Kornel Demeter | Institute of Experimental Medicine (original) (raw)

Papers by Kornel Demeter

Investigative Ophthalmology & Visual Science, Apr 28, 2009

Optics Express, Aug 27, 2021

The appearance of the common artifacts of laser speckle contrast imaging (LSCI), namely the granu... more The appearance of the common artifacts of laser speckle contrast imaging (LSCI), namely the granularity in flow rate estimation caused by static scatterers, is a well-known phenomenon. This artifact can be greatly reduced in spatial speckle contrast calculation using interframe decorrelated illumination, forcing true ensemble averaging. We propose a statistical model, which describes the effect of multiple image acquisitions on the contrast map quality when the illumination stable and when the illumination is decorrelated frame by frame. We investigate the improvement as a function of the ratio of dynamic and static scatterers by formulating a statistical distribution based model, using in simulation, flow phantom and in vivo experiments. Our main finding is that the ensemble averaging yields limited improvement in several practical cases due to the highly heterogeneous scatterer structure of living tissues.

Journal of Cerebral Blood Flow and Metabolism, Apr 1, 2017

Introduction: Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculatio... more Introduction: Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculation such as microthrombosis, microvasospasms, and lack of CO 2 reactivity. New findings ex vivo suggest that neurovascular coupling (NVC), the process that increases cerebral blood flow upon neuronal activity, may also be impaired after SAH. The aim of the current study was to investigate NVC after SAH in vivo. Methods: C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. Neurovascular reactivity was tested 24 hours later by either forepaw stimulation or CO 2 inhalation and visualized in pial and parenchymal arterioles by two-photon microscopy. NVC was also investigated ex vivo on acute brain slice preparations. Results: In sham-operated mice, cerebral vessels dilated to about 130% of baseline after CO 2 inhalation or forepaw stimulation. By contrast, SAH resulted in a complete loss of CO 2 reactivity in vivo, and pial and parenchymal vessels did not dilate upon neuronal activation either in vivo or ex vivo-the majority of vessels even constricted by 10-15%. Conclusions: These findings indicate that after SAH cerebral vessels do not dilate but constrict upon neuronal activation. This process may further aggravate SAH-induced brain damage. Based on previous results showing that NVC is preserved three hours after SAH, the current results demonstrate that the impairment of NVC is progressive and therapeutic efforts need to be initiated as early as possible after SAH.

The International Journal of Neuropsychopharmacology, Apr 20, 2022

Background: Immunological markers and related signaling molecules in the blood are altered in sch... more Background: Immunological markers and related signaling molecules in the blood are altered in schizophrenia mouse models, in acutely relapsed patients with schizophrenia, and in persons at a clinically high risk for subsequently developing psychosis, highlighting their potential as prognostic and theranostic biomarkers. Therefore, we herein aimed to identify novel potential biomarkers in the serum that are associated with purinergic signaling. Methods: To our knowledge, this is the first study to assess the correlations among the levels of human serum adenine nucleotides (ATP, ADP), adenosine, P2X7 receptor, and disease activity in patients hospitalized due to an acute relapse of schizophrenia (n = 53) and healthy controls (n = 47). In addition, to validate these findings using a reverse translational approach, we examined the same parameters in an acute phencyclidine-induced schizophrenia mouse model. Results: We found consistently elevated levels of ATP, ADP, interleukin (IL)-6, and IL-10 in both schizophrenia groups compared with the controls. The levels of adenosine, IL-1β, IL-12, and C-reactive protein were also increased in the human patient samples. Moreover, ATP and ADP were significantly positively correlated with the Positive and Negative Symptom Scale item "lack of judgment and insight"; IL-1β, IL-12, and tumour necrosis factor alpha were significantly positively correlated with "tension" and "depression"; and "disorientation" and "poor attention" were correlated significantly with IL-6 and IL-8. Conclusions: Our study suggests the promising potential of blood purines and inflammatory markers as future prognostic tools.

