, Peng; Amoroso, Mackenzie W.; Kam, Lance C.; Wichterle, Hynek

    2012-01-01

    Formation of functional motor circuits relies on the ability of distinct spinal motor neuron subtypes to project their axons with high precision to appropriate muscle targets. While guidance cues contributing to motor axon pathfinding have been identified, the intracellular pathways underlying subtype specific responses to these cues remain poorly understood. In particular, it remains controversial whether responses to axon guidance cues depend on axonal protein synthesis. Using a growth cone collapse assay, we demonstrate that mouse embryonic stem cell (ESC) derived spinal motor neurons (ES-MNs) respond to ephrin-A5, Sema3f and Sema3a in a concentration dependent manner. At low doses, ES-MNs exhibit segmental or subtype specific responses, while this selectivity is lost at higher concentrations. Response to high doses of semaphorins and to all doses of ephrin-A5 is protein synthesis independent. In contrast, using microfluidic devices and stripe assays, we show that growth cone collapse and guidance at low concentrations of semaphorins relies on local protein synthesis in the axonal compartment. Similar bimodal response to low and high concentrations of guidance cues is observed in human ES-MNs, pointing to a general mechanism by which neurons increase their repertoire of responses to the limited set of guidance cues involved in neural circuit formation. PMID:22279234

  13. Ionotropic NMDA receptor evokes an excitatory response in superior salivatory nucleus neurons in anaesthetized rats.

    PubMed

    Oskutyte, Diana; Ishizuka, Ken'Ichi; Satoh, Yoshihide; Murakami, Toshiki

    2004-02-27

    Extracellular recordings were taken from preganglionic superior salivatory nucleus (SSN) neurons projecting to submandibular and intra-lingual ganglia, in order to study the action of SSN neurons resulting from ionophoretic application of ionotropic NMDA receptor agonist in urethane-chloralose anaesthetized rats. Single SSN neurons were identified by their antidromic spike responses following stimulation of the chorda-lingual nerve (CLN), chorda tympani branches (CTBs) and the lingual nerve (LN). About one-third (33%, 10/30) of the identified SSN neurons were induced to fire by ionophoretic application of the NMDA receptor agonists used, dl-homocysteic acid (DLH) and N-methyl-D-aspartic acid (NMDA). More than half exhibited firing at high frequencies, often exceeding 40 Hz. About one-fifth (20%; 6/30) of the identified SSN neurons exhibited orthodromic spike responses to the combination of NMDA receptor agonist application and sensory nerve (CLN or LN) stimulus. These excitatory responses evoked by application of NMDA receptor agonist were attenuated (n = 4) by ionophoretic application of DL-2-amino-5-phosphonovaleric acid (AP5; NMDA receptor antagonist). About half (47%) of the neurons did not respond to any combination of NMDA receptor agonist and sensory nerve stimuli. No differences were observed between SSN neurons with B fibre axons and those with C fibre axons in response to ionophoresis of the NMDA receptor agonists. The NMDA-sensitive neurons, which exhibited high frequency firing, were predominantly found in the rostral part of the SSN. In summary, activation of ionotropic NMDA receptors exerts an excitatory effect on about half of the SSN neurons. These data support the view that NMDA receptors are involved in information processing and transmission on SSN neurons.

  14. Prolonged wakefulness alters neuronal responsiveness to local electrical stimulation of the neocortex in awake rats

    PubMed Central

    Vyazovskiy, Vladyslav V.; Olcese, Umberto; Cirelli, Chiara; Tononi, Giulio

    2012-01-01

    Summary Prolonged wakefulness or a lack of sleep lead to cognitive deficits, but little is known about the underlying cellular mechanisms. We recently found that sleep deprivation affects spontaneous neuronal activity in the neocortex of sleeping and awake rats. While it is well known that synaptic responses are modulated by ongoing cortical activity, it remains unclear whether prolonged waking affects responsiveness of cortical neurons to incoming stimuli. By applying local electrical microstimulation to the frontal area of the neocortex, we found that after a 4-hour period of waking the initial neuronal response in the contralateral frontal cortex was stronger and more synchronous, and was followed by a more profound inhibition of neuronal spiking as compared to the control condition. These changes in evoked activity suggest increased neuronal excitability and indicate that after staying awake cortical neurons become transiently bistable. We propose that some of the detrimental effects of sleep deprivation may be a result of altered neuronal responsiveness to incoming intrinsic and extrinsic inputs. PMID:23607417

  15. Frequency response properties of primary afferent neurons in the posterior lateral line system of larval zebrafish

    PubMed Central

    Levi, Rafael; Akanyeti, Otar; Ballo, Aleksander

    2014-01-01

    The ability of fishes to detect water flow with the neuromasts of their lateral line system depends on the physiology of afferent neurons as well as the hydrodynamic environment. Using larval zebrafish (Danio rerio), we measured the basic response properties of primary afferent neurons to mechanical deflections of individual superficial neuromasts. We used two types of stimulation protocols. First, we used sine wave stimulation to characterize the response properties of the afferent neurons. The average frequency-response curve was flat across stimulation frequencies between 0 and 100 Hz, matching the filtering properties of a displacement detector. Spike rate increased asymptotically with frequency, and phase locking was maximal between 10 and 60 Hz. Second, we used pulse train stimulation to analyze the maximum spike rate capabilities. We found that afferent neurons could generate up to 80 spikes/s and could follow a pulse train stimulation rate of up to 40 pulses/s in a reliable and precise manner. Both sine wave and pulse stimulation protocols indicate that an afferent neuron can maintain their evoked activity for longer durations at low stimulation frequencies than at high frequencies. We found one type of afferent neuron based on spontaneous activity patterns and discovered a correlation between the level of spontaneous and evoked activity. Overall, our results establish the baseline response properties of lateral line primary afferent neurons in larval zebrafish, which is a crucial step in understanding how vertebrate mechanoreceptive systems sense and subsequently process information from the environment. PMID:25355959

  16. Noise-modulated-microwave-induced response in snail neurons

    SciTech Connect

    Lin, J.C.; Arber, S.L.

    1983-01-01

    Helix aspersa neurons were irradiated with noise-amplitude-modulated microwaves (carrier frequency 2450 MHz, 20% AM, 0-20 kHz, specific absorption rate 6.8 and 14.4 mW/g). It was found that such an exposure caused an appearance of high frequency bursts and a rise in membrane resistance.

  17. Primary motor cortex of the parkinsonian monkey: altered neuronal responses to muscle stretch

    PubMed Central

    Pasquereau, Benjamin; Turner, Robert S.

    2013-01-01

    Exaggeration of the long-latency stretch reflex (LLSR) is a characteristic neurophysiologic feature of Parkinson's disease (PD) that contributes to parkinsonian rigidity. To explore one frequently-hypothesized mechanism, we studied the effects of fast muscle stretches on neuronal activity in the macaque primary motor cortex (M1) before and after the induction of parkinsonism by unilateral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We compared results from the general population of M1 neurons and two antidromically-identified subpopulations: distant-projecting pyramidal-tract type neurons (PTNs) and intra-telecenphalic-type corticostriatal neurons (CSNs). Rapid rotations of elbow or wrist joints evoked short-latency responses in 62% of arm-related M1 neurons. As in PD, the late electromyographic responses that constitute the LLSR were enhanced following MPTP. This was accompanied by a shortening of M1 neuronal response latencies and a degradation of directional selectivity, but surprisingly, no increase in single unit response magnitudes. The results suggest that parkinsonism alters the timing and specificity of M1 responses to muscle stretch. Observation of an exaggerated LLSR with no change in the magnitude of proprioceptive responses in M1 is consistent with the idea that the increase in LLSR gain that contributes to parkinsonian rigidity is localized to the spinal cord. PMID:24324412

  18. Responses of mirror neurons in area F5 to hand and tool grasping observation.

    PubMed

    Rochat, Magali J; Caruana, Fausto; Jezzini, Ahmad; Escola, Ludovic; Intskirveli, Irakli; Grammont, Franck; Gallese, Vittorio; Rizzolatti, Giacomo; Umiltà, Maria Alessandra

    2010-08-01

    Mirror neurons are a distinct class of neurons that discharge both during the execution of a motor act and during observation of the same or similar motor act performed by another individual. However, the extent to which mirror neurons coding a motor act with a specific goal (e.g., grasping) might also respond to the observation of a motor act having the same goal, but achieved with artificial effectors, is not yet established. In the present study, we addressed this issue by recording mirror neurons from the ventral premotor cortex (area F5) of two monkeys trained to grasp objects with pliers. Neuron activity was recorded during the observation and execution of grasping performed with the hand, with pliers and during observation of an experimenter spearing food with a stick. The results showed that virtually all neurons responding to the observation of hand grasping also responded to the observation of grasping with pliers and, many of them to the observation of spearing with a stick. However, the intensity and pattern of the response differed among conditions. Hand grasping observation determined the earliest and the strongest discharge, while pliers grasping and spearing observation triggered weaker responses at longer latencies. We conclude that F5 grasping mirror neurons respond to the observation of a family of stimuli leading to the same goal. However, the response pattern depends upon the similarity between the observed motor act and the one executed by the hand, the natural motor template.

  19. Measuring Physiological Responses of Drosophila Sensory Neurons to Lipid Pheromones Using Live Calcium Imaging.

    PubMed

    Shankar, Shruti; Calvert, Meredith E K; Yew, Joanne Y

    2016-01-01

    Unlike mammals, insects such as Drosophila have multiple taste organs. The chemosensory neurons on the legs, proboscis, wings and ovipositor of Drosophila express gustatory receptors(1,2), ion channels(3-6), and ionotropic receptors(7) that are involved in the detection of volatile and non-volatile sensory cues. These neurons directly contact tastants such as food, noxious substances and pheromones and therefore influence many complex behaviors such as feeding, egg-laying and mating. Electrode recordings and calcium imaging have been widely used in insects to quantify the neuronal responses evoked by these tastants. However, electrophysiology requires specialized equipment and obtaining measurements from a single taste sensillum can be technically challenging depending on the cell-type, size, and position. In addition, single neuron resolution in Drosophila can be difficult to achieve since taste sensilla house more than one type of chemosensory neuron. The live calcium imaging method described here allows responses of single gustatory neurons in live flies to be measured. This method is especially suitable for imaging neuronal responses to lipid pheromones and other ligand types that have low solubility in water-based solvents. PMID:27168110

  20. The linearity and selectivity of neuronal responses in awake visual cortex

    PubMed Central

    Chen, Yao; Anand, Sanjiv; Martinez-Conde, Susana; Macknik, Stephen L.; Bereshpolova, Yulia; Swadlow, Harvey A.; Alonso, Jose-Manuel

    2011-01-01

    Neurons in primary visual cortex (V1) are frequently classified based on their response linearity: the extent in which their visual responses to drifting gratings resemble a linear replica of the stimulus. This classification is supported by the finding that response linearity is bimodally distributed across neurons in area V1 of anesthetized animals. However, recent studies suggest that such bimodal distribution may not reflect two neuronal types but a nonlinear relationship between the membrane potential and the spike output. A main limitation of these previous studies is that they measured response linearity in anesthetized animals, where the distance between the neuronal membrane potential and spike threshold is artificially increased by anesthesia. Here, we measured V1 response linearity in the awake brain and its correlation with the neuronal spontaneous firing rate, which is related to the distance between membrane potential and threshold. Our results demonstrate that response linearity is bimodally distributed in awake V1 but that it is poorly correlated with spontaneous firing rate. In contrast, the spontaneous firing rate is best correlated to the response selectivity and response latency to stimuli. PMID:19761345

  1. Attenuated infrared neuron stimulation response in cochlea of deaf animals may associate with the degeneration of spiral ganglion neurons

    PubMed Central

    Xie, Bingbin; Dai, Chunfu; Li, Huawei

    2015-01-01

    Hypothesis: We hypothesize that degenerated spiral ganglion neurons (SGNs) in guinea pigs reduces auditory brainstem responses evoked by pulsed infrared stimulation. Background: Pulsed infrared laser excitation can directly evoke physiological responses in neuronal and other excitable cells in vivo and in vitro. Laser pulses could benefit patients with cochlear implants to stimulate the auditory system. Methods: Pulsed infrared lasers were used to study evoked optical auditory brainstem responses (oABRs) in normal hearing and deafened animals. Aslo, the morphology and anatomy of SGNs in normal hearing and deafened guinea pigs were compared. Results: By recording oABRs evoked by varying infrared laser pulse durations, it is suggested that degeneration of SGNs in deafened guinea pigs was associated with an elevated oABR threshold and with lower amplitudes. Moreover, oABR threshold decreased while amplitudes increased in both normal hearing and deafened animals as the pulse duration prolonged. Electron microscopy revealed that SGNs in deafened guinea pigs had swollen and vacuolar mitochondria, as well as demyelinated soma and axons. Conclusion: Infrared laser pulses can stimulate SGNs to evoke oABRs in guinea pigs. Deafened guinea pigs have elevated thresholds and smaller amplitude responses, likely a result of degenerated SGNs. Short pulse durations are more suitable to evoke responses in both normal hearing and deafened animals. PMID:26114024

  2. Responses of protocerebral neurons in Manduca sexta to sex-pheromone mixtures

    PubMed Central

    Lei, Hong; Chiu, Hong-Yan; Hildebrand, John G.

    2013-01-01

    Male Manduca sexta moths are attracted to a mixture of two components of the female's sex pheromone at the natural concentration ratio. Deviation from this ratio results in reduced attraction. Projection neurons innervating prominent male-specific glomeruli in the male's antennal lobe produce maximal synchronized spiking activity in response to synthetic mixtures of the two components centering around the natural ratio, suggesting that behaviorally effective mixture ratios are encoded by synchronous neuronal activity. We investigated the physiological activity and morphology of downstream protocerebral neurons that responded to antennal stimulation with single pheromone components and their mixtures at various concentration ratios. Among the tested neurons, only a few gave stronger responses to the mixture at the natural ratio whereas most did not distinguish among the mixtures that were tested. We also found that the population response distinguished among the two pheromone components and their mixtures, prior to the peak population response. This observation is consistent with our previous finding that synchronous firing of antennal-lobe projection neurons reaches its maximum before the firing rate reaches its peak. Moreover, the response patterns of protocerebral neurons are diverse, suggesting that the representation of olfactory stimuli at the level of protocerebrum is complex. PMID:23974854

  3. The essential role of p53-up-regulated modulator of apoptosis (Puma) and its regulation by FoxO3a transcription factor in β-amyloid-induced neuron death.

    PubMed

    Akhter, Rumana; Sanphui, Priyankar; Biswas, Subhas Chandra

    2014-04-11

    Neurodegeneration underlies the pathology of Alzheimer disease (AD). The molecules responsible for such neurodegeneration in AD brain are mostly unknown. Recent findings indicate that the BH3-only proteins of the Bcl-2 family play an essential role in various cell death paradigms, including neurodegeneration. Here we report that Puma (p53-up-regulated modulator of apoptosis), an important member of the BH3-only protein family, is up-regulated in neurons upon toxic β-amyloid 1-42 (Aβ(1-42)) exposure both in vitro and in vivo. Down-regulation of Puma by specific siRNA provides significant protection against neuron death induced by Aβ(1-42). We further demonstrate that the activation of p53 and inhibition of PI3K/Akt pathways induce Puma. The transcription factor FoxO3a, which is activated when PI3K/Akt signaling is inhibited, directly binds with the Puma gene and induces its expression upon exposure of neurons to oligomeric Aβ(1-42). Moreover, Puma cooperates with another BH3-only protein, Bim, which is already implicated in AD. Our results thus suggest that Puma is activated by both p53 and PI3K/Akt/FoxO3a pathways and cooperates with Bim to induce neuron death in response to Aβ(1-42).

  4. Nucleus accumbens neuronal activity correlates to the animal's behavioral response to acute and chronic methylphenidate.

    PubMed

    Claussen, Catherine M; Chong, Samuel L; Dafny, Nachum

    2014-04-22

    Acute and chronic methylphenidate (MPD) exposure was recorded simultaneously for the rat's locomotor activity and the nucleus accumbens (NAc) neuronal activity. The evaluation of the neuronal events was based on the animal's behavior response to chronic MPD administration: 1) Animals exhibiting behavioral sensitization, 2) Animals exhibiting behavioral tolerance. The experiment lasted for 10days with four groups of animals; saline, 0.6, 2.5, and 10.0mg/kg MPD. For the main behavioral findings, about half of the animals exhibited behavioral sensitization or behavioral tolerance to 0.6, 2.5, and/or 10mg/kg MPD respectively. Three hundred and forty one NAc neuronal units were evaluated. Approximately 80% of NAc units responded to 0.6, 2.5, and 10.0mg/kg MPD. When the neuronal activity was analyzed based on the animals' behavioral response to chronic MPD exposure, significant differences were seen between the neuronal population responses recorded from animals that expressed behavioral sensitization when compared to the NAc neuronal responses recorded from animals exhibiting behavioral tolerance. Three types of neurophysiological sensitization and neurophysiological tolerance can be recognized following chronic MPD administration to the neuronal populations. Collectively, these findings show that the same dose of chronic MPD can elicit either behavioral tolerance or behavioral sensitization. Differential statistical analyses were used to verify our hypothesis that the neuronal activity recorded from animals exhibiting behavioral sensitization will respond differently to MPD compared to those animals exhibiting behavioral tolerance, thus, suggesting that it is essential to record the animal's behavior concomitantly with neuronal recordings.

  5. Learning of anticipatory responses in single neurons of the human medial temporal lobe

    PubMed Central

    Reddy, Leila; Poncet, Marlene; Self, Matthew W.; Peters, Judith C.; Douw, Linda; van Dellen, Edwin; Claus, Steven; Reijneveld, Jaap C.; Baayen, Johannes C.; Roelfsema, Pieter R.

    2015-01-01

    Neuronal processes underlying the formation of new associations in the human brain are not yet well understood. Here human participants, implanted with depth electrodes in the brain, learned arbitrary associations between images presented in an ordered, predictable sequence. During learning we recorded from medial temporal lobe (MTL) neurons that responded to at least one of the pictures in the sequence (the preferred stimulus). We report that as a result of learning, single MTL neurons show asymmetric shifts in activity and start firing earlier in the sequence in anticipation of their preferred stimulus. These effects appear relatively early in learning, after only 11 exposures to the stimulus sequence. The anticipatory neuronal responses emerge while the subjects became faster in reporting the next item in the sequence. These results demonstrate flexible representations that could support learning of new associations between stimuli in a sequence, in single neurons in the human MTL. PMID:26449885

  6. Lateral orbitofrontal neurons acquire responses to upshifted, downshifted, or blocked cues during unblocking.

    PubMed

    Lopatina, Nina; McDannald, Michael A; Styer, Clay V; Sadacca, Brian F; Cheer, Joseph F; Schoenbaum, Geoffrey

    2015-12-15

    The lateral orbitofrontal cortex (lOFC) has been described as signaling either outcome expectancies or value. Previously, we used unblocking to show that lOFC neurons respond to a predictive cue signaling a 'valueless' change in outcome features (McDannald, 2014). However, many lOFC neurons also fired to a cue that simply signaled more reward. Here, we recorded lOFC neurons in a variant of this task in which rats learned about cues that signaled either more (upshift), less (downshift) or the same (blocked) amount of reward. We found that neurons acquired responses specifically to one of the three cues and did not fire to the other two. These results show that, at least early in learning, lOFC neurons fire to valued cues in a way that is more consistent with signaling of the predicted outcome's features than with signaling of a general, abstract or cached value that is independent of the outcome.

  7. Quantized response times are a signature of a neuronal bottleneck in decision

    PubMed Central

    Perona, Pietro

    2014-01-01

    The histograms of response times of optimal YES/NO decisions that are computed from a single sensory Poisson neuron are highly structured. In particular, response times in NO decisions are quantized to a small set of times, while response times in YES decisions have a multimodal structure. Both the times of NO decisions, as well as the modes of the the histogram of YES decisions, are associated to the number of action potentials that were necessary to reach the decision. Their value is a function of the firing rate of the neuron in response to the states of the stimulus. PMID:24782750

  8. Cognition-Enhancing Doses of Methylphenidate Preferentially Increase Prefrontal Cortical Neuronal Responsiveness

    PubMed Central

    Devilbiss, David M.; Berridge, Craig W.

    2008-01-01

    Background Despite widespread use of low-dose psychostimulants for the treatment of attention deficit hyperactivity disorder (ADHD), the neural basis for the therapeutic actions of these drugs are not well-understood. We recently demonstrated that low-dose methylphenidate (MPH) increases catecholamine efflux preferentially within the prefrontal cortex (PFC), suggesting the PFC is a principal site of action in the behavioral-calming and cognition-enhancing effects of low-dose psychostimulants. To better understand the neural mechanisms involved in the behavioral actions of low-dose stimulants, the current study examined the effects of low-dose MPH on the discharge properties of individual and ensembles of PFC neurons. Methods Extracellular activity of multiple individual PFC neurons was recorded in freely moving rats using multi-channel recording techniques. Behavioral studies identified optimal, working memory-enhancing doses of intraperitoneal MPH. The effects of these low-doses of MPH on PFC neuronal discharge properties were compared to: 1) the effects of high-dose MPH on PFC neuronal discharge; 2) the effects of low-dose MPH on neuronal discharge within the somatosensory cortex. Results Only working memory-enhancing doses of MPH increased the responsivity of individual PFC neurons and altered neuronal ensemble responses within the PFC. These effects were not observed outside the PFC (i.e. within somatosensory cortex). In contrast, high-dose MPH profoundly suppressed evoked discharge of PFC neurons. Conclusions These observations suggest that preferential enhancement of signal processing within the PFC, including alterations in the discharge properties of individual PFC neurons and PFC neuronal ensembles, underlie the behavioral/cognitive actions of low-dose psychostimulants. PMID:18585681

  9. Neuronal activity in the primate dorsomedial prefrontal cortex contributes to strategic selection of response tactics.

    PubMed

    Matsuzaka, Yoshiya; Akiyama, Tetsuya; Tanji, Jun; Mushiake, Hajime

    2012-03-20

    The functional roles of the primate posterior medial prefrontal cortex have remained largely unknown. Here, we show that this region participates in the regulation of actions in the presence of multiple response tactics. Monkeys performed a forelimb task in which a visual cue required prompt decision of reaching to a left or a right target. The location of the cue was either ipsilateral (concordant) or contralateral (discordant) to the target. As a result of extensive training, the reaction times for the concordant and discordant trials were indistinguishable, indicating that the monkeys developed tactics to overcome the cue-response conflict. Prefrontal neurons exhibited prominent activity when the concordant and discordant trials were randomly presented, requiring rapid selection of a response tactic (reach toward or away from the cue). The following findings indicate that these neurons are involved in the selection of tactics, rather than the selection of action or monitoring of response conflict: (i) The response period activity of neurons in this region disappeared when the monkeys performed the task under the behavioral condition that required a single tactic alone, whereas the action varied across trials. (ii) The neuronal activity was found in the dorsomedial prefrontal cortex but not in the anterior cingulate cortex that has been implicated for the response conflict monitoring. These results suggest that the medial prefrontal cortex participates in the selection of a response tactic that determines an appropriate action. Furthermore, the observation of dynamic, task-dependent neuronal activity necessitates reconsideration of the conventional concept of cortical motor representation.

  10. Responses of monkey prefrontal neurons during the execution of transverse patterning.

    PubMed

    Nejime, Masafumi; Inoue, Masato; Saruwatari, Masanori; Mikami, Akichika; Nakamura, Katsuki; Miyachi, Shigehiro

    2015-02-01

    Recent functional imaging studies have suggested that the prefrontal cortex (PF) is engaged in the performance of transverse patterning (TP), which consists of 3 conflicting discriminations (A+/B-, B+/C-, C+/A-). However, the roles of PF in TP are still unclear. To address this issue, we examined the neuronal responses in 3 regions [the principal sulcus (PS), dorsal convexity (DC), and medial prefrontal cortex (MPF)] of the macaque PF during the performance of an oculomotor version of TP. A delayed matching-to-sample (DMS) task was used as a control task. The TP task-responsive neurons were most abundant in MPF. We analyzed the dependency of each neuronal response on the task type (TP or DMS), target shape (A, B, or C), and target location (left or right). Immediately after the choice cue presentation, many MPF neurons showed task dependency. Interestingly, some of them already exhibited differential activity between the 2 tasks before the choice cue presentation. Immediately before the saccade, the number of target location-dependent neurons increased in MPF and PS. Among them, many MPF neurons were also influenced by the task type, whereas PS neurons tended to show location dependency without task dependency. These results suggest that MPF and PS are involved in the execution of TP: MPF appears to be more important in the target selection based on the TP rule, whereas PS is apparently more related to the response preparation. In addition, some neurons showed a postsaccadic response, which may be related to the feedback mechanism. PMID:25453739

  11. Response properties of neurons in the cat's putamen during auditory discrimination.

    PubMed

    Zhao, Zhenling; Sato, Yu; Qin, Ling

    2015-10-01

    The striatum integrates diverse convergent input and plays a critical role in the goal-directed behaviors. To date, the auditory functions of striatum are less studied. Recently, it was demonstrated that auditory cortico-striatal projections influence behavioral performance during a frequency discrimination task. To reveal the functions of striatal neurons in auditory discrimination, we recorded the single-unit spike activities in the putamen (dorsal striatum) of free-moving cats while performing a Go/No-go task to discriminate the sounds with different modulation rates (12.5 Hz vs. 50 Hz) or envelopes (damped vs. ramped). We found that the putamen neurons can be broadly divided into four groups according to their contributions to sound discrimination. First, 40% of neurons showed vigorous responses synchronized to the sound envelope, and could precisely discriminate different sounds. Second, 18% of neurons showed a high preference of ramped to damped sounds, but no preference for modulation rate. They could only discriminate the change of sound envelope. Third, 27% of neurons rapidly adapted to the sound stimuli, had no ability of sound discrimination. Fourth, 15% of neurons discriminated the sounds dependent on the reward-prediction. Comparing to passively listening condition, the activities of putamen neurons were significantly enhanced by the engagement of the auditory tasks, but not modulated by the cat's behavioral choice. The coexistence of multiple types of neurons suggests that the putamen is involved in the transformation from auditory representation to stimulus-reward association.

  12. Odorant Responses and Courtship Behaviors Influenced by at4 Neurons in Drosophila

    PubMed Central

    Pitts, Svetlana; Pelser, Elizabeth; Meeks, Julian

    2016-01-01

    In insects, pheromones function as triggers to elicit complex behavior programs, such as courtship and mating behavior. In most species, the neurons tuned to pheromones are localized in a specific subset of olfactory sensilla located on the antenna called trichoid sensilla. In Drosophila there are two classes of trichoid sensilla, at1 sensilla that contain the dendrites of a single neuron that is specifically tuned to the male-specific pheromone 11-cis vaccenyl acetate (cVA), and at4 sensilla that contain three neurons with relatively poorly defined chemical specificity and function. Using a combination of odorant receptor mutant analysis, single sensillum electrophysiology and optogenetics, we have examined the chemical tuning and behavioral consequences of the three at4 olfactory neuron classes. Our results indicate that one class, Or65abc neurons, are unresponsive to cVA pheromone, and function to inhibit courtship behaviors in response to an unknown ligand, while the other two neuron classes, Or88a and Or47b neurons, are sensitive to a diverse array of fly and non-fly odors, and activation of these neurons has little direct impact on courtship behaviors. PMID:27617442

  13. Odorant Responses and Courtship Behaviors Influenced by at4 Neurons in Drosophila.

    PubMed

    Pitts, Svetlana; Pelser, Elizabeth; Meeks, Julian; Smith, Dean

    2016-01-01

    In insects, pheromones function as triggers to elicit complex behavior programs, such as courtship and mating behavior. In most species, the neurons tuned to pheromones are localized in a specific subset of olfactory sensilla located on the antenna called trichoid sensilla. In Drosophila there are two classes of trichoid sensilla, at1 sensilla that contain the dendrites of a single neuron that is specifically tuned to the male-specific pheromone 11-cis vaccenyl acetate (cVA), and at4 sensilla that contain three neurons with relatively poorly defined chemical specificity and function. Using a combination of odorant receptor mutant analysis, single sensillum electrophysiology and optogenetics, we have examined the chemical tuning and behavioral consequences of the three at4 olfactory neuron classes. Our results indicate that one class, Or65abc neurons, are unresponsive to cVA pheromone, and function to inhibit courtship behaviors in response to an unknown ligand, while the other two neuron classes, Or88a and Or47b neurons, are sensitive to a diverse array of fly and non-fly odors, and activation of these neurons has little direct impact on courtship behaviors. PMID:27617442

  14. Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons.

    PubMed

    Wang, Jian; McFadden, Sandra L; Caspary, Donald; Salvi, Richard

    2002-07-19

    Neurons containing gamma aminobutyric acid (GABA) are widely distributed throughout the primary auditory cortex (AI). We investigated the effects of endogenous GABA by comparing response properties of 110 neurons in chinchilla AI before and after iontophoresis of bicuculline, a GABA(A) receptor antagonist, and/or CGP35348, a GABA(B) receptor antagonist. GABA(A) receptor blockade significantly increased spontaneous and driven discharge rates, dramatically decreased the thresholds of many neurons, and constricted the range of thresholds across the neural population. Some neurons with 'non-onset' temporal discharge patterns developed an onset pattern that was followed by a long pause. Interestingly, the excitatory response area typically expanded on both sides of the characteristic frequency; this expansion exceeded one octave in a third of the sample. Although GABA(B) receptor blockade had little effect alone, the combination of CGP35348 and bicuculline produced greater increases in driven rate and expansion of the frequency response area than GABA(A) receptor blockade alone, suggesting a modulatory role of local GABA(B) receptors. The results suggest that local GABA inhibition contributes significantly to intensity and frequency coding by controlling the range of intensities over which cortical neurons operate and the range of frequencies to which they respond. The inhibitory circuits that generate nonmonotonic rate-level functions are separate from those that influence other response properties of AI neurons. PMID:12106684

  15. Synaptic responses in cochlear nucleus neurons evoked by activation of the olivocochlear system.

    PubMed

    Mulders, W H A M; Paolini, A G; Needham, K; Robertson, D

    2009-10-01

    The action of olivocochlear collaterals to the cochlear nucleus is not fully established. Synaptic ultrastructure suggests an excitatory role. Extracellular recordings show spikes evoked by electrical stimulation of olivocochlear axons, but these spikes in the cochlear nucleus may be antidromic (activation of output axons) or orthodromic (synaptic input). We therefore recorded intracellular responses to shocks to olivocochlear axons in anaesthetized guinea pigs. In chopper and primary-like neurons shocks caused either no response or an inhibitory synaptic response (IPSP), but never an excitatory one (EPSP). In contrast, onset neurons never showed IPSPs but showed a variety of other responses; antidromic spikes, EPSPs, orthodromic spikes or no effect. The results agree with earlier extracellular observations in that olivocochlear collaterals provide excitatory input to onset neurons. Because some onset neurons are inhibitory they may be the source of the IPSPs observed in other cochlear nucleus neurons. The data also show that electrical stimulation at the floor of the IVth ventricle results in antidromic spikes as well. However, intracellular recording enabled the orthodromic action to be verified and the presumed olivocochlear action to be better understood. Our data support the hypothesis that olivocochlear collaterals initiate excitatory input onto onset-chopper neurons. PMID:19607895

  16. Responses of central vestibular neurons to sinusoidal yaw rotation in compensated macaques after unilateral labyrinthectomy

    PubMed Central

    Wei, Min

    2013-01-01

    After vestibular labyrinth injury, behavioral measures of vestibular function partially recover through the process of vestibular compensation. The present study was performed to improve our understanding of the physiology of macaque vestibular nucleus neurons in the compensated state (>6 wk) after unilateral labyrinthectomy (UL). The responses of neurons to sinusoidal yaw rotation at a series of frequencies (0.1–2.0 Hz) and peak velocities (7.5–210°/s) were examined to determine how the behavior of these cells differed from those in animals with intact labyrinths. The sensitivity of neurons responding to ipsilateral rotation (type I) did not differ between the intact and injured sides after UL, although this sensitivity was lower bilaterally after lesion than before lesion. The sensitivity of neurons that increase firing with contralateral rotation (type II) was higher ipsilateral to the UL than before lesion or in the nucleus contralateral to the UL. UL did not increase asymmetry in the responses of individual type I or II neurons to ipsilateral vs. contralateral rotation, nor does it change the power law relationship between neuronal firing and level of stimulation. Increased sensitivities of contralesional type I neurons to the remaining vestibular nerve input and increased efficacy of inhibitory vestibular commissures projecting to the ipsilesional vestibular nucleus appear to be responsible for recovery of dynamic function of central vestibular neurons in compensated animals. The portion of type I neurons on the ipsilesional side is reduced in compensated animals, which likely accounts for the asymmetries in vestibular reflexes and perception that characterize vestibular function after UL. PMID:23864379

  17. Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction

    PubMed Central

    Sangha, Susan

    2015-01-01

    Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al. (2013) have previously reported several neural microcircuits within the basal amygdala (BA) which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these “safety” neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of “safety” neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the “safety” neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated BA circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes. PMID:26733838

  18. Nociceptive stimuli induce changes in somatosensory responses of rat dorsal column nuclei neurons.

    PubMed

    Costa-García, Miguel; Nuñez, Angel

    2004-10-29

    Accumulating evidence suggest that the dorsal column nuclei (DCN) neurons play a role in nociception. To evaluate DCN neuronal responses to nociceptive stimuli, unit recordings were performed in urethane-anesthesized rats. Neurons selected for this analysis displayed a low spontaneous firing rate and some of them were antidromically activated by electrical stimulation of the ventral posterolateral thalamic nucleus. Formalin injections into receptive fields (RFs) of DCN cells, or applications of short-lasting and long-lasting thermal nociceptive stimuli were used. DCN neurons displayed smaller responses when long-lasting nociceptive thermal stimuli were applied to their RFs in comparison with values obtained from the innocuous cutaneous stimulation (5.2+/-1.0 and 4.0+/-0.6 spikes/stimuli, respectively; p=0.02). Formalin also decreased the responses to innocuous cutaneous stimuli when these stimuli were applied to the formalin injection site (2.6+/-0.3 spikes/stimuli in control conditions and 1.8+/-0.3 spikes/stimuli 20 min after formalin; p=0.002). In contrast, responses to sensory stimuli applied at the periphery of the RF after formalin injection increased (2.2+/-0.2 to 2.8+/-0.3 spikes/stimuli; p=0.005). In some cases, DCN neurons expanded their RF. Fiber input to the DCN did not modify their somatosensory responses when nociceptive stimuli were applied. Results demonstrate that thermal and formalin nociceptive stimuli modify the somatosensory responses of DCN neurons. Thus, decreasing somatosensory responses at the pain induction site or the generation of allodynia may be due to the activity of DCN neurons.

  19. Mushroom body efferent neurons responsible for aversive olfactory memory retrieval in Drosophila.

    PubMed

    Séjourné, Julien; Plaçais, Pierre-Yves; Aso, Yoshinori; Siwanowicz, Igor; Trannoy, Séverine; Thoma, Vladimiros; Tedjakumala, Stevanus R; Rubin, Gerald M; Tchénio, Paul; Ito, Kei; Isabel, Guillaume; Tanimoto, Hiromu; Preat, Thomas

    2011-06-19

    Aversive olfactory memory is formed in the mushroom bodies in Drosophila melanogaster. Memory retrieval requires mushroom body output, but the manner in which a memory trace in the mushroom body drives conditioned avoidance of a learned odor remains unknown. To identify neurons that are involved in olfactory memory retrieval, we performed an anatomical and functional screen of defined sets of mushroom body output neurons. We found that MB-V2 neurons were essential for retrieval of both short- and long-lasting memory, but not for memory formation or memory consolidation. MB-V2 neurons are cholinergic efferent neurons that project from the mushroom body vertical lobes to the middle superiormedial protocerebrum and the lateral horn. Notably, the odor response of MB-V2 neurons was modified after conditioning. As the lateral horn has been implicated in innate responses to repellent odorants, we propose that MB-V2 neurons recruit the olfactory pathway involved in innate odor avoidance during memory retrieval.

  20. [Structure of Response and Dynamics of Preferred Orientation in Cat's V1 Neurons].

    PubMed

    Kozhukhov, S A; Saltykov, K A; Lazareva, N A

    2016-01-01

    Preferred orientation of V1 neurons was changed during the respons time course. In order to reveal mechanisms of such changes, spike trains of single neurons to flashed bars of different orientations were studied by means of principal component and frequency-domain analysis of the spike density functions. There was found out that: 1. contribution of each of the components was dependent on the stimulus orientation. 2. the principal components of V1 neurons responses contain different kinds of transient and sustained parts and rhythmic oscillations in the theta/alpha and beta-bands. 3. There was no correlation between transient parts as well as between rhythmic oscillations within the same frequency band in different components. Taken together, the data obtained allow us to suggest that during generation of response there is a shift of dominance of the components with different orientations which determines the dynamics of the preferred orientations of V1 neurons. PMID:27263274

  1. Phase Response Synchronization in Neuronal Population with Time-Varying Coupling Strength

    PubMed Central

    Jiao, Xianfa; Zhao, Wanyu; Cao, Jinde

    2015-01-01

    We present the dynamic model of global coupled neuronal population subject to external stimulus by the use of phase sensitivity function. We investigate the effect of time-varying coupling strength on the synchronized phase response of neural population subjected to external harmonic stimulus. For a time-periodic coupling strength, we found that the stimulus with increasing intensity or frequency can reinforce the phase response synchronization in neuronal population of the weakly coupled neural oscillators, and the neuronal population with stronger coupling strength has good adaptability to stimulus. When we consider the dynamics of coupling strength, we found that a strong stimulus can quickly cause the synchronization in the neuronal population, the degree of synchronization grows with the increasing stimulus intensity, and the period of synchronized oscillation induced by external stimulation is related to stimulus frequency. PMID:26640514

  2. Escape behavior and neuronal responses to looming stimuli in the crab Chasmagnathus granulatus (Decapoda: Grapsidae).

    PubMed

    Oliva, Damián; Medan, Violeta; Tomsic, Daniel

    2007-03-01

    Behavioral responses to looming stimuli have been studied in many vertebrate and invertebrate species, but neurons sensitive to looming have been investigated in very few animals. In this paper we introduce a new experimental model using the crab Chasmagnathus granulatus, which allows investigation of the processes of looming detection and escape decision at both the behavioral and neuronal levels. By analyzing the escape response of the crab in a walking simulator device we show that: (i) a robust and reliable escape response can be elicited by computer-generated looming stimuli in all tested animals; (ii) parameters such as distance, speed, timing and directionality of the escape run, are easy to record and quantify precisely in the walking device; (iii) although the magnitude of escape varies between animals and stimulus presentations, the timing of the response is remarkably consistent and does not habituate at 3 min stimulus intervals. We then study the response of neurons from the brain of the crab by means of intracellular recordings in the intact animal and show that: (iv) two subclasses of previously identified movement detector neurons from the lobula (third optic neuropil) exhibit robust and reliable responses to the same looming stimuli that trigger the behavioral response; (v) the neurons respond to the object approach by increasing their rate of firing in a way that closely matches the dynamics of the image expansion. Finally, we compare the neuronal with the behavioral response showing that: (vi) differences in the neuronal responses to looming, receding or laterally moving stimuli closely reflect the behavioral differences to such stimuli; (vii) during looming, the crab starts to run soon after the looming-sensitive neurons begin to increase their firing rate. The increase in the running speed during stimulus approach faithfully follows the increment in the firing rate, until the moment of maximum stimulus expansion. Thereafter, the neurons abruptly

  3. Leptin-Responsive GABAergic Neurons Regulate Fertility through Pathways That Result in Reduced Kisspeptinergic Tone

    PubMed Central

    Martin, Cecilia; Navarro, Víctor M.; Simavli, Serap; Vong, Linh; Carroll, Rona S.; Lowell, Bradford B.

    2014-01-01

    The adipocyte-derived hormone leptin plays a critical role in the central transmission of energy balance to modulate reproductive function. However, the neurocircuitry underlying this interaction remains elusive, in part due to incomplete knowledge of first-order leptin-responsive neurons. To address this gap, we explored the contribution of predominantly inhibitory (GABAergic) neurons versus excitatory (glutamatergic) neurons in the female mouse by selective ablation of the leptin receptor in each neuronal population: Vgat-Cre;Leprlox/lox and Vglut2-Cre;Leprlox/lox mice, respectively. Female Vgat-Cre;Leprlox/lox but not Vglut2-Cre;Leprlox/lox mice were obese. Vgat-Cre;Leprlox/lox mice had delayed or absent vaginal opening, persistent diestrus, and atrophic reproductive tracts with absent corpora lutea. In contrast, Vglut2-Cre;Leprlox/lox females exhibited reproductive maturation and function comparable to Leprlox/lox control mice. Intracerebroventricular administration of kisspeptin-10 to Vgat-Cre;Leprlox/lox female mice elicited robust gonadotropin responses, suggesting normal gonadotropin-releasing hormone neuronal and gonadotrope function. However, adult ovariectomized Vgat-Cre;Leprlox/lox mice displayed significantly reduced levels of Kiss1 (but not Tac2) mRNA in the arcuate nucleus, and a reduced compensatory luteinizing hormone increase compared with control animals. Estradiol replacement after ovariectomy inhibited gonadotropin release to a similar extent in both groups. These animals also exhibited a compromised positive feedback response to sex steroids, as shown by significantly lower Kiss1 mRNA levels in the AVPV, compared with Leprlox/lox mice. We conclude that leptin-responsive GABAergic neurons, but not glutamatergic neurons, act as metabolic sensors to regulate fertility, at least in part through modulatory effects on kisspeptin neurons. PMID:24760864

  4. Neurokinins inhibit low threshold inactivating K+ currents in capsaicin responsive DRG neurons

    PubMed Central

    Sculptoreanu, Adrian; Artim, Debra E.; de Groat, William C.

    2009-01-01

    Neurokinins (NK) released from terminals of dorsal root ganglion (DRG) neurons may control firing of these neurons by an autofeedback mechanism. In this study we used patch clamp recording techniques to determine if NKs alter excitability of rat L4-S3 DRG neurons by modulating K+ currents. In capsaicin (CAPS)-responsive phasic neurons substance P (SP) lowered action potential (AP) threshold and increased the number of APs elicited by depolarizing current pulses. SP and a selective NK2 agonist, [βAla8]-neurokinin A (4–10) also inhibited low threshold inactivating K+ currents isolated by blocking non-inactivating currents with a combination of high TEA, (−) verapamil and nifedipine. Currents recorded under these conditions were heteropodatoxin-sensitive (Kv4 blocker) and α-dendrotoxin insensitive (Kv1.1 and Kv1.2 blocker). SP and NKA elicited a >10 mV positive shift of the voltage dependence of activation of the low threshold currents. This effect was absent in CAPS-unresponsive neurons. The effect of SP or NKA on K+ currents in CAPS-responsive phasic neurons was fully reversed by an NK2 receptor antagonist (MEN10376) but only partially reversed by a PKC inhibitor (bisindolylmaleimide). An NK1 selective agonist ([Sar9, Met11]-substance P) or direct activation of PKC with phorbol 12,13-dibutyrate, did not change firing in CAPS-responsive neurons, but did inhibit various types of K+ currents that activated over a wide range of voltages. These data suggest that the excitability of CAPS-responsive phasic afferent neurons is increased by activation of NK2 receptors and that this is due in part to inhibition and a positive voltage shift in the activation of heteropodatoxin-sensitive Kv4 channels. PMID:19631644

  5. Glial cells, but not neurons, exhibit a controllable response to a localized inflammatory microenvironment in vitro.

    PubMed

    Sommakia, Salah; Rickus, Jenna L; Otto, Kevin J

    2014-01-01

    The ability to design long-lasting intracortical implants hinges on understanding the factors leading to the loss of neuronal density and the formation of the glial scar. In this study, we modify a common in vitro mixed cortical culture model using lipopolysaccharide (LPS) to examine the responses of microglia, astrocytes, and neurons to microwire segments. We also use dip-coated polyethylene glycol (PEG), which we have previously shown can modulate impedance changes to neural microelectrodes, to control the cellular responses. We find that microglia, as expected, exhibit an elevated response to LPS-coated microwire for distances of up to 150 μm, and that this elevated response can be mitigated by co-depositing PEG with LPS. Astrocytes exhibit a more complex, distance-dependent response, whereas neurons do not appear to be affected by the type or magnitude of glial response within this in vitro model. The discrepancy between our in vitro responses and typically observed in vivo responses suggest the importance of using a systems approach to understand the responses of the various brain cell types in a chronic in vivo setting, as well as the necessity of studying the roles of cell types not native to the brain. Our results further indicate that the loss of neuronal density observed in vivo is not a necessary consequence of elevated glial activation. PMID:25452724

  6. Quantification and classification of neuronal responses in kernel-smoothed peristimulus time histograms.

    PubMed

    Hill, Michael R H; Fried, Itzhak; Koch, Christof

    2015-02-15

    Peristimulus time histograms are a widespread form of visualizing neuronal responses. Kernel convolution methods transform these histograms into a smooth, continuous probability density function. This provides an improved estimate of a neuron's actual response envelope. We here develop a classifier, called the h-coefficient, to determine whether time-locked fluctuations in the firing rate of a neuron should be classified as a response or as random noise. Unlike previous approaches, the h-coefficient takes advantage of the more precise response envelope estimation provided by the kernel convolution method. The h-coefficient quantizes the smoothed response envelope and calculates the probability of a response of a given shape to occur by chance. We tested the efficacy of the h-coefficient in a large data set of Monte Carlo simulated smoothed peristimulus time histograms with varying response amplitudes, response durations, trial numbers, and baseline firing rates. Across all these conditions, the h-coefficient significantly outperformed more classical classifiers, with a mean false alarm rate of 0.004 and a mean hit rate of 0.494. We also tested the h-coefficient's performance in a set of neuronal responses recorded in humans. The algorithm behind the h-coefficient provides various opportunities for further adaptation and the flexibility to target specific parameters in a given data set. Our findings confirm that the h-coefficient can provide a conservative and powerful tool for the analysis of peristimulus time histograms with great potential for future development. PMID:25475352

  7. Double sliding-window technique: a new method to calculate the neuronal response onset latency.

    PubMed

    Berényi, Antal; Benedek, György; Nagy, Attila

    2007-10-31

    Neuronal response onset latency provides important data on the information processing within the central nervous system. In order to enhance the quality of the onset latency estimation, we have developed a 'double sliding-window' technique, which combines the advantages of mathematical methods with the reliability of standard statistical processes. This method is based on repetitive series of statistical probes between two virtual time windows. The layout of the significance curve reveals the starting points of changes in neuronal activity in the form of break-points between linear segments. A second-order difference function is applied to determine the position of maximum slope change, which corresponds to the onset of the response. In comparison with Poisson spike-train analysis, the cumulative sum technique and the method of Falzett et al., this 'double sliding-window, technique seems to be a more accurate automated procedure to calculate the response onset latency of a broad range of neuronal response characteristics.

  8. Temperature response of the neuronal cytoskeleton mapped via atomic force and fluorescence microscopy

    NASA Astrophysics Data System (ADS)

    Spedden, Elise; Kaplan, David L.; Staii, Cristian

    2013-10-01

    Neuronal cells change their growth properties in response to external physical stimuli such as variations in external temperature, stiffness of the growth substrate, or topographical guidance cues. Detailed knowledge of the mechanisms that control these biomechanical responses is necessary for understanding the basic principles that underlie neuronal growth and regeneration. Here, we present elasticity maps of living cortical neurons (embryonic rat) as a function of temperature, and correlate these maps to the locations of internal structural components of the cytoskeleton. Neurons display a significant increase in the average elastic modulus upon a decrease in ambient temperature from 37 to 25 °C. We demonstrate that the dominant mechanism by which the elasticity of the neurons changes in response to temperature is the stiffening of the actin components of the cytoskeleton induced by myosin II. We also report a reversible shift in the location and composition of the high-stiffness areas of the neuron cytoskeleton with temperature. At 37 °C the areas of the cell displaying high elastic modulus overlap with the tubulin-dense regions, while at 25 °C these high-stiffness areas correspond to the actin-dense regions of the cytoskeleton. These results demonstrate the importance of considering temperature effects when investigating cytoskeletal dynamics in cells.

  9. Amino acids modify thalamo-cortical response transformation expressed by neurons of the ventrobasal complex.

    PubMed

    Vahle-Hinz, C; Hicks, T P; Gottschaldt, K M

    1994-02-21

    The hypothesis has been tested that inhibitory mechanisms, active spatially and temporally between the input and the output of thalamic neurons, determine the nature of the information transmitted to the cerebral cortex. To enable this assessment, in barbiturate-anesthetized cats and urethane-anesthetized rats juxtacellular recordings were performed together with microiontophoretic ejection of transmitter agonists and antagonists. The effects of these drugs were studied on responses evoked by mechanical stimulation of cutaneous receptive fields (RFs) of neurons in the thalamic ventrobasal complex (VB). Neurons from different parts of the VB were investigated: 29 units were located medially, in the ventral posteromedial nucleus (VPM; facial RFs), and 11 units were located laterally, in the ventral posterolateral nucleus (VPL; forepaw and body RFs). A further eleven VB units had no detectable RF. Twenty-six neurons were tested with electrical stimulation of the somatosensory cortex (SI), 17 of these being identified as thalamo-cortical relay neurons and 5 being classified as presumed interneurons; the remaining 4 could not be activated. Four additional recordings were from trigemino-thalamic or thalamo-cortical fibers. For the quantitative assessment of the neurons' input and output, neuronal activity was induced by feedback-controlled, mechanical trapezoidal and/or sinusoidal stimuli applied to sinus hairs, fur or skin and the numbers of prepotentials and soma spikes were compared in peristimulus time histograms (PSTHs) generated simultaneously for both types of signal from 'DC' recordings. Iontophoretic administration of excitatory amino acids (EAAs) or bicuculline methiodide (BMI) increased output-input ratios in 87% of the cases tested, due to a higher rate of conversion of prepotentials into soma spikes taking place. In cases of neurons exhibiting a sustained-to-transient response pattern, changes to sustained-to-sustained patterns were demonstrated. Tests with

  10. Phase response curves of subthalamic neurons measured with synaptic input and current injection

    PubMed Central

    Wilson, Charles J.

    2012-01-01

    Infinitesimal phase response curves (iPRCs) provide a simple description of the response of repetitively firing neurons and may be used to predict responses to any pattern of synaptic input. Their simplicity makes them useful for understanding the dynamics of neurons when certain conditions are met. For example, the sizes of evoked phase shifts should scale linearly with stimulus strength, and the form of the iPRC should remain relatively constant as firing rate varies. We measured the PRCs of rat subthalamic neurons in brain slices using corticosubthalamic excitatory postsynaptic potentials (EPSPs; mediated by both AMPA- and NMDA-type receptors) and injected current pulses and used them to calculate the iPRC. These were relatively insensitive to both the size of the stimulus and the cell's firing rate, suggesting that the iPRC can predict the response of subthalamic nucleus cells to extrinsic inputs. However, the iPRC calculated using EPSPs differed from that obtained using current pulses. EPSPs (normalized for charge) were much more effective at altering the phase of subthalamic neurons than current pulses. The difference was not attributable to the extended time course of NMDA receptor-mediated currents, being unaffected by blockade of NMDA receptors. The iPRC provides a good description of subthalamic neurons' response to input, but iPRCs are best estimated using synaptic inputs rather than somatic current injection. PMID:22786957

  11. Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure.

    PubMed

    Claussen, Catherine M; Dafny, Nachum

    2015-09-01

    The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long-term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization was also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals were observed for the 2.5 and 10.0mg/kg MPD exposed groups. For 2.5mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and

  12. Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure

    PubMed Central

    Claussen, Catherine M; Dafny, Nachum

    2016-01-01

    The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0 mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization were also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals was observed for the 2.5 and 10.0 mg/kg MPD exposed groups. For 2.5 mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0 mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0 mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure

  13. A physiological and structural study of neuron types in the cochlear nucleus. II. Neuron types and their structural correlation with response properties.

    PubMed

    Ostapoff, E M; Feng, J J; Morest, D K

    1994-08-01

    The present study examined the morphological cell types of neurons labeled with intracellular horseradish peroxidase injections, many of them following electrophysiological recordings in the cochlear nucleus of gerbils and chinchillas. Most of the subdivisions and neuronal types previously described in the cat were identified in the present material, including spherical and globular bushy cells, stellate, bushy multipolar, elongate, octopus, and giant cells in the ventral cochlear nucleus, and a cartwheel cell in the dorsal cochlear nucleus. In many cases these structurally distinct neurons were correlated with their characteristic responses to stimulation by sound or intracellular injection of depolarizing current. The dendritic terminals of the elongate, antenniform, and clavate cells of the posteroventral cochlear nucleus link each of these cell types with neighboring structures in distinct patterns, which may provide a basis for differences in synaptic organization. These cell types differ from each other and from the stellate cells of the anteroventral cochlear nucleus. Despite their heterogeneous morphology, most of these neurons had a regular discharge in response to stimulation (choppers). Irregularly firing neurons (primary-like) had very different structures, e.g., the spherical and globular bushy cells and the bushy multipolar neuron. They, too, represent a heterogeneous population. An onset neuron was identified as an octopus cell. This paper compares the morphological observations with the electrophysiological properties of different cell types reported in a companion paper (Feng et al. [1994] J. Comp. Neurol.). Together, these findings imply that response properties may be partially independent of neuronal structure. Morphologically distinct neurons can generate similar temporal patterns in response to simple acoustic stimuli. Nevertheless, the synaptic organization of these different neuron types, including their connections, would be expected to

  14. Differences in in vitro cerebellar neuronal responses to hypoxia in eider ducks, chicken and rats.

    PubMed

    Ludvigsen, Stian; Folkow, Lars P

    2009-11-01

    Ducks are well-known to be more tolerant to asphyxia than non-diving birds, but it is not known if their defences include enhanced neuronal hypoxia tolerance. To test this, we compared extracellular recordings of spontaneous activity in the Purkinje cell layer of 400 mum thick isolated cerebellar slices from eider ducks, chickens and rats, before, during and after 60 min hypoxia (95%N(2)-5%CO(2)) or chemical anoxia (hypoxia + 2 mM NaCN). Most slices rapidly lost activity in hypoxia, with or without recovery after rinse and return to normoxia (95%O(2)-5%CO(2)), but some maintained spontaneous activity throughout the insult. Proportions of 'surviving' (i.e. recovering or active) duck slices were significantly higher than for chickens in anoxia, and relative activity levels were higher for ducks than for chickens during hypoxia, anoxia and recovery. Survival of rat slices was significantly poorer than for birds under all conditions. Results suggest that (1) duck cerebellar neurons are intrinsically more hypoxia-tolerant than chicken neurons; (2) avian neurons are more hypoxia-tolerant than rat neurons, and (3) the enhanced hypoxic tolerance of duck neurons largely depended on efficient anaerobiosis since it mainly manifested itself in chemical anoxia. Mechanisms underlying the observed differences in neuronal hypoxic responses remain to be elucidated. PMID:19779726

  15. Mitochondrial fission is an acute and adaptive response in injured motor neurons

    PubMed Central

    Kiryu-Seo, Sumiko; Tamada, Hiromi; Kato, Yukina; Yasuda, Katsura; Ishihara, Naotada; Nomura, Masatoshi; Mihara, Katsuyoshi; Kiyama, Hiroshi

    2016-01-01

    Successful recovery from neuronal damage requires a huge energy supply, which is provided by mitochondria. However, the physiological relevance of mitochondrial dynamics in damaged neurons in vivo is poorly understood. To address this issue, we established unique bacterial artificial chromosome transgenic (BAC Tg) mice, which develop and function normally, but in which neuronal injury induces labelling of mitochondria with green fluorescent protein (GFP) and expression of cre recombinase. GFP-labelled mitochondria in BAC Tg mice appear shorter in regenerating motor axons soon after nerve injury compared with mitochondria in non-injured axons, suggesting the importance of increased mitochondrial fission during the early phase of nerve regeneration. Crossing the BAC Tg mice with mice carrying a floxed dynamin-related protein 1 gene (Drp1), which is necessary for mitochondrial fission, ablates mitochondrial fission specifically in injured neurons. Injury-induced Drp1-deficient motor neurons show elongated or abnormally gigantic mitochondria, which have impaired membrane potential and axonal transport velocity during the early phase after injury, and eventually promote neuronal death. Our in vivo data suggest that acute and prominent mitochondrial fission during the early stage after nerve injury is an adaptive response and is involved in the maintenance of mitochondrial and neuronal integrity to prevent neurodegeneration. PMID:27319806

  16. Hippocampal adaptive response following extensive neuronal loss in an inducible transgenic mouse model.

    PubMed

    Myczek, Kristoffer; Yeung, Stephen T; Castello, Nicholas; Baglietto-Vargas, David; LaFerla, Frank M

    2014-01-01

    Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease) and brain traumas (stroke, epilepsy, and traumatic brain injury). One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DT(A) mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DTA mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery. PMID:25184527

  17. Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1

    PubMed Central

    Valdés, Pamela; Mercado, Gabriela; Vidal, Rene L.; Molina, Claudia; Parsons, Geoffrey; Court, Felipe A.; Martinez, Alexis; Galleguillos, Danny; Armentano, Donna; Schneider, Bernard L.; Hetz, Claudio

    2014-01-01

    Parkinson disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Although growing evidence indicates that endoplasmic reticulum (ER) stress is a hallmark of PD, its exact contribution to the disease process is not well understood. Here we report that developmental ablation of X-Box binding protein 1 (XBP1) in the nervous system, a key regulator of the unfolded protein response (UPR), protects dopaminergic neurons against a PD-inducing neurotoxin. This survival effect was associated with a preconditioning condition that resulted from induction of an adaptive ER stress response in dopaminergic neurons of the SNpc, but not in other brain regions. In contrast, silencing XBP1 in adult animals triggered chronic ER stress and dopaminergic neuron degeneration. Supporting this finding, gene therapy to deliver an active form of XBP1 provided neuroprotection and reduced striatal denervation in animals injected with 6-hydroxydopamine. Our results reveal a physiological role of the UPR in the maintenance of protein homeostasis in dopaminergic neurons that may help explain the differential neuronal vulnerability observed in PD. PMID:24753614

  18. Accounting for network effects in neuronal responses using L1 regularized point process models.

    PubMed

    Kelly, Ryan C; Kass, Robert E; Smith, Matthew A; Lee, Tai Sing

    2010-01-01

    Activity of a neuron, even in the early sensory areas, is not simply a function of its local receptive field or tuning properties, but depends on global context of the stimulus, as well as the neural context. This suggests the activity of the surrounding neurons and global brain states can exert considerable influence on the activity of a neuron. In this paper we implemented an L1 regularized point process model to assess the contribution of multiple factors to the firing rate of many individual units recorded simultaneously from V1 with a 96-electrode "Utah" array. We found that the spikes of surrounding neurons indeed provide strong predictions of a neuron's response, in addition to the neuron's receptive field transfer function. We also found that the same spikes could be accounted for with the local field potentials, a surrogate measure of global network states. This work shows that accounting for network fluctuations can improve estimates of single trial firing rate and stimulus-response transfer functions. PMID:22162918

  19. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication

    PubMed Central

    Jiang, Zhiwu; Gu, Liming; Chen, Yanxia

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  20. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication.

