| 1. |
- Edoff, Karin, 1973-, et al.
(författare)
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Neuropeptide content and physiological properties of rat cartilage-projecting sensory neurones co-cultured with perichondrial cells
- 2001
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Ingår i: Neuroscience Letters. - 0304-3940 .- 1872-7972. ; 315:3, s. 141-144
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Granseth, Björn, 1973-, et al.
(författare)
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Augmentation of corticogeniculate EPSCs in principal cells of the dorsal lateral geniculate nucleus of the rat investigated in vitro
- 2004
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 556:1, s. 147-157
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
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| 4. |
- Granseth, Björn, 1973-, et al.
(författare)
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Paired pulse facilitation of corticogeniculate EPSCs in the dorsal lateral geniculate nucleus of the rat investigated in vitro
- 2002
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 544:2, s. 477-486
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Granseth, Björn, 1973-, et al.
(författare)
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Regulation of thalamocortical axon branching by BDNF and synaptic vesicle cycling
- 2013
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Ingår i: Frontiers in Neural Circuits. - : Frontiers Media SA. - 1662-5110. ; 7:202
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Granseth, Björn, 1973-
(författare)
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The corticogeniculate synapse : a neuronal amplifier?
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 7. |
- Granseth, Björn, 1973-, et al.
(författare)
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The role of endocytosis in regulating the strength of hippocampal synapses
- 2008
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 586, s. 5969-5982
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Granseth, Björn, 1973-, et al.
(författare)
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Unitary EPSCs of corticogeniculate fibers in the rat dorsal lateral geniculate nucleus in vitro
- 2003
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Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 89:6, s. 2952-2960
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Klawonn, Anna, 1985-, et al.
(författare)
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Motivational valence is determined by striatal melanocortin 4 receptors
- 2018
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 128:7, s. 3160-3170
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Sundberg, Sofie, 1984-
(författare)
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Neuromodulation, Short-Term and Long-Term Plasticity in Corticothalamic and Hippocampal Neuronal Networks
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Research in neuroscience relies to a large extent on the use of genetically modified animals. Extensive validation of new and existing models is a requirement for the acquisition of trustworthy data and to enable generalization to human physiology and disease. This thesis includes, as one part (project I and II), validation of a transgenic mouse model with the expression of the enzyme Cre-recombinase restricted to neurons in a band in the deepest layer of the cerebral cortex. Secondly, in project III we use this mouse model to study the process of short-term plasticity in neuronal cultures. Lastly, we investigate synaptic plasticity by studying the effect that the developmental signaling factor Hedgehog (Hh) has on mature hippocampal cultures (project IV). In project I and II, we identified the transgenic mouse Neurotensin receptor 1-Cre GN220 (Ntsr1-Cre) to have Cre expression targeted to the corticothalamic (CT) pyramidal neuron population in neocortical layer 6. Further, we identified a small group of Ntsr1-Cre positive neurons present in the white matter that is distinct from the CT population. We also identified that the transcription factor Forkhead box protein 2 (FoxP2) was specifically expressed by CT neurons in neocortex. In project I, we further explored the sensitivity of CT neurons to cholinergic modulation and found that they are sensitive to even low concentrations of acetylcholine. Both nicotinic and muscarinic acetylcholine receptors depolarize the neurons. Presenting CT neurons as a potential target for cholinergic modulation in wakefulness and arousal. In project III we studied Ntsr1-Cre neurons in cortical cultures and found that cultured neurons have similar properties to CT neurons in the intact nervous system. Ntsr1-Cre neurons in culture often formed synapses with itself, i. e. autapses, with short-term synaptic plasticity that was different to ordinary synapses. By expressing the light-controlled ion channel channelrhodopsin-2 (ChR2) in Ntsr1-Cre neurons we could compare paired pulse ratios with either electrical or light stimulation. Electrical stimulation typically produced paired-pulse facilitation while light stimulation produced paired pulse depression, presumably due to unphysiological Ca2+ influx in presynaptic terminals. Thus, cultured Ntsr1- Cre neurons can be used to study facilitation, and ChR2 could be used as a practical tool to further study the dependence of Ca2+ for short-term plasticity. In project IV we investigated the role of Hedgehog (Hh) for hippocampal neuron plasticity. Non-canonical Hh-signaling negatively regulated NMDA- receptor function through an unknown mechanism resulting in changes in NMDA-receptor mediated currents and subsequent changes in AMPA- receptors in an LTP/LTD manner in mature neurons. Proposing Hh as a slow-acting factor with ability to scale down excitation for instances of excessive activity, e.g. during an epileptic seizure, as a mechanism to make the activity in the neuronal networks stable.
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