Optics Letters, Feb 3, 2021

Laser Speckle Contrast Imaging is a technique to determine blood flow rate with a limitation of l... more Laser Speckle Contrast Imaging is a technique to determine blood flow rate with a limitation of low dynamic range. In this Letter, we introduce a varied illumination speckle contrast imaging method. It utilizes varying illumination during exposure to customize the correlation time (flow rate) to speckle contrast relation. The method can cover an order of magnitude larger range flow rate in a single exposure compared to constant illumination methods. The proposed method enables high dynamic range flow rate imaging that is advantageous in studying larger vessels and small arteries. We demonstrate the theory by simulations, ex vivo and in vivo measurements.

Behavioural Pharmacology, Dec 1, 2017

Optogenetics was the method of the year in 2010 according to Nature Neuroscience. Since then, thi... more Optogenetics was the method of the year in 2010 according to Nature Neuroscience. Since then, this method has become widespread, the use of virally delivered genetic tools has extended to other fields such as pharmacogenetics, and optogenetic techniques have become frequently applied in genetically manipulated animals for in-vivo circuit analysis and behavioral studies. However, several issues should be taken into consideration when planning such experiments. We aimed to summarize the critical points concerning optogenetic manipulation of a specific brain area in mutant mice. First, the appropriate vector should be chosen to allow optimal optogenetic manipulation. Adeno-associated viral vectors are the most common carriers with different available serotypes. Lightsensitive channels are available in many forms, and the expression of the delivered genetic material can be influenced in many ways. Second, selecting the adequate stimulation protocol is also essential. The pattern, intensity, and timing could be determinative parameters. Third, the mutant strain might have a phenotype that influences the observed behavior. In conclusion, detailed preliminary experiments and numerous control groups are required to choose the best vector and stimulation protocol and to ensure that the mutant animals do not have a specific phenotype that can influence the examined behavior.

Behavioural Brain Research, Mar 1, 2023

International Journal of Molecular Sciences, 2022

The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine str... more The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine stress axis and related behaviour is still under discussion. We aimed to obtain deeper insight into this process. To rescue magnocellular AVP synthesis, a vasopressin-containing adeno-associated virus vector (AVP-AAV) was injected into the supraoptic nucleus (SON) of AVP-deficient Brattleboro rats (di/di). We compared +/+, di/di, and AVP-AAV treated di/di male rats. The AVP-AAV treatment rescued the AVP synthesis in the SON both morphologically and functionally. It also rescued the peak of adrenocorticotropin release triggered by immune and metabolic challenges without affecting corticosterone levels. The elevated corticotropin-releasing hormone receptor 1 mRNA levels in the anterior pituitary of di/di-rats were diminished by the AVP-AAV-treatment. The altered c-Fos synthesis in di/di-rats in response to a metabolic stressor was normalised by AVP-AAV in both the SON and medial amygdala (MeA...

PLOS ONE

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencin... more The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex.

Anesthesiology, 2017

General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induc... more General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induce a persistent decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)-mediated inhibition controlled by the developmental up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2). In utero electroporation of KCC2 was used to prematurely increase the efficacy of (GABAA)-mediated inhibition in layer 2/3 pyramidal neurons in the immature rat somatosensory cortex. Parallel experiments with expression of the inward-rectifier potassium channel Kir2.1 were done to reduce intrinsic neuronal excitability. The effects of these genetic manipulations (n = 3 to 4 animals per experimental group) were evaluated using iontophoretic injection of Lucifer Yellow (n = 8 to 12 cells per animal). The total number of spines analyzed per group ranged between 907 and 3,371. The authors found a robust effect of the developmental up-regulation of KCC2-mediated Cl transport on the age-dependent action of propofol on dendritic spines. Premature expression of KCC2, unlike expression of a transport-inactive KCC2 variant, prevented a propofol-induced decrease in spine density. In line with a reduction in neuronal excitability, the above result was qualitatively replicated by overexpression of Kir2.1. The KCC2-dependent developmental increase in the efficacy of GABAA-mediated inhibition is a major determinant of the age-dependent actions of propofol on dendritic spinogenesis.

