| 1. |
- Adermark, Louise, 1974, et al.
(författare)
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Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition.
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 126
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Aguggia, Julieta P., et al.
(författare)
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Growth hormone secretagogue receptor signaling in the supramammillary nucleus targets nitric oxide-producing neurons and controls recognition memory in mice
- 2022
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 139
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.
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| 3. |
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| 4. |
- Balter, Leonie J. T., et al.
(författare)
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Lipopolysaccharide-induced changes in the kynurenine pathway and symptoms of sickness behavior in humans
- 2023
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Ingår i: Psychoneuroendocrinology. - 0306-4530 .- 1873-3360. ; 153
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Tidskriftsartikel (refereegranskat)abstract
- Metabolites of the kynurenine pathway are hypothesized to be implicated in inflammation-associated depression, but there is a lack of experimental studies in humans assessing the kinetics of kynurenine metabolites in relation to experimentally-induced sickness. The aim of the present study was to assess changes in the kynurenine pathway and to explore its relation to symptoms of sickness behavior during an acute experimental immune challenge.This double-blind placebo-controlled randomized cross-over study included 22 healthy human participants (n = 21 both sessions, Mage = 23.4, SD = 3.6, nine women) who received an intravenous injection of 2.0 ng/kg lipopolysaccharide (LPS) and saline (placebo) on two different occasions in a randomized order. Blood samples (0 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h post-injection) were analyzed for kynurenine metabolites and inflammatory cytokines. The intensity of symptoms of sickness behavior was assessed using the 10-item Sickness Questionnaire at 0 h, 1.5 h, 3 h, 5 h, and 7 h post-injection.LPS induced significantly lower concentrations of plasma tryptophan (at 2 h, 4 h, 5 h, and 7 h post-injection), kynurenine (at 2 h, 3 h, 4 h, and 5 h post-injection), nicotinamide (at 4 h, 5 h, and 7 h post-injection), and higher levels for quinolinic acid at 5 h post-injection as compared to placebo. LPS did not affect kynurenic acid, 3-hydroxykynurenine, and picolinic acid. The development of the sickness symptoms was largely similar across items, with the highest levels around 1.5–3 h post-injection. Changes in plasma levels of kynurenine metabolites seem to coincide rather than precede or follow changes in subjective sickness. Exploratory analyses indicate that higher Sickness Questionnaire total scores at 1.5–5 h post-injection were correlated with lower kynurenic acid and nicotinamide levels.These results lend further support for LPS-induced changes in the kynurenine pathway, but may not, as interpreted from blood levels, causally link to LPS-induced acute symptoms of sickness behavior. Future research may consider a larger sample to further scrutinize the role of the kynurenine pathway in the sickness response.
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| 5. |
- Barrile, Franco, et al.
(författare)
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Ghrelin's orexigenic action in the lateral hypothalamic area involves indirect recruitment of orexin neurons and arcuate nucleus activation
- 2023
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 156
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Ghrelin is a potent orexigenic hormone, and the lateral hypothalamic area (LHA) has been suggested as a putative target mediating ghrelin's effects on food intake. Here, we aimed to investigate the presence of neurons expressing ghrelin receptor (a.k.a. growth hormone secretagogue receptor, GHSR) in the mouse LHA (LHAGHSR neurons), its physiological implications and the neuronal circuit recruited by local ghrelin action.Methods: We investigated the distribution of LHAGHSR neurons using different histologic strategies, including the use of a reporter mice expressing enhanced green fluorescent protein under the control of the GHSR promoter. Also, we investigated the physiological implications of local injections of ghrelin within the LHA, and the extent to which the orexigenic effect of intra-LHA-injected ghrelin involves the arcuate nucleus (ARH) and orexin neurons of the LHA (LHAorexin neurons)Results: We found that: 1) LHAGHSR neurons are homogeneously distributed throughout the entire LHA; 2) intraLHA injections of ghrelin transiently increase food intake and locomotor activity; 3) ghrelin's orexigenic effect in the LHA involves the indirect recruitment of LHAorexin neurons and the activation of ARH neurons; and 4) LHAGHSR neurons are not targeted by plasma ghrelin.Conclusions: We provide a compelling neuroanatomical and functional characterization of LHAGHSR neurons in male mice that indicates that LHAGHSR cells are part of a hypothalamic neuronal circuit that potently induces food intake.
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| 6. |
- Björvang, Richelle D., et al.
(författare)
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Mid-pregnancy allopregnanolone levels and trajectories of perinatal depressive symptoms
- 2024
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 164
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal depression is a major cause of disability for individuals giving birth worldwide, with detrimental effects on short- and long-term parental and child outcomes. There is emerging evidence that the neuroactive steroid hormone allopregnanolone is implicated in the pathophysiology and course of perinatal mood symptoms. However, no study thus far has examined allopregnanolone levels whilst making use of longitudinal data on depressive symptom trajectories throughout the perinatal period. The present study investigated levels of allopregnanolone at gestational week 17 of 252 participants in relation to perinatal depressive symptom trajectories, with a secondary aim of exploring the role of history of depression as an effect modifier. Four perinatal depressive symptom trajectories were investigated: controls (no depressive symptoms throughout perinatal period) (N=161), antepartum (depressive symptoms prenatally with postpartum remission) (N=31), postpartumonset (no depressive symptoms during pregnancy, development of depressive symptoms postpartum) (N=23), and persistent (depressive symptoms throughout the perinatal period) (N=37). Results show that for every one nmol/l increase in allopregnanolone, there was 7% higher odds for persistent depressive symptoms (OR 1.07, 95% CI 1.01-1.14) compared to controls. No association was seen for antepartum and postpartum-onset depressive symptoms. History of depression did not modify the association between allopregnanolone and perinatal depressive symptom trajectories. These results show the role of allopregnanolone for persistent depressive symptoms and strengthen the hypothesis of differences in pathophysiology among the trajectories.
