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  • 1.
    Alkhori, Liza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Sanchez, Gonzalo M.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian W.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kuzhandaivel, Anujaianthi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, The Institute of Technology.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hh signalling regulates odorant receptor cilia localization in Drosophila2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development. Here, we show that in adult OSNs the Hh pathway regulate 􀁒dorant receptor transport to cilia and put forward a novel non-developmental function of the pathway as a neuromodulator. We demonstrate that the level of Hh signal modulate the OSNs response to odors. We show that knock down of Hh and Smoothened (Smo), a transmembrane protein that transduce the signal, are required for receptor transport. We further show that the coreceptor, Orco, has an Hh independent transport path and that knock down of Smo segregate OR and Orco to different vesicular compartments. Last, we show that the odor response to the second receptor type in Drosophila olfaction, the ionotropic receptors (IRs), also require Hh signalling. Thus, Hh signalling is a general regulator of the odorant response that fulfils the criteria of being a potential player in Drosophila odorant adaptation.

  • 2.
    Edoff, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Granseth, Björn
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Neuropeptide content and physiological properties of rat cartilage-projecting sensory neurones co-cultured with perichondrial cells2001In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 315, no 3, p. 141-144Article in journal (Refereed)
    Abstract [en]

    In young rats the cartilaginous epiphyses forming the knee joint are supplied with blood vessels and peptidergic sensory nerve fibres through the perichondrium and cartilage canals. In the present study we show that cartilage-related dorsal root ganglion neurones co-cultured with perichondrial cells develop extensive neurite trees and express calcitonin gene-related peptide (CGRP) and substance P (SP) in in vivo-like proportions using retrograde tracing and immunohistochemistry. Moreover, whole cell patch clamp recordings from these cells showed that the majority is depolarised by application of H+-ions. These results are compatible with the hypothesis that a local imbalance of blood flow and metabolism during normal skeletal maturation may cause tissue acidosis eliciting release of CGRP/SP from sensory nerve endings.

  • 3.
    Granseth, B
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ahlstrand, Erik
    Lindstrom, S
    Effects of extracellullar calcium ions on paired pulse facilitation and depression in the dorsal lateral geniculate nucleus in vitro.2000Conference paper (Other academic)
  • 4.
    Granseth, Björn
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Dynamic properties of corticogeniculate excitatory transmission in the rat dorsal lateral geniculate nucleus in vitro2004In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 556, no 1, p. 135-146Article in journal (Refereed)
    Abstract [en]

    The feedback excitation from the primary visual cortex to principal cells in the dorsal lateral geniculate nucleus (dLGN) is markedly enhanced with firing frequency. This property presumably reflects the ample short-term plasticity at the corticogeniculate synapse. The present study aims to explore corticogeniculate excitatory postsynaptic currents (EPSCs) evoked by brief trains of stimulation with whole-cell patch-clamp recordings in dLGN slices from DA-HAN rats. The EPSCs rapidly increased in amplitude with the first two or three impulses followed by a more gradual growth. A double exponential function with time constants 39 and 450 ms empirically described the growth for 5–25Hz trains. For lower train frequencies (down to 1Hz) a third component with time constant 4.8 s had to be included. The different time constants are suggested to represent fast and slow components of facilitation and augmentation. The time constant of the fast component changed with the extracellular calcium ion concentration as expected for a facilitation mechanism involving an endogenous calcium buffer that is more efficiently saturated with larger calcium influx. Concerning the function of the corticogeniculate feedback pathway, the different components of short-term plasticity interacted to increase EPSC amplitudes on a linear scale to firing frequency in the physiological range. This property makes the corticogeniculate synapse well suited to function as a neuronal amplifier that enhances the thalamic transfer of visual information to the cortex.

  • 5.
    Granseth, Björn
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    The corticogeniculate synapse: a neuronal amplifier?2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Consciousness is a nervous process that handles only a limited amount of information. Therefore the nervous system needs to select the most relevant input for aware processing. For the visual system, it has been suggested that recurrent excitation from the cortex to neurones in the lateral geniculate nucleus provides a "spotlight of attention", that selectively enhances the relay of information to the cortex. Such feedback excitation could be supplied by corticogeniculate neurones in layer 6 of the primary visual cortex. The corticogeniculate synaptic strength increases with neuronal firing frequency. From this property it can be hypothesised that the feedback excitation would function as a variable neuronal amplifier for boosting the information transfer in the attentive state. The general aim of this thesis was to study the synaptic mechanisms that make the corticogeniculate synapse frequency sensitive and evaluate this property in relation to the proposed neuronal amplifier function.