Physiology & behavior, Jan 3, 2016

Vasopressin can contribute to the development of stress-related psychiatric disorders, anxiety an... more Vasopressin can contribute to the development of stress-related psychiatric disorders, anxiety and depression. Although these disturbances are more common in females, most of the preclinical studies have been done in males. We compared female vasopressin-deficient and +/+ Brattleboro rats. To test anxiety we used open-field, elevated plus maze (EPM), marble burying, novelty-induced hypophagia, and social avoidance tests. Object and social recognition were used to assess short term memory. To test depression-like behavior consumption of sweet solutions (sucrose and saccharin) and forced swim test (FST) were studied. The stress-hormone levels were followed by radioimmunoassay and underlying brain areas were studied by c-Fos immunohistochemistry. In the EPM the vasopressin-deficient females showed more entries towards the open arms and less stretch attend posture, drank more sweet fluids and struggled more (in FST) than the +/+ rats. The EPM-induced stress-hormone elevations were small...

Behavioural Brain Research, 2016

h i g h l i g h t s • AVP deficient Brattleboro rat strain is a valuable model to study schizophr... more h i g h l i g h t s • AVP deficient Brattleboro rat strain is a valuable model to study schizophrenia. • Lack of AVP resulted in changes of histone acetylation in the frontal brain and hippocampus. • Influencing histone acetylation may provide therapeutic alternatives for schizophrenia.

Experimental Neurology, 2011

Journal of Cellular Biochemistry, 2008

Nephrology Dialysis Transplantation

Background and Aims Perinatal asphyxia (PA) is associated with more than half a million mature ne... more Background and Aims Perinatal asphyxia (PA) is associated with more than half a million mature newborn deaths yearly. It may lead to severe complications including hypoxic encephalopathy, renal- hepatic- and cardiovascular injury, as well as respiratory distress, Basic research and clinical trials mainly focus on mitigating central nervous system damage by selective head or whole body cooling, which is currently the only routinely used treatment in clinical practice. However, the extent of PA-associated multi-organ damage is not clarified yet and effective therapies are lacking. Our aim was to investigate the acute renal, hepatic and cardiac impairment following PA and to identify pathways involved in the pathomechanism. In addition, we aimed to explore long-term effects of PA on permanent organ damage and susceptibility to ischemia/-reperfusion injury in adulthood. Method Postnatal 7 day-old male Wistar rat pups (n=5-10/group) were randomly grouped as follows: (i) Baseline; (ii) Co...

Nephrology Dialysis Transplantation

Background and Aims Perinatal asphyxia (PA) leads to the death of more than half a million mature... more Background and Aims Perinatal asphyxia (PA) leads to the death of more than half a million mature newborns yearly. PA is associated with several serious complications, including hypoxic encephalopathy, renal- hepatic- and cardiovascular injury, as well as respiratory distress. Basic research and clinical trials mainly focus on mitigating central nervous system damage by selective head or whole body cooling, which is currently the only routinely used treatment in clinical practice. However, the extent of PA-associated multi-organ damage is not clarified yet and effective therapies are lacking. The aim of the present study was to determine the acute renal, hepatic and cardiac impairment following PA and to identify pathways involved in the pathomechanism. In addition, we aimed to investigate long-term effects of PA on permanent organ damage and susceptibility to ischemia/-reperfusion injury in adulthood. Method Postnatal 7 day-old male Wistar rat pups (n=5-10/group) were randomly grou...

Frontiers in behavioral neuroscience, 2018

Serotonergic mechanisms hosted by raphe nuclei have important roles in affiliative and agonistic ... more Serotonergic mechanisms hosted by raphe nuclei have important roles in affiliative and agonistic behaviors but the separate roles of the two nuclei are poorly understood. Here we studied the roles of the dorsal (DR) and median raphe region (MRR) in aggression by optogenetically stimulating the two nuclei. Mice received three 3 min-long stimulations, which were separated by non-stimulation periods of 3 min. The stimulation of the MRR decreased aggression in a phasic-like manner. Effects were rapidly expressed during stimulations, and vanished similarly fast when stimulations were halted. No carryover effects were observed in the subsequent three trials performed at 2-day intervals. No effects on social behaviors were observed. By contrast, DR stimulation rapidly and tonically promoted social behaviors: effects were present during both the stimulation and non-stimulation periods of intermittent stimulations. Aggressive behaviors were marginally diminished by acute DR stimulations, but...