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| 7. |
- Boström, Adrian Desai E., et al.
(författare)
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HPA-axis dysregulation is not associated with accelerated epigenetic aging in patients with hypersexual disorder
- 2022
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 141
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundHypersexual disorder (HD) - a nonparaphilic sexual desire disorder with impulsivity component - was evaluated for inclusion as a diagnosis in the DSM-5 and the diagnosis compulsive sexual behavior disorder is included as an impulse control disorder in the ICD-11. Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity is believed to affect cellular senescence and has been implicated in HD. No previous study investigated HD or HPA-axis dysregulation in relation to measures of epigenetic age (EA) acceleration.MethodsThis study reports on a case-control study set-up from a well-characterized cohort, contrasting EA predictors in relation to 60 HD patients and 33 healthy volunteers (HV) and 19 mixed HD/HV exhibiting dexamethasone suppression test (DST) non-suppression to 73 mixed HD/HV DST controls. The genome-wide methylation pattern was measured in whole blood from 94 subjects using the Illumina Infinium Methylation EPIC BeadChip and preprocessed according to specialized protocols suitable for epigenetic age estimation. The online DNAm Age Calculator (https://dnamage.genetics.ucla.edu/) was implemented to retrieve various EA predictors, which were compared between the in-silico generated subgroups.ResultsQuality control analyses indicated strong correlations between the EA measure DNA methylation GrimAge (DNAm GrimAge – the EA clock most reliably associated with mortality risk) and chronological age in all sub-groups. The study was adequately powered to detect differences of 2.5 and 3.0 years in DNAm GrimAge minus age in relation to both HD and HPA-axis dysregulation, respectively. Baseline DNAm GrimAge exceeded chronological age by 2.8 years on average across all samples. No EA acceleration marker was associated with HD or DST suppression status (p > 0.05).ConclusionEA acceleration markers shown to be strongly predictive of physiological dysregulation and mortality-risk, are not related to HD or DST non-suppression status (measured after 0.5 mg dexamethasone). The independency of HPA-axis dysregulation to EA acceleration does not support the biological relevance of this dosage-regimen when applied to patients with HD. These findings do not support the notion of accelerated cellular senescence in HD. Studies stratifying DST non-suppressors according to established dosage-regimens in somatic settings are needed to fully elucidate the putative contribution of HPA-axis dysregulation to EA.
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| 8. |
- Braenden, Astrid, et al.
(författare)
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Excessive hair cortisol concentration as an indicator of psychological disorders in children
- 2023
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Ingår i: Psychoneuroendocrinology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0306-4530 .- 1873-3360. ; 157
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Tidskriftsartikel (refereegranskat)abstract
- Cortisol in hair is a new biomarker assessing long-term hypothalamic-pituitary-adrenal (HPA) axis activity, which is related to emotion regulation. We compare hair cortisol concentrations (HCC), in clinically referred children with disruptive mood dysregulation disorder (DMDD) (n = 19), children with other types of psychological disorders (n = 48), and healthy subjects (n = 36). We also investigate the association between HCC and irritability, age, and sex. Our results show that children with DMDD or other types of psychological disorders have higher HCC than healthy subjects, p < .001, ?(2)(p) = .39. No difference between children with DMDD and those with other types of psychological disorders was found, p = .91, nor an association between HCC and irritability in the clinical sample, p = .32. We found a significant negative correlation between HCC and age in those with DMDD, r = -0.54, p < .05, but not in the normative sample, r = -0.20, p = .25. No differences in HCC between girls and boys were found in the normative sample, p = .49. Children in need of psychological treatment, including those with DMDD, seem to have dysregulated HPA-axis activity over time. Excessive accumulated cortisol concentrations in hair could be an indicator of a psychological disorder in children.
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| 9. |
- Bäckström, Torbjörn, et al.
(författare)
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A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 133
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Tidskriftsartikel (refereegranskat)abstract
- Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified.
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| 10. |
- Börchers, Stina, et al.
(författare)
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Commonly-used rodent tests of anxiety-like behavior lack predictive validity for human sex differences.
- 2022
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 141
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Tidskriftsartikel (refereegranskat)abstract
- Women are more likely to develop an anxiety disorder than men. Yet, preclinical models of anxiety were largely developed in male rodents, with poorly understood predictive validity for sex differences. Here, we investigate whether commonly-used anxiety-like behavior tests, elevated plus maze (EPM) and open field (OF), represent the human sex difference in adult Sprague-Dawley rats. When interpreted by EPM or OF, female rats displayed less anxiety-like behavior compared to males, as they spent twice as much time in the open arms of the EPM or the center of the OF compared to males. However, they also displayed vastly different levels of locomotor activity, possibly confounding interpretation of these locomotion-dependent tests. To exclude locomotion from the assessment, the acoustic startle response (ASR) test was used. When interpreted by the ASR test, females displayed more anxiety-like behavior compared to males, as indicated by a nearly two-fold higher startle amplitude. The observed sex differences were not driven by gonadal steroids. Overall, all but one of the tests fail to mirror the sex difference in anxiety reported in humans. Our findings suggest that the ASR might be a better fit in modelling female anxiety-like behavior.
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