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  • 1. Alvarez, S.
    et al.
    Calin, A.
    Sixtensdotter Graffmo, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Moldovan, M.
    Krarup, C.
    PERIPHERAL MOTOR AXONS OF SOD1(G127X) MUTANT MICE ARE SUSCEPTIBLE TO ACTIVITY-DEPENDENT DEGENERATION2013In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 241, 239-249 p.Article in journal (Refereed)
    Abstract [en]

    Motor neuron disorders may be associated with mitochondrial dysfunction, and repetitive electrical impulse conduction during energy restriction has been found to cause neuronal degeneration. The aim of this study was to investigate the vulnerability of motor axons of a presymptomatic late-onset, fast-progression SOD1(G127x) mouse model of amyotrophic lateral sclerosis to long-lasting, high-frequency repetitive activity. Tibial nerves were stimulated at ankle in 7 to 8-month-old SOD1(G127X) mice when they were clinically indistinguishable from wild-type (WT) mice. The evoked compound muscle action potentials and ascending compound nerve action potentials were recorded from plantar muscles and from the sciatic nerve, respectively. Repetitive stimulation (RS) was carried out in interrupted trains of 200-Hz for 3 h. During the stimulation-sequence there was progressive conduction failure in WT and, to a lesser extent, in the SOD1(G127x). By contrast, 3 days after RS the electrophysiological responses remained reduced in the SOD1(G127x) but recovered completely in WT. Additionally, morphological studies showed Wallerian degeneration in the disease model. Nerve excitability testing by "threshold-tracking" showed that axons recovering from RS had changes in excitability suggestive of membrane hyperpolarization, which was smaller in the SOD1(G127x) than in WT. Our data provide proof-of-principle that SOD1(G127x) axons are less resistant to activity-induced changes in ion-concentrations. It is possible that in SOD1(G127x) there is inadequate energy-dependent Na+/K+ pumping, which may lead to a lethal Na+ overload. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 2.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Haage, D.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, I. M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, J.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, S.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andreen, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ossewaarde, L.
    van Wingen, G. A.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bengtsson, S. K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 191, no Special issue, 46-54 p.Article, review/survey (Refereed)
    Abstract [en]

    Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane C1(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. (C) 2011 Published by Elsevier Ltd on behalf of IBRO.

  • 3.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Schouten, P
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Nevalainen, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 270, 1-11 p.Article in journal (Refereed)
    Abstract [en]

    Glial cell-derived neurotrophic factor (GDNF) exerts neuroprotective and neurorestorative effects on neurons and GDNF plays a significant role in maintenance of the dopamine neurons utilizing grafting to create a nigrostriatal microcircuit of Gdnf knockout (Gdnf(-/-)) tissue. To further evaluate the role of GDNF on organization of the nigrostriatal system, single or double grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) with mismatches in Gdnf genotypes were performed. The survival of single grafts was monitored utilizing magnetic resonance imaging (MRI) and cell survival and graft organization were evaluated with immunohistochemistry. The results revealed that the size of VM single grafts did not change over time independent of genotype, while the size of the LGE transplants was significantly reduced already at 2weeks postgrafting when lacking GDNF. Lack of GDNF did not significantly affect the survival of tyrosine hydroxylase (TH)-positive neurons in single VM grafts. However, the survival of TH-positive neurons was significantly reduced in VM derived from Gdnf(+/+) when co-grafted with LGE from the Gdnf(-/-) tissue. In contrast, lack of GDNF in the VM portion of co-grafts had no effect on the survival of TH-positive neurons when co-grafted with LGE from Gdnf(+/+) mice. The TH-positive innervation of co-grafts was sparse when the striatal co-grafts were derived from the Gdnf(-/-) tissue while dense and patchy when innervating LGE producing GDNF. The TH-positive innervation overlapped with the organization of dopamine and cyclic AMP-regulated phosphoprotein-relative molecular mass 32,000 (DARPP-32)-positive neurons, that was disorganized in LGE lacking GDNF production. In conclusion, GDNF is important for a proper striatal organization and for survival of TH-positive neurons in the presence of the striatal tissue.