    PubMed

    Wang, Gefei; Li, Rui; Jiang, Zhiwu; Gu, Liming; Chen, Yanxia; Dai, Jianping; Li, Kangsheng

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  1. Apoptotic neurons induce proliferative responses of progenitor cells in the postnatal neocortex.

    PubMed

    Petrenko, Volodymyr; Mihhailova, Jevgenia; Salmon, Patrick; Kiss, Jozsef Z

    2015-11-01

    Apoptotic cell death is the leading cause of neuronal loss after neonatal brain injury. Little is known about the intrinsic capacity of the immature cerebral cortex for replacing dead cells. Here we test the hypothesis that neuronal apoptosis is able to trigger compensatory proliferation in surrounding cells. In order to establish a "pure" apoptotic cell death model and to avoid the confounding effects of broken blood-brain barrier and inflammatory reactions, we used a diphtheria toxin (DT) and diphtheria toxin receptor (DTR) system to induce ablation of layer IV neurons in the rodent somatosensory cortex during the early postnatal period. We found that DT-triggered apoptosis is a slowly progressing event lasting about for 7 days. While dying cells expressed the morphological features of apoptosis, we could not detect immunoreactivity for activated caspase-3 in these cells. Microglia activation and proliferation represented the earliest cellular responses to apoptotic cell death. In addition, we found that induced apoptosis triggered a massive proliferation of undifferentiated progenitor cell pool including Sox2 as well as NG2 cells. The default differentiation pattern of proliferating progenitors appears to be the glial phenotype; we could not find evidence for newly generated neurons in response to apoptotic neuronal death. These results suggest that mitotically active progenitor populations are intrinsically capable to contribute to the repair process of injured cortical tissue and may represent a potential target for neuronal replacement strategies.

  2. Spatiotemporal processing of linear acceleration: primary afferent and central vestibular neuron responses

    NASA Technical Reports Server (NTRS)

    Angelaki, D. E.; Dickman, J. D.

    2000-01-01

    Spatiotemporal convergence and two-dimensional (2-D) neural tuning have been proposed as a major neural mechanism in the signal processing of linear acceleration. To examine this hypothesis, we studied the firing properties of primary otolith afferents and central otolith neurons that respond exclusively to horizontal linear accelerations of the head (0.16-10 Hz) in alert rhesus monkeys. Unlike primary afferents, the majority of central otolith neurons exhibited 2-D spatial tuning to linear acceleration. As a result, central otolith dynamics vary as a function of movement direction. During movement along the maximum sensitivity direction, the dynamics of all central otolith neurons differed significantly from those observed for the primary afferent population. Specifically at low frequencies (neurons peaked in phase with linear velocity, in contrast to primary afferents that peaked in phase with linear acceleration. At least three different groups of central response dynamics were described according to the properties observed for motion along the maximum sensitivity direction. "High-pass" neurons exhibited increasing gains and phase values as a function of frequency. "Flat" neurons were characterized by relatively flat gains and constant phase lags (approximately 20-55 degrees ). A few neurons ("low-pass") were characterized by decreasing gain and phase as a function of frequency. The response dynamics of central otolith neurons suggest that the approximately 90 degrees phase lags observed at low frequencies are not the result of a neural integration but rather the effect of nonminimum phase behavior, which could arise at least partly through spatiotemporal convergence. Neither afferent nor central otolith neurons discriminated between gravitational and inertial components of linear acceleration. Thus response sensitivity was indistinguishable during 0.5-Hz pitch oscillations and fore-aft movements

  3. Neuronal responses to face-like and facial stimuli in the monkey superior colliculus

    PubMed Central

    Nguyen, Minh Nui; Matsumoto, Jumpei; Hori, Etsuro; Maior, Rafael Souto; Tomaz, Carlos; Tran, Anh H.; Ono, Taketoshi; Nishijo, Hisao

    2014-01-01

    The superficial layers of the superior colliculus (sSC) appear to function as a subcortical visual pathway that bypasses the striate cortex for the rapid processing of coarse facial information. We investigated the responses of neurons in the monkey sSC during a delayed non-matching-to-sample (DNMS) task in which monkeys were required to discriminate among five categories of visual stimuli [photos of faces with different gaze directions, line drawings of faces, face-like patterns (three dark blobs on a bright oval), eye-like patterns, and simple geometric patterns]. Of the 605 sSC neurons recorded, 216 neurons responded to the visual stimuli. Among the stimuli, face-like patterns elicited responses with the shortest latencies. Low-pass filtering of the images did not influence the responses. However, scrambling of the images increased the responses in the late phase, and this was consistent with a feedback influence from upstream areas. A multidimensional scaling (MDS) analysis of the population data indicated that the sSC neurons could separately encode face-like patterns during the first 25-ms period after stimulus onset, and stimulus categorization developed in the next three 25-ms periods. The amount of stimulus information conveyed by the sSC neurons and the number of stimulus-differentiating neurons were consistently higher during the 2nd to 4th 25-ms periods than during the first 25-ms period. These results suggested that population activity of the sSC neurons preferentially filtered face-like patterns with short latencies to allow for the rapid processing of coarse facial information and developed categorization of the stimuli in later phases through feedback from upstream areas. PMID:24672448

  4. The neuronal response at extended timescales: long-term correlations without long-term memory

    PubMed Central

    Soudry, Daniel; Meir, Ron

    2014-01-01

    Long term temporal correlations frequently appear at many levels of neural activity. We show that when such correlations appear in isolated neurons, they indicate the existence of slow underlying processes and lead to explicit conditions on the dynamics of these processes. Moreover, although these slow processes can potentially store information for long times, we demonstrate that this does not imply that the neuron possesses a long memory of its input, even if these processes are bidirectionally coupled with neuronal response. We derive these results for a broad class of biophysical neuron models, and then fit a specific model to recent experiments. The model reproduces the experimental results, exhibiting long term (days-long) correlations due to the interaction between slow variables and internal fluctuations. However, its memory of the input decays on a timescale of minutes. We suggest experiments to test these predictions directly. PMID:24744724

  5. In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders

    PubMed Central

    Carnemolla, Alisia; Lazell, Hayley; Moussaoui, Saliha; Bates, Gillian P.

    2015-01-01

    The heat shock response (HSR) is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders. PMID:26134141

  6. In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.

    PubMed

    Carnemolla, Alisia; Lazell, Hayley; Moussaoui, Saliha; Bates, Gillian P

    2015-01-01

    The heat shock response (HSR) is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders. PMID:26134141

  7. Activity of Somatosensory-Responsive Neurons in High Subdivisions of SI Cortex during Locomotion

    PubMed Central

    Favorov, Oleg V.; Nilaweera, Wijitha U.; Miasnikov, Alexandre A.

    2015-01-01

    Responses of neurons in the primary somatosensory cortex during movements are poorly understood, even during such simple tasks as walking on a flat surface. In this study, we analyzed spike discharges of neurons in the rostral bank of the ansate sulcus (areas 1–2) in 2 cats while the cats walked on a flat surface or on a horizontal ladder, a complex task requiring accurate stepping. All neurons (n = 82) that had receptive fields (RFs) on the contralateral forelimb exhibited frequency modulation of their activity that was phase locked to the stride cycle during simple locomotion. Neurons with proximal RFs (upper arm/shoulder) and pyramidal tract-projecting neurons (PTNs) with fast-conducting axons tended to fire at peak rates in the middle of the swing phase, whereas neurons with RFs on the distal limb (wrist/paw) and slow-conducting PTNs typically showed peak firing at the transition between swing and stance phases. Eleven of 12 neurons with tactile RFs on the volar forepaw began firing toward the end of swing, with peak activity occurring at the moment of foot contact with floor, thereby preceding the evoked sensory volley from touch receptors. Requirement to step accurately on the ladder affected 91% of the neurons, suggesting their involvement in control of accuracy of stepping. During both tasks, neurons exhibited a wide variety of spike distributions within the stride cycle, suggesting that, during either simple or ladder locomotion, they represent the cycling somatosensory events in their activity both predictively before and reflectively after these events take place. PMID:25995465

  8. Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis.

    PubMed

    Hu, Youtian; Liu, Zhenyu; Yu, Xiaoyun; Pasricha, Pankaj J; Undem, Bradley J; Yu, Shaoyong

    2014-07-15

    Eosinophilic esophagitis (EoE) is characterized with eosinophils and mast cells predominated allergic inflammation in the esophagus and present with esophageal dysfunctions such as dysphagia, food impaction, and heartburn. However, the underlying mechanism of esophageal dysfunctions is unclear. This study aims to determine whether neurons in the vagal sensory ganglia are modulated in a guinea pig model of EoE. Animals were actively sensitized by ovalbumin (OVA) and then challenged with aerosol OVA inhalation for 2 wk. This results in a mild esophagitis with increases in mast cells and eosinophils in the esophageal wall. Vagal nodose and jugular neurons were disassociated, and their responses to acid, capsaicin, and transient receptor potential vanilloid type 1 (TRPV1) antagonist AMG-9810 were studied by calcium imaging and whole cell patch-clamp recording. Compared with naïve animals, antigen challenge significantly increased acid responsiveness in both nodose and jugular neurons. Their responses to capsaicin were also increased after antigen challenge. AMG-9810, at a concentration that blocked capsaicin-evoked calcium influx, abolished the increase in acid-induced activation in both nodose and jugular neurons. Vagotomy strongly attenuated those increased responses of nodose and jugular neurons to both acid and capsaicin induced by antigen challenge. These data for the first time demonstrated that prolonged antigen challenge significantly increases acid responsiveness in vagal nodose and jugular ganglia neurons. This sensitization effect is mediated largely through TRPV1 and initiated at sensory nerve endings in the peripheral tissues. Allergen-induced enhancement of responsiveness to noxious stimulation by acid in sensory nerve may contribute to the development of esophageal dysfunctions such as heartburn in EoE.

  9. Electrosensory Midbrain Neurons Display Feature Invariant Responses to Natural Communication Stimuli

    PubMed Central

    Aumentado-Armstrong, Tristan; Metzen, Michael G.; Sproule, Michael K. J.; Chacron, Maurice J.

    2015-01-01

    Neurons that respond selectively but in an invariant manner to a given feature of natural stimuli have been observed across species and systems. Such responses emerge in higher brain areas, thereby suggesting that they occur by integrating afferent input. However, the mechanisms by which such integration occurs are poorly understood. Here we show that midbrain electrosensory neurons can respond selectively and in an invariant manner to heterogeneity in behaviorally relevant stimulus waveforms. Such invariant responses were not seen in hindbrain electrosensory neurons providing afferent input to these midbrain neurons, suggesting that response invariance results from nonlinear integration of such input. To test this hypothesis, we built a model based on the Hodgkin-Huxley formalism that received realistic afferent input. We found that multiple combinations of parameter values could give rise to invariant responses matching those seen experimentally. Our model thus shows that there are multiple solutions towards achieving invariant responses and reveals how subthreshold membrane conductances help promote robust and invariant firing in response to heterogeneous stimulus waveforms associated with behaviorally relevant stimuli. We discuss the implications of our findings for the electrosensory and other systems. PMID:26474395

  10. Electrosensory Midbrain Neurons Display Feature Invariant Responses to Natural Communication Stimuli.

    PubMed

    Aumentado-Armstrong, Tristan; Metzen, Michael G; Sproule, Michael K J; Chacron, Maurice J

    2015-10-01

    Neurons that respond selectively but in an invariant manner to a given feature of natural stimuli have been observed across species and systems. Such responses emerge in higher brain areas, thereby suggesting that they occur by integrating afferent input. However, the mechanisms by which such integration occurs are poorly understood. Here we show that midbrain electrosensory neurons can respond selectively and in an invariant manner to heterogeneity in behaviorally relevant stimulus waveforms. Such invariant responses were not seen in hindbrain electrosensory neurons providing afferent input to these midbrain neurons, suggesting that response invariance results from nonlinear integration of such input. To test this hypothesis, we built a model based on the Hodgkin-Huxley formalism that received realistic afferent input. We found that multiple combinations of parameter values could give rise to invariant responses matching those seen experimentally. Our model thus shows that there are multiple solutions towards achieving invariant responses and reveals how subthreshold membrane conductances help promote robust and invariant firing in response to heterogeneous stimulus waveforms associated with behaviorally relevant stimuli. We discuss the implications of our findings for the electrosensory and other systems.

  11. Environmental enrichment improves response strength, threshold, selectivity, and latency of auditory cortex neurons.

    PubMed

    Engineer, Navzer D; Percaccio, Cherie R; Pandya, Pritesh K; Moucha, Raluca; Rathbun, Daniel L; Kilgard, Michael P

    2004-07-01

    Over the last 50 yr, environmental enrichment has been shown to generate more than a dozen changes in brain anatomy. The consequences of these physical changes on information processing have not been well studied. In this study, rats were housed in enriched or standard conditions either prior to or after reaching sexual maturity. Evoked potentials from awake rats and extracellular recordings from anesthetized rats were used to document responses of auditory cortex neurons. This report details several significant, new findings about the influence of housing conditions on the responses of rat auditory cortex neurons. First, enrichment dramatically increases the strength of auditory cortex responses. Tone-evoked potentials of enriched rats, for example, were more than twice the amplitude of rats raised in standard laboratory conditions. Second, cortical responses of both young and adult animals benefit from exposure to an enriched environment and are degraded by exposure to an impoverished environment. Third, housing condition resulted in rapid remodeling of cortical responses in <2 wk. Fourth, recordings made under anesthesia indicate that enrichment increases the number of neurons activated by any sound. This finding shows that the evoked potential plasticity documented in awake rats was not due to differences in behavioral state. Finally, enrichment made primary auditory cortex (A1) neurons more sensitive to quiet sounds, more selective for tone frequency, and altered their response latencies. These experiments provide the first evidence of physiologic changes in auditory cortex processing resulting from generalized environmental enrichment.

  12. Morphology, PKCδ expression, and synaptic responsiveness of different types of rat central lateral amygdala neurons

    PubMed Central

    Amano, Taiju; Amir, Alon; Goswami, Sonal

    2012-01-01

    Recent findings implicate the central lateral amygdala (CeL) in conditioned fear. Indeed, CeL contains neurons exhibiting positive (CeL-On) or negative (CeL-Off) responses to fear-inducing conditioned stimuli (CSs). In mice, these cells differ in their expression of protein kinase Cδ (PKCδ) and physiological properties. CeL-Off cells are PKCδ+ and late firing (LF), whereas CeL-On cells are PKCδ− and express a regular-spiking (RS) or low-threshold bursting (LTB) phenotype. However, the scarcity of LF cells in rats raises questions about the correspondence between the organization of CeL in mice and rats. Therefore, we studied the PKCδ expression, morphological properties, synaptic responsiveness, and fear conditioning-induced plasticity of rat CeL neurons. No PKCδ+ LF cells were encountered, but ≈20–25% of RS and LTB neurons were PKCδ+. Compared with RS neurons, a higher proportion of LTB cells projected to central medial amygdala (CeM) and they had fewer primary dendritic branches, yet the amplitude of excitatory postsynaptic potentials (EPSPs) evoked by lateral amygdala (LA) stimulation was similar in RS and LTB cells. In contrast, LA-evoked inhibitory postsynaptic potentials (IPSPs) had a higher amplitude in LTB than RS neurons. Finally, fear conditioning did not induce plasticity at LA inputs to RS or LTB neurons. These findings point to major species differences in the organization of CeL. Since rat LTB cells are subjected to stronger feedforward inhibition, they are more likely to exhibit inhibitory CS responses than RS cells. This is expected to cause a disinhibition of CeM fear output neurons and therefore an increase in fear expression. PMID:22972957

  13. Complete Firing-Rate Response of Neurons with Complex Intrinsic Dynamics.

    PubMed

    Puelma Touzel, Maximilian; Wolf, Fred

    2015-12-01

    The response of a neuronal population over a space of inputs depends on the intrinsic properties of its constituent neurons. Two main modes of single neuron dynamics-integration and resonance-have been distinguished. While resonator cell types exist in a variety of brain areas, few models incorporate this feature and fewer have investigated its effects. To understand better how a resonator's frequency preference emerges from its intrinsic dynamics and contributes to its local area's population firing rate dynamics, we analyze the dynamic gain of an analytically solvable two-degree of freedom neuron model. In the Fokker-Planck approach, the dynamic gain is intractable. The alternative Gauss-Rice approach lifts the resetting of the voltage after a spike. This allows us to derive a complete expression for the dynamic gain of a resonator neuron model in terms of a cascade of filters on the input. We find six distinct response types and use them to fully characterize the routes to resonance across all values of the relevant timescales. We find that resonance arises primarily due to slow adaptation with an intrinsic frequency acting to sharpen and adjust the location of the resonant peak. We determine the parameter regions for the existence of an intrinsic frequency and for subthreshold and spiking resonance, finding all possible intersections of the three. The expressions and analysis presented here provide an account of how intrinsic neuron dynamics shape dynamic population response properties and can facilitate the construction of an exact theory of correlations and stability of population activity in networks containing populations of resonator neurons. PMID:26720924

  14. Complete Firing-Rate Response of Neurons with Complex Intrinsic Dynamics

    PubMed Central

    Puelma Touzel, Maximilian; Wolf, Fred

    2015-01-01

    The response of a neuronal population over a space of inputs depends on the intrinsic properties of its constituent neurons. Two main modes of single neuron dynamics–integration and resonance–have been distinguished. While resonator cell types exist in a variety of brain areas, few models incorporate this feature and fewer have investigated its effects. To understand better how a resonator’s frequency preference emerges from its intrinsic dynamics and contributes to its local area’s population firing rate dynamics, we analyze the dynamic gain of an analytically solvable two-degree of freedom neuron model. In the Fokker-Planck approach, the dynamic gain is intractable. The alternative Gauss-Rice approach lifts the resetting of the voltage after a spike. This allows us to derive a complete expression for the dynamic gain of a resonator neuron model in terms of a cascade of filters on the input. We find six distinct response types and use them to fully characterize the routes to resonance across all values of the relevant timescales. We find that resonance arises primarily due to slow adaptation with an intrinsic frequency acting to sharpen and adjust the location of the resonant peak. We determine the parameter regions for the existence of an intrinsic frequency and for subthreshold and spiking resonance, finding all possible intersections of the three. The expressions and analysis presented here provide an account of how intrinsic neuron dynamics shape dynamic population response properties and can facilitate the construction of an exact theory of correlations and stability of population activity in networks containing populations of resonator neurons. PMID:26720924

  15. Imaging Calcium Responses in GFP-tagged Neurons of Hypothalamic Mouse Brain Slices

    PubMed Central

    Schauer, Christian; Leinders-Zufall, Trese

    2012-01-01

    Despite an enormous increase in our knowledge about the mechanisms underlying the encoding of information in the brain, a central question concerning the precise molecular steps as well as the activity of specific neurons in multi-functional nuclei of brain areas such as the hypothalamus remain. This problem includes identification of the molecular components involved in the regulation of various neurohormone signal transduction cascades. Elevations of intracellular Ca2+ play an important role in regulating the sensitivity of neurons, both at the level of signal transduction and at synaptic sites. New tools have emerged to help identify neurons in the myriad of brain neurons by expressing green fluorescent protein (GFP) under the control of a particular promoter. To monitor both spatially and temporally stimulus-induced Ca2+ responses in GFP-tagged neurons, a non-green fluorescent Ca2+ indicator dye needs to be used. In addition, confocal microscopy is a favorite method of imaging individual neurons in tissue slices due to its ability to visualize neurons in distinct planes of depth within the tissue and to limit out-of-focus fluorescence. The ratiometric Ca2+ indicator fura-2 has been used in combination with GFP-tagged neurons1. However, the dye is excited by ultraviolet (UV) light. The cost of the laser and the limited optical penetration depth of UV light hindered its use in many laboratories. Moreover, GFP fluorescence may interfere with the fura-2 signals2. Therefore, we decided to use a red fluorescent Ca2+ indicator dye. The huge Stokes shift of fura-red permits multicolor analysis of the red fluorescence in combination with GFP using a single excitation wavelength. We had previously good results using fura-red in combination with GFP-tagged olfactory neurons3. The protocols for olfactory tissue slices seemed to work equally well in hypothalamic neurons4. Fura-red based Ca2+ imaging was also successfully combined with GFP-tagged pancreatic β-cells and GFP

  16. Mouse V1 population correlates of visual detection rely on heterogeneity within neuronal response patterns

    PubMed Central

    Montijn, Jorrit S; Goltstein, Pieter M; Pennartz, Cyriel MA

    2015-01-01

    Previous studies have demonstrated the importance of the primary sensory cortex for the detection, discrimination, and awareness of visual stimuli, but it is unknown how neuronal populations in this area process detected and undetected stimuli differently. Critical differences may reside in the mean strength of responses to visual stimuli, as reflected in bulk signals detectable in functional magnetic resonance imaging, electro-encephalogram, or magnetoencephalography studies, or may be more subtly composed of differentiated activity of individual sensory neurons. Quantifying single-cell Ca2+ responses to visual stimuli recorded with in vivo two-photon imaging, we found that visual detection correlates more strongly with population response heterogeneity rather than overall response strength. Moreover, neuronal populations showed consistencies in activation patterns across temporally spaced trials in association with hit responses, but not during nondetections. Contrary to models relying on temporally stable networks or bulk signaling, these results suggest that detection depends on transient differentiation in neuronal activity within cortical populations. DOI: http://dx.doi.org/10.7554/eLife.10163.001 PMID:26646184

  17. Odorant response properties of individual neurons in an olfactory glomerular module

    PubMed Central

    Kikuta, Shu; Fletcher, Max L.; Homma, Ryota; Yamasoba, Tatsuya; Nagayama, Shin

    2013-01-01

    Summary Neuronal networks that are directly associated with glomeruli in the olfactory bulb are thought to comprise functional modules. However, this has not yet been experimentally proven. In this study, we explored the anatomical and functional architecture of glomerular modules using in vivo two-photon calcium imaging. Surprisingly, the deep portions of the glomerular modules showed considerable spatial overlap with other modules. Juxtaglomerular cells showed similar excitatory odorant response profiles to presynaptic olfactory sensory neuron inputs. Mitral cells exhibited a more sharply tuned molecular receptive range compared to juxtaglomerular cells, and their odorant response profiles varied depending on their interneuronal horizontal distances. These data suggest that glomerular modules are composed of functionally distinct neurons, and that homogenous odor inputs to each glomerulus may be parsed and processed in different fashions within the modules before being sent to higher olfactory centers. PMID:23522047

  18. SNX27 regulation of GIRK channels in VTA dopamine neurons attenuates in vivo cocaine response

    PubMed Central

    Munoz, Michaelanne B.; Slesinger, Paul A.

    2014-01-01

    The subcellular pathways that regulate G protein-gated inwardly rectifying potassium (GIRK or Kir3) channels are important for controlling the excitability of neurons. Sorting nexin 27 (SNX27) is a PDZ-containing protein known to bind GIRK2c/3 channels but its function in vivo is poorly understood. Here, we investigated the role of SNX27 in regulating GIRK currents in dopamine (DA) neurons of the ventral tegmental area (VTA). Mice lacking SNX27 in DA neurons exhibited reduced GABABR-activated GIRK currents but had normal Ih currents and dopamine D2R-activated GIRK currents. Expression of GIRK2a, a SNX27-insensitive splice-variant, restored GABABR-activated GIRK currents in SNX27-deficient DA neurons. Remarkably, mice with significantly reduced GABABR-activated GIRK currents in only DA neurons were hypersensitive to cocaine, and could be restored to a normal locomotor response with GIRK2a expression. These results identify a novel pathway for regulating excitability of VTA DA neurons, highlighting SNX27 as a promising target for treating addiction. PMID:24811384

  19. MeCP2 regulates activity-dependent transcriptional responses in olfactory sensory neurons.

    PubMed

    Lee, Wooje; Yun, Jung-Mi; Woods, Rima; Dunaway, Keith; Yasui, Dag H; Lasalle, Janine M; Gong, Qizhi

    2014-12-01

    During postnatal development, neuronal activity controls the remodeling of initially imprecise neuronal connections through the regulation of gene expression. MeCP2 binds to methylated DNA and modulates gene expression during neuronal development and MECP2 mutation causes the autistic disorder Rett syndrome. To investigate a role for MeCP2 in neuronal circuit refinement and to identify activity-dependent MeCP2 transcription regulations, we leveraged the precise organization and accessibility of olfactory sensory axons to manipulation of neuronal activity through odorant exposure in vivo. We demonstrate that olfactory sensory axons failed to develop complete convergence when Mecp2 is deficient in olfactory sensory neurons (OSNs) in an otherwise wild-type animal. Furthermore, we demonstrate that expression of selected adhesion genes was elevated in Mecp2-deficient glomeruli, while acute odor stimulation in control mice resulted in significantly reduced MeCP2 binding to these gene loci, correlating with increased expression. Thus, MeCP2 is required for both circuitry refinement and activity-dependent transcriptional responses in OSNs.

  20. Responses from two firing patterns in inferior colliculus neurons to stimulation of the lateral lemniscus dorsal nucleus

    PubMed Central

    Li, Xiao-ting; Wang, Ning-yu; Wang, Yan-jun; Xu, Zhi-qing; Liu, Jin-feng; Bai, Yun-fei; Dai, Jin-sheng; Zhao, Jing-yi

    2016-01-01

    The γ-aminobutyric acid neurons (GABAergic neurons) in the inferior colliculus are classified into various patterns based on their intrinsic electrical properties to a constant current injection. Although this classification is associated with physiological function, the exact role for neurons with various firing patterns in acoustic processing remains poorly understood. In the present study, we analyzed characteristics of inferior colliculus neurons in vitro, and recorded responses to stimulation of the dorsal nucleus of the lateral lemniscus using the whole-cell patch clamp technique. Seven inferior colliculus neurons were tested and were classified into two firing patterns: sustained-regular (n = 4) and sustained-adapting firing patterns (n = 3). The majority of inferior colliculus neurons exhibited slight changes in response to stimulation and bicuculline. The responses of one neuron with a sustained-adapting firing pattern were suppressed after stimulation, but recovered to normal levels following application of the γ-aminobutyric acid receptor antagonist. One neuron with a sustained-regular pattern showed suppressed stimulation responses, which were not affected by bicuculline. Results suggest that GABAergic neurons in the inferior colliculus exhibit sustained-regular or sustained-adapting firing patterns. Additionally, GABAergic projections from the dorsal nucleus of the lateral lemniscus to the inferior colliculus are associated with sound localization. The different neuronal responses of various firing patterns suggest a role in sound localization. A better understanding of these mechanisms and functions will provide better clinical treatment paradigms for hearing deficiencies. PMID:27335563

  1. Alternate task inhibits single-neuron category-selective responses in the human hippocampus while preserving selectivity in the amygdala.

    PubMed

    Steinmetz, Peter N

    2009-02-01

    One fifth of neurons in the medial-temporal lobe of human epilepsy patients respond selectively to categories of images, such as faces or cars. Here we show that responses of hippocampal neurons are rapidly modified as subjects alternate (over 60 sec) between two tasks (1) identifying images from a category, or (2) playing a simple video game superimposed on the same images. Category-selective responses, present when a subject identifies categories, are eliminated when the subject shifts to playing the game for 87% of category-selective hippocampal neurons. By contrast, responses in the amygdala are present during both tasks for 72% of category-selective amygdalar neurons. These results suggest that attention to images is required to evoke selective responses from single neurons in the hippocampus, but is not required by neurons in the amygdala.

  2. The response of retinal neurons to high-frequency stimulation

    NASA Astrophysics Data System (ADS)

    Cai, Changsi; Twyford, Perry; Fried, Shelley

    2013-06-01

    Objective. High-rate pulse trains have proven to be effective in cochlear prosthetics and, more recently, have been shown to elicit a wide range of interesting response properties in axons of the peripheral nervous system. Surprisingly, the effectiveness of such trains for use in retinal prostheses has not been explored. Approach. Using cell-attached patch clamp methods, we measured the in vitro response of two rabbit retinal ganglion cell types, OFF-brisk transient (OFF-BT) and ON-OFF directionally selective (DS), to trains of biphasic pulses delivered at 2000 pulses per second (PPS). Main Results. For OFF-BT cells, response onset occurred at ˜20 µA, and maximum response occurred at ˜40 µA. Interestingly, spiking levels decreased for further increases in amplitude. In contrast, DS cells had a spiking onset at ˜25 µA and maintained strong spiking as stimulus amplitude was increased, even at the highest levels tested. Thus, a low-amplitude stimulus train at 2000 PPS (˜25 µA) will activate OFF-BT cells strongly, while simultaneously activating DS cells only weakly. In contrast, a high amplitude train (˜75 µA) will activate DS cells strongly while suppressing responses in OFF-BT cells. Significance. The response differences between cell types suggest some forms of preferential activation may be possible, and further testing is warranted. Further, the scope of the response differences found here suggests activation mechanisms that are more complex than those described in previous studies.

  3. [Changes in neuronal responses of area 7 of the cat cerebral cortex to unconditional and conditional stimulation with additional stimuli].

    PubMed

    Busel', B I; Kniga, A P

    1991-01-01

    Influence of external stimuli and food motivation on neuronal spike responses (area 7) induced by conditional and unconditional stimulation were studied in the awake cats. The beginning of external stimuli and food motivation inhibited neuronal responses after electro-cutaneous stimulation. During external stimulation after the reflex onset conditional neuronal reactions were later by 50-250 ms, but the latencies of conditional movements did not change. Identical changes of neuronal responses were during variation of food motivation. It is supposed that the reason of the studied phenomenon is variation of the exteroceptive attention level of cats induced by changes in experiment conditions.

  4. Predicting spike occurrence and neuronal responsiveness from LFPs in primary somatosensory cortex.

    PubMed

    Storchi, Riccardo; Zippo, Antonio G; Caramenti, Gian Carlo; Valente, Maurizio; Biella, Gabriele E M

    2012-01-01

    Local Field Potentials (LFPs) integrate multiple neuronal events like synaptic inputs and intracellular potentials. LFP spatiotemporal features are particularly relevant in view of their applications both in research (e.g. for understanding brain rhythms, inter-areal neural communication and neuronal coding) and in the clinics (e.g. for improving invasive Brain-Machine Interface devices). However the relation between LFPs and spikes is complex and not fully understood. As spikes represent the fundamental currency of neuronal communication this gap in knowledge strongly limits our comprehension of neuronal phenomena underlying LFPs. We investigated the LFP-spike relation during tactile stimulation in primary somatosensory (S-I) cortex in the rat. First we quantified how reliably LFPs and spikes code for a stimulus occurrence. Then we used the information obtained from our analyses to design a predictive model for spike occurrence based on LFP inputs. The model was endowed with a flexible meta-structure whose exact form, both in parameters and structure, was estimated by using a multi-objective optimization strategy. Our method provided a set of nonlinear simple equations that maximized the match between models and true neurons in terms of spike timings and Peri Stimulus Time Histograms. We found that both LFPs and spikes can code for stimulus occurrence with millisecond precision, showing, however, high variability. Spike patterns were predicted significantly above chance for 75% of the neurons analysed. Crucially, the level of prediction accuracy depended on the reliability in coding for the stimulus occurrence. The best predictions were obtained when both spikes and LFPs were highly responsive to the stimuli. Spike reliability is known to depend on neuron intrinsic properties (i.e. on channel noise) and on spontaneous local network fluctuations. Our results suggest that the latter, measured through the LFP response variability, play a dominant role. PMID:22586452

  5. Single-unit responses of serotonergic medullary raphe neurons to cardiovascular challenges in freely moving cats.

    PubMed

    Martin-Cora, Francisco J; Fornal, Casimir A; Jacobs, Barry L

    2005-12-01

    Single-unit activity of serotonergic neurons in the nuclei raphe obscurus (NRO) and raphe pallidus (NRP) were recorded in conjunction with heart rate in freely moving cats in response to systemic administration of vasoactive drugs and to graded haemorrhage. Bolus administration of phenylephrine hydrochloride and sodium nitroprusside (20 microg/kg, i.v.) produced a marked, transient reflex bradycardia (-42 b.p.m.) and tachycardia (+60 b.p.m.), respectively. The activity of NRO/NRP serotonergic neurons remained unchanged after phenylephrine and nitroprusside administration. The administration of hydralazine (1 mg/kg, i.v.), a long-acting vasodilator, produced sustained tachycardia (+60 b.p.m.), which was not accompanied by changes in neuronal activity, despite prolonged reflex activation of the sympathetic nervous system. The initial withdrawal of up to 15% of total blood volume increased heart rate (+12 b.p.m.), whereas the removal of 22.5% of total blood decreased heart rate (-44 b.p.m.). The activity of NRO/NRP serotonergic neurons remained unaltered throughout graded haemorrhage trials, despite the changes in sympathetic outflow. Thus, serotonergic NRO and NRP neurons appear to be insensitive to alterations in blood pressure and baroreceptor activity, and this lack of responsiveness does not support a specific role for these cells in cardiovascular regulation. Furthermore, these neurons do not appear to be involved in physiological mechanisms underlying alterations in autonomic outflow invoked by hypertension and hypotension. Taken within the context of our previous work, the present data suggest that medullary serotonergic neurons may modulate autonomic outflow, but only in relation to their primary role in motor control. PMID:16367786

  6. The serotonin releaser fenfluramine alters the auditory responses of inferior colliculus neurons.

    PubMed

    Hall, Ian C; Hurley, Laura M

    2007-06-01

    Local direct application of the neuromodulator serotonin strongly influences auditory response properties of neurons in the inferior colliculus (IC), but endogenous stores of serotonin may be released in a distinct spatial or temporal pattern. To explore this issue, the serotonin releaser fenfluramine was iontophoretically applied to extracellularly recorded neurons in the IC of the Mexican free-tailed bat (Tadarida brasiliensis). Fenfluramine mimicked the effects of serotonin on spike count and first spike latency in most neurons, and its effects could be blocked by co-application of serotonin receptor antagonists, consistent with fenfluramine-evoked serotonin release. Responses to fenfluramine did not vary during single applications or across multiple applications, suggesting that fenfluramine did not deplete serotonin stores. A predicted gradient in the effects of fenfluramine with serotonin fiber density was not observed, but neurons with fenfluramine-evoked increases in latency occurred at relatively greater recording depths compared to other neurons with similar characteristic frequencies. These findings support the conclusion that there may be spatial differences in the effects of exogenous and endogenous sources of serotonin, but that other factors such as the identities and locations of serotonin receptors are also likely to play a role in determining the dynamics of serotonergic effects. PMID:17339086

  7. Ethanol withdrawal hyper-responsiveness mediated by NMDA receptors in spinal cord motor neurons

    PubMed Central

    Li, Hui-Fang; Kendig, Joan J

    2003-01-01

    Following ethanol (EtOH) exposure, population excitatory postsynaptic potentials (pEPSPs) in isolated spinal cord increase to a level above control (withdrawal hyper-responsiveness). The present studies were designed to characterize this phenomenon and in particular to test the hypothesis that protein kinases mediate withdrawal. Patch-clamp studies were carried out in motor neurons in rat spinal cord slices. Currents were evoked by brief pulses of glutamate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA). Of 15 EtOH-sensitive neurons in which currents were evoked by glutamate, four (27%) displayed withdrawal hyper-responsiveness in the washout period. Mean current area after washout was 129.6±5% of control. When currents were evoked by AMPA, two of 10 neurons (20%) displayed withdrawal hyper-responsiveness, with a mean current area 122±8% of control on washout. Of a group of 11 neurons in which currents were evoked by NMDA, nine (82%) displayed withdrawal hyper-responsiveness. Mean increase in current area at the end of the washout period was to 133±6% of control (n=9, P<0.001). When NMDA applications were stopped durithe period of EtOH exposure, mean area of NMDA-evoked responses on washout was only 98.0±5% of control (n=6, P>0.05). The tyrosine kinase inhibitor genistein (10–20 μM) blocked withdrawal hyper-responsiveness. Of six EtOH-sensitive neurons, the mean NMDA-evoked current area after washout was 89±6% of control, P>0.05. The protein kinase A (PKA) inhibitor Rp-cAMP (20–500 μM) did not block withdrawal hyper-responsiveness. On washout, the mean NMDA-evoked current area was 124±6% of control (n=5, P<0.05). Two broad-spectrum specific protein kinase C (PKC) inhibitors, GF-109203X (0.3 μM) and chelerythrine chloride (0.5–2 nM), blocked withdrawal hyper-responsiveness. Responses on washout were 108±7%, n=5 and 88±4%, n=4 of control, respectively, P>0.05. NMDA activation during EtOH exposure

  8. Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses.

    PubMed

    Royer, S; Paré, D

    2002-01-01

    Classical fear conditioning is believed to result from potentiation of conditioned synaptic inputs in the basolateral amygdala. That is, the conditioned stimulus would excite more neurons in the central nucleus and, via their projections to the brainstem and hypothalamus, evoke fear responses. However, much data suggests that extinction of fear responses does not depend on the reversal of these changes but on a parallel NMDA-dependent learning that competes with the first one. Because they control impulse traffic from the basolateral amygdala to the central nucleus, GABAergic neurons of the intercalated cell masses are ideally located to implement this second learning. Consistent with this hypothesis, the present study shows that low- and high-frequency stimulation of basolateral afferents respectively induce long-term depression (LTD) and potentiation (LTP) of responses in intercalated cells. Moreover, induction of LTP and LTD is prevented by application of an NMDA antagonist. To determine how these activity-dependent changes are expressed, we tested whether LTD and LTP induction are associated with modifications in paired-pulse facilitation, an index of transmitter release probability. Only LTP induction was associated with a change in paired-pulse facilitation. Depotentiation of previously potentiated synapses did not revert the modification in paired pulse facilitation, suggesting that LTP is associated with presynaptic alterations, but that LTD and depotentiation depend on postsynaptic changes. Taken together, our results suggest that basolateral synapses onto intercalated neurons can express NMDA-dependent LTP and LTD, consistent with the possibility that intercalated neurons are a critical locus of plasticity for the extinction of conditioned fear responses. Ultimately, these plastic events may prevent conditioned amygdala responses from exciting neurons of the central nucleus, and thus from evoking conditioned fear responses.

  9. Progressive loss of nigrostriatal dopaminergic neurons induced by inflammatory responses to fipronil.

    PubMed

    Park, Jae Hyeon; Park, Youn Sun; Koh, Hyun Chul

    2016-09-01

    Inflammatory responses are involved in mechanisms of neuronal cell damage in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We investigated the mechanisms whereby inflammatory responses contribute to loss of dopaminergic neurons in fipronil (FPN)-treated rats. After stereotaxic injection of FPN in the substantia nigra (SN), the number of tyrosine hydroxylase (TH)-positive neurons and the levels of TH expression in the SN decreased at 7days, and a significant decrease was observed at 14days with a subsequent reduction in striatal TH expression. Decreases in dopamine (DA) levels, however, began at 3days post-injection, preceding the changes in TH expression. In contrast, glial fibrillary acidic protein (GFAP) expression was significantly increased at 3days and persisted for up to 14days post-lesion; these changes in GFAP expression appeared to be inversely correlated with TH expression. Furthermore, we found that FPN administration induced an inflammatory response characterized by increased levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), which was mediated by activated microglia following infusion of FPN unilaterally into the SN. Intranigral injection of FPN underwent an inflammatory response with a resultant ongoing loss of dopaminergic neurons, indicating that pesticides may have important implication for the study of PD.

  10. Dietary Restriction Affects Neuronal Response Property and GABA Synthesis in the Primary Visual Cortex.

    PubMed

    Yang, Jinfang; Wang, Qian; He, Fenfen; Ding, Yanxia; Sun, Qingyan; Hua, Tianmiao; Xi, Minmin

    2016-01-01

    Previous studies have reported inconsistent effects of dietary restriction (DR) on cortical inhibition. To clarify this issue, we examined the response properties of neurons in the primary visual cortex (V1) of DR and control groups of cats using in vivo extracellular single-unit recording techniques, and assessed the synthesis of inhibitory neurotransmitter GABA in the V1 of cats from both groups using immunohistochemical and Western blot techniques. Our results showed that the response of V1 neurons to visual stimuli was significantly modified by DR, as indicated by an enhanced selectivity for stimulus orientations and motion directions, decreased visually-evoked response, lowered spontaneous activity and increased signal-to-noise ratio in DR cats relative to control cats. Further, it was shown that, accompanied with these changes of neuronal responsiveness, GABA immunoreactivity and the expression of a key GABA-synthesizing enzyme GAD67 in the V1 were significantly increased by DR. These results demonstrate that DR may retard brain aging by increasing the intracortical inhibition effect and improve the function of visual cortical neurons in visual information processing. This DR-induced elevation of cortical inhibition may favor the brain in modulating energy expenditure based on food availability. PMID:26863207

  11. Dietary Restriction Affects Neuronal Response Property and GABA Synthesis in the Primary Visual Cortex

    PubMed Central

    Sun, Qingyan; Hua, Tianmiao; Xi, Minmin

    2016-01-01

    Previous studies have reported inconsistent effects of dietary restriction (DR) on cortical inhibition. To clarify this issue, we examined the response properties of neurons in the primary visual cortex (V1) of DR and control groups of cats using in vivo extracellular single-unit recording techniques, and assessed the synthesis of inhibitory neurotransmitter GABA in the V1 of cats from both groups using immunohistochemical and Western blot techniques. Our results showed that the response of V1 neurons to visual stimuli was significantly modified by DR, as indicated by an enhanced selectivity for stimulus orientations and motion directions, decreased visually-evoked response, lowered spontaneous activity and increased signal-to-noise ratio in DR cats relative to control cats. Further, it was shown that, accompanied with these changes of neuronal responsiveness, GABA immunoreactivity and the expression of a key GABA-synthesizing enzyme GAD67 in the V1 were significantly increased by DR. These results demonstrate that DR may retard brain aging by increasing the intracortical inhibition effect and improve the function of visual cortical neurons in visual information processing. This DR-induced elevation of cortical inhibition may favor the brain in modulating energy expenditure based on food availability. PMID:26863207

  12. Relating Neuronal to Behavioral Performance: Variability of Optomotor Responses in the Blowfly

    PubMed Central

    Rosner, Ronny; Warzecha, Anne-Kathrin

    2011-01-01

    Behavioral responses of an animal vary even when they are elicited by the same stimulus. This variability is due to stochastic processes within the nervous system and to the changing internal states of the animal. To what extent does the variability of neuronal responses account for the overall variability at the behavioral level? To address this question we evaluate the neuronal variability at the output stage of the blowfly's (Calliphora vicina) visual system by recording from motion-sensitive interneurons mediating head optomotor responses. By means of a simple modelling approach representing the sensory-motor transformation, we predict head movements on the basis of the recorded responses of motion-sensitive neurons and compare the variability of the predicted head movements with that of the observed ones. Large gain changes of optomotor head movements have previously been shown to go along with changes in the animals' activity state. Our modelling approach substantiates that these gain changes are imposed downstream of the motion-sensitive neurons of the visual system. Moreover, since predicted head movements are clearly more reliable than those actually observed, we conclude that substantial variability is introduced downstream of the visual system. PMID:22066014

  13. Modulation of Neuronal Responses by Exogenous Attention in Macaque Primary Visual Cortex.

    PubMed

    Wang, Feng; Chen, Minggui; Yan, Yin; Zhaoping, Li; Li, Wu

    2015-09-30

    Visual perception is influenced by attention deployed voluntarily or triggered involuntarily by salient stimuli. Modulation of visual cortical processing by voluntary or endogenous attention has been extensively studied, but much less is known about how involuntary or exogenous attention affects responses of visual cortical neurons. Using implanted microelectrode arrays, we examined the effects of exogenous attention on neuronal responses in the primary visual cortex (V1) of awake monkeys. A bright annular cue was flashed either around the receptive fields of recorded neurons or in the opposite visual field to capture attention. A subsequent grating stimulus probed the cue-induced effects. In a fixation task, when the cue-to-probe stimulus onset asynchrony (SOA) was <240 ms, the cue induced a transient increase of neuronal responses to the probe at the cued location during 40-100 ms after the onset of neuronal responses to the probe. This facilitation diminished and disappeared after repeated presentations of the same cue but recurred for a new cue of a different color. In another task to detect the probe, relative shortening of monkey's reaction times for the validly cued probe depended on the SOA in a way similar to the cue-induced V1 facilitation, and the behavioral and physiological cueing effects remained after repeated practice. Flashing two cues simultaneously in the two opposite visual fields weakened or diminished both the physiological and behavioral cueing effects. Our findings indicate that exogenous attention significantly modulates V1 responses and that the modulation strength depends on both novelty and task relevance of the stimulus. Significance statement: Visual attention can be involuntarily captured by a sudden appearance of a conspicuous object, allowing rapid reactions to unexpected events of significance. The current study discovered a correlate of this effect in monkey primary visual cortex. An abrupt, salient, flash enhanced neuronal

  14. Modulation of Neuronal Responses by Exogenous Attention in Macaque Primary Visual Cortex.

    PubMed

    Wang, Feng; Chen, Minggui; Yan, Yin; Zhaoping, Li; Li, Wu

    2015-09-30

    Visual perception is influenced by attention deployed voluntarily or triggered involuntarily by salient stimuli. Modulation of visual cortical processing by voluntary or endogenous attention has been extensively studied, but much less is known about how involuntary or exogenous attention affects responses of visual cortical neurons. Using implanted microelectrode arrays, we examined the effects of exogenous attention on neuronal responses in the primary visual cortex (V1) of awake monkeys. A bright annular cue was flashed either around the receptive fields of recorded neurons or in the opposite visual field to capture attention. A subsequent grating stimulus probed the cue-induced effects. In a fixation task, when the cue-to-probe stimulus onset asynchrony (SOA) was <240 ms, the cue induced a transient increase of neuronal responses to the probe at the cued location during 40-100 ms after the onset of neuronal responses to the probe. This facilitation diminished and disappeared after repeated presentations of the same cue but recurred for a new cue of a different color. In another task to detect the probe, relative shortening of monkey's reaction times for the validly cued probe depended on the SOA in a way similar to the cue-induced V1 facilitation, and the behavioral and physiological cueing effects remained after repeated practice. Flashing two cues simultaneously in the two opposite visual fields weakened or diminished both the physiological and behavioral cueing effects. Our findings indicate that exogenous attention significantly modulates V1 responses and that the modulation strength depends on both novelty and task relevance of the stimulus. Significance statement: Visual attention can be involuntarily captured by a sudden appearance of a conspicuous object, allowing rapid reactions to unexpected events of significance. The current study discovered a correlate of this effect in monkey primary visual cortex. An abrupt, salient, flash enhanced neuronal

  15. Visual and noxious electrical stimulus-evoked membrane-potential responses in anterior cingulate cortical neurons.

    PubMed

    Ma, Li-Qing; Ning, Li; Wang, Zhiru; Wang, Ying-Wei

    2016-01-01

    Anterior cingulate cortex (ACC) is known to participate in numerous brain functions, such as memory storage, emotion, attention, as well as perception of acute and chronic pain. ACC-dependent brain functions often rely on ACC processing of various forms of environmental information. To understand the neural basis of ACC functions, previous studies have investigated ACC responses to environmental stimulation, particularly complex sensory stimuli as well as award and aversive stimuli, but this issue remains to be further clarified. Here, by performing whole-cell recording in vivo in anaesthetized adult rats, we examined membrane-potential (MP) responses of layer II/III ACC neurons that were evoked by a brief flash of visual stimulation and pain-related electrical stimulation delivered to hind paws. We found that ~54 and ~81 % ACC neurons exhibited excitatory MP responses, subthreshold or suprathreshold, to the visual stimulus and the electrical stimulus, respectively, with no cell showing inhibitory MP responses. We further found that the visually evoked ACC response could be greatly diminished by local lidocaine infusion in the visual thalamus, and only their temporal patterns but not amplitudes could be changed by large-scale visual cortical lesions. Our in vivo whole-cell recording data characterized in ACC neurons a visually evoked response, which was largely dependent on the visual thalamus but not visual cortex, as well as a noxious electrical stimulus-evoked response. These findings may provide potential mechanisms that are used for ACC functions on the basis of sensory information processing. PMID:27585569

  16. The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons

    PubMed Central

    Lanoue, V; Usardi, A; Sigoillot, S M; Talleur, M; Iyer, K; Mariani, J; Isope, P; Vodjdani, G; Heintz, N; Selimi, F

    2013-01-01

    Adhesion-G protein-coupled receptors (GPCRs) are a poorly studied subgroup of the GPCRs, which have diverse biological roles and are major targets for therapeutic intervention. Among them, the Brain Angiogenesis Inhibitor (BAI) family has been linked to several psychiatric disorders, but despite their very high neuronal expression, the function of these receptors in the central nervous system has barely been analyzed. Our results, obtained using expression knockdown and overexpression experiments, reveal that the BAI3 receptor controls dendritic arborization growth and branching in cultured neurons. This role is confirmed in Purkinje cells in vivo using specific expression of a deficient BAI3 protein in transgenic mice, as well as lentivirus driven knockdown of BAI3 expression. Regulation of dendrite morphogenesis by BAI3 involves activation of the RhoGTPase Rac1 and the binding to a functional ELMO1, a critical Rac1 regulator. Thus, activation of the BAI3 signaling pathway could lead to direct reorganization of the actin cytoskeleton through RhoGTPase signaling in neurons. Given the direct link between RhoGTPase/actin signaling pathways, neuronal morphogenesis and psychiatric disorders, our mechanistic data show the importance of further studying the role of the BAI adhesion-GPCRs to understand the pathophysiology of such brain diseases. PMID:23628982

  17. Responses of tectal neurons to contrasting stimuli: an electrophysiological study in the barn owl.

    PubMed

    Zahar, Yael; Wagner, Hermann; Gutfreund, Yoram

    2012-01-01

    The saliency of visual objects is based on the center to background contrast. Particularly objects differing in one feature from the background may be perceived as more salient. It is not clear to what extent this so called "pop-out" effect observed in humans and primates governs saliency perception in non-primates as well. In this study we searched for neural-correlates of pop-out perception in neurons located in the optic tectum of the barn owl. We measured the responses of tectal neurons to stimuli appearing within the visual receptive field, embedded in a large array of additional stimuli (the background). Responses were compared between contrasting and uniform conditions. In a contrasting condition the center was different from the background while in the uniform condition it was identical to the background. Most tectal neurons responded better to stimuli in the contrsating condition compared to the uniform condition when the contrast between center and background was the direction of motion but not when it was the orientation of a bar. Tectal neurons also preferred contrasting over uniform stimuli when the center was looming and the background receding but not when the center was receding and the background looming. Therefore, our results do not support the hypothesis that tectal neurons are sensitive to pop-out per-se. The specific sensitivity to the motion contrasting stimulus is consistent with the idea that object motion and not large field motion (e.g., self-induced motion) is coded in the neural responses of tectal neurons. PMID:22745787

  18. Effects of bicuculline application on the somatosensory responses of secondary vestibular neurons.

    PubMed

    Grasso, C; Li Volsi, G; Cataldo, E; Manzoni, D; Barresi, M

    2016-10-29

    Limb somatosensory signals modify the discharge of vestibular neurons and elicit postural reflexes, which stabilize the body position. The aim of this study was to investigate the contribution of the γ-amino-butyric-acid (GABA) to the responsiveness of vestibular neurons to somatosensory inputs. The activity of 128 vestibular units was recorded in anesthetized rats in resting conditions and during sinusoidal foreleg rotation around the elbow or shoulder joints (0.026-0.625Hz, 45° peak amplitude). None of the recorded units was influenced by elbow rotation, while 40% of them responded to shoulder rotation. The selective GABAA antagonist receptor, bicuculline methiodine (BIC), was applied by microiontophoresis on single vestibular neurons and the changes in their activity at rest and during somatosensory stimulation was studied. In about half of cells the resting activity increased after the BIC application: 75% of these neurons showed also an increased response to somatosensory inputs whereas 17% exhibited a decrease. Changes in responsiveness in both directions were detected also in the units whose resting activity was not influenced by BIC. These data suggest that the responses of vestibular neurons to somatosensory inputs are modulated by GABA through a tonic release, which modifies the membrane response to the synaptic current. It is also possible that a phasic release of GABA occurs during foreleg rotation, shaping the stimulus-elicited current passing through the membrane. If this is the case, the changes in the relative position of body segments would modify the GABA release inducing changes in the vestibular reflexes and in learning processes that modify their spatio-temporal development.

  19. Effects of bicuculline application on the somatosensory responses of secondary vestibular neurons.

    PubMed

    Grasso, C; Li Volsi, G; Cataldo, E; Manzoni, D; Barresi, M

    2016-10-29

    Limb somatosensory signals modify the discharge of vestibular neurons and elicit postural reflexes, which stabilize the body position. The aim of this study was to investigate the contribution of the γ-amino-butyric-acid (GABA) to the responsiveness of vestibular neurons to somatosensory inputs. The activity of 128 vestibular units was recorded in anesthetized rats in resting conditions and during sinusoidal foreleg rotation around the elbow or shoulder joints (0.026-0.625Hz, 45° peak amplitude). None of the recorded units was influenced by elbow rotation, while 40% of them responded to shoulder rotation. The selective GABAA antagonist receptor, bicuculline methiodine (BIC), was applied by microiontophoresis on single vestibular neurons and the changes in their activity at rest and during somatosensory stimulation was studied. In about half of cells the resting activity increased after the BIC application: 75% of these neurons showed also an increased response to somatosensory inputs whereas 17% exhibited a decrease. Changes in responsiveness in both directions were detected also in the units whose resting activity was not influenced by BIC. These data suggest that the responses of vestibular neurons to somatosensory inputs are modulated by GABA through a tonic release, which modifies the membrane response to the synaptic current. It is also possible that a phasic release of GABA occurs during foreleg rotation, shaping the stimulus-elicited current passing through the membrane. If this is the case, the changes in the relative position of body segments would modify the GABA release inducing changes in the vestibular reflexes and in learning processes that modify their spatio-temporal development. PMID:27579770

  20. On the dynamical mechanisms of influence of synaptic currents on the neuron model with response differentiation

    NASA Astrophysics Data System (ADS)

    Zakharov, D. G.; Kuznetsov, A. S.

    2015-08-01

    The combined effect of synaptic NMDA, AMPA, and GABA currents on the neuron model with response differentiation has been considered. It has been shown that the GABA and NMDA currents can compensate the effects of each other, whereas the AMPA current not only leads to the suppression of oscillations but also significantly amplifies the high-frequency activity of the neuron induced by the NMDA current. Two bifurcation scenarios underlying these effects have been revealed. It has been predicted which scenario takes place under the combined influence of all three currents.

