| 1. |
- Lindberg, Frida A.
(författare)
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The Biological Importance of the Amino Acid Transporter SLC38A10 : Characterization of a Knockout Mouse
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The biggest group of transporters, the solute carriers (SLCs), has more than 400 members, and about 30% of these are still orphan. In order to decipher their biological function and possible role in disease, there is a need for characterization of these. Around 25% of SLCs are estimated to have amino acids as substrates, including transporters belonging to the SLC38 family. The SLC38 members are sometimes referred to their alternative name: sodium-coupled neutral amino acid transporters (SNATs). One of these transporters, SNAT10 (or SLC38A10), has been characterized as a bidirectional transporter of glutamate, glutamine, alanine and aspartate, as well as having an efflux of serine, and is ubiquitously expressed in the body. However, its biological importance is not yet understood. The aim with this thesis was to characterize a mouse model deficient in SNAT10 protein in order to find the biological importance of this transporter. In paper I, this is done by using a series of behavioral tests, including the open field test, elevated plus maze, rotarod and Y-maze, among others. The SNAT10 knockout mouse was found to have an increased risk-taking behavior, but no motor or spatial working memory impairments. Furthermore, the knockout mouse was found to have a decreased body weight. In paper II, an additional behavioral characterization was performed by using the multivariate concentric square field™ (MCSF) test. The MCSF test is an arena with different zones associated to different behavioral traits, which generates a behavioral profile depending on where the mouse spends its time. The result from this test implies that the SNAT10 deficient mouse has a lower explorative behavior than its wild type littermates. In paper III, gene expression was studied in whole brain and some genes related to cell cycle regulation and p53 expression were found to be differentially expressed in the knockout brain. Additional gene expression was studied in kidney, liver, lung and muscle, but no changes were found. Plasma levels of histidine and threonine were altered in males, but no altered amino acid levels were found in knockout females, suggesting a possible sex-specific effect. These studies together imply that SNAT10 might be involved in processes related to risk-taking and explorative behavior in the open field and MCSF tests. SNAT10 deficiency also affected amino acid levels in plasma, indicating a disrupted amino acid homeostasis.
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| 2. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 3. |
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| 4. |
- Lindberg, Frida A, et al.
(författare)
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Behavioral profiling of SLC38A10 knockout mice using the multivariate concentric square field™ test
- 2022
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media S.A.. - 1662-5153. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: SLC38A10 is a gene that encodes the SLC38A10 protein, also known as SNAT10. The SLC38 family is evolutionary old, and SLC38A10 is one of the oldest members of the family. It is ubiquitously expressed, and its substrates are glutamine, glutamate, alanine, aspartate, and serine. However, little is known about its biological importance.Methods: In the current study, an SLC38A10 knockout mouse was run in the multivariate concentric square field (TM) (MCSF) test. The MCSF test gives the mouse a choice of areas to explore; sheltered areas, elevated and illuminated areas, or open spaces, and a behavioral profile is obtained. The multivariate data obtained were analyzed (i) for each parameter, (ii) parameters grouped into functional categories, and (iii) with a principal component analysis.Results: In the trend analysis, knockout mice had a decreased exploratory behavior compared to controls but did not show a distinct grouping in the principal component analysis.Discussion: There was not a pronounced difference in the behavioral profile in SLC38A10 knockout mice compared to their wild-type controls, although subtle alterations in zones associated with exploratory behavior and risk assessment in female and male knockout mice, respectively, could be observed. These results imply that a loss of function of the SLC38A10 protein in mice does not drastically alter behavior in the MSCF test.
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| 5. |
- Hultman, Cathrine, et al.
(författare)
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Exploring decision-making strategies in the Iowa gambling task and rat gambling task
- 2022
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media S.A.. - 1662-5153. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Decision-making requires that individuals perceive the probabilities and risks associated with different options. Experimental human and animal laboratory testing provide complimentary insights on the psychobiological underpinnings of decision-making. The Iowa gambling task (IGT) is a widely used instrument that assesses decision-making under uncertainty and risk. In the task participants are faced with a choice conflict between cards with varying monetary reinforcer/loss contingencies. The rat gambling task (rGT) is a pre-clinical version using palatable reinforcers as wins and timeouts mimicking losses. However, interspecies studies elaborating on human and rat behavior in these tasks are lacking. This study explores decision-making strategies among young adults (N = 270) performing a computerized version of the IGT, and adult outbred male Lister Hooded rats (N = 72) performing the rGT. Both group and individual data were explored by normative scoring approaches and subgroup formations based on individual choices were investigated. Overall results showed that most humans and rats learned to favor the advantageous choices, but to a widely different extent. Human performance was characterized by both exploration and learning as the task progressed, while rats showed relatively consistent pronounced preferences for the advantageous choices throughout the task. Nevertheless, humans and rats showed similar variability in individual choice preferences during end performance. Procedural differences impacting on the performance in both tasks and their potential to study different aspects of decision-making are discussed. This is a first attempt to increase the understanding of similarities and differences regarding decision-making processes in the IGT and rGT from an explorative perspective.