  • 4.
    Dahlqvist, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Zhao, L
    Johansson, I M
    Mattsson, B
    Johansson, B B
    Seckl, J R
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Environmental enrichment alters nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression after middle cerebral artery occlusion in rats.1999In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 93, no 2, 527-35 p.Article in journal (Refereed)
    Abstract [en]

    Housing rats in an enriched environment after focal brain ischemia improves functional outcome without changes in infarct volume, suggesting neuroplastic changes outside the lesion. In this study, permanent occlusion of the middle cerebral artery was followed by housing in an enriched or a standard environment. Nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression were determined by in situ hybridization two to 30 days after middle cerebral artery occlusion. Stroke induced a decrease in nerve growth factor-induced gene A messenger RNA expression in cortical areas outside the ischemic lesion and in the CA1 subregion of the hippocampus two to three days after ischemia. This decrease was more prolonged with environmental enrichment, lasting until 20 days. However, 30 days after focal cerebral ischemia, environmental enrichment increased nerve growth factor-induced gene A expression compared to standard housing. A reduction of hippocampal glucocorticoid receptor (type II) messenger RNA two to 12 days after stroke in standard housed rats was restored by environmental enrichment. These data suggest that improved functional outcome induced by environmental enrichment after middle cerebral artery occlusion is associated with dynamically altered expression of nerve growth factor-induced gene A messenger RNA in brain regions outside the ischemic lesion, and sustained levels of hippocampal glucocorticoid receptor messenger RNA expression.

  • 5.
    di Summa, Pietro G
    et al.
    University Hospital of Lausanne, University of Manchester.
    Kalbermatten, Daniel F
    University Hospital of Lausanne, University Hospital of Basel.
    Pralong, E
    University Hospital of Lausanne.
    Raffoul, W
    University Hospital of Lausanne.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    University of Manchester.
    Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 181, no 5, 278-291 p.Article in journal (Refereed)
    Abstract [en]

    Although autologous nerve graft is still the first choice strategy in nerve reconstruction, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to improve nerve regeneration. Nerve fibrin conduits were seeded with various cell types: primary Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC). Two further control groups were fibrin conduits without cells and autografts. Conduits were used to bridge a 1 cm rat sciatic nerve gap in a long term experiment (16 weeks). Functional and morphological properties of regenerated nerves were investigated. A reduction in muscle atrophy was observed in the autograft and in all cell-seeded groups, when compared with the empty fibrin conduits. SC showed significant improvement in axon myelination and average fiber diameter of the regenerated nerves. dASC were the most effective cell population in terms of improvement of axonal and fiber diameter, evoked potentials at the level of the gastrocnemius muscle and regeneration of motoneurons, similar to the autografts. Given these results and other advantages of adipose derived stem cells such as ease of harvest and relative abundance, dASC could be a clinically translatable route towards new methods to enhance peripheral nerve repair.

  • 6.
    Hansson, C
    et al.
    Sahlgrenska Academy at the University of Gothenburg.
    Haage, D
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Sahlgrenska Academy at the University of Gothenburg.
    Taube, M
    Sahlgrenska Academy at the University of Gothenburg.
    Egecioglu, E
    Sahlgrenska Academy at the University of Gothenburg.
    Salomé, N
    Sahlgrenska Academy at the University of Gothenburg.
    Dickson, S L
    Sahlgrenska Academy at the University of Gothenburg.
    Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 180, 201-211 p.Article in journal (Refereed)
    Abstract [en]