  1. A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction

    PubMed Central

    Fusco, Salvatore; Ripoli, Cristian; Podda, Maria Vittoria; Ranieri, Sofia Chiatamone; Leone, Lucia; Toietta, Gabriele; McBurney, Michael W.; Schütz, Günther; Riccio, Antonella; Grassi, Claudio; Galeotti, Tommaso; Pani, Giovambattista

    2012-01-01

    Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD+-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes. PMID:22190495

  2. A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction.

    PubMed

    Fusco, Salvatore; Ripoli, Cristian; Podda, Maria Vittoria; Ranieri, Sofia Chiatamone; Leone, Lucia; Toietta, Gabriele; McBurney, Michael W; Schütz, Günther; Riccio, Antonella; Grassi, Claudio; Galeotti, Tommaso; Pani, Giovambattista

    2012-01-10

    Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD(+)-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes. PMID:22190495

  3. Effects of Dimethyl Sulfoxide on Neuronal Response Characteristics in Deep Layers of Rat Barrel Cortex

    PubMed Central

    Soltani, Narjes; Mohammadi, Elham; Allahtavakoli, Mohammad; Shamsizadeh, Ali; Roohbakhsh, Ali; Haghparast, Abbas

    2016-01-01

    Introduction: Dimethyl sulfoxide (DMSO) is a chemical often used as a solvent for water-insoluble drugs. In this study, we evaluated the effect of intracerebroventricular (ICV) administration of DMSO on neural response characteristics (in 1200–1500 μm depth) of the rat barrel cortex. Methods: DMSO solution was prepared in 10% v/v concentration and injected into the lateral ventricle of rats. Neuronal spontaneous activity and neuronal responses to deflection of the principal whisker (PW) and adjacent whisker (AW) were recorded in barrel cortex. A condition test ratio (CTR) was used to measure inhibitory receptive fields in barrel cortex. Results: The results showed that both PW and AW evoked ON and OFF responses, neuronal spontaneous activity and inhibitory receptive fields did not change following ICV administration of DMSO. Conclusion: Results of this study suggest that acute ICV administration of 10% DMSO did not modulate the electrophysiological characteristics of neurons in the l deep ayers of rat barrel cortex. PMID:27563414

  4. Equilibrium and Response Properties of the Integrate-and-Fire Neuron in Discrete Time

    PubMed Central

    Helias, Moritz; Deger, Moritz; Diesmann, Markus; Rotter, Stefan

    2009-01-01

    The integrate-and-fire neuron with exponential postsynaptic potentials is a frequently employed model to study neural networks. Simulations in discrete time still have highest performance at moderate numerical errors, which makes them first choice for long-term simulations of plastic networks. Here we extend the population density approach to investigate how the equilibrium and response properties of the leaky integrate-and-fire neuron are affected by time discretization. We present a novel analytical treatment of the boundary condition at threshold, taking both discretization of time and finite synaptic weights into account. We uncover an increased membrane potential density just below threshold as the decisive property that explains the deviations found between simulations and the classical diffusion approximation. Temporal discretization and finite synaptic weights both contribute to this effect. Our treatment improves the standard formula to calculate the neuron's equilibrium firing rate. Direct solution of the Markov process describing the evolution of the membrane potential density confirms our analysis and yields a method to calculate the firing rate exactly. Knowing the shape of the membrane potential distribution near threshold enables us to devise the transient response properties of the neuron model to synaptic input. We find a pronounced non-linear fast response component that has not been described by the prevailing continuous time theory for Gaussian white noise input. PMID:20130755

  5. Gender differences in human single neuron responses to male emotional faces

    PubMed Central

    Newhoff, Morgan; Treiman, David M.; Smith, Kris A.; Steinmetz, Peter N.

    2015-01-01

    Well-documented differences in the psychology and behavior of men and women have spurred extensive exploration of gender's role within the brain, particularly regarding emotional processing. While neuroanatomical studies clearly show differences between the sexes, the functional effects of these differences are less understood. Neuroimaging studies have shown inconsistent locations and magnitudes of gender differences in brain hemodynamic responses to emotion. To better understand the neurophysiology of these gender differences, we analyzed recordings of single neuron activity in the human brain as subjects of both genders viewed emotional expressions. This study included recordings of single-neuron activity of 14 (6 male) epileptic patients in four brain areas: amygdala (236 neurons), hippocampus (n = 270), anterior cingulate cortex (n = 256), and ventromedial prefrontal cortex (n = 174). Neural activity was recorded while participants viewed a series of avatar male faces portraying positive, negative or neutral expressions. Significant gender differences were found in the left amygdala, where 23% (n = 15∕66) of neurons in men were significantly affected by facial emotion, vs. 8% (n = 6∕76) of neurons in women. A Fisher's exact test comparing the two ratios found a highly significant difference between the two (p < 0.01). These results show specific differences between genders at the single-neuron level in the human amygdala. These differences may reflect gender-based distinctions in evolved capacities for emotional processing and also demonstrate the importance of including subject gender as an independent factor in future studies of emotional processing by single neurons in the human amygdala. PMID:26441597

  6. Spatially selective reward site responses in tonically active neurons of the nucleus accumbens in behaving rats.

    PubMed

    Mulder, A B; Shibata, R; Trullier, O; Wiener, S I

    2005-05-01

    To study how hippocampal output signals conveying spatial and other contextual information might be integrated in the nucleus accumbens, tonically active accumbens neurons were recorded in three unrestrained rats as they performed spatial orientation tasks on an elevated round rotatable platform with four identical reward boxes symmetrically placed around the edge. The partially water-deprived rats were required to shuttle either between the pair of reward boxes indicated by beacon cues (lights in the boxes) or between the pair of boxes occupying particular locations in relation to environmental landmark cues. In 43/82 neurons, behaviorally correlated phasic modulations in discharge activity occurred, primarily prior to or after water was provided at the reward boxes. Twenty-two had inhibitory modulation, 12 excitatory, and nine were mixed excitatory and inhibitory. Although tonically active neurons (TANs) have rarely been reported in the rodent, the inhibitory and mixed responses correspond to previously reports in the macaque accumbens of tonically active neurons with activity correlated with reward delivery and, following conditioning, to sensory stimuli associated with rewards. Eighteen of the 43 tonically active accumbens neurons showed spatial selectivity, i.e., behaviorally correlated increases or decreases in firing rate were of different magnitudes at the respective reward boxes. This is the first demonstration that the configuration of environmental sensory cues associated with reward sites are also an effective stimulus for these neurons and that different neurons are selective for different places. These results are consistent with a role for the nucleus accumbens in the initiation of goal-directed displacement behaviors.

  7. Effects of urethane on the response properties of visual cortical neurons in young adult and old cats.

    PubMed

    Peng, Qing-Song; Zhou, Jun; Shi, Xia-Ming; Hua, Guo-Peng; Hua, Tian-Miao

    2011-06-01

    Previous studies have shown that visual cortical neurons in old mammals exhibit higher spontaneous activity, higher responsiveness to visual stimuli, and lower selectivity for stimulus orientations and motion directions than did neurons in young adult counterparts. However, whether the responsive difference in cortical neurons between young and old animals resulted from different effects induced by anesthetics has remained unclear. To clarify this issue, we recorded the response properties of individual neurons in the primary visual cortex of old and young adult cats while systematically varying the anesthesia level of urethane, a widely used anesthetic in physiology experiments. Our results showed that cumulatively administrating 50 mg and 100 mg of urethane upon the minimal level of urethane required to anesthetize an old or young adult cat did not significantly alter the degree of neuronal response selectivity for stimulus orientations and motion directions nor significantly change the visually-driven response and spontaneous activity of neurons in old and young adult cats. Cumulatively administrating 150 mg of urethane decreased neuronal responsiveness similarly in both age groups. Therefore, urethane appears to exert similar effects on neuronal response properties of old and young adult animals. PMID:21698802

  8. Neuronal migration in the murine rostral migratory stream requires serum response factor

    PubMed Central

    Alberti, Siegfried; Krause, Sven M.; Kretz, Oliver; Philippar, Ulrike; Lemberger, Thomas; Casanova, Emilio; Wiebel, Franziska F.; Schwarz, Heinz; Frotscher, Michael; Schütz, Günther; Nordheim, Alfred

    2005-01-01

    The central nervous system is fundamentally dependent on guided cell migration, both during development and in adulthood. We report an absolute requirement of the transcription factor serum response factor (SRF) for neuronal migration in the mouse forebrain. Conditional, late-prenatal deletion of Srf causes neurons to accumulate ectopically at the subventricular zone (SVZ), a prime neurogenic region in the brain. SRF-deficient cells of the SVZ exhibit impaired tangential chain migration along the rostral migratory stream into the olfactory bulb. SVZ explants display retarded chain migration in vitro. Regarding target genes, SRF deficiency impairs expression of the β-actin and gelsolin genes, accompanied by reduced cytoskeletal actin fiber density. At the posttranslational level, cofilin, a key regulator of actin dynamics, displays dramatically elevated inhibitory phosphorylation at Ser-3. Our studies indicate that SRF-controlled gene expression directs both the structure and dynamics of the actin microfilament, thereby determining cell-autonomous neuronal migration. PMID:15837932

  9. Visual response properties of neurons in four areas of the avian pallium.

    PubMed

    Scarf, Damian; Stuart, Michael; Johnston, Melissa; Colombo, Michael

    2016-03-01

    In the present study we investigate the visual responsiveness of neurons in the entopallium, arcopallium, nidopallium, and hippocampus of pigeons. Pigeons were presented with 12 different stimuli, including three stimuli of a pigeon (a portrait of a pigeon's face, a profile view of a pigeon's face, and a picture of a whole pigeon). A total of 53 cells were recorded from the entopallium, 65 from the arcopallium, 32 from the nidopallium, and 67 from the hippocampus. Although a number of neurons were selective for certain colours and shapes, no neurons were solely selective for the three pigeon stimuli. This finding contrasts with previous studies across a range of mammals demonstrating selective firing to images of conspecifics. Rather than reflecting an absence of these cells in pigeons, we argue our findings may reflect the difficulty pigeons have in understanding the correspondence between 2D representations of 3D stimuli.

  10. Single-cell RNA-seq reveals distinct injury responses in different types of DRG sensory neurons.

    PubMed

    Hu, Ganlu; Huang, Kevin; Hu, Youjin; Du, Guizhen; Xue, Zhigang; Zhu, Xianmin; Fan, Guoping

    2016-01-01

    Peripheral nerve injury leads to various injury-induced responses in sensory neurons including physiological pain, neuronal cell death, and nerve regeneration. In this study, we performed single-cell RNA-sequencing (scRNA-seq) analysis of mouse nonpeptidergic nociceptors (NP), peptidergic nociceptors (PEP), and large myelinated sensory neurons (LM) under both control and injury conditions at 3 days after sciatic nerve transection (SNT). After performing principle component and weighted gene co-expression network analysis, we categorized dorsal root ganglion (DRG) neurons into different subtypes and discovered co-regulated injury-response genes including novel regeneration associated genes (RAGs) in association with neuronal development, protein translation and cytoplasm transportation. In addition, we found significant up-regulation of the genes associated with cell death such as Pdcd2 in a subset of NP neurons after axotomy, implicating their actions in neuronal cell death upon nerve injury. Our study revealed the distinctive and sustained heterogeneity of transcriptomic responses to injury at single neuron level, implicating the involvement of different gene regulatory networks in nerve regeneration, neuronal cell death and neuropathy in different population of DRG neurons. PMID:27558660

  11. Single-cell RNA-seq reveals distinct injury responses in different types of DRG sensory neurons

    PubMed Central

    Hu, Ganlu; Huang, Kevin; Hu, Youjin; Du, Guizhen; Xue, Zhigang; Zhu, Xianmin; Fan, Guoping

    2016-01-01

    Peripheral nerve injury leads to various injury-induced responses in sensory neurons including physiological pain, neuronal cell death, and nerve regeneration. In this study, we performed single-cell RNA-sequencing (scRNA-seq) analysis of mouse nonpeptidergic nociceptors (NP), peptidergic nociceptors (PEP), and large myelinated sensory neurons (LM) under both control and injury conditions at 3 days after sciatic nerve transection (SNT). After performing principle component and weighted gene co-expression network analysis, we categorized dorsal root ganglion (DRG) neurons into different subtypes and discovered co-regulated injury-response genes including novel regeneration associated genes (RAGs) in association with neuronal development, protein translation and cytoplasm transportation. In addition, we found significant up-regulation of the genes associated with cell death such as Pdcd2 in a subset of NP neurons after axotomy, implicating their actions in neuronal cell death upon nerve injury. Our study revealed the distinctive and sustained heterogeneity of transcriptomic responses to injury at single neuron level, implicating the involvement of different gene regulatory networks in nerve regeneration, neuronal cell death and neuropathy in different population of DRG neurons. PMID:27558660

  12. Lateral orbitofrontal neurons acquire responses to upshifted, downshifted, or blocked cues during unblocking

    PubMed Central

    Lopatina, Nina; McDannald, Michael A; Styer, Clay V; Sadacca, Brian F; Cheer, Joseph F; Schoenbaum, Geoffrey

    2015-01-01

    The lateral orbitofrontal cortex (lOFC) has been described as signaling either outcome expectancies or value. Previously, we used unblocking to show that lOFC neurons respond to a predictive cue signaling a ‘valueless’ change in outcome features (McDannald, 2014). However, many lOFC neurons also fired to a cue that simply signaled more reward. Here, we recorded lOFC neurons in a variant of this task in which rats learned about cues that signaled either more (upshift), less (downshift) or the same (blocked) amount of reward. We found that neurons acquired responses specifically to one of the three cues and did not fire to the other two. These results show that, at least early in learning, lOFC neurons fire to valued cues in a way that is more consistent with signaling of the predicted outcome’s features than with signaling of a general, abstract or cached value that is independent of the outcome. DOI: http://dx.doi.org/10.7554/eLife.11299.001 PMID:26670544

  13. Single Cell Transcriptomics of Hypothalamic Warm Sensitive Neurons that Control Core Body Temperature and Fever Response

    PubMed Central

    Eberwine, James; Bartfai, Tamas

    2011-01-01

    We report on an ‘unbiased’ molecular characterization of individual, adult neurons, active in a central, anterior hypothalamic neuronal circuit, by establishing cDNA libraries from each individual, electrophysiologically identified warm sensitive neuron (WSN). The cDNA libraries were analyzed by Affymetrix microarray. The presence and frequency of cDNAs was confirmed and enhanced with Illumina sequencing of each single cell cDNA library. cDNAs encoding the GABA biosynthetic enzyme. GAD1 and of adrenomedullin, galanin, prodynorphin, somatostatin, and tachykinin were found in the WSNs. The functional cellular and in vivo studies on dozens of the more than 500 neurotransmitter -, hormone- receptors and ion channels, whose cDNA was identified and sequence confirmed, suggest little or no discrepancy between the transcriptional and functional data in WSNs; whenever agonists were available for a receptor whose cDNA was identified, a functional response was found.. Sequencing single neuron libraries permitted identification of rarely expressed receptors like the insulin receptor, adiponectin receptor2 and of receptor heterodimers; information that is lost when pooling cells leads to dilution of signals and mixing signals. Despite the common electrophysiological phenotype and uniform GAD1 expression, WSN- transcriptomes show heterogenity, suggesting strong epigenetic influence on the transcriptome. Our study suggests that it is well-worth interrogating the cDNA libraries of single neurons by sequencing and chipping. PMID:20970451

  14. Neuronal detection thresholds during vestibular compensation: contributions of response variability and sensory substitution

    PubMed Central

    Jamali, Mohsen; Mitchell, Diana E; Dale, Alexis; Carriot, Jerome; Sadeghi, Soroush G; Cullen, Kathleen E

    2014-01-01

    The vestibular system is responsible for processing self-motion, allowing normal subjects to discriminate the direction of rotational movements as slow as 1–2 deg s−1. After unilateral vestibular injury patients’ direction–discrimination thresholds worsen to ∼20 deg s−1, and despite some improvement thresholds remain substantially elevated following compensation. To date, however, the underlying neural mechanisms of this recovery have not been addressed. Here, we recorded from first-order central neurons in the macaque monkey that provide vestibular information to higher brain areas for self-motion perception. Immediately following unilateral labyrinthectomy, neuronal detection thresholds increased by more than two-fold (from 14 to 30 deg s−1). While thresholds showed slight improvement by week 3 (25 deg s−1), they never recovered to control values – a trend mirroring the time course of perceptual thresholds in patients. We further discovered that changes in neuronal response variability paralleled changes in sensitivity for vestibular stimulation during compensation, thereby causing detection thresholds to remain elevated over time. However, we found that in a subset of neurons, the emergence of neck proprioceptive responses combined with residual vestibular modulation during head-on-body motion led to better neuronal detection thresholds. Taken together, our results emphasize that increases in response variability to vestibular inputs ultimately constrain neural thresholds and provide evidence that sensory substitution with extravestibular (i.e. proprioceptive) inputs at the first central stage of vestibular processing is a neural substrate for improvements in self-motion perception following vestibular loss. Thus, our results provide a neural correlate for the patient benefits provided by rehabilitative strategies that take advantage of the convergence of these multisensory cues. PMID:24366259

  15. Heterogeneity of Voltage- and Chemosignal-Activated Response Profiles in Vomeronasal Sensory Neurons

    PubMed Central

    Labra, Antonieta; Brann, Jessica H.; Fadool, Debra A.

    2009-01-01

    Liolaemus lizards were explored to ascertain whether they would make an amenable model to study single-cell electrophysiology of neurons in the vomeronasal organ (VNO). Despite a rich array of chemosensory-related behaviors chronicled for this genus, no anatomical or functional data exist for the VNO, the organ mediating these types of behaviors. Two Liolaemus species (L. bellii and L. nigroviridis) were collected in Central Chile in the Farellones Mountains and transported to the United States. Lizards were subjected to hypothermia and then a lethal injection of sodium pentabarbitol prior to all experiments described in the following text. Retrograde dye perfusion combined with histological techniques demonstrated a compartmentalization of the proportionally large VNO from the main olfactory epithelium (MOE) in cryosections of L. bellii. SDS-PAGE analysis of the VNO of both species demonstrated the expression of three G protein subunits, namely, Gαo, Gαi2, and Gβ, and the absence of Gαolf, Gα11, and Gq, the latter of which are traditionally found in the MOE. Vomeronasal (VN) neurons were enzymatically isolated for whole cell voltage-clamp electrophysiology of single neurons. Both species demonstrated a tetrodotoxin (TTX)-sensitive, rapidly inactivating sodium current and a tetraethylammonium (TEA)-sensitive potassium current that had a transient and sustained component. VN neurons were classified into two types dependent on the ratio of sodium over sustained potassium current. VN neurons exhibited outward and inward chemosignal-evoked currents when stimulated with pheromone-containing secretions taken from the feces, skin, and precloacal pores. Fifty-nine percent of the neurons were responsive to at least one compound when presented with a battery of five different secretions. The breadth of responsiveness (H metric) demonstrated a heterogeneous population of tuning with a mean of 0.29. PMID:15972830

  16. Differential responses of Aplysia siphon motor neurons and interneurons to tail and mantle stimuli: implications for behavioral response specificity.

    PubMed

    Fang, X; Clark, G A

    1996-12-01

    1. Tail shock and mantle shock elicit different forms of siphon responses in Aplysia (flaring and backward bending vs. constriction and forward bending, respectively). Moreover, training with these two unconditioned stimuli (USs) in US-alone or classical conditioning paradigms differentially modifies the direction of the response to a siphon tap subsequently presented. As a first step toward addressing neural mechanisms underlying this response specificity, we systematically mapped the central siphon withdrawal circuit to determine which motor neurons and interneurons are differentially engaged by, and potentially modified by, tail and mantle USs. We utilized semi-intact preparations consisting of the intact mantle organs (including the gill and siphon), the tail, and the abdominal and circumesophageal ganglia. USs were delivered either cutaneously through silver wires implanted in the tail and mantle or via suction electrodes to the tail and branchial nerves. 2. We found that one class of central siphon motor neurons, the LFSB cells, was preferentially activated by tail USs, whereas other siphon motor neurons, the LBs cells and RDs cells, were preferentially activated by mantle USs. These motor neurons thus appear to be the final common path for the differential siphon movements to these USs. In addition, because activation of these cells can elicit neuromuscular facilitation and thereby enhance siphon movements, this differential activation may contribute to behavioral response specificity by imposing a specific response bias. 3. L29 interneurons, which both mediate and modulate the siphon withdrawal response, responded preferentially and exhibited synaptic facilitation selectively in response to tail shock USs. In contrast, L34 and the interneuron II network did not show differential activation. Facilitation at L29-LFSB connections following training with tail shock may contribute to tail-directed siphon responses to siphon tap and may thus be an additional

  17. Temporal response dynamics of Drosophila olfactory sensory neurons depends on receptor type and response polarity

    PubMed Central

    Getahun, Merid N.; Wicher, Dieter; Hansson, Bill S.; Olsson, Shannon B.

    2012-01-01

    Insect olfactory sensory neurons (OSN) express a diverse array of receptors from different protein families, i.e. ionotropic receptors (IR), gustatory receptors (GR) and odorant receptors (OR). It is well known that insects are exposed to a plethora of odor molecules that vary widely in both space and time under turbulent natural conditions. In addition to divergent ligand specificities, these different receptors might also provide an increased range of temporal dynamics and sensitivities for the olfactory system. To test this, we challenged different Drosophila OSNs with both varying stimulus durations (10–2000 ms), and repeated stimulus pulses of key ligands at various frequencies (1–10 Hz). Our results show that OR-expressing OSNs responded faster and with higher sensitivity to short stimulations as compared to IR- and Gr21a-expressing OSNs. In addition, OR-expressing OSNs could respond to repeated stimulations of excitatory ligands up to 5 Hz, while IR-expressing OSNs required ~5x longer stimulations and/or higher concentrations to respond to similar stimulus durations and frequencies. Nevertheless, IR-expressing OSNs did not exhibit adaptation to longer stimulations, unlike OR- and Gr21a-OSNs. Both OR- and IR-expressing OSNs were also unable to resolve repeated pulses of inhibitory ligands as fast as excitatory ligands. These differences were independent of the peri-receptor environment in which the receptors were expressed and suggest that the receptor expressed by a given OSN affects both its sensitivity and its response to transient, intermittent chemical stimuli. OR-expressing OSNs are better at resolving low dose, intermittent stimuli, while IR-expressing OSNs respond more accurately to long-lasting odor pulses. This diversity increases the capacity of the insect olfactory system to respond to the diverse spatiotemporal signals in the natural environment. PMID:23162431

  18. Response of autaptic Hodgkin-Huxley neuron with noise to subthreshold sinusoidal signals

    NASA Astrophysics Data System (ADS)

    Wang, Hengtong; Chen, Yong

    2016-11-01

    In this work, we investigated the response of a stochastic Hodgkin-Huxley (HH) neuron with an autapse to subthreshold sinusoidal signals. It is found that the autapse not only adjusts the stochastic responses, but also improves the detection of subthreshold signals. In the case of weak noise, the autapse facilitates the response of neuron to the subthreshold sinusoidal signals with a small parameter region in tdelay- ω space. The increased noise intensity enlarges this parameter region and increases the corresponding response frequency in such range. As the autaptic intensity increases, however, this parameter region shrunks. We also observed that there is an optimal range of the delay time of autapse, within which the stochastic HH neuron fires action potentials with high frequency. The corresponding response spike train for the optimal delay time is nearly a regular sequence with the interspike intervals approximated to the delay time. The current results reveal a novel resonance phenomenon facilitated by autapse, named autaptic delay-induced coherence resonance.

  19. The effect of satiety on responses of gustatory neurons in the amygdala of alert cynomolgus macaques.

    PubMed

    Yan, J; Scott, T R

    1996-11-18

    An alert cynomolgus macaque was fed a sweet solution to satiety as the activity of a gustatory neuron in the amygdala was recorded to that solution and to four other taste stimuli. This experiment was conducted a total of 14 times in two monkeys. The responses of individual neurons to the satiety stimuli were suppressed by as little as 1%, and as much as 100% by the induction of satiety (mean suppression = 58%). Nine of the 14 cells responded to the satiety solution with excitation, and their responses were suppressed by a mean of 62% by satiety. Five neurons responded with inhibition, and their responses were suppressed by a mean of 50%. Responses to other taste stimuli, not associated with satiety, were affected to a lesser extent. The amygdala is a taste relay between the primary gustatory cortex, where satiety has no influence on responses to taste stimuli, and the lateral hypothalamic area where the effect of satiety is total. The data presented here indicate that the amygdala is a functional as well as anatomical intermediary between these two areas, and serves as a stage in the process through which sensory stimuli are imbued with motivational significance.

  20. RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing

    PubMed Central

    Chen, Pin-Fang; Hsiao, Jack S.; Sirois, Carissa L.; Chamberlain, Stormy J.

    2016-01-01

    Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function of the maternally inherited copy of UBE3A, an imprinted gene expressed biallelically in most tissues, but expressed exclusively from the maternal allele in neurons. Active transcription of the neuron-specific long non-coding RNA (lncRNA), UBE3A-ATS, has been shown to silence paternal UBE3A. We hypothesized that alternative splicing factors RBFOX2 and RBFOX1 might mediate splicing changes and result in the transcription of UBE3A-ATS in neurons. We found that RBFOX2 and RBFOX1 both bind to UBE3A-ATS transcript in neurons, but are not required for gene expression and/or neuron-specific processing in the SNURF/SNRPN-UBE3A region. However, we found that depletion of RBFOX2 causes a proliferation phenotype in immature neural cultures, suggesting that RBFOX2 is involved in division versus differentiation decisions in iPSC-derived neural progenitors. Absence of RBFOX2 also altered the expression of some genes that are important for glutamatergic neocortical development and Wnt-Frizzled signalling in mature neuronal cultures. Our data show that while RBFOX1 and RBFOX2 do not mediate neuron-specific processing of UBE3A-ATS, these proteins play important roles in developing neurons and are not completely functionally redundant. PMID:27146458

  1. RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing.

    PubMed

    Chen, Pin-Fang; Hsiao, Jack S; Sirois, Carissa L; Chamberlain, Stormy J

    2016-01-01

    Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function of the maternally inherited copy of UBE3A, an imprinted gene expressed biallelically in most tissues, but expressed exclusively from the maternal allele in neurons. Active transcription of the neuron-specific long non-coding RNA (lncRNA), UBE3A-ATS, has been shown to silence paternal UBE3A. We hypothesized that alternative splicing factors RBFOX2 and RBFOX1 might mediate splicing changes and result in the transcription of UBE3A-ATS in neurons. We found that RBFOX2 and RBFOX1 both bind to UBE3A-ATS transcript in neurons, but are not required for gene expression and/or neuron-specific processing in the SNURF/SNRPN-UBE3A region. However, we found that depletion of RBFOX2 causes a proliferation phenotype in immature neural cultures, suggesting that RBFOX2 is involved in division versus differentiation decisions in iPSC-derived neural progenitors. Absence of RBFOX2 also altered the expression of some genes that are important for glutamatergic neocortical development and Wnt-Frizzled signalling in mature neuronal cultures. Our data show that while RBFOX1 and RBFOX2 do not mediate neuron-specific processing of UBE3A-ATS, these proteins play important roles in developing neurons and are not completely functionally redundant. PMID:27146458

  2. Visual responses of neurones in cat superior colliculus in relation to fixation of targets.

    PubMed Central

    Peck, C K

    1989-01-01

    1. Visually elicited discharges were recorded from single cells in the intermediate and deep layers of the superior colliculus of alert, trained cats. With the behavioural protocols used, vigorous and consistent visual responses to the onset and offset of small, stationary targets were encountered in all layers of the colliculus. In addition, the responses of many cells depended on the behavioural context in which the response occurred. Specifically, thirty-nine cells were encountered in which discharge was contingent upon prolonged fixation of the visual stimulus. Thirty of these were located in the intermediate and deep layers and comprised 22% of the 134 isolated cells which were not related to saccadic eye movement. 2. Fixation-related cells showed sustained increases or decreases in firing during fixation of a visual target. Responses to presentation of a visual target at the same retinal location, without active fixation by the animal, were either absent, much weaker, or had extremely variable latencies. 3. Changes in activity were well established by the end of the fixation saccade. The neuronal response was sustained if fixation was sustained. Moreover, the neuronal response began to decrease before the onset of the saccade which broke fixation even though the receptive field location of the target had not yet changed. 4. In these neurones, the discharge rate was not a function of the position of the eye in the orbit. 5. Neurones in which the discharge rate was suppressed during fixation had larger receptive fields than cells in which the discharge rate was enhanced during fixation. There were fewer fixation-suppressed cells (n = 7, 5%) than fixation-activated cells (n = 23, 17%). PMID:2607434

  3. Emotion processing fails to modulate putative mirror neuron response to trained visuomotor associations.

    PubMed

    Fitzgibbon, Bernadette M; Kirkovski, Melissa; Fornito, Alex; Paton, Bryan; Fitzgerald, Paul B; Enticott, Peter G

    2016-04-01

    Recent neuroimaging studies have demonstrated that activation of the putative human mirror neuron system (MNS) can be elicited via visuomotor training. This is generally interpreted as supporting an associative learning account of the mirror neuron system (MNS) that argues against the ontogeny of the MNS to be an evolutionary adaptation for social cognition. The current study assessed whether a central component of social cognition, emotion processing, would influence the MNS activity to trained visuomotor associations, which could support a broader role of the MNS in social cognition. Using functional magnetic resonance imaging (fMRI), we assessed repetition suppression to the presentation of stimulus pairs involving a simple hand action and a geometric shape that was either congruent or incongruent with earlier association training. Each pair was preceded by an image of positive, negative, or neutral emotionality. In support of an associative learning account of the MNS, repetition suppression was greater for trained pairs compared with untrained pairs in several regions, primarily supplementary motor area (SMA) and right inferior frontal gyrus (rIFG). This response, however, was not modulated by the valence of the emotional images. These findings argue against a fundamental role of emotion processing in the mirror neuron response, and are inconsistent with theoretical accounts linking mirror neurons to social cognition.

  4. Partitioning non-linearities in the response of honey bee olfactory receptor neurons to binary odors.

    PubMed

    Getz, W M; Akers, R P

    1995-01-01

    In many organisms, of which honey bees are one example, a general (i.e., non-pheromonal) olfactory receptor neuron may respond to some odorants by increasing its firing rate and to others by decreasing its firing rate. In the latter case, this decrease will be with respect to a background firing rate determined by intrinsic (internal noise) and extrinsic (background odors) factors. To analyse receptor neurons of this complexity, we extend Beidler's model of receptor protein activation dynamics to account for the competition between depolarizing and hyperpolarizing pathways and couple the model to a phenomenological description of the non-linear relationship between the proportion of activate membrane receptors and the receptor cell spike generation rates. We then examine the implications of this theory for predicting the response of receptor neurons to odor mixtures based on their response to pure odorants at concentrations matched to the mixture. We derive inequalities that must be satisfied under our normative model, and propose that deviations from the model be designated as synergisms and inhibitions, depending on the direction in which various equalities and inequalities are violated. We then apply our inequalities to identifying synergisms and inhibitions in data analysed in a different way elsewhere (Akers, R.P. and Getz, W.M. Response of olfactory receptor neurons in honey bees to odorants and their binary mixtures. J. Comp. Physiol. (in press)). In these data regarding the response of honey bee placode sensilla to a number of odorants and their binary combinations, we demonstrate the presence of synergisms and inhibitions--that is, elevated or repressed responses that are not due to competitive interactions of mixture component odorants for receptor sites or Beidler (Beidler, L.M., 1962. Taste receptor stimulation. Prog. Biophys. Biophys. Chem. 12, 107-151) saturation mechanisms. PMID:7727704

  5. Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells.

    PubMed

    Chalovich, Elisabeth M; Zhu, Jian-hui; Caltagarone, John; Bowser, Robert; Chu, Charleen T

    2006-06-30

    Impaired survival signaling may represent a central mechanism in neurodegeneration. 6-Hydroxydopamine (6-OHDA) is an oxidative neurotoxin used to injure catecholaminergic cells of the central and peripheral nervous systems. Although 6-OHDA elicits phosphorylation of several kinases, downstream transcriptional effects that influence neuronal cell death are less defined. The cAMP response element (CRE) is present in the promoter sequences of several important neuronal survival factors. Treatment of catecholaminergic neuronal cell lines (B65 and SH-SY5Y) with 6-OHDA resulted in repression of basal CRE transactivation. Message levels of CRE-driven genes such as brain-derived neurotrophic factor and the survival factor Bcl-2 were decreased in 6-OHDA-treated cells, but message levels of genes lacking CRE sequences were not affected. Repression of CRE could be reversed by delayed treatment with cAMP several hours after initiation of 6-OHDA injury. Furthermore, restoration of CRE-driven transcription was associated with significant neuroprotection. In contrast to observations in other model systems, the mechanism of CRE repression did not involve decreased phosphorylation of its binding protein CREB. Instead, total CREB and phospho-CREB (pCREB) were increased in the cytoplasm and decreased in the nucleus of 6-OHDA-treated cells. 6-OHDA also decreased nuclear pCREB in dopaminergic neurons of primary mouse midbrain cultures. Co-treatment with cAMP promoted/restored nuclear localization of pCREB in both immortalized and primary culture systems. Increased cytoplasmic pCREB was observed in degenerating human Parkinson/Lewy body disease substantia nigra neurons but not in age-matched controls. Notably, cytoplasmic accumulation of activated upstream CREB kinases has been observed previously in both 6-OHDA-treated cells and degenerating human neurons, supporting a potential role for impaired nuclear import of phosphorylated signaling proteins.

  6. Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response

    PubMed Central

    Benedetti, Fabrizio; Lanotte, Michele; Colloca, Luana; Ducati, Alessandro; Zibetti, Maurizio; Lopiano, Leonardo

    2009-01-01

    Placebo administration to Parkinson patients is known to induce dopamine release in the striatum and to affect the activity of subthalamic nucleus (STN) neurons. By using intraoperative single-neuron recording techniques in awake patients, here we extend our previous study on STN recording, and characterize part of the neuronal circuit which is affected by placebos. In those patients who showed a clinical placebo response, there was a decrease in firing rate in STN neurons that was associated with a decrease in the substantia nigra pars reticulata (SNr) and an increase in the ventral anterior (VA) and anterior ventral lateral (VLa) thalamus. These data show that placebo decreases STN and SNr activity whereas it increases VA/VLa activity. By contrast, placebo non-responders showed either a lack of changes in this circuit or partial changes in the STN only. Thus, changes in activity in the whole basal ganglia–VA/VLa circuit appear to be important in order to observe a clinical placebo improvement, although the involvement of other circuits, such as the direct pathway bypassing the STN, cannot be ruled out. The circuit we describe in the present study is likely to be a part of a more complex circuitry, including the striatum and the internal globus pallidus (GPi), that is modified by placebo administration. These findings indicate that a placebo treatment, which is basically characterized by verbal suggestions of benefit, can reverse the malfunction of a complex neuronal circuit, although these placebo-associated neuronal changes are short-lasting and occur only in some patients but not in others. PMID:19546163

  7. Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response.

    PubMed

    Benedetti, Fabrizio; Lanotte, Michele; Colloca, Luana; Ducati, Alessandro; Zibetti, Maurizio; Lopiano, Leonardo

    2009-08-01

    Placebo administration to Parkinson patients is known to induce dopamine release in the striatum and to affect the activity of subthalamic nucleus (STN) neurons. By using intraoperative single-neuron recording techniques in awake patients, here we extend our previous study on STN recording, and characterize part of the neuronal circuit which is affected by placebos. In those patients who showed a clinical placebo response, there was a decrease in firing rate in STN neurons that was associated with a decrease in the substantia nigra pars reticulata (SNr) and an increase in the ventral anterior (VA) and anterior ventral lateral (VLa) thalamus. These data show that placebo decreases STN and SNr activity whereas it increases VA/VLa activity. By contrast, placebo non-responders showed either a lack of changes in this circuit or partial changes in the STN only. Thus, changes in activity in the whole basal ganglia-VA/VLa circuit appear to be important in order to observe a clinical placebo improvement, although the involvement of other circuits, such as the direct pathway bypassing the STN, cannot be ruled out. The circuit we describe in the present study is likely to be a part of a more complex circuitry, including the striatum and the internal globus pallidus (GPi), that is modified by placebo administration. These findings indicate that a placebo treatment, which is basically characterized by verbal suggestions of benefit, can reverse the malfunction of a complex neuronal circuit, although these placebo-associated neuronal changes are short-lasting and occur only in some patients but not in others.

  8. The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons.

    PubMed

    Anand, U; Otto, W R; Casula, M A; Day, N C; Davis, J B; Bountra, C; Birch, R; Anand, P

    2006-05-15

    We have studied the effect of key neurotrophic factors (NTFs) on morphology, levels of the vanilloid receptor-1 (TRPV1) and responses to capsaicin in adult human sensory neurons in vitro. Avulsed dorsal root ganglia (DRG, n = 5) were cultured with or without a combination of nerve growth factor (NGF), glial cell (line)-derived growth factor (GDNF) and neurotrophin3 (NT3) for 5 days. In the absence of NTFs, the diameter of neurons ranged from 20 to 100 microm (mean 42 +/- 4 microm). Adding NTFs caused a significant increase in neuronal sizes, up to 120 microm (mean diameter 62 +/- 5 microm, P < 0.01, t-test), an overall 35% increase of TRPV1-positive neurons (P < 0.003), and notably of large TRPV1-positive neurons > 80 microm (P < 0.05). Responses to capsaicin were significantly enhanced with calcium ratiometry (P < 0.0001). Short duration (1h) exposure of dissociated sensory neurons to NTFs increased numbers of TRPV1-positive neurons, but not of TRPV3, Nav 1.8 and IK1 and the morphological size-distribution remained similar to intact post-mortem DRG neurons. NTFs thus increase size, elevate TRPV1 levels and enhance capsaicin responses in cultured human DRG neurons; these changes may relate to pathophysiology in disease states, and provide an in vitro model to study novel analgesics. PMID:16481104

  9. The mouse neuronal cell surface protein F3: a phosphatidylinositol- anchored member of the immunoglobulin superfamily related to chicken contactin

    PubMed Central

    1989-01-01

    Several members of the Ig superfamily are expressed on neural cells where they participate in surface interactions between cell bodies and processes. Their Ig domains are more closely related to each other than to Ig variable and constant domains and have been grouped into the C2 set. Here, we report the cloning and characterization of another member of this group, the mouse neuronal cell surface antigen F3. The F3 cDNA sequence contains an open reading frame that could encode a 1,020-amino acid protein consisting of a signal sequence, six Ig-like domains of the C2 type, a long premembrane region containing two segments that exhibit sequence similarity to fibronectin type III repeats and a moderately hydrophobic COOH-terminal sequence. The protein does not contain a typical transmembrane segment but appears to be attached to the membrane by a phosphatidylinositol anchor. Antibodies against the F3 protein recognize a prominent 135-kD protein in mouse brain. In fetal brain cultures, they stain the neuronal cell surface and, in cultures maintained in chemically defined medium, most prominently neurites and neurite bundles. The mouse f3 gene maps to band F of chromosome 15. The gene transcripts detected in the brain by F3 cDNA probes are developmentally regulated, the highest amounts being expressed between 1 and 2 wk after birth. The F3 nucleotide and deduced amino acid sequence show striking similarity to the recently published sequence of the chicken neuronal cell surface protein contactin. However, there are important differences between the two molecules. In contrast to F3, contactin has a transmembrane and a cytoplasmic domain. Whereas contactin is insoluble in nonionic detergent and is tightly associated with the cytoskeleton, about equal amounts of F3 distribute between buffer-soluble, nonionic detergent-soluble, and detergent- insoluble fractions. Among other neural cell surface proteins, F3 most resembles the neuronal cell adhesion protein L1, with 25% amino

  10. Improved system identification using artificial neural networks and analysis of individual differences in responses of an identified neuron.

    PubMed

    Costalago Meruelo, Alicia; Simpson, David M; Veres, Sandor M; Newland, Philip L

    2016-03-01

    Mathematical modelling is used routinely to understand the coding properties and dynamics of responses of neurons and neural networks. Here we analyse the effectiveness of Artificial Neural Networks (ANNs) as a modelling tool for motor neuron responses. We used ANNs to model the synaptic responses of an identified motor neuron, the fast extensor motor neuron, of the desert locust in response to displacement of a sensory organ, the femoral chordotonal organ, which monitors movements of the tibia relative to the femur of the leg. The aim of the study was threefold: first to determine the potential value of ANNs as tools to model and investigate neural networks, second to understand the generalisation properties of ANNs across individuals and to different input signals and third, to understand individual differences in responses of an identified neuron. A metaheuristic algorithm was developed to design the ANN architectures. The performance of the models generated by the ANNs was compared with those generated through previous mathematical models of the same neuron. The results suggest that ANNs are significantly better than LNL and Wiener models in predicting specific neural responses to Gaussian White Noise, but not significantly different when tested with sinusoidal inputs. They are also able to predict responses of the same neuron in different individuals irrespective of which animal was used to develop the model, although notable differences between some individuals were evident.

  11. Responses of neurons in the rat's ventral nucleus of the lateral lemniscus to amplitude-modulated tones.

    PubMed

    Zhang, Huiming; Kelly, Jack B

    2006-12-01

    Recordings were made from single neurons in the rat's ventral nucleus of the lateral lemniscus (VNLL) to determine responses to amplitude-modulated (AM) tones. The neurons were first characterized on the basis of their response to tone bursts presented to the contralateral ear and a distinction was made between those with transient onset responses and those with sustained responses. Sinusoidal AM tones were then presented to the contralateral ear with a carrier that matched the neuron's characteristic frequency (CF). Modulation transfer functions were generated on the basis of firing rate (MTF(FR)) and vector strength (MTF(VS)). Ninety-two percent of onset neurons that responded continuously to AM tones had band-pass MTF(FR)s with best modulation frequencies from 10 to 300 Hz. Fifty-four percent of sustained neurons had band-pass MTF(FR)s with best modulation frequencies from 10 to 500 Hz; other neurons had band-suppressed, all-pass, low-pass, or high-pass functions. Most neurons showed either band-pass or low-pass MTF(VS). Responses were well synchronized to the modulation cycle with maximum vector strengths ranging from 0.37 to 0.98 for sustained neurons and 0.78 to 0.99 for onset neurons. The upper frequency limit for response synchrony was higher than that reported for inferior colliculus, but lower than that seen in more peripheral structures. Results suggest that VNLL neurons, especially those with onset responses to tone bursts, are sensitive to temporal features of sounds and narrowly tuned to different modulation rates. However, there was no evidence of a topographic relation between dorsoventral position along the length of VNLL and best modulation frequency as determined by either firing rate or vector strength. PMID:16928797

  12. Response of pontomedullary reticulospinal neurons to vestibular stimuli in vertical planes. Role in vertical vestibulospinal reflexes of the decerebrate cat

    NASA Technical Reports Server (NTRS)

    Bolton, P. S.; Goto, T.; Schor, R. H.; Wilson, V. J.; Yamagata, Y.; Yates, B. J.

    1992-01-01

    1. To investigate the neural substrate of vestibulospinal reflexes in decerebrate cats, we studied the responses of pontomedullary reticulospinal neurons to natural stimulation of the labyrinth in vertical planes. Our principal aim was to determine whether reticulospinal neurons that terminate in, or are likely to give off collaterals to, the upper cervical segments had properties similar to those of the vestibulocollic reflex (VCR). 2. Antidromic stimulation was used to determine whether the neurons projected to the neck, lower cervical, thoracic, or lumbar levels. Dynamics of the responses of spontaneously firing neurons were studied with sinusoidal stimuli delivered at 0.05-1 Hz and aligned to the plane of body rotation, that produced maximal modulation of the neuron (response vector orientation). Each neuron was assigned a vestibular input classification of otolith, vertical canal, otolith + canal, or spatial-temporal convergence (STC). 3. We found, in agreement with previous studies, that the largest fraction of pontomedullary reticulospinal neurons projected to the lumbar cord, and that only a small number ended in the neck segments. Neurons projecting to all levels of the spinal cord had similar responses to labyrinth stimulation. 4. Reticulospinal neurons that received only vertical canal inputs were rare (1 of 67 units). Most reticulospinal neurons (48%) received predominant otolith inputs, 18% received otolith + canal input, and only 9% had STC behavior. These data are in sharp contrast to the results of our previous studies of vestibulospinal neurons. A considerable portion of vestibulospinal neurons receives vertical canal input (38%), fewer receive predominantly otolith input (22%), whereas the proportion that have otolith + canal input or STC behavior is similar to our present reticulospinal data. 5. The response vector orientations of our reticulospinal neurons, particularly those with canal inputs (canal, otolith + canal, STC) were predominantly in

  13. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons.

    PubMed

    Diochot, Sylvie; Baron, Anne; Rash, Lachlan D; Deval, Emmanuel; Escoubas, Pierre; Scarzello, Sabine; Salinas, Miguel; Lazdunski, Michel

    2004-04-01

    From a systematic screening of animal venoms, we isolated a new toxin (APETx2) from the sea anemone Anthopleura elegantissima, which inhibits ASIC3 homomeric channels and ASIC3-containing heteromeric channels both in heterologous expression systems and in primary cultures of rat sensory neurons. APETx2 is a 42 amino-acid peptide crosslinked by three disulfide bridges, with a structural organization similar to that of other sea anemone toxins that inhibit voltage-sensitive Na+ and K+ channels. APETx2 reversibly inhibits rat ASIC3 (IC50=63 nM), without any effect on ASIC1a, ASIC1b, and ASIC2a. APETx2 directly inhibits the ASIC3 channel by acting at its external side, and it does not modify the channel unitary conductance. APETx2 also inhibits heteromeric ASIC2b+3 current (IC50=117 nM), while it has less affinity for ASIC1b+3 (IC50=0.9 microM), ASIC1a+3 (IC50=2 microM), and no effect on the ASIC2a+3 current. The ASIC3-like current in primary cultured sensory neurons is partly and reversibly inhibited by APETx2 with an IC50 of 216 nM, probably due to the mixed inhibitions of various co-expressed ASIC3-containing channels. PMID:15044953

  14. Orbital cortex neuronal responses during an odor-based conditioned associative task in rats.

    PubMed

    Yonemori, M; Nishijo, H; Uwano, T; Tamura, R; Furuta, I; Kawasaki, M; Takashima, Y; Ono, T

    2000-01-01

    Neuronal activity in the rat orbital cortex during discrimination of various odors [five volatile organic compounds (acetophenone, isoamyl acetate, cyclohexanone, p-cymene and 1,8-cineole), and food- and cosmetic-related odorants (black pepper, cheese, rose and perfume)] and other conditioned sensory stimuli (tones, light and air puff) was recorded and compared with behavioral responses to the same odors (black pepper, cheese, rose and perfume). In a neurophysiological study, the rats were trained to lick a spout that protruded close to its mouth to obtain sucrose or intracranial self-stimulation reward after presentation of conditioned stimuli. Of 150 orbital cortex neurons recorded during the task, 65 responded to one or more types of sensory stimuli. Of these, 73.8% (48/65) responded during presentation of an odor. Although the mean breadth of responsiveness (entropy) of the olfactory neurons based on the responses to five volatile organic compounds and air (control) was rather high (0.795), these stimuli were well discriminated in an odor space resulting from multidimensional scaling using Pearson's correlation coefficients between the stimuli. In a behavioral study, a rat was housed in an equilateral octagonal cage, with free access to food and choice among eight levers, four of which elicited only water (no odor, controls), and four of which elicited both water and one of four odors (black pepper, cheese, rose or perfume). Lever presses for each odor and control were counted. Distributions of these five stimuli (four odors and air) in an odor space derived from the multidimensional scaling using Pearson's correlation coefficients based on behavioral responses were very similar to those based on neuronal responses to the same five stimuli. Furthermore, Pearson's correlation coefficients between the same five stimuli based on the neuronal responses and those based on behavioral responses were significantly correlated. The results demonstrated a pivotal role of

  15. Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons

    PubMed Central

    Srinivasan, Rahul; Henley, Beverley M.; Henderson, Brandon J.; Indersmitten, Tim; Cohen, Bruce N.; Kim, Charlene H.; McKinney, Sheri; Deshpande, Purnima; Xiao, Cheng

    2016-01-01

    Retrospective epidemiological studies show an inverse correlation between susceptibility to Parkinson's disease and a person's history of tobacco use. Animal model studies suggest nicotine as a neuroprotective agent and nicotinic acetylcholine (ACh) receptors (nAChRs) as targets for neuroprotection, but the underlying neuroprotective mechanism(s) are unknown. We cultured mouse ventral midbrain neurons for 3 weeks. Ten to 20% of neurons were dopaminergic (DA), revealed by tyrosine hydroxylase (TH) immunoreactivity. We evoked mild endoplasmic reticulum (ER) stress with tunicamycin (Tu), producing modest increases in the level of nuclear ATF6, phosphorylated eukaryotic initiation factor 2α, nuclear XBP1, and the downstream proapoptotic effector nuclear C/EBP homologous protein. We incubated cultures for 2 weeks with 200 nm nicotine, the approximate steady-state concentration between cigarette smoking or vaping, or during nicotine patch use. Nicotine incubation suppressed Tu-induced ER stress and the unfolded protein response (UPR). Study of mice with fluorescent nAChR subunits showed that the cultured TH+ neurons displayed α4, α6, and β3 nAChR subunit expression and ACh-evoked currents. Gene expression profile in cultures from TH-eGFP mice showed that the TH+ neurons also express several other genes associated with DA release. Nicotine also upregulated ACh-induced currents in DA neurons by ∼2.5-fold. Thus, nicotine, at a concentration too low to activate an appreciable fraction of plasma membrane nAChRs, induces two sequelae of pharmacological chaperoning in the ER: UPR suppression and nAChR upregulation. Therefore, one mechanism of neuroprotection by nicotine is pharmacological chaperoning, leading to UPR suppression. Measuring this pathway may help in assessing neuroprotection. SIGNIFICANCE STATEMENT Parkinson's disease (PD) cannot yet be cured or prevented. However, many retrospective epidemiological studies reveal that PD is diagnosed less frequently in

  16. Responses of neurons in chinchilla auditory cortex to frequency-modulated tones.

    PubMed

    Brown, Trecia A; Harrison, Robert V

    2009-04-01

    Frequency-modulated (FM) stimuli have been used to explore the behavior of neurons in the auditory cortex of several animal models; however, the properties of FM-sensitive auditory cortical neurons in the chinchilla are still unknown. Single-unit responses to FM stimulation were obtained from the auditory cortex of anesthetized adult chinchillas (Chinchilla laniger). Upward and downward linear FM sweeps spanning frequencies from 0.1 to 20 kHz were presented at speeds of 0.05 to 0.82 kHz/ms. Results indicated that >90% of sampled neurons were responsive to FM sweeps. The population preference was for upward FM sweeps and for medium to fast speeds (> or =0.3 kHz/ms). Few units (3%) were selective for downward FM sweeps, whereas <22% of units preferred slow speeds (< or =0.1 kHz/ms). Velocity preference and direction sensitivity were positively correlated for upward sweeps only (r = 0.40, P = 0.0021, t-test). Three types of firing rate patterns were observed in the FM response peristimulus time histograms: a single peak at sweep onset/offset ("onset") and a single peak ("late") or multiple peaks ("burst") during the sweep. "Late" units expressed the highest mean values for direction sensitivity and speed selectivity; "onset" units were selective only for direction and "burst" units were not selective for either direction or speed. The robust responsiveness of these neurons to FM sweeps suggests a functional role for FM detection such as the identification of FM sweeps present in vocalizations of other organisms within the chinchilla's natural environment. PMID:19211659

  17. Plasma leptin inhibits the response of nucleus of the solitary tract neurons to aortic baroreceptor stimulation.

    PubMed

    Ciriello, John

    2013-08-01

    Leptin receptors have been identified within the nucleus of the solitary tract (NTS) and leptin injections into the caudal NTS inhibit the baroreceptor reflex. However, whether plasma leptin alters the discharge of NTS neurons mediating aortic baroreceptor reflex activity is not known. A series of electrophysiological single unit recording experiments was done in the urethane-chloralose anesthetized, paralyzed and artificially ventilated Wistar and Zucker obese rat with either their neuroaxis intact or with mid-collicular transections. Single units in NTS antidromically activated by electrical stimulation of depressor sites in the caudal ventrolateral medulla (CVLM) were found to display a cardiac cycle-related rhythmicity. These units were tested for their responses to stimulation of the aortic depressor nerve (ADN) and intra-carotid injections of leptin (50-200ng/0.1ml). Of 63 single units tested in NTS, 33 were antidromically activated by stimulation of CVLM depressor sites and 18 of these single units responded with a decrease in discharge rate after intracarotid injections of leptin. Thirteen of these leptin responsive neurons (∼72%) were excited by ADN stimulation. Furthermore, the excitatory response of these single units to ADN stimulation was attenuated by about 50% after the intracarotid leptin injection. Intracarotid injections of leptin (200ng/0.1ml) in the Zucker obese rat did not alter the discharge rate of NTS-CVLM projecting neurons. These data suggest that leptin exerts a modulatory effect on brainstem neuronal circuits that control cardiovascular responses elicited during the reflex activation of arterial baroreceptors. PMID:23792336

  18. Plasma leptin inhibits the response of nucleus of the solitary tract neurons to aortic baroreceptor stimulation.

    PubMed

    Ciriello, John

    2013-08-01

    Leptin receptors have been identified within the nucleus of the solitary tract (NTS) and leptin injections into the caudal NTS inhibit the baroreceptor reflex. However, whether plasma leptin alters the discharge of NTS neurons mediating aortic baroreceptor reflex activity is not known. A series of electrophysiological single unit recording experiments was done in the urethane-chloralose anesthetized, paralyzed and artificially ventilated Wistar and Zucker obese rat with either their neuroaxis intact or with mid-collicular transections. Single units in NTS antidromically activated by electrical stimulation of depressor sites in the caudal ventrolateral medulla (CVLM) were found to display a cardiac cycle-related rhythmicity. These units were tested for their responses to stimulation of the aortic depressor nerve (ADN) and intra-carotid injections of leptin (50-200ng/0.1ml). Of 63 single units tested in NTS, 33 were antidromically activated by stimulation of CVLM depressor sites and 18 of these single units responded with a decrease in discharge rate after intracarotid injections of leptin. Thirteen of these leptin responsive neurons (∼72%) were excited by ADN stimulation. Furthermore, the excitatory response of these single units to ADN stimulation was attenuated by about 50% after the intracarotid leptin injection. Intracarotid injections of leptin (200ng/0.1ml) in the Zucker obese rat did not alter the discharge rate of NTS-CVLM projecting neurons. These data suggest that leptin exerts a modulatory effect on brainstem neuronal circuits that control cardiovascular responses elicited during the reflex activation of arterial baroreceptors.

  19. What Response Properties Do Individual Neurons Need to Underlie Position and Clutter “Invariant” Object Recognition?

    PubMed Central

    Li, Nuo; Cox, David D.; Zoccolan, Davide; DiCarlo, James J.

    2009-01-01

    Primates can easily identify visual objects over large changes in retinal position—a property commonly referred to as position “invariance.” This ability is widely assumed to depend on neurons in inferior temporal cortex (IT) that can respond selectively to isolated visual objects over similarly large ranges of retinal position. However, in the real world, objects rarely appear in isolation, and the interplay between position invariance and the representation of multiple objects (i.e., clutter) remains unresolved. At the heart of this issue is the intuition that the representations of nearby objects can interfere with one another and that the large receptive fields needed for position invariance can exacerbate this problem by increasing the range over which interference acts. Indeed, most IT neurons' responses are strongly affected by the presence of clutter. While external mechanisms (such as attention) are often invoked as a way out of the problem, we show (using recorded neuronal data and simulations) that the intrinsic properties of IT population responses, by themselves, can support object recognition in the face of limited clutter. Furthermore, we carried out extensive simulations of hypothetical neuronal populations to identify the essential individual-neuron ingredients of a good population representation. These simulations show that the crucial neuronal property to support recognition in clutter is not preservation of response magnitude, but preservation of each neuron's rank-order object preference under identity-preserving image transformations (e.g., clutter). Because IT neuronal responses often exhibit that response property, while neurons in earlier visual areas (e.g., V1) do not, we suggest that preserving the rank-order object preference regardless of clutter, rather than the response magnitude, more precisely describes the goal of individual neurons at the top of the ventral visual stream. PMID:19439676

  20. Responses of Ventral Posterior Thalamus Neurons to Three-Dimensional Vestibular and Optic Flow Stimulation

    PubMed Central

    Meng, Hui

    2010-01-01

    Multisensory neurons tuned to both vestibular and visual motion (optic flow) signals are found in several cortical areas in the dorsal visual stream. Here we examine whether such convergence occurs subcortically in the macaque thalamus. We searched the ventral posterior nuclei, including the anterior pulvinar, as well as the ventro-lateral and ventral posterior lateral nuclei, areas that receive vestibular signals from brain stem and deep cerebellar nuclei. Approximately a quarter of cells responded to three-dimensional (3D) translational and/or rotational motion. More than half of the responsive cells were convergent, thus responded during both rotation and translation. The preferred axes of translation/rotation were distributed throughout 3D space. The majority of the neurons were excited, but some were inhibited, during rotation/translation in darkness. Only a couple of neurons were multisensory being tuned to both vestibular and optic flow stimuli. We conclude that multisensory vestibular/optic flow neurons, which are commonly found in cortical visual and visuomotor areas, are rare in the ventral posterior thalamus. PMID:19955294

  1. Response functions for electrically coupled neuronal network: a method of local point matching and its applications.

    PubMed

    Yihe, Lu; Timofeeva, Yulia

    2016-06-01

    Neuronal networks connected by electrical synapses, also referred to as gap junctions, are present throughout the entire central nervous system. Many instances of gap-junctional coupling are formed between dendritic arbours of individual cells, and these dendro-dendritic gap junctions are known to play an important role in mediating various brain rhythms in both normal and pathological states. The dynamics of such neuronal networks modelled by passive or quasi-active (resonant) membranes can be described by the Green's function which provides the fundamental input-output relationships of the entire network. One of the methods for calculating this response function is the so-called 'sum-over-trips' framework which enables the construction of the Green's function for an arbitrary network as a convergent infinite series solution. Here we propose an alternative and computationally efficient approach for constructing the Green's functions on dendro-dendritic gap junction-coupled neuronal networks which avoids any infinite terms in the solutions. Instead, the Green's function is constructed from the solution of a system of linear algebraic equations. We apply this new method to a number of systems including a simple single cell model and two-cell neuronal networks. We also demonstrate that the application of this novel approach allows one to reduce a model with complex dendritic formations to an equivalent model with a much simpler morphological structure. PMID:26994016

  2. RESPONSE PROPERTIES OF LOCAL FIELD POTENTIALS AND NEIGHBORING SINGLE NEURONS IN AWAKE PRIMARY VISUAL CORTEX

    PubMed Central

    Lashgari, Reza; Li, Xiaobing; Chen, Yao; Kremkow, Jens; Bereshpolova, Yulia; Swadlow, Harvey A.; Alonso, Jose M.