Scientific Reports

Larval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availabil... more Larval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availability of resource-efficient, high-throughput screening and high-resolution imaging techniques. Although behavioural models are available in larvae, only a few can be employed to assess anxiety. Here we present the swimming plus-maze (SPM) test paradigm, a tool to assess anxiety-related avoidance of shallow water bodies in early developmental stages. The "+" shaped apparatus consists of arms of different depth, representing different levels of aversiveness similarly to the rodent elevated plus-maze. The paradigm was validated (i) in larval and juvenile zebrafish, (ii) after administration of compounds affecting anxiety and (iii) in differentially aversive experimental conditions. Furthermore, we compared the SPM with conventional "anxiety tests" of zebrafish to identify their shared characteristics. We have clarified that the preference of deeper arms is ontogenetically conserved and can be abolished by anxiolytic or enhanced by anxiogenic agents, respectively. The behavioural readout is insensitive to environmental aversiveness and is unrelated to behaviours assessed by conventional tests involving young zebrafish. Taken together, we have developed a sensitive high-throughput test allowing the assessment of anxiety-related responses of zebrafish regardless of developmental stage, granting the opportunity to combine larva-based state-of-the-art methods with detailed behavioral analysis.

Frontiers in molecular neuroscience, 2017

Serotonergic and glutamatergic neurons of median raphe region (MRR) play a pivotal role in the mo... more Serotonergic and glutamatergic neurons of median raphe region (MRR) play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors (P2rx7) are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release. P2rx7s are implicated in various neuropsychiatric conditions such as schizophrenia and depression. Here we investigated whether 5-HT release released from the hippocampal terminals of MRR is subject to modulation by P2rx7s. To achieve this goal, an optogenetic approach was used to selectively activate subpopulation of serotonergic terminals derived from the MRR locally, and one of its target area, the hippocampus. Optogenetic activation of neurons in the MRR with 20 Hz was correlated with freezing and enhanced locomotor activity of freely moving mice and elevated extracellular levels of 5-HT, glutamate ...

Investigative Ophthalmology & Visual Science, Apr 28, 2009

Optics Express, Aug 27, 2021

The appearance of the common artifacts of laser speckle contrast imaging (LSCI), namely the granu... more The appearance of the common artifacts of laser speckle contrast imaging (LSCI), namely the granularity in flow rate estimation caused by static scatterers, is a well-known phenomenon. This artifact can be greatly reduced in spatial speckle contrast calculation using interframe decorrelated illumination, forcing true ensemble averaging. We propose a statistical model, which describes the effect of multiple image acquisitions on the contrast map quality when the illumination stable and when the illumination is decorrelated frame by frame. We investigate the improvement as a function of the ratio of dynamic and static scatterers by formulating a statistical distribution based model, using in simulation, flow phantom and in vivo experiments. Our main finding is that the ensemble averaging yields limited improvement in several practical cases due to the highly heterogeneous scatterer structure of living tissues.

Journal of Cerebral Blood Flow and Metabolism, Apr 1, 2017

Introduction: Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculatio... more Introduction: Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculation such as microthrombosis, microvasospasms, and lack of CO 2 reactivity. New findings ex vivo suggest that neurovascular coupling (NVC), the process that increases cerebral blood flow upon neuronal activity, may also be impaired after SAH. The aim of the current study was to investigate NVC after SAH in vivo. Methods: C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. Neurovascular reactivity was tested 24 hours later by either forepaw stimulation or CO 2 inhalation and visualized in pial and parenchymal arterioles by two-photon microscopy. NVC was also investigated ex vivo on acute brain slice preparations. Results: In sham-operated mice, cerebral vessels dilated to about 130% of baseline after CO 2 inhalation or forepaw stimulation. By contrast, SAH resulted in a complete loss of CO 2 reactivity in vivo, and pial and parenchymal vessels did not dilate upon neuronal activation either in vivo or ex vivo-the majority of vessels even constricted by 10-15%. Conclusions: These findings indicate that after SAH cerebral vessels do not dilate but constrict upon neuronal activation. This process may further aggravate SAH-induced brain damage. Based on previous results showing that NVC is preserved three hours after SAH, the current results demonstrate that the impairment of NVC is progressive and therapeutic efforts need to be initiated as early as possible after SAH.

