ABSTRACT
Malfunctioning of system xc–, responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress and excitotoxicity, both important phenomena in the ...pathogenesis of Parkinson's disease (PD). We used mice lacking xCT (xCT_/_ mice), the specific subunit of system xc˜, to investigate the involvement of this antiporter in PD. Although cystine that is imported via system xc˜ is reduced to cysteine, the rate‐limiting substrate in the synthesis of glutathione, deletion of xCT did not result in decreased glutathione levels in striatum. Accordingly, no signs of increased oxidative stress could be observed in striatum or substantia nigra of xCT_/_ mice. In sharp contrast to expectations, xCT_/_ mice were less susceptible to 6‐hydroxydopamine (6‐OHDA)‐induced neurodegeneration in the substantia nigra pars compacta compared to their age‐matched wild‐type littermates. This reduced sensitivity to a PD‐inducing toxin might be related to the decrease of 70% in striatal extracellular glutamate levels that was observed in mice lacking xCT. The current data point toward system xc˜ as a possible target for the development of new pharmacotherapies for the treatment of PD and emphasize the need to continue the search for specific ligands for system xc˜.—Massie, A., Schallier, A., Kim, S. W., Fernando, R., Kobayashi, S., Beck, H., De Bundel, D., Vermoesen, K., Bannai, S., Smolders, I., Conrad, M., Plesnila, N., Sato, H., Michotte, Y. Dopaminergic neurons of system xc “‐deficient mice are highly protected against 6‐hydroxydopamine‐induced toxicity. FASEB J. 25, 1359–1369 (2011). www.fasebj.org
Psychedelic-assisted psychotherapy gained considerable interest as a novel treatment strategy for fear-related mental disorders but the underlying mechanism remains poorly understood. The serotonin ...2A (5-HT2A) receptor is a key target underlying the effects of psychedelics on emotional arousal but its role in fear processing remains controversial. Using the psychedelic 5-HT2A/5-HT2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-HT2A receptor knockout (KO) mice we investigated the effect of 5-HT2A receptor activation on emotional processing. We show that DOI administration did not impair performance in a spontaneous alternation task but reduced anxiety-like avoidance behavior in the elevated plus maze and elevated zero maze tasks. Moreover, we found that DOI did not block memory recall but diminished fear expression in a passive avoidance task. Likewise, DOI administration reduced fear expression in an auditory fear conditioning paradigm, while it did not affect retention of fear extinction when administered prior to extinction learning. The effect of DOI on fear expression was abolished in 5-HT2A receptor KO mice. Administration of DOI induced a significant increase of c-Fos expression in specific amygdalar nuclei. Moreover, local infusion of the 5-HT2A receptor antagonist M100907 into the amygdala reversed the effect of systemic administration of DOI on fear expression while local administration of DOI into the amygdala was sufficient to suppress fear expression. Our data demonstrate that activation of 5-HT2A receptors in the amygdala suppresses fear expression but provide no evidence for an effect on retention of fear extinction.
Abstract Depression and anxiety are disabling and highly prevalent psychiatric disorders. To better understand the neurobiological basis of mood and anxiety disorders, relevant animal models are ...needed. The corticosterone mouse model is frequently used to study depression. Chronic stress and accompanying glucocorticoid elevation causes pathological changes in the central nervous system, which are related to psychiatric symptoms. Exogenous administration of corticosterone is therefore often used to induce depressive-like behavior in mice and in some cases also features of anxiety-like behavior are shown. However, a thorough characterization of this model has never been conducted and housing conditions of the used subjects often differ between the implemented protocols. We chronically administered a subcutaneous corticosterone bolus injection to single- and group-housed mice, and we subsequently evaluated the face validity of this model by performing a battery of behavioral tests (forced swim test, mouse-tail suspension test, saccharin intake test, novelty-suppressed feeding test, elevated plus maze, light/dark paradigm and open field test). Our results show that corticosterone treatment has a substantial overall effect on depressive-like behavior. Increases in anxiety-like behavior on the other hand are mainly seen in single housed animals, independent of treatment. The current study therefore does not only show a detailed behavioral characterization of the corticosterone mouse model, but furthermore also elucidates the critical influence of housing conditions on the behavioral outcome in this model.
Microglia and border-associated macrophages (BAMs) are brain-resident self-renewing cells. Here, we examined the fate of microglia, BAMs, and recruited macrophages upon neuroinflammation and through ...resolution. Upon infection, Trypanosoma brucei parasites invaded the brain via its border regions, triggering brain barrier disruption and monocyte infiltration. Fate mapping combined with single-cell sequencing revealed microglia accumulation around the ventricles and expansion of epiplexus cells. Depletion experiments using genetic targeting revealed that resident macrophages promoted initial parasite defense and subsequently facilitated monocyte infiltration across brain barriers. These recruited monocyte-derived macrophages outnumbered resident macrophages and exhibited more transcriptional plasticity, adopting antimicrobial gene expression profiles. Recruited macrophages were rapidly removed upon disease resolution, leaving no engrafted monocyte-derived cells in the parenchyma, while resident macrophages progressively reverted toward a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Thus, brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and resolution.
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•T. brucei parasites invade the brain via its borders and evoke macrophage expansion•Brain-resident and blood-recruited macrophages show divergent responses•Upon disease resolution, recruited macrophages rapidly disappear and do not engraft•While disease-associated microglia revert toward homeostasis, BAMs remain altered
De Vlaminck et al. examine the fate of microglia, border-associated macrophages, and recruited macrophages upon Trypanosoma brucei infection and resolution of neuroinflammation. They show how different types of brain macrophages orchestrate the immune response to invading parasites, revealing that brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and the return to homeostasis.
Abstract
The cystine/glutamate antiporter system x
c
−
has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and ...genetic deletion of its specific subunit xCT (xCT
−/−
) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT
−/−
mice led to the hypothesis that system x
c
−
deletion would negatively affect life- and healthspan. Still, till now the role of system x
c
−
in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT
−/−
mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT
+/+
mice, was attenuated in xCT
−/−
mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT
−/−
mice. Targeting system x
c
−
is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.
Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been ...involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT)2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions.
Ghrelin is a peptide hormone released by specialized X/A cells in the stomach and activated by acylation. Following its secretion, it binds to ghrelin receptors in the periphery to regulate energy ...balance, but it also acts on the central nervous system where it induces a potent orexigenic effect. Several types of stressors have been shown to stimulate ghrelin release in rodents, including nutritional stressors like food deprivation, but also physical and psychological stressors such as foot shocks, social defeat, forced immobilization or chronic unpredictable mild stress. The mechanism through which these stressors drive ghrelin release from the stomach lining remains unknown