Papers by Krisztina Kovacs
1.Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (Pa) ... more 1.Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (Pa) are in the position to integrate stress-related information and initiate adaptive neuroendocrine-, autonomic-, metabolic- and behavioral responses. In addition to hypophyseotropic cells, CRH is widely expressed in the CNS, however their involvement in organization of the stress response is not fully understood. In these experiments, we took the advantage of recently available Crh-IRES-Cre; Ai9 mouse line to study the recruitment of hypothalamic and extrahypothalamic CRH neurons in categorically distinct, acute stress reactions. Reporter mice were exposed to restraint, ether, high salt and lipopolisacharide stress. The induced activation of CRH neurons was detected by colocalization of immediate early gene c-Fos in Td tomato expressing cells. We found differential activation of CRH neurons in central amygdaloid nucleus (Ce), bed nucleus stria terminalis lateral division, ventral posterior...
Toxins, 2020
Ochratoxin-A (OTA) is a carcinogenic and nephrotoxic mycotoxin, which may cause health problems i... more Ochratoxin-A (OTA) is a carcinogenic and nephrotoxic mycotoxin, which may cause health problems in humans and animals, and it is a contaminant in foods and feeds. The purpose of the present study is to evaluate the effect of oral OTA exposure on the antioxidant defense and lipid peroxidation in the kidney. In vivo administration of OTA in CD1, male mice (1 or 10 mg/kg body weight in a single oral dose for 24 h and repeated daily oral dose for 72 h or repeated daily oral dose of 0.5 mg/kg bodyweight for 21 days) resulted in a significant elevation of OTA levels in blood plasma. Some histopathological alterations, transcriptional changes in the glutathione system, and oxidative stress response-related genes were also found. In the renal cortex, the activity of the glutathione-system-related enzymes and certain metabolites of the lipid peroxidation (conjugated dienes, trienes, and thiobarbituric reactive substances) also changed.
Scientific Reports, 2019
Glucose is a major fuel for the central nervous system and hypoglycemia is a significant homeosta... more Glucose is a major fuel for the central nervous system and hypoglycemia is a significant homeostatic stressor, which elicits counterregulatory reactions. Hypothalamic metabolic- and stress-related neurons initiate these actions, however recruitment of glia in control such adaptive circuit remain unknown. Groups of fed- and fasted-, vehicle-injected, and fasted + insulin-injected male mice were compared in this study. Bolus insulin administration to fasted mice resulted in hypoglycemia, which increased hypothalamo-pituitary-adrenal (HPA) axis- and sympathetic activity, increased transcription of neuropeptide Y (Npy) and agouti-related peptide (Agrp) in the hypothalamic arcuate nucleus and activated IBA1+ microglia in the hypothalamus. Activated microglia were found in close apposition to hypoglycemia-responsive NPY neurons. Inhibition of microglia by minocycline increased counterregulatory sympathetic response to hypoglycemia. Fractalkine-CX3CR1 signaling plays a role in control of m...
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016
Brown adipose tissue (BAT) plays essential role in metabolicand thermoregulation and displays mor... more Brown adipose tissue (BAT) plays essential role in metabolicand thermoregulation and displays morphological and functional plasticity in response to environmental and metabolic challenges. BAT is a heterogeneous tissue containing adipocytes and various immune-related cells, however, their interaction in regulation of BAT function is not fully elucidated. Fractalkine is a chemokine synthesized by adipocytes, which recruits fractalkine receptor (CX3CR1)-expressing leukocytes into the adipose tissue. Using transgenic mice, in which the fractalkine receptor, Cx3cr1 gene was replaced by Gfp, we evaluated whether deficiency in fractalkine signaling affects BAT remodeling and function in high-fat-diet-induced obesity. Homo-and heterozygote male CX3CR1-GFP mice were fed with normal or fat enriched (FatED) diet for 10 weeks. Interscapular BAT was collected for histological and qPCR analysis. Heterozygous animals in which fractalkine signaling remains intact, gain more weight during FatED than CX3CR1 deficient gfp/gfp homozygotes. FatED in controls resulted in macrophage recruitment in the BAT with increased expression of proinflammatory mediators (Il1a,b, Tnfa and Ccl2). Local BAT inflammation was accompanied by increased expression of lipogenic enzymes and resulted in BAT "whitening". By contrast, fractalkine receptor deficiency prevented accumulation of tissue macrophages, selectively attenuated the expression of Tnfa, Il1a and Ccl2, increased BAT expression of lipolytic enzymes (Atgl, Hsl and Mgtl) and upregulated genes involved thermo-metabolism (Ucp1, Pparg Pgc1a) in response to FatED. These results highlight the importance of fractalkine-CX3CR1 interaction in recruitment of macrophages into the BAT of obese mice which might contribute to local tissue inflammation, adipose tissue remodeling and regulation of metabolic-related genes.