    Experiments were performed with whole-cell patch-clamp recordings from principal cells in a slice preparation of the rat dorsal lateral geniculate nucleus. Ex citatory postsynaptic currents (EPSCs) evoked by stimulation of corticogeniculate axons consistently displayed paired pulse facilitation. The ratio EPSC2 I EPSC1 was 3.7 ± 1.6 (mean ± standard deviation) for two pulses separated 40 ms. The paired pulse facilitation comprised a fast and slow component, evident from its double exponential decay. EPSCs evoked in the same cells by stimulating axons from the retina displayed paired pulse depression. The two types of EPSCs differed in their response to alterations in the extracellular calcium ion concentration ([Ca2+]o). The paired pulse depression at retinogeniculate synapses was attenuated by decreasing [Ca2+]o, apparently from lowering the level of transmitter release. At the corticogeniculate synapse, paired pulse facilitation was optimal at physiological [Ca2+]o. The facilitation was presynaptic in origin since the facilitated EPSC2 quantal size (q = - 5.2 ± 0.8 pA) was essentially the same as for EPSC1 (q = - 4.9 ± 0.9 pA). Each corticogeniculate axon terminated with 1 - 2 functional synapses (nsyn) per principal cell and the basal transmitter release probability was low (psyn = 0.09 ± 0.04) but increased with facilitation (psyn = 0.25 ± 0.10).

    When short trains of pulses were used for stimulation of corticogeniculate axons, the EPSCs rapidly increased in amplitude with the first 2 - 3 stimuli followed by a more gradual growth. A double exponential function, likely to represent the fast and slow components of facilitation could describe the EPSC build-up in amplitude. The time constant of fast facilitation was dependent on [Ca2+]o , presumably representing Ca2+ binding to a saturable intraterminal Ca2+ buffer. When pulse trains were repeated at 1 - 10 s intervals, EPSC1 in each train was progressively enhanced by augmentation, leaving late EPSCs unaffected. When [Ca2+]o was altered, augmented EPSCs changed in proportion to the basal EPSC amplitude, i.e. EPSC1:n / EPSC1,1 remained the same. The results indicate that augmentation is determined by a Ca2+ residue in the presynaptic terminal after repetitive spike firing, competing with the mechanism of the fast component of facilitation.

    The two components of facilitation and augmentation at the corticogeniculate synapse define the function of the suggested neuronal amplifier. The low basal synaptic strength ascertains that single random spikes will be virtually ineffective at the target cell, which protects the ex citatory feedback system from self-generated cyclic activity. Since the different forms of synaptic enhancement are presynaptic, the neuronal amplifier will be strictly stimulus specific in increasing synaptic strength. Furthermore, the different components seem to interact to increase EPSC amplitudes on a linear scale to firing frequency, that will increase the dynamic range of neuronal firing without distorting the basic characteristics of thalamic relay. Fast facilitation would account for most of the gain of the neuronal amplifier, while augmentation primarily reduces the time required to reach an effective level of synaptic strength. Thus it might serve to preserve the gain of the neuronal amplifier during attentive visual exploration, when the gaze may return repeatedly to the same fixation point.

  • 6.
    Granseth, Björn
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ahlstrand, Erik
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Sivert
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Paired pulse facilitation of corticogeniculate EPSCs in the dorsal lateral geniculate nucleus of the rat investigated in vitro2002In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 544, no 2, p. 477-486Article in journal (Refereed)
    Abstract [en]