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| 6. |
- Lundberg, Stina, 1990-, et al.
(författare)
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Behavioral profiling in early adolescence and early adulthood of male Wistar rats after short and prolonged maternal separation
- 2020
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media SA. - 1662-5153. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Early-life stress and its possible correlations to genes, environment, and later health outcomes can only be studied retrospectively in humans. Animal models enable the exploration of such connections with prospective, well-controlled study designs. However, with the recent awareness of replicability issues in preclinical research, the reproducibility of results from animal models has been highlighted. The present study aims to reproduce the behavioral effects of maternal separation (MS) previously observed in the multivariate concentric square fieldTM (MCSF) test. A second objective was to replicate the adolescent behavioral profiles previously described in the MCSF test. Male rats, subjected to short or prolonged MS or standard rearing, were subjected to behavioral testing in early adolescence and early adulthood. As seen in previous studies, the behavioral effects of MS in the MCSF were small at both tested time points. When tested in early adolescence, the animals exhibited a similar behavioral profile as previously seen, and the finding of adolescent behavioral types was also reproduced. The distribution of animals into the behavioral types was different than in the initial study, but in a manner consistent with developmental theories, as the current cohort was younger than the previous. Notably, the Shelter seeker behavioral type persisted through development, while the Explorer type did not. The lack of basal behavioral effect after MS is in line with the literature on this MS paradigm; the working hypothesis is that the prolonged MS gives rise to a phenotype predisposed to negative health outcomes but which is not apparent without additional provocation.
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| 7. |
- Karlsson, Oskar, et al.
(författare)
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Neonatal exposure to the cyanobacterial toxin BMAA induces changes in protein expression and neurodegeneration in adult hippocampus.
- 2012
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-0929 .- 1096-6080. ; 130:2, s. 391-404
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Tidskriftsartikel (refereegranskat)abstract
- The cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 9-10) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150 mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460 mg/kg) also induced changes in the expression of S100β, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.
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| 8. |
- Titulaer, Joep
(författare)
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Finding improved drug strategies for schizophrenia : Preclinical studies on lumateperone and sodium nitroprusside
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Schizophrenia is a severe psychiatric disorder affecting approximately 20 million people worldwide. The disease consists of positive symptoms e.g. hallucinations, negative symptoms such as anhedonia, and cognitive deficits, e.g. impaired episodic memory. Most of the currently available treatment options for schizophrenia only target the positive symptoms, possess severe side effects and do not work for a large group of patients. In this thesis, the unique antipsychotic drug lumateperone and adjunctive treatment of sodium nitroprusside (SNP) to sub-maximal doses of conventional antipsychotic drugs are investigated in preclinical tests as novel treatment options for schizophrenia In paper I we showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test in rats. Moreover, by using microdialysis we showed that SNP significantly enhances risperidone-induced dopamine release in the rat medial prefrontal cortex (mPFC) but not in the nucleus accumbens, indicating that adjunct SNP could be used to improve the efficacy of antipsychotic drugs, while reducing their dose and subsequently lower the risk of side effects.In paper II we used microdialysis combined to the behavioral novel object recognition test in rats to show that the release of both dopamine and norepinephrine is increased in the ventral hippocampus in response to a novel object, suggesting that dopamine and norepinephrine may play a crucial role in recognition memory. In paper III we showed that SNP significantly enhanced the antipsychotic-like effect of sub-effective doses of olanzapine in the CAR test, but not of clozapine, this could be explained by the developed tolerance towards clozapine after repeated administrations.In paper IV we used enzyme-coated microelectrode arrays to show that lumateperone significantly increased cortical glutamate release in the mPFC of anaesthetized rats. By using electrophysiology, we also show that lumateperone facilitates NMDA and AMPA-mediated currents in a dopamine D1 dependent manner in layer V/VI pyramidal neurons in the mPFC of rats. Moreover, lumateperone increases dopamine release in the mPFC of freely moving rats as shown by using microdialysis. These mechanisms may improve cognitive deficits and contribute to the clinically demonstrated antidepressant effects of lumateperone. Taken together, these results show that lumateperone is a promising novel treatment option for schizophrenia, and that adjunct SNP treatment may allow for improved efficacy at maintained or even reduced dosage of conventional antipsychotic medication.
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| 9. |
- Vossen, Laura E., et al.
(författare)
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The zebrafish Multivariate Concentric Square Field : A Standardized Test for Behavioral Profiling of Zebrafish (Danio rerio)
- 2022
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media S.A.. - 1662-5153. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- The zebrafish (Danio rerio) is an important model organism in the study of the neurobiological basis of human mental disorders. Yet the utility of this species is limited by the quality of the phenotypical characterization tools available. Here, we present a complex testing environment for the quantification of explorative behavior in adult zebrafish, the zebrafish Multivariate Concentric Square Field (TM) (zMCSF), adapted from the rodent equivalent that has been used in > 40 studies. The apparatus consists of a central open area which is surrounded by a dark corner with a roof (DCR), corridors, and an inclined ramp. These areas differ in illumination, water depth, and are sheltered or exposed to different degrees. We quantified behavior of male and female wild-caught and AB strain zebrafish in the zMCSF (day 1) and cross-validated these results using the novel tank diving test (NTDT) (day 2). To assess the effect of repeated testing, AB zebrafish we tested a second time in both tests 1 week later (on days 7 and 8). We detected strong differences between the strains, with wild zebrafish swimming faster and spending more time in the corridors and on the ramp, while they avoided the open area in the center. AB zebrafish were less hesitant to enter the center but avoided the ramp, and often left one or more zones unexplored. No major sex differences in exploratory behavior were detected in either strain, except for a slightly higher velocity of AB males which has been reported before. Importantly, the zMCSF was largely resilient to repeated testing. The diving test revealed only one difference confined to one sex; wild females paid more visits to the top third than AB females. In isolation, this finding could lead to the conclusion that wild zebrafish are more risk-taking, which is incorrect given this strain's avoidance of open areas. To conclude, our results suggest that the zMCSF presents a sophisticated behavioral tool that can distinguish between different magnitudes and types of risk, allowing the user to create an intricate behavioral profile of individual adult zebrafish.
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| 10. |
- Scott, Hayden, et al.
(författare)
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Effects of pair housing on voluntary alcohol intake in male and female Wistar rats
- 2020
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Ingår i: Alcohol. - : Elsevier BV. - 0741-8329 .- 1873-6823. ; 86, s. 121-128
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Tidskriftsartikel (refereegranskat)abstract
- A number of different voluntary alcohol intake paradigms are available for home cage drinking studies. Traditionally, these paradigms involve single housing in order for individual intake to be measured. This study aimed at investigating the effects of pair housing on voluntary alcohol intake. Male and female Wistar rats were housed in pairs or individually for studies of voluntary alcohol intake using the modified intermittent access paradigm with alcohol access during three consecutive days per week followed by four days of water only. Individual intake of 20% alcohol solution and water was measured during 12 sessions, i.e., 4 weeks. Pair-housed animals could interact freely with their cage mate for four consecutive days each week and were then separated by an inserted mesh divider for three consecutive days each week during alcohol intake sessions. Alcohol intake and preference were compared between pair-housed and individually housed rats. The results revealed higher alcohol intake in females than in males. Pair-housed males had a higher alcohol intake and preference during the first 3 weeks, but not during the fourth week, compared to individually housed males No effect of housing condition was observed in female rats. The alcohol intake was higher on the first day of access relative to the two consecutive days in pair-housed males and higher on the first two days relative to the third day in female rats. Social rank or female estrus cycle had no effect on alcohol intake or preference. Taken together, the use of a divider during alcohol intake sessions had no impact on alcohol intake in female rats and may not exert long-term influences in male rats. Future studies are needed in order to elucidate whether the use of a divider can constitute an experimental refinement as an alternative to individual housing in studies of voluntary alcohol intake using the limited access and/or intermittent access paradigms.
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