Journal of Neuroinflammation, 2011
Background: Systemic inflammation impairs outcome in stroke patients and experimental animals via... more Background: Systemic inflammation impairs outcome in stroke patients and experimental animals via mechanisms which are poorly understood. Circulating inflammatory mediators can activate cerebrovascular endothelium or glial cells in the brain and impact on ischaemic brain injury. One of the most serious early clinical complications of cerebral ischaemia is brain oedema, which compromises survival in the first 24-48 h. It is not understood whether systemic inflammatory challenges impair outcome after stroke by increasing brain injury only or whether they have direct effects on brain oedema, cerebrovascular inflammation and blood-brain barrier damage. Methods: We used two different systemic inflammatory stimuli, acute endotoxin treatment and anaphylaxis to study mechanisms of brain injury after middle cerebral artery occlusion (MCAo). Ischaemic brain injury, blood-brain barrier damage and oedema were analysed by histological techniques. Systemic cytokine responses and inflammatory changes in the brain were analysed by cytometric bead array, immunofluorescence, in situ hibridization and quantitative real-time PCR. Results: Systemic inflammatory challenges profoundly impaired survival in the first 24 h after experimental stroke in mice, independently of an increase in infarct size. Systemic lipopolysaccharide (LPS) dose-dependently increased mortality (50-100%) minutes to hours after cerebral ischaemia. Acute anaphylactic challenge in ovalbuminsensitised mice affected stroke more seriously when induced via intraperitoneal administration compared to intravenous. Both LPS and anaphylaxis induced inflammatory changes in the blood and in the brain prior to experimental stroke. Plasma cytokine levels were significantly higher after LPS, while increased IL-10 levels were seen after anaphylaxis. After MCAo, both LPS and anaphylaxis increased microglial interleukin-1α (IL-1α) expression and blood-brain barrier breakdown. LPS caused marked granulocyte recruitment throughout the ipsilateral hemisphere. To investigate whether reduction of ischaemic damage can improve outcome in systemic inflammation, controlled hypothermia was performed. Hypothermia reduced infarct size in all treatment groups and moderately improved survival, but failed to reduce excess oedema formation after anaphylaxis and LPSinduced neuroinflammation. Conclusions: Our results suggest that systemic inflammatory conditions induce cerebrovascular inflammation via diverse mechanisms. Increased brain inflammation, blood-brain barrier injury and brain oedema formation can be major contributors to impaired outcome in mice after experimental stroke with systemic inflammatory stimuli, independently of infarct size.
Brain, Behavior, and Immunity, 2014
Diet-induced obesity and related peripheral and central inflammation are major risk factors for m... more Diet-induced obesity and related peripheral and central inflammation are major risk factors for metabolic, neurological and psychiatric diseases. The chemokine fractalkine (Cx3CL1) and its receptor Cx3CR1 play a pivotal role in recruitment, infiltration and proinflammatory polarization of leukocytes and micoglial cells, however, the role of fractalkine signaling in the development of metabolic inflammation is not fully resolved. To address this issue, fractalkine receptor deficient (Cx3CR1 gfp/gfp) mice were exposed to normal or fat-enriched diet (FatED) for 10 weeks and physiological-, metabolic-and immune parameters were compared to those animals in which the fractalkine signaling is maintained by the presence of one functioning allele (Cx3CR1 +/gfp). Mice with intact fractalkine signaling develop obesity characterized by increased epididymal white fat depots and mild glucose intolerance, recruit leukocytes into the visceral adipose tissue and display increased expression of subset of pro-and anti-inflammatory cytokines when exposed to fat-enriched diet. By contrast, Cx3CR1-deficient (gfp/gfp) mice gain significantly less weight on fat-enriched diet and have smaller amount of white adipose tissue (WAT) in the visceral compartment than heterozygote controls. Furthermore, Cx3CR1 gfp/gfp mice fed a fat-enriched diet do not develop glucose intolerance, recruit proportionally less number of gfp-positive cells and express significantly less MCP-1, IL-1a and TNFa in the WAT than control animals with fat-enriched diet induced obesity. Furthermore, heterozygote obese, but not fractalkine receptor deficient mice express high levels of anti-inflammatory IL-10 and arginase1 markers in the visceral fat. The effect of fat-enriched diet on cytokine expression pattern was specific for the WAT, as we did not detect significant elevation of interleukin-1, tumor necrosis factor-alpha and monocyte chemoatracting protein (MCP-1) expression in the liver or in the hypothalamus in either genotype. These results highlight the importance of fractalkine signaling in recruitment and polarization of adipose tissue immune cells and identify fractalkine as a target to fight obesity-induced inflammatory complications.