    To investigate paired pulse facilitation of corticogeniculate EPSCs, whole-cell patch-clamp recordings were made from principal cells in the rat dorsal lateral geniculate nucleus (dLGN) in vitro. Thalamic slices, oriented so that both corticogeniculate and retinogeniculate axons could be stimulated, were cut from young (16- to 37-day-old) DA-HAN rats. Corticogeniculate EPSCs displayed pronounced paired pulse facilitation at stimulus intervals up to 400 ms. The facilitation had a fast and a slow component of decay with time constants of 12 ± 7 and 164 ± 47 ms (means ± s.d.), respectively. Maximum paired pulse ratio (EPSC2 × EPSC1−1) was 3.7 ± 1.1 at the 20-30 ms interval. Similar to other systems, the facilitation was presynaptic. Retinogeniculate EPSCs recorded in the same dLGN cells displayed paired pulse depression at intervals up to at least 700 ms. The two types of EPSCs differed in their calcium response curves. At normal [Ca2+]o, the corticogeniculate synapse functioned over the early rising part of a Hill function, while the retinogeniculate synapse operated over the middle and upper parts of the curve. The paired pulse ratio of corticogeniculate EPSCs was maximal at physiological [Ca2+]o. The facilitation is proposed to have an important role in the function of the corticogeniculate circuit as a neuronal amplifier.

  • 7.
    Granseth, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Fredrik K
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lindström, Sarah H
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    The initial stage of reversal learning is impaired in mice hemizygous for the vesicular glutamate transporter (VGluT1)2015In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 14, no 6, p. 477-485Article in journal (Refereed)
    Abstract [en]

    Behavioral flexibility is a complex cognitive function that is necessary for survival in changeable environments. Patients with schizophrenia or Parkinsons disease often suffer from cognitive rigidity, reducing their capacity to function in society. Patients and rodent models with focal lesions in the prefrontal cortex (PFC) show similar rigidity, owing to the loss of PFC regulation of subcortical reward circuits involved in behavioral flexibility. The vesicular glutamate transporter (VGluT1) is preferentially expressed at modulatory synapses, including PFC neurons that project to components of the reward circuit (such as the nucleus accumbens, NAc). VGluT1(+/-) mice display behavioral phenotypes matching many symptoms of schizophrenia, and VGluT1 expression is reduced in the PFC of patients with schizophrenia and Parkinsons disease. Thus, it appears likely that VGluT1-expressing synapses from PFC play a key role in behavioral flexibility. To examine this hypothesis, we studied behavioral flexibility in VGluT1(+/-) mice by testing reversal learning in a visual discrimination task. Here, we show that VGluT1(+/-) mice acquired the initial visual discrimination at the same rate as controls. However, they failed to suppress responses to the previously rewarded stimulus following reversal of reward contingencies. Thus, our genetic disruption of modulatory glutamatergic signaling, including that arising from PFC, appears to have impaired the first stage of reversal learning (extinguishing responses to previously rewarded stimuli). Our data show that this deficit stems from a preservative phenotype. These findings suggest that glutamatergic regulation from the cortex is important for behavioral flexibility and the disruption of this pathway may be relevant in diseases such as schizophrenia.

  • 8.
    Granseth, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Osaka University, Suita, Japan.
    Fukushima, Yuichi
    Osaka University, Suita, Japan.
    Sugo, Noriuki
    Osaka University, Suita, Japan.
    Lagnado, Leon
    Osaka University, Suita, Japan.
    Yamamoto, Nobuhiko
    Osaka University, Suita, Japan.
    Regulation of thalamocortical axon branching by BDNF and synaptic vesicle cycling2013In: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 7, no 202Article in journal (Refereed)
    Abstract [en]

    During development, axons form branches in response to extracellular molecules. Little is known about the underlying molecular mechanisms. Here, we investigate how neurotrophin-induced axon branching is related to synaptic vesicle cycling for thalamocortical axons. The exogenous application of brain-derived neurotrophic factor (BDNF) markedly increased axon branching in thalamocortical co-cultures, while removal of endogenous BDNF reduced branching. Over-expression of a C-terminal fragment of AP180 that inhibits clathrin-mediated endocytosis affected the laminar distribution and the number of branch points. A dominant-negative synaptotagmin mutant that selectively targets synaptic vesicle cycling, strongly suppressed axon branching. Moreover, axons expressing the mutant synaptotagmin were resistant to the branch-promoting effect of BDNF. These results suggest that synaptic vesicle cycling might regulate BDNF induced branching during the development of the axonal arbor.