The International Journal of Neuropsychopharmacology, Apr 20, 2022

Background: Immunological markers and related signaling molecules in the blood are altered in sch... more Background: Immunological markers and related signaling molecules in the blood are altered in schizophrenia mouse models, in acutely relapsed patients with schizophrenia, and in persons at a clinically high risk for subsequently developing psychosis, highlighting their potential as prognostic and theranostic biomarkers. Therefore, we herein aimed to identify novel potential biomarkers in the serum that are associated with purinergic signaling. Methods: To our knowledge, this is the first study to assess the correlations among the levels of human serum adenine nucleotides (ATP, ADP), adenosine, P2X7 receptor, and disease activity in patients hospitalized due to an acute relapse of schizophrenia (n = 53) and healthy controls (n = 47). In addition, to validate these findings using a reverse translational approach, we examined the same parameters in an acute phencyclidine-induced schizophrenia mouse model. Results: We found consistently elevated levels of ATP, ADP, interleukin (IL)-6, and IL-10 in both schizophrenia groups compared with the controls. The levels of adenosine, IL-1β, IL-12, and C-reactive protein were also increased in the human patient samples. Moreover, ATP and ADP were significantly positively correlated with the Positive and Negative Symptom Scale item "lack of judgment and insight"; IL-1β, IL-12, and tumour necrosis factor alpha were significantly positively correlated with "tension" and "depression"; and "disorientation" and "poor attention" were correlated significantly with IL-6 and IL-8. Conclusions: Our study suggests the promising potential of blood purines and inflammatory markers as future prognostic tools.

Optics Letters, Feb 3, 2021

Laser Speckle Contrast Imaging is a technique to determine blood flow rate with a limitation of l... more Laser Speckle Contrast Imaging is a technique to determine blood flow rate with a limitation of low dynamic range. In this Letter, we introduce a varied illumination speckle contrast imaging method. It utilizes varying illumination during exposure to customize the correlation time (flow rate) to speckle contrast relation. The method can cover an order of magnitude larger range flow rate in a single exposure compared to constant illumination methods. The proposed method enables high dynamic range flow rate imaging that is advantageous in studying larger vessels and small arteries. We demonstrate the theory by simulations, ex vivo and in vivo measurements.

Behavioural Pharmacology, Dec 1, 2017

Optogenetics was the method of the year in 2010 according to Nature Neuroscience. Since then, thi... more Optogenetics was the method of the year in 2010 according to Nature Neuroscience. Since then, this method has become widespread, the use of virally delivered genetic tools has extended to other fields such as pharmacogenetics, and optogenetic techniques have become frequently applied in genetically manipulated animals for in-vivo circuit analysis and behavioral studies. However, several issues should be taken into consideration when planning such experiments. We aimed to summarize the critical points concerning optogenetic manipulation of a specific brain area in mutant mice. First, the appropriate vector should be chosen to allow optimal optogenetic manipulation. Adeno-associated viral vectors are the most common carriers with different available serotypes. Lightsensitive channels are available in many forms, and the expression of the delivered genetic material can be influenced in many ways. Second, selecting the adequate stimulation protocol is also essential. The pattern, intensity, and timing could be determinative parameters. Third, the mutant strain might have a phenotype that influences the observed behavior. In conclusion, detailed preliminary experiments and numerous control groups are required to choose the best vector and stimulation protocol and to ensure that the mutant animals do not have a specific phenotype that can influence the examined behavior.