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...
Brain, Behavior, and Immunity
Chronic stress is often accompanied by gastrointestinal symptoms, which might be due to stress-in... more Chronic stress is often accompanied by gastrointestinal symptoms, which might be due to stress-induced shift of gut microbiome to pathogenic bacteria. It has been hypothesized that stress alters gut permeability and results in mild endotoxemia which exaggerates HPA activity and contributes to anxiety and depression. To reveal the relationship between microbiome composition, stress-induced gastrointestinal functions and behavior, we treated chronically stressed mice with non-absorbable antibiotic, rifaximin. The "two hits" stress paradigm was used, where newborn mice were separated from their mothers for 3 h daily as early life adversity (maternal separation, MS) and exposed to 4 weeks chronic variable stress (CVS) as adults. 16S rRNA based analysis of gut microbiome revealed increases of Bacteroidetes and Proteobacteria and more specifically, Clostridium species in chronically stressed animals. In mice exposed to MS + CVS, we found extenuation of colonic mucosa, increased bacterial translocation to mesenteric lymph node, elevation of plasma LPS levels and infiltration of F4/80 positive macrophages into the colon lamina propria. Chronically stressed mice displayed behavioral signs of anxiety-like behavior and neophobia. Rifaximin treatment decreased Clostridium concentration, gut permeability and LPS plasma concentration and increased colonic expression of tight junction proteins (TJP1, TJP2) and occludin. However, these beneficial effects of rifaximin in chronically stressed mice was not accompanied by positive changes in behavior. Our results suggest that non-absorbable antibiotic treatment alleviates stress-induced local pathologies, however, does not affect stress-induced behavior.
Acta neuropathologica, 2018
Neurotropic herpesviruses can establish lifelong infection in humans and contribute to severe dis... more Neurotropic herpesviruses can establish lifelong infection in humans and contribute to severe diseases including encephalitis and neurodegeneration. However, the mechanisms through which the brain's immune system recognizes and controls viral infections propagating across synaptically linked neuronal circuits have remained unclear. Using a well-established model of alphaherpesvirus infection that reaches the brain exclusively via retrograde transsynaptic spread from the periphery, and in vivo two-photon imaging combined with high resolution microscopy, we show that microglia are recruited to and isolate infected neurons within hours. Selective elimination of microglia results in a marked increase in the spread of infection and egress of viral particles into the brain parenchyma, which are associated with diverse neurological symptoms. Microglia recruitment and clearance of infected cells require cell-autonomous P2Y12 signalling in microglia, triggered by nucleotides released fro...
Stress (Amsterdam, Netherlands), 2018
Glutamatergic neurons, characterized by vesicular glutamate transporters (VGluT1-3) provide the m... more Glutamatergic neurons, characterized by vesicular glutamate transporters (VGluT1-3) provide the main excitation in the brain. Their disturbances have been linked to various brain disorders, which could be also modeled by the contextual fear test in rodents. We aimed to characterize the participation of VGluT3 in the development of contextual fear through its contribution to hypothalamic-pituitary-adrenocortical axis (HPA) regulation using knockout (KO) mice. Contextual fear conditioning was induced by foot shock and mice were examined 1 and 7 d later in the same environment comparing wild type with KO. Foot shock increased the immobility time without context specificity. Additionally, foot shock reduced open arm time in the elevated plus maze (EPM) test, and distance traveled in the open field (OF) test, representing the generalization of fear. Moreover, KO mice spent more time with freezing during the contextual fear test, less time in the open arm of the EPM, and traveled a smalle...
Psychoneuroendocrinology, Dec 28, 2016
Drug-withdrawal aversive memories generate a motivational state leading to compulsive drug taking... more Drug-withdrawal aversive memories generate a motivational state leading to compulsive drug taking, with plasticity changes in the basolateral amygdala (BLA) being essential in aversive motivational learning. The conditioned-place aversion (CPA) paradigm allows for measuring the negative affective component of drug withdrawal. First, CPA triggers association between negative affective consequences of withdrawal with context (memory consolidation). Afterwards, when the animals are re-exposed to the paired environment, they avoid it due to the association between the context and aversive memories (memory retrieval). We examined the influence of glucocorticoids (GCs) for a morphine-withdrawal CPA paradigm, along with plasticity changes in the BLA, in sham-operated and adrenalectomized (ADX) animals. We demonstrated that sham+morphine animals robustly displayed CPA, whereas ADX-dependent animals lacked the affective-like signs of opiate withdrawal but displayed increased somatic signs of...