  • 9.
    Granseth, Björn
    et al.
    MRC Laboratory of Molecular Biology, Cambridge.
    Lagnado, Leon
    MRC Laboratory of Molecular Biology, Cambridge.
    The role of endocytosis in regulating the strength of hippocampal synapses2008In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 586, p. 5969-5982Article in journal (Refereed)
    Abstract [en]

    The readily releasable pool of vesicles (RRP) varies in size during synaptic activity and is replenished by recruitment from the reserve pool as well as vesicle retrieval after fusion. To investigate which of these steps is rate limiting in supplying vesicles to the RRP, we measured the effects of changes in temperature in cultured hippocampal neurons, where higher average rates of release can be maintained as the temperature is increased. Using a pHluorin-based reporter of exocytosis and endocytosis (sypHy), we find that changes in temperature between 25 degrees C and 35 degrees C do not significantly alter the rate of recruitment from the reserve pool. In contrast, the time constant of endocytosis fell from approximately 17 s at 25 degrees C to approximately 10 s at 35 degrees C (Q(10) = 1.7), while the time constant of vesicle reacidification fell from approximately 5.5 s to approximately 1 s (Q(10) = 5.5). A kinetic model of the vesicle cycle constructed using measured parameters was found to describe variations in vesicle release rate observed during long trains of spikes as well as recovery from synaptic depression after bursts of activity. These results indicate that endocytosis operating with time constants of 10-15 s is the rate-limiting process determining replenishment of the RRP during long-term activity. A fast mode of vesicle retrieval could not be detected at any temperature, nor was it necessary to invoke such a mechanism to account for use-dependent changes in synaptic release probability.

  • 10.
    Granseth, Björn
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Sivert
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Augmentation of corticogeniculate EPSCs in principal cells of the dorsal lateral geniculate nucleus of the rat investigated in vitro2004In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 556, no 1, p. 147-157Article in journal (Refereed)
    Abstract [en]

    Augmentation is a component of short-term synaptic plasticity with a gradual onset and duration in seconds. To investigate this component at the corticogeniculate synapse, whole cell patch-clamp recordings were obtained from principal cells in a slice preparation of the rat dorsal lateral geniculate nucleus. Trains with 10 stimuli at 25 Hz evoked excitatory postsynaptic currents (EPSCs) that grew in amplitude, primarily from facilitation. Such trains also induced augmentation that decayed exponentially with a time constant τ= 4.6 ± 2.6 s (mean ± standard deviation). When the trains were repeated at 1–10 s intervals, augmentation markedly increased the size of the first EPSCs, leaving late EPSCs unaffected. The magnitude of augmentation was dependent on the number of pulses, pulse rate and intervals between trains. Augmented EPSCs changed proportionally to basal EPSC amplitudes following alterations in extracellular calcium ion concentration. The results indicate that augmentation is determined by residual calcium remaining in the presynaptic terminal after repetitive spikes, competing with fast facilitation. We propose that augmentation serves to maintain a high synaptic strength in the corticogeniculate positive feedback system during attentive visual exploration.

  • 11.
    Granseth, Björn
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Sivert
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Unitary EPSCs of corticogeniculate fibers in the rat dorsal lateral geniculate nucleus in vitro2003In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 89, no 6, p. 2952-2960Article in journal (Refereed)
    Abstract [en]

    To investigate unitary corticogeniculate excitatory postsynaptic currents (EPSCs), whole cell patch-clamp recordings were obtained from 20 principal cells in slices of the dorsal lateral geniculate nucleus (dLGN) of DA-HAN rats. EPSCs, evoked by electrical stimulation of corticogeniculate axons, had size distributions with one or more quantal peaks. Gaussian curves fitted to such distributions gave a mean quantal size (q) of -5.0 ± 0.7 (SD) pA for the EPSCs. Paired-pulse ratio (EPSC2/EPSC1) was 3.3 ± 0.9 for stimuli separated by 40 ms. The mean quantal size was similar for facilitated EPSCs (-5.2 ± 0.8 pA), implying an increase in mean quantal content (m). Most corticogeniculate axons were capable of releasing only one or two quanta onto individual principal cells. Mean resting release probability (p) was low, 0.09 ± 0.04. Binomial models, with the same n but increased p, could account for both the basal and facilitated EPSC size distributions in 6/8 cells. It is suggested that the low resting efficacy of corticogeniculate synapses serves to stabilize this excitatory feedback system. The pronounced facilitation in conjunction with large convergence from many corticogeniculate cells would provide a transient, potent excitation of dLGN cells, compliant with the idea of a visually driven neuronal amplifier.

