| 39971. |
- Singh, Anand Kumar, et al.
(författare)
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Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain
- 2017
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 127:4, s. 1370-1374
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Tidskriftsartikel (refereegranskat)abstract
- Pain is fundamentally unpleasant and induces a negative affective state. The affective component of pain is mediated by circuits that are distinct from those mediating the sensory-discriminative component. Here, we have investigated the role of prostaglandins in the affective dimension of pain using a rodent pain assay based on conditioned place aversion to formalin injection, an inflammatory noxious stimulus. We found that place aversion induced by inflammatory pain depends on prostaglandin E-2 that is synthesized by cyclooxygenase 2 in neural cells. Further, mice lacking the prostaglandin E-2 receptor EP3 selectively on serotonergic cells or selectively in the area of the dorsal raphe nucleus failed to form an aversion to formalininduced pain, as did mice lacking the serotonin transporter. Chemogenetic manipulations revealed that EP3 receptor activation elicited conditioned place aversion to pain via inhibition of serotonergic neurons. In contrast to their role in inflammatory pain aversion, EP3 receptors on serotonergic cells were dispensable for acute nociceptive behaviors and for aversion induced by thermal pain or a kappa opioid receptor agonist. Collectively, our findings show that prostaglandin-mediated modulation of serotonergic transmission controls the affective component of inflammatory pain.
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| 39972. |
- Singh, Laura, et al.
(författare)
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Qualitative analysis of hotspots and intrusive memories after viewing an aversive film highlights their sensory and spatial features
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 7049-
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Tidskriftsartikel (refereegranskat)abstract
- Intrusive memories of trauma are recurrent distressing sensory-perceptual impressions of the traumatic event that enter consciousness spontaneously and unwanted. They often contain the worst moment/s (‘hotspots’) of the trauma memory and have primarily been studied in clinical populations after real trauma. Intrusive memories can also be studied using analogue trauma as an ‘experimental psychology model’. Little is known about the features of analogue trauma hotspots. Here we report an ancillary analysis of data from a randomized controlled trial. Seventy non-clinical participants viewed a trauma film containing COVID-19 related footage. Features of hotspots/intrusive memories of the film were explored using linguistic analysis and qualitative content coding. Participants reported on average five hotspots (M = 9.5 words/hotspot). Akin to hotspots soon after real trauma, analogue hotspots/intrusions primarily contained words related to space. Most contained sensory features, yet few cognitions and emotions. Results indicate that features of analogue trauma hotspots mirror those of hotspots soon after real trauma, speaking to the clinical validity of this ‘experimental psychology model’.ClinicalTrials.gov ID: NCT04608097, registered on 29/10/2020.
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| 39973. |
- Sirohi, Sunil, et al.
(författare)
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Alcohol-induced plasticity in the dynorphin/kappa-opioid receptor system
- 2012
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 5:Artcle 95, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Alcoholism is a chronic relapsing disorder characterized by continued alcohol use despite numerous adverse consequences. Alcohol has been shown to interact with numerous neurotransmitter systems to exert its pharmacological effects. The endogenous opioid system (EOS) has been strongly implicated in the positive and negative reinforcing effects of alcohol. Traditionally recognized as dysphoric/anhedonic in nature, the dynorphin/kappa-opioid receptor (DYN/KOR) system has recently received considerable attention due to evidence suggesting that an upregulated DYN/KOR system may be a critical contributor to the complex factors that result in escalated alcohol consumption once dependent. The present review will discuss alcohol-induced plasticity in the DYN/KOR system and how these neuroadaptations could contribute to excessive alcohol seeking and consumption.
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| 39974. |
- Sivertsson, Ebba, et al.
(författare)
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Dose-dependent regulation of kidney mitochondrial function by angiotensin II
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration. Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury. Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased. Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling.
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| 39975. |
- Sivertsson, Ebba, et al.
(författare)
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Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability
- 2018
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Ingår i: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 314:5, s. F864-F872
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Tidskriftsartikel (refereegranskat)abstract
- An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys. which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.