Molecular neurobiology, Jan 11, 2016
Drug-withdrawal-associated aversive memories might trigger relapse to drug-seeking behavior. Howe... more Drug-withdrawal-associated aversive memories might trigger relapse to drug-seeking behavior. However, changes in structural and synaptic plasticity, as well as epigenetic mechanisms, which may be critical for long-term aversive memory, have yet to be elucidated. We used male Wistar rats and performed conditioned-place aversion (CPA) paradigm to uncover the role of glucocorticoids (GCs) on plasticity-related processes that occur within the dentate gyrus (DG) during opiate-withdrawal conditioning (memory formation-consolidation) and after reactivation by re-exposure to the conditioned environment (memory retrieval). Rats subjected to conditioned morphine-withdrawal robustly expressed CPA, while adrenalectomy impaired naloxone-induced CPA. Importantly, while activity-regulated cytoskeletal-associated protein (Arc) expression was induced in sham- and ADX-dependent animals during the conditioning phase, Arc and early growth response 1 (Egr-1) induction was restricted to sham-dependent ra...
Life sciences, Jan 12, 2016
In vasopressin-deficient rat pups stressor-induced adrenocorticotropin (ACTH) and corticosterone ... more In vasopressin-deficient rat pups stressor-induced adrenocorticotropin (ACTH) and corticosterone elevations markedly dissociate. We have shown recently that during the postnatal period mineralocorticoid secretion is more sensitive to stressor exposure than that of glucocorticoids. We have therefore hypothesized that in vasopressin-deficient pups during hypoglycemia, a stressor triggering aldosterone release mainly via ACTH, aldosterone release will change in parallel with ACTH. An additional aim was to reveal at which stage of the development occurs the shift from aldosterone to corticosterone as primarily stressor-induced adrenocortical hormone. Vasopressin-deficient (di/di) and control Brattleboro rats were used both postnatally (10-day-old rats) and in adulthood. Hypoglycemia induced similar ACTH elevations in pups and adults with significantly lower levels in di/di rats. In contrast, vasopressin-deficiency resulted in elevated resting aldosterone and stressor-induced corticoster...
Scientific reports, Jan 23, 2016
Inflammatory bowel disease shows increasing prevalence, however its pathomechanism and treatment ... more Inflammatory bowel disease shows increasing prevalence, however its pathomechanism and treatment is not fully resolved. Prebiotics are non-digestible carbohydrates which might provide an alternative to treat inflammatory conditions in the gut due to their positive effects either on the microbiome or through their direct effect on macrophages and mucosa. To test the protective effects of an oligomannan prebiotic, yeast cell wall mannooligosaccharide (MOS) was administered in dextran-sulphate-sodium (DSS)-induced mouse model of acute colitis. MOS reduced DSS-induced clinical- (weight loss, diarrhea) and histological scores (mucosal damage) as well as sickness-related anxiety. DSS treatment resulted in changes in colon microbiome with selective increase of Coliform bacteria. MOS administration attenuated colitis-related increase of Coliforms, normalized colonic muc2 expression and attenuated local expression of proinflammatory cytokines IL-1a, IL1b, IL6, KC, G-CSF and MCP1 as well as t...
Neuroscience Letters, Sep 1, 2000
To reveal central mechanisms that transduce photic stimuli to sexually related neuroendocrine cha... more To reveal central mechanisms that transduce photic stimuli to sexually related neuroendocrine changes, Fra-2-ir, an inducible immediate-early gene marker of neuronal activation has been consecutively localized with that of GnRH-I in the brain of mallards that were triggered by arti®cial light at the photosensitive phase of the reproductive cycle. Strong neuronal activation was found in the POM and PVN in response to 1£ or 4£ 20 h light exposure that was accompanied with an increase of GnRH-ir in the hypothalamus and a dramatic depletion of GnRH-ir from terminals in the median eminence. The Fra-2 and GnRH-ir pro®les, however, were not co-localized in any region at any phase of photostimulation. These results demonstrate profound changes of GnRH-ir in the hypothalamus and reveal a distinct, photoresponsive cell population in the anterior hypothalamic area of the mallard.