  • 12.
    Granseth, Björn
    et al.
    MRC Laboratory of Molecular Biology, Cambridge.
    Odermatt, Benjamin
    MRC-LMB, Cambridge.
    Royle, Stephen J
    MRC-LMB, Cambridge.
    Lagnado, Leon
    MRC-LMB, Cambridge.
    Clathrin-mediated endocytosis is the dominant mechanism of vesicle retrieval at hippocampal synapses2006In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 51, no 6, p. 773-786Article in journal (Refereed)
    Abstract [en]

    The maintenance of synaptic transmission requires that vesicles be recycled after releasing neurotransmitter. Several modes of retrieval have been proposed to operate at small synaptic terminals of central neurons, including a fast "kiss-and-run" mechanism that releases neurotransmitter through a fusion pore. Using an improved fluorescent reporter comprising pHluorin fused to synaptophysin, we find that only a slow mode of endocytosis (tau = 15 s) operates at hippocampal synapses when vesicle fusion is triggered by a single nerve impulse or short burst. This retrieval mechanism is blocked by overexpression of the C-terminal fragment of AP180 or by knockdown of clathrin using RNAi, and it is associated with the movement of clathrin and vesicle proteins out of the synapse. These results indicate that clathrin-mediated endocytosis is the major, if not exclusive, mechanism of vesicle retrieval after physiological stimuli.

  • 13.
    Granseth, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Odermatt, Benjamin
    MRC-LMB, Cambridge.
    Royle, Stephen J
    MRC-LMB, Cambridge.
    Lagnado, Leon
    MRC-LMB, Cambridge.
    Clathrin-mediated endocytosis: the physiological mechanism of vesicle retrieval at hippocampal synapses2007In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 585, no 3, p. 681-686Article, review/survey (Refereed)
    Abstract [en]

    The maintenance of synaptic transmission requires that vesicles are recycled after releasing neurotransmitter. Several modes of retrieval have been proposed to operate at small synaptic terminals of central neurons, but the relative importance of these has been controversial. It is established that synaptic vesicles can collapse on fusion and the machinery for retrieving this membrane by clathrin-mediated endocytosis (CME) is enriched in the presynaptic terminal. But it has also been suggested that the majority of vesicles released by physiological stimulation are recycled by a second, faster mechanism called 'kiss-and-run', which operates in 1 s or less to retrieve a vesicle before it has collapsed. The most recent evidence argues against the occurrence of 'kiss-and-run' in hippocampal synapses. First, an improved fluorescent reporter of exocytosis (sypHy), indicates that only a slow mode of endocytosis (tau = 15 s) operates when vesicle fusion is triggered by a single nerve impulse or short burst. Second, this retrieval mechanism is blocked by overexpressing the C-terminal fragment of AP180 or by knockdown of clathrin using RNAi. Third, vesicle fusion is associated with the movement of clathrin and vesicle proteins out of the synapse into the neighbouring axon. These observations indicate that clathrin-mediated endocytosis is the major, if not exclusive, mechanism of retrieval in small hippocampal synapses.

  • 14.
    Granseth, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Odermatt, Benjamin
    Medical Research Council, Cambridge.
    Royle, Stephen J.
    University of Liverpool.
    Lagnado, Leon
    Medical Research Council, Cambridge.
    Comment on "The Dynamic Control of Kiss-and-Run and Vesicular Reuse Probed with Single Nanoparticles": in Science(ISSN 0036-8075) vol 325, issue 5947, pp 14992009In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 323, no 5947, p. 1499-Article in journal (Other academic)
    Abstract [en]

    Zhang et al. (Research Articles, 13 March 2009, p. 1448) reported that synaptic vesicles usually release neurotransmitter through a kiss-and-run mechanism occurring within 1 second but that full collapse of the vesicles becomes more prevalent with repeated stimuli. We report that the kinetics of vesicle retrieval do not change during a stimulus train, with endocytosis occurring in 10 to 15 seconds.

  • 15.
    Klawonn, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Fritz, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bonaventura, Jordi
    NIDA, MD USA.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Urban
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Michaelides, Michael
    NIDA, MD USA; Johns Hopkins Sch Med, MD USA.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Motivational valence is determined by striatal melanocortin 4 receptors2018In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 7, p. 3160-3170Article in journal (Refereed)
    Abstract [en]

    It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

  • 16.
    Klawonn, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rådberg, Carl F.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindström, Sarah
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Ericson, Mia
    University of Gothenburg, Sweden.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Fritz, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 714Article in journal (Refereed)
    Abstract [en]

    Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatmentresistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and in vivo microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via in vivo microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.