    2012-01-01

    Recordings from local field potentials (LFPs) are becoming increasingly common in research and clinical applications, however, we still have a poor understanding of how LFP stimulus selectivity originates from the combined activity of single neurons. Here, we systematically compared the stimulus selectivity of LFP and neighboring single unit activity (SUA) recorded in area V1 of awake primates. We demonstrate that LFP and SUA have similar stimulus preferences for orientation, direction of motion, contrast, size, temporal frequency and even spatial phase. However, the average SUA had 50 times better signal to noise, 20% higher contrast sensitivity, 45% higher direction selectivity and 15% more tuning depth than the average LFP. Low LFP frequencies (< 30 Hz) were most strongly correlated with the spiking frequencies of neurons with non-linear spatial summation and poor orientation/direction selectivity that were located near cortical current sinks (negative LFPs). In contrast, LFP gamma frequencies (> 30 Hz) were correlated with a more diverse group of neurons located near cortical sources (positive LFPs). In summary, our results indicate that low- and high-frequency LFP pools signals from V1 neurons with similar stimulus preferences but different response properties and cortical depths. PMID:22895722

  3. The neuronal response at extended timescales: a linearized spiking input–output relation

    PubMed Central

    Soudry, Daniel; Meir, Ron

    2014-01-01

    Many biological systems are modulated by unknown slow processes. This can severely hinder analysis – especially in excitable neurons, which are highly non-linear and stochastic systems. We show the analysis simplifies considerably if the input matches the sparse “spiky” nature of the output. In this case, a linearized spiking Input–Output (I/O) relation can be derived semi-analytically, relating input spike trains to output spikes based on known biophysical properties. Using this I/O relation we obtain closed-form expressions for all second order statistics (input – internal state – output correlations and spectra), construct optimal linear estimators for the neuronal response and internal state and perform parameter identification. These results are guaranteed to hold, for a general stochastic biophysical neuron model, with only a few assumptions (mainly, timescale separation). We numerically test the resulting expressions for various models, and show that they hold well, even in cases where our assumptions fail to hold. In a companion paper we demonstrate how this approach enables us to fit a biophysical neuron model so it reproduces experimentally observed temporal firing statistics on days-long experiments. PMID:24765073

  4. The neuronal response at extended timescales: a linearized spiking input-output relation.

    PubMed

    Soudry, Daniel; Meir, Ron

    2014-01-01

    Many biological systems are modulated by unknown slow processes. This can severely hinder analysis - especially in excitable neurons, which are highly non-linear and stochastic systems. We show the analysis simplifies considerably if the input matches the sparse "spiky" nature of the output. In this case, a linearized spiking Input-Output (I/O) relation can be derived semi-analytically, relating input spike trains to output spikes based on known biophysical properties. Using this I/O relation we obtain closed-form expressions for all second order statistics (input - internal state - output correlations and spectra), construct optimal linear estimators for the neuronal response and internal state and perform parameter identification. These results are guaranteed to hold, for a general stochastic biophysical neuron model, with only a few assumptions (mainly, timescale separation). We numerically test the resulting expressions for various models, and show that they hold well, even in cases where our assumptions fail to hold. In a companion paper we demonstrate how this approach enables us to fit a biophysical neuron model so it reproduces experimentally observed temporal firing statistics on days-long experiments.

  5. Osmotic and hormonal stimulation of the third ventricular region of ducks: antidiuretic, circulatory and local neuronal responses.

    PubMed

    Simon-Oppermann, C; Kanosue, K; Günther, O; Schmid, H

    1989-01-01

    By means of local microperfusion of the 3rd cerebral ventricle, antidiuretic and circulatory responses to stimulations with various hypertonic solutions and norepinephrine were analyzed in conscious ducks. The results suggest ionic rather than osmometric responsiveness of periventricular osmoreceptive elements, which is in line with single unit recordings of periventricular neurons tested in vitro for their osmoresponsiveness. These neurons were located subependymally at the site of greatest responsiveness in vivo, and corresponded to morphologically identified neurons projecting to the neuroendocrine hypothalamo-pituitary system. Antidiuresis was combined with increases in arterial pressure and heart rate in response to hypertonic stimulations with monovalent cations; divalent cations produced long-lasting antidiuresis and equivocal circulatory responses. Norepinephrine elicited antidiuresis which was accompanied by arterial hypotension and bradycardia. Osmotically and norepinephrine induced antidiuresis was combined with increases of plasma ADH concentration. Different modulatory actions of intrinsic adrenergic, angiotensinergic and vasotocinergic neurons are suggested in hypothalamic control of autonomic functions. PMID:2554682

  6. Responses of primate caudal parabrachial nucleus and Kolliker-fuse nucleus neurons to whole body rotation

    NASA Technical Reports Server (NTRS)

    Balaban, Carey D.; McGee, David M.; Zhou, Jianxun; Scudder, Charles A.

    2002-01-01

    The caudal aspect of the parabrachial (PBN) and Kolliker-Fuse (KF) nuclei receive vestibular nuclear and visceral afferent information and are connected reciprocally with the spinal cord, hypothalamus, amygdala, and limbic cortex. Hence, they may be important sites of vestibulo-visceral integration, particularly for the development of affective responses to gravitoinertial challenges. Extracellular recordings were made from caudal PBN cells in three alert, adult female Macaca nemestrina through an implanted chamber. Sinusoidal and position trapezoid angular whole body rotation was delivered in yaw, roll, pitch, and vertical semicircular canal planes. Sites were confirmed histologically. Units that responded during rotation were located in lateral and medial PBN and KF caudal to the trochlear nerve at sites that were confirmed anatomically to receive superior vestibular nucleus afferents. Responses to whole-body angular rotation were modeled as a sum of three signals: angular velocity, a leaky integration of angular velocity, and vertical position. All neurons displayed angular velocity and integrated angular velocity sensitivity, but only 60% of the neurons were position-sensitive. These responses to vertical rotation could display symmetric, asymmetric, or fully rectified cosinusoidal spatial tuning about a best orientation in different cells. The spatial properties of velocity and integrated velocity and position responses were independent for all position-sensitive neurons; the angular velocity and integrated angular velocity signals showed independent spatial tuning in the position-insensitive neurons. Individual units showed one of three different orientations of their excitatory axis of velocity rotation sensitivity: vertical-plane-only responses, positive elevation responses (vertical plane plus ipsilateral yaw), and negative elevation axis responses (vertical plane plus negative yaw). The interactions between the velocity and integrated velocity components

  7. Correlation of 125I-LSD autoradiographic labeling with serotonin voltage clamp responses in Aplysia neurons

    SciTech Connect

    Evans, M.L.; Kadan, M.J.; Hartig, P.R.; Carpenter, D.O. )

    1991-05-01

    Autoradiographic receptor binding studies using 125I-LSD (2-(125I)lysergic acid diethyamide) revealed intense labelling on the soma of a symmetrically located pair of cells in the abdominal ganglion of Aplysia californica. This binding was blocked by micromolar concentrations of serotonin and lower concentrations of the serotonergic antagonists, cyproheptadine and mianserin. Electrophysiological investigation of responses to serotonin of neurons in the left upper quadrant, where one of the labeled neurons is located, revealed a range of serotonin responses. Cells L3 and L6 have a K+ conductance increase in response to serotonin that is not blocked by cyproheptadine or mianserin. Cells L2 and L4 have a biphasic response to serotonin: a Na+ conductance increase, which can be blocked by cyproheptadine and mianserin, followed by a voltage dependent Ca2+ conductance which is blocked by Co2+ but not the serotonergic antagonists. Cell L1, and its symmetrical pair, R1, have in addition to the Na+ and Ca2+ responses observed in L2 and L4, a Cl- conductance increase blocked by LSD, cyproheptadine and mianserin. LSD had little effect on the other responses. The authors conclude that the symmetrically located cells L1 and R1 have a Cl- channel linked to a cyproheptadine- and mianserin-sensitive serotonin receptor that is selectively labelled by 125I-LSD. This receptor has many properties in common with the mammalian serotonin 1C receptor.

  8. Unique responses of midbrain CART neurons in macaques to ovarian steroids.

    PubMed

    Lima, F B; Henderson, J A; Reddy, A P; Tokuyama, Y; Hubert, G W; Kuhar, M J; Bethea, C L

    2008-08-28

    CART (cocaine and amphetamine regulated transcript) is a neuropeptide involved in the control of several physiological processes, such as response to psychostimulants, food intake, depressive diseases and neuroprotection. It is robustly expressed in the brain, mainly in regions that control emotional and stress responses and it is regulated by estrogen in the hypothalamus. There is a distinct population of CART neurons located in the vicinity of the Edinger-Westphal nucleus of the midbrain that also colocalize urocortin-1. The aims of this study were 1) to determine the distribution of CART immunoreactive neurons in the monkey midbrain, 2) to examine the effects of estrogen (E) and progesterone (P) on midbrain CART mRNA and peptide expression and 3) to determine whether midbrain CART neurons contain steroid receptors. Adult female rhesus monkeys (Macaca mulatta) were spayed and either treated with placebo (OVX), estrogen alone (E), progesterone alone (P) or E+P. Animals were prepared (a) for RNA extraction followed by microarray analysis and quantitative (q) RT-PCR (n=3/group); (b) for immunohistochemical analysis of CART and CART+tryptophan hydroxylase (TPH), CART+estrogen receptors (ER) or CART+progesterone receptors (n=5/group) and (c) for Western blots (n=3/group). Both E- and E+P-administration decreased CART gene expression on the microarray and with qRT-PCR. Stereological analysis of CART immunostaining at five levels of the Edinger-Westphal nucleus indicated little effect of E or E+P administration on the area of CART immunostaining. However, P administration increased CART-immunopositive area in comparison to the OVX control group with Student's t-test, but not with ANOVA. CART 55-102 detection on Western blot was unchanged by hormone administration. ERbeta and PR were detected in CART neurons and CART fibers appeared to innervate TPH-positive serotonin neurons in the dorsal raphe. In summary, E decreased CART mRNA, but this effect did not translate to the

  9. Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation.

    PubMed

    Berrios, Janet; Stamatakis, Alice M; Kantak, Pranish A; McElligott, Zoe A; Judson, Matthew C; Aita, Megumi; Rougie, Marie; Stuber, Garret D; Philpot, Benjamin D

    2016-01-01

    Motivated reward-seeking behaviours are governed by dopaminergic ventral tegmental area projections to the nucleus accumbens. In addition to dopamine, these mesoaccumbal terminals co-release other neurotransmitters including glutamate and GABA, whose roles in regulating motivated behaviours are currently being investigated. Here we demonstrate that loss of the E3-ubiquitin ligase, UBE3A, from tyrosine hydroxylase-expressing neurons impairs mesoaccumbal, non-canonical GABA co-release and enhances reward-seeking behaviour measured by optical self-stimulation. PMID:26869263

  10. Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation.

    PubMed

    Berrios, Janet; Stamatakis, Alice M; Kantak, Pranish A; McElligott, Zoe A; Judson, Matthew C; Aita, Megumi; Rougie, Marie; Stuber, Garret D; Philpot, Benjamin D

    2016-02-12

    Motivated reward-seeking behaviours are governed by dopaminergic ventral tegmental area projections to the nucleus accumbens. In addition to dopamine, these mesoaccumbal terminals co-release other neurotransmitters including glutamate and GABA, whose roles in regulating motivated behaviours are currently being investigated. Here we demonstrate that loss of the E3-ubiquitin ligase, UBE3A, from tyrosine hydroxylase-expressing neurons impairs mesoaccumbal, non-canonical GABA co-release and enhances reward-seeking behaviour measured by optical self-stimulation.

  11. Responses of rat medial prefrontal cortical neurons to Pavlovian conditioned stimuli and to delivery of appetitive reward.

    PubMed

    Petykó, Zoltán; Gálosi, Rita; Tóth, Attila; Máté, Kálmán; Szabó, Imre; Szabó, István; Karádi, Zoltán; Lénárd, László

    2015-01-01

    In the present experiments, medial prefrontal cortical (mPFC) neurons were extracellularly recorded by means of tetrode electrodes to examine their possible role in the prediction of appetitive reward. Two different cue tones (CS) and sucrose solution or water reward (US) were associated in a Pavlovian conditioning paradigm. In order to test behavioral correlate of the CS-US association, the head acceleration before the first lick of licking cluster was measured. Neuronal activity changes in the mPFC were analyzed (i) during the CS presentations; (ii) before the first lick of licking clusters; (iii) during consummation; and (iv) we also examined whether consummation was represented in neurons responding to the CSs. There was a difference between the head accelerations to the different USs during early or late occurring first approaches, but there was no such a difference during intercluster approaches. A significant proportion of neurons changed their firing rate during the CS presentation, before the first lick of licking cluster or during licking of the reward. Both, excitatory and inhibitory responses were observed. A subpopulation of neurons responding to the CSs also responded during reward consumption. Differential population activities of excitatory neurons were recorded in response to the different CSs, CS evoked approach behaviors and consumption of different rewards. Neuronal responses also discriminated among the CSs and trials with or without consummation. These results provided evidence for the involvement of mPFC neurons in the prediction, representation and organization of conditioned behavioral actions, such as approaches to rewards and consummation.

  12. Dynamics of Elongation Factor 2 Kinase Regulation in Cortical Neurons in Response to Synaptic Activity

    PubMed Central

    Kenney, Justin W.; Sorokina, Oksana; Genheden, Maja; Sorokin, Anatoly

    2015-01-01

    The rapid regulation of cell signaling in response to calcium in neurons is essential for real-time processing of large amounts of information in the brain. A vital regulatory component, and one of the most energy-intensive biochemical processes in cells, is the elongation phase of mRNA translation, which is controlled by the Ca2+/CaM-dependent elongation factor 2 kinase (eEF2K). However, little is known about the dynamics of eEF2K regulation in neurons despite its established role in learning and synaptic plasticity. To explore eEF2K dynamics in depth, we stimulated synaptic activity in mouse primary cortical neurons. We find that synaptic activity results in a rapid, but transient, increase in eEF2K activity that is regulated by a combination of AMPA and NMDA-type glutamate receptors and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) pathways. We then used computational modeling to test the hypothesis that considering Ca2+-coordinated MEK/ERK, mTORC1, and eEF2k activation is sufficient to describe the observed eEF2K dynamics. Although such a model could partially fit the empirical findings, it also suggested that a crucial positive regulator of eEF2K was also necessary. Through additional modeling and empirical evidence, we demonstrate that AMP kinase (AMPK) is also an important regulator of synaptic activity-driven eEF2K dynamics in neurons. Our combined modeling and experimental findings provide the first evidence that it is necessary to consider the combined interactions of Ca2+ with MEK/ERK, mTORC1, and AMPK to adequately explain eEF2K regulation in neurons. PMID:25698741

  13. [Variations of neuronal responses in cat cerebral cortex to somatic stimulation in the presence of additional stimulants].

    PubMed

    Busel', B I; Kniga, A P

    1992-01-01

    Neuronal responses (areas 3, 4, 5) were registered in awake cats after electric stimulation of the contralateralis limb. External stimuli, food and defensive motivation inhibit short-latency neuronal reactions which were registered in control. When in the experiment there was electric stimulation of another limb instead of an external stimuli the neuronal reaction did not change. If subthreshold electric stimulation (SES) was given with a perceptible stimulation of such modality the spike neuronal responses appeared in either cases. This SES may be used as a conditional signal during defensive conditioning. It is established that the neuronal pattern under somatic stimulation is not constant. Its character is connected with fluctuation of cat's exteroceptive attention under external stimuli and internal motivational condition.

  14. Multiphasic temporal dynamics in responses of midbrain dopamine neurons to appetitive and aversive stimuli.

    PubMed

    Fiorillo, Christopher D; Song, Minryung R; Yun, Sora R

    2013-03-13

    The transient response of dopamine neurons has been described as reward prediction error (RPE), with activation or suppression by events that are better or worse than expected, respectively. However, at least a minority of neurons are activated by aversive or high-intensity stimuli, casting doubt on the generality of RPE in describing the dopamine signal. To overcome limitations of previous studies, we studied neuronal responses to a wider variety of high-intensity and aversive stimuli, and we quantified and controlled aversiveness through a choice task in which macaques sacrificed juice to avoid aversive stimuli. Whereas most previous work has portrayed the RPE as a single impulse or "phase," here we demonstrate its multiphasic temporal dynamics. Aversive or high-intensity stimuli evoked a triphasic sequence of activation-suppression-activation extending over a period of 40-700 ms. The initial activation at short latencies (40-120 ms) reflected sensory intensity. The influence of motivational value became dominant between 150 and 250 ms, with activation in the case of appetitive stimuli, and suppression in the case of aversive and neutral stimuli. The previously unreported late activation appeared to be a modest "rebound" after strong suppression. Similarly, strong activation by reward was often followed by suppression. We suggest that these "rebounds" may result from overcompensation by homeostatic mechanisms in some cells. Our results are consistent with a realistic RPE, which evolves over time through a dynamic balance of excitation and inhibition.

  15. Decreased Interleukin-4 Release from the Neurons of the Locus Coeruleus in Response to Immobilization Stress

    PubMed Central

    Park, Hyun-Jung; Starkweather, Angela; An, Kyungeh

    2016-01-01

    It has been demonstrated that immobilization (IMO) stress affects neuroimmune systems followed by alterations of physiology and behavior. Interleukin-4 (IL-4), an anti-inflammatory cytokine, is known to regulate inflammation caused by immune challenge but the effect of IMO on modulation of IL-4 expression in the brain has not been assessed yet. Here, it was demonstrated that IL-4 was produced by noradrenergic neurons in the locus coeruleus (LC) of the brain and release of IL-4 was reduced in response to IMO. It was observed that IMO groups were more anxious than nontreated groups. Acute IMO (2 h/day, once) stimulated secretion of plasma corticosterone and tyrosine hydroxylase (TH) in the LC whereas these increments were diminished in exposure to chronic stress (2 h/day, 21 consecutive days). Glucocorticoid receptor (GR), TH, and IL-4-expressing cells were localized in identical neurons of the LC, indicating that hypothalamic-pituitary-adrenal- (HPA-) axis and sympathetic-adrenal-medullary- (SAM-) axis might be involved in IL-4 secretion in the stress response. Accordingly, it was concluded that stress-induced decline of IL-4 concentration from LC neurons may be related to anxiety-like behavior and an inverse relationship exists between IL-4 secretion and HPA/SAM-axes activation. PMID:26903707

  16. Prefrontal neurons encode context-based response execution and inhibition in reward seeking and extinction.

    PubMed

    Moorman, David E; Aston-Jones, Gary

    2015-07-28

    The prefrontal cortex (PFC) guides execution and inhibition of behavior based on contextual demands. In rodents, the dorsal/prelimbic (PL) medial PFC (mPFC) is frequently considered essential for execution of goal-directed behavior ("go") whereas ventral/infralimbic (IL) mPFC is thought to control behavioral suppression ("stop"). This dichotomy is commonly seen for fear-related behaviors, and for some behaviors related to cocaine seeking. Overall, however, data for reward-directed behaviors are ambiguous, and few recordings of PL/IL activity have been performed to demonstrate single-neuron correlates. We recorded neuronal activity in PL and IL during discriminative stimulus driven sucrose seeking followed by multiple days of extinction of the reward-predicting stimulus. Contrary to a generalized PL-go/IL-stop hypothesis, we found cue-evoked activity in PL and IL during reward seeking and extinction. Upon analyzing this activity based on resultant behavior (lever press or withhold), we found that neurons in both areas encoded contextually appropriate behavioral initiation (during reward seeking) and withholding (during extinction), where context was dictated by response-outcome contingencies. Our results demonstrate that PL and IL signal contextual information for regulation of behavior, irrespective of whether that involves initiation or suppression of behavioral responses, rather than topographically encoding go vs. stop behaviors. The use of context to optimize behavior likely plays an important role in maximizing utility-promoting exertion of activity when behaviors are rewarded and conservation of energy when not. PMID:26170333

  17. Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress.

    PubMed

    Milior, Giampaolo; Lecours, Cynthia; Samson, Louis; Bisht, Kanchan; Poggini, Silvia; Pagani, Francesca; Deflorio, Cristina; Lauro, Clotilde; Alboni, Silvia; Limatola, Cristina; Branchi, Igor; Tremblay, Marie-Eve; Maggi, Laura

    2016-07-01

    Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling - which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in the healthy brain - has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx3cr1 gene affects the brain's response to chronic stress. To this purpose, we housed Cx3cr1 knockout and wild-type adult mice in either control or stressful environments for 2weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron-microglia communication via the CX3CR1-CX3CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression.

  18. Distinct Spatiotemporal Response Properties of Excitatory Versus Inhibitory Neurons in the Mouse Auditory Cortex

    PubMed Central

    Maor, Ido; Shalev, Amos; Mizrahi, Adi

    2016-01-01

    In the auditory system, early neural stations such as brain stem are characterized by strict tonotopy, which is used to deconstruct sounds to their basic frequencies. But higher along the auditory hierarchy, as early as primary auditory cortex (A1), tonotopy starts breaking down at local circuits. Here, we studied the response properties of both excitatory and inhibitory neurons in the auditory cortex of anesthetized mice. We used in vivo two photon-targeted cell-attached recordings from identified parvalbumin-positive neurons (PVNs) and their excitatory pyramidal neighbors (PyrNs). We show that PyrNs are locally heterogeneous as characterized by diverse best frequencies, pairwise signal correlations, and response timing. In marked contrast, neighboring PVNs exhibited homogenous response properties in pairwise signal correlations and temporal responses. The distinct physiological microarchitecture of different cell types is maintained qualitatively in response to natural sounds. Excitatory heterogeneity and inhibitory homogeneity within the same circuit suggest different roles for each population in coding natural stimuli. PMID:27600839

  19. Spatial Attention and Temporal Expectation Under Timed Uncertainty Predictably Modulate Neuronal Responses in Monkey V1.

    PubMed

    Sharma, Jitendra; Sugihara, Hiroki; Katz, Yarden; Schummers, James; Tenenbaum, Joshua; Sur, Mriganka

    2015-09-01

    The brain uses attention and expectation as flexible devices for optimizing behavioral responses associated with expected but unpredictably timed events. The neural bases of attention and expectation are thought to engage higher cognitive loci; however, their influence at the level of primary visual cortex (V1) remains unknown. Here, we asked whether single-neuron responses in monkey V1 were influenced by an attention task of unpredictable duration. Monkeys covertly attended to a spot that remained unchanged for a fixed period and then abruptly disappeared at variable times, prompting a lever release for reward. We show that monkeys responded progressively faster and performed better as the trial duration increased. Neural responses also followed monkey's task engagement-there was an early, but short duration, response facilitation, followed by a late but sustained increase during the time monkeys expected the attention spot to disappear. This late attentional modulation was significantly and negatively correlated with the reaction time and was well explained by a modified hazard function. Such bimodal, time-dependent changes were, however, absent in a task that did not require explicit attentional engagement. Thus, V1 neurons carry reliable signals of attention and temporal expectation that correlate with predictable influences on monkeys' behavioral responses. PMID:24836689

  20. A Convolutional Subunit Model for Neuronal Responses in Macaque V1

    PubMed Central

    Vintch, Brett; Movshon, J. Anthony

    2015-01-01

    The response properties of neurons in the early stages of the visual system can be described using the rectified responses of a set of self-similar, spatially shifted linear filters. In macaque primary visual cortex (V1), simple cell responses can be captured with a single filter, whereas complex cells combine a set of filters, creating position invariance. These filters cannot be estimated using standard methods, such as spike-triggered averaging. Subspace methods like spike-triggered covariance can recover multiple filters but require substantial amounts of data, and recover an orthogonal basis for the subspace in which the filters reside, rather than the filters themselves. Here, we assume a linear-nonlinear-linear-nonlinear (LN-LN) cascade model in which the first LN stage consists of shifted (“convolutional”) copies of a single filter, followed by a common instantaneous nonlinearity. We refer to these initial LN elements as the “subunits” of the receptive field, and we allow two independent sets of subunits, each with its own filter and nonlinearity. The second linear stage computes a weighted sum of the subunit responses and passes the result through a final instantaneous nonlinearity. We develop a procedure to directly fit this model to electrophysiological data. When fit to data from macaque V1, the subunit model significantly outperforms three alternatives in terms of cross-validated accuracy and efficiency, and provides a robust, biologically plausible account of receptive field structure for all cell types encountered in V1. SIGNIFICANCE STATEMENT We present a new subunit model for neurons in primary visual cortex that significantly outperforms three alternative models in terms of cross-validated accuracy and efficiency, and provides a robust and biologically plausible account of the receptive field structure in these neurons across the full spectrum of response properties. PMID:26538653

  1. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

    SciTech Connect

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun; Park, Yong Seek; Park, Cheung-Seog; Jin, Young-Ho

    2015-01-02

    Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin

  2. Imaging neuronal responses in slice preparations of vomeronasal organ expressing a genetically encoded calcium sensor.

    PubMed

    Ma, Limei; Haga-Yamanaka, Sachiko; Yu, Qingfeng Elden; Qiu, Qiang; Kim, Sangseong; Yu, C Ron

    2011-01-01

    The vomeronasal organ (VNO) detects chemosensory signals that carry information about the social, sexual and reproductive status of the individuals within the same species. These intraspecies signals, the pheromones, as well as signals from some predators, activate the vomeronasal sensory neurons (VSNs) with high levels of specificity and sensitivity. At least three distinct families of G-protein coupled receptors, V1R, V2R and FPR, are expressed in VNO neurons to mediate the detection of the chemosensory cues. To understand how pheromone information is encoded by the VNO, it is critical to analyze the response profiles of individual VSNs to various stimuli and identify the specific receptors that mediate these responses. The neuroepithelia of VNO are enclosed in a pair of vomer bones. The semi-blind tubular structure of VNO has one open end (the vomeronasal duct) connecting to the nasal cavity. VSNs extend their dendrites to the lumen part of the VNO, where the pheromone cues are in contact with the receptors expressed at the dendritic knobs. The cell bodies of the VSNs form pseudo-stratified layers with V1R and V2R expressed in the apical and basal layers respectively. Several techniques have been utilized to monitor responses of VSNs to sensory stimuli. Among these techniques, acute slice preparation offers several advantages. First, compared to dissociated VSNs, slice preparations maintain the neurons in their native morphology and the dendrites of the cells stay relatively intact. Second, the cell bodies of the VSNs are easily accessible in coronal slice of the VNO to allow electrophysiology studies and imaging experiments as compared to whole epithelium and whole-mount preparations. Third, this method can be combined with molecular cloning techniques to allow receptor identification. Sensory stimulation elicits strong Ca2+ influx in VSNs that is indicative of receptor activation. We thus develop transgenic mice that express G-CaMP2 in the olfactory sensory

  3. Response of an ensemble of noisy neuron models to a single input.

    PubMed

    Tanabe, S; Sato, S; Pakdaman, K

    1999-12-01

    Spike timing precision in response to a subthreshold stimulation can be enhanced by noise in ensembles of neurons [X. Pei, L. Wilkens, and F. Moss, Phys. Rev. Lett. 77, 4679 (1996)]. We elucidate the mechanism underlying this phenomenon by computing the membrane potential distributions of ensembles of Hodgkin-Huxley neuron models. For small noise amplitudes, the membrane potential distribution takes on a Gaussian form centered on the resting potential, while for large fluctuations, there is a significant spread to lower potentials. These two regimes are separated by a relatively narrow band where the distributions transit rapidly from the Gaussian-like shapes to the spread ones. We argue that the optimal noise that maximizes the spike timing precision is situated close to this boundary. PMID:11970667

  4. Correlation of hippocampal theta rhythm with changes in cutaneous temperature. [evoked neuron response in thermoregulation

    NASA Technical Reports Server (NTRS)

    Horowitz, J. M.; Saleh, M. A.; Karem, R. D.

    1974-01-01

    A possible role for the hippocampus in alerting an animal to changes in cutaneous temperature was examined. Following local warming or cooling of the ears of unanesthetized, loosely restrained rabbits, theta waves (4-7 Hz EEG waves) were recorded from electrodes straddling the hippocampus. The onset of the hippocampal theta rhythm was correlated with changes in cutaneous temperature, an observation consistent with studies indicating that the theta rhythm is a nonspecific response evoked by stimulation of several sensory modalities. Additional data from cats and rabbits were correlated with specific neurons within the hippocampus, namely pyramidal cells. Post stimulus time histograms obtained by excitation of the dorsal fornix were interpreted in terms of excitatory and inhibitory inputs to pyramidal cells. Thus, the theta rhythm, which appears to be evoked by changes in cutaneous temperature, can be related to a specific type of hippocampal neuron which is in turn connected with other areas of the brain involved in temperature regulation.

  5. Motor neuronal control of tail-directed and head-directed siphon responses in Aplysia californica.

    PubMed

    Hickie, C; Walters, E T

    1995-07-01

    1. Cutaneous stimulation of opposite ends of the body causes qualitatively different siphon responses: tail stimulation causes flaring and backward bending (the siphon T response), whereas head stimulation causes constriction and slight anterior bending (the siphon H response). This paper characterizes the motor neuronal control of siphon T and siphon H responses. 2. The siphon response to tail nerve (p9) shock in a semi-intact preparation was indistinguishable from the siphon T response in intact or parapodectomized animals. Similarly, the siphon response to head nerve (c2) shock in this preparation was indistinguishable from the siphon H response in intact or parapodectomized animals. 3. Central siphon motor neurons (SMNs) were found to cause a wider variety of movements than previously reported. The movements produced by the LFSB cells strongly resemble the flaring response of the siphon to tail or tail nerve stimulation. The movements produced by RDS and LDS1 resemble components of the constricting response of the siphon to head or head nerve stimulation. 4. Among central SMNs, the LFSB cells show the strongest activation by posterior stimulation, whereas RDS and LDS1 show the strongest activation by anterior stimulation. The LFSA cells, which produce much weaker siphon constriction, are only activated slightly by posterior stimulation and are inhibited by anterior stimulation. Peripheral SMNs are inhibited by stimulation of head and tail nerves, and thus their activity does not directly contribute to siphon T and H responses. 5. Artificially activating central SMNs with the pattern of activity previously exhibited after tail or head nerve stimulation indicated the sufficiency of the LFSB cells for the siphon T response, and of RDS and LDS1 for the siphon H response. 6. Dramatic behavioral deficits produced by hyperpolarizing the LFSB cells during tail nerve stimulation, or by hyperpolarizing RDS and LDS1 during head nerve stimulation, indicated the necessity

  6. Visual Responsiveness of Neurons in the Secondary Somatosensory Area and its Surrounding Parietal Operculum Regions in Awake Macaque Monkeys

    PubMed Central

    Hihara, Sayaka; Taoka, Miki; Tanaka, Michio; Iriki, Atsushi

    2015-01-01

    Previous neurophysiological studies performed in macaque monkeys have shown that the secondary somatosensory cortex (SII) is essentially engaged in the processing of somatosensory information and no other sensory input has been reported. In contrast, recent human brain-imaging studies have revealed the effects of visual and auditory stimuli on SII activity, which suggest multisensory integration in the human SII. To determine whether multisensory responses of the SII also exist in nonhuman primates, we recorded single-unit activity in response to visual and auditory stimuli from the SII and surrounding regions in 8 hemispheres from 6 awake monkeys. Among 1157 recorded neurons, 306 neurons responded to visual stimuli. These visual neurons usually responded to rather complex stimuli, such as stimulation of the peripersonal space (40.5%), observation of human action (29.1%), and moving-object stimulation outside the monkey's reach (23.9%). We occasionally applied auditory stimuli to visual neurons and found 10 auditory-responsive neurons that exhibited somatosensory responses. The visual neurons were distributed continuously along the lateral sulcus covering the entire SII, along with other somatosensory neurons. These results highlight the need to investigate novel functional roles—other than somesthetic sensory processing—of the SII. PMID:25962920

  7. Visual Responsiveness of Neurons in the Secondary Somatosensory Area and its Surrounding Parietal Operculum Regions in Awake Macaque Monkeys.

    PubMed

    Hihara, Sayaka; Taoka, Miki; Tanaka, Michio; Iriki, Atsushi

    2015-11-01

    Previous neurophysiological studies performed in macaque monkeys have shown that the secondary somatosensory cortex (SII) is essentially engaged in the processing of somatosensory information and no other sensory input has been reported. In contrast, recent human brain-imaging studies have revealed the effects of visual and auditory stimuli on SII activity, which suggest multisensory integration in the human SII. To determine whether multisensory responses of the SII also exist in nonhuman primates, we recorded single-unit activity in response to visual and auditory stimuli from the SII and surrounding regions in 8 hemispheres from 6 awake monkeys. Among 1157 recorded neurons, 306 neurons responded to visual stimuli. These visual neurons usually responded to rather complex stimuli, such as stimulation of the peripersonal space (40.5%), observation of human action (29.1%), and moving-object stimulation outside the monkey's reach (23.9%). We occasionally applied auditory stimuli to visual neurons and found 10 auditory-responsive neurons that exhibited somatosensory responses. The visual neurons were distributed continuously along the lateral sulcus covering the entire SII, along with other somatosensory neurons. These results highlight the need to investigate novel functional roles-other than somesthetic sensory processing-of the SII.

  8. Reduced expression of plasma membrane calcium ATPase 2 and collapsin response mediator protein 1 promotes death of spinal cord neurons.

    PubMed

    Kurnellas, M P; Li, H; Jain, M R; Giraud, S N; Nicot, A B; Ratnayake, A; Heary, R F; Elkabes, S

    2010-09-01

    The mechanisms underlying neuronal pathology and death in the spinal cord (SC) during inflammation remain elusive. We previously showed the important role of plasma membrane calcium ATPases (PMCAs) in the survival of SC neurons, in vitro. We also postulated that a decrease in PMCA2 expression could cause neuronal death during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The current studies were undertaken to define the specific contribution of PMCA2 to degeneration of SC neurons, the effectors downstream to PMCA2 mediating neuronal death and the triggers that reduce PMCA2 expression. We report that knockdown of PMCA2 in SC neurons decreases collapsin response mediator protein 1 (CRMP1) levels. This is followed by cell death. Silencing of CRMP1 expression also leads to neuronal loss. Kainic acid reduces both PMCA2 and CRMP1 levels and induces neuronal death. Administration of an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonist, at onset or peak of EAE, restores the decreased PMCA2 and CRMP1 levels to control values and ameliorates clinical deficits. Thus, our data link the reduction in PMCA2 expression with perturbations in the expression of CRMP1 and the ensuing death of SC neurons. This represents an additional mechanism underlying AMPA/kainate receptor-mediated excitotoxicity with relevance to neurodegeneration in EAE. PMID:20489728

  9. Blocking miRNA Biogenesis in Adult Forebrain Neurons Enhances Seizure Susceptibility, Fear Memory, and Food Intake by Increasing Neuronal Responsiveness.

    PubMed

    Fiorenza, Anna; Lopez-Atalaya, Jose P; Rovira, Victor; Scandaglia, Marilyn; Geijo-Barrientos, Emilio; Barco, Angel

    2016-04-01

    The RNase Dicer is essential for the maturation of most microRNAs, a molecular system that plays an essential role in fine-tuning gene expression. To gain molecular insight into the role of Dicer and the microRNA system in brain function, we conducted 2 complementary RNA-seq screens in the hippocampus of inducible forebrain-restricted Dicer1 mutants aimed at identifying the microRNAs primarily affected by Dicer loss and their targets, respectively. Functional genomics analyses predicted the main biological processes and phenotypes associated with impaired microRNA maturation, including categories related to microRNA biology, signal transduction, seizures, and synaptic transmission and plasticity. Consistent with these predictions, we found that, soon after recombination, Dicer-deficient mice exhibited an exaggerated seizure response, enhanced induction of immediate early genes in response to different stimuli, stronger and more stable fear memory, hyperphagia, and increased excitability of CA1 pyramidal neurons. In the long term, we also observed slow and progressive excitotoxic neurodegeneration. Overall, our results indicate that interfering with microRNA biogenesis causes an increase in neuronal responsiveness and disrupts homeostatic mechanisms that protect the neuron against overactivation, which may explain both the initial and late phenotypes associated with the loss of Dicer in excitatory neurons. PMID:25595182

  10. Cholecystokinin (CCK)-expressing neurons in the suprachiasmatic nucleus: innervation, light responsiveness and entrainment in CCK-deficient mice.

    PubMed

    Hannibal, Jens; Hundahl, Christian; Fahrenkrug, Jan; Rehfeld, Jens F; Friis-Hansen, Lennart

    2010-09-01

    The suprachiasmatic nucleus (SCN) is the principal pacemaker driving circadian rhythms of physiology and behaviour. Neurons within the SCN express both classical and neuropeptide transmitters which regulate clock functions. Cholecyctokinin (CCK) is a potent neurotransmitter expressed in neurons of the mammalian SCN, but its role in circadian timing is not known. In the present study, CCK was demonstrated in a distinct population of neurons located in the shell region of the SCN and in a few cells in the core region. The CCK neurons did not express vasopressin or vasoactive intestinal peptide. However, CCK-containing processes make synaptic contacts with both groups of neurons and some CCK cell bodies were innervated by VIPergic neurons. The CCK neurons received no direct input from the three major pathways to the SCN, and the CCK neurons were not light-responsive as evaluated by induction of cFOS, and did not express the core clock protein PER1. Accordingly, CCK-deficient mice showed normal entrainment and had similar τ, light-induced phase shift and negative masking behaviour as wild-type animals. In conclusion, CCK signalling seems not to be involved directly in light-induced resetting of the clock or in regulating core clock function. The expression of CCK in a subpopulation of neurons, which do not belonging to either the VIP or AVP cells but which have synaptic contacts to both cell types and reverse innervation of CCK neurons from VIP neurons, suggests that the CCK neurons may act in non-photic regulation within the clock and/or, via CCK projections, mediate clock information to hypothalamic nuclei.

  11. Parabrachial nucleus neuronal responses to off-vertical axis rotation in macaques

    PubMed Central

    McCandless, Cyrus H.; Balaban, Carey D.

    2010-01-01

    The caudal aspect of the parabrachial nucleus (PBN) contains neurons responsive to whole body, periodic rotational stimulation in alert monkeys. This study characterizes the angular and linear motion-sensitive response properties of PBN unit responses during off-vertical axis rotation (OVAR) and position trapezoid stimulation. The OVAR responses displayed a constant firing component which varied from the firing rate at rest. Nearly two-thirds of the units also modulated their discharges with respect to head orientation (re: gravity) during constant velocity OVAR stimulation. The modulated response magnitudes were equal during ipsilateral and contralateral OVARs, indicative of a one-dimensional accelerometer. These response orientations during OVAR divided the units into three spatially tuned populations, with peak modulation responses centered in the ipsilateral ear down, contralateral anterior semicircular canal down, and occiput down orientations. Because the orientation of the OVAR modulation response was opposite in polarity to the orientation of the static tilt component of responses to position trapezoids for the majority of units, the linear acceleration responses were divided into colinear dynamic linear and static tilt components. The orientations of these unit responses formed two distinct population response axes: (1) units with an interaural linear response axis and (2) units with an ipsilateral anterior semicircular canal-contralateral posterior semicircular canal plane linear response axis. The angular rotation sensitivity of these units is in a head-vertical plane that either contains the linear acceleration response axis or is perpendicular to the linear acceleration axis. Hence, these units behave like head-based (‘strap-down’) inertial guidance sensors. Because the PBN contributes to sensory and interoceptive processing, it is suggested that vestibulo-recipient caudal PBN units may detect potentially dangerous anomalies in control of postural

  12. Neuronal cell adhesion genes and antidepressant response in three independent samples.

    PubMed

    Fabbri, C; Crisafulli, C; Gurwitz, D; Stingl, J; Calati, R; Albani, D; Forloni, G; Calabrò, M; Martines, R; Kasper, S; Zohar, J; Juven-Wetzler, A; Souery, D; Montgomery, S; Mendlewicz, J; Girolamo, G D; Serretti, A

    2015-12-01

    Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response. PMID:25850031

  13. Contrasting responses within a single neuron class enable sex-specific attraction in Caenorhabditis elegans.

    PubMed

    Narayan, Anusha; Venkatachalam, Vivek; Durak, Omer; Reilly, Douglas K; Bose, Neelanjan; Schroeder, Frank C; Samuel, Aravinthan D T; Srinivasan, Jagan; Sternberg, Paul W

    2016-03-01

    Animals find mates and food, and avoid predators, by navigating to regions within a favorable range of available sensory cues. How are these ranges set and recognized? Here we show that male Caenorhabditis elegans exhibit strong concentration preferences for sex-specific small molecule cues secreted by hermaphrodites, and that these preferences emerge from the collective dynamics of a single male-specific class of neurons, the cephalic sensory neurons (CEMs). Within a single worm, CEM responses are dissimilar, not determined by anatomical classification and can be excitatory or inhibitory. Response kinetics vary by concentration, suggesting a mechanism for establishing preferences. CEM responses are enhanced in the absence of synaptic transmission, and worms with only one intact CEM show nonpreferential attraction to all concentrations of ascaroside for which CEM is the primary sensor, suggesting that synaptic modulation of CEM responses is necessary for establishing preferences. A heterogeneous concentration-dependent sensory representation thus appears to allow a single neural class to set behavioral preferences and recognize ranges of sensory cues. PMID:26903633

  14. Contrasting responses within a single neuron class enable sex-specific attraction in Caenorhabditis elegans

    PubMed Central

    Narayan, Anusha; Venkatachalam, Vivek; Durak, Omer; Reilly, Douglas K.; Bose, Neelanjan; Schroeder, Frank C.; Samuel, Aravinthan D. T.; Srinivasan, Jagan; Sternberg, Paul W.

    2016-01-01

    Animals find mates and food, and avoid predators, by navigating to regions within a favorable range of available sensory cues. How are these ranges set and recognized? Here we show that male Caenorhabditis elegans exhibit strong concentration preferences for sex-specific small molecule cues secreted by hermaphrodites, and that these preferences emerge from the collective dynamics of a single male-specific class of neurons, the cephalic sensory neurons (CEMs). Within a single worm, CEM responses are dissimilar, not determined by anatomical classification and can be excitatory or inhibitory. Response kinetics vary by concentration, suggesting a mechanism for establishing preferences. CEM responses are enhanced in the absence of synaptic transmission, and worms with only one intact CEM show nonpreferential attraction to all concentrations of ascaroside for which CEM is the primary sensor, suggesting that synaptic modulation of CEM responses is necessary for establishing preferences. A heterogeneous concentration-dependent sensory representation thus appears to allow a single neural class to set behavioral preferences and recognize ranges of sensory cues. PMID:26903633

  15. Sucralose Promotes Food Intake through NPY and a Neuronal Fasting Response.

    PubMed

    Wang, Qiao-Ping; Lin, Yong Qi; Zhang, Lei; Wilson, Yana A; Oyston, Lisa J; Cotterell, James; Qi, Yue; Khuong, Thang M; Bakhshi, Noman; Planchenault, Yoann; Browman, Duncan T; Lau, Man Tat; Cole, Tiffany A; Wong, Adam C N; Simpson, Stephen J; Cole, Adam R; Penninger, Josef M; Herzog, Herbert; Neely, G Gregory

    2016-07-12

    Non-nutritive sweeteners like sucralose are consumed by billions of people. While animal and human studies have demonstrated a link between synthetic sweetener consumption and metabolic dysregulation, the mechanisms responsible remain unknown. Here we use a diet supplemented with sucralose to investigate the long-term effects of sweet/energy imbalance. In flies, chronic sweet/energy imbalance promoted hyperactivity, insomnia, glucose intolerance, enhanced sweet taste perception, and a sustained increase in food and calories consumed, effects that are reversed upon sucralose removal. Mechanistically, this response was mapped to the ancient insulin, catecholamine, and NPF/NPY systems and the energy sensor AMPK, which together comprise a novel neuronal starvation response pathway. Interestingly, chronic sweet/energy imbalance promoted increased food intake in mammals as well, and this also occurs through an NPY-dependent mechanism. Together, our data show that chronic consumption of a sweet/energy imbalanced diet triggers a conserved neuronal fasting response and increases the motivation to eat. PMID:27411010

  16. Response Patterns of Single Neurons in the Tortoise Olfactory Epithelium and Olfactory Bulb

    PubMed Central

    Mathews, Donald F.

    1972-01-01

    The responses to odor stimulation of 40 single units in the olfactory mucosa and of 18 units in the olfactory bulb of the tortoise (Gopherus polyphemus) were recorded with indium-filled, Pt-black-tipped microelectrodes. The test battery consisted of 27 odorants which were proved effective by recording from small bundles of olfactory nerve. Two concentrations of each odorant were employed. These values were adjusted for response magnitudes equal to those for amyl acetate at –2.5 and –3.5 log concentration in olfactory twig recording. Varying concentrations were generated by an injection-type olfactometer. The mucosal responses were exclusively facilitory with a peak frequency of 16 impulses/sec. 19 mucosal units responded to at least one odorant and each unit was sensitive to a limited number of odorants (1–15). The sensitivity pattern of each unit was highly individual, with no clear-cut types, either chemical or qualitative, emerging. Of the 18 olfactory bulb units sampled, all responded to at least one odorant. The maximum frequency observed during a response was 39 impulses/sec. The bulbar neurons can be classified into two types. There are neurons that respond exclusively with facilitation and others that respond with facilitation to some odorants and with inhibition to others. Qualitatively or chemically similar odorants did not generate similar patterns across bulbar units. PMID:5049077

  17. On the Firing Rate Dependency of the Phase Response Curve of Rat Purkinje Neurons In Vitro

    PubMed Central

    Couto, João; Linaro, Daniele; De Schutter, E; Giugliano, Michele

    2015-01-01

    Synchronous spiking during cerebellar tasks has been observed across Purkinje cells: however, little is known about the intrinsic cellular mechanisms responsible for its initiation, cessation and stability. The Phase Response Curve (PRC), a simple input-output characterization of single cells, can provide insights into individual and collective properties of neurons and networks, by quantifying the impact of an infinitesimal depolarizing current pulse on the time of occurrence of subsequent action potentials, while a neuron is firing tonically. Recently, the PRC theory applied to cerebellar Purkinje cells revealed that these behave as phase-independent integrators at low firing rates, and switch to a phase-dependent mode at high rates. Given the implications for computation and information processing in the cerebellum and the possible role of synchrony in the communication with its post-synaptic targets, we further explored the firing rate dependency of the PRC in Purkinje cells. We isolated key factors for the experimental estimation of the PRC and developed a closed-loop approach to reliably compute the PRC across diverse firing rates in the same cell. Our results show unambiguously that the PRC of individual Purkinje cells is firing rate dependent and that it smoothly transitions from phase independent integrator to a phase dependent mode. Using computational models we show that neither channel noise nor a realistic cell morphology are responsible for the rate dependent shift in the phase response curve. PMID:25775448

  18. GFRalpha-3, a protein related to GFRalpha-1, is expressed in developing peripheral neurons and ensheathing cells.

    PubMed

    Widenfalk, J; Tomac, A; Lindqvist, E; Hoffer, B; Olson, L

    1998-04-01

    We report here the identification of a gene, termed GFRalpha-3 (glial cell line-derived neurotrophic factor family receptor alpha-3), related to GFRalpha-1 and GFRalpha-2 (also known as GDNFR-alpha and GDNFR-beta), and describe distribution of GDNFalpha-3 in the nervous system and other parts of the mouse body during development and in the adult. GFRalpha-3 in situ hybridization signals were found mainly in the peripheral nervous system, with prominent signals in developing dorsal root and trigeminal ganglia. Sympathetic ganglia were also positive. Developing nerves manifested strong GFRalpha-3 mRNA signals, presumably generated by the Schwann cells. Olfactory ensheathing cells were also positive. Other non-neuronal cells appearing positive during development included chromaffin cells in the adrenal gland and small clusters of cells in the intestinal epithelium. In the central nervous system no robust signals could be detected at any stage investigated with the present probes. Compared with the previously described GFRalpha-1 and GFRalpha-2 mRNAs, which are widely distributed in the central nervous system and peripheral organs, the expression of GFRalpha-3 mRNA is much more restricted. The prominent expression in Schwann cells during development suggests a key role for GFRalpha-3 in the development of the peripheral nervous system. As Schwann cells are known to lack expression of the transducing RET receptor, we propose that a possible function of GFRalpha-3 during development could be to bind Schwann cell-derived GDNF-like ligands, thus presenting such molecules to growing axons. PMID:9749804

  19. Effect of sharp jumps at the edges of phase response curves on synchronization of electrically coupled neuronal oscillators.

    PubMed

    Dodla, Ramana; Wilson, Charles J

    2013-01-01

    We study synchronization phenomenon of coupled neuronal oscillators using the theory of weakly coupled oscillators. The role of sudden jumps in the phase response curve profiles found in some experimental recordings and models on the ability of coupled neurons to exhibit synchronous and antisynchronous behavior is investigated, when the coupling between the neurons is electrical. The level of jumps in the phase response curve at either end, spike width and frequency of voltage time course of the coupled neurons are parameterized using piecewise linear functional forms, and the conditions for stable synchrony and stable antisynchrony in terms of those parameters are computed analytically. The role of the peak position of the phase response curve on phase-locking is also investigated.

  20. The cellular and genomic response of rat dopaminergic neurons (N27) to coated nanosilver.

    PubMed

    Chorley, Brian; Ward, William; Simmons, Steven O; Vallanat, Beena; Veronesi, Bellina

    2014-12-01

    This study examined if nanosilver (nanoAg) of different sizes and coatings were differentially toxic to oxidative stress-sensitive neurons. N27 rat dopaminergic neurons were exposed (0.5-5 ppm) to a set of nanoAg of different sizes (10nm, 75 nm) and coatings (PVP, citrate) and their physicochemical, cellular and genomic response measured. Both coatings retained their manufactured sizes in culture media, however, the zeta potentials of both sizes of PVP-coated nanoAg were significantly less electronegative than those of their citrate-coated counterparts. Markers of oxidative stress, measured at 0.5-5 ppm exposure concentrations, indicated that caspase 3/7 activity and glutathione levels were significantly increased by both sizes of PVP-coated nanoAg and by the 75 nm citrate-coated nanoAg. Both sizes of PVP-coated nanoAg also increased intra-neuronal nitrite levels and activated ARE/NRF2, a reporter gene for the oxidative stress-protection pathway. Global gene expression on N27 neurons, exposed to 0.5 ppm for 8h, indicated a dominant effect by PVP-coated nanoAg over citrate. The 75 nm PVP-coated material altered 196 genes that were loosely associated with mitochondrial dysfunction. In contrast, the 10nm PVP-coated nanoAg altered 82 genes that were strongly associated with NRF2 oxidative stress pathways. Less that 20% of the affected genes were shared by both sizes of PVP-coated nanoAg. These cellular and genomic findings suggest that PVP-coated nanoAg is more bioactive than citrate-coated nanoAg. Although both sizes of PVP-coated nanoAg altered the genomic expression of N27 neurons along oxidative stress pathways, exposure to the 75 nm nanoAg favored pathways associated with mitochondrial dysfunction, whereas the 10nm PVP-coated nanoAg affected NRF2 neuronal protective pathways.

  1. Recording Light-evoked Postsynaptic Responses in Neurons in Dark-adapted, Mouse Retinal Slice Preparations Using Patch Clamp Techniques

    PubMed Central

    Hellmer, Chase B.; Ichinose, Tomomi

    2015-01-01

    The retina is the gateway to the visual system. To understand visual signal processing mechanisms, we investigate retinal neural network functions. Retinal neurons in the network comprise of numerous subtypes. More than 10 subtypes of bipolar cells, ganglion cells, and amacrine cells have been identified by morphological studies. Multiple subtypes of retinal neurons are thought to encode distinct features of visual signaling, such as motion and color, and form multiple neural pathways. However, the functional roles of each neuron in visual signal processing are not fully understood. The patch clamp method is useful to address this fundamental question. Here, a protocol to record light-evoked synaptic responses in mouse retinal neurons using patch clamp recordings in dark-adapted conditions is provided. The mouse eyes are dark-adapted O/N, and retinal slice preparations are dissected in a dark room using infrared illumination and viewers. Infrared light does not activate mouse photoreceptors and thus preserves their light responsiveness. Patch clamp is used to record light-evoked responses in retinal neurons. A fluorescent dye is injected during recordings to characterize neuronal morphological subtypes. This procedure enables us to determine the physiological functions of each neuron in the mouse retina. PMID:25741904

  2. Leptin-inhibited PBN neurons enhance counter-regulatory responses to hypoglycemia in negative energy balance

    PubMed Central

    D’Agostino, Giuseppe; Goforth, Paulette B.; Sutton, Amy K.; Malec, Paige A.; Wong, Jenny-Marie T.; Germani, Mark; Jones, Justin C.; Rajala, Michael; Satin, Leslie; Rhodes, Christopher J.; Olson, David P.; Kennedy, Robert T.; Heisler, Lora K.; Myers, Martin G.

    2014-01-01

    Hypoglycemia initiates the counter regulatory response (CRR), in which the sympathetic nervous system, glucagon, and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin restrains energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here, we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates leptin receptor (LepRb) and cholecystokinin (CCK)-expressing neurons of the parabrachial nucleus (PBN), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells and Cckcre-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, while their activation mimics the CRR in a CCK-dependent manner. PBN LepRbCCK neurons represent a crucial component of the CRR system, and may represent a therapeutic target in hypoglycemia. PMID:25383904

  3. The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation.

    PubMed

    Muley, P D; McNeill, E M; Marzinke, M A; Knobel, K M; Barr, M M; Clagett-Dame, M

    2008-11-01

    Neuron navigator 2 (Nav2) was first identified as an all-trans retinoic acid (atRA)-responsive gene in human neuroblastoma cells (retinoic acid-induced in neuroblastoma 1, RAINB1) that extend neurites after exposure to atRA. It is structurally related to the Caenorhabditis elegans unc-53 gene that is required for cell migration and axonal outgrowth. To gain insight into NAV2 function, the full-length human protein was expressed in C. elegans unc-53 mutants under the control of a mechanosensory neuron promoter. Transgene expression of NAV2 rescued the defects in unc-53 mutant mechanosensory neuron elongation, indicating that Nav2 is an ortholog of unc-53. Using a loss-of-function approach, we also show that Nav2 induction is essential for atRA to induce neurite outgrowth in SH-SY5Y cells. The NAV2 protein is located both in the cell body and along the length of the growing neurites of SH-SY5Y cells in a pattern that closely mimics that of neurofilament and microtubule proteins. Transfection of Nav2 deletion constructs in Cos-1 cells reveals a region of the protein (aa 837-1065) that directs localization with the microtubule cytoskeleton. Collectively, this work supports a role for NAV2 in neurite outgrowth and axonal elongation and suggests this protein may act by facilitating interactions between microtubules and other proteins such as neurofilaments that are key players in the formation and stability of growing neurites.

  4. Nucleus accumbens neuronal activity correlates to the animal’s behavioral response to acute and chronic methylphenidate

    PubMed Central

    Claussen, Catherine M; Chong, Samuel L; Dafny, Nachum

    2014-01-01

    Acute and chronic Methylphenidate (MPD) exposure was recorded simultaneously for the rat’s locomotor activity and the nucleus accumbens (NAc) neuronal activity. The evaluation of the neuronal events was based on the animal’s behavior response to chronic MPD administration: 1) Animals exhibiting behavioral sensitization 2) Animals exhibiting behavioral tolerance. The experiment lasted for 10 days with four groups of animals; saline, 0.6, 2.5, and 10.0mg/kg MPD. For the main behavioral findings, about half of the animals exhibited behavioral sensitization or behavioral tolerance to 0.6, 2.5, and/or 10 mg/kg MPD respectively. Three hundred and forty one NAc neuronal units were evaluated. Approximately 80% of NAc units responded to 0.6, 2.5, and 10.0 mg/kg MPD. When the neuronal activity was analyzed based on the animals behavioral response to chronic MPD exposure, significant differences were seen between the neuronal populations responses recorded from animals that expressed behavioral sensitization when compared to the NAc neuronal responses recorded from animals exhibiting behavioral tolerance. Three types of neurophysiological sensitization and neurophysiological tolerance can be recognized following chronic MPD administration to the neuronal populations. Collectively, these findings show that the same dose of chronic MPD can elicit either behavioral tolerance or behavioral sensitization. Differential statistical analysis were used to verify our hypothesis that the neuronal activity recorded from animals exhibiting behavioral sensitization will respond differently to MPD compared to those animals exhibiting behavioral tolerance. Thus, suggesting that it is essential to record the animals behavior concomitantly with neuronal recordings. PMID:24534179

  5. Attenuation of homeostatic responses to hypotension and glucoprivation after destruction of catecholaminergic rostral ventrolateral medulla neurons.