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| 39976. |
- Sivertsson, Ebba, et al.
(författare)
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Inhibition of Mammalian Target of Rapamycin Induces Renal Mitochondrial Uncoupling in Rats
- 2013
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Ingår i: Oxygen Transport To Tissue XXXV. - New York, NY : Springer New York. - 9781461474111 - 9781461472568 ; , s. 309-314
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Konferensbidrag (refereegranskat)abstract
- The mechanisms underlying diabetic nephropathy are not fully understood. However, recent research indicates mitochondria dysfunction as a contributing factor. Mammalian target of rapamycin (mTOR) is a known regulator of mitochondria function and could therefore also be involved in the development of diabetic nephropathy. The present study investigates the role of mTOR for controlling the function of mitochondria isolated from normal and diabetic rat kidneys. Control and streptozotocin-induced diabetic rats were treated with the mTOR inhibitor rapamycin (0.2 mg/day) by oral gavage for 14 days, after which mitochondria function was investigated using high-resolution respirometry. Mitochondrial uncoupling was defined as increased oxygen usage unrelated to ATP production. mTOR inhibition induced mitochondria uncoupling in control rats, but did not affect the already occurring uncoupling in kidney mitochondria from diabetic animals. Inhibition of mTOR using rapamycin induces mitochondria uncoupling in control rats, suggesting a role of mTOR as a moderator of mitochondria efficiency. No effect of mTOR inhibition was observed in mitochondria from diabetic animals, suggesting that there are other pathways in addition to the mTOR pathway regulating mitochondria function in diabetes. The functional significance of the mTOR pathway in regulating mitochondria efficiency warrants further attention.
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| 39977. |
- Sivertsson, Ebba, et al.
(författare)
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Thyroid hormone increases oxygen metabolism causing intrarenal tissue hypoxia; a pathway to kidney disease
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- The proposed mechanisms for the development of nephropathy are many, complex and often overlapping. Although recent literature strongly supports a role of kidney hypoxia as an independent pathway to nephropathy, the evidence remains inconclusive since the role of hypoxia is difficult to differentiate from confounding factors such as hyperglycemia, hypertension and oxidative stress. By increasing kidney oxygen consumption using triiodothyronine (T-3) and, thus, avoiding these confounding factors, the aim of the present study was to investigate renal hypoxia per se as a causal pathway for the development of nephropathy. Healthy Sprague-Dawley rats were treated with T-3 (10 mu g/kg/day) and the angiotensin II AT(1)-receptor antagonist candesartan (1 mg/kg in drinking water) to eliminate effects of T-3-induced renin release; and compared to a candesartan treated control group. After 7 weeks of treatment in vivo kidney function, oxygen metabolism and mitochondrial function were evaluated. T-3 did not affect glomerular filtration rate or renal blood flow, but increased total kidney oxygen consumption resulting in cortical hypoxia. Nephropathy, demonstrated as albuminuria and tubulointerstitial fibrosis, developed in T-3-treated animals. Mitochondria uncoupling mediated by uncoupling protein 2 and the adenosine nucleotide transporter was demonstrated as a mechanism causing the increased kidney oxygen consumption. Importantly, blood glucose levels, mean arterial blood pressure and oxidative stress levels were not affected by T-3. In conclusion, the present study provides further evidence for increased kidney oxygen consumption causing intrarenal tissue hypoxia, as a causal pathway for development of nephropathy.
