| 221. |
- Adelöf, Julia, 1990, et al.
(author)
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PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age.
- 2021
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In: Aging cell. - : Wiley. - 1474-9726 .- 1474-9718. ; 4:29
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Journal article (peer-reviewed)abstract
- With age, protein damage accumulates and increases the risk of age-related diseases. The proteasome activator PA28αβ is involved in protein damage clearance during early embryogenesis and has demonstrated protective effects against proteinopathy. We have recently discovered that adult female mice overexpressing PA28α (PA28αOE) have enhanced learning and memory, and protein extracts from their hippocampi prevent aggregation more efficiently than wild type. In this study, we investigated the effect of overexpressing PA28α on aging using C57BL/6N×BALB/c F2 hybrid mice. We found that the hippocampal anti-aggregation effect was maintained in young adult (7months) to middle-aged (15months) and old (22months) PA28αOE females. While the PA28αOE influence on learning and memory gradually decreased with aging, old PA28αOE females did not display the typical drop in explorative behavior-a behavioral hallmark of aging-but were as explorative as young mice. PA28αOE lowered PA28-dependent proteasome capacity in both heart and hippocampus, and there was no indication of lower protein damage load in PA28αOE. The life span of PA28αOE was also similar to wild type. In both wild type and PA28αOE, PA28-dependent proteasome capacity increased with aging in the heart, while 26S and 20S proteasome capacities were unchanged in the timepoints analyzed. Thus, PA28αOE females exhibit improved hippocampal ability to prevent aggregation throughout life and enhanced cognitive capabilities with different behavioral outcomes dependent on age; improved memory at early age and a youth-like exploration at old age. The cognitive effects of PA28αβ combined with its anti-aggregation molecular effect highlight the therapeutical potential of PA28αβ in combating proteinopathies.
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| 222. |
- Adelöf, Julia, 1990, et al.
(author)
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Survival-Span Method: How to Qualitatively Estimate Lifespan to Improve the Study of Aging, and not Disease, in Aging Studies
- 2021
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In: Frontiers in Aging. - : Frontiers Media SA. - 1663-4365 .- 2673-6217. ; 2
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Journal article (peer-reviewed)abstract
- Lifespan analyses are important for advancing our understanding of the aging process. There are two major issues in performing lifespan studies: 1) late-stage animal lifespan analysis may include animals with non-terminal, yet advanced illnesses, which can pronounce indirect processes of aging rather than the aging process per se and 2) they often involves challenging welfare considerations. Herein, we present an option to the traditional way of performing lifespan studies by using a novel method that generates high-quality data and allows for the inclusion of excluded animals, even animals removed at early signs of disease. This Survival-span method is designed to be feasibly done with simple means by any researcher and strives to improve the quality of aging studies and increase animal welfare.
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| 223. |
- Ademar, Karin, et al.
(author)
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Acamprosate reduces ethanol intake in the rat by a combined action of different drug components
- 2023
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In: Scientific Reports. - 2045-2322. ; 13:1
-
Journal article (peer-reviewed)abstract
- Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral (R) (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as relapse prevention therapy. The mechanism underlying its effect has in some studies been attributed to the calcium moiety and not to the N-acetylhomotaurine part of the compound. We recently suggested that the dopamine elevating effect of acamprosate is mediated both by N-acetylhomotaurine and calcium in a glycine receptor dependent manner. Here we aimed to explore, by means of in vivo microdialysis, if our previous study using local administration was functionally relevant and if systemic administration of the sodium salt of N-acetylhomotaurine (sodium acamprosate; 200 mg/kg, i.p.) enhanced the effects of calcium chloride (CaCl2; 73.5 mg/kg, i.p.) on nucleus accumbens (nAc) dopamine and/or taurine levels in male Wistar rats. In addition, we investigated the impact of regular acamprosate and the combination of CaCl(2 )and N-acetylhomotaurine on the alcohol deprivation effect (ADE). Finally, we assessed if N-acetylhomotaurine potentiates the ethanol-intake reducing effect of CaCl(2 )in a two-bottle choice voluntary ethanol consumption model followed by an ADE paradigm. Systemic administration of regular acamprosate, sodium acamprosate and CaCl(2 )all trended to increase nAc dopamine whereas the combination of CaCl(2)and sodium acamprosate produced a significant increase. Sodium acamprosate elevated extracellular taurine levels without additional effects of CaCl2. Ethanol intake was significantly reduced by systemic administration of CaCl(2 )without additional effects of the combination of CaCl(2 )and sodium acamprosate. Both acamprosate and CaCl(2 )combined with sodium acamprosate blocked the ADE following acute treatment. The data presented suggest that CaCl(2 )and N-acetylhomotaurine act in concert on a neurochemical level, but calcium appears to have the predominant effect on ethanol intake.
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| 224. |
- Ademar, Karin, et al.