Behavioural Brain Research, Mar 1, 2023

International Journal of Molecular Sciences, 2022

The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine str... more The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine stress axis and related behaviour is still under discussion. We aimed to obtain deeper insight into this process. To rescue magnocellular AVP synthesis, a vasopressin-containing adeno-associated virus vector (AVP-AAV) was injected into the supraoptic nucleus (SON) of AVP-deficient Brattleboro rats (di/di). We compared +/+, di/di, and AVP-AAV treated di/di male rats. The AVP-AAV treatment rescued the AVP synthesis in the SON both morphologically and functionally. It also rescued the peak of adrenocorticotropin release triggered by immune and metabolic challenges without affecting corticosterone levels. The elevated corticotropin-releasing hormone receptor 1 mRNA levels in the anterior pituitary of di/di-rats were diminished by the AVP-AAV-treatment. The altered c-Fos synthesis in di/di-rats in response to a metabolic stressor was normalised by AVP-AAV in both the SON and medial amygdala (MeA...

PLOS ONE

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencin... more The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex.

Anesthesiology, 2017

General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induc... more General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induce a persistent decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)-mediated inhibition controlled by the developmental up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2). In utero electroporation of KCC2 was used to prematurely increase the efficacy of (GABAA)-mediated inhibition in layer 2/3 pyramidal neurons in the immature rat somatosensory cortex. Parallel experiments with expression of the inward-rectifier potassium channel Kir2.1 were done to reduce intrinsic neuronal excitability. The effects of these genetic manipulations (n = 3 to 4 animals per experimental group) were evaluated using iontophoretic injection of Lucifer Yellow (n = 8 to 12 cells per animal). The total number of spines analyzed per group ranged between 907 and 3,371. The authors found a robust effect of the developmental up-regulation of KCC2-mediated Cl transport on the age-dependent action of propofol on dendritic spines. Premature expression of KCC2, unlike expression of a transport-inactive KCC2 variant, prevented a propofol-induced decrease in spine density. In line with a reduction in neuronal excitability, the above result was qualitatively replicated by overexpression of Kir2.1. The KCC2-dependent developmental increase in the efficacy of GABAA-mediated inhibition is a major determinant of the age-dependent actions of propofol on dendritic spinogenesis.

Physiology & behavior, Jan 3, 2016

Vasopressin can contribute to the development of stress-related psychiatric disorders, anxiety an... more Vasopressin can contribute to the development of stress-related psychiatric disorders, anxiety and depression. Although these disturbances are more common in females, most of the preclinical studies have been done in males. We compared female vasopressin-deficient and +/+ Brattleboro rats. To test anxiety we used open-field, elevated plus maze (EPM), marble burying, novelty-induced hypophagia, and social avoidance tests. Object and social recognition were used to assess short term memory. To test depression-like behavior consumption of sweet solutions (sucrose and saccharin) and forced swim test (FST) were studied. The stress-hormone levels were followed by radioimmunoassay and underlying brain areas were studied by c-Fos immunohistochemistry. In the EPM the vasopressin-deficient females showed more entries towards the open arms and less stretch attend posture, drank more sweet fluids and struggled more (in FST) than the +/+ rats. The EPM-induced stress-hormone elevations were small...

Behavioural Brain Research, 2016

h i g h l i g h t s • AVP deficient Brattleboro rat strain is a valuable model to study schizophr... more h i g h l i g h t s • AVP deficient Brattleboro rat strain is a valuable model to study schizophrenia. • Lack of AVP resulted in changes of histone acetylation in the frontal brain and hippocampus. • Influencing histone acetylation may provide therapeutic alternatives for schizophrenia.

Experimental Neurology, 2011

Journal of Cellular Biochemistry, 2008

Nephrology Dialysis Transplantation

Background and Aims Perinatal asphyxia (PA) is associated with more than half a million mature ne... more Background and Aims Perinatal asphyxia (PA) is associated with more than half a million mature newborn deaths yearly. It may lead to severe complications including hypoxic encephalopathy, renal- hepatic- and cardiovascular injury, as well as respiratory distress, Basic research and clinical trials mainly focus on mitigating central nervous system damage by selective head or whole body cooling, which is currently the only routinely used treatment in clinical practice. However, the extent of PA-associated multi-organ damage is not clarified yet and effective therapies are lacking. Our aim was to investigate the acute renal, hepatic and cardiac impairment following PA and to identify pathways involved in the pathomechanism. In addition, we aimed to explore long-term effects of PA on permanent organ damage and susceptibility to ischemia/-reperfusion injury in adulthood. Method Postnatal 7 day-old male Wistar rat pups (n=5-10/group) were randomly grouped as follows: (i) Baseline; (ii) Co...