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| 39978. |
- Siwani, Samer
(författare)
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Hippocampal circuit dynamics in learning and value processing of sensory cues : A study into the function of hippocampal microcircuits involving OLMα2 cells
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The anatomical signatures of the mnemonic/emotional processes share many brain structures, one of which seems to constitute a bridge, the hippocampus. It functions as a structure that consolidates engrams. It is connected to the prefrontal cortex, nucleus accumbens and amygdala, structures that provide emotional salience. This is, from an evolutionary perspective, likely a selection of fitness relevant engrams. Inputs from such structures to the hippocampus increase the likelihood of engram consolidation and behavioral response into long-term deposits. The hippocampal input pathways appear to be of importance for encoding and retrieval processes. During first encounters, entorhinal temporoammonic inputs are necessary for identifying probable threats and encoding of environmental cues. We find that artificial silencing of gate keeper neurons, named oriens lacunosum-moleculare (OLM) cells, increases approach and memory recall of novel cues in several tasks. Further, silencing of OLM cells mediates effective learning by increasing promiscuity in pyramidal cells in response to incoming sensory and/or emotional value inputs from other limbic structures, such as the basolateral amygdala. Depending on the dorsoventral position of the OLM cells, different phenotypes can be observed in different tasks. This is likely, at least in part, because of dorso-ventral differences in the connections between the hippocampus and other structures. In addition, OLM cells can control the specific oscillation frequency theta II (6-8 Hz), which appears in the ventral hippocampus and facilitates approach to predator odors. In conclusion, we show that the hippocampal circuit involving a subtype of OLM cells, is processing value of sensory cues through the temporoammonic pathway, and possibly affecting the basolateral amygdala inputs.
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| 39979. |
- Siwani, Samer, et al.
(författare)
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Hippocampal OLMα2 cells gate basolateral amygdala inputs for threat processing
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- It is becoming increasingly clear that the hippocampus is functionally diverse across its longitudinal axis. The ventral hippocampus is known to participate anxiety-related behaviors and may, together with the basolateral amygdala (BLA), facilitate threat aversion. Nevertheless, studies of mechanisms and circuit organization for processing value related cues are scarce. Here we investigate a microcircuit involving a subgroup of interneurons, referred to as Oriens lacunosum-moleculare cells, defined by their expression of the nicotinic receptor alpha2 subunit (OLMα2). Such cells can bidirectionally affect the response to predator odor as well as the encoding of object memories. In tracing experiments, we found that the basolateral amygdala mainly projects to the ventral hippocampus, whereas the medial amygdala and claustrum projects to the intermediate hippocampus. Moreover, we found that BLA inputs inhibit intrinsic hippocampal slow oscillation. Optogenetic stimulation of OLMα2 cells in the intermediate hippocampus caused an increase in approach of objects. Inhibition of ventrally located OLMα2 cells cause an increased avoidance to natural aversive stimuli and could entrain aversion to value neutral odors. In contrast, theta II oscillations, which predominantly appear in the ventral hippocampus during anxiety related behaviors, were absent during object recognition. Theta II oscillations only appeared when the animal was naïve to the arena setting. We conclude that there are functional differences between the intermediate and ventral hippocampus and that OLMα2 cells, in addition to sensory inputs, process emotional value signals from the amygdala.
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| 39980. |
- Siwani, Samer, et al.
(författare)
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Inhibition of hippocampal OLMα2 cells rescue nicotine induced memory impairment
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Nicotine is a commonly used drug that has been extensively studied for decades. Some of these studies have found cognitive enhancing effects; however, they were usually based on moderate and not the higher doses to which the regular consumer might be accustomed. Here we investigate how higher doses of nicotine may influence the performance of mice in object recognition and in the Y-maze. Further, we examined specific circuits underlying the hippocampal-dependent effects by targeting a subgroup of inhibitory interneurons, referred to as OLMα2 cells. We subjected mice to nicotine during an object recognition task and a working memory task. We found that a high dose of 1.5 mg/kg nicotine impaired memory performance in the object recognition task but not in the working memory task. It was previously demonstrated that OLMα2 cells bidirectionally affect learning in the object recognition task and that these cells respond to nicotine. Subsequently, we subjected mice to nicotine while optogenetically inhibiting OLMα2 cells and found that this intervention reversed the nicotine-induced memory impairment. We conclude that some learning and memory effects from nicotine are hippocampus dependent and are probably mediated by OLMα2 cells.
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