J Endocrinol, 1992
ABSTRACT Stimulation of the immune system or experimental conditions (bacterial lipopolysaccharid... more ABSTRACT Stimulation of the immune system or experimental conditions (bacterial lipopolysaccharide (LPS) treatment) provoke a broad spectrum of physiological responses. It was recently shown that one of them is the activation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism and the site or sites through which LPS stimulates the HPA axis are not well understood. To establish whether the effect of bacterial LPS is related in vivo to the presence of hypothalamic hypophysiotrophic peptides (corticotrophin-releasing factor-41, arginine vasopressin, etc.), plasma ACTH and corticosterone levels were monitored in intact and sham-operated rats, and in rats with paraventricular nucleus lesions in order to remove the main source of these neuropeptides. Evidence was obtained that 4 h after treatment, LPS was able to activate the hypophysial-adrenal system in the absence of hypophysiotrophic neuropeptides of paraventricular origin. It is suggested that, in vivo, LPS could have a direct effect on the pituitary gland or that it acts through an extrapituitary, non-paraventricular pathway to activate the HPA axis. Journal of Endocrinology (1992) 133, 231–236
Effect of ether stress on dialysate concentration of extracellular amino acids in the hippocampus... more Effect of ether stress on dialysate concentration of extracellular amino acids in the hippocampus was studied by microdialysis in freely moving rats that have been either sham operated (SHAM) or adrenalectomized and supplemented with subcutaneous steroid pellets (ADX+CORT) providing constant corticosterone (CORT) plasma levels. In SHAM rats, ether stress resulted in a peak of glutamate and taurine 30 min after stress, while extracellular aspartate concentration was increased 120 min after challenge. These changes in amino acid levels as well as in glutamate/glutamine ratio were paralleled by stress-induced rise of plasma CORT. No significant alterations were detected in the concentration of hippocampal arginine, alanine, glycine, glutamine, threonine or serine. In contrast to SHAM animals, ether stress failed to have an effect on dialysate concentration of amino acid transmitters in the hippocampus of adrenalectomized rats supplemented with 50 mg CORT-pellets. Our results demonstrate that ether stress alters aspartate, glutamate, glutamate/glutamine ratio and taurine concentration in the hippocampus and indicate that stress-induced CORT release in plasma may be responsible for these amino acid alterations. These changes may also contribute to negative feedback effect of CORT on hypothalamo-pituitary-adrenocortical (HPA) axis via the hippocampus during stress.
Neuro Endocrinology Letters, 1990
Ideggyogyaszati Szemle, Apr 1, 2007
Bevezetés-A (-)deprenyl B típusú monoaminoxidázbénító, amelyet újabban sikeresen alkalmaznak a Pa... more Bevezetés-A (-)deprenyl B típusú monoaminoxidázbénító, amelyet újabban sikeresen alkalmaznak a Parkinson-és az Alzheimer-kór gyógyításában. Bár neuroprotektív hatásának mechanizmusa nem ismert pontosan, annyi bizonyos, hogy ez a hatás független a MAO-B-gátlástól. Módszerek-A deprenyl ischaemiával szembeni védôhatását in vitro vizsgáltuk a patkány hippocampusából készített organotipikus szelettenyészeteken. A sejtpusztulás idôbeni alakulását propidium-jodid-felvétellel követtük az után, hogy a szelettenyészeteket 45 percig oxigén-és glükózmentes körülmények között (OGD) inkubáltuk. Az apoptózisban szereplô egyes faktorok mRNS-szintjét RT-PCR reakcióval mértük. Eredmények-A neuronalis pusztulás elsô jeleit két órával az OGD után tapasztaltuk, amely 24 órával az ischaemia után a hippocampus összes rétegére kiterjedt. A deprenylkezelés (10-9 M) szignifikánsan késleltette az OGD által indukált sejtpusztulást. RT-PCR módszerrel kimutattuk, hogy kontroll-szelettenyészeteken a deprenyl emeli a Bcl-2 és a Bcl-xl mRNS szintjét. Az OGD ugyancsak növelte az antiapoptotikus faktorok expresszióját, míg a proapoptotikus bax mRNS-szintje változatlan maradt. Következtetés-Eredményeink szerint a deprenyl neuronvédô hatású az ischaemia in vitro modelljében. Bár a deprenyl kontrollkörülmények közt fokozza a Bcl-2 expresszióját, antiapoptotikus hatása nem mutatkozik szignifikánsan oxigén-glükóz megvonás után.
Uploads
Papers by Krisztina Kovacs