(author)
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Sodium acamprosate and calcium exert additive effects on nucleus accumbens dopamine in the rat
- 2022
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In: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 27:5
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Journal article (peer-reviewed)abstract
- Acamprosate (Campral (R) - calcium-bis[N-acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect. The aim of the present study was to, by means of reversed in vivo microdialysis, elucidate if the dopamine elevating properties of acamprosate are mediated by N-acetylhomotaurine or by the calcium moiety. Male rats were equipped with a microdialysis probe in the nAc and received acute local treatment with regular acamprosate (CaAcamp 0.5 mM), calcium chloride (CaCl2 0.5 mM), sodium acamprosate (NaAcamp 0.5-1 mM), the glycine receptor (GlyR) antagonist strychnine (Stry 20 mu M), or vehicle. In all experiments, extracellular levels of dopamine and taurine were examined. We found that local perfusion with both CaAcamp and CaCl2 increased dopamine levels in a GlyR-dependent manner. NaAcamp did not influence dopamine levels, but concomitant administration with CaCl2 resulted in an additive dopamine output compared to the drugs administrated alone. We also found CaAcamp and the combination of CaCl2 and NaAcamp to increase accumbal taurine levels, suggesting that CaAcamp may act indirectly on GlyRs via taurine release. The present results indicate that both N-acetylhomotaurine and the calcium moiety of acamprosate have dopamine elevating properties within the nAc and that, in this respect, these substances are beneficial in combination.
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| 225. |
- Aden, Hassan
(author)
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Building futures through Refugee Education: Aspirations, Navigation, and (Non- )citizenship
- 2023
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Doctoral thesis (other academic/artistic)abstract
- This study explores how Somali secondary school and graduate-level youth in Kenya’s Dadaab camps attempt to build their futures through education, despite challenges posed by their non-citizen status. Using ethnographic data, the study specifically analyses the educational journeys, aspirations, and experiences of these refugee youth, shedding light on the everyday practices and dynamic strategies they employ to pursue their goals and manage obstacles. The study demonstrates how secondary school youth actively pursue educational aspirations, which they believe can enable them to exit the camps and potentially overcome their non-citizen status – through routes such as the resettlement-based scholarships for post-secondary education in Canada. Anchoring in their hopes in education, these students leverage various social resources, networks, and strategies to cope with challenges facing their education and aspirations, while simultaneously reflecting on various pathways to navigate post-graduation crossroads. Graduate-level youth, faced with limited opportunities, often adjust their aspirations to align with the available options to move forward, such as scholarships or incentive- (as opposed to wage-) paying jobs in the camps. More and more graduate youth opt to return to Somalia in seek of better employment opportunities, despite the potential security risks. The study also underscores the intergenerational solidarity and support system that emerge as academically successful refugee youth establish and manage nationally accredited schools, significantly contributing to students’ performance in national exams and the quality of education overall. By examining refugee youths’ enterprise of future-building through education within the context of long-term camps –characterised by perpetual precarity and uncertainty due to inhabitants’ exclusion from citizenship rights, freedoms, and advantages – this study provides theoretical insights into the complex and dynamic interplay among aspirations, navigational strategies, and non-citizenship status.
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| 226. |
- Aden, Hassan, et al.
(author)
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From Refugees to Citizens? How Refugee Youth in the Dadaab Camps of Kenya Use Education to Challenge Their Status as Non-Citizens
- 2023
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In: Journal of Refugee Studies. - 0951-6328. ; 36:4, s. 736-755
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Journal article (peer-reviewed)abstract
- The Dadaab camps of Kenya have 'warehoused' refugees from Somalia and elsewhere since 1991, providing their inhabitants with little hope to (re)gain the legal rights, participation, and membership that citizenship provides. Refugee youth in Dadaab hope that education can enable their access to citizenship rights-in particular, physical mobility and the right to work. Drawing on ethnographic research, semi-structured interviews, and life history interviews conducted in Dadaab and Mogadishu, this article discusses how refugee youth from Dadaab attempt to challenge their status as non-citizens through secondary education. Our study underscores that achieving citizenship rights, as well as civic participation and belonging, are key aspirations for these young people independent of whether they remain in Dadaab or (re)turn to Mogadishu. Yet, their ideas about what these key aspects of citizenship are and how to achieve them shift with their geographical location and in the presence or absence of citizenship rights.
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| 227. |
- Adermark, Louise, 1974, et al.