  • 17. Lindström, Sarah H
    et al.
    Sundberg, Sofie C
    Larsson, Max
    Andersson, Fredrik K
    Broman, Jonas
    Granseth, Björn
    Linköping University.
    VGluT1 Deficiency Impairs Visual Attention and Reduces the Dynamic Range of Short-Term Plasticity at Corticothalamic Synapses.2019In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, article id bhz204Article in journal (Refereed)
    Abstract [en]

    The most common excitatory neurotransmitter in the central nervous system, glutamate, is loaded into synaptic vesicles by vesicular glutamate transporters (VGluTs). The primary isoforms, VGluT1 and 2, are expressed in complementary patterns throughout the brain and correlate with short-term synaptic plasticity. VGluT1 deficiency is observed in certain neurological disorders, and hemizygous (VGluT1+/-) mice display increased anxiety and depression, altered sensorimotor gating, and impairments in learning and memory. The synaptic mechanisms underlying these behavioral deficits are unknown. Here, we show that VGluT1+/- mice had decreased visual processing speeds during a sustained visual-spatial attention task. Furthermore, in vitro recordings of corticothalamic (CT) synapses revealed dramatic reductions in short-term facilitation, increased initial release probability, and earlier synaptic depression in VGluT1+/- mice. Our electron microscopy results show that VGluT1 concentration is reduced at CT synapses of hemizygous mice, but other features (such as vesicle number and active zone size) are unchanged. We conclude that VGluT1-haploinsuficiency decreases the dynamic range of gain modulation provided by CT feedback to the thalamus, and this deficiency contributes to the observed attentional processing deficit. We further hypothesize that VGluT1 concentration regulates release probability by applying a "brake" to an unidentified presynaptic protein that typically acts as a positive regulator of release.

  • 18.
    Nath, Sangeeta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Roshan, Firoz
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 26, p. 8767-8777Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of beta-amyloid (A beta) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A beta oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A beta. Additional studies conducted in a human donor-acceptor cell model show that this A beta transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A beta oligomers play a role in neurodegeneration, and they explain the manner in which A beta can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

  • 19.
    Nersisyan, Syune
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bekisz, Marek
    Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
    Kublik, Ewa
    Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Wrobel, Andrzej
    Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
    Cholinergic modulation of synaptic properties of cortical layer VI input to posteromedial thalamic nucleus of the rat investigated in vitro2012In: Acta Neurobiologiae Experimentalis, ISSN 0065-1400, E-ISSN 1689-0035, Vol. 72, no 4, p. 461-467Article in journal (Refereed)
    Abstract [en]

    The second order somatosensory thalamic nucleus (posteromedial nucleus, PoM) receives excitatory projection from layer VI of somatosensory cortex. While it is known that layer VI cortical input to first order, ventrobasal nucleus (VB) is modulated by cholinergic projections from the brainstem, no such data exists concerning the PoM nucleus. In order to study if layer VI corticothalamic transmission to PoM is also modulated we used patch-clamp recording in thalamocortical slices from the rat's brain. Excitatory postsynaptic potentials (EPSPs) were evoked in PoM cells by trains of 5 electrical pulses at 20 Hz frequency applied to corticothalamic fibers. After carbachol was applied to mimic activation of the cholinergic neuromodulatory system corticothalamic EPSP amplitudes were reduced, while facilitation of EPSP amplitudes was enhanced for each next pulse in the series. Such cholinergic control of layer VI corticothalamic synapses in PoM may be used as gain modulator for the transfer of the peripheral sensory information to the cortex.

  • 20.
    Royle, Stephen J
    et al.
    School of Biomedical Sciences, University of Liverpool, Liverpool, UK.
    Granseth, Björn
    MRC Laboratory of Molecular Biology, Cambridge, UK.
    Odermatt, Benjamin
    MRC Laboratory of Molecular Biology, Cambridge, UK.
    Derevier, Aude
    MRC Laboratory of Molecular Biology, Cambridge, UK.
    Lagnado, Leon
    MRC Laboratory of Molecular Biology, Cambridge, UK.
    Imaging phluorin-based probes at hippocampal synapses2008In: Membrane Trafficking / [ed] Ales Vancura, Humana Press, 2008, Vol. 457, p. 293-303Chapter in book (Other academic)
    Abstract [en]