    PubMed

    Madden, Christopher J; Stocker, Sean D; Sved, Alan F

    2006-09-01

    This study determined the effect of destruction of rostral ventrolateral medulla (RVLM)-C1 cells on integrated sympathetic and hormonal responses to hypotension or glucoprivation. Injection of anti-dopamine beta-hydroxylase-saporin into the RVLM resulted in 29-99% depletion of RVLM-C1 neurons and approximately 60% reduction in the number of A5 neurons. As in our previous study in unanesthetized rats, resting mean arterial pressure (MAP) was reduced by approximately 10 mmHg in rats with >80% depletion of RVLM-C1 cells compared with control rats, although resting heart rate (HR) did not differ significantly. In the present study, resting plasma levels of norepinephrine (NE) did not differ significantly between control rats and rats with >80% depletion of RVLM-C1 cells, although there was a tendency for RVLM-C1 lesioned rats to have lower levels. Also consistent with our previous study, hydralazine (HDZ)-evoked hypotension resulted in smaller increases in HR and plasma levels of NE in rats with >80% depletion of RVLM-C1 cells compared with control rats. Furthermore, the elevated plasma levels of posterior pituitary hormones vasopressin and oxytocin evoked by HDZ were blunted in RVLM-C1 lesioned rats compared with control rats, even though MAP fell to lower levels in the lesioned rats. Plasma renin activity, plasma osmolality, and plasma protein concentrations did not differ between control rats and rats with >80% depletion of RVLM-C1 neurons. In response to systemic administration of 2-deoxyglucose, the circulating level of epinephrine and the resulting hyperglycemia were attenuated in rats with >80% depletion of RVLM-C1 cells compared with control rats. These results demonstrate that RVLM-C1 cells, in addition to playing a role in acute cardiovascular reflexes, play an important role in integrated sympathetic and hormonal responses to homeostatic challenges such as hypotension and glucoprivation.

  6. Hypothalamic thermo-responsive neurones in the new-born rat.

    PubMed Central

    Hori, T; Shinohara, K

    1979-01-01

    1. Single unit activities were recorded from the neurones in the preoptic area and anterior hypothalamus of developing new-born rats (aged 1-24 days old) during thermal stimulation of the brain. During the first 2 weeks of life, about 80% of these neurones had low spontaneous firing rates between 0.1 and 5 impulses/sec at 38 degrees C hypothalamic temperature (Thyp). 2. Out of 640 units studied, 118 units increased the firing rate upon elevation of Thyp (warm-units) and fourteen showed the opposite type of response to temperature changes (cold-units). Warm-units were found in the rats of all the age span studied and cold-units were recorded in the rats more than 8 days old. 3. Thermal coefficients of warm-units and cold-units varied between +0.11 and +2.47 and between -0.10 and -0.49 impulses/sec, degrees C, respectively. Number of warm-units with higher rates of firing and greater thermal coefficients, comparable to those of warm-units in the adult, gradually increased with growth. The thermal responsiveness of warm-units, when expressed by Q10, are already high even in the immediate neonatal period. Their Q10 values were in the range between 2 and 38.5 (mean 6.4). 4. Units responding to extrahypothalamic temperatures were only found in the rats more than 14 days old. 5. All the six warm-units tested increased the firing rates following subcutaneous injections of capsaicin, while the majority of thermo-unresponsive units were not affected by this drug. 6. It is suggested that thermo-responsive neurones in the preoptic area and anterior hypothalamus in the new-born rat have attained some degree of electrophysiological maturity, despite their slowly firing characteristics. Images Fig. 2 Fig. 3 Fig. 5 Fig. 7 Fig. 8 PMID:512957

  7. Minocycline attenuates microglial response and reduces neuronal death after cardiac arrest and cardiopulmonary resuscitation in mice.

    PubMed

    Wang, Qian-yan; Sun, Peng; Zhang, Qing; Yao, Shang-long

    2015-04-01

    The possible role of minocycline in microglial activation and neuronal death after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in mice was investigated in this study. The mice were given potassium chloride to stop the heart beating for 8 min to achieve CA, and they were subsequently resuscitated with epinephrine and chest compressions. Forty adult C57BL/6 male mice were divided into 4 groups (n=10 each): sham-operated group, CA/CPR group, CA/CPR+minocycline group, and CA/CPR+vehicle group. Animals in the latter two groups were intraperitoneally injected with minocycline (50 mg/kg) or vehicle (normal saline) 30 min after recovery of spontaneous circulation (ROSC). Twenty-four h after CA/CPR, the brains were removed for histological evaluation of the hippocampus. Microglial activation was evaluated by detecting the expression of ionized calcium-binding adapter molecule-1 (Iba1) by immunohistochemistry. Neuronal death was analyzed by hematoxylin and eosin (H&E) staining and the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that the neuronal death was aggravated, most microglia were activated and TNF-α levels were enhanced in the hippocampus CA1 region of mice subjected to CA/CPR as compared with those in the sham-operated group (P<0.05). Administration with minocycline 30 min after ROSC could significantly decrease the microglial response, TNF-α levels and neuronal death (P<0.05). It was concluded that early administration with minocycline has a strong therapeutic potential for CA/CPR-induced brain injury.

  8. Arsenic moiety in gallium arsenide is responsible for neuronal apoptosis and behavioral alterations in rats

    SciTech Connect

    Flora, Swaran J.S. Bhatt, Kapil; Mehta, Ashish

    2009-10-15

    Gallium arsenide (GaAs), an intermetallic semiconductor finds widespread applications in high frequency microwave and millimeter wave, and ultra fast supercomputers. Extensive use of GaAs has led to increased exposure to humans working in semiconductor industry. GaAs has the ability to dissociate into its constitutive moieties at physiological pH and might be responsible for the oxidative stress. The present study was aimed at evaluating, the principle moiety (Ga or As) in GaAs to cause neurological dysfunction based on its ability to cause apoptosis, in vivo and in vitro and if this neuronal dysfunction translated to neurobehavioral changes in chronically exposed rats. Result indicated that arsenic moiety in GaAs was mainly responsible for causing oxidative stress via increased reactive oxygen species (ROS) and nitric oxide (NO) generation, both in vitro and in vivo. Increased ROS further caused apoptosis via mitochondrial driven pathway. Effects of oxidative stress were also confirmed based on alterations in antioxidant enzymes, GPx, GST and SOD in rat brain. We noted that ROS induced oxidative stress caused changes in the brain neurotransmitter levels, Acetylcholinesterase and nitric oxide synthase, leading to loss of memory and learning in rats. The study demonstrates for the first time that the slow release of arsenic moiety from GaAs is mainly responsible for oxidative stress induced apoptosis in neuronal cells causing behavioral changes.

  9. Inhibition of Neuronal Nitric Oxide Reduces Anxiety-Like Responses to Pair Housing

    PubMed Central

    Workman, Joanna L.; Trainor, Brian C.; Sima Finy, M.; Nelson, Randy J.

    2008-01-01

    Many psychological disorders are characterized by anxiety and alterations in social interactions. Recent studies demonstrate that the chemical messenger nitric oxide (NO) can regulate both anxiety and social behaviours. We tested whether an enzyme that produces NO in the brain, neuronal nitric oxide synthase (nNOS), serves as an interface between social interactions and anxiety-like behaviour. Several investigators have observed that mice increase anxiety-like responses in the elevated plus-maze after pair housing. nNOS gene deletion and 3-Bromo-7-Nitroindazole were used to inhibit the production of neuronal NO. Similar to previous studies, pair housing reduced open arm exploration in the elevated plus-maze. Pair housing also increased corticotropin-releasing hormone (CRH) immunoreactive cells in the paraventricular nucleus (PVN) of the hypothalamus. Inhibition of NO production increased open arm exploration in pair-housed mice but decreased open arm exploration in individually-housed mice. These results suggest that the effect of nNOS inhibition on anxiety-like responses is context dependent and that behavioural responses to social housing are altered after nNOS inhibition. This research suggests that NO may play an important role in mediating the effect social interactions have on anxiety. PMID:17928072

  10. Arsenic moiety in gallium arsenide is responsible for neuronal apoptosis and behavioral alterations in rats.

    PubMed

    Flora, Swaran J S; Bhatt, Kapil; Mehta, Ashish

    2009-10-15

    Gallium arsenide (GaAs), an intermetallic semiconductor finds widespread applications in high frequency microwave and millimeter wave, and ultra fast supercomputers. Extensive use of GaAs has led to increased exposure to humans working in semiconductor industry. GaAs has the ability to dissociate into its constitutive moieties at physiological pH and might be responsible for the oxidative stress. The present study was aimed at evaluating, the principle moiety (Ga or As) in GaAs to cause neurological dysfunction based on its ability to cause apoptosis, in vivo and in vitro and if this neuronal dysfunction translated to neurobehavioral changes in chronically exposed rats. Result indicated that arsenic moiety in GaAs was mainly responsible for causing oxidative stress via increased reactive oxygen species (ROS) and nitric oxide (NO) generation, both in vitro and in vivo. Increased ROS further caused apoptosis via mitochondrial driven pathway. Effects of oxidative stress were also confirmed based on alterations in antioxidant enzymes, GPx, GST and SOD in rat brain. We noted that ROS induced oxidative stress caused changes in the brain neurotransmitter levels, Acetylcholinesterase and nitric oxide synthase, leading to loss of memory and learning in rats. The study demonstrates for the first time that the slow release of arsenic moiety from GaAs is mainly responsible for oxidative stress induced apoptosis in neuronal cells causing behavioral changes.

  11. Response profiles of murine spiral ganglion neurons on multi-electrode arrays

    NASA Astrophysics Data System (ADS)

    Hahnewald, Stefan; Tscherter, Anne; Marconi, Emanuele; Streit, Jürg; Widmer, Hans Rudolf; Garnham, Carolyn; Benav, Heval; Mueller, Marcus; Löwenheim, Hubert; Roccio, Marta; Senn, Pascal

    2016-02-01

    Objective. Cochlear implants (CIs) have become the gold standard treatment for deafness. These neuroprosthetic devices feature a linear electrode array, surgically inserted into the cochlea, and function by directly stimulating the auditory neurons located within the spiral ganglion, bypassing lost or not-functioning hair cells. Despite their success, some limitations still remain, including poor frequency resolution and high-energy consumption. In both cases, the anatomical gap between the electrode array and the spiral ganglion neurons (SGNs) is believed to be an important limiting factor. The final goal of the study is to characterize response profiles of SGNs growing in intimate contact with an electrode array, in view of designing novel CI devices and stimulation protocols, featuring a gapless interface with auditory neurons. Approach. We have characterized SGN responses to extracellular stimulation using multi-electrode arrays (MEAs). This setup allows, in our view, to optimize in vitro many of the limiting interface aspects between CIs and SGNs. Main results. Early postnatal mouse SGN explants were analyzed after 6-18 days in culture. Different stimulation protocols were compared with the aim to lower the stimulation threshold and the energy needed to elicit a response. In the best case, a four-fold reduction of the energy was obtained by lengthening the biphasic stimulus from 40 μs to 160 μs. Similarly, quasi monophasic pulses were more effective than biphasic pulses and the insertion of an interphase gap moderately improved efficiency. Finally, the stimulation with an external electrode mounted on a micromanipulator showed that the energy needed to elicit a response could be reduced by a factor of five with decreasing its distance from 40 μm to 0 μm from the auditory neurons. Significance. This study is the first to show electrical activity of SGNs on MEAs. Our findings may help to improve stimulation by and to reduce energy consumption of CIs and

  12. Using Single Sensillum Recording to Detect Olfactory Neuron Responses of Bed Bugs to Semiochemicals.

    PubMed

    Liu, Feng; Liu, Nannan

    2016-01-01

    The insect olfactory system plays an important role in detecting semiochemicals in the environment. In particular, the antennal sensilla which house single or multiple neurons inside, are considered to make the major contribution in responding to the chemical stimuli. By directly recording action potential in the olfactory sensillum after exposure to stimuli, single sensillum recording (SSR) technique provides a powerful approach for investigating the neural responses of insects to chemical stimuli. For the bed bug, which is a notorious human parasite, multiple types of olfactory sensillum have been characterized. In this study, we demonstrated neural responses of bed bug olfactory sensilla to two chemical stimuli and the dose-dependent responses to one of them using the SSR method. This approach enables researchers to conduct early screening for individual chemical stimuli on the bed bug olfactory sensilla, which would provide valuable information for the development of new bed bug attractants or repellents and benefits the bed bug control efforts. PMID:26862929

  13. Cholinergic Responses and Intrinsic Membrane Properties of Developing Thalamic Parafascicular Neurons

    PubMed Central

    Ye, Meijun; Hayar, Abdallah; Garcia-Rill, Edgar

    2009-01-01

    Parafascicular (Pf) neurons receive cholinergic input from the pedunculopontine nucleus (PPN), which is active during waking and REM sleep. There is a developmental decrease in REM sleep in humans between birth and puberty and 10–30 days in rat. Previous studies have established an increase in muscarinic and 5-HT1 serotonergic receptor–mediated inhibition and a transition from excitatory to inhibitory GABAA responses in the PPN during the developmental decrease in REM sleep. However, no studies have been conducted on the responses of Pf cells to the cholinergic input from the PPN during development, which is a major target of ascending cholinergic projections and may be an important mechanism for the generation of rhythmic oscillations in the cortex. Whole cell patch-clamp recordings were performed in 9- to 20-day-old rat Pf neurons in parasagittal slices, and responses to the cholinergic agonist carbachol (CAR) were determined. Three types of responses were identified: inhibitory (55.3%), excitatory (31.1%), and biphasic (fast inhibitory followed by slow excitatory, 6.8%), whereas 6.8% of cells showed no response. The proportion of CAR-inhibited Pf neurons increased with development. Experiments using cholinergic antagonists showed that M2 receptors mediated the inhibitory response, whereas excitatory modulation involved M1, nicotinic, and probably M3 or M5 receptors, and the biphasic response was caused by the activation of multiple types of muscarinic receptors. Compared with CAR-inhibited cells, CAR-excited Pf cells showed 1) a decreased membrane time constant, 2) higher density of hyperpolarization-activated channels (Ih), 3) lower input resistance (Rin), 4) lower action potential threshold, and 5) shorter half-width duration of action potentials. Some Pf cells exhibited spikelets, and all were excited by CAR. During development, we observed decreases in Ih density, Rin, time constant, and action potential half-width. These results suggest that cholinergic

  14. Cholinergic responses and intrinsic membrane properties of developing thalamic parafascicular neurons.

    PubMed

    Ye, Meijun; Hayar, Abdallah; Garcia-Rill, Edgar

    2009-08-01

    Parafascicular (Pf) neurons receive cholinergic input from the pedunculopontine nucleus (PPN), which is active during waking and REM sleep. There is a developmental decrease in REM sleep in humans between birth and puberty and 10-30 days in rat. Previous studies have established an increase in muscarinic and 5-HT1 serotonergic receptor-mediated inhibition and a transition from excitatory to inhibitory GABA(A) responses in the PPN during the developmental decrease in REM sleep. However, no studies have been conducted on the responses of Pf cells to the cholinergic input from the PPN during development, which is a major target of ascending cholinergic projections and may be an important mechanism for the generation of rhythmic oscillations in the cortex. Whole cell patch-clamp recordings were performed in 9- to 20-day-old rat Pf neurons in parasagittal slices, and responses to the cholinergic agonist carbachol (CAR) were determined. Three types of responses were identified: inhibitory (55.3%), excitatory (31.1%), and biphasic (fast inhibitory followed by slow excitatory, 6.8%), whereas 6.8% of cells showed no response. The proportion of CAR-inhibited Pf neurons increased with development. Experiments using cholinergic antagonists showed that M2 receptors mediated the inhibitory response, whereas excitatory modulation involved M1, nicotinic, and probably M3 or M5 receptors, and the biphasic response was caused by the activation of multiple types of muscarinic receptors. Compared with CAR-inhibited cells, CAR-excited Pf cells showed 1) a decreased membrane time constant, 2) higher density of hyperpolarization-activated channels (I(h)), 3) lower input resistance (R(in)), 4) lower action potential threshold, and 5) shorter half-width duration of action potentials. Some Pf cells exhibited spikelets, and all were excited by CAR. During development, we observed decreases in I(h) density, R(in), time constant, and action potential half-width. These results suggest that

  15. Increased nicotine response in iPSC-derived human neurons carrying the CHRNA5 N398 allele

    PubMed Central

    Oni, Eileen N.; Halikere, Apoorva; Li, Guohui; Toro-Ramos, Alana J.; Swerdel, Mavis R.; Verpeut, Jessica L.; Moore, Jennifer C.; Bello, Nicholas T.; Bierut, Laura J.; Goate, Alison; Tischfield, Jay A.; Pang, Zhiping P.; Hart, Ronald P.

    2016-01-01

    Genetic variation in nicotinic receptor alpha 5 (CHRNA5) has been associated with increased risk of addiction-associated phenotypes in humans yet little is known the underlying neural basis. Induced pluripotent stem cells (iPSCs) were derived from donors homozygous for either the major (D398) or the minor (N398) allele of the nonsynonymous single nucleotide polymorphism (SNP), rs16969968, in CHRNA5. To understand the impact of these nicotinic receptor variants in humans, we differentiated these iPSCs to dopamine (DA) or glutamatergic neurons and then tested their functional properties and response to nicotine. Results show that N398 variant human DA neurons differentially express genes associated with ligand receptor interaction and synaptic function. While both variants exhibited physiological properties consistent with mature neuronal function, the N398 neuronal population responded more actively with an increased excitatory postsynaptic current response upon the application of nicotine in both DA and glutamatergic neurons. Glutamatergic N398 neurons responded to lower nicotine doses (0.1 μM) with greater frequency and amplitude but they also exhibited rapid desensitization, consistent with previous analyses of N398-associated nicotinic receptor function. This study offers a proof-of-principle for utilizing human neurons to study gene variants contribution to addiction. PMID:27698409

  16. Pressor response to L-cysteine injected into the cisterna magna of conscious rats involves recruitment of hypothalamic vasopressinergic neurons.

    PubMed

    Takemoto, Yumi

    2013-03-01

    The sulfur-containing non-essential amino acid L-cysteine injected into the cisterna magna of adult conscious rats produces an increase in blood pressure. The present study examined if the pressor response to L-cysteine is stereospecific and involves recruitment of hypothalamic vasopressinergic neurons and medullary noradrenergic A1 neurons. Intracisternally injected D-cysteine produced no cardiovascular changes, while L-cysteine produced hypertension and tachycardia in freely moving rats, indicating the stereospecific hemodynamic actions of L-cysteine via the brain. The double labeling immunohistochemistry combined with c-Fos detection as a marker of neuronal activation revealed significantly higher numbers of c-Fos-positive vasopressinergic neurons both in the supraoptic and paraventricular nuclei and tyrosine hydroxylase containing medullary A1 neurons, of L-cysteine-injected rats than those injected with D-cysteine as iso-osmotic control. The results indicate that the cardiovascular responses to intracisternal injection of L-cysteine in the conscious rat are stereospecific and include recruitment of hypothalamic vasopressinergic neurons both in the supraoptic and paraventricular nuclei, as well as of medullary A1 neurons. The findings may suggest a potential function of L-cysteine as an extracellular signal such as neuromodulators in central regulation of blood pressure.

  17. Lack of response of serotonergic neurons in the dorsal raphe nucleus of freely moving cats to stressful stimuli.

    PubMed

    Wilkinson, L O; Jacobs, B L

    1988-09-01

    Changes in brain serotonin (5-HT) neurotransmission have been implicated in the mammalian response to stressful stimuli. The purpose of this study was to examine the extracellular single-unit activity of 5-HT neurons in cats exposed to three stressors: loud (100 dB) white noise, restraint, and confrontation with a dog. Serotonergic neurons were recorded in the dorsal raphe nucleus (DRN) and were identified by (i) slow and regular spontaneous activity, (ii) long duration (approximately 2 ms) waveform, (iii) complete suppression of activity during REM sleep and after systemic administration of 5-methoxy-N-N-dimethyltryptamine (250 micrograms/kg i.m.), and (iv) histological localization in the DRN. Despite behavioral and physiological evidence that all three manipulations induced a stress response, the maximal firing rate of 5-HT neurons was not significantly different from that observed under unstressed conditions. These data are consistent with previous studies from our laboratory which have indicated that very few manipulations are able to perturb the slow and regular activity of these neurons. In contrast, previous work has shown that the firing rate of noradrenergic neurons in the locus ceruleus is dramatically increased by these stressors. The relative imbalance in the activity of these two neuronal groups observed during stress may affect postsynaptic neuronal processing patterns and have adaptive significance during stressful conditions.

  18. Modeling Neuronal Response to Simultaneous and Sequential Multi-Site Synaptic Stimulation

    NASA Astrophysics Data System (ADS)

    Johnston, David; Mekhail, Simon Peter; Go, Mary Ann; Daria, Vincent R.

    The flow of information in the brain theorizes that each neuron in a network receives synaptic inputs and sends off its processed signals to neighboring neurons. Here, we model these synaptic inputs to understand how each neuron processes these inputs and transmits neurotransmitters to neighboring neurons. We use the NEURON simulation package to stimulate a neuron at multiple synaptic locations along its dendritic tree. Accumulation of multiple synaptic inputs causes changes in the neuron's membrane potential leading to firing of an action potential. Our simulations show that simultaneous synaptic stimulation approaches firing of an action potential at lesser inputs compared to sequential stimulation at multiple sites distributed along several dendritic branches.

  19. Method of unconfounding orientation and direction tunings in neuronal response to moving bars and gratings

    NASA Astrophysics Data System (ADS)

    Zhang, Jun

    2005-10-01

    When an oriented bar or grating is drifted across the receptive field of a cortical neuron at various orientations, the tuning function reflects both, and thus confounds the orientation (ORI) and the direction-of-motion (DIR) selectivity of the cell. Since ORI (or DIR), by definition, has a period of 180(or 360) deg/cycle, a popular method for separating these two components, due to Wörgötter and Eysel [Biol. Cybern. 57, 349 (1987)], is to Fourier decompose the neuron's response along the angular direction and then identify the first and the second harmonic with DIR and ORI, respectively (the SDO method). Zhang [Biol. Cybern. 63, 135 (1990)] pointed out that this interpretation is misconceived-all odd harmonics (not just the first harmonic) reflect the DIR component, whereas all even harmonics (including the second harmonic) contain contributions from both DIR and ORI. Here, a simplified procedure is proposed to accomplish the goal of unconfounding ORI and DIR. We first construct the sum of all odd harmonics of the overall tuning curve, denoted ODDSUM, by calculating the difference in the neuronal response to opposite drifting directions. Then we construct ODDSUM+|ODDSUM| and identify it with DIR (here |.| denotes the absolute value). Subtracting DIR, that is ODDSUM+|ODDSUM|, from the overall tuning curve gives ORI. Our method ensures that (i) the reconstructed DIR contains only one, positive peak at the preferred direction and can have power in all harmonics, and (ii) the reconstructed ORI has two peaks separated by 180° and has zero power for all odd harmonics. Using this procedure, we have unconfounded orientation and direction components for a considerable sample of macaque striate cortical cells, and compared the results with those obtained using Wörgötter and Eysel's SDO method. We found that whereas the estimate of the peak angle of ORI remains largely unaffected, Wörgötter and Eysel's method considerably overestimated the relative strength of ORI. To

  20. Microfluidic culture platform for studying neuronal response to mild to very mild axonal stretch injurya)

    PubMed Central

    Yap, Yiing C.; Dickson, Tracey C.; King, Anna E.; Breadmore, Michael C.; Guijt, Rosanne M.

    2014-01-01

    A new model for studying localised axonal stretch injury is presented, using a microfluidic device to selectively culture axons on a thin, flexible poly (dimethylsiloxane) membrane which can be deflected upward to stretch the axons. A very mild (0.5% strain) or mild stretch injury (5% strain) was applied to primary cortical neurons after 7 days growth in vitro. The extent of distal degeneration was quantified using the degenerative index (DI, the ratio of fragmented axon area to total axon area) of axons fixed at 24 h and 72 h post injury (PI), and immunolabelled for the axon specific, microtubule associated protein-tau. At 24 h PI following very mild injuries (0.5%), the majority of the axons remained intact and healthy with no significant difference in DI when compared to the control, but at 72 h PI, the DI increased significantly (DI = 0.11 ± 0.03). Remarkably, dendritic beading in the somal compartment was observed at 24 h PI, indicative of dying back degeneration. When the injury level was increased (5% stretch, mild injury), microtubule fragmentation along the injured axons was observed, with a significant increase in DI at 24 h PI (DI = 0.17 ± 0.02) and 72 h PI (DI = 0.18 ± 0.01), relative to uninjured axons. The responses observed for both mild and very mild injuries are similar to those observed in the in vivo models of traumatic brain injury, suggesting that this model can be used to study neuronal trauma and will provide new insights into the cellular and molecular alterations characterizing the neuronal response to discrete axonal injury. PMID:25379095

  1. Social Isolation Blunted the Response of Mesocortical Dopaminergic Neurons to Chronic Ethanol Voluntary Intake

    PubMed Central

    Lallai, Valeria; Manca, Letizia; Dazzi, Laura

    2016-01-01

    Previous studies have shown that stress can increase the response of mesolimbic dopaminergic neurons to acute administration of drugs of abuse included ethanol. In this study, we investigated the possible involvement of the mesocortical dopaminergic pathway in the development of ethanol abuse under stress conditions. To this aim we trained both socially isolated (SI) and group housed (GH) rats to self administer ethanol which was made available only 2 ha day (from 11:00 to 13:00 h). Rats have been trained for 3 weeks starting at postnatal day 35. After training, rats were surgically implanted with microdialysis probes under deep anesthesia, and 24 hlater extracellular dopamine concentrations were monitored in medial prefrontal cortex (mPFC) for the 2 hpreceding ethanol administration (anticipatory phase), during ethanol exposure (consummatory phase) and for 2 hafter ethanol removal. Results show that, in GH animals, dopamine extracellular concentration in the mPFC increased as early as 80 min before ethanol presentation (+50% over basal values) and remained elevated for 80 min during ethanol exposure. In SI rats, on the contrary, dopamine extracellular concentration did not show any significant change at any time point. Ethanol consumption was significantly higher in SI than in GH rats. Moreover, mesocortical dopaminergic neurons in SI animals also showed a decreased sensitivity to an acute administration of ethanol with respect to GH rats. Our results show that prolonged exposure to stress, as in social isolation, is able to induce significant changes in the response of mesocortical dopaminergic neurons to ethanol exposure and suggest that these changes might play an important role in the compulsivity observed in ethanol addiction. PMID:27378852

  2. The earliest neuronal responses to hypoxia in the neocortical circuit are glutamate-dependent.

    PubMed

    Revah, Omer; Lasser-Katz, Efrat; Fleidervish, Ilya A; Gutnick, Michael J

    2016-11-01

    Soon after exposure to hypoxia or ischemia, neurons in cortical tissues undergo massive anoxic depolarization (AD). This precipitous event is preceded by more subtle neuronal changes, including enhanced excitatory and inhibitory synaptic transmitter release. Here, we have used patch-in-slice techniques to identify the earliest effects of acute hypoxia on the synaptic and intrinsic properties of Layer 5 neurons, to determine their time course and to evaluate the role of glutamate receptors in their generation. Coronal slices of mouse somatosensory cortex were maintained at 36°C in an interface chamber and challenged with episodes of hypoxia. In recordings with cell-attached electrodes, the open probability of Ca(2+)-dependent BK channels began to increase within seconds of hypoxia onset, indicating a sharp rise in [Ca(2+)]i just beneath the membrane. By using a high concentration of K(+) in the pipette, we simultaneously monitored the membrane potential and showed that the [Ca(2+)]i rise was not associated with membrane depolarization. The earliest hypoxia-induced synaptic disturbance was a marked increase in the frequency of sPSCs, which also began soon after the removal of oxygen and long before AD. This synaptic effect was accompanied by depletion of the readily releasable transmitter pools, as demonstrated by a decreased response to hyperosmotic solutions. The early [Ca(2+)]i rise, the early increase in transmitter release and the subsequent AD itself were all prevented by bathing in a cocktail containing blockers of ionotropic glutamate receptors. We found no evidence for involvement of pannexin hemichannels or TRPM7 channels in the early responses to hypoxia in this experimental preparation. Our data indicate that the earliest cellular consequences of cortical hypoxia are triggered by activation of glutamate-gated channels. PMID:27443966

  3. Social Isolation Blunted the Response of Mesocortical Dopaminergic Neurons to Chronic Ethanol Voluntary Intake.

    PubMed

    Lallai, Valeria; Manca, Letizia; Dazzi, Laura

    2016-01-01

    Previous studies have shown that stress can increase the response of mesolimbic dopaminergic neurons to acute administration of drugs of abuse included ethanol. In this study, we investigated the possible involvement of the mesocortical dopaminergic pathway in the development of ethanol abuse under stress conditions. To this aim we trained both socially isolated (SI) and group housed (GH) rats to self administer ethanol which was made available only 2 ha day (from 11:00 to 13:00 h). Rats have been trained for 3 weeks starting at postnatal day 35. After training, rats were surgically implanted with microdialysis probes under deep anesthesia, and 24 hlater extracellular dopamine concentrations were monitored in medial prefrontal cortex (mPFC) for the 2 hpreceding ethanol administration (anticipatory phase), during ethanol exposure (consummatory phase) and for 2 hafter ethanol removal. Results show that, in GH animals, dopamine extracellular concentration in the mPFC increased as early as 80 min before ethanol presentation (+50% over basal values) and remained elevated for 80 min during ethanol exposure. In SI rats, on the contrary, dopamine extracellular concentration did not show any significant change at any time point. Ethanol consumption was significantly higher in SI than in GH rats. Moreover, mesocortical dopaminergic neurons in SI animals also showed a decreased sensitivity to an acute administration of ethanol with respect to GH rats. Our results show that prolonged exposure to stress, as in social isolation, is able to induce significant changes in the response of mesocortical dopaminergic neurons to ethanol exposure and suggest that these changes might play an important role in the compulsivity observed in ethanol addiction. PMID:27378852

  4. Amygdalar neuronal activity mediates the cardiovascular responses evoked from the dorsolateral periaqueductal gray in conscious rats.

    PubMed

    de Abreu, A R; Abreu, A R; Santos, L T; de Souza, A A; da Silva, L G; Chianca, D A; de Menezes, R C

    2015-01-22

    There is ample evidence that both lateral/dorsolateral periaqueductal gray (l/dlPAG) and basolateral amygdala (BLA) are essential for the regulation of the autonomic responses evoked during innate reactions to threatening stimuli. However, it is not well established to what extent the BLA regulates the upstream functional connection from the l/dlPAG. Here we evaluated the role of the BLA and its glutamatergic receptors in the cardiovascular responses induced by l/dlPAG stimulation in rats. We examined the influence of acute inhibition of the BLA, unilaterally, by injecting muscimol on the cardiovascular responses evoked by the injection of N-methyl D-aspartate (NMDA) into the l/dlPAG. We also evaluated the role of BLA ionotropic glutamate receptors in these responses by injecting antagonists of NMDA and AMPA/kainate receptor subtypes into the BLA. Our results show that the microinjection of NMDA in the BLA increased the mean arterial pressure (MAP) and heart rate (HR). Injection of NMDA into the l/dlPAG caused similar increases in these variables, which was prevented by the prior injection of muscimol, a GABAA agonist, into the BLA. Moreover, injection of glutamatergic antagonists (2-amino-5-phosphonopentanoate (AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)) into the BLA reduced the increase in MAP and HR induced by l/dlPAG activation. Finally, the inhibition of the central amygdala neurons failed to reduce the cardiovascular changes induced by l/dlPAG activation. These results indicate that physiological responses elicited by l/dlPAG activation require the neuronal activity in the BLA. This ascending excitatory pathway from the l/dlPAG to the BLA might ensure the expression of the autonomic component of the defense reaction. PMID:25451289

  5. Long Non-coding RNA in Neurons: New Players in Early Response to BDNF Stimulation

    PubMed Central

    Aliperti, Vincenza; Donizetti, Aldo

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin family member that is highly expressed and widely distributed in the brain. BDNF is critical for neural survival and plasticity both during development and in adulthood, and dysfunction in its signaling may contribute to a number of neurodegenerative disorders. Deep understanding of the BDNF-activated molecular cascade may thus help to find new biomarkers and therapeutic targets. One interesting direction is related to the early phase of BDNF-dependent gene expression regulation, which is responsible for the activation of selective gene programs that lead to stable functional and structural remodeling of neurons. Immediate-early coding genes activated by BDNF are under investigation, but the involvement of the non-coding RNAs is largely unexplored, especially the long non-coding RNAs (lncRNAs). lncRNAs are emerging as key regulators that can orchestrate different aspects of nervous system development, homeostasis, and plasticity, making them attractive candidate markers and therapeutic targets for brain diseases. We used microarray technology to identify differentially expressed lncRNAs in the immediate response phase of BDNF stimulation in a neuronal cell model. Our observations on the putative functional role of lncRNAs provide clues to their involvement as master regulators of gene expression cascade triggered by BDNF. PMID:26973456

  6. Responses of Neurons in Primary and Inferior Temporal Visual Cortices to Natural Scenes

    NASA Astrophysics Data System (ADS)

    Baddeley, Roland; Abbott, L. F.; Booth, Michael C. A.; Sengpiel, Frank; Freeman, Tobe; Wakeman, Edward A.; Rolls, Edmund T.

    1997-12-01

    The primary visual cortex (V1) is the first cortical area to receive visual input, and inferior temporal (IT) areas are among the last along the ventral visual pathway. We recorded, in area V1 of anaesthetized cats and area IT of awake macaque monkeys, responses of neurons to videos of natural scenes. Responses were analysed to test various hypotheses concerning the nature of neural coding in these two regions. A variety of spike-train statistics were measured including spike-count distributions, interspike interval distributions, coefficients of variation, power spectra, Fano factors and different sparseness measures. All statistics showed non-Poisson characteristics and several revealed self-similarity of the spike trains. Spike-count distributions were approximately exponential in both visual areas for eight different videos and for counting windows ranging from 50 ms to 5 seconds. The results suggest that the neurons maximize their information carrying capacity while maintaining a fixed long-term-average firing rate, or equivalently, minimize their average firing rate for a fixed information carrying capacity.

  7. Ventral premotor-motor cortex interactions in the macaque monkey during grasp: response of single neurons to intracortical microstimulation.

    PubMed

    Kraskov, Alexander; Prabhu, Gita; Quallo, Marsha M; Lemon, Roger N; Brochier, Thomas

    2011-06-15

    Recent stimulation studies in monkeys and humans have shown strong interactions between ventral premotor cortex (area F5) and the hand area of primary motor cortex (M1). These short-latency interactions usually involve facilitation from F5 of M1 outputs to hand muscles, although suppression has also been reported. This study, performed in three awake macaque monkeys, sought evidence that these interactions could be mediated by short-latency excitatory and inhibitory responses of single M1 neurons active during grasping tasks. We recorded responses of these M1 neurons to single low-threshold (≤40 μA) intracortical microstimuli delivered to F5 sites at which grasp-related neurons were recorded. In 29 sessions, we tested 232 M1 neurons with stimuli delivered to between one and four sites in F5. Of the 415 responses recorded, 142 (34%) showed significant effects. The most common type of response was pure excitation (53% of responses), with short latency (1.8-3.0 ms) and brief duration (∼1 ms); purely inhibitory responses had slightly longer latencies (2-5 ms) and were of small amplitude and longer duration (5-7 ms). They accounted for 13% of responses, whereas mixed excitation then inhibition was seen in 34%. Remarkably, a rather similar set of findings applied to 280 responses of 138 F5 neurons to M1 stimulation; 109 (34%) responses showed significant effects. Thus, with low-intensity stimuli, the dominant interaction between these two cortical areas is one of short-latency, brief excitation, most likely mediated by reciprocal F5-M1 connections. Some neurons were tested with stimuli at both 20 and 40 μA; inhibition tended to dominate at the higher intensity. PMID:21677165

  8. Quantification of the response of rat medullary raphe neurones to independent changes in pHo and PCO2

    PubMed Central

    Wang, Wengang; Bradley, Stefania Risso; Richerson, George B

    2002-01-01

    The medullary raphe nuclei contain putative central respiratory chemoreceptor neurones that are highly sensitive to acidosis. To define the primary stimulus for chemosensitivity in these neurones, the response to hypercapnic acidosis was quantified and compared with the response to independent changes in PCO2 and extracellular pH (pHo). Neurones from the ventromedial medulla of neonatal rats (P0-P2) were dissociated and maintained in tissue culture for long enough to develop a mature response (up to 70 days). Perforated patch clamp recordings were used to record membrane potential and firing rate while changes were made in pHo, PCO2 and/or [NaHCO3]o from baseline values of 7.4, 5 % and 26 mm, respectively. Hypercapnic acidosis (PCO2 9 %; pHo 7.17) induced an increase in firing rate to 285 % of control in one subset of neurones (‘stimulated neurones’) and induced a decrease in firing rate to 21 % of control in a different subset of neurones (‘inhibited neurones’). Isocapnic acidosis (pHo 7.16; [NaHCO3]o 15 mm) induced an increase in firing rate of stimulated neurones to 309 % of control, and a decrease in firing rate of inhibited neurones to 38 % of control. In a different group of neurones, isohydric hypercapnia (9 % PCO2; [NaHCO3]o 40 mm) induced an increase in firing rate of stimulated neurones by the same amount (to 384 % of control) as in response to hypercapnic acidosis (to 327 % of control). Inhibited neurones also responded to isohydric hypercapnia in the same way as they did to hypercapnic acidosis. In Hepes-buffered solution, both types of neurone responded to changes in pHo in the same way as they responded to changes in pHo in bicarbonate-buffered Ringer solution. It has previously been shown that all acidosis-stimulated neurones in the medullary raphe are immunoreactive for tryptophan hydroxylase (TpOH-ir). Here it was found that TpOH-ir neurones in the medullary raphe were immunoreactive for carbonic anhydrase type II and type IV (CA II and CA

  9. Analysis and classification of delay-sensitive cortical neurons based on response to temporal parameters in echolocation signals.

    PubMed

    Chittajallu, S K; Palakal, M J; Wong, D

    1995-04-01

    Echolocating bats generate an acoustic image of their target by processing target-reflected echoes of their emitted biosonar pulses. Efforts in building computational models of auditory processing in the bat auditory system, using extensive neurophysiological data from cortical studies are challenged by the intrinsic complexity and the significant variability in neural response to stimuli. In this paper, we use a computerized method for the analysis and classification of delay-sensitive neurons to classify neurons from the auditory cortex of Myotis lucifugus, a species that echolocates with FM signals. The coefficients of the bi-linear fit to the best delay response surfaces (mean R2 = 0.01) were used in classifying the neurons. Six classes were derived that corresponded to the four previously characterized neurophysiologically. The first class corresponded to delay-tuned neurons which exhibited a constant best delay at different pulse repetition rates and pulse durations. Three other classes corresponded to the different subtypes of tracking neurons which changed their best delay to one or both of these stimulus temporal parameters. Two additional classes were differentiated although their best-delay response were similar to either the delay-tuned or the duration and pulse-repetition rate sensitive class. Artificial delay-sensitive neurons built from the parameters of the centroid of each class, will serve a key role in the FM bat auditory system model that we are building. PMID:7642448

  10. Neuronal Serotonin Release Triggers the Heat Shock Response in C. elegans in the Absence of Temperature Increase

    PubMed Central

    Tatum, Marcus C.; Ooi, Felicia K.; Chikka, Madhusudana Rao; Chauve, Laetitia; Martinez-Velazquez, Luis A.; Steinbusch, Harry W.M.; Morimoto, Richard I.; Prahlad, Veena

    2016-01-01

    Summary Background Cellular mechanisms aimed at repairing protein damage and maintaining homeostasis, widely understood to be triggered by the damage itself, have recently been shown to be under cell nonautonomous control in the metazoan C. elegans. The heat shock response (HSR) is one such conserved mechanism, activated by cells upon exposure to proteotoxic conditions such as heat. Previously, we had shown that this conserved cytoprotective response is regulated by the thermosensory neuronal circuitry of C. elegans. Here, we investigate the mechanisms and physiological relevance of neuronal control. Results By combining optogenetic methods with live visualization of the dynamics of the heat shock transcription factor (HSF1), we show that excitation of the AFD thermosensory neurons is sufficient to activate HSF1 in another cell, even in the absence of temperature increase. Excitation of the AFD thermosensory neurons enhances serotonin release. Serotonin release elicited by direct optogenetic stimulation of serotonergic neurons activates HSF1 and upregulates molecular chaperones through the metabotropic serotonin receptor SER-1. Consequently, excitation of serotonergic neurons alone can suppress protein misfolding in C. elegans peripheral tissue. Conclusions These studies imply that thermosensory activity coupled to serotonergic signaling is sufficient to activate the protective HSR prior to frank proteotoxic damage. The ability of neurosensory release of serotonin to control cellular stress responses and activate HSF1 has powerful implications for the treatment of protein conformation diseases. PMID:25557666

  11. Neuronal expression of sodium/bicarbonate cotransporter NBCn1 (SLC4A7) and its response to chronic metabolic acidosis

    PubMed Central

    Park, Hae Jeong; Rajbhandari, Ira; Yang, Han Soo; Lee, Soojung; Cucoranu, Delia; Cooper, Deborah S.; Klein, Janet D.; Sands, Jeff M.

    2010-01-01

    The sodium-bicarbonate cotransporter NBCn1 (SLC4A7) is an acid-base transporter that normally moves Na+ and HCO3− into the cell. This membrane protein is sensitive to cellular and systemic pH changes. We examined NBCn1 expression and localization in the brain and its response to chronic metabolic acidosis. Two new NBCn1 antibodies were generated by immunizing a rabbit and a guinea pig. The antibodies stained neurons in a variety of rat brain regions, including hippocampal pyramidal neurons, dentate gyrus granular neurons, posterior cortical neurons, and cerebellar Purkinje neurons. Choroid plexus epithelia were also stained. Double immunofluorescence labeling showed that NBCn1 and the postsynaptic density protein PSD-95 were found in the same hippocampal CA3 neurons and partially colocalized in dendrites. PSD-95 was pulled down from rat brain lysates with the GST/NBCn1 fusion protein and was also coimmunoprecipitated with NBCn1. Chronic metabolic acidosis was induced by feeding rats with normal chow or 0.4 M HCl-containing chow for 7 days. Real-time PCR and immunoblot showed upregulation of NBCn1 mRNA and protein in the hippocampus of acidotic rats. NBCn1 immunostaining was enhanced in CA3 neurons, posterior cortical neurons, and cerebellar granular cells. Intraperitoneal administration of N-methyl-d-aspartate caused neuronal death determined by caspase-3 activity, and this effect was more severe in acidotic rats. Administering N-methyl-d-aspartate also inhibited NBCn1 upregulation in acidotic rats. We conclude that NBCn1 in neurons is upregulated by chronic acid loads, and this upregulation is associated with glutamate excitotoxicity. PMID:20147654

  12. Response enhancement of olfactory sensory neurons-based biosensors for odorant detection*

    PubMed Central

    Wu, Chun-sheng; Chen, Pei-hua; Yuan, Qing; Wang, Ping

    2009-01-01

    This paper presents a novel strategy for the response enhancement of olfactory sensory neurons (OSNs)-based biosensors by monitoring the enhancive responses of OSNs to odorants. An OSNs-based biosensor was developed on the basis of the light addressable potentiometric sensor (LAPS), in which rat OSNs were cultured on the surface of LAPS chip and served as sensing elements. LY294002, the specific inhibitor of phosphatidylinositol 3-kinase (PI3K), was used to enhance the responses of OSNs to odorants. The responses of OSNs to odorants with and without the treatment of LY294002 were recorded by LAPS. The results show that the enhancive effect of LY294002 was recorded efficiently by LAPS and the responses of this OSNs-LAPS hybrid biosensor were enhanced by LY294002 by about 1.5-fold. We conclude that this method can enhance the responses of OSNs-LAPS hybrid biosensors, which may provide a novel strategy for the bioelectrical signal monitor of OSNs in biosensors. It is also suggested that this strategy may be applicable to other kinds of OSNs-based biosensors for cellular activity detection, such as microelectrode array (MEA) and field effect transistor (FET). PMID:19353747

  13. Pαx6 Expression in Postmitotic Neurons Mediates the Growth of Axons in Response to SFRP1

    PubMed Central

    Sebastián-Serrano, Alvaro; Sandonis, Africa; Cardozo, Marcos; Rodríguez-Tornos, Fernanda M.; Bovolenta, Paola; Nieto, Marta

    2012-01-01

    During development, the mechanisms that specify neuronal subclasses are coupled to those that determine their axonal response to guidance cues. Pax6 is a homedomain transcription factor required for the specification of a variety of neural precursors. After cell cycle exit, Pax6 expression is often shut down in the precursor progeny and most postmitotic neurons no longer express detectable levels of the protein. There are however exceptions and high Pax6 protein levels are found, for example, in postmitotic retinal ganglion cells (RGCs), dopaminergic neurons of the olfactory bulb and the limbic system in the telencephalon. The function of Pax6 in these differentiating neurons remains mostly elusive. Here, we demonstrate that Pax6 mediates the response of growing axons to SFRP1, a secreted molecule expressed in several Pax6-positive forebrain territories. Forced expression of Pax6 in cultured postmitotic cortical neurons, which do not normally express Pax6, was sufficient to increment axonal length. Growth was blocked by the addition of anti-SFRP1 antibodies, whereas exogenously added SFRP1 increased axonal growth of Pax6-transfected neurons but not that of control or untransfected cortical neurons. In the reverse scenario, shRNA-mediated knock-down of Pax6 in mouse retinal explants specifically abolished RGCs axonal growth induced by SFRP1, but had no effect on RGCs differentiation and it did not modify the effect of Shh or Netrin on axon growth. Taken together these results demonstrate that expression of Pax6 is necessary and sufficient to render postmitotic neurons competent to respond to SFRP1. These results reveal a novel and unexpected function of Pax6 in postmitotic neurons and situate Pax6 and SFRP1 as pair regulators of axonal connectivity. PMID:22359602

  14. Intensity invariant dynamics and odor-specific latencies in olfactory receptor neuron response

    PubMed Central

    Martelli, Carlotta; Carlson, John R.; Emonet, Thierry

    2013-01-01

    Odors elicit spatio-temporal patterns of activity in the brain. Spatial patterns arise from the specificity of the interaction between odorants and odorant receptors expressed in different olfactory receptor neurons (ORNs). But the origin of temporal patterns of activity and their role in odor coding remain unclear. We investigate how physiological aspects of ORN response and physical aspects of odor stimuli give rise to diverse responses in Drosophila ORNs. We show that odor stimuli have intrinsic dynamics that depend on odor type and strongly affect ORN response. Using linear-nonlinear modeling to remove the contribution of the stimulus dynamics from the ORN dynamics we study the physiological properties of the response to different odorants and concentrations. For several odorants and receptor types the ORN response dynamics normalized by the peak response are independent of stimulus intensity for a large portion of the neuron’s dynamic range. Adaptation to a background odor changes the gain and dynamic range of the response but does not affect normalized response dynamics. Stimulating ORNs with various odorants reveals significant odor-dependent delays in the ORN response functions. These differences however can be dominated by differences in stimulus dynamics. In one case the response of one ORN to two odorants is predicted solely from measurements of the odor signals. Within a large portion of their dynamic range ORNs can capture information about stimulus dynamics independently from intensity while introducing odor-dependent delays. How insects might use odor-specific stimulus dynamics and ORN dynamics in discrimination and navigation tasks remains an open question. PMID:23575828

  15. Influence of stimulus and oral adaptation temperature on gustatory responses in central taste-sensitive neurons.

    PubMed

    Li, Jinrong; Lemon, Christian H

    2015-04-01

    The temperature of taste stimuli can modulate gustatory processing. Perceptual data indicate that the adapted temperature of oral epithelia also influences gustation, although little is known about the neural basis of this effect. Here, we electrophysiologically recorded orosensory responses (spikes) to 25°C (cool) and 35°C (warm) solutions of sucrose (0.1 and 0.3 M), NaCl (0.004, 0.1, and 0.3 M), and water from taste-sensitive neurons in the nucleus of the solitary tract in mice under varied thermal adaptation of oral epithelia. Conditions included presentation of taste stimuli isothermal to adaptation temperatures of 25°C (constant cooling) and 35°C (constant warming), delivery of 25°C stimuli following 35°C adaptation (relative cooling), and presentation of 35°C stimuli following 25°C adaptation (relative warming). Responses to sucrose in sucrose-oriented cells (n = 15) were enhanced under the constant and relative warming conditions compared with constant cooling, where contiguous cooling across adaptation and stimulus periods induced the lowest and longest latency responses to sucrose. Yet compared with constant warming, cooling sucrose following warm adaptation (relative cooling) only marginally reduced activity to 0.1 M sucrose and did not alter responses to 0.3 M sucrose. Thus, warmth adaptation counteracted the attenuation in sucrose activity associated with stimulus cooling. Analysis of sodium-oriented (n = 25) neurons revealed adaptation to cool water, and cooling taste solutions enhanced unit firing to 0.004 M (perithreshold) NaCl, whereas warmth adaptation and stimulus warming could facilitate activity to 0.3 M NaCl. The concentration dependence of this thermal effect may reflect a dual effect of temperature on the sodium reception mechanism that drives sodium-oriented cells.

  16. Influence of stimulus and oral adaptation temperature on gustatory responses in central taste-sensitive neurons.

    PubMed

    Li, Jinrong; Lemon, Christian H

    2015-04-01

    The temperature of taste stimuli can modulate gustatory processing. Perceptual data indicate that the adapted temperature of oral epithelia also influences gustation, although little is known about the neural basis of this effect. Here, we electrophysiologically recorded orosensory responses (spikes) to 25°C (cool) and 35°C (warm) solutions of sucrose (0.1 and 0.3 M), NaCl (0.004, 0.1, and 0.3 M), and water from taste-sensitive neurons in the nucleus of the solitary tract in mice under varied thermal adaptation of oral epithelia. Conditions included presentation of taste stimuli isothermal to adaptation temperatures of 25°C (constant cooling) and 35°C (constant warming), delivery of 25°C stimuli following 35°C adaptation (relative cooling), and presentation of 35°C stimuli following 25°C adaptation (relative warming). Responses to sucrose in sucrose-oriented cells (n = 15) were enhanced under the constant and relative warming conditions compared with constant cooling, where contiguous cooling across adaptation and stimulus periods induced the lowest and longest latency responses to sucrose. Yet compared with constant warming, cooling sucrose following warm adaptation (relative cooling) only marginally reduced activity to 0.1 M sucrose and did not alter responses to 0.3 M sucrose. Thus, warmth adaptation counteracted the attenuation in sucrose activity associated with stimulus cooling. Analysis of sodium-oriented (n = 25) neurons revealed adaptation to cool water, and cooling taste solutions enhanced unit firing to 0.004 M (perithreshold) NaCl, whereas warmth adaptation and stimulus warming could facilitate activity to 0.3 M NaCl. The concentration dependence of this thermal effect may reflect a dual effect of temperature on the sodium reception mechanism that drives sodium-oriented cells. PMID:25673737

  17. Grin1 deletion in CRF neurons sex-dependently enhances fear, sociability, and social stress responsivity.

    PubMed

    Gilman, T Lee; DaMert, Jeffrey P; Meduri, Jeremy D; Jasnow, Aaron M

    2015-08-01

    The corticotropin releasing factor (CRF) system plays a critical role in responses to stressful stimuli, and is expressed in many areas of the brain involved in processing fear, anxiety, and social behaviors. To better understand the mechanisms by which the CRF system modulates responses to stressful events and social stimuli, we employed a mouse model that selectively disrupts NMDA receptor function via NMDA receptor subunit NR1 (Grin1) knockout specifically in Cre-expressing CRF neurons. These animals (Cre+/(fGrin1+)) were compared with littermates lacking Cre expression (Cre-/(fGrin1+)). Following cue discrimination fear conditioning, male Cre+/(fGrin1+) mice showed increased fear expression to the tone paired with a foot shock (CS+) while still discriminating the CS+ from a tone never paired with a foot shock (CS-). In contrast to males, female mice learned and discriminated fear cues equivalently across the genotypes. Similarly, no genotype differences in sociability or social novelty were observed in female mice, but Cre+/(fGrin1+) males displayed greater naive sociability and preference for social novelty than Cre-/(fGrin1+) littermates. Furthermore, the level of social withdrawal exhibited by male Cre+/(fGrin1+) mice susceptible to social defeat stress relative to same genotype controls was significantly more pronounced than that displayed by susceptible Cre-/(fGrin1+) mice compared to control Cre-/(fGrin1+) mice. Together, these results demonstrate increased fear, social, and stress responsiveness specifically in male Cre+/(fGrin1+) mice. Our findings indicate that NMDA-mediated glutamatergic regulation of CRF neurons is important for appropriately regulating fear and social responses, likely functioning to promote survival under aversive circumstances.

  18. Potential confounds in estimating trial-to-trial correlations between neuronal response and behavior using choice probabilities

    PubMed Central

    Maunsell, John H. R.

    2012-01-01

    Correlations between trial-to-trial fluctuations in the responses of individual sensory neurons and perceptual reports, commonly quantified with choice probability (CP), have been widely used as an important tool for assessing the contributions of neurons to behavior. These correlations are usually weak and often require a large number of trials for a reliable estimate. Therefore, working with measures such as CP warrants care in data analysis as well as rigorous controls during data collection. Here we identify potential confounds that can arise in data analysis and lead to biased estimates of CP, and suggest methods to avoid the bias. In particular, we show that the common practice of combining neuronal responses across different stimulus conditions with z-score normalization can result in an underestimation of CP when the ratio of the numbers of trials for the two behavioral response categories differs across the stimulus conditions. We also discuss the effects of using variable time intervals for quantifying neuronal response on CP measurements. Finally, we demonstrate that serious artifacts can arise in reaction time tasks that use varying measurement intervals if the mean neuronal response and mean behavioral performance vary over time within trials. To emphasize the importance of addressing these concerns in neurophysiological data, we present a set of data collected from V1 cells in macaque monkeys while the animals performed a detection task. PMID:22993262

  19. Neuronal correlates of the visually elicited escape response of the crab Chasmagnathus upon seasonal variations, stimuli changes and perceptual alterations.

    PubMed

    Sztarker, Julieta; Tomsic, Daniel

    2008-06-01

    When confronted with predators, animals are forced to take crucial decisions such as the timing and manner of escape. In the case of the crab Chasmagnathus, cumulative evidence suggests that the escape response to a visual danger stimulus (VDS) can be accounted for by the response of a group of lobula giant (LG) neurons. To further investigate this hypothesis, we examined the relationship between behavioral and neuronal activities within a variety of experimental conditions that affected the level of escape. The intensity of the escape response to VDS was influenced by seasonal variations, changes in stimulus features, and whether the crab perceived stimuli monocularly or binocularly. These experimental conditions consistently affected the response of LG neurons in a way that closely matched the effects observed at the behavioral level. In other words, the intensity of the stimulus-elicited spike activity of LG neurons faithfully reflected the intensity of the escape response. These results support the idea that the LG neurons from the lobula of crabs are deeply involved in the decision for escaping from VDS.

  20. Responses of pyriform cortex neurons to excitatory amino acids: voltage dependence, conductance changes, and effects of divalent cations.