    The orexigenic and pro-obesity hormone ghrelin targets key hypothalamic and mesolimbic circuits involved in energy balance, appetite and reward. Given that such circuits are closely integrated with those regulating mood and cognition, we sought to determine whether chronic (>2 weeks) CNS exposure to ghrelin alters anxiety- and depression-like behaviour in rats as well as some physiological correlates. Rats bearing chronically implanted i.c.v. catheters were treated with ghrelin (10 μg/d) or vehicle for 4 weeks. Tests used to assess anxiety- and depression-like behaviour were undertaken during weeks 3-4 of the infusion. These revealed an increase in anxiety- and depression-like behaviour in the ghrelin-treated rats relative to controls. At the end of the 4-week infusion, brains were removed and the amygdala dissected for subsequent qPCR analysis that revealed changes in expression of a number of genes representing key systems implicated in these behavioural changes. Finally, given the key role of the dorsal raphe serotonin system in emotional reactivity, we examined the electrophysiological response of dorsal raphe neurons after a ghrelin challenge, and found mainly inhibitory responses in this region. We demonstrate that the central ghrelin signalling system is involved in emotional reactivity in rats, eliciting pro-anxiety and pro-depression effects and have begun to explore novel target systems for ghrelin that may be of importance for these effects.

  • 7.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury.2004In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 125, no 1, 91-101 p.Article in journal (Refereed)
    Abstract [en]

    Neuronal death is a major factor in many neuropathologies, particularly traumatic, and yet no neuroprotective therapies are currently available clinically, although antioxidants and mitochondrial protection appear to be fruitful avenues of research. The simplest system involving neuronal death is that of the dorsal root ganglion after peripheral nerve trauma, where the loss of approximately 40% of primary sensory neurons is a major factor in the overwhelmingly poor clinical outcome of the several million nerve injuries that occur each year worldwide. N-acetyl-cysteine (NAC) is a glutathione substrate which is neuroprotective in a variety of in vitro models of neuronal death, and which may enhance mitochondrial protection. Using TdT uptake nick-end labelling (TUNEL), optical disection, and morphological studies, the effect of systemic NAC treatment upon L4 and 5 primary sensory neuronal death after sciatic nerve transection was investigated. NAC (150 mg/kg/day) almost totally eliminated the extensive neuronal loss found in controls both 2 weeks (no treatment 21% loss, NAC 3%, P=0.03) and 2 months after axotomy (no treatment 35% loss, NAC 3%, P=0.002). Glial cell death was reduced (mean number TUNEL positive cells 2 months after axotomy: no treatment 51/ganglion pair, NAC 16/ganglion pair), and mitochondrial architecture was preserved. The effects were less profound when a lower dose was examined (30 mg/kg/day), although significant neuroprotection still occurred. This provides evidence of the importance of mitochondrial dysregulation in axotomy-induced neuronal death in the peripheral nervous system, and suggests that NAC merits investigation in CNS trauma. NAC is already in widespread clinical use for applications outside the nervous system; it therefore has immediate clinical potential in the prevention of primary sensory neuronal death, and has therapeutic potential in other neuropathological systems.

  • 8.
    Karalija, Amar
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Ludmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The effects of N-acetyl-cysteine and acetyl-l-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 269, 143-151 p.Article in journal (Refereed)
    Abstract [en]

    Traumatic spinal cord injury induces a long-standing inflammatory response in the spinal cord tissue, leading to a progressive apoptotic death of spinal cord neurons and glial cells. We have recently demonstrated that immediate treatment with the antioxidants N-acetyl-cysteine (NAC) and acetyl-l-carnitine (ALC) attenuates neuroinflammation, induces axonal sprouting, and reduces the death of motoneurons in the vicinity of the trauma zone 4weeks after initial trauma. The objective of the current study was to investigate the effects of long-term antioxidant treatment on the survival of descending rubrospinal neurons after spinal cord injury in rats. It also examines the short- and long-term effects of treatment on apoptosis, inflammation, and regeneration in the spinal cord trauma zone. Spinal cord hemisection performed at the level C3 induced a significant loss of rubrospinal neurons 8weeks after injury. At 2weeks, an increase in the expression of the apoptosis-associated markers BCL-2-associated X protein (BAX) and caspase 3, as well as the microglial cell markers OX42 and ectodermal dysplasia 1 (ED1), was seen in the trauma zone. After 8weeks, an increase in immunostaining for OX42 and the serotonin marker 5HT was detected in the same area. Antioxidant therapy reduced the loss of rubrospinal neurons by approximately 50%. Treatment also decreased the expression of BAX, caspase 3, OX42 and ED1 after 2weeks. After 8weeks, treatment decreased immunoreactivity for OX42, whereas it was increased for 5HT. In conclusion, this study provides further insight in the effects of treatment with NAC and ALC on descending pathways, as well as short- and long-term effects on the spinal cord trauma zone.