    Accurate measurement of synaptic vesicle exocytosis and endocytosis is crucial to understanding the molecular basis of synaptic transmission. The fusion of a pH-sensitive green fluorescent protein (pHluorin) to various synaptic vesicle proteins has allowed the study of synaptic vesicle recycling in real time. Two such probes, synaptopHluorin and sypHy, have been imaged at synapses of hippocampal neurons in culture. The combination of these reporters with techniques for molecular interference, such as RNAi allows for the study of molecules involved in synaptic vesicle recycling. Here the authors describe methods for the culture and transfection of hippocampal neurons, imaging of pHluorin-based probes at synapses and analysis of pHluorin signals down to the resolution of individual synaptic vesicles.

  • 21.
    Sanchez, Gonzalo Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Alkhori Franzén, Liza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hatano, Eduardo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Oslo University Hospital, Norway.
    Kuzhandaivel, Anujaianthi
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Illinois, IL 60612 USA.
    Jafari, Shadi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 3, p. 464-470Article in journal (Refereed)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.

  • 22.
    Sanchez, Gonzalo Manuel
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Alkhori Franzén, Liza
    Linköpings universitet, Avdelningen för cellbiologi.
    Hatano, Eduardo
    Linköpings universitet, Avdelningen för cellbiologi.
    Schultz, Sebastian
    Linköpings universitet, Avdelningen för cellbiologi.
    Kuzhandaivel, Anujaianthi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Jafari, Shadi
    Linköpings universitet, Avdelningen för cellbiologi.
    Granseth, Björn
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 3, p. 464-470Article in journal (Refereed)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.

  • 23.
    Sundberg, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Cre-expressing neurons in the cortical white matter of Ntsr1-Cre GN220 mice2018In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 675, p. 36-40Article in journal (Refereed)
    Abstract [en]

    Genetically modified mouse strains that express Cre-recombinase in specific neuronal sub-populations have become widely used tools for investigating neuronal function. The Ntsr1-Cre GN220 mouse expresses this enzyme in corticothalamic neurons in layer 6 of cerebral cortex. We observed that about 7% of Cre-expressing cells in the primary visual cortex are found within the white matter bordering layer 6. By using the immunohistochemical marker for layer 6 neurons, Forkhead box protein 2 (FoxP2), and fluorescently conjugated latex beads injected into the dorsal lateral geniculate nucleus, we show that about half of these cells are similar to and could belong to the layer 6 corticothalamic neuron population. The other half seems to be a distinct white matter (WM) neuron sub-population that we estimate to constitute 2-4% of the total cortical Cre expressing population. Staining for the neuronal marker Neuronal nuclei (NeuN) revealed that about 15-40% of WM neurons are Cre-expressing. Thus, the potential contribution from WM neurons needs to be considered when interpreting the results from experiments using the Ntsr1-Cre GN220 mouse for investigating corticothalamic neuronal function.

  • 24.
    Sundberg, Sofie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lindström, Sarah
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Sanchez, Gonzalo Manuel
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Cre-expressing neurons in visual cortex of Ntsr1-Cre GN220 mice are corticothalamic and are depolarized by acetylcholine2018In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 526, no 1, p. 120-132Article in journal (Refereed)
    Abstract [en]

    The Ntsr1-Cre GN220 mouse expresses Cre-recombinase in corticothalamic (CT) neurons in neocortical layer 6. It is not known if the other major types of pyramidal neurons in this layer also express this enzyme. By electrophysiological recordings in slices and histological analysis of the uptake of retrogradely transported beads we show that Cre-positive neurons are CT and not corticocortical or corticoclaustral types. Furthermore, we show that Ntsr1-Cre-positive cells are immuno-positive for the nuclear transcription factor Forkhead box protein P2 (FoxP2). We conclude that Cre-expression is limited to a specific type of pyramidal neuron: CT. However, it appears as not all CT neurons are Cre-expressing; there are indications that the penetrance of the gene is about 90%. We demonstrate the utility of assigning a specific identity to individual neurons by determining that the CT neurons are potently modulated by acetylcholine acting on both nicotinic and muscarinic acetylcholine receptors. These results corroborate the suggested function of these neurons in regulating the gain of thalamocortical transfer of sensory information depending on attentional demand and state of arousal.

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