    PubMed

    Hori, N; Galeno, T; Carpenter, D O

    1987-03-01

    The actions of ionophoretically applied N-methyl aspartate (NMA), quisqualate, and kainate, thought to activate three different types of excitatory amino acid receptors, were studied on pyramidal neurons of the rat pyriform cortex, maintained in an isolated, submerged, and perfused brain slice. Intracellular recordings were made with either K acetate or CsCl electrodes. In most neurons all three agonists elicited monophasic responses which could be evoked at 20-sec intervals. Some neurons showed biphasic responses, most commonly to kainate but, on occasion, also for quisqualate. The slower component appeared to be correlated with excitotoxicity and, consequently, was difficult to study. As a result the kainate responses studied were from neurons selected for having a single component. In neurons selected for having a linear current-voltage relationship or neurons loaded with Cs to suppress K conductance and linearize the current-voltage relationship, the average changes in resistance recorded during ionophoretic responses at resting potential were as follows: NMA, 131.2 +/- 6.7% of control; kainate, 104.7 +/- 5.8% of control; and quisqualate, 92.8 +/- 2.8% of control. The magnitude and direction of the conductance change were very reproducible in any one neuron, but especially for kainate some cells showed clear conductance increases, while others showed clear conductance decreases. Using CsCl electrodes it was possible to reduce K+ conductance and depolarize the neurons over a wider range. By passing depolarizing current it was possible to reverse the responses. The response to all three agonists reversed at the same depolarized potential. This observation indicates that while there are differences in the ionic channels associated with the three agonists at resting potential, the channels have similar properties at more depolarized potentials. Responses to all three agonists were influenced by the concentrations of divalent cations in the perfusion medium. The NMA

  1. A codimension-2 bifurcation controlling endogenous bursting activity and pulse-triggered responses of a neuron model.

    PubMed

    Barnett, William H; Cymbalyuk, Gennady S

    2014-01-01

    The dynamics of individual neurons are crucial for producing functional activity in neuronal networks. An open question is how temporal characteristics can be controlled in bursting activity and in transient neuronal responses to synaptic input. Bifurcation theory provides a framework to discover generic mechanisms addressing this question. We present a family of mechanisms organized around a global codimension-2 bifurcation. The cornerstone bifurcation is located at the intersection of the border between bursting and spiking and the border between bursting and silence. These borders correspond to the blue sky catastrophe bifurcation and the saddle-node bifurcation on an invariant circle (SNIC) curves, respectively. The cornerstone bifurcation satisfies the conditions for both the blue sky catastrophe and SNIC. The burst duration and interburst interval increase as the inverse of the square root of the difference between the corresponding bifurcation parameter and its bifurcation value. For a given set of burst duration and interburst interval, one can find the parameter values supporting these temporal characteristics. The cornerstone bifurcation also determines the responses of silent and spiking neurons. In a silent neuron with parameters close to the SNIC, a pulse of current triggers a single burst. In a spiking neuron with parameters close to the blue sky catastrophe, a pulse of current temporarily silences the neuron. These responses are stereotypical: the durations of the transient intervals-the duration of the burst and the duration of latency to spiking-are governed by the inverse-square-root laws. The mechanisms described here could be used to coordinate neuromuscular control in central pattern generators. As proof of principle, we construct small networks that control metachronal-wave motor pattern exhibited in locomotion. This pattern is determined by the phase relations of bursting neurons in a simple central pattern generator modeled by a chain of

  2. Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM)-Mediated Protection of Ischemic Brain

    PubMed Central

    Lin, Chi-Hsin; Wang, Chen-Hsuan; Hsu, Shih-Lan; Liao, Li-Ya; Lin, Ting-An; Hsueh, Chi-Mei

    2016-01-01

    The protective value of neuron-derived conditioned medium (NCM) in cerebral ischemia and the underlying mechanism(s) responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD) for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO) animal model, we discovered that ischemia/reperfusion (I/R)-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFβ1, NT-3 and GDNF) and p-ERK dependent manner. Brain injection with TGFβ1, NT3, GDNF and ERK agonist (DADS) alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1β release from GOSD-treated microglia and limit the infiltration of IL-β-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti-oxidant and potentially anti-glutamate activities (NCM-induced IL-1β can inhibit the glutamate-mediated neurotoxicity) and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFβ1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation. PMID:26745377

  3. Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM)-Mediated Protection of Ischemic Brain.

    PubMed

    Lin, Chi-Hsin; Wang, Chen-Hsuan; Hsu, Shih-Lan; Liao, Li-Ya; Lin, Ting-An; Hsueh, Chi-Mei

    2016-01-01

    The protective value of neuron-derived conditioned medium (NCM) in cerebral ischemia and the underlying mechanism(s) responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD) for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO) animal model, we discovered that ischemia/reperfusion (I/R)-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFβ1, NT-3 and GDNF) and p-ERK dependent manner. Brain injection with TGFβ1, NT3, GDNF and ERK agonist (DADS) alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1β release from GOSD-treated microglia and limit the infiltration of IL-β-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti-oxidant and potentially anti-glutamate activities (NCM-induced IL-1β can inhibit the glutamate-mediated neurotoxicity) and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFβ1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation. PMID:26745377

  4. Prefrontal neurons encode context-based response execution and inhibition in reward seeking and extinction

    PubMed Central

    Moorman, David E.; Aston-Jones, Gary

    2015-01-01

    The prefrontal cortex (PFC) guides execution and inhibition of behavior based on contextual demands. In rodents, the dorsal/prelimbic (PL) medial PFC (mPFC) is frequently considered essential for execution of goal-directed behavior (“go”) whereas ventral/infralimbic (IL) mPFC is thought to control behavioral suppression (“stop”). This dichotomy is commonly seen for fear-related behaviors, and for some behaviors related to cocaine seeking. Overall, however, data for reward-directed behaviors are ambiguous, and few recordings of PL/IL activity have been performed to demonstrate single-neuron correlates. We recorded neuronal activity in PL and IL during discriminative stimulus driven sucrose seeking followed by multiple days of extinction of the reward-predicting stimulus. Contrary to a generalized PL-go/IL-stop hypothesis, we found cue-evoked activity in PL and IL during reward seeking and extinction. Upon analyzing this activity based on resultant behavior (lever press or withhold), we found that neurons in both areas encoded contextually appropriate behavioral initiation (during reward seeking) and withholding (during extinction), where context was dictated by response–outcome contingencies. Our results demonstrate that PL and IL signal contextual information for regulation of behavior, irrespective of whether that involves initiation or suppression of behavioral responses, rather than topographically encoding go vs. stop behaviors. The use of context to optimize behavior likely plays an important role in maximizing utility-promoting exertion of activity when behaviors are rewarded and conservation of energy when not. PMID:26170333

  5. Antinociception induced by motor cortex stimulation: somatotopy of behavioral response and profile of neuronal activation.

    PubMed

    França, Nubia R M; Toniolo, Elaine F; Franciosi, Adriano C; Alves, Adilson S; de Andrade, Daniel C; Fonoff, Erich T; Britto, Luiz R; Dale, Camila S

    2013-08-01

    Motor cortex stimulation (MCS) is used as a therapy for patients with refractory neuropathic pain. Experimental evidence suggests that the motor cortex (MC) is involved in the modulation of normal nociceptive response, but the underlying mechanisms have not been clarified yet. In previous studies, we demonstrated that MCS increases the nociceptive threshold of naive conscious rats by inhibiting thalamic sensory neurons and disinhibiting the neurons in periaqueductal gray (PAG), with the involvement of the opioid system. The aim of this study was to investigate the possible somatotopy of the motor cortex on MCS-induced antinociception and the pattern of neuronal activation evaluated by Fos and Egr-1 immunolabel in an attempt to better understand the relation between MC and analgesia. Rats received epidural electrode implants placed over the MC, in three distinct areas (forelimb, hindlimb or tail), according to a functional mapping established in previous studies. Nociceptive threshold was evaluated under 15-min electrical stimulating sessions. MCS induced selective antinociception in the limb related to the stimulated cortex, with no changes in other evaluated areas. MCS decreased Fos immunoreactivity (Fos-IR) in the superficial layers of the dorsal horn of the spinal cord for all evaluated groups and increased Fos-IR in the PAG, although no changes were observed in the PAG for the tail group. Egr-1 results were similar to those obtained for Fos. Data shown herein demonstrate that MCS elicits a substantial and selective antinociceptive effect, which is mediated, at least in part, by the activation of descendent inhibitory pain pathway.

  6. A neuronal GPCR is critical for the induction of the heat shock response in the nematode C. elegans.

    PubMed

    Maman, Moria; Carvalhal Marques, Filipa; Volovik, Yuli; Dubnikov, Tatyana; Bejerano-Sagie, Michal; Cohen, Ehud

    2013-04-01

    In the nematode Caenorhabditis elegans, the heat shock response (HSR) is regulated at the organismal level by a network of thermosensory neurons that senses elevated temperatures and activates the HSR in remote tissues. Which neuronal receptors are required for this signaling mechanism and in which neurons they function are largely unanswered questions. Here we used worms that were engineered to exhibit RNA interference hypersensitivity in neurons to screen for neuronal receptors that are required for the activation of the HSR and identified a putative G-protein coupled receptor (GPCR) as a novel key component of this mechanism. This gene, which we termed GPCR thermal receptor 1 (gtr-1), is expressed in chemosensory neurons and has no role in heat sensing but is critically required for the induction of genes that encode heat shock proteins in non-neural tissues upon exposure to heat. Surprisingly, the knock-down of gtr-1 by RNA interference protected worms expressing the Alzheimer's-disease-linked aggregative peptide Aβ3-42 from proteotoxicity but had no effect on lifespan. This study provides several novel insights: (1) it shows that chemosensory neurons play important roles in the nematode's HSR-regulating mechanism, (2) it shows that lifespan and heat stress resistance are separable, and (3) it strengthens the emerging notion that the ability to respond to heat comes at the expense of protein homeostasis (proteostasis). PMID:23554491

  7. Face inversion decreased information about facial identity and expression in face-responsive neurons in macaque area TE.

    PubMed

    Sugase-Miyamoto, Yasuko; Matsumoto, Narihisa; Ohyama, Kaoru; Kawano, Kenji

    2014-09-10

    To investigate the effect of face inversion and thatcherization (eye inversion) on temporal processing stages of facial information, single neuron activities in the temporal cortex (area TE) of two rhesus monkeys were recorded. Test stimuli were colored pictures of monkey faces (four with four different expressions), human faces (three with four different expressions), and geometric shapes. Modifications were made in each face-picture, and its four variations were used as stimuli: upright original, inverted original, upright thatcherized, and inverted thatcherized faces. A total of 119 neurons responded to at least one of the upright original facial stimuli. A majority of the neurons (71%) showed activity modulations depending on upright and inverted presentations, and a lesser number of neurons (13%) showed activity modulations depending on original and thatcherized face conditions. In the case of face inversion, information about the fine category (facial identity and expression) decreased, whereas information about the global category (monkey vs human vs shape) was retained for both the original and thatcherized faces. Principal component analysis on the neuronal population responses revealed that the global categorization occurred regardless of the face inversion and that the inverted faces were represented near the upright faces in the principal component analysis space. By contrast, the face inversion decreased the ability to represent human facial identity and monkey facial expression. Thus, the neuronal population represented inverted faces as faces but failed to represent the identity and expression of the inverted faces, indicating that the neuronal representation in area TE cause the perceptual effect of face inversion.

  8. Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death

    PubMed Central

    Carriba, P; Jimenez, S; Navarro, V; Moreno-Gonzalez, I; Barneda-Zahonero, B; Moubarak, R S; Lopez-Soriano, J; Gutierrez, A; Vitorica, J; Comella, J X

    2015-01-01

    The brains of patients with Alzheimer's disease (AD) present elevated levels of tumor necrosis factor-α (TNFα), a cytokine that has a dual function in neuronal cells. On one hand, TNFα can activate neuronal apoptosis, and on the other hand, it can protect these cells against amyloid-β (Aβ) toxicity. Given the dual behavior of this molecule, there is some controversy regarding its contribution to the pathogenesis of AD. Here we examined the relevance of the long form of Fas apoptotic inhibitory molecule (FAIM) protein, FAIM-L, in regulating the dual function of TNFα. We detected that FAIM-L was reduced in the hippocampi of patients with AD. We also observed that the entorhinal and hippocampal cortex of a mouse model of AD (PS1M146LxAPP751sl) showed a reduction in this protein before the onset of neurodegeneration. Notably, cultured neurons treated with the cortical soluble fractions of these animals showed a decrease in endogenous FAIM-L, an effect that is mimicked by the treatment with Aβ-derived diffusible ligands (ADDLs). The reduction in the expression of FAIM-L is associated with the progression of the neurodegeneration by changing the inflammatory response mediated by TNFα in neurons. In this sense, we also demonstrate that the protection afforded by TNFα against Aβ toxicity ceases when endogenous FAIM-L is reduced by short hairpin RNA (shRNA) or by treatment with ADDLs. All together, these results support the notion that levels of FAIM-L contribute to determine the protective or deleterious effect of TNFα in neuronal cells. PMID:25675299

  9. Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death.

    PubMed

    Carriba, P; Jimenez, S; Navarro, V; Moreno-Gonzalez, I; Barneda-Zahonero, B; Moubarak, R S; Lopez-Soriano, J; Gutierrez, A; Vitorica, J; Comella, J X

    2015-02-12

    The brains of patients with Alzheimer's disease (AD) present elevated levels of tumor necrosis factor-α (TNFα), a cytokine that has a dual function in neuronal cells. On one hand, TNFα can activate neuronal apoptosis, and on the other hand, it can protect these cells against amyloid-β (Aβ) toxicity. Given the dual behavior of this molecule, there is some controversy regarding its contribution to the pathogenesis of AD. Here we examined the relevance of the long form of Fas apoptotic inhibitory molecule (FAIM) protein, FAIM-L, in regulating the dual function of TNFα. We detected that FAIM-L was reduced in the hippocampi of patients with AD. We also observed that the entorhinal and hippocampal cortex of a mouse model of AD (PS1(M146L)xAPP(751sl)) showed a reduction in this protein before the onset of neurodegeneration. Notably, cultured neurons treated with the cortical soluble fractions of these animals showed a decrease in endogenous FAIM-L, an effect that is mimicked by the treatment with Aβ-derived diffusible ligands (ADDLs). The reduction in the expression of FAIM-L is associated with the progression of the neurodegeneration by changing the inflammatory response mediated by TNFα in neurons. In this sense, we also demonstrate that the protection afforded by TNFα against Aβ toxicity ceases when endogenous FAIM-L is reduced by short hairpin RNA (shRNA) or by treatment with ADDLs. All together, these results support the notion that levels of FAIM-L contribute to determine the protective or deleterious effect of TNFα in neuronal cells.

  10. Responses of neurons in the medial column of the inferior olive in pigeons to translational and rotational optic flowfields.

    PubMed

    Winship, I R; Wylie, D R

    2001-11-01

    The responses of neurons in the medial column of the inferior olive to translational and rotational optic flow were recorded from anaesthetized pigeons. Panoramic translational or rotational flowfields were produced by mechanical devices that projected optic flow patterns onto the walls, ceiling and floor of the room. The axis of rotation/translation could be positioned to any orientation in three-dimensional space such that axis tuning could be determined. Each neuron was assigned a vector representing the axis about/along which the animal would rotate/translate to produce the flowfield that elicited maximal modulation. Both translation-sensitive and rotation-sensitive neurons were found. For neurons responsive to translational optic flow, the preferred axis is described with reference to a standard right-handed coordinate system, where +x, +y and +z represent rightward, upward and forward translation of the animal, respectively (assuming that all recordings were from the right side of the brain). t(+y) neurons were maximally excited in response to a translational optic flowfield that results from self-translation upward along the vertical (y) axis. t(-y) neurons also responded best to translational optic flow along the vertical axis but showed the opposite direction preference. The two remaining groups, t(-x+z) and t(-x-z) neurons, responded best to translational optic flow along horizontal axes that were oriented 45 degrees to the midline. There were two types of neurons responsive to rotational optic flow: rVA neurons preferred rotation about the vertical axis, and rH135c neurons preferred rotation about a horizontal axis at 135 degrees contralateral azimuth. The locations of marking lesions indicated a clear topographical organization of the six response types. In summary, our results reinforce that the olivo-cerebellar system dedicated to the analysis of optic flow is organized according to a reference frame consisting of three approximately orthogonal axes

  11. Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses.

    PubMed

    Klein, A H; Joe, C L; Davoodi, A; Takechi, K; Carstens, M I; Carstens, E

    2014-06-20

    Eugenol and carvacrol from clove and oregano, respectively, are agonists of the warmth-sensitive transient receptor potential channel TRPV3 and the irritant-sensitive transient receptor potential ankyrin (TRPA)-1. Eugenol and carvacrol induce oral irritation that rapidly desensitizes, accompanied by brief enhancement of innocuous warmth and heat pain in humans. We presently investigated if eugenol and carvacrol activate nociceptive primary afferent and higher order trigeminal neurons and enhance their heat-evoked responses, using calcium imaging of cultured trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, and in vivo single-unit recordings in trigeminal subnucleus caudalis (Vc) of rats. Eugenol and carvacrol activated 20-30% of TG and 7-20% of DRG cells, the majority of which additionally responded to menthol, mustard oil and/or capsaicin. TG cell responses to innocuous (39°) and noxious (42 °C) heating were enhanced by eugenol and carvacrol. We identified dorsomedial Vc neurons responsive to noxious heating of the tongue in pentobarbital-anesthetized rats. Eugenol and carvacrol dose-dependently elicited desensitizing responses in 55% and 73% of heat-sensitive units, respectively. Responses to noxious heat were briefly enhanced by eugenol and carvacrol. Many eugenol- and carvacrol-responsive units also responded to menthol, cinnamaldehyde and capsaicin. These data support a peripheral site for eugenol and carvacrol to enhance warmth- and noxious heat-evoked responses of trigeminal neurons, and are consistent with the observation that these agonists briefly enhance warmth and heat pain on the human tongue.

  12. Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses

    PubMed Central

    Klein, Amanda H.; Joe, Christopher L.; Davoodi, Auva; Takechi, Kenichi; Carstens, Mirela Iodi; Carstens, E

    2014-01-01

    Eugenol and carvacrol from clove and oregano, respectively, are agonists of the warmth-sensitive transient receptor potential channel TRPV3 and the irritant-sensitive TRPA1. Eugenol and carvacrol induce oral irritation that rapidly desensitizes, accompanied by brief enhancement of innocuous warmth and heat pain in humans. We presently investigated if eugenol and carvacrol activate nociceptive primary afferent and higher-order trigeminal neurons and enhance their heat-evoked responses, using calcium imaging of cultured trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, and in vivo single-unit recordings in trigeminal subnucleus caudalis (Vc) of rats. Eugenol and carvacrol activated 20-30% of TG and 7-20% of DRG cells, the majority of which additionally responded to menthol, mustard oil and/or capsaicin. TG cell responses to innocuous (39°) and noxious (42°C) heating were enhanced by eugenol and carvacrol. We identified dorsomedial Vc neurons responsive to noxious heating of the tongue in pentobarbital-anesthetized rats. Eugenol and carvacrol dose-dependently elicited desensitizing responses in 55% and 73% of heat-sensitive units, respectively. Responses to noxious heat were briefly enhanced by eugenol and carvacrol. Many eugenol- and carvacrol-responsive units also responded to menthol, cinnamaldehyde and capsaicin. These data support a peripheral site for eugenol and carvacrol to enhance warmth- and noxious heat-evoked responses of trigeminal neurons, and are consistent with the observation that these agonists briefly enhance warmth and heat pain on the human tongue. PMID:24759772

  13. Impaired neuronal nitric oxide synthase-mediated vasodilator responses to mental stress in essential hypertension.

    PubMed

    Khan, Sitara G; Geer, Amber; Fok, Henry W; Shabeeh, Husain; Brett, Sally E; Shah, Ajay M; Chowienczyk, Philip J

    2015-04-01

    Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress. To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 μmol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the α-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37±7% versus 70±8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40±11% versus 3.0±14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89±14% to 43±14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39±8% to 67±13% (P<0.02). Essential hypertension is associated with impaired mental stress-induced nNOS-mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events.

  14. Disrupting astrocyte–neuron lactate transfer persistently reduces conditioned responses to cocaine

    PubMed Central

    Boury-Jamot, B; Carrard, A; Martin, J L; Halfon, O; Magistretti, P J; Boutrel, B

    2016-01-01

    A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte–neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine. PMID:26503760

  15. Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

    PubMed

    Boury-Jamot, B; Carrard, A; Martin, J L; Halfon, O; Magistretti, P J; Boutrel, B

    2016-08-01

    A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine. PMID:26503760

  16. Copper deficiency elicits glial and neuronal response typical of neurodegenerative disorders.

    PubMed

    Zucconi, G G; Cipriani, S; Scattoni, R; Balgkouranidou, I; Hawkins, D P; Ragnarsdottir, K V

    2007-04-01

    Dysregulation of copper homeostasis has been associated with neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and prion diseases. The investigation of the role of abnormal copper level in the development of neuropathological damage is essential for the understanding of pathogenetic mechanisms of these neurodegenerative disorders. Using a mouse model of perinatally induced copper deficiency, the present study analysed the response of neuronal and glial cells to copper deficiency from infancy to young adult age. In mice born and maintained after weaning on copper-deficient diet, copper measurements indicated that at 6-8 weeks the copper levels in the brain were decreased by about 80% with respect to controls. In the brain of copper-deficient mice, microglial and astrocytic activation was observed, mostly in the cerebral cortex and thalamus. In addition, small vacuolated globoid cells confined to the subgranular zone of the dentate gyrus were found in the third postnatal week, and larger vacuolar profiles, identified as neuronal vacuoles, were observed in layer V of the cortex after the fourth week. The spatial distribution and temporal onset of vacuolation appeared to be unrelated to those of activated microglia and astrocytes. Nitrotyrosine-positivity was found to reflect the distribution of vacuoles in the cortex. The specific histopathological features here reported, as well as the severity of neurological deficits observed in this murine model of copper deficiency, strongly suggest that some hallmarks of neurodegenerative disorders could be mediated by multifactorial pathogenetic mechanisms that include copper dysregulation.

  17. Altered responsiveness of BNST and amygdala neurons in trauma-induced anxiety.

    PubMed

    Rodríguez-Sierra, O E; Goswami, S; Turesson, H K; Pare, D

    2016-01-01

    A highly conserved network of brain structures regulates the expression of fear and anxiety in mammals. Many of these structures display abnormal activity levels in post-traumatic stress disorder (PTSD). However, some of them, like the bed nucleus of the stria terminalis (BNST) and amygdala, are comprised of several small sub-regions or nuclei that cannot be resolved with human neuroimaging techniques. Therefore, we used a well-characterized rat model of PTSD to compare neuronal properties in resilient vs PTSD-like rats using patch recordings obtained from different BNST and amygdala regions in vitro. In this model, a persistent state of extreme anxiety is induced in a subset of susceptible rats following predatory threat. Previous animal studies have revealed that the central amygdala (CeA) and BNST are differentially involved in the genesis of fear and anxiety-like states, respectively. Consistent with these earlier findings, we found that between resilient and PTSD-like rats were marked differences in the synaptic responsiveness of neurons in different sectors of BNST and CeA, but whose polarity was region specific. In light of prior data about the role of these regions, our results suggest that control of fear/anxiety expression is altered in PTSD-like rats such that the influence of CeA is minimized whereas that of BNST is enhanced. A model of the amygdalo-BNST interactions supporting the PTSD-like state is proposed. PMID:27434491

  18. Visual Responses of Neurons in Somatosensory Cortex of Hamsters with Experimentally Induced Retinal Projections to Somatosensory Thalamus

    NASA Astrophysics Data System (ADS)

    Metin, Christine; Frost, Douglas O.

    1989-01-01

    These experiments investigate the capacity of thalamic and cortical structures in a sensory system to process information of a modality normally associated with another system. Retinal ganglion cells in newborn Syrian hamsters were made to project permanently to the main thalamic somatosensory (ventrobasal) nucleus. When the animals were adults, single unit recordings were made in the somatosensory cortices, the principal targets of the ventrobasal nucleus. The somatosensory neurons responded to visual stimulation of distinct receptive fields, and their response properties resembled, in several characteristic features, those of normal visual cortical neurons. In the visual cortex of normal animals and the somatosensory cortex of operated animals, the same functional categories of neurons occurred in similar proportions, and the neurons' selectivity for the orientation or direction of movement of visual stimuli was comparable. These results suggest that thalamic nuclei or cortical areas at corresponding levels in the visual and somatosensory pathways perform similar transformations on their inputs.

  19. Characterization of prostanoid receptor-evoked responses in rat sensory neurones

    PubMed Central

    Smith, Jacqueline A M; Amagasu, Shanti M; Eglen, Richard M; Hunter, John C; Bley, Keith R

    1998-01-01

    Prostanoid receptor-mediated sensitization, or excitation, of sensory nerve fibres contributes to the generation of hyperalgesia. To characterize the prostanoid receptors present on sensory neurones, biochemical assays were performed on primary cultures of adult rat dorsal root ganglia (DRG) and the F-11 (embryonic rat DRG×neuroblastoma hybrid) cell line.In DRG cultures, the IP receptor agonists, cicaprost and carbaprostacyclin (cPGI2) stimulated cyclic AMP accumulation. Prostaglandin E2 (PGE2) also increased cyclic AMP levels, but to a lesser extent, while carbocyclic thromboxane A2 (cTxA2), PGD2 and PGF2α had negligible effects. The rank order of agonist potency was cicaprost >PGE2=BMY45778=cPGI2=PGI2. In the F-11 cells, the rank order of agonist potency for the stimulation of cyclic AMP accumulation was: cicaprost>iloprost=cPGI2=PGI2=BMY45778>PGE2=cTXA2. In DRG cultures, cicaprost induced significantly more accumulation of inositol phosphates than PGE2.To examine the effects of prostanoids on C-fibre activity, extracellular recordings of d.c. potentials from the rat isolated vagus nerve were made with the ‘grease-gap' technique. PGI2 (0.1 nM–10 μM) produced the largest depolarizations of the nerve. The rank order of agonist potency was: PGI2=cPGI2=PGE1>cTXA2>PGE2=PGD2=TXB2>PGF2α.Prior depolarization of nerves with either forskolin (10 μM) or phorbol dibutyrate (1 μM) alone significantly reduced the response to PGI2 (10 μM), while simultaneous application of both forskolin and phorbol dibutyrate attenuated PGI2 responses almost completely.Putative EP1 and/or TP receptor-selective antagonists had no effect on the responses to PGI2, cPGI2 or PGE2 in the three preparations studied.Collectively, these data are consistent with a positive coupling of IP receptors to both adenylyl cyclase and phospholipase C in sensory neurones. These findings suggest that IP receptors play a major role in the sensitization of rat sensory neurones. PMID:9647476

  20. Differential Tiam1/Rac1 activation in hippocampal and cortical neurons mediates differential spine shrinkage in response to oxygen/glucose deprivation

    PubMed Central

    Blanco-Suárez, Elena; Fiuza, Maria; Liu, Xun; Chakkarapani, Elavazhagan; Hanley, Jonathan G

    2014-01-01

    Distinct neuronal populations show differential sensitivity to global ischemia, with hippocampal CA1 neurons showing greater vulnerability compared to cortical neurons. The mechanisms that underlie differential vulnerability are unclear, and we hypothesize that intrinsic differences in neuronal cell biology are involved. Dendritic spine morphology changes in response to ischemic insults in vivo, but cell type-specific differences and the molecular mechanisms leading to such morphologic changes are unexplored. To directly compare changes in spine size in response to oxygen/glucose deprivation (OGD) in cortical and hippocampal neurons, we used separate and equivalent cultures of each cell type. We show that cortical neurons exhibit significantly greater spine shrinkage compared to hippocampal neurons. Rac1 is a Rho-family GTPase that regulates the actin cytoskeleton and is involved in spine dynamics. We show that Rac1 and the Rac guanine nucleotide exchange factor (GEF) Tiam1 are differentially activated by OGD in hippocampal and cortical neurons. Hippocampal neurons express more Tiam1 than cortical neurons, and reducing Tiam1 expression in hippocampal neurons by shRNA enhances OGD-induced spine shrinkage. Tiam1 knockdown also reduces hippocampal neuronal vulnerability to OGD. This work defines fundamental differences in signalling pathways that regulate spine morphology in distinct neuronal populations that may have a role in the differential vulnerability to ischemia. PMID:25248834

  1. Prenatal exposure to urban air nanoparticles in mice causes altered neuronal differentiation and depression-like responses.

    PubMed

    Davis, David A; Bortolato, Marco; Godar, Sean C; Sander, Thomas K; Iwata, Nahoko; Pakbin, Payam; Shih, Jean C; Berhane, Kiros; McConnell, Rob; Sioutas, Constantinos; Finch, Caleb E; Morgan, Todd E

    2013-01-01

    Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m(3)) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols.

  2. Characterization of lobula giant neurons responsive to visual stimuli that elicit escape behaviors in the crab Chasmagnathus.

    PubMed

    Medan, Violeta; Oliva, Damián; Tomsic, Daniel

    2007-10-01

    In the grapsid crab Chasmagnathus, a visual danger stimulus elicits a strong escape response that diminishes rapidly on stimulus repetition. This behavioral modification can persist for several days as a result of the formation of an associative memory. We have previously shown that a generic group of large motion-sensitive neurons from the lobula of the crab respond to visual stimuli and accurately reflect the escape performance. Additional evidence indicates that these neurons play a key role in visual memory and in the decision to initiate an escape. Although early studies recognized that the group of lobula giant (LG) neurons consisted of different classes of motion-sensitive cells, a distinction between these classes has been lacking. Here, we recorded in vivo the responses of individual LG neurons to a wide range of visual stimuli presented in different segments of the animal's visual field. Physiological characterizations were followed by intracellular dye injections, which permitted comparison of the functional and morphological features of each cell. All LG neurons consisted of large tangential arborizations in the lobula with axons projecting toward the midbrain. Functionally, these cells proved to be more sensitive to single objects than to flow field motion. Despite these commonalities, clear differences in morphology and physiology allowed us to identify four distinct classes of LG neurons. These results will permit analysis of the role of each neuronal type for visually guided behaviors and will allow us to address specific questions on the neuronal plasticity of LGs that underlie the well-recognized memory model of the crab.

  3. Post-spike hyperpolarization participates in the formation of auditory behavior-related response patterns of inferior collicular neurons in Hipposideros pratti.

    PubMed

    Li, Y-L; Fu, Z-Y; Yang, M-J; Wang, J; Peng, K; Yang, L-J; Tang, J; Chen, Q-C

    2015-03-19

    To probe the mechanism underlying the auditory behavior-related response patterns of inferior collicular neurons to constant frequency-frequency modulation (CF-FM) stimulus in Hipposideros pratti, we studied the role of post-spike hyperpolarization (PSH) in the formation of response patterns. Neurons obtained by in vivo extracellular (N=145) and intracellular (N=171) recordings could be consistently classified into single-on (SO) and double-on (DO) neurons. Using intracellular recording, we found that both SO and DO neurons have a PSH with different durations. Statistical analysis showed that most SO neurons had a longer PSH duration than DO neurons (p<0.01). These data suggested that the PSH directly participated in the formation of SO and DO neurons, and the PSH elicited by the CF component was the main synaptic mechanism underlying the SO and DO response patterns. The possible biological significance of these findings relevant to bat echolocation is discussed. PMID:25617651

  4. Background complexity affects response of a looming-sensitive neuron to object motion.

    PubMed

    Silva, Ana C; McMillan, Glyn A; Santos, Cristina P; Gray, John R

    2015-01-01

    An increasing number of studies show how stimulus complexity affects the responses of looming-sensitive neurons across multiple animal taxa. Locusts contain a well-described, descending motion-sensitive pathway that is preferentially looming sensitive. However, the lobula giant movement detector/descending contralateral movement detector (LGMD/DCMD) pathway responds to more than simple objects approaching at constant, predictable trajectories. In this study, we presented Locusta migratoria with a series of complex three-dimensional visual stimuli presented while simultaneously recording DCMD activity extracellularly. In addition to a frontal looming stimulus, we used a combination of compound trajectories (nonlooming transitioning to looming) presented at different velocities and onto a simple, scattered, or progressive flow field background. Regardless of stimulus background, DCMD responses to looming were characteristic and related to previously described effects of azimuthal approach angle and velocity of object expansion. However, increasing background complexity caused reduced firing rates, delayed peaks, shorter rise phases, and longer fall phases. DCMD responded to transitions to looming with a characteristic drop in a firing rate that was relatively invariant across most stimulus combinations and occurred regardless of stimulus background. Spike numbers were higher in the presence of the scattered background and reduced in the flow field background. We show that DCMD response time to a transition depends on unique expansion parameters of the moving stimulus irrespective of background complexity. Our results show how background complexity shapes DCMD responses to looming stimuli, which is explained within a behavioral context.

  5. Neuronal nitric oxide synthase is phosphorylated in response to insulin stimulation in skeletal muscle

    PubMed Central

    Hinchee-Rodriguez, Kathryn; Garg, Neha; Venkatakrishnan, Priya; Roman, Madeline G.; Adamo, Martin L.; Masters, Bettie Sue; Roman, Linda J.

    2013-01-01

    Type 2 Diabetes (T2DM) is the seventh leading cause of death in the United States, and is quickly becoming a global pandemic. T2DM results from reduced insulin sensitivity coupled with a relative failure of insulin secretion. Reduced insulin sensitivity has been associated with reduced nitric oxide synthase (NOS) activity and impaired glucose uptake in T2DM skeletal muscle. Upon insulin stimulation, NO synthesis increases in normal adult skeletal muscle, whereas no such increase is observed in T2DM adults. Endothelial NOS is activated by phosphorylation in the C-terminal tail in response to insulin. Neuronal NOS (nNOS), the primary NOS isoform in skeletal muscle, contains a homologous phosphorylation site, raising the possibility that nNOS, too, may undergo an activating phosphorylation event upon insulin treatment. Yet it remains unknown if or how nNOS is regulated by insulin in skeletal muscle. Data shown herein indicate that nNOS is phosphorylated in response to insulin in skeletal muscle and that this phosphorylation event occurs rapidly in C2C12 myotubes, resulting in increased NO production. In vivo phosphorylation of nNOS was also observed in response to insulin in mouse skeletal muscle. These results indicate, for the first time, that nNOS is phosphorylated in skeletal muscle in response to insulin and in association with increased NO production. PMID:23680665

  6. Neuronal nitric oxide synthase is phosphorylated in response to insulin stimulation in skeletal muscle.

    PubMed

    Hinchee-Rodriguez, Kathryn; Garg, Neha; Venkatakrishnan, Priya; Roman, Madeline G; Adamo, Martin L; Masters, Bettie Sue; Roman, Linda J

    2013-06-01

    Type 2 Diabetes (T2DM) is the seventh leading cause of death in the United States, and is quickly becoming a global pandemic. T2DM results from reduced insulin sensitivity coupled with a relative failure of insulin secretion. Reduced insulin sensitivity has been associated with reduced nitric oxide synthase (NOS) activity and impaired glucose uptake in T2DM skeletal muscle. Upon insulin stimulation, NO synthesis increases in normal adult skeletal muscle, whereas no such increase is observed in T2DM adults. Endothelial NOS is activated by phosphorylation in the C-terminal tail in response to insulin. Neuronal NOS (nNOS), the primary NOS isoform in skeletal muscle, contains a homologous phosphorylation site, raising the possibility that nNOS, too, may undergo an activating phosphorylation event upon insulin treatment. Yet it remains unknown if or how nNOS is regulated by insulin in skeletal muscle. Data shown herein indicate that nNOS is phosphorylated in response to insulin in skeletal muscle and that this phosphorylation event occurs rapidly in C2C12 myotubes, resulting in increased NO production. In vivo phosphorylation of nNOS was also observed in response to insulin in mouse skeletal muscle. These results indicate, for the first time, that nNOS is phosphorylated in skeletal muscle in response to insulin and in association with increased NO production. PMID:23680665

  7. Controlled noxious chemical stimulation: responses of rat trigeminal brainstem neurones to CO2 pulses applied to the nasal mucosa.

    PubMed

    Anton, F; Peppel, P; Euchner, I; Handwerker, H O

    1991-02-25

    The nasal mucosa of halothane-anesthetized rats was stimulated with defined CO2 pulses. Recordings were performed from single trigeminal brainstem neurons to characterize their responses to this controlled chemical irritation. All cells examined with this stimulus displayed graded discharges to increasing concentrations of CO2. Enhanced responses were obtained in a group of neurons when the duration of the interstimulus interval was increased. The application of chemical irritants, notably mustard oil or acetic acid induced vigorous ongoing discharges in all cells tested. The CO2 stimulation method described here thus provides an ideal model for the quantitative physiological and pharmacological examination of chemically induced nociception.

  8. Stimulus-response curves of a neuronal model for noisy subthreshold oscillations and related spike generation.

    PubMed

    Huber, Martin Tobias; Braun, Hans Albert

    2006-04-01

    We investigate the stimulus-dependent tuning properties of a noisy ionic conductance model for intrinsic subthreshold oscillations in membrane potential and associated spike generation. Upon depolarization by an applied current, the model exhibits subthreshold oscillatory activity with an occasional spike generation when oscillations reach the spike threshold. We consider how the amount of applied current, the noise intensity, variation of maximum conductance values, and scaling to different temperature ranges alter the responses of the model with respect to voltage traces, interspike intervals and their statistics, and the mean spike frequency curves. We demonstrate that subthreshold oscillatory neurons in the presence of noise can sensitively and also selectively be tuned by the stimulus-dependent variation of model parameters. PMID:16711858

  9. 5-HT1A receptor-responsive pedunculopontine tegmental neurons suppress REM sleep and respiratory motor activity.

    PubMed

    Grace, Kevin P; Liu, Hattie; Horner, Richard L

    2012-02-01

    Serotonin type 1A (5-HT(1A)) receptor-responsive neurons in the pedunculopontine tegmental nucleus (PPTn) become maximally active immediately before and during rapid eye movement (REM) sleep. A prevailing model of REM sleep generation indicates that activation of such neurons contributes significantly to the generation of REM sleep, and if correct then inactivation of such neurons ought to suppress REM sleep. We test this hypothesis using bilateral microperfusion of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 10 μm) into the PPTn; this tool has been shown to selectively silence REM sleep-active PPTn neurons while the activity of wake/REM sleep-active PPTn neurons is unaffected. Contrary to the prevailing model, bilateral microperfusion of 8-OH-DPAT into the PPTn (n = 23 rats) significantly increased REM sleep both as a percentage of the total recording time and sleep time, compared with both within-animal vehicle controls and between-animal time-controls. This increased REM sleep resulted from an increased frequency of REM sleep bouts but not their duration, indicating an effect on mechanisms of REM sleep initiation but not maintenance. Furthermore, an increased proportion of the REM sleep bouts stemmed from periods of low REM sleep drive quantified electrographically. Targeted suppression of 5-HT(1A) receptor-responsive PPTn neurons also increased respiratory rate and respiratory-related genioglossus activity, and increased the frequency and amplitude of the sporadic genioglossus activations occurring during REM sleep. These data indicate that 5-HT(1A) receptor-responsive PPTn neurons normally function to restrain REM sleep by elevating the drive threshold for REM sleep induction, and restrain the expression of respiratory rate and motor activities.

  10. TRF2 dysfunction elicits DNA damage responses associated with senescence in proliferating neural cells and differentiation of neurons.

    PubMed

    Zhang, Peisu; Furukawa, Katsutoshi; Opresko, Patricia L; Xu, Xiangru; Bohr, Vilhelm A; Mattson, Mark P

    2006-04-01

    Telomeres are specialized structures at the ends of chromosomes that consist of tandem repeats of the DNA sequence TTAGGG and several proteins that protect the DNA and regulate the plasticity of the telomeres. The telomere-associated protein TRF2 (telomeric repeat binding factor 2) is critical for the control of telomere structure and function; TRF2 dysfunction results in the exposure of the telomere ends and activation of ATM (ataxia telangiectasin mutated)-mediated DNA damage response. Recent findings suggest that telomere attrition can cause senescence or apoptosis of mitotic cells, but the function of telomeres in differentiated neurons is unknown. Here, we examined the impact of telomere dysfunction via TRF2 inhibition in neurons (primary embryonic hippocampal neurons) and mitotic neural cells (astrocytes and neuroblastoma cells). We demonstrate that telomere dysfunction induced by adenovirus-mediated expression of dominant-negative TRF2 (DN-TRF2) triggers a DNA damage response involving the formation of nuclear foci containing phosphorylated histone H2AX and activated ATM in each cell type. In mitotic neural cells DN-TRF2 induced activation of both p53 and p21 and senescence (as indicated by an up-regulation of beta-galactosidase). In contrast, in neurons DN-TRF2 increased p21, but neither p53 nor beta-galactosidase was induced. In addition, TRF2 inhibition enhanced the morphological, molecular and biophysical differentiation of hippocampal neurons. These findings demonstrate divergent molecular and physiological responses to telomere dysfunction in mitotic neural cells and neurons, indicate a role for TRF2 in regulating neuronal differentiation, and suggest a potential therapeutic application of inhibition of TRF2 function in the treatment of neural tumors. PMID:16539655

  11. Responses of primary vestibular neurons to galvanic vestibular stimulation (GVS) in the anaesthetised guinea pig.

    PubMed

    Kim, Juno; Curthoys, Ian S

    2004-09-30

    Previous studies in humans and animals which have shown that DC galvanic vestibular stimulation (GVS) induces horizontal and torsional eye movements have been interpreted as being due to a preferential activation of primary vestibular afferents innervating the horizontal semicircular canals and otoliths by GVS. The present study sought to determine in guinea pigs whether GVS does indeed selectively activate primary horizontal canal and otolith afferents. Constant-current GVS was passed between electrodes implanted in the tensor-tympani muscle of each middle ear or between electrodes on the skin over the mastoid. During this stimulation, responses from single primary vestibular neurons were recorded extracellularly by glass microelectrodes in Scarpa's ganglion. Afferents from all vestibular sensory regions were activated by both surface and tensor-tympani galvanic stimulation. Tensor tympani GVS was approximately 10 times more effective than surface GVS. At larger current intensities irregularly discharging afferents showed an asymmetrical response: cathodal stimulation resulted in a larger change in firing (increase) than anodal stimulation (decrease), whereas regularly discharging afferents responded symmetrically to the two polarities of GVS. Across all afferents tuned for different types of natural vestibular stimulation, neuronal sensitivity for GVS was found to increase with discharge variability (as indexed by CV*). Anterior canal afferents showed a slightly higher sensitivity than afferents from other vestibular sensory regions. Hence, the present study concluded that GVS activates primary vestibular afferents innervating all sensory regions in a uniform fashion. Therefore, the specific pattern of GVS-induced eye movements reported in previous studies are not due to differential sensitivity between different vestibular sensory regions, but are likely to reflect an involvement of central processing.

  12. The effects of energy balance, obesity-proneness and sex on the neuronal response to sweet taste.

    PubMed

    Cornier, Marc-Andre; Shott, Megan E; Thomas, Elizabeth A; Bechtell, Jamie L; Bessesen, Daniel H; Tregellas, Jason R; Frank, Guido K

    2015-02-01

    We have previously shown that propensity for weight gain, energy balance state and sex are important determinants of the neuronal response to visual food cues. It is not clear, though, whether these factors also impact the neuronal response to taste. The objective of this study was to examine the neuronal response to sweet taste during energy imbalance in men and women recruited to be obesity-prone (OP) or obesity-resistant (OR). OP (13 men and 12 women) and OR (12 men and 12 women) subjects were studied after 1 day of eucaloric, overfed and underfed conditions in a randomized crossover design. On each test day, fMRI was performed in the respective acute fed state while subjects received in random order 60 trials each of 1M sucrose solution (SU), or artificial saliva (AS) following a visual cue predicting the taste. The neuronal response to SU versus AS expectation was significantly greater in the amygdala, orbitofrontal cortex, putamen and insula in OR versus OP; SU receipt was not different between groups. There were also sex-based differences with men having greater neuronal response to SU versus AS receipt in the caudate than women. The results, however, were not impacted by the state of energy balance. In summary, response to expectation but not receipt of basic sweet taste was different in OR compared to OP, highlighting the importance of learning and conditioning in the propensity to gain weight. Response to sucrose taste receipt was stronger in men than women, raising questions about the effect of sex hormones on brain response to food. PMID:25447301

  13. Response properties of cochlear efferent neurons: monaural vs. binaural stimulation and the effects of noise.

    PubMed

    Liberman, M C

    1988-11-01

    1. Discharge properties of olivocochlear efferent neurons were measured in anesthetized cats. Previous studies of these neurons concentrated on monaural stimulation with tones and found sound-evoked discharge rates rarely exceeded 60 spikes/s (16, 20). In the present study, rates as high as 140 spikes/s were achieved by binaural stimulation and/or the addition of noise. Based on studies on the known effects of electrically stimulating the efferents such high rates of sound-evoked efferent activity probably have significant feedback effects on the auditory periphery. 2. Spontaneous discharge rate (SR) was weakly correlated with threshold among efferent neurons: those with SRs greater than 1 spikes/s were generally more sensitive than spontaneously inactive fibers. The discharge rate measured in the absence of acoustic stimulation was shown to be dependent on stimulation history: some units with zero SR became spontaneously active after several minutes of continuous noise stimulation. 3. For stimulation with monaural tones, efferent excitability varied with characteristic frequency (CF): units with CF less than 10 kHz tended to have lower thresholds, higher discharge rates, and shorter latencies than higher CF units. These differences could be minimized by the addition of broadband noise (see below). 4. When tones were presented to one ear at a time, most efferent units appeared monaural (91%), with roughly two-thirds excited by ipsilateral stimuli and one-third by contralateral stimuli. However, the effects of simultaneous stimulation of the two ears suggested that the great majority of efferent units have binaural inputs: the addition of opposite-ear noise or tones, which presented alone were not excitatory, typically enhanced the response to main-ear stimulation. This type of binaural facilitation was strongest among low-CF efferents when the opposite-ear stimuli were tones, and strongest among high-CF units when the opposite-ear stimulus was broadband noise. 5

  14. Reduction in host-finding behaviour in fungus-infected mosquitoes is correlated with reduction in olfactory receptor neuron responsiveness

    PubMed Central

    2011-01-01

    Background Chemical insecticides against mosquitoes are a major component of malaria control worldwide. Fungal entomopathogens formulated as biopesticides and applied as insecticide residual sprays could augment current control strategies and mitigate the evolution of resistance to chemical-based insecticides. Methods Anopheles stephensi mosquitoes were exposed to Beauveria bassiana or Metarhizium acridum fungal spores and sub-lethal effects of exposure to fungal infection were studied, especially the potential for reductions in feeding and host location behaviours related to olfaction. Electrophysiological techniques, such as electroantennogram, electropalpogram and single sensillum recording techniques were then employed to investigate how fungal exposure affected the olfactory responses in mosquitoes. Results Exposure to B. bassiana caused significant mortality and reduced the propensity of mosquitoes to respond and fly to a feeding stimulus. Exposure to M. acridum spores induced a similar decline in feeding propensity, albeit more slowly than B. bassiana exposure. Reduced host-seeking responses following fungal exposure corresponded to reduced olfactory neuron responsiveness in both antennal electroantennogram and maxillary palp electropalpogram recordings. Single cell recordings from neurons on the palps confirmed that fungal-exposed behavioural non-responders exhibited significantly impaired responsiveness of neurons tuned specifically to 1-octen-3-ol and to a lesser degree, to CO2. Conclusions Fungal infection reduces the responsiveness of mosquitoes to host odour cues, both behaviourally and neuronally. These pre-lethal effects are likely to synergize with fungal-induced mortality to further reduce the capacity of mosquito populations exposed to fungal biopesticides to transmit malaria. PMID:21812944

  15. Influences of sensory input from the limbs on feline corticospinal neurons during postural responses

    PubMed Central

    Karayannidou, A; Deliagina, T G; Tamarova, Z A; Sirota, M G; Zelenin, P V; Orlovsky, G N; Beloozerova, I N

    2008-01-01

    The dorsal-side-up body posture of standing quadrupeds is maintained by coordinated activity of all limbs. Somatosensory input from the limbs evokes postural responses when the supporting surface is perturbed. The aim of this study was to reveal the contribution of sensory inputs from individual limbs to the posture-related modulation of pyramidal tract neurons (PTNs) arising in the primary motor cortex. We recorded the activity of PTNs from the limb representation of motor cortex in the cat maintaining balance on a platform periodically tilted in the frontal plane. Each PTN was recorded during standing on four limbs, and when two or three limbs were lifted from the platform and thus did not signal its displacement to motor cortex. By comparing PTN responses to tilts in different tests we found that the amplitude and the phase of the response in the majority of them were determined primarily by the sensory input from the corresponding contralateral limb. In a portion of PTNs, this input originated from afferents of the peripheral receptive field. Sensory input from the ipsilateral limb, as well as input from limbs of the other girdle made a much smaller contribution to the PTN modulation. These results show that, during postural activity, a key role of PTNs is the feedback control of the corresponding contralateral limb and, to a lesser extent, the coordination of posture within a girdle and between the two girdles. PMID:17974591

  16. GABAergic neurons in the medial septal-diagonal band (MSDB) are important for acquisition of the classically conditioned eyeblink response

    PubMed Central

    Roland, J.J.; Janke, K.L.; Servatius, R.J; Pang, K.C.H.

    2013-01-01

    The medial septum and diagonal band of Broca (MSDB) influence hippocampal function through cholinergic, GABAergic and glutamatergic septohippocampal neurons. Nonselective damage of the MSDB or intraseptal scopolamine impairs classical conditioning of the eyeblink response (CCER). Scopolamine preferentially inhibits GABAergic MSDB neurons suggesting that these neurons may be an important modulator of delay CCER, a form of CCER not dependent on the hippocampus. The current study directly examined the importance of GABAergic MSDB neurons in acquisition of delay CCER. Adult male Sprague-Dawley rats received either a sham (PBS) or GABAergic MSDB lesion using GAT1-saporin (SAP). Rats were given two consecutive days of delay eyeblink conditioning with 100 conditioned stimulus (CS)-unconditioned stimulus (US) paired trials. Intraseptal GAT1-SAP impaired acquisition of CCER. The impairment was observed on the first day with sham and lesion groups reaching similar performance by the end of the second day. Our results provide evidence that GABAergic MSDB neurons are an important modulator of delay CCER. The pathways by which MSDB neurons influence the neural circuits necessary for delay CCER are discussed. PMID:24965560

  17. Sustained, neuron-specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging

    PubMed Central

    2013-01-01

    Background Increasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively active allele of IKK2 in principal forebrain neurons (IKK2nCA). Proinflammatory gene and growth factor expression, histopathology, microgliosis, astrogliosis, immune cell infiltration and spatial learning were assessed at different timepoints after persistent canonical IKK2/NF-κB activation. Results In contrast to other cell types and organ systems, chronic IKK2/NF-κB signalling in forebrain neurons of adult IKK2nCA animals did not cause a full-blown inflammatory response including infiltration of immune cells. Instead, we found a selective inflammatory response in the dentate gyrus characterized by astrogliosis, microgliosis and Tnf-α upregulation. Furthermore, downregulation of the neurotrophic factor Bdnf correlated with a selective and progressive atrophy of the dentate gyrus and a decline in hippocampus-dependent spatial learning. Neuronal degeneration was associated with increased Fluoro-jade staining, but lacked activation of apoptosis. Remarkably, neuronal loss could be

  18. A1 Noradrenergic Neurons Lesions Reduce Natriuresis and Hypertensive Responses to Hypernatremia in Rats

    PubMed Central

    da Silva, Elaine Fernanda; Freiria-Oliveira, André Henrique; Custódio, Carlos Henrique Xavier; Ghedini, Paulo César; Bataus, Luiz Artur Mendes; Colombari, Eduardo; de Castro, Carlos Henrique; Colugnati, Diego Basile; Rosa, Daniel Alves; Cravo, Sergio L. D.; Pedrino, Gustavo Rodrigues

    2013-01-01

    Noradrenergic neurons in the caudal ventrolateral medulla (CVLM; A1 group) contribute to cardiovascular regulation. The present study assessed whether specific lesions in the A1 group altered the cardiovascular responses that were evoked by hypertonic saline (HS) infusion in non-anesthetized rats. Male Wistar rats (280–340 g) received nanoinjections of antidopamine-β-hydroxylase-saporin (A1 lesion, 0.105 ng.nL−1) or free saporin (sham, 0.021 ng.nL−1) into their CVLMs. Two weeks later, the rats were anesthetized (2% halothane in O2) and their femoral artery and vein were catheterized and led to exit subcutaneously between the scapulae. On the following day, the animals were submitted to HS infusion (3 M NaCl, 1.8 ml • kg−1, b.wt., for longer than 1 min). In the sham-group (n = 8), HS induced a sustained pressor response (ΔMAP: 35±3.6 and 11±1.8 mmHg, for 10 and 90 min after HS infusion, respectively; P<0.05 vs. baseline). Ten min after HS infusion, the pressor responses of the anti-DβH-saporin-treated rats (n = 11)were significantly smaller(ΔMAP: 18±1.4 mmHg; P<0.05 vs. baseline and vs. sham group), and at 90 min, their blood pressures reached baseline values (2±1.6 mmHg). Compared to the sham group, the natriuresis that was induced by HS was reduced in the lesioned group 60 min after the challenge (196±5.5 mM vs. 262±7.6 mM, respectively; P<0.05). In addition, A1-lesioned rats excreted only 47% of their sodium 90 min after HS infusion, while sham animals excreted 80% of their sodium. Immunohistochemical analysis confirmed a substantial destruction of the A1 cell group in the CVLM of rats that had been nanoinjected withanti-DβH-saporin. These results suggest that medullary noradrenergic A1 neurons are involved in the excitatory neural pathway that regulates hypertensive and natriuretic responses to acute changes in the composition of body fluid. PMID:24039883

  19. Inhibitory responses in Aplysia pleural sensory neurons act to block excitability, transmitter release, and PKC Apl II activation.

    PubMed

    Dunn, Tyler W; Farah, Carole A; Sossin, Wayne S

    2012-01-01

    Expression of the 5-HT(1Apl(a)) receptor in Aplysia pleural sensory neurons inhibited 5-HT-mediated translocation of the novel PKC Apl II in sensory neurons and prevented PKC-dependent synaptic facilitation at sensory to motoneuron synapses (Nagakura et al. 2010). We now demonstrate that the ability of inhibitory receptors to block PKC activation is a general feature of inhibitory receptors and is found after expression of the 5-HT(1Apl(b)) receptor and with activation of endogenous dopamine and FMRFamide receptors in sensory neurons. Pleural sensory neurons are heterogeneous for their inhibitory response to endogenous transmitters, with dopamine being the most prevalent, followed by FMRFamide, and only a small number of neurons with inhibitory responses to 5-HT. The inhibitory response is dominant, reduces membrane excitability and synaptic efficacy, and can reverse 5-HT facilitation at both naive and depressed synapses. Indeed, dopamine can reverse PKC translocation during the continued application of 5-HT. Reversal of translocation can also be seen after translocation mediated by an analog of diacylglycerol, suggesting inhibition is not through blockade of diacylglycerol production. The effects of inhibition on PKC translocation can be rescued by phosphatidic acid, consistent with the inhibitory response involving a reduction or block of production of this lipid. However, phosphatidic acid could not recover PKC-dependent synaptic facilitation due to an additional inhibitory effect on the non-L-type calcium flux linked to synaptic transmission. In summary, we find a novel mechanism downstream of inhibitory receptors linked to inhibition of PKC activation in Aplysia sensory neurons. PMID:21994260

  20. Theory of input spike auto- and cross-correlations and their effect on the response of spiking neurons.

    PubMed

    Moreno-Bote, Rubén; Renart, Alfonso; Parga, Néstor

    2008-07-01

    Spike correlations between neurons are ubiquitous in the cortex, but their role is not understood. Here we describe the firing response of a leaky integrate-and-fire neuron (LIF) when it receives a temporarily correlated input generated by presynaptic correlated neuronal populations. Input correlations are characterized in terms of the firing rates, Fano factors, correlation coefficients, and correlation timescale of the neurons driving the target neuron. We show that the sum of the presynaptic spike trains cannot be well described by a Poisson process. In fact, the total input current has a nontrivial two-point correlation function described by two main parameters: the correlation timescale (how precise the input correlations are in time) and the correlation magnitude (how strong they are). Therefore, the total current generated by the input spike trains is not well described by a white noise gaussian process. Instead, we model the total current as a colored gaussian process with the same mean and two-point correlation function, leading to the formulation of the problem in terms of a Fokker-Planck equation. Solutions of the output firing rate are found in the limit of short and long correlation timescales. The solutions described here expand and improve on our previous results (Moreno, de la Rocha, Renart, & Parga, 2002) by presenting new analytical expressions for the output firing rate for general IF neurons, extending the validity of the results for arbitrarily large correlation magnitude, and by describing the differential effect of correlations on the mean-driven or noise-dominated firing regimes. Also the details of this novel formalism are given here for the first time. We employ numerical simulations to confirm the analytical solutions and study the firing response to sudden changes in the input correlations. We expect this formalism to be useful for the study of correlations in neuronal networks and their role in neural processing and information

  1. Relaxation oscillator-realized artificial electronic neurons, their responses, and noise

    NASA Astrophysics Data System (ADS)

    Lim, Hyungkwang; Ahn, Hyung-Woo; Kornijcuk, Vladimir; Kim, Guhyun; Seok, Jun Yeong; Kim, Inho; Hwang, Cheol Seong; Jeong, Doo Seok

    2016-05-01

    A proof-of-concept relaxation oscillator-based leaky integrate-and-fire (ROLIF) neuron circuit is realized by using an amorphous chalcogenide-based threshold switch and non-ideal operational amplifier (op-amp). The proposed ROLIF neuron offers biologically plausible features such as analog-type encoding, signal amplification, unidirectional synaptic transmission, and Poisson noise. The synaptic transmission between pre- and postsynaptic neurons is achieved through a passive synapse (simple resistor). The synaptic resistor coupled to the non-ideal op-amp realizes excitatory postsynaptic potential (EPSP) evolution that evokes postsynaptic neuron spiking. In an attempt to generalize our proposed model, we theoretically examine ROLIF neuron circuits adopting different non-ideal op-amps having different gains and slew rates. The simulation results indicate the importance of gain in postsynaptic neuron spiking, irrespective of the slew rate (as long as the rate exceeds a particular value), providing the basis for the ROLIF neuron circuit design. Eventually, the behavior of a postsynaptic neuron in connection to multiple presynaptic neurons via synapses is highlighted in terms of EPSP evolution amid simultaneously incident asynchronous presynaptic spikes, which in fact reveals an important role of the random noise in spatial integration.A proof-of-concept relaxation oscillator-based leaky integrate-and-fire (ROLIF) neuron circuit is realized by using an amorphous chalcogenide-based threshold switch and non-ideal operational amplifier (op-amp). The proposed ROLIF neuron offers biologically plausible features such as analog-type encoding, signal amplification, unidirectional synaptic transmission, and Poisson noise. The synaptic transmission between pre- and postsynaptic neurons is achieved through a passive synapse (simple resistor). The synaptic resistor coupled to the non-ideal op-amp realizes excitatory postsynaptic potential (EPSP) evolution that evokes postsynaptic

  2. Binaural neurons in the mustache bat's inferior colliculus. I. Responses of 60-kHz EI units to dichotic sound stimulation.