  • 9.
    Koskinen, Lars-Owe
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olivecrona, Magnus
    Department of Anaesthesia and Intensive Care, University of Örebro, Sweden.
    Grande, P. O.
    Department of Clinical Science in Lund, Anaesthesia and Intensive Care, Lund University, Sweden.
    Severe traumatic brain injury management and clinical outcome using the Lund concept2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 283, 245-255 p.Article, review/survey (Refereed)
    Abstract [en]

    This review covers the main principles of the Lund concept for treatment of severe traumatic brain injury. This is followed by a description of results of clinical studies in which this therapy or a modified version of the therapy has been used. Unlike other guidelines, which are based on meta-analytical approaches, important components of the Lund concept are based on physiological mechanisms for regulation of brain volume and brain perfusion and to reduce transcapillary plasma leakage and the need for plasma volume expanders. There have been nine non-randomized and two randomized outcome studies with the Lund concept or modified versions of the concept. The non-randomized studies indicated that the Lund concept is beneficial for outcome. The two randomized studies were small but showed better outcome in the groups of patients treated according to the modified principles of the Lund concept than in the groups given a more conventional treatment. This article is part of a Special Issue entitled: Brain compensation. For good?. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 10. Ljubisavljevic, M
    et al.
    Kalezic, Ivana
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Radovanovic, S
    Milanovic, S
    Blesic, S
    Anastasijevic, R
    Changes in fusimotor activity during repetitive lengthening muscle contractions in decerebrate cats1998In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 86, no 4, 1337-1342 p.Article in journal (Refereed)
    Abstract [en]

    Responses of fusimotor neurons to lengthening vs isometric contractions have been studied in decerebrate cats. Spike discharges of fusimotor neurons to the medial gastrocnemius muscle were recorded from this muscle nerve filament during sequences of contractions and/or stretches of the lateral gastrocnemius and soleus muscles. The sequences lasted for 250-450s (duty cycle 4:2 s). Isometric contractions were elicited by electrical stimulation (40 Hz, 1.3 times motor threshold) of the muscle nerves. Lengthening contractions were elicited in the same way while the muscles were stretched by 4 mm at a velocity of 1 mm/s. Of 25 fusimotor neurons studied, 23 responded to muscle contractions with an increase in firing rate, subsiding towards the end of the sequence. The increase was either modulated with each subsequent contraction or smooth throughout the sequence. Approximately 64% of fusimotor neurons, responding to muscle contractions, responded in a similar way to the sequences of muscle stretches, applied alone. Responses to sequences of the lengthening contractions were significantly larger, on average, than those to the isometric ones, but smaller than the sum of the responses to the contractions and stretches applied separately. On the other hand, they were also larger in fusimotor units, showing no overt responses to muscle stretches alone.