Nephrology Dialysis Transplantation

Background and Aims Perinatal asphyxia (PA) leads to the death of more than half a million mature... more Background and Aims Perinatal asphyxia (PA) leads to the death of more than half a million mature newborns yearly. PA is associated with several serious complications, including hypoxic encephalopathy, renal- hepatic- and cardiovascular injury, as well as respiratory distress. Basic research and clinical trials mainly focus on mitigating central nervous system damage by selective head or whole body cooling, which is currently the only routinely used treatment in clinical practice. However, the extent of PA-associated multi-organ damage is not clarified yet and effective therapies are lacking. The aim of the present study was to determine the acute renal, hepatic and cardiac impairment following PA and to identify pathways involved in the pathomechanism. In addition, we aimed to investigate long-term effects of PA on permanent organ damage and susceptibility to ischemia/-reperfusion injury in adulthood. Method Postnatal 7 day-old male Wistar rat pups (n=5-10/group) were randomly grou...

Frontiers in behavioral neuroscience, 2018

Serotonergic mechanisms hosted by raphe nuclei have important roles in affiliative and agonistic ... more Serotonergic mechanisms hosted by raphe nuclei have important roles in affiliative and agonistic behaviors but the separate roles of the two nuclei are poorly understood. Here we studied the roles of the dorsal (DR) and median raphe region (MRR) in aggression by optogenetically stimulating the two nuclei. Mice received three 3 min-long stimulations, which were separated by non-stimulation periods of 3 min. The stimulation of the MRR decreased aggression in a phasic-like manner. Effects were rapidly expressed during stimulations, and vanished similarly fast when stimulations were halted. No carryover effects were observed in the subsequent three trials performed at 2-day intervals. No effects on social behaviors were observed. By contrast, DR stimulation rapidly and tonically promoted social behaviors: effects were present during both the stimulation and non-stimulation periods of intermittent stimulations. Aggressive behaviors were marginally diminished by acute DR stimulations, but...

Scientific Reports

Larval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availabil... more Larval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availability of resource-efficient, high-throughput screening and high-resolution imaging techniques. Although behavioural models are available in larvae, only a few can be employed to assess anxiety. Here we present the swimming plus-maze (SPM) test paradigm, a tool to assess anxiety-related avoidance of shallow water bodies in early developmental stages. The "+" shaped apparatus consists of arms of different depth, representing different levels of aversiveness similarly to the rodent elevated plus-maze. The paradigm was validated (i) in larval and juvenile zebrafish, (ii) after administration of compounds affecting anxiety and (iii) in differentially aversive experimental conditions. Furthermore, we compared the SPM with conventional "anxiety tests" of zebrafish to identify their shared characteristics. We have clarified that the preference of deeper arms is ontogenetically conserved and can be abolished by anxiolytic or enhanced by anxiogenic agents, respectively. The behavioural readout is insensitive to environmental aversiveness and is unrelated to behaviours assessed by conventional tests involving young zebrafish. Taken together, we have developed a sensitive high-throughput test allowing the assessment of anxiety-related responses of zebrafish regardless of developmental stage, granting the opportunity to combine larva-based state-of-the-art methods with detailed behavioral analysis.

Frontiers in molecular neuroscience, 2017

Serotonergic and glutamatergic neurons of median raphe region (MRR) play a pivotal role in the mo... more Serotonergic and glutamatergic neurons of median raphe region (MRR) play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors (P2rx7) are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release. P2rx7s are implicated in various neuropsychiatric conditions such as schizophrenia and depression. Here we investigated whether 5-HT release released from the hippocampal terminals of MRR is subject to modulation by P2rx7s. To achieve this goal, an optogenetic approach was used to selectively activate subpopulation of serotonergic terminals derived from the MRR locally, and one of its target area, the hippocampus. Optogenetic activation of neurons in the MRR with 20 Hz was correlated with freezing and enhanced locomotor activity of freely moving mice and elevated extracellular levels of 5-HT, glutamate ...