    PubMed

    Wenstrup, J J; Fuzessery, Z M; Pollak, G D

    1988-10-01

    1. Single-unit responses to closed-field, dichotic sound stimuli were obtained from EI neurons in the mustache bat's inferior colliculus; these neurons are excited by sound to the contralateral ear and inhibited by sound to the ipsilateral ear. All units were tuned to the 60-kHz component of the bat's sonar signal. The goal of the study was to describe basic features of the sensitivity to interaural intensity differences (IIDs) and sound intensity among an isofrequency population of EI neurons. The following paper describes how these features of IID sensitivity shape the response to free-field sounds. 2. Three features of IID sensitivity were considered. The inhibitory threshold (Figs. 1 and 2) described the IID at which inhibitory effects became pronounced; it was defined as the IID at which the excitatory response to contralateral sound was suppressed by 50%. Most units (68%) were inhibited at positive IID values, for which the ipsilateral (inhibitory) sound was more intense. The maximum inhibition (Figs. 1 and 3) described the strength of ipsilateral inhibition; it was defined as the percent that each unit was inhibited below its response to monaural stimulation of the contralateral ear. The majority of units (58%) were almost totally suppressed by a sufficiently intense ipsilateral sound. The IID range (Figs. 1 and 4) described the sharpness or slope of the IID cutoff; it was defined as the IID range over which the response changed from nearly unsuppressed (80% of maximum response) to near maximum suppression (20% of maximum response). Most units (71%) had IID ranges of less than or equal to 15 dB. 3. A significant correlation between the inhibitory threshold and the maximum inhibition (Fig. 5) among the sample of EI units suggests that some common neural mechanisms underlie these features of IID sensitivity. 4. The response of EI neurons to binaural stimuli was a function of sound intensity as well as IID (Fig. 7). In part, this resulted from intensity

  3. Excitability and responsiveness of rat barrel cortex neurons in the presence and absence of spontaneous synaptic activity in vivo

    PubMed Central

    Altwegg-Boussac, Tristan; Chavez, Mario; Mahon, Séverine; Charpier, Stéphane

    2014-01-01

    The amplitude and temporal dynamics of spontaneous synaptic activity in the cerebral cortex vary as a function of brain states. To directly assess the impact of different ongoing synaptic activities on neocortical function, we performed in vivo intracellular recordings from barrel cortex neurons in rats under two pharmacological conditions generating either oscillatory or tonic synaptic drive. Cortical neurons membrane excitability and firing responses were compared, in the same neurons, before and after complete suppression of background synaptic drive following systemic injection of a high dose of anaesthetic. Compared to the oscillatory state, the tonic pattern resulted in a more depolarized and less fluctuating membrane potential (Vm), a lower input resistance (Rm) and steeper relations of firing frequency versus injected current (F–I). Whatever their temporal dynamics, suppression of background synaptic activities increased mean Vm, without affecting Rm, and induced a rightward shift of F–I curves. Both types of synaptic drive generated a high variability in current-induced firing rate and patterns in cortical neurons, which was much reduced after removal of spontaneous activity. These findings suggest that oscillatory and tonic synaptic patterns differentially facilitate the input–output function of cortical neurons but result in a similar moment-to-moment variability in spike responses to incoming depolarizing inputs. PMID:24732430

  4. Responses of neurons in the medial temporal lobe during encoding and recognition of face-scene pairs.

    PubMed

    Viskontas, Indre V; Knowlton, Barbara J; Fried, Itzhak

    2016-09-01

    Associations between co-occurring stimuli are formed in the medial temporal lobe (MTL). Here, we recorded from 508 single and multi-units in the MTL while participants learned and retrieved associations between unfamiliar faces and unfamiliar scenes. Participant's memories for the face-scene pairs were later tested using cued recall and recognition tests. The results show that neurons in the parahippocampal cortex are most likely to respond with changes from baseline firing to these stimuli during both encoding and recognition, and this region showed the greatest proportion of cells showing differential responses depending on the phase of the task. Furthermore, we found that cells in the parahippocampal cortex that responded during both encoding and recognition were more likely to show decreases from baseline firing than cells that were only recruited during recognition, which were more likely to show increases in firing. Since all stimuli shown during recognition were familiar to the patients, these findings suggest that with familiarity, cell responses become more sharply tuned. No neurons in this region, however, were found to be affected by recombining face/scene pairs. Neurons in other MTL regions, particularly the hippocampus, were sensitive to stimulus configurations. Thus, the results support the idea that neurons in the parahippocampal cortex code for features of stimuli and neurons in the hippocampus are more likely to represent their specific configurations.

  5. Morphology, axonal projection pattern, and responses to optic nerve stimulation of thalamic neurons in the fire-bellied toad Bombina orientalis.

    PubMed

    Roth, Gerhard; Grunwald, Wolfgang; Dicke, Ursula

    2003-06-16

    Intracellular recording and biocytin labeling were carried out in the fire-bellied toad Bombina orientalis to study the morphology and axonal projections of thalamic (TH) neurons and their responses to electrical optic nerve stimulation. Labeled neurons (n = 142) were divided into the following groups: TH1 neurons projecting to the dorsal striatum; TH2 neurons projecting to the amygdala, nucleus accumbens, and septal nuclei; TH3 neurons projecting to the medial or dorsal pallium; TH4 neurons with projections ascending to the dorsal striatum or ventral striatum/amygdala and descending to the optic tectum, tegmentum, and rostral medulla oblongata; TH5 neurons with projections to the tegmentum, rostral medulla oblongata, prectectum, or tectum; and TH6 neurons projecting to the hypothalamus. TH1 neurons are found in the central, TH2 neurons in the anterior and central, TH3 neurons in the anterior dorsal nucleus, and TH4 and TH5 neurons in the posterior dorsal or ventral nucleus. Neurons with descending projections arborize in restricted parts of retinal afferents; neurons with ascending projections do not substantially arborize within retinal afferents. At electrical optic nerve stimulation, neurons in the ventral thalamus respond with excitation at latencies of 10.8 msec; one-third of them follow repetitive stimulation and possibly are monosynaptically driven. Neurons in the dorsal thalamus respond mostly with inhibition at latencies of 42.3 msec and are polysynaptically driven. This corroborates the view that neurons in the dorsal thalamus projecting to the telencephalon receive no substantial direct retinal input and that the thalamopallial pathway of amphibians is not homologous to the mammalian retinogeniculocortical pathway.

  6. The immunosuppressant FK506 elicits a neuronal heat shock response and protects against acrylamide neuropathy.

    PubMed

    Gold, Bruce G; Voda, Jan; Yu, Xiaolin; Gordon, Heidi

    2004-05-01

    Acrylamide (AC) is a known industrial neurotoxic chemical that has been recently found in carbohydrate-rich foods cooked at high temperatures. Repeated AC administration produces a pronounced neuropathy characterized by flaccid paralysis and ataxia and represents a well-established animal model of progressive axonal loss. AC also elicits prominent morphologic alterations (e.g., eccentrically placed nuclei, infolding of the nuclear membrane, accumulations of dense bodies, and clusters of smooth endoplasmic reticulum (SER) associated with numerous microtubules) in cerebellar Purkinje cells that may contribute to the pronounced ataxia in these animals. Here, we examined the neuroprotective action of FK506 (tacrolimus) in male and female rats given daily intraperitoneal injections of AC (30 mg/kg) for 4 weeks. Daily subcutaneous injections of FK506 (2 mg/kg/day) dramatically reduced the behavioral signs of neuropathy (i.e., paralysis and ataxia), markedly protected against axonal loss (by 82% and 73% in the tibial nerves of male and female rats, respectively), and reduced the pathologic changes in Purkinje cells. In a separate study, subcutaneous injections of FK506 (2 or 10 mg/kg) for 2 weeks markedly increased heat shock protein-70 (Hsp-70) immunostaining in sensory neurons, motor neurons, Purkinje cells, and other regions of the brain (in particular, the amygdala) from nonintoxicated and AC-intoxicated rats compared to controls. In contrast, AC-intoxicated animals not given FK506 demonstrated reduced Hsp-70 staining. Thus, the ability of FK506 to increase Hsp-70 expression may underlie its neuroprotective action. We suggest that compounds capable of eliciting a heat shock response may be useful for the treatment of human neuropathies.

  7. Directional responses of visual wulst neurones to grating and plaid patterns in the awake owl.

    PubMed

    Baron, Jerome; Pinto, Lucas; Dias, Marcelo Oliveira; Lima, Bruss; Neuenschwander, Sergio

    2007-10-01

    The avian retinothalamofugal pathway reaches the telencephalon in an area known as visual wulst. A close functional analogy between this area and the early visual cortex of mammals has been established in owls. The goal of the present study was to assess quantitatively the directional selectivity and motion integration capability of visual wulst neurones, aspects that have not been previously investigated. We recorded extracellularly from a total of 101 cells in awake burrowing owls. From this sample, 88% of the units exhibited modulated directional responses to sinusoidal gratings, with a mean direction index of 0.74 +/- 0.03 and tuning bandwidth of 28 +/- 1.16 degrees . A direction index higher than 0.5 was observed in 66% of the cells, thereby qualifying them as direction selective. Motion integration was tested with moving plaids, made by adding two sinusoidal gratings of different orientations. We found that 80% of direction-selective cells responded optimally to the motion direction of the component gratings, whereas none responded to the global motion of plaids, whose direction was intermediate to that of the gratings. The remaining 20% were unclassifiable. The strength of component motion selectivity rapidly increased over a 200 ms period following stimulus onset, maintaining a relatively sustained profile thereafter. Overall, our data suggest that, as in the mammalian primary visual cortex, the visual wulst neurones of owls signal the local orientated features of a moving object. How and where these potentially ambiguous signals are integrated in the owl brain might be important for understanding the mechanisms underlying global motion perception. PMID:17897399

  8. Thiopental sodium preserves the responsiveness to glutamate but not acetylcholine in rat primary cultured neurons exposed to hypoxia.

    PubMed

    Morita, Tomotaka; Shibuta, Satoshi; Kosaka, Jun; Fujino, Yuji

    2016-06-15

    Although many in vitro studies demonstrated that thiopental sodium (TPS) is a promising neuroprotective agent, clinical attempts to use TPS showed mainly unsatisfactory results. We investigated the neuroprotective effects of TPS against hypoxic insults (HI), and the responses of the neurons to l-glutamate and acetylcholine application. Neurons prepared from E17 Wistar rats were used after 2weeks in culture. The neurons were exposed to 12-h HI with or without TPS. HI-induced neurotoxicity was evaluated morphologically. Moreover, we investigated the dynamics of the free intracellular calcium ([Ca(2+)]i) in the surviving neurons after HI with or without TPS pretreatment following the application of neurotransmitters. TPS was neuroprotective against HI according to the morphological examinations (0.73±0.06 vs. 0.52±0.07, P=0.04). While the response to l-glutamate was maintained (0.89±0.08 vs. 1.02±0.09, P=0.60), the [Ca(2+)]i response to acetylcholine was notably impaired (0.59±0.02 vs. 0.94±0.04, P<0.01). Though TPS to cortical cultures was neuroprotective against HI morphologically, the [Ca(2+)]i response not to l-glutamate but to acetylcholine was impaired. This may partially explain the inconsistent results regarding the neuroprotective effects of TPS between experimental studies and clinical settings. PMID:27206889

  9. Neuronal activation induced BOLD and CBF responses upon acetazolamide administration in patients with steno-occlusive artery disease.

    PubMed

    Siero, Jeroen C W; Hartkamp, Nolan S; Donahue, Manus J; Harteveld, Anita A; Compter, Annette; Petersen, Esben T; Hendrikse, Jeroen

    2015-01-15

    Blood-oxygenation-level-dependent (BOLD) MRI is widely used for inferring neuronal activation and is becoming increasingly popular for assessing cerebrovascular reactivity (CVR) when combined with a vasoactive stimulus. The BOLD signal contains changes in cerebral blood flow (CBF) and thus information regarding neurovascular coupling and CVR. The BOLD signal, however, is also modulated by changes in cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2), as well as changes in the physiological baseline state. Here, we measured BOLD and CBF responses upon neuronal (visual) activation, before and after a vasodilatory challenge (acetazolamide, ACZ) in patients with vertebrobasilar steno-occlusive disease. After ACZ, the neuronal activation induced BOLD response was reduced or even negative (3 out of 8 subjects), whereas the CBF response remained similar. We show that BOLD alone cannot correctly assess the neuronal activation and underlying neurovascular coupling. The generally assumed positive relationship between BOLD and CBF responses may be severely compromised under changes in the physiological baseline state. Accompanying CBF measurements contain crucial information, and simulations suggest an altered flow-metabolism coupling in these patients.

  10. Inverted optical intrinsic response accompanied by decreased cerebral blood flow are related to both neuronal inhibition and excitation

    PubMed Central

    Ma, Zengguang; Cao, Pengjia; Sun, Pengcheng; Zhao, Linna; Li, Liming; Tong, Shanbao; Lu, Yiliang; Yan, Yan; Chen, Yao; Chai, Xinyu

    2016-01-01

    Negative hemodynamic response has been widely reported in blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging studies, however its origin is still controversial. Optical intrinsic signal (OIS) imaging can be used to study brain activity by simultaneously recording hemodynamic signals at different wavelengths with high spatial resolution. In this study, we found transcorneal electrical stimulation (TcES) could elicit both positive OIS response (POR) and negative OIS response (NOR) in cats’ visual cortex. We then investigated the property of this negative response to TcES and its relationship with cerebral blood flow (CBF) and neuronal activity. Results from laser speckle contrast imaging showed decreased CBF in the NOR region while increased CBF in the POR region. Both planar and laminar electrophysiological recordings in the middle (500–700 μm) cortical layers demonstrated that decreased and increased neuronal activities were coexisted in the NOR region. Furthermore, decreased neuronal activity was also detected in the deep cortical layers in the NOR region. This work provides evidence that the negative OIS together with the decreased CBF should be explained by mechanisms of both neuronal inhibition and excitation within middle cortical layers. Our results would be important for interpreting neurophysiological mechanisms underlying the negative BOLD signals. PMID:26860040

  11. Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons.

    PubMed

    Zhou, Chengwen; Sun, Hongyu; Klein, Peter M; Jensen, Frances E

    2015-01-01

    Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48-96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg(2+) sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain. PMID:26441533

  12. Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons

    PubMed Central

    Zhou, Chengwen; Sun, Hongyu; Klein, Peter M.; Jensen, Frances E.

    2015-01-01

    Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48–96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg2+ sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain. PMID:26441533

  13. Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain.

    PubMed

    Imai, Satoshi; Saeki, Mai; Yanase, Makoto; Horiuchi, Hiroshi; Abe, Minako; Narita, Michiko; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

    2011-10-26

    Neuropathic pain is the most difficult type of pain to control, and patients lose their motivation for the purposive pursuit with a decrease in their quality of life. Using a functional magnetic resonance imaging analysis, we demonstrated that blood oxygenation level-dependent signal intensity was increased in the ipsilateral nucleus accumbens (N.Acc.) following peripheral nerve injury. microRNAs are small, noncoding RNA molecules that direct the post-transcriptional suppression of gene expression, and play an important role in regulating synaptic plasticity. In this study, we found that sciatic nerve ligation induced a drastic decrease in the expression of miR200b and miR429 in N.Acc. neurons. The expression of DNA methyltransferase 3a (DNMT3a), which is the one of the predicted targets of miR200b/429, was significantly increased in the limbic forebrain including N.Acc. at 7 d after sciatic nerve ligation. Double-immunolabeling with antibodies specific to DNMT3a and NR1 showed that DNMT3a-immunoreactivity in the N.Acc. was located in NR1-labeled neurons, indicating that increased DNMT3a proteins were dominantly expressed in postsynaptic neurons in the N.Acc. area under a neuropathic pain-like state. The results of these analyses provide new insight into an epigenetic modification that is accompanied by a dramatic decrease in miR200b and miR429 along with the dysfunction of "mesolimbic motivation/valuation circuitry" under a neuropathic pain-like state. These phenomena may result in an increase in DNMT3a in neurons of the N.Acc. under neuropathic pain, which leads to the long-term transcription-silencing of several genes.

  14. Adult axolotls can regenerate original neuronal diversity in response to brain injury.

    PubMed

    Amamoto, Ryoji; Huerta, Violeta Gisselle Lopez; Takahashi, Emi; Dai, Guangping; Grant, Aaron K; Fu, Zhanyan; Arlotta, Paola

    2016-01-01

    The axolotl can regenerate multiple organs, including the brain. It remains, however, unclear whether neuronal diversity, intricate tissue architecture, and axonal connectivity can be regenerated; yet, this is critical for recovery of function and a central aim of cell replacement strategies in the mammalian central nervous system. Here, we demonstrate that, upon mechanical injury to the adult pallium, axolotls can regenerate several of the populations of neurons present before injury. Notably, regenerated neurons acquire functional electrophysiological traits and respond appropriately to afferent inputs. Despite the ability to regenerate specific, molecularly-defined neuronal subtypes, we also uncovered previously unappreciated limitations by showing that newborn neurons organize within altered tissue architecture and fail to re-establish the long-distance axonal tracts and circuit physiology present before injury. The data provide a direct demonstration that diverse, electrophysiologically functional neurons can be regenerated in axolotls, but challenge prior assumptions of functional brain repair in regenerative species. PMID:27156560

  15. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-01

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. PMID:27574304

  16. Modulatory Effects of Sex Steroids Progesterone and Estradiol on Odorant Evoked Responses in Olfactory Receptor Neurons

    PubMed Central

    Scholz, Paul; Mohrhardt, Julia; Gisselmann, Günter; Hatt, Hanns

    2016-01-01

    The influence of the sex steroid hormones progesterone and estradiol on physiology and behavior during menstrual cycles and pregnancy is well known. Several studies indicate that olfactory performance changes with cyclically fluctuating steroid hormone levels in females. Knowledge of the exact mechanisms behind how female sex steroids modulate olfactory signaling is limited. A number of different known genomic and non-genomic actions that are mediated by progesterone and estradiol via interactions with different receptors may be responsible for this modulation. Next generation sequencing-based RNA-Seq transcriptome data from the murine olfactory epithelium (OE) and olfactory receptor neurons (ORNs) revealed the expression of several membrane progestin receptors and the estradiol receptor Gpr30. These receptors are known to mediate rapid non-genomic effects through interactions with G proteins. RT-PCR and immunohistochemical staining results provide evidence for progestin and estradiol receptors in the ORNs. These data support the hypothesis that steroid hormones are capable of modulating the odorant-evoked activity of ORNs. Here, we validated this hypothesis through the investigation of steroid hormone effects by submerged electro-olfactogram and whole cell patch-clamp recordings of ORNs. For the first time, we demonstrate that the sex steroid hormones progesterone and estradiol decrease odorant-evoked signals in the OE and ORNs of mice at low nanomolar concentrations. Thus, both of these sex steroids can rapidly modulate the odor responsiveness of ORNs through membrane progestin receptors and the estradiol receptor Gpr30. PMID:27494699

  17. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-01

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'.

  18. Possible neuronal refractory or recovery artifacts associated with recording the mismatch negativity response.

    PubMed

    Walker, L J; Carpenter, M; Downs, C R; Cranford, J L; Stuart, A; Pravica, D

    2001-01-01

    The mismatch negativity (MMN) is an event-related potential that involves a negative voltage shift of baseline electroencephalographic (EEG) activity in the approximate latency window of the N1 and P2 cortical potentials in response to new or novel sounds. The MMN is present at birth and has been hypothesized to serve as an automatic preconscious detector of changes in the auditory environment. Research paradigms used to extract the MMN response from EEG activity have a potential problem related to neuronal refractoriness or recovery. Both N1 and P2 are known to increase in amplitude with longer interstimulus intervals (ISIs). The MMN extraction procedures involve mathematical subtraction of waveforms elicited by standard sounds (with short ISIs) from those recorded to rare deviant sounds (with longer ISIs). Any ISI-dependent amplitude changes in N1 and/or P2 could therefore alter the morphology of the resulting difference wave and lead to misinterpretation of the nature of the underlying MMN generators. We tested 12 young females and found that the MMN can be influenced by ISI-dependent refractory effects that may modify the waveform morphology. This has important clinical implications since the MMN is being investigated as an assessment tool. PMID:11500009

  19. The amygdala modulates neuronal activation in the hippocampus in response to spatial novelty.

    PubMed

    Sheth, Archana; Berretta, Sabina; Lange, Nicholas; Eichenbaum, Howard

    2008-01-01

    Emerging evidence indicates that the amygdala and the hippocampus play an important role in the pathophysiology of major psychotic disorders. Consistent with this evidence, and with data indicating amygdala modulation of hippocampal activity, animal model investigations have shown that a disruption of amygdala activity induces neurochemical changes in the hippocampus that are similar to those detected in subjects with schizophrenia. With the present study, we used induction of the immediate early gene Fos, to test the hypothesis that the amygdala may affect neuronal activation of the hippocampus in response to different spatial environments (familiar, modified, and novel). Exploratory and anxiety related behaviors were also assessed. In vehicle-treated rats, exposure to a modified version of the familiar environment was associated with an increase of numerical densities of Fos-immunoreactive nuclei in sectors CA1 and CA2, while exposure to a completely novel environment was associated with an increase in sectors CA1, CA4, and DG, compared with the familiar environment. Pharmacological disruption of amygdala activity resulted in a failure to increase Fos induction in the hippocampus in response to these environments. Exploratory behavior in response to the different environments was not altered by manipulation of amygdala activity. These findings support the idea that the amygdala modulates spatial information processing in the hippocampus and may affect encoding of specific environmental features, while complex behavioral responses to environment may be the result of broader neural circuits. These findings also raise the possibility that amygdala abnormalities may contribute to impairments in cognitive information processing in subjects with major psychoses.

  20. Response surface methodology for the modelling of 85Sr adsorption on zeolite 3A and pumice.

    PubMed

    Ciçek, Ekrem; Cojocaru, Corneliu; Zakrzewska-Trznadel, Grazyna; Harasimowicz, Marian; Miskiewicz, Agnieszka

    2012-01-01

    The adsorption of 85Sr from aqueous solutions on to zeolite 3A and three types of pumice materials (i.e. Kayseri, Isparta and Nevsehir) was investigated in this study. Experiments with radioactive 85Sr were performed to test the sorption ability of the sorbents to remove this radioisotope from liquid radioactive wastes. The influence of sorbent dosage and initial activity of feed solution on the decontamination factor were analysed and optimized by means of response surface methodology. The parameters of the experiments, namely temperature, pH, time, stirring efficiency, were selected in preliminary tests. The experimental results showed that the most efficient pumice sorbent for 85Sr is Isparta, for which a maximal decontamination factor of 76.92 was obtained by using the sorbent dosage of 0.5% w/v. However, the commercial zeolite 3A was 2.71-fold more efficient than Isparta pumice for decontamination of strontium radioactive solutions. Isparta pumice is a low-cost natural sorbent, and its ability to effectively bind strontium radioisotope from water solutions suggests that this material has further applications for radioactive waste treatment.

  1. Relaxation oscillator-realized artificial electronic neurons, their responses, and noise.

    PubMed

    Lim, Hyungkwang; Ahn, Hyung-Woo; Kornijcuk, Vladimir; Kim, Guhyun; Seok, Jun Yeong; Kim, Inho; Hwang, Cheol Seong; Jeong, Doo Seok

    2016-05-14

    A proof-of-concept relaxation oscillator-based leaky integrate-and-fire (ROLIF) neuron circuit is realized by using an amorphous chalcogenide-based threshold switch and non-ideal operational amplifier (op-amp). The proposed ROLIF neuron offers biologically plausible features such as analog-type encoding, signal amplification, unidirectional synaptic transmission, and Poisson noise. The synaptic transmission between pre- and postsynaptic neurons is achieved through a passive synapse (simple resistor). The synaptic resistor coupled to the non-ideal op-amp realizes excitatory postsynaptic potential (EPSP) evolution that evokes postsynaptic neuron spiking. In an attempt to generalize our proposed model, we theoretically examine ROLIF neuron circuits adopting different non-ideal op-amps having different gains and slew rates. The simulation results indicate the importance of gain in postsynaptic neuron spiking, irrespective of the slew rate (as long as the rate exceeds a particular value), providing the basis for the ROLIF neuron circuit design. Eventually, the behavior of a postsynaptic neuron in connection to multiple presynaptic neurons via synapses is highlighted in terms of EPSP evolution amid simultaneously incident asynchronous presynaptic spikes, which in fact reveals an important role of the random noise in spatial integration. PMID:27103542

  2. Responses of single corticospinal neurons to intracortical stimulation of primary motor and premotor cortex in the anesthetized macaque monkey.

    PubMed

    Maier, Marc A; Kirkwood, Peter A; Brochier, Thomas; Lemon, Roger N

    2013-06-01

    The responses of individual primate corticospinal neurons to localized electrical stimulation of primary motor (M1) and of ventral premotor cortex (area F5) are poorly documented. To rectify this and to study interactions between responses from these areas, we recorded corticospinal axons, identified by pyramidal tract stimulation, in the cervical spinal cord of three chloralose-anesthetized macaque monkeys. Single stimuli (≤400 μA) were delivered to the hand area of M1 or F5 through intracortical microwire arrays. Only 14/112 (13%) axons showed responses to M1 stimuli that indicated direct intracortical activation of corticospinal neurons (D-responses); no D-responses were seen from F5. In contrast, 62 axons (55%) exhibited consistent later responses to M1 stimulation, corresponding to indirect activation (I-responses), showing that single-pulse intracortical stimulation of motor areas can result in trans-synaptic activation of a high proportion of the corticospinal output. A combined latency histogram of all axon responses was nonperiodic, clearly different from the periodic surface-recorded corticospinal volleys. This was readily explained by correcting for conduction velocities of individual axons. D-responding axons, taken as originating in neurons close to the M1 stimulating electrodes, showed more I-responses from M1 than those without a D-response, and 8/10 of these axons also responded to F5 stimulation. Altogether, 33% of tested axons responded to F5 stimulation, most of which also showed I-responses from M1. These excitatory effects are in keeping with facilitation of hand muscles evoked from F5 being relayed via M1. This was further demonstrated by facilitation of test responses from M1 by conditioning F5 stimuli. PMID:23536718

  3. Face inversion decreased information about facial identity and expression in face-responsive neurons in macaque area TE.

    PubMed

    Sugase-Miyamoto, Yasuko; Matsumoto, Narihisa; Ohyama, Kaoru; Kawano, Kenji

    2014-09-10

    To investigate the effect of face inversion and thatcherization (eye inversion) on temporal processing stages of facial information, single neuron activities in the temporal cortex (area TE) of two rhesus monkeys were recorded. Test stimuli were colored pictures of monkey faces (four with four different expressions), human faces (three with four different expressions), and geometric shapes. Modifications were made in each face-picture, and its four variations were used as stimuli: upright original, inverted original, upright thatcherized, and inverted thatcherized faces. A total of 119 neurons responded to at least one of the upright original facial stimuli. A majority of the neurons (71%) showed activity modulations depending on upright and inverted presentations, and a lesser number of neurons (13%) showed activity modulations depending on original and thatcherized face conditions. In the case of face inversion, information about the fine category (facial identity and expression) decreased, whereas information about the global category (monkey vs human vs shape) was retained for both the original and thatcherized faces. Principal component analysis on the neuronal population responses revealed that the global categorization occurred regardless of the face inversion and that the inverted faces were represented near the upright faces in the principal component analysis space. By contrast, the face inversion decreased the ability to represent human facial identity and monkey facial expression. Thus, the neuronal population represented inverted faces as faces but failed to represent the identity and expression of the inverted faces, indicating that the neuronal representation in area TE cause the perceptual effect of face inversion. PMID:25209284

  4. Spatiotemporal Changes of Neuronal Responses in the Primary Somatosensory Cortex to Noxious Tail Stimulation in Awake and Pentobarbital-Anesthetized Rats.

    PubMed

    Kuo, Chung-Chih; Lee, Jye-Chang; Chiou, Ruei-Jen; Tsai, Meng-Li; Yen, Chen-Tung

    2015-10-31

    Primary somatosensory cortex (SI) is a key area in the processing of nociceptor inputs to our consciousness. To clarify the columnar and laminar organization of SI for pain processing, we compared spatiotemporal changes in neuronal activities of the primary sensorimotor cortex (SmI) of the rat in response to noxious laser heat stimulation applied to the mid-tail. Longitudinal and vertical array microelectrodes were chronically implanted in the cerebral cortex. Evoked neuronal activities, including intracortical local field potentials (LFP) and ensemble single-unit activity (SU) around SmI were simultaneously recorded. The effect of pentobarbital on the neuronal responses was evaluated in comparison with the neuronal responses in conscious animals to explore the potential substrate of nociceptive processing in the conscious state. The results from the experiment with longitudinal microelectrode arrays indicated that noxious stimulation induced a neuronal response which was spread widely around the SmI of the conscious rat, and the range of neuronal responses was limited to the tail region of the SmI under anesthesia. The results from the experiment with vertical microelectrode arrays showed the universal neuronal responses through all cortical layers of the SmI in conscious rats, and sodium pentobarbital suppressed these neuronal responses in the supragranular layers significantly relative to the deeper layers and basal activity. These results imply that a wider range of cortical activation, both in the horizontal or vertical dimension, might be important for nociceptive processing in the conscious state. PMID:26387657

  5. Melatonin elicits protein kinase C-mediated calcium response in immortalized GT1-7 GnRH neurons.

    PubMed

    Kelestimur, Haluk; Ozcan, Mete; Kacar, Emine; Alcin, Ergul; Yılmaz, Bayram; Ayar, Ahmet

    2012-01-30

    Melatonin is suggested to have effects on hypothalamic-pituitary-gonadal (HPG) axis. The pulsatile pattern of GnRH release, which results in the intermittent release of gonadotropic hormones from the pituitary, has a critical importance for reproductive function but the factors responsible from this release pattern are not known. Calcium is a second messenger involved in hormone release. Therefore, investigation of the effects of melatonin on intracellular free calcium levels ([Ca(2+)](i)) would provide critical information on hormone release in immortalized GnRH neurons. The pattern of melatonin-induced intracellular calcium signaling was investigated by fluorescence calcium imaging using the immortalized GnRH-secreting GT1-7 hypothalamic neurons. Melatonin caused a significant increase in [Ca(2+)](i,) which was greatly blocked by luzindole, a melatonin antagonist, or attenuated by pre-treatment with protein kinase C inhibitor. This study suggests that melatonin seems to have a direct effect on GnRH neurons.

  6. Heterogeneous responses of nucleus incertus neurons to corticotrophin-releasing factor and coherent activity with hippocampal theta rhythm in the rat

    PubMed Central

    Ma, Sherie; Blasiak, Anna; Olucha-Bordonau, Francisco E; Verberne, Anthony J M; Gundlach, Andrew L

    2013-01-01

    The nucleus incertus (NI) of the rat hindbrain is a putative node in the ascending control of the septohippocampal system and hippocampal theta rhythm and is stress and arousal responsive. NI contains GABA neurons that express multiple neuropeptides, including relaxin-3 (RLN3) and neuropeptide receptors, including corticotrophin-releasing factor receptor-1 (CRF-R1), but the precise anatomical and physiological characteristics of NI neurons are unclear. Therefore, we examined the firing properties of NI neurons and their responses to CRF, the correlation of these responses with occurrence of relaxin-3, and NI neuron morphology in the rat. Most NI neurons excited by intracerebroventricular CRF infusion were RLN3-positive (9 of 10), whereas all inhibited cells were RLN3-negative (8 of 8). The spontaneous firing of RLN3 (n= 6) but not non-RLN3 neurons (n= 6) was strongly modulated and phase-locked with the initial ascending phase of hippocampal theta oscillations. In brain slices, the majority of recorded NI neurons (15 of 19) displayed excitatory responses to CRF, which uniformly increased action potential frequency and membrane potential depolarization in the presence of tetrodotoxin, indicating a direct, postsynaptic action of CRF on NI neurons. This excitation was associated with reduction in the slow component of afterhyperpolarization and a strong depolarization. Quantitative analysis in naïve rats of validated CRF-R1, RLN3 and neuronal nuclear antigen (NeuN) immunoreactivity revealed 52% of NI neurons as CRF-R1 positive, of which 53% were RLN3 positive, while 48% of NI neurons lacked CRF-R1 and RLN3. All RLN3 neurons expressed CRF-R1. CRF neurons that projected to the NI were identified in lateral preoptic hypothalamus, but not in paraventricular hypothalamus, bed nucleus of stria terminalis or central amygdala. Our findings suggest NI is an important site for CRF modulation of hippocampal theta rhythm via effects on GABA/RLN3 transmission. PMID:23671163

  7. Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses.

    PubMed

    Klein, A H; Joe, C L; Davoodi, A; Takechi, K; Carstens, M I; Carstens, E

    2014-06-20

    Eugenol and carvacrol from clove and oregano, respectively, are agonists of the warmth-sensitive transient receptor potential channel TRPV3 and the irritant-sensitive transient receptor potential ankyrin (TRPA)-1. Eugenol and carvacrol induce oral irritation that rapidly desensitizes, accompanied by brief enhancement of innocuous warmth and heat pain in humans. We presently investigated if eugenol and carvacrol activate nociceptive primary afferent and higher order trigeminal neurons and enhance their heat-evoked responses, using calcium imaging of cultured trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, and in vivo single-unit recordings in trigeminal subnucleus caudalis (Vc) of rats. Eugenol and carvacrol activated 20-30% of TG and 7-20% of DRG cells, the majority of which additionally responded to menthol, mustard oil and/or capsaicin. TG cell responses to innocuous (39°) and noxious (42 °C) heating were enhanced by eugenol and carvacrol. We identified dorsomedial Vc neurons responsive to noxious heating of the tongue in pentobarbital-anesthetized rats. Eugenol and carvacrol dose-dependently elicited desensitizing responses in 55% and 73% of heat-sensitive units, respectively. Responses to noxious heat were briefly enhanced by eugenol and carvacrol. Many eugenol- and carvacrol-responsive units also responded to menthol, cinnamaldehyde and capsaicin. These data support a peripheral site for eugenol and carvacrol to enhance warmth- and noxious heat-evoked responses of trigeminal neurons, and are consistent with the observation that these agonists briefly enhance warmth and heat pain on the human tongue. PMID:24759772

  8. Noise-enhanced nonlinear response and the role of modular structure for signal detection in neuronal networks.

    PubMed

    Lopes, M A; Lee, K-E; Goltsev, A V; Mendes, J F F

    2014-11-01

    We show that sensory noise can enhance the nonlinear response of neuronal networks, and when delivered together with a weak signal, it improves the signal detection by the network. We reveal this phenomenon in neuronal networks that are in a dynamical state preceding a saddle-node bifurcation corresponding to the appearance of sustained network oscillations. In this state, even a weak subthreshold pulse can evoke a large-amplitude oscillation of neuronal activity. The signal-to-noise ratio reaches a maximum at an optimum level of sensory noise, manifesting stochastic resonance (SR) at the population level. We demonstrate SR by use of simulations and numerical integration of rate equations in a cortical model. Using this model, we mimic the experiments of Gluckman et al. [Phys. Rev. Lett. 77, 4098 (1996)PRLTAO0031-900710.1103/PhysRevLett.77.4098] that have given evidence of SR in mammalian brain. We also study neuronal networks in which neurons are grouped in modules and every module works in the regime of SR. We find that even a few modules can strongly enhance the reliability of signal detection in comparison with the case when a modular organization is absent.

  9. Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity.

    PubMed

    Chen, W; Liu, P; Volkow, N D; Pan, Y; Du, C

    2016-10-01

    Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced changes in cerebral blood flow (CBF) reflect neuronal activation or its vasoactive effects. Here we assessed the effects of acute cocaine on both resting-state and stimulation responses to investigate cocaine's effects on neurovascular coupling and to differentiate its effects on neuronal activity from its vasoactive actions. We concurrently measured cortical field potentials via thinned-skull electroencephalography recordings and CBF with laser Doppler flowmetry in the rat's somatosensory cortex for both resting state and forepaw stimulation before and following cocaine administration (1 mg kg(-1), intravenously). Results show both resting-state field potentials and CBF were depressed after cocaine administration (19.8±4.7% and 52.1±13.4%, respectively) and these changes were strongly correlated with each other (r=0.81, P<0.001), indicating that cocaine did not affect neurovascular coupling at rest and that the reduction in resting CBF reflected reduction in synchronized spontaneous neuronal activity rather than vasoconstriction. In contrast, the forepaw stimulation-evoked neuronal activity was not changed by cocaine (P=0.244), whereas the CBF to the stimulation was reduced 49.9±2.6% (P=0.028) gradually recovering ∼20 min after cocaine injection, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling by cocaine during stimulation but not during rest indicates that distinct processes might underlie neurovascular regulation for both stimulation and spontaneous activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting functional MRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine

  10. Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity

    PubMed Central

    Chen, Wei; Liu, Peng; Volkow, Nora D.; Pan, Yingtian; Du, Congwu

    2016-01-01

    Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced changes in cerebral blood flow (CBF) reflect neuronal activation or its vasoactive effects. Here we assessed the effects of acute cocaine on both resting-state and stimulation responses to investigate cocaine’s effects on neurovascular coupling and to differentiate its effects on neuronal activity from its vasoactive actions. We concurrently measured cortical field potentials via thinned skull EEG recordings and CBF with laser Doppler flowmetry in the rat’s somatosensory cortex for both resting state and forepaw stimulation prior to and following cocaine administration (1mg/kg, i.v.). Results show both resting-state field potentials and CBF were depressed after cocaine administration (19.8±4.7% and 52.1±13.4%, respectively) and these changes were strongly correlated with each other (r=0.81, p<0.001) indicating that cocaine did not affect neurovascular coupling at rest and that the reduction in resting CBF reflected reduction in synchronized spontaneous neuronal activity rather than vasoconstriction. In contrast, the forepaw-stimulation-evoked neuronal activity was not changed by cocaine (p=0.244) whereas the CBF to the stimulation was reduced 49.9±2.6% (p=0.028) gradually recovering ~20min post cocaine injection, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling by cocaine during stimulation but not during rest indicates that distinct processes might underlie regulation of neurovascular coupling for spontaneous than for stimulation-induced activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting fMRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine’s neurotoxicity particularly for

  11. The cellular and Genomic response of rat dopaminergic neurons (N27) to coated nanosilver

    EPA Science Inventory

    This study examined if nanosilver (nanoAg) of different sizes and coatings were differentially toxic to oxidative stress-sensitive neurons. N27 rat dopaminergic neurons were exposed (0.5-5ppm) to a set of nanoAg of different sizes (10nm, 75nm) and coatings (PVP, citrate) and thei...

  12. Effect of protons on the mechanical response of rat muscle nociceptive fibers and neurons in vitro.

    PubMed

    Hotta, Norio; Kubo, Asako; Mizumura, Kazue

    2015-03-01

    Strong exercise makes muscle acidic, and painful. The stimulus that activates muscle nociceptors in such instance may be protons. Reportedly, however, not many afferents are excited by protons alone. We, therefore, posited that protons sensitize muscular nociceptors to mechanical stimuli. We examined effects of protons on mechanical sensitivity of muscle nociceptors by single-fiber recording from rat muscle-nerve preparations in vitro and by whole cell patch-clamp recording of mechanically activated (MA) currents from cultured rat dorsal root ganglion neurons. We recorded 38 Aδ- and C-fibers. Their response magnitude was increased by both pH 6.2 and pH 6.8; in addition the mechanical threshold was lowered by pH 6.2. Decrease in the threshold by pH6.2 was also observed in MA currents. Presently observed sensitization by protons could be involved in several types of ischemic muscle pain, and may also be involved in cardiovascular and respiratory controls during exercise.

  13. TGFβ induces GDNF responsiveness in neurons by recruitment of GFRα1 to the plasma membrane

    PubMed Central

    Peterziel, H.; Unsicker, K.; Krieglstein, K.

    2002-01-01

    We have previously shown that the neurotrophic effect of glial cell line–derived neurotrophic factor (GDNF) in vitro and in vivo requires the presence of transforming growth factor (TGF)β. Using primary neurons (chick E8 ciliary) we show that the combination of GDNF plus TGFβ promotes survival, whereas the single factors do not. This cooperative effect is inhibited by blocking the extracellular signal-regulated kinase (ERK)/MAPK pathway, but not by interfering with the PI3 kinase signaling cascade. Although there is no functional GDNF signaling in the absence of TGFβ, pretreatment with TGFβ confers GDNF responsiveness to the cells. This is not due to upregulation of GDNF receptors mRNA and protein, but to TGFβ-induced recruitment of the glycosyl-phosphatidylinositol-anchored GDNF receptor (GFR)α1 to the plasma membrane. This is supported by the fact that GDNF in the presence of a soluble GFRα1 can promote survival in the absence of TGFβ. Our data suggest that TGFβ is involved in GFRα1 membrane translocation, thereby permitting GDNF signaling and neurotrophic effects. PMID:12370242

  14. Intermittent cortical stimulation evokes sensitization to cocaine and enduring changes in matrix and striosome neuron responsiveness.

    PubMed

    Canales, Juan J

    2005-07-01

    Both the behavioral sensitization syndrome and the changes in the responsiveness of striatal neurons evoked by chronic cocaine exposure may be linked to enhanced neocortical activity, yet a direct demonstration of the effects of cortical stimulation on these parameters is lacking. We have found that repeated stimulation of the rat prelimbic cortex with picrotoxin (0.25 microg/0.25 microl, five injections on alternate days followed by 7-day withdrawal) contributed to increase c-Fos protein expression in the striosomes of the dorsolateral striatum, while producing the opposite effect in the matrix compartment, after a single exposure to cocaine (25 mg/kg). Moreover, rats exposed to cortical stimulation showed decreased locomotor activation but enhanced stereotypy following acute cocaine treatment. Thus, pulsatile stimulation of the prelimbic cortex facilitated modifications in striatal activity typically produced by chronic cocaine treatment and sensitized drug-naive animals to acute cocaine challenge. These results suggest that enhanced activation of the prelimbic cortex may contribute to the long-term adaptations induced by cocaine on neural activity and behavior.

  15. Dynamic modeling of neuronal responses in fMRI using cubature Kalman filtering.

    PubMed

    Havlicek, Martin; Friston, Karl J; Jan, Jiri; Brazdil, Milan; Calhoun, Vince D

    2011-06-15

    This paper presents a new approach to inverting (fitting) models of coupled dynamical systems based on state-of-the-art (cubature) Kalman filtering. Crucially, this inversion furnishes posterior estimates of both the hidden states and parameters of a system, including any unknown exogenous input. Because the underlying generative model is formulated in continuous time (with a discrete observation process) it can be applied to a wide variety of models specified with either ordinary or stochastic differential equations. These are an important class of models that are particularly appropriate for biological time-series, where the underlying system is specified in terms of kinetics or dynamics (i.e., dynamic causal models). We provide comparative evaluations with generalized Bayesian filtering (dynamic expectation maximization) and demonstrate marked improvements in accuracy and computational efficiency. We compare the schemes using a series of difficult (nonlinear) toy examples and conclude with a special focus on hemodynamic models of evoked brain responses in fMRI. Our scheme promises to provide a significant advance in characterizing the functional architectures of distributed neuronal systems, even in the absence of known exogenous (experimental) input; e.g., resting state fMRI studies and spontaneous fluctuations in electrophysiological studies. Importantly, unlike current Bayesian filters (e.g. DEM), our scheme provides estimates of time-varying parameters, which we will exploit in future work on the adaptation and enabling of connections in the brain. PMID:21396454

  16. Effect of phase response curve skewness on synchronization of electrically coupled neuronal oscillators.

    PubMed

    Dodla, Ramana; Wilson, Charles J

    2013-10-01

    We investigate why electrically coupled neuronal oscillators synchronize or fail to synchronize using the theory of weakly coupled oscillators. Stability of synchrony and antisynchrony is predicted analytically and verified using numerical bifurcation diagrams. The shape of the phase response curve (PRC), the shape of the voltage time course, and the frequency of spiking are freely varied to map out regions of parameter spaces that hold stable solutions. We find that type 1 and type 2 PRCs can hold both synchronous and antisynchronous solutions, but the shape of the PRC and the voltage determine the extent of their stability. This is achieved by introducing a five-piecewise linear model to the PRC and a three-piecewise linear model to the voltage time course, and then analyzing the resultant eigenvalue equations that determine the stability of the phase-locked solutions. A single time parameter defines the skewness of the PRC, and another single time parameter defines the spike width and frequency. Our approach gives a comprehensive picture of the relation of the PRC shape, voltage time course, and stability of the resultant synchronous and antisynchronous solutions.

  17. WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma

    PubMed Central

    Wen, Jing; Lee, Juhyun; Malhotra, Anshu; Nahta, Rita; Arnold, Amanda R.; Buss, Meghan C.; Brown, Briana D.; Maier, Caroline; Kenney, Anna M.; Remke, Marc; Ramaswamy, Vijay; Taylor, Michael D.; Castellino, Robert C.

    2016-01-01

    High-level amplification of the protein phosphatase PPM1D (WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor (cGNP) cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer in early post-natal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with a Shh-activated MB mouse model. Conversely, Wip1 knock out significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1 knock-down or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB. PMID:27086929

  18. Transcranial electrical stimulation modifies the neuronal response to psychosocial stress exposure.

    PubMed

    Antal, Andrea; Fischer, Thomas; Saiote, Catarina; Miller, Robert; Chaieb, Leila; Wang, Danny J J; Plessow, Franziska; Paulus, Walter; Kirschbaum, Clemens

    2014-08-01

    Stress is a constant characteristic of everyday life in our society, playing a role in triggering several chronic disorders. Therefore, there is an ongoing need to develop new methods in order to manage stress reactions. The regulatory function of right medial-prefrontal cortex (mPFC) is frequently reported by imaging studies during psychosocial stress situations. Here, we examined the effects of inhibitory and excitatory preconditioning stimulation via cathodal and anodal transcranial direct current stimulation (tDCS) on psychosocial stress related behavioral indicators and physiological factors, including the cortisol level in the saliva and changes in brain perfusion. Twenty minutes real or sham tDCS was applied over the right mPFC of healthy subjects before the performance of the Trier Social Stress Test (TSST). Regional cerebral blood flow (rCBF) was measured during stimulation and after TSST, using pseudo-continuous arterial spin labeling (pCASL). Comparing the effect of the different stimulation conditions, during anodal stimulation we found higher rCBF in the right mPFC, compared to the sham and in the right amygdala, superior PFC compared to the cathodal condition. Salivary cortisol levels showed a decrease in the anodal and increase in cathodal groups after completion of the TSST. The behavioral stress indicators indicated the increase of stress level, however, did not show any significant differences among groups. In this study we provide the first insights into the neuronal mechanisms mediating psychosocial stress responses by prefrontal tDCS.

  19. Neuronal response of the hippocampal formation to injury: blood flow, glucose metabolism, and protein synthesis

    SciTech Connect

    Kameyama, M.; Wasterlain, C.G.; Ackermann, R.F.; Finch, D.; Lear, J.; Kuhl, D.E.

    1983-02-01

    The reaction of the hippocampal formation to entorhinal lesions was studied from the viewpoints of cerebral blood flow ((/sup 123/I)isopropyl-iodoamphetamine(IMP))-glucose utilization ((/sup 14/C)2-deoxyglucose), and protein synthesis ((/sup 14/C)leucine), using single- and double-label autoradiography. Researchers' studies showed decreased glucose utilization in the inner part, and increased glucose utilization in the outer part of the molecular layer of the dentate gyrus, starting 3 days after the lesion; increased uptake of (/sup 123/I)IMP around the lesion from 1 to 3 days postlesion; and starting 3 days after the lesion, marked decrease in (/sup 14/C)leucine incorporation into proteins and cell loss in the dorsal CA1 and dorsal subiculum in about one-half of the rats. These changes were present only in animals with lesions which invaded the ventral hippocampal formation in which axons of CA1 cells travel. By contrast, transsection of the 3rd and 4th cranial nerves resulted, 3 to 9 days after injury, in a striking increase in protein synthesis in the oculomotor and trochlear nuclei. These results raise the possibility that in some neurons the failure of central regeneration may result from the cell's inability to increase its rate of protein synthesis in response to axonal injury.

  20. Odorant-induced Responses Recorded from Olfactory Receptor Neurons using the Suction Pipette Technique

    PubMed Central

    Matthews, Hugh R.; Reisert, Johannes

    2012-01-01

    Animals sample the odorous environment around them through the chemosensory systems located in the nasal cavity. Chemosensory signals affect complex behaviors such as food choice, predator, conspecific and mate recognition and other socially relevant cues. Olfactory receptor neurons (ORNs) are located in the dorsal part of the nasal cavity embedded in the olfactory epithelium. These bipolar neurons send an axon to the olfactory bulb (see Fig. 1, Reisert & Zhao1, originally published in the Journal of General Physiology) and extend a single dendrite to the epithelial border from where cilia radiate into the mucus that covers the olfactory epithelium. The cilia contain the signal transduction machinery that ultimately leads to excitatory current influx through the ciliary transduction channels, a cyclic nucleotide-gated (CNG) channel and a Ca2+-activated Cl- channel (Fig. 1). The ensuing depolarization triggers action potential generation at the cell body2-4. In this video we describe the use of the "suction pipette technique" to record odorant-induced responses from ORNs. This method was originally developed to record from rod photoreceptors5 and a variant of this method can be found at jove.com modified to record from mouse cone photoreceptors6. The suction pipette technique was later adapted to also record from ORNs7,8. Briefly, following dissociation of the olfactory epithelium and cell isolation, the entire cell body of an ORN is sucked into the tip of a recording pipette. The dendrite and the cilia remain exposed to the bath solution and thus accessible to solution changes to enable e.g. odorant or pharmacological blocker application. In this configuration, no access to the intracellular environment is gained (no whole-cell voltage clamp) and the intracellular voltage remains free to vary. This allows the simultaneous recording of the slow receptor current that originates at the cilia and fast action potentials fired by the cell body9. The difference in

  1. Central regulation of motor cortex neuronal responses to forelimb nerve inputs during precision walking in the cat.

    PubMed

    Marple-Horvat, D E; Armstrong, D M

    1999-08-15

    1. The responses of neurones in forelimb motor cortex to impulse volleys evoked by single pulse electrical stimulation (at 1.5 or 2 times the threshold for most excitable nerve fibres) of the superficial radial (SR) and ulnar (UL) nerves of the contralateral forelimb were studied in awake cats both resting quietly and walking on a horizontal ladder. Nerve volley amplitude was monitored by recording the compound action potential elicited by the stimulus. 2. In the resting animal 34/82 (41%) cells yielded statistically significant responses to SR stimulation, and 20/72 (28%) responded to UL stimulation. Some responses were confined to or began with an increase in firing probability ('excitatory' responses) and others with a decrease in firing ('inhibitory' responses), typically including a brief interruption of the spike train (zero rate). Cells responding to both nerves usually yielded responses similar in type. Most (78%) response onset latencies were less than 30 ms. Responses involved the addition or subtraction of from 3.4 to 0.1 impulses stimulus-1 (most <1 impulse stimulus-1). The distribution of response sizes was continuous down to the smallest values, i.e. there was no 'gap' which would represent a clear separation into 'responsive' and 'unresponsive' categories. Responses were commonest in the lateral part of the pericruciate cortex, and commoner among pyramidal tract neurones (PTNs) than non-PTNs. 3. During ladder walking most cells generated a rhythmic step-related discharge; in assessing the size of responses to nerve stimulation (20 studied, from 13 cells) this activity was first subtracted. Response onset latencies (90% <30 ms) and durations showed little or no change. Although most cells were overall more active than during rest both 'excitatory' and 'inhibitory' responses in both PTNs and non-PTNs were often markedly reduced in large parts of the step cycle; over some (usually brief) parts responses approached or exceeded their size during rest, i

  2. Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss

    PubMed Central

    Henry, Fredrick E; Sugino, Ken; Tozer, Adam; Branco, Tiago; Sternson, Scott M

    2015-01-01

    Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. Agouti related protein (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders. DOI: http://dx.doi.org/10.7554/eLife.09800.001 PMID:26329458

  3. Neurons in the Amygdala with Response-Selectivity for Anxiety in Two Ethologically Based Tests

    PubMed Central

    Wang, Dong V.; Wang, Fang; Liu, Jun; Zhang, Lu; Wang, Zhiru; Lin, Longnian

    2011-01-01

    The amygdala is a key area in the brain for detecting potential threats or dangers, and further mediating anxiety. However, the neuronal mechanisms of anxiety in the amygdala have not been well characterized. Here we report that in freely-behaving mice, a group of neurons in the basolateral amygdala (BLA) fires tonically under anxiety conditions in both open-field and elevated plus-maze tests. The firing patterns of these neurons displayed a characteristic slow onset and progressively increased firing rates. Specifically, these firing patterns were correlated to a gradual development of anxiety-like behaviors in the open-field test. Moreover, these neurons could be activated by any impoverished environment similar to an open-field; and introduction of both comfortable and uncomfortable stimuli temporarily suppressed the activity of these BLA neurons. Importantly, the excitability of these BLA neurons correlated well with levels of anxiety. These results demonstrate that this type of BLA neuron is likely to represent anxiety and/or emotional values of anxiety elicited by anxiogenic environmental stressors. PMID:21494567

  4. In vitro imaging and human serum albumin responsive dimeric lanthanide DO3A complex.

    PubMed

    Fung, Yuen On; Wu, Wanqing; Yeung, Chi-Tung; Kong, Hoi-Kuan; Wong, Kenny Kam-Cheng; Lo, Wai-Sum; Law, Ga-Lai; Wong, Ka-Leung; Lau, Chi-Kong; Lee, Chi-Sing; Wong, Wing-Tak

    2011-06-20

    Two series of dimeric DO3A (1,4,7,10-tetraazacyclodecane-1,4,7-triacetate) lanthanide complexes (LnL(1)-LnL(2), Ln = Eu, Gd, and Tb) have been synthesized with two different bridged chromophores. The X-ray structures of dimeric LnL(1) (Ln = Gd and Tb) complexes show that each metal ion has nine coordination numbers with eight directly bound donor atoms of the ligand and one oxygen donor from the water molecule. Photophysical measurements indicate that the bridged antenna in LnL(2) gives a higher efficiency than that of LnL(1) and is responsive to the protein Human Serum Albumin (HSA), giving an f-f luminescence signal enhancement with a binding constant log K = 4.84. In vitro imaging of EuL(1) and EuL(2) in HeLa cells has been recorded, and EuL(2) has demonstrated a higher rate of cellular uptake and low cytotoxicity (IC(50) = 3 mM).

  5. The p38 MAP kinase pathway modulates the hypoxia response and glutamate receptor trafficking in aging neurons.

    PubMed

    Park, Eun Chan; Rongo, Christopher

    2016-01-01

    Neurons are sensitive to low oxygen (hypoxia) and employ a conserved pathway to combat its effects. Here, we show that p38 MAP Kinase (MAPK) modulates this hypoxia response pathway in C. elegans. Mutants lacking p38 MAPK components pmk-1 or sek-1 resemble mutants lacking the hypoxia response component and prolyl hydroxylase egl-9, with impaired subcellular localization of Mint orthologue LIN-10, internalization of glutamate receptor GLR-1, and depression of GLR-1-mediated behaviors. Loss of p38 MAPK impairs EGL-9 protein localization in neurons and activates the hypoxia-inducible transcription factor HIF-1, suggesting that p38 MAPK inhibits the hypoxia response pathway through EGL-9. As animals age, p38 MAPK levels decrease, resulting in GLR-1 internalization; this age-dependent downregulation can be prevented through either p38 MAPK overexpression or removal of CDK-5, an antagonizing kinase. Our findings demonstrate that p38 MAPK inhibits the hypoxia response pathway and determines how aging neurons respond to hypoxia through a novel mechanism. PMID:26731517

  6. Prior high corticosterone exposure reduces activation of immature neurons in the ventral hippocampus in response to spatial and nonspatial memory.

    PubMed

    Workman, Joanna L; Chan, Melissa Y T; Galea, Liisa A M

    2015-03-01

    Chronic stress or chronically high glucocorticoids attenuate adult hippocampal neurogenesis by reducing cell proliferation, survival, and differentiation in male rodents. Neurons are still produced in the dentate gyrus during chronically high glucocorticoids, but it is not known whether these new neurons are appropriately activated in response to spatial memory. Thus, the goal of this study was to determine whether immature granule neurons generated during chronically high glucocorticoids (resulting in a depressive-like phenotype) are differentially activated by spatial memory retrieval. Male Sprague Dawley rats received either 40 mg/kg corticosterone (CORT) or vehicle for 18 days prior to behavioral testing. Rats were tested in the forced swim test (FST) and then tested in a spatial (hippocampus-dependent) or cued (hippocampus-independent) Morris Water Maze. Tissue was then processed for doublecortin (DCX) to identify immature neurons and zif268, an immediate early gene product. As expected, CORT increased depressive-like behavior (greater immobility in the FST) however, prior CORT modestly enhanced spatial learning and memory compared with oil. Prior CORT reduced the number of DCX-expressing cells and proportion of DCX-expressing cells colabeled for zif268, but only in the ventral hippocampus. Prior CORT shifted the proportion of cells in the ventral hippocampus away from postmitotic cells and toward immature, proliferative cells, likely due to the fact that postmitotic cells were produced and matured during CORT exposure but proliferative cells were produced after high CORT exposure ceased. Compared with cue training, spatial training slightly increased DCX-expressing cells and shifted cells toward the postmitotic stage in the ventral hippocampus. These data suggest that the effects of CORT and spatial training on immature neurons are more pronounced in the ventral hippocampus. Further, high CORT reduced activation of immature neurons, suggesting that exposure

  7. Prior high corticosterone exposure reduces activation of immature neurons in the ventral hippocampus in response to spatial and nonspatial memory.