  • 11.
    Ljubisavljevic, M
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Vukcevic, I
    Radovanovic, S
    Milanovic, S
    Anastasijevic, R
    Effects of cutaneous afferent input on fatigue-induced changes in fusimotor activity of decerebrate cats1997In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 79, no 3, 935-942 p.Article in journal (Refereed)
    Abstract [en]

    Interaction of cutaneous and small-diameter, primarily fatigue-induced, muscle afferent inputs on fusimotor neurons has been studied in decerebrate cats. Spike discharges of fusimotor neurons to medial gastrocnemius were recorded from filaments dissected free from this muscle nerve. Non-noxious mechanical stimuli (10 Hz, 2 mm vibration) were applied to the skin area on the lateral side of the heel, innervated by sural nerve, during long-lasting (250 s) fatiguing contraction of lateral gastrocnemius and soleus muscles, elicited by electrical stimulation (40 Hz, 1.3 x motor threshold) of the muscle nerves. In 15 units (58%) the pattern of responses to muscle contraction and/or fatigue (initial transient, and late long-lasting increase in firing rate, respectively) was preserved in the presence of skin vibration which, by itself, provoked either a slight increase or no changes in fusimotor discharge rate. Pattern of the response to skin vibration prevailed in the presence of muscle contraction and fatigue only if the vibration by itself induced marked increase in fusimotor discharge rate (three units). In the remaining eight units the responses to both stimuli applied simultaneously were dissimilar in pattern to the response to either stimulus applied alone: the initial, tension-related, increase in firing rate was prolonged, while the late, fatigue-induced one was attenuated and its post-contraction part almost abolished. Possible mechanisms and functional role of interaction between cutaneous and muscle afferent inflows are discussed.

  • 12.
    Medini, Paolo
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cell-type-specific sub- and suprathreshold receptive fields of layer 4 and layer 2/3 pyramids in rat primary visual cortex.2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 190, 112-26 p.Article in journal (Refereed)
    Abstract [en]

    Connectivity of cortical pyramidal neurons is layer-specific in the primary visual cortex (V1) and this is thought to be reflected in different receptive field (RF) properties of layer 4 and layer 2/3 pyramidal neurons (L4Ps and L2/3Ps, respectively). However, it remains unclear how the two cell populations convert incoming visually driven synaptic inputs into action potential (AP) outputs. Here I compared postsynaptic potentials (PSPs) and AP responses of L4Ps and L2/3Ps in the binocular portion of rat V1 by intrinsic optical imaging (IOI)-targeted whole-cell recordings followed by anatomical identification and dendritic reconstructions. L2/3Ps had about 2-fold longer dendritic branches and a higher number of branch points and endings in their apical portions. Functionally, L2/3Ps had more hyperpolarized resting potentials and lower rates of spontaneous APs (medians: 0.07 vs. 0.60 AP/s). PSP responses to optimally oriented moving bars were comparable in terms of amplitude (16.0±0.9 vs. 17.3±1.1 mV for L2/3Ps and L4Ps, respectively), reliability and size of the RF. The modulated component of subthreshold responses of L4Ps to optimal sinusoidal drifting gratings was larger and their PSP onset latency in response to bars flashed in the cell's RF center were shorter (60 vs. 86 ms). In contrast to the similarities of PSP responses to moving bars, AP responses of L2/3Ps were more sparse (medians: 0.7 vs. 2.9 APs/stimulus passage), less reliable, but sharper in terms of angular size. Based on the differences of subthreshold inputs, I conclude that L4Ps may receive mostly thalamic inputs, whereas L2/3Ps may receive both thalamic and cortical inputs from layer 4. The comparable subthreshold responses to moving bars are converted by L2/3Ps into sparser but sharper AP outputs possibly by cell-type-specific AP-generating mechanisms or differences in visually driven inhibitory inputs.

  • 13.
    Medini, Paolo
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Experience-dependent plasticity of visual cortical microcircuits2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 278, 367-384 p.Article, review/survey (Refereed)
    Abstract [en]

    The recent decade testified a tremendous increase in our knowledge on how cell-type-specific microcircuits process sensory information in the neocortex and on how such circuitry reacts to manipulations of the sensory environment. Experience-dependent plasticity has now been investigated with techniques endowed with cell resolution during both postnatal development and in adult animals. This review recapitulates the main recent findings in the field using mainly the primary visual cortex as a model system to highlight the more important questions and physiological principles (such as the role of non-competitive mechanisms, the role of inhibition in excitatory cell plasticity, the functional importance of spine and axonal plasticity on a microscale level). I will also discuss on which scientific problems the debate and controversies are more pronounced. New technologies that allow to perturbate cell-type-specific subcircuits will certainly shine new light in the years to come at least on some of the still open questions. (C) 2014 The Author. Published by Elsevier Ltd. on behalf of IBRO.

  • 14.
    Nevalainen, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. nina.nevalainen@diagrad.umu.se.
    Af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Gerhardt, G A
    Department of Anatomy, Neurobiology, and Neurology, University of Kentucky Medical Center, Lexington, KY, USA.
    Strömberg, Iingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 260, 73-86 p.Article in journal (Refereed)
    Abstract [en]

    The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (∼30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.

  • 15.
    Nevalainen, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Chermenina, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Rehnmark, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Berglöf, Elisabeth
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Glial cell line-derived neurotrophic factor is crucial for long-term maintenance of the nigrostriatal system2010In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 171, no 4, 1357-1366 p.Article in journal (Refereed)
    Abstract [en]

    Glial cell line-derived neurotrophic factor (GDNF) is a potent factor for the ventral mesencephalic dopamine neurons. However, studies on the Gdnf gene deleted (Gdnf(-/-)) mouse have been limited to fetal tissue since these mice die prematurely. To evaluate long-term effects of Gdnf gene deletion, this study involves co-grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) derived from different Gdnf genotypes. The VM/LGE co-grafts were evaluated at 3, 6, and 12 months for tyrosine hydroxylase (TH) -positive cell survival and nerve fiber formation in the LGE co-transplant, visualized by dopamine- and cyclic AMP-regulated phosphoprotein relative molecular mass 32,000 (DARPP-32) -immunoreactivity. Cell counts revealed no difference in TH-positive neurons between Gdnf genotypes at 3 months postgrafting. At 6 months, a significant reduction in cell number was observed in the Gdnf(-/-) grafts. In fact, in the majority of the Gdnf(-/-) VM/LGE transplant had degenerated. At 12 months, a reduction in cell number was seen in both Gdnf(-/-) and Gdnf(+/-) compared to wild type transplants. In the Gdnf(-/-) grafts, TH-negative inclusion-like structures were present in the cytoplasm of the TH-positive neurons at 3 months. These structures were also found in the Gdnf(+/-) transplants at 12 months, but not in Gdnf(+/+) controls at any time point. In Gdnf(+/+) grafts, TH-positive nerve fiber innervation of the striatal co-grafts was dense and patchy and overlapped with clusters of DARPP-32-positive neurons. This overlap did mismatch in the Gdnf(+/-) grafts, while the TH-positive innervation was sparse in the Gdnf(-/-) transplants and the DARPP-32-positive neurons were widespread distributed. In conclusion, GDNF is essential for long-term maintenance of both the VM TH-positive neurons and for the striatal tissue, and appears crucial for generation of a proper organization of the striatum.

  • 16.
    Novikov, Lev N
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, P
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kellerth, J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Exogenous brain-derived neurotrophic factor regulates the synaptic composition of axonally lesioned and normal adult rat motoneurons2000In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 100, no 1, 171-181 p.Article in journal (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor has previously been shown to promote survival and axonal regeneration in injured spinal motoneurons and, also, to modulate synaptic transmission and regulate the density of synaptic innervation in a variety of neurons. The present light and electron microscopic study demonstrates synaptotrophic effects of exogenously applied brain-derived neurotrophic factor on the synaptic composition of both normal and axonally lesioned adult rat spinal motoneurons. After L5-L6 ventral root avulsion, a massive loss of all types of boutons occurred on the somata of the lesioned motoneurons which persisted for at least 12 weeks postoperatively. We found that (i) intrathecal infusion of brain-derived neurotrophic factor during the first postoperative week did not prevent the synaptic detachment and activation of glial cells; (ii) prolonged treatment for four weeks restored synaptic covering and significantly reduced microglial reaction; (iii) the synaptotrophic effect remained significant for at least eight weeks after cessation of the treatment; (iv) brain-derived neurotrophic factor mainly supported F-type boutons with presumably inhibitory function, while it had little effect on S-type boutons associated with excitatory action; and (v) in normal unlesioned motoneurons, four weeks of treatment with brain-derived neurotrophic factor induced sprouting of F-type boutons, a loss of S-type boutons and motoneuron atrophy. The present data show that exogenous neurotrophins not only help to restore synaptic circuitry in axonally injured motoneurons, but also strongly influence the synaptic composition in normal motoneurons.

  • 17.
    Olmedo-Díaz, Sonia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Estévez-Silva, Héctor
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Institute of Biomedical Technologies (CIBICAN), Tenerife, Spain; Department of Basic Medical Sciences, University of La Laguna, Tenerife, Spain.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    af Bjérken, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Institute of Biomedical Technologies (CIBICAN), Tenerife, Spain.
    Virel, Ana
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    An altered blood–brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson's disease2017In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 362, 141-151 p.Article in journal (Refereed)
    Abstract [en]

    Brain iron accumulation is a common feature shared by several neurodegenerative disorders including Parkinson's disease. However, what produces this accumulation of iron is still unknown. In this study, the 6-hydroxydopamine (6-OHDA) hemi-parkinsonian rat model was used to investigate abnormal iron accumulation in substantia nigra. We investigated three possible causes of iron accumulation; a compromised blood-brain barrier (BBB), abnormal expression of ferritin, and neuroinflammation. We identified alterations in the BBB subsequent to the injection of 6-OHDA using gadolinium-enhanced magnetic resonance imaging (MRI). Moreover, detection of extravasated IgG suggested that peripheral components are able to enter the brain through a leaky BBB. Presence of iron following dopamine cell degeneration was studied by MRI, which revealed hypointense signals in the substantia nigra. The presence of iron deposits was further validated in histological evaluations. Furthermore, iron inclusions were closely associated with active microglia and with increased levels of L-ferritin indicating a putative role for microglia and L-ferritin in brain iron accumulation and dopamine neurodegeneration.

  • 18.
    Reid, Adam J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. University of Manchester.
    Sun, M
    University of Manchester.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Downes, S
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Manchester.
    Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 199, 515-522 p.Article in journal (Refereed)
    Abstract [en]

    Novel approaches are required in the clinical management of peripheral nerve injuries because current surgical techniques result in deficient sensory recovery. Microsurgery alone fails to address extensive cell death in the dorsal root ganglia (DRG), in addition to poor axonal regeneration. Incorporation of cultured cells into nerve conduits may offer a novel approach in which to combine nerve repair and enhance axonal regeneration with neuroprotective therapies. We examined apoptotic mediator expression in rat DRG neurons following repair of a 10-mm sciatic nerve gap using a novel synthetic conduit made of poly epsilon-caprolactone (PCL) and primed with adipose-derived stem cells (ADSC) differentiated towards a Schwann cell phenotype or with primary adult Schwann cells. Differentiated ADSC expressed a range of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and neurotrophin-4 (NT4). Incorporation of either differentiated ADSC or Schwann cells significantly increased anti-apoptotic Bcl-2 mRNA expression (P<0.001) in the DRG, while significantly decreasing proapoptotic Bax (P<0.001) and caspase-3 mRNA (P<0.01) expression. Cleaved caspase-3 protein was observed in the DRG following nerve injury which was attenuated when nerve repair was performed using conduits seeded with cells. Cell incorporation into conduit repair of peripheral nerves demonstrates experimental promise as a novel intervention to prevent DRG neuronal loss. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 19. Singh, I N
    et al.
    Goody, R J
    Goebel, S M
    Martin, K M
    Knapp, P E
    Marinova, Z
    Hirschberg, Daniel
    Yakovleva, T
    Bergman, T
    Bakalkin, G
    Hauser, K F
    Dynorphin A (1-17) induces apoptosis in striatal neurons in vitro through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome c release and caspase-3 activation.2003In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 122, no 4Article in journal (Refereed)
    Abstract [en]

