Abstract
As the title of this thesis indicates I have during my PhD studied the effects of cortical spreading depression (CSD) on synaptic activity, blood flow and oxygen consumption in rat cerebral cortex.
This was performed in vivo using an open cranial window approach in anesthetized rats. I applied Laser-Doppler Flowmetry for measurements of cerebral blood flow, glass microelectrodes for recording of synaptic activity – local field potentials – and ongoing cortical electrical activity and a Clark type electrode for measurements of tissue partial pressure of oxygen (tpO2). Offline
calculations of cerebral metabolic rate of oxygen (CMRO2) were performed using a compartment model as described Gjedde1.
In the first study we characterized the frequency dependency of evoked responses of the transcallosal fiber network (TC) in the somatosensory cortex concerning: synaptic activity, cerebral blood flow (CBF), tissue partial pressure of oxygen (tpO2) and cerebral metabolic rate of oxygen (CMRO2). Furthermore the subpopulation of inhibitory interneurons activated during TC stimulation was characterized.
Once characterized the investigated parameters in the TC network
were compared to the equivalent parameters of the whisker/infraorbital nerve etwork (IO) targeting the same cortical area. We tested the hypothesis that the relation between increases in CBF and CMRO2 evoked by stimulation and synaptic activity differed for the two activated networks and that activation of two distinct networks activate two different sets of interneurons.
Our data imply that for a given cortical area the amplitude of vascular signals will depend critically on the type of input and hence on the type of neurons activated. In the second study I investigated the effect of cortical spreading depression (CSD) on the evoked responses of synaptic activity (LFP), CBF, tpO2 and CMRO2 in the TC network. Also the impact on neurovascular and neurometabolic coupling were examined. Last but not least the influence of CSD on ongoing (baseline) CBF and CMRO2 was examined.
The results demonstrate a long lasting effect of CSD on baseline parameters as well as on neurovascular coupling. A preserved neurometabolic coupling in the wake of CSD was evident in the TC network. During CSD intracellular Ca2+ concentration increases. This amongst other factors increases the likelihood of activation of the calcineurin pathway (CaN) and opening of the mitochondrial permeability transition pore (mPTP).
In the third study I investigated the possible contribution of CaN and mPTP to the changes in basal CMRO2 and CBF as well as the change in neurovascular coupling found in the second study. I found an amelioration of oligemia after CSD on 50 % and apreservation of neurovascular coupling after topical pretreatment with either inhibitor of CaN pathway (FK506), inhibitor of mPTP formation (NIM811) and combined inhibition of both pathways (FK506+NIM811 or cyclosporin A). A result indicating a potential new treatment aspect for disease states where CSD is known to be involved like in migraine, stroke and traumatic brain injury.
This was performed in vivo using an open cranial window approach in anesthetized rats. I applied Laser-Doppler Flowmetry for measurements of cerebral blood flow, glass microelectrodes for recording of synaptic activity – local field potentials – and ongoing cortical electrical activity and a Clark type electrode for measurements of tissue partial pressure of oxygen (tpO2). Offline
calculations of cerebral metabolic rate of oxygen (CMRO2) were performed using a compartment model as described Gjedde1.
In the first study we characterized the frequency dependency of evoked responses of the transcallosal fiber network (TC) in the somatosensory cortex concerning: synaptic activity, cerebral blood flow (CBF), tissue partial pressure of oxygen (tpO2) and cerebral metabolic rate of oxygen (CMRO2). Furthermore the subpopulation of inhibitory interneurons activated during TC stimulation was characterized.
Once characterized the investigated parameters in the TC network
were compared to the equivalent parameters of the whisker/infraorbital nerve etwork (IO) targeting the same cortical area. We tested the hypothesis that the relation between increases in CBF and CMRO2 evoked by stimulation and synaptic activity differed for the two activated networks and that activation of two distinct networks activate two different sets of interneurons.
Our data imply that for a given cortical area the amplitude of vascular signals will depend critically on the type of input and hence on the type of neurons activated. In the second study I investigated the effect of cortical spreading depression (CSD) on the evoked responses of synaptic activity (LFP), CBF, tpO2 and CMRO2 in the TC network. Also the impact on neurovascular and neurometabolic coupling were examined. Last but not least the influence of CSD on ongoing (baseline) CBF and CMRO2 was examined.
The results demonstrate a long lasting effect of CSD on baseline parameters as well as on neurovascular coupling. A preserved neurometabolic coupling in the wake of CSD was evident in the TC network. During CSD intracellular Ca2+ concentration increases. This amongst other factors increases the likelihood of activation of the calcineurin pathway (CaN) and opening of the mitochondrial permeability transition pore (mPTP).
In the third study I investigated the possible contribution of CaN and mPTP to the changes in basal CMRO2 and CBF as well as the change in neurovascular coupling found in the second study. I found an amelioration of oligemia after CSD on 50 % and apreservation of neurovascular coupling after topical pretreatment with either inhibitor of CaN pathway (FK506), inhibitor of mPTP formation (NIM811) and combined inhibition of both pathways (FK506+NIM811 or cyclosporin A). A result indicating a potential new treatment aspect for disease states where CSD is known to be involved like in migraine, stroke and traumatic brain injury.
| Originalsprog | Engelsk |
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| Antal sider | 155 |
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| Status | Udgivet - 2010 |