    PubMed

    Workman, Joanna L; Chan, Melissa Y T; Galea, Liisa A M

    2015-03-01

    Chronic stress or chronically high glucocorticoids attenuate adult hippocampal neurogenesis by reducing cell proliferation, survival, and differentiation in male rodents. Neurons are still produced in the dentate gyrus during chronically high glucocorticoids, but it is not known whether these new neurons are appropriately activated in response to spatial memory. Thus, the goal of this study was to determine whether immature granule neurons generated during chronically high glucocorticoids (resulting in a depressive-like phenotype) are differentially activated by spatial memory retrieval. Male Sprague Dawley rats received either 40 mg/kg corticosterone (CORT) or vehicle for 18 days prior to behavioral testing. Rats were tested in the forced swim test (FST) and then tested in a spatial (hippocampus-dependent) or cued (hippocampus-independent) Morris Water Maze. Tissue was then processed for doublecortin (DCX) to identify immature neurons and zif268, an immediate early gene product. As expected, CORT increased depressive-like behavior (greater immobility in the FST) however, prior CORT modestly enhanced spatial learning and memory compared with oil. Prior CORT reduced the number of DCX-expressing cells and proportion of DCX-expressing cells colabeled for zif268, but only in the ventral hippocampus. Prior CORT shifted the proportion of cells in the ventral hippocampus away from postmitotic cells and toward immature, proliferative cells, likely due to the fact that postmitotic cells were produced and matured during CORT exposure but proliferative cells were produced after high CORT exposure ceased. Compared with cue training, spatial training slightly increased DCX-expressing cells and shifted cells toward the postmitotic stage in the ventral hippocampus. These data suggest that the effects of CORT and spatial training on immature neurons are more pronounced in the ventral hippocampus. Further, high CORT reduced activation of immature neurons, suggesting that exposure

  8. Different responses of astrocytes and neurons to nitric oxide: The role of glycolytically generated ATP in astrocyte protection

    PubMed Central

    Almeida, Angeles; Almeida, Julia; Bolaños, Juan P.; Moncada, Salvador

    2001-01-01

    It was recently proposed that in Jurkat cells, after inhibition of respiration by NO, glycolytically generated ATP plays a critical role in preventing the collapse of mitochondrial membrane potential (Δψm) and thus apoptotic cell death. We have investigated this observation further in primary cultures of rat cortical neurons and astrocytes—cell types that differ greatly in their glycolytic capacity. Continuous and significant (≈85%) inhibition of respiration by NO (1.4 μM at 175 μM O2) generated by [(z)-1-[2-aminoethyl]-N-[2-ammonioethyl]amino]diazen-1-ium-1,2 diolate (DETA-NO) initially (10 min) depleted ATP concentrations by ≈25% in both cell types and increased the rate of glycolysis in astrocytes but not in neurons. Activation of glycolysis in astrocytes, as judged by lactate production, prevented further ATP depletion, whereas in neurons, which do not invoke this mechanism, there was a progressive decrease in ATP concentrations over the next 60 min. During this time, there was a persistent mitochondrial hyperpolarization and absence of apoptotic cell death in astrocytes, whereas in the neurons there was a progressive fall in Δψm and increased apoptosis. After glucose deprivation or treatment with inhibitors of the F1F0-ATPase and adenine nucleotide translocase, astrocytes responded to NO with a fall in Δψm and apoptotic cell death similar to the response in neurons. Finally, although treatment of astrocytes with NO partially prevented staurosporin-induced collapse in Δψm and cell death, NO and staurosporin synergized in decreasing Δψm and inducing apoptosis in neurons. These results demonstrate that although inhibition of cellular respiration by NO leads to neurotoxicity, it may also result in initial neuroprotection, depending on the glycolytic capacity of the particular cell. PMID:11742096

  9. Postsynaptic Odorant Concentration Dependent Inhibition Controls Temporal Properties of Spike Responses of Projection Neurons in the Moth Antennal Lobe

    PubMed Central

    Fujiwara, Terufumi; Kazawa, Tomoki; Haupt, Stephan Shuichi; Kanzaki, Ryohei

    2014-01-01

    Although odorant concentration-response characteristics of olfactory neurons have been widely investigated in a variety of animal species, the effect of odorant concentration on neural processing at circuit level is still poorly understood. Using calcium imaging in the silkmoth (Bombyx mori) pheromone processing circuit of the antennal lobe (AL), we studied the effect of odorant concentration on second-order projection neuron (PN) responses. While PN calcium responses of dendrites showed monotonic increases with odorant concentration, calcium responses of somata showed decreased responses at higher odorant concentrations due to postsynaptic inhibition. Simultaneous calcium imaging and electrophysiology revealed that calcium responses of PN somata but not dendrites reflect spiking activity. Inhibition shortened spike response duration rather than decreasing peak instantaneous spike frequency (ISF). Local interneurons (LNs) that were specifically activated at high odorant concentrations at which PN responses were suppressed are the putative source of inhibition. Our results imply the existence of an intraglomerular mechanism that preserves time resolution in olfactory processing over a wide odorant concentration range. PMID:24586546

  10. Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice.

    PubMed

    Ruka, Kristen A; Burger, Laura L; Moenter, Suzanne M

    2016-02-01

    Gonadal steroids regulate the pattern of GnRH secretion. Arcuate kisspeptin (kisspeptin, neurokinin B, and dynorphin [KNDy]) neurons may convey steroid feedback to GnRH neurons. KNDy neurons increase action potential firing upon the activation of neurokinin B receptors (neurokinin-3 receptor [NK3R]) and decrease firing upon the activation of dynorphin receptors (κ-opioid receptor [KOR]). In KNDy neurons from intact vs castrated male mice, NK3R-mediated stimulation is attenuated and KOR-mediated inhibition enhanced, suggesting gonadal secretions are involved. Estradiol suppresses spontaneous GnRH neuron firing in male mice, but the mediators of the effects on firing in KNDy neurons are unknown. We hypothesized the same gonadal steroids affecting GnRH firing pattern would regulate KNDy neuron response to NK3R and KOR agonists. To test this possibility, extracellular recordings were made from KNDy neurons in brain slices from intact, untreated castrated or castrated adult male mice treated in vivo with steroid receptor agonists. As observed previously, the stimulation of KNDy neurons by the NK3R agonist senktide was attenuated in intact vs castrated mice and suppression by dynorphin was enhanced. In contrast to observations of steroid effects on the GnRH neuron firing pattern, both estradiol and DHT suppressed senktide-induced KNDy neuron firing and enhanced the inhibition caused by dynorphin. An estrogen receptor-α agonist but not an estrogen receptor-β agonist mimicked the effects of estradiol on NK3R activation. These observations suggest the steroid modulation of responses to activation of NK3R and KOR as mechanisms for negative feedback in KNDy neurons and support the contribution of these neurons to steroid-sensitive elements of a GnRH pulse generator.

  11. Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice.

    PubMed

    Ruka, Kristen A; Burger, Laura L; Moenter, Suzanne M

    2016-02-01

    Gonadal steroids regulate the pattern of GnRH secretion. Arcuate kisspeptin (kisspeptin, neurokinin B, and dynorphin [KNDy]) neurons may convey steroid feedback to GnRH neurons. KNDy neurons increase action potential firing upon the activation of neurokinin B receptors (neurokinin-3 receptor [NK3R]) and decrease firing upon the activation of dynorphin receptors (κ-opioid receptor [KOR]). In KNDy neurons from intact vs castrated male mice, NK3R-mediated stimulation is attenuated and KOR-mediated inhibition enhanced, suggesting gonadal secretions are involved. Estradiol suppresses spontaneous GnRH neuron firing in male mice, but the mediators of the effects on firing in KNDy neurons are unknown. We hypothesized the same gonadal steroids affecting GnRH firing pattern would regulate KNDy neuron response to NK3R and KOR agonists. To test this possibility, extracellular recordings were made from KNDy neurons in brain slices from intact, untreated castrated or castrated adult male mice treated in vivo with steroid receptor agonists. As observed previously, the stimulation of KNDy neurons by the NK3R agonist senktide was attenuated in intact vs castrated mice and suppression by dynorphin was enhanced. In contrast to observations of steroid effects on the GnRH neuron firing pattern, both estradiol and DHT suppressed senktide-induced KNDy neuron firing and enhanced the inhibition caused by dynorphin. An estrogen receptor-α agonist but not an estrogen receptor-β agonist mimicked the effects of estradiol on NK3R activation. These observations suggest the steroid modulation of responses to activation of NK3R and KOR as mechanisms for negative feedback in KNDy neurons and support the contribution of these neurons to steroid-sensitive elements of a GnRH pulse generator. PMID:26562263

  12. Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input☆

    PubMed Central

    Tsantoulas, Christoforos; Zhu, Lan; Yip, Ping; Grist, John; Michael, Gregory J.; McMahon, Stephen B.

    2014-01-01

    Peripheral nerve injuries caused by trauma are associated with increased sensory neuron excitability and debilitating chronic pain symptoms. Axotomy-induced alterations in the function of ion channels are thought to largely underlie the pathophysiology of these phenotypes. Here, we characterise the mRNA distribution of Kv2 family members in rat dorsal root ganglia (DRG) and describe a link between Kv2 function and modulation of sensory neuron excitability. Kv2.1 and Kv2.2 were amply expressed in cells of all sizes, being particularly abundant in medium-large neurons also immunoreactive for neurofilament-200. Peripheral axotomy led to a rapid, robust and long-lasting transcriptional Kv2 downregulation in the DRG, correlated with the onset of mechanical and thermal hypersensitivity. The consequences of Kv2 loss-of-function were subsequently investigated in myelinated neurons using intracellular recordings on ex vivo DRG preparations. In naïve neurons, pharmacological Kv2.1/Kv2.2 inhibition by stromatoxin-1 (ScTx) resulted in shortening of action potential (AP) after-hyperpolarization (AHP). In contrast, ScTx application on axotomized neurons did not alter AHP duration, consistent with the injury-induced Kv2 downregulation. In accordance with a shortened AHP, ScTx treatment also reduced the refractory period and improved AP conduction to the cell soma during high frequency stimulation. These results suggest that Kv2 downregulation following traumatic nerve lesion facilitates greater fidelity of repetitive firing during prolonged input and thus normal Kv2 function is postulated to limit neuronal excitability. In summary, we have profiled Kv2 expression in sensory neurons and provide evidence for the contribution of Kv2 dysfunction in the generation of hyperexcitable phenotypes encountered in chronic pain states. PMID:24252178

  13. Adult axolotls can regenerate original neuronal diversity in response to brain injury

    PubMed Central

    Amamoto, Ryoji; Huerta, Violeta Gisselle Lopez; Takahashi, Emi; Dai, Guangping; Grant, Aaron K; Fu, Zhanyan; Arlotta, Paola

    2016-01-01

    The axolotl can regenerate multiple organs, including the brain. It remains, however, unclear whether neuronal diversity, intricate tissue architecture, and axonal connectivity can be regenerated; yet, this is critical for recovery of function and a central aim of cell replacement strategies in the mammalian central nervous system. Here, we demonstrate that, upon mechanical injury to the adult pallium, axolotls can regenerate several of the populations of neurons present before injury. Notably, regenerated neurons acquire functional electrophysiological traits and respond appropriately to afferent inputs. Despite the ability to regenerate specific, molecularly-defined neuronal subtypes, we also uncovered previously unappreciated limitations by showing that newborn neurons organize within altered tissue architecture and fail to re-establish the long-distance axonal tracts and circuit physiology present before injury. The data provide a direct demonstration that diverse, electrophysiologically functional neurons can be regenerated in axolotls, but challenge prior assumptions of functional brain repair in regenerative species. DOI: http://dx.doi.org/10.7554/eLife.13998.001 PMID:27156560

  14. Expression of α5 integrin rescues fibronectin responsiveness in NT2N CNS neuronal cells

    PubMed Central

    Meland, Marit N.; Herndon, Mary E.; Stipp, Christopher S.

    2010-01-01

    The extracellular matrix protein fibronectin is implicated in neuronal regeneration in the peripheral nervous system. In the central nervous system (CNS), fibronectin is upregulated at sites of penetrating injuries and stroke; however, CNS neurons downregulate the fibronectin receptor, α5β1 integrin, during differentiation and generally respond poorly to fibronectin. NT2N CNS neuron-like cells (derived from NT2 precursor cells) have been used in pre-clinical and clinical studies for treatment of stroke and a variety of CNS injury and disease models. Here we show that, like primary CNS neurons, NT2N cells downregulate α5β1 integrin during differentiation and respond poorly to fibronectin. The poor neurite outgrowth by NT2N cells on fibronectin can be rescued by transducing NT2 precursors with a retroviral vector expressing α5 integrin under the control of the Murine Stem Cell Virus 5′ long terminal repeat. Sustained α5 integrin expression is compatible with the CNS-like neuronal differentiation of NT2N cells and does not prevent robust neurite outgrowth on other integrin ligands. Thus, α5 integrin expression in CNS neuronal precursor cells may provide a strategy for enhancing the outgrowth and survival of implanted cells in cell replacement therapies for CNS injury and disease. PMID:19598247

  15. Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

    PubMed Central

    Pope, Holly M.; Voigt, Mark M.

    2014-01-01

    Axon degeneration is a feature of many peripheral neuropathies. Understanding the organismal response to this degeneration may aid in identifying new therapeutic targets for treatment. Using a transgenic zebrafish line expressing a bacterial nitroreductase (Ntr)/mCherry fusion protein in the peripheral sensory neurons of the V, VII, IX, and X cranial nerves, we were able to induce and visualize the pathology of axon degeneration in vivo. Exposure of 4 days post fertilization Ntr larvae to the prodrug metronidazole (Met), which Ntr metabolizes into cytotoxic metabolites, resulted in dose-dependent cell death and axon degeneration. This was limited to the Ntr-expressing sensory neurons, as neighboring glia and motor axons were unaffected. Cell death was rapid, becoming apparent 3–4 hours after Met treatment, and was followed by phagocytosis of soma and axon debris by cells within the nerves and ganglia beginning at 4–5 hours of exposure. Although neutrophils appear to be activated in response to the degenerating neurons, they did not accumulate at the sites of degeneration. In contrast, macrophages were found to be attracted to the sites of the degenerating axons, where they phagocytosed debris. We demonstrated that peripheral glia are critical for both the phagocytosis and inflammatory response to degenerating neurons: mutants that lack all peripheral glia (foxD3−/−; Ntr) exhibit a much reduced reaction to axonal degeneration, resulting in a dramatic decrease in the clearance of debris, and impaired macrophage recruitment. Overall, these results show that this zebrafish model of peripheral sensory axon degeneration exhibits many aspects common to peripheral neuropathies and that peripheral glia play an important role in the initial response to this process. PMID:25058656

  16. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists.

    PubMed

    Sprouse, J S; Aghajanian, G K

    1987-01-01

    A direct comparison was made of the effects of serotonin 5-HT1A and 5-HT1B selective compounds on the spontaneous firing rate of dorsal raphe serotoninergic neurons in chloral-hydrate-anesthetized rats. Following intravenous administration, the 5-HT1A selective compounds ipsapirone (TVX Q 7821) and LY 165163 potently inhibited single-unit activity in a dose-dependent manner whereas the 5-HT1B selective compounds, m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP), displayed only weak or irregular actions. Low microiontophoretic currents of ipsapirone and LY 165163 were also effective in suppressing spontaneous firing; dose-response relationships for the 5-HT1A compounds were indistinguishable from that of 5-HT itself. In contrast, dorsal raphe neurons were only weakly responsive to microiontophoretic application of mCPP and TFMPP; dose-response relationships for the 5-HT1B compounds were significantly displaced from that of 5-HT. In intracellular studies, ipsapirone and LY 165163, when added to the media bathing brain slices, mimicked the actions of 5-HT in hyperpolarizing dorsal raphe cell membranes and decreasing input resistance; however, the maximal effects of the 5-HT1A compounds on these membrane properties exceeded those of 5-HT. In summary, dorsal raphe 5-HT neurons appear highly responsive to 5-HT1A, but not to 5-HT1B compounds; these findings are discussed with regard to the 5-HT receptor subtypes as candidates for the somatodendritic autoreceptor of dorsal raphe neurons. PMID:3505364

  17. Neuronal cellular responses to extremely low frequency electromagnetic field exposure: implications regarding oxidative stress and neurodegeneration.

    PubMed

    Reale, Marcella; Kamal, Mohammad A; Patruno, Antonia; Costantini, Erica; D'Angelo, Chiara; Pesce, Miko; Greig, Nigel H

    2014-01-01

    Neurodegenerative diseases comprise both hereditary and sporadic conditions characterized by an identifying progressive nervous system dysfunction and distinctive neuopathophysiology. The majority are of non-familial etiology and hence environmental factors and lifestyle play key roles in their pathogenesis. The extensive use of and ever increasing worldwide demand for electricity has stimulated societal and scientific interest on the environmental exposure to low frequency electromagnetic fields (EMFs) on human health. Epidemiological studies suggest a positive association between 50/60-Hz power transmission fields and leukemia or lymphoma development. Consequent to the association between EMFs and induction of oxidative stress, concerns relating to development of neurodegenerative diseases, such as Alzheimer disease (AD), have been voiced as the brain consumes the greatest fraction of oxygen and is particularly vulnerable to oxidative stress. Exposure to extremely low frequency (ELF)-EMFs are reported to alter animal behavior and modulate biological variables, including gene expression, regulation of cell survival, promotion of cellular differentiation, and changes in cerebral blood flow in aged AD transgenic mice. Alterations in inflammatory responses have also been reported, but how these actions impact human health remains unknown. We hence evaluated the effects of an electromagnetic wave (magnetic field intensity 1 mT; frequency, 50-Hz) on a well-characterized immortalized neuronal cell model, human SH-SY5Y cells. ELF-EMF exposure elevated the expession of NOS and O2(-), which were countered by compensatory changes in antioxidant catylase (CAT) activity and enzymatic kinetic parameters related to CYP-450 and CAT activity. Actions of ELF-EMFs on cytokine gene expression were additionally evaluated and found rapidly modified. Confronted with co-exposure to H2O2-induced oxidative stress, ELF-EMF proved not as well counteracted and resulted in a decline in CAT

  18. Chronic intermittent hypoxia-hypercapnia blunts heart rate responses and alters neurotransmission to cardiac vagal neurons.

    PubMed

    Dyavanapalli, Jhansi; Jameson, Heather; Dergacheva, Olga; Jain, Vivek; Alhusayyen, Mona; Mendelowitz, David

    2014-07-01

    Patients with obstructive sleep apnoea experience chronic intermittent hypoxia-hypercapnia (CIHH) during sleep that elicit sympathetic overactivity and diminished parasympathetic activity to the heart, leading to hypertension and depressed baroreflex sensitivity. The parasympathetic control of heart rate arises from pre-motor cardiac vagal neurons (CVNs) located in nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX). The mechanisms underlying diminished vagal control of heart rate were investigated by studying the changes in blood pressure, heart rate, and neurotransmission to CVNs evoked by acute hypoxia-hypercapnia (H-H) and CIHH. In vivo telemetry recordings of blood pressure and heart rate were obtained in adult rats during 4 weeks of CIHH exposure. Retrogradely labelled CVNs were identified in an in vitro brainstem slice preparation obtained from adult rats exposed either to air or CIHH for 4 weeks. Postsynaptic inhibitory or excitatory currents were recorded using whole cell voltage clamp techniques. Rats exposed to CIHH had increases in blood pressure, leading to hypertension, and blunted heart rate responses to acute H-H. CIHH induced an increase in GABAergic and glycinergic neurotransmission to CVNs in NA and DMNX, respectively; and a reduction in glutamatergic neurotransmission to CVNs in both nuclei. CIHH blunted the bradycardia evoked by acute H-H and abolished the acute H-H evoked inhibition of GABAergic transmission while enhancing glycinergic neurotransmission to CVNs in NA. These changes with CIHH inhibit CVNs and vagal outflow to the heart, both in acute and chronic exposures to H-H, resulting in diminished levels of cardioprotective parasympathetic activity to the heart as seen in OSA patients.

  19. 5-HT potentiation of the GABAA response in the rat sacral dorsal commissural neurones

    PubMed Central

    Xu, Tian-Le; Pang, Zhi-Ping; Li, Ji-Shuo; Akaike, Norio

    1998-01-01

    The modulatory effect of 5-hydroxytryptamine (5-HT) on the γ-aminobutyric acidA (GABAA) response was investigated in the neurones freshly dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin perforated patch recording configuration under the voltage-clamp conditions.5-HT potentiated GABA-induced Cl− current (IGABA) without affecting the reversal potential of IGABA and the apparent affinity of GABA to its receptor.α-Methyl-5-HT mimicked the potentiation effect of 5-HT on IGABA while ketanserine blocked it. 1-Oleoyl-2-acetyl-glycerol (OAG) potentiated IGABA, and the effect of 5-HT on IGABA was occluded by OAG pretreatment. In the presence of chelerythrine, 5-HT failed to potentiate IGABA, suggesting that protein kinase C (PKC) is involved in the pathway through which the activation of the 5-HT2 receptor potentiates the IGABA.The facilitatory effect of 5-HT on IGABA remained in the presence of BAPTA-AM. LiCl also had no effect on 5-HT-induced potentiation of IGABA.H-89, genistein, okadaic acid and pervanadate all had no effects on 5-HT potentiation of IGABA. Pertussis toxin treatment for 6–8 h did not block the facilitatory effect of 5-HT on IGABA.The present results show that GABAA receptor in the rat SDCN could be modulated in situ by 5-HT, one of the major transmitters involved in the supraspinal control of nociception, and that the phosphorylation of GABAA receptor by PKC may be sufficient to support such modulation. The results also strongly support the hypothesis that the cotransmission by 5-HT and GABA has an important role in the spinal cord. PMID:9690871

  20. Neuron-specific enolase as a novel biomarker reflecting tuberculosis activity and treatment response

    PubMed Central

    Nam, Sung-Jin; Jeong, Jee-Yeong; Jang, Tae-Won; Jung, Mann-Hong; Chun, Bong-Kwon; Cha, Hee-Jae; Oak, Chul-Ho

    2016-01-01

    Background/Aims: It is not clear which tests are indicative of the activity and severity of tuberculosis (TB). This study aimed to investigate the predictive value of neuron-specific enolase (NSE) and to determine the origin of NSE in TB patients. Methods: A single-center retrospective analysis was conducted on newly diagnosed TB patients between January and December 2010. Patients were categorized into one of two disease groups (focal segmental or extensive) based on chest X-ray. Pre- and post-treatment NSE concentrations were evaluated. To determine the origin of serum NSE concentration, NSE staining was compared with macrophage-specific CD68 staining in lung tissues and with a tissue microarray using immunohistochemistry and immunofluorescence. Results: A total of 60 newly diagnosed TB patients were analyzed. In TB patients, NSE serum concentration was significantly increased and NSE level decreased after treatment (p < 0.001). In proportion to serum high-sensitivity C-reactive protein concentration, the mean serum concentration of NSE in the extensive group (25.12 ng/mL) was significantly higher than that in the focal segmental group (20.23 ng/mL, p = 0.04). Immunohistochemical staining revealed a large number of macrophages that stained positively for both NSE and CD68 in TB tissues. In addition, NSE signals mostly co-localized with CD68 signals in the tissue microarray of TB patients. Conclusions: Our results suggest that NSE may be a practical parameter that can be used to monitor TB activity and treatment response. Elevated serum NSE level originates, at least in part, from macrophages in granulomatous lesions. PMID:27271274

  1. Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation.

    PubMed

    Threlfell, Sarah; Sammut, Stephen; Menniti, Frank S; Schmidt, Christopher J; West, Anthony R

    2009-03-01

    The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium-sized spiny projection neurons (MSNs), apparently playing a critical role in the regulation of both cGMP and cAMP signaling cascades. Genetic disruption or pharmacological inhibition of PDE10A reverses behavioral abnormalities associated with subcortical hyperdopaminergia. Here, we investigate the effect of PDE10A inhibition on the activity of MSNs using single-unit extracellular recordings performed in the dorsal striatum of anesthetized rats. Antidromic stimulation of the substantia nigra pars reticulata was used to identify striatonigral (SNr+) MSNs. Intrastriatal infusion of the selective PDE10A inhibitors papaverine or TP-10 [2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid] by reverse microdialysis did not affect spontaneous firing but robustly increased measures of cortically evoked spike activity in a stimulus intensity-dependent manner. Systemic administration of TP-10 also increased cortically evoked spike activity in a stimulus intensity- and dose-dependent manner. A robust increase in cortically evoked activity was apparent in SNr- MSNs (primarily striatopallidal). It is interesting that TP-10 administration did not affect cortically evoked activity in SNr+ MSNs. However, TP-10 administration increased the incidence of antidromically activated (i.e., SNr+) MSNs. These findings indicate that inhibition of striatal PDE10A activity increases the responsiveness of MSNs to depolarizing stimuli. Furthermore, given the lack of effect of TP-10 on SNr+ MSNs, we speculate that PDE10A inhibition may have a greater facilitatory effect on corticostriatal synaptic activity in striatopallidal MSNs. These data support further investigation of selective targeting of PDE signaling pathways in MSN subpopulations because this may represent a promising novel approach for treating brain disorders involving dysfunctional glutamatergic

  2. The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4

    PubMed Central

    Li, Yan; Adamek, Pavel; Zhang, Haijun; Tatsui, Claudio Esteves; Rhines, Laurence D.; Mrozkova, Petra; Li, Qin; Kosturakis, Alyssa K.; Cassidy, Ryan M.; Harrison, Daniel S.; Cata, Juan P.; Sapire, Kenneth; Zhang, Hongmei; Kennamer-Chapman, Ross M.; Jawad, Abdul Basit; Ghetti, Andre; Yan, Jiusheng; Palecek, Jiri

    2015-01-01

    Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1+ neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1+ neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. SIGNIFICANCE STATEMENT In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1

  3. Photoperiod alters fear responses and basolateral amygdala neuronal spine density in white-footed mice (Peromyscus leucopus).

    PubMed

    Walton, James C; Haim, Achikam; Spieldenner, James M; Nelson, Randy J

    2012-08-01

    Photoperiodism is a biological phenomenon in which environmental day length is monitored to ascertain time of year to engage in seasonally appropriate adaptations. This trait is common among organisms living outside of the tropics. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive responses to short day lengths, including reduced hippocampal volume, impairments in hippocampal-mediated memory, and enhanced hypothalamic-pituitary-adrenal axis reactivity. Because these photoperiodic changes in brain and behavior mirror some of the etiology of post-traumatic stress disorder (PTSD), we hypothesized that photoperiod may also alter fear memory and neuronal morphology within the hippocampus-basolateral amygdala-prefrontal cortex fear circuit. Ten weeks of exposure to short days increased fear memory in an auditory-cued fear conditioning test. Short days also increased dendritic spine density of the neurons of the basolateral amygdala, without affecting morphology of pyramidal neurons within the infralimbic region of the medial prefrontal cortex. Taken together, photoperiodic phenotypic changes in brain morphology and physiology induced by a single environmental factor, exposure to short day lengths, affect responses to fearful stimuli in white-footed mice. These results have potential implications for understanding seasonal changes in fear responsiveness, as well as for expanding translational animal models for studying gene-environment interactions underlying psychiatric diseases, such as PTSD. PMID:22652395

  4. Arctigenin reduces neuronal responses in the somatosensory cortex via the inhibition of non-NMDA glutamate receptors.

    PubMed

    Borbély, Sándor; Jócsák, Gergely; Moldován, Kinga; Sedlák, Éva; Preininger, Éva; Boldizsár, Imre; Tóth, Attila; Atlason, Palmi T; Molnár, Elek; Világi, Ildikó

    2016-07-01

    Lignans are biologically active phenolic compounds related to lignin, produced in different plants. Arctigenin, a dibenzylbutyrolactone-type lignan, has been used as a neuroprotective agent for the treatment of encephalitis. Previous studies of cultured rat cerebral cortical neurones raised the possibility that arctigenin inhibits kainate-induced excitotoxicity. The aims of the present study were: 1) to analyse the effect of arctigenin on normal synaptic activity in ex vivo brain slices, 2) to determine its receptor binding properties and test the effect of arctigenin on AMPA/kainate receptor activation and 3) to establish its effects on neuronal activity in vivo. Arctigenin inhibited glutamatergic transmission and reduced the evoked field responses. The inhibitory effect of arctigenin on the evoked field responses proved to be substantially dose dependent. Our results indicate that arctigenin exerts its effects under physiological conditions and not only on hyper-excited neurons. Furthermore, arctigenin can cross the blood-brain barrier and in the brain it interacts with kainate sensitive ionotropic glutamate receptors. These results indicate that arctigenin is a potentially useful new pharmacological tool for the inhibition of glutamate-evoked responses in the central nervous system in vivo.

  5. Photoperiod alters fear responses and basolateral amygdala neuronal spine density in white-footed mice (Peromyscus leucopus).

    PubMed

    Walton, James C; Haim, Achikam; Spieldenner, James M; Nelson, Randy J

    2012-08-01

    Photoperiodism is a biological phenomenon in which environmental day length is monitored to ascertain time of year to engage in seasonally appropriate adaptations. This trait is common among organisms living outside of the tropics. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive responses to short day lengths, including reduced hippocampal volume, impairments in hippocampal-mediated memory, and enhanced hypothalamic-pituitary-adrenal axis reactivity. Because these photoperiodic changes in brain and behavior mirror some of the etiology of post-traumatic stress disorder (PTSD), we hypothesized that photoperiod may also alter fear memory and neuronal morphology within the hippocampus-basolateral amygdala-prefrontal cortex fear circuit. Ten weeks of exposure to short days increased fear memory in an auditory-cued fear conditioning test. Short days also increased dendritic spine density of the neurons of the basolateral amygdala, without affecting morphology of pyramidal neurons within the infralimbic region of the medial prefrontal cortex. Taken together, photoperiodic phenotypic changes in brain morphology and physiology induced by a single environmental factor, exposure to short day lengths, affect responses to fearful stimuli in white-footed mice. These results have potential implications for understanding seasonal changes in fear responsiveness, as well as for expanding translational animal models for studying gene-environment interactions underlying psychiatric diseases, such as PTSD.

  6. Arctigenin reduces neuronal responses in the somatosensory cortex via the inhibition of non-NMDA glutamate receptors.

    PubMed

    Borbély, Sándor; Jócsák, Gergely; Moldován, Kinga; Sedlák, Éva; Preininger, Éva; Boldizsár, Imre; Tóth, Attila; Atlason, Palmi T; Molnár, Elek; Világi, Ildikó

    2016-07-01

    Lignans are biologically active phenolic compounds related to lignin, produced in different plants. Arctigenin, a dibenzylbutyrolactone-type lignan, has been used as a neuroprotective agent for the treatment of encephalitis. Previous studies of cultured rat cerebral cortical neurones raised the possibility that arctigenin inhibits kainate-induced excitotoxicity. The aims of the present study were: 1) to analyse the effect of arctigenin on normal synaptic activity in ex vivo brain slices, 2) to determine its receptor binding properties and test the effect of arctigenin on AMPA/kainate receptor activation and 3) to establish its effects on neuronal activity in vivo. Arctigenin inhibited glutamatergic transmission and reduced the evoked field responses. The inhibitory effect of arctigenin on the evoked field responses proved to be substantially dose dependent. Our results indicate that arctigenin exerts its effects under physiological conditions and not only on hyper-excited neurons. Furthermore, arctigenin can cross the blood-brain barrier and in the brain it interacts with kainate sensitive ionotropic glutamate receptors. These results indicate that arctigenin is a potentially useful new pharmacological tool for the inhibition of glutamate-evoked responses in the central nervous system in vivo. PMID:26972612

  7. The Cholinergic Signaling Responsible for the Expression of a Memory-Related Protein in Primary Rat Cortical Neurons.

    PubMed

    Chen, Tsan-Ju; Chen, Shun-Sheng; Wang, Dean-Chuan; Hung, Hui-Shan

    2016-11-01

    Cholinergic dysfunction in the brain is closely related to cognitive impairment including memory loss. In addition to the degeneration of basal forebrain cholinergic neurons, deficits in the cholinergic receptor signaling may also play an important role. In the present study, to examine the cholinergic signaling pathways responsible for the induction of a memory-related postsynaptic protein, a cholinergic agonist carbachol was used to induce the expression of activity-regulated cytoskeleton associated protein (Arc) in primary rat cortical neurons. After pretreating neurons with various antagonists or inhibitors, the levels of carbachol-induced Arc protein expression were detected by Western blot analysis. The results show that carbachol induces Arc protein expression mainly through activating M1 acetylcholine receptors and the downstream phospholipase C pathway, which may lead to the activation of the MAPK/ERK signaling pathway. Importantly, carbachol-mediated M2 receptor activation exerts negative effects on Arc protein expression and thus counteracts the enhanced effects of M1 activation. Furthermore, it is suggested for the first time that M1-mediated enhancement of N-methyl-D-aspartate receptor (NMDAR) responses, leading to Ca(2+) entry through NMDARs, contributes to carbachol-induced Arc protein expression. These findings reveal a more complete cholinergic signaling that is responsible for carbachol-induced Arc protein expression, and thus provide more information for developing treatments that can modulate cholinergic signaling and consequently alleviate cognitive impairment. J. Cell. Physiol. 231: 2428-2438, 2016. © 2016 Wiley Periodicals, Inc. PMID:26895748

  8. Proteomic Identification of Proteins Suggestive of Immune-Mediated Response or Neuronal Degeneration in Serum of Achalasia Patients

    PubMed Central

    Im, Seon Kyo; Yeo, Mari

    2013-01-01

    Background/Aims The primary pathophysiologic abnormality in achalasia is known to be a loss of inhibitory myenteric ganglion cells, which may result from an immune-mediated response or neuronal degeneration. The aim of this study was to identify proteins suggestive of an immune-mediated response or neuronal degeneration in the serum of achalasia patients using a proteomic analysis. Methods Blood samples were collected from five symptomatic achalasia patients and five sex- and age-matched healthy controls. Serum proteomic analysis was conducted, and the protein spots were identified using matrix-assisted laser desorption ionization/time-of-flight and a proteomics analyzer. The serum level of C3 was measured by enzyme-linked immunosorbent assay in nine patients with achalasia and 18 sex- and age-matched healthy controls. Results Of the 658 matched protein spots, 28 spots were up-regulated over 2-fold in the serum from achalasia patients compared with that from controls. The up-regulated proteins included complement C4B5, complement C3, cyclin-dependent kinase 5, transthyretin, and alpha 2 macroglobulin. The serum levels of C3 in achalasia patients were significantly higher than those of controls. Conclusions The serum proteomic analysis of achalasia patients suggests an immune-mediated response or neuronal degeneration. Further validation studies in larger samples and the esophageal tissue of achalasia patients are required. PMID:23898380

  9. Differential contribution of TRPV1 to thermal responses and tissue injury-induced sensitization of dorsal horn neurons in laminae I and V in the mouse.

    PubMed

    Eckert, W A; Julius, D; Basbaum, A I

    2006-12-15

    Our previous recordings from dorsal root ganglion and spinal lamina V neurons from TRPV1-mutant mice showed dramatic decreases in responses to temperatures near the activation threshold of this channel (43-49 degrees C). Somewhat unexpectedly, we only observed behavioral deficits in these mice at higher temperatures (50-58 degrees C). In the present study, we tested the hypothesis that the noxious heat-evoked pain behavior that persists in TRPV1-mutant mice reflects residual responsiveness of neurons in the superficial, but not deep, dorsal horn. To this end, we performed in vivo extracellular recordings of spinal nociresponsive neurons in laminae I and V in wild type (WT) and TRPV1 mutant mice. Neurons in WT and mutant mice from both laminae did not differ in their spontaneous activity or evoked responses to mechanical or cold stimuli. By contrast, most lamina I neurons from mutant mice responded to noxious heat with significantly higher thresholds than in WT mice. In contrast, lamina V neurons from mutant mice were virtually unresponsive to noxious heat before and after topical mustard oil-induced tissue injury. Interestingly, lamina I neurons in mutant mice displayed thermal sensitization following tissue injury, comparable in magnitude, but of shorter duration, than in WT mice. We conclude that TRPV1 is necessary for noxious heat-evoked responses of lamina V neurons, both before and after tissue injury. It is also an essential contributor to the normal activation threshold of lamina I neurons to noxious heat and for the full duration of thermal sensitization of lamina I neurons following injury. Finally, our results suggest that the processing of noxious thermal messages by neurons in lamina I involves convergent inputs from a heterogeneous population of primary afferent thermal nociceptors.

  10. PEDOT:PSS Interfaces Support the Development of Neuronal Synaptic Networks with Reduced Neuroglia Response In vitro

    PubMed Central

    Cellot, Giada; Lagonegro, Paola; Tarabella, Giuseppe; Scaini, Denis; Fabbri, Filippo; Iannotta, Salvatore; Prato, Maurizio; Salviati, Giancarlo; Ballerini, Laura

    2016-01-01

    The design of electrodes based on conductive polymers in brain-machine interface technology offers the opportunity to exploit variably manufactured materials to reduce gliosis, indeed the most common brain response to chronically implanted neural electrodes. In fact, the use of conductive polymers, finely tailored in their physical-chemical properties, might result in electrodes with improved adaptability to the brain tissue and increased charge-transfer efficiency. Here we interfaced poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) doped with different amounts of ethylene glycol (EG) with rat hippocampal primary cultures grown for 3 weeks on these synthetic substrates. We used immunofluorescence and scanning electron microscopy (SEM) combined to single cell electrophysiology to assess the biocompatibility of PEDOT:PSS in terms of neuronal growth and synapse formation. We investigated neuronal morphology, density and electrical activity. We reported the novel observation that opposite to neurons, glial cell density was progressively reduced, hinting at the ability of this material to down regulate glial reaction. Thus, PEDOT:PSS is an attractive candidate for the design of new implantable electrodes, controlling the extent of glial reactivity without affecting neuronal viability and function. PMID:26834546

  11. The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO₂.

    PubMed

    Ruffault, Pierre-Louis; D'Autréaux, Fabien; Hayes, John A; Nomaksteinsky, Marc; Autran, Sandra; Fujiyama, Tomoyuki; Hoshino, Mikio; Hägglund, Martin; Kiehn, Ole; Brunet, Jean-François; Fortin, Gilles; Goridis, Christo

    2015-04-13

    Maintaining constant CO2 and H(+) concentrations in the arterial blood is critical for life. The principal mechanism through which this is achieved in mammals is the respiratory chemoreflex whose circuitry is still elusive. A candidate element of this circuitry is the retrotrapezoid nucleus (RTN), a collection of neurons at the ventral medullary surface that are activated by increased CO2 or low pH and project to the respiratory rhythm generator. Here, we use intersectional genetic strategies to lesion the RTN neurons defined by Atoh1 and Phox2b expression and to block or activate their synaptic output. Photostimulation of these neurons entrains the respiratory rhythm. Conversely, abrogating expression of Atoh1 or Phox2b or glutamatergic transmission in these cells curtails the phrenic nerve response to low pH in embryonic preparations and abolishes the respiratory chemoreflex in behaving animals. Thus, the RTN neurons expressing Atoh1 and Phox2b are a necessary component of the chemoreflex circuitry.

  12. Comparison of somatostatin and corticotrophin releasing hormone immunoreactivity in forebrain neurons projecting to taste responsive and non responsive regions of the parabrachial nucleus in rat

    PubMed Central

    Panguluri, Siva; Saggu, Shalini; Lundy, Robert

    2009-01-01

    Several forebrain areas have been shown to project to the parabrachial nucleus (PBN) and exert inhibitory and excitatory influences on taste processing. The neurochemicals by which descending forebrain inputs modulate neural taste-evoked responses remain to be established. This study investigated the existence of somatostatin (SS) and corticotrophin releasing factor (CRF) in forebrain neurons that project to caudal regions of the PBN responsive to chemical stimulation of the anterior tongue as well as more rostral unresponsive regions. Retrograde tracer was iontophoretically or pressure ejected from glass micropipettes, and seven days later the animals were euthanized for subsequent immunohistochemical processing for co-localization of tracer with SS and CRF in tissue sections containing the lateral hypothalamus (LH), central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), and insular cortex (IC). In each forebrain site, robust labeling of cells with distinguishable nuclei and short processes was observed for SS and CRF. The results indicate that CRF neurons in each forebrain site send projections throughout the rostral caudal extent of the PBN with a greater percentage terminating in regions rostral to the anterior tongue responsive area. For SS, the percentage of double-labeled neurons was more forebrain site specific in that only BNST and CeA exhibited significant numbers of double labeled neurons. Few retrogradely labeled cells in LH co-expressed SS, while no double labeled cells were observed in IC. Again, tracer injections into rostral PBN resulted in a greater percentage of double labeled neurons in BNST and CeA compared to caudal injections. The present results suggest that some sources of descending forebrain input might utilize somatostatin and/or CRF to exert a broad influence on sensory information processing in the PBN. PMID:19699720

  13. Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass

    PubMed Central

    Farman, H. H.; Windahl, S. H.; Westberg, L.; Isaksson, H.; Egecioglu, E.; Schele, E.; Ryberg, H.; Jansson, J. O.; Tuukkanen, J.; Koskela, A.; Xie, S. K.; Hahner, L.; Zehr, J.; Clegg, D. J.; Lagerquist, M. K.

    2016-01-01

    Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα−/−). Female POMC-ERα−/− and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα−/− mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice. PMID:27254004

  14. Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass.

    PubMed

    Farman, H H; Windahl, S H; Westberg, L; Isaksson, H; Egecioglu, E; Schele, E; Ryberg, H; Jansson, J O; Tuukkanen, J; Koskela, A; Xie, S K; Hahner, L; Zehr, J; Clegg, D J; Lagerquist, M K; Ohlsson, C

    2016-08-01

    Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα(-/-)). Female POMC-ERα(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα(-/-) mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.

  15. Bilateral inhibition generates neuronal responses tuned to interaural level differences in the auditory brainstem of the barn owl.

    PubMed

    Adolphs, R

    1993-09-01

    I investigated the neural algorithms by which neurons gain selectivity for interaural level difference in the brainstem of the barn owl (Tyto alba). Differences in the timing and in the level of sounds at the ears are used by this owl to encode, respectively, azimuthal and vertical position of sound sources in space. These two cues are processed in two parallel neural pathways. Below the level of the inferior colliculus, all neurons in the pathway that processes level differences show responses to this cue that are monotonic, and thus not selective for a particular level difference. Only in the inferior colliculus, which contains a map of auditory space, are neurons sharply tuned to specific interaural level differences. How are these response properties generated from those of the nuclei that provide input to the inferior colliculus? I show that the posterior subdivision of the nucleus ventralis lemnisci lateralis (VLVp) projects bilaterally to the lateral shell of the central nucleus of the inferior colliculus, the input stage to the map of auditory space. Both these nuclei are part of the pathway that processes interaural level differences. Manipulations of the responses in VLVp affected the responses to level differences in the inferior colliculus; responses to time differences were unaffected. By systematically increasing or decreasing neural activity in VLVp, I show that the VLVp on each side provides inhibition to the colliculus at large level differences. This results in a peaked response that is tuned to level differences in the inferior colliculus. Some cells in the lateral shell of the inferior colliculus appear to receive direct GABAergic inhibition from VLVp. I suggest that this circuitry and the algorithms it supports are the neural substrates that allow the barn owl to exploit level differences for computation of sound source elevation. PMID:7690063

  16. A temperature rise reduces trial-to-trial variability of locust auditory neuron responses

    PubMed Central

    Schleimer, Jan-Hendrik; Schreiber, Susanne; Ronacher, Bernhard

    2015-01-01

    The neurophysiology of ectothermic animals, such as insects, is affected by environmental temperature, as their body temperature fluctuates with ambient conditions. Changes in temperature alter properties of neurons and, consequently, have an impact on the processing of information. Nevertheless, nervous system function is often maintained over a broad temperature range, exhibiting a surprising robustness to variations in temperature. A special problem arises for acoustically communicating insects, as in these animals mate recognition and mate localization typically rely on the decoding of fast amplitude modulations in calling and courtship songs. In the auditory periphery, however, temporal resolution is constrained by intrinsic neuronal noise. Such noise predominantly arises from the stochasticity of ion channel gating and potentially impairs the processing of sensory signals. On the basis of intracellular recordings of locust auditory neurons, we show that intrinsic neuronal variability on the level of spikes is reduced with increasing temperature. We use a detailed mathematical model including stochastic ion channel gating to shed light on the underlying biophysical mechanisms in auditory receptor neurons: because of a redistribution of channel-induced current noise toward higher frequencies and specifics of the temperature dependence of the membrane impedance, membrane potential noise is indeed reduced at higher temperatures. This finding holds under generic conditions and physiologically plausible assumptions on the temperature dependence of the channels' kinetics and peak conductances. We demonstrate that the identified mechanism also can explain the experimentally observed reduction of spike timing variability at higher temperatures. PMID:26041833

  17. Flattening plasma corticosterone levels increases the prevalence of serotonergic dorsal raphe neurons inhibitory responses to nicotine in adrenalectomised rats.

    PubMed

    Frías-Domínguez, Carmen; Garduño, Julieta; Hernández, Salvador; Drucker-Colin, René; Mihailescu, Stefan

    2013-09-01

    Major depression is characterized by a diminished activity of the brain serotonergic system as well as by the flattening of plasma cortisol levels. Nicotine improves mood in patients with major depression and in experimentally depressed animals by increasing brain serotonin (5-HT), noradrenaline and dopamine levels. The present study was directed to determine if flattening plasma glucocorticoid levels changes nicotine's stimulatory effects upon 5-HT DRN neurons. The experiments were performed in brain slices obtained from rats previously (14 days) adrenalectomised and implanted subcutaneously with one pellet containing 75mg of corticosterone (Adx+CSR rats). Whole cell voltage and current clamp techniques were used to study the activity of immunocitochemically identified 5-HT DRN neurons. Administration of nicotine (1μM) in sham-operated animals produced stimulatory effects in all 5-HT DRN neurons studied. In Adx+CSR rats however, nicotine inhibited 75% of 5-HT DRN neurons and increased the potassium-dependent inward rectifying current. The inhibitory effect of nicotine upon 5-HT DRN neurons was dependent on serotonin release inside the DRN, since it was converted into a stimulatory response by the selective antagonist of 5-HT1A receptors N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY100635, 25nM). Adx+CSR rats also presented an increased function of 5-HT1A autoreceptors, since, in these rats, serotonin (1-10μM) produced a higher increase in the potassium dependent inward rectifying current in comparison with sham-operated animals. Serotonin release inside DRN was mediated by α4β2 nicotinic acetylcholine receptors since the selective antagonist of these receptors dihydro-β-erytroidine hydrobromide (DHβE, 100nM) blocked the inhibitory effects of nicotine 5-HT DRN neurons. These data indicate that, in the experimental model of adrenalectomised rats implanted with corticosterone pellets, nicotine increases the function of

  18. The reducing agent dithiothreitol (DTT) does not abolish the inhibitory nicotinic response recorded from rat dorsolateral septal neurons

    NASA Technical Reports Server (NTRS)

    Sorenson, E. M.; Gallagher, J. P.

    1993-01-01

    Previous intracellular recordings have demonstrated that dorsolateral septal nucleus (DLSN) neurons express a novel nicotinic receptor which produces a direct membrane hyperpolarization when activated by nicotinic agonists. Activation of the classical excitatory nicotinic receptors has been shown to require a disulfide bond involving the cysteines at positions 192 and 193 of the alpha subunits of the receptor. Reduction of this cystine bond with dithiothreitol (DTT) abolishes agonist activation of excitatory nicotinic receptors. We have now examined whether DTT treatment of the inhibitory nicotinic receptor on DLSN neurons also abolishes the inhibitory nicotinic response. We find that the inhibitory response persists after treatment of the neurons with 1 mM DTT, even if the reduction is followed by alkylation of the receptor with bromoacetylcholine to prevent possible reformation of disulfide bonds. This result suggests that the agonist binding site on the inhibitory nicotinic receptor does not require an intact disulfide bond, similar to the bond on the alpha subunit of the excitatory nicotinic receptor, for agonist activation of the receptor. Some of these results have been previously reported in abstract form.

  19. Response properties and location of neurons selective for sinusoidal frequency modulations in the inferior colliculus of the big brown bat.

    PubMed

    Yue, Qi; Casseday, John H; Covey, Ellen

    2007-09-01

    Most animal vocalizations, including echolocation signals used by bats, contain frequency-modulated (FM) components. Previous studies have described a class of neurons in the inferior colliculus (IC) of the big brown bat that respond exclusively to sinusoidally frequency modulated (SFM) signals and fail to respond to pure tones, noise, amplitude-modulated tones, or single FM sweeps. The aims of this study were to further characterize these neurons' response properties and to determine whether they are localized within a specific area of the IC. We recorded extracellularly from 214 neurons throughout the IC. Of these, 47 (22%) responded exclusively to SFM. SFM-selective cells were tuned to relatively low carrier frequencies (9-50 kHz), low modulation rates (20-210 Hz), and shallow modulation depths (3-10 kHz). Most had extremely low thresholds, with an average of 16.5 +/- 7.6 dB SPL, and 89% had upper thresholds and closed response areas. For SFM-selective cells with spontaneous activity, the spontaneous activity was eliminated when sound amplitude exceeded their upper threshold and resumed after the stimulus was over. These findings suggest that SFM-selective cells receive low-threshold excitatory inputs and high-threshold inhibitory inputs. SFM-selective cells were clustered in the rostrodorsal part of the IC. Within this area, best modulation rate appeared to be correlated with best carrier frequency and depth within the IC.

  20. Electrophysiological properties and cholinergic responses of rat ventral oral pontine reticular neurons in vitro.

    PubMed

    Nuñez, A; De la Roza, C; Rodrigo-Angulo, M L; Buño, W; Reinoso-Suárez, F

    1997-04-18

    In order to characterize the electrophysiological properties of morphologically identified neurons of the ventral part of the oral pontine reticular (vRPO) nucleus and the effects of cholinergic agonists on them, intracellular recordings were obtained from 45 cells in a rat brain-slice preparation. Intracellular staining was performed with 2% biocytin in potassium acetate (1 M)-filled micropipettes. Results demonstrated the presence of two types of vRPO neurons. Type I cells (n = 12, 24%) were characterized by a break with a decrease of the depolarizing slope following hyperpolarizing pulses which delayed the return to the resting Vm and subsequent spike-firing. The delay was antagonized by 4-AP (200-500 microM) which specifically blocks the transient outward K+-mediated current I(A). Type II neurons (n = 38, 76%) displayed a typical depolarizing sag during hyperpolarizing current pulses which was blocked by Cs+. This behavior is characteristic of the hyperpolarization-activated current I(Q). These two neuronal types displayed different morphological features. Most type I and II cells (100 and 73.7%, respectively) were depolarized by acetylcholine (1-15 microM), carbachol (0.5-1 microM) and muscarine (1-10 microM) through the activation of post-synaptic muscarinic receptors. The remaining type II cells (26.3%) were hyperpolarized (1-10 min, 3-15 mV) through the activation of post-synaptic muscarinic receptors. Results are consistent with the hypothesis that the vRPO could be a neuronal target of Cch in eliciting paradoxical sleep because most of its neurons are activated by muscarinic agonists.

  1. Effects of pharmacological treatment and photoinactivation on the directional responses of an insect neuron.

    PubMed

    Molina, Jorge; Stumpner, Andreas

    2005-12-01

    Soma-ipsilateral branches of the large segmental omega neuron of the phaneropterid bush cricket Ancistrura nigrovittata have smooth endings, which extend through most of the auditory neuropile. Correspondingly, it shows a broad frequency tuning. Large excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) are observed when recording from soma-ipsilateral branches. Stimulation from the soma-ipsilateral side leads to a strong excitation. Soma-contralateral branches have a strong, beaded appearance. IPSPs, which seem to be of soma-contralateral origin, can be recorded from these branches. Stimulation from the soma-contralateral side leads to a strong inhibition of the omega neuron. Soma-contralateral stimulation must be 30-40 dB more intense than soma-ipsilateral stimulation to evoke similar spike numbers in the omega neuron. The side-to-side difference is reduced to 10-15 dB after cutting the input from the soma-contralateral leg (tympanic nerve). The thresholds for eliciting IPSPs by soma-contralateral stimulation correspond roughly to excitatory thresholds of the mirror-image omega with the same stimuli. Pharmacological treatment with picrotoxin (PTX) or photoinactivation of the Lucifer Yellow filled mirror-image omega neuron reduces contralateral inhibition considerably and eliminates all visible IPSPs. Nevertheless, an additional contralateral inhibition survives both procedures and is only eliminated after cutting the soma-contralateral tympanic nerve. These results demonstrate that the mirror-image partners of the omega neuron mutually inhibit each other in bush crickets--as in crickets. This mutual inhibition is PTX-sensitive. At least one additional element exerts contralateral PTX-insensitive inhibition on the omega neuron.

  2. Anaphylatoxin-mediated regulation of the immune response. I. C3a- mediated suppression of human and murine humoral immune responses

    PubMed Central

    1982-01-01

    The C3a fragment of the third component of complement was found to have immunosuppressive properties. C3a is capable of suppressing both specific and polyclonal antibody responses. In contrast, C3a had no effect on antigen- or mitogen-induced B or T cell proliferative responses. The carboxy-terminal arginine is essential for C3a to exhibit its immunosuppressive properties. The serum carboxypeptidase inhibitor 2-mercaptomethyl-5-guanodinopentanoic acid, which prevents cleavage of the terminal arginine that would produce C3ades Arg-77, allowed us to assay the effects of C3a on in vitro immune response systems where serum is required. When the terminal arginine is removed from C3a, the resulting C3ades Arg-77 molecule is nonsuppressive. Helper T lymphocytes are the target of C3a-mediated suppression of the immune response. Substitution of T cells by soluble T cell factors was found to abrogate the C3a suppressive activity. PMID:6978374

  3. Non-neuronal release of ACh plays a key role in secretory response to luminal propionate in rat colon.

    PubMed

    Yajima, Takaji; Inoue, Ryo; Matsumoto, Megumi; Yajima, Masako

    2011-02-15

    Colonic chloride secretion is induced by chemical stimuli via the enteric nervous reflex. We have previously demonstrated that propionate stimulates chloride secretion via sensory and cholinergic systems of the mucosa in rat distal colon. In this study, we demonstrate non-neuronal release of ACh in the secretory response to propionate using an Ussing chamber. Mucosa preparations from the colon, not including the myenteric and submucosal plexuses, were used. Luminal addition of propionate and serosal addition of ACh caused biphasic changes in short-circuit current (Isc). TTX (1 μm) had no effects, while atropine (10 μm) significantly inhibited the Isc response to propionate and abolished that to ACh. In response to luminal propionate stimulation, ACh was released into the serosal fluid. A linear relationship was observed between the maximal increase in Isc and the amounts of ACh released 5 min after propionate stimulation. This ACh release induced by propionate was not affected by atropine and bumetanide, although both drugs significantly reduced the Isc responses to propionate. Luminal addition of 3-chloropropionate, an inactive analogue of propionate, abolished both ACh release and Isc response produced by propionate. RT-PCR analysis indicated that isolated crypt cells from the distal colon expressed an enzyme of ACh synthesis (ChAT) and transporters of organic cation (OCTs), but not neuronal CHT1 and VAChT. The isolated crypt cells contained comparable amounts of ACh to the residual muscle tissues including nerve plexuses. In conclusion, the non-neuronal release of ACh from colonocytes coupled with propionate stimulation plays a key role in chloride secretion, via the paracrine action of ACh on muscarinic receptors of colonocytes.

  4. The response of neurons in the bed nucleus of the stria terminalis to serotonin: Implications for anxiety

    PubMed Central

    Hammack, Sayamwong E.; Guo, JiDong; Hazra, Rimi; Dabrowska, Joanna; Myers, Karyn M.; Rainnie, Donald G.

    2009-01-01

    Substantial evidence has suggested that the activity of the bed nucleus of the stria terminalis (BNST) mediates many forms of anxiety-like behavior in human and non-human animals. These data have led many investigators to suggest that abnormal processing within this nucleus may underlie anxiety disorders in humans, and effective anxiety treatments may restore normal BNST functioning. Currently some of the most effective treatments for anxiety disorders are drugs that modulate serotonin (5-HT) systems, and several decades of research have suggested that the activation of 5-HT can modulate anxiety-like behavior. Despite these facts, relatively few studies have examined how activity within the BNST is modulated by 5-HT. Here we review our own investigations using in vitro whole-cell patch-clamp electrophysiological methods on brain sections containing the BNST to determine the response of BNST neurons to exog