    Dynorphin A (1-17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1-17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using dizocilpine maleate (MK(+)801), a non-equilibrium N-methyl-D-aspartate (NMDA) antagonist; 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (-)-naloxone, a general opioid antagonist. The results show that dynorphin A (1-17) (>or=10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, caspase-3 inhibitor-II (z-DEVD-FMK), further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors.

  • 20.
    Strömberg, Jessica
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Taube, Magdalena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundgren, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor2006In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 143, no 1, 73-81 p.Article in journal (Refereed)
  • 21.
    Türkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tolerance development to Morris water maze test impairments induced by acute allopregnanolone2006In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 139, no 2, 651-659 p.Article in journal (Refereed)
    Abstract [en]

    The progesterone metabolite allopregnanolone, like benzodiazepines, reduces learning and impairs memory in rats. Both substances act as GABA agonists at the GABA-A receptor and impair the performance in the Morris water maze test. Women are during the menstrual cycle, pregnancy, and during hormone replacement therapy exposed to allopregnanolone or allopregnanolone-like substances for extended periods. Long-term benzodiazepine treatment can cause tolerance against benzodiazepine-induced learning impairments. In this study we evaluated whether a corresponding allopregnanolone tolerance develops in rats. Adult male Wistar rats were pretreated for 3 days with i.v. allopregnanolone injections (2 mg/kg) one or two times a day, or for 7 days with allopregnanolone injections 20 mg/kg intraperitoneally, twice a day. Thereafter the rats were tested in the Morris water maze for 5 days and compared with relevant controls. Rats pretreated with allopregnanolone twice a day had decreased escape latency, path length and thigmotaxis compared with the acute allopregnanolone group that was pretreated with vehicle. Pretreatment for 7 days resulted in learning of the platform position. However, the memory of the platform position was in these tolerant rats not as strong as in controls only given vehicle. Allopregnanolone treatment was therefore seen to induce a partial tolerance against acute allopregnanolone effects in the Morris water maze.

  • 22. van Wingen, G. A.
    et al.
    Ossewaarde, L.
    Bäckstrom, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hermans, E. J.
    Fernandez, G.
    Gonadal hormone regulation of the emotion circuitry in humans2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 191, 38-45 p.Article, review/survey (Refereed)
    Abstract [en]

    Gonadal hormones are known to influence the regulation of emotional responses and affective states. Whereas fluctuations in progesterone and estradiol are associated with increased vulnerability for mood disorders, testosterone is mainly associated with social dominance, aggressive, and antisocial behavior. Here, we review recent functional neuroimaging studies that have started to elucidate how these hormones modulate the neural circuitry that is important for emotion regulation, which includes the amygdala and the medial prefrontal (mPFC) and orbitofrontal cortex (OFC). The amygdala is thought to generate emotional responses, and the prefrontal brain regions to regulate those responses. Overall, studies that have investigated women during different phases of the menstrual cycle suggest that progesterone and estradiol may have opposing actions on the amygdala and prefrontal cortex. In addition, the influence of exogenous progesterone appears to be dose-dependent. Endogenous testosterone concentrations are generally positively correlated to amygdala and OFC responses, and exogenous testosterone increases amygdala reactivity. Whereas the administration of progesterone increases amygdala reactivity and its connectivity with the mPFC, testosterone administration increases amygdala reactivity but decreases its connectivity with the OFC. We propose that this opposing influence on amygdala-prefrontal coupling may contribute to the divergent effects of progesterone and testosterone on emotion regulation and behavioral inhibition, respectively, which may promote the differential vulnerability to various psychiatric disorders between women and men. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

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