(author)
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Astrocytes modulate extracellular neurotransmitter levels and excitatory neurotransmission in dorsolateral striatum via dopamine D2 receptor signaling
- 2022
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In: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 47:8, s. 1493-1502
-
Journal article (peer-reviewed)abstract
- Astrocytes provide structural and metabolic support of neuronal tissue, but may also be involved in shaping synaptic output. To further define the role of striatal astrocytes in modulating neurotransmission we performed in vivo microdialysis and ex vivo slice electrophysiology combined with metabolic, chemogenetic, and pharmacological approaches. Microdialysis recordings revealed that intrastriatal perfusion of the metabolic uncoupler fluorocitrate (FC) produced a robust increase in extracellular glutamate levels, with a parallel and progressive decline in glutamine. In addition, FC significantly increased the microdialysate concentrations of dopamine and taurine, but did not modulate the extracellular levels of glycine or serine. Despite the increase in glutamate levels, ex vivo electrophysiology demonstrated a reduced excitability of striatal neurons in response to FC. The decrease in evoked potentials was accompanied by an increased paired pulse ratio, and a reduced frequency of spontaneous excitatory postsynaptic currents, suggesting that FC depresses striatal output by reducing the probability of transmitter release. The effect by FC was mimicked by chemogenetic inhibition of astrocytes using G(i)-coupled designer receptors exclusively activated by designer drugs (DREADDs) targeting GFAP, and by the glial glutamate transporter inhibitor TFB-TBOA. Both FC- and TFB-TBOA-mediated synaptic depression were inhibited in brain slices pre-treated with the dopamine D2 receptor antagonist sulpiride, but insensitive to agents acting on presynaptic glutamatergic autoreceptors, NMDA receptors, gap junction coupling, cannabinoid 1 receptors, mu-opioid receptors, P2 receptors or GABA(A) receptors. In conclusion, our data collectively support a role for astrocytes in modulating striatal neurotransmission and suggest that reduced transmission after astrocytic inhibition involves dopamine.
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| 228. |
- Adermark, Louise, 1974, et al.
(author)
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Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum
- 2024
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In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 25:1
-
Journal article (peer-reviewed)abstract
- Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.
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| 229. |
- Adermark, Louise, 1974, et al.
(author)
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Prospective association between use of electronic cigarettes and use of conventional cigarettes: a systematic review and meta-analysis
- 2021
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In: Erj Open Research. - Sheffield : European Respiratory Society (ERS). - 2312-0541. ; 7:3
-
Journal article (peer-reviewed)abstract
- Objective The aim of this systematic review and meta-analysis was to assess the association between e-cigarette use and subsequent initiation or recurrence of cigarette smoking. Data sources A systematic literature search was finalised on 11 November 2019 using PubMed (including MEDLINE), EMBASE, Cochrane Library, Scopus, PubMed Health, NICE Evidence Search, PROSPERO, CRD and PsycInfo. Study selection Studies were included if meeting the following criteria: reporting empirical results; longitudinal observational design with a minimum of 3 months of follow-up; including general population samples; allowing for the comparison between users and nonusers of e-cigarettes. Studies rated as having high risk of bias were excluded. Studies were independently assessed by at least two authors. The procedures described by PRISMA were followed, and the quality of evidence was rated using GRADE. Data synthesis 30 longitudinal studies from 22 different cohorts assessing e-cigarette use among nonsmokers or never-smokers at baseline, and subsequent use of cigarette smoking at follow-up, were included in this review. A random-effects meta-analysis based on 89076 participants showed a pooled unadjusted odds ratio (OR) of cigarette smoking among baseline nonsmoker e-cigarette users compared with nonusers of 4.68 (CI 3.64-6.02), while the adjusted OR was 3.37 (CI 2.68-4.24). These results were consistent irrespective of whether the outcome was measured as ever-smoking or as past 30-day smoking. The evidence was graded as moderate. Conclusions Use of e-cigarettes may predict the initiation or recurrence of cigarette smoking.
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| 230. |
- Adermark, Louise, 1974, et al.
(author)
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Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition.
- 2021
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In: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 126
-
Journal article (peer-reviewed)abstract
- Overconsumption of food is a major health concern in the western world. Palatable food has been shown to alter the activity of neural circuits, and obesity has been linked to alterations in the connectivity between the hypothalamus and cortical regions involved in decision-making and reward processing, putatively modulating the incentive value of food. Outlining neurophysiological adaptations induced by dietary intake of high fat diets (HFD) is thus valuable to establish how the diet by itself may promote overeating. To this end, C57BL/6 mice were fed HFD rich in either saturated fatty acids (HFD-S) or polyunsaturated fatty acids (HFD-P), or a low-fat control diet (LFD) for four weeks. Food and energy intake were monitored and ex vivo electrophysiology was employed to assess neuroadaptations in lateral hypothalamus (LH) and corticostriatal circuits, previously associated with food intake. In addition, the effects of dietary saturated and polyunsaturated fatty acids on the gene expression of NMDA, AMPA and GABAA receptor subunits in the hypothalamus were investigated. Our data shows that mice fed HFD-P had increased daily food and energy intake compared with mice fed HFD-S or LFD. However, this increase in energy intake had no obesogenic effects. Electrophysiological recordings demonstrated that HFD-P had a selective effect on glutamatergic neurotransmission in the LH, which was concomitant with a change in mRNA expression of AMPA receptor subtypes Gria1, Gria3 and Gria4, with no effect on the mRNA expression of NMDA receptor subtypes or GABAA receptor subtypes. Furthermore, while synaptic output from corticostriatal subregions was not significantly modulated by diet, synaptic plasticity in the form of long-term depression (LTD) was impaired in the dorsomedial striatum of mice fed HFD-S. In conclusion, this study suggests that the composition of fatty acids in the diet not only affects weight gain, but may also modulate neuronal function and plasticity in brain regions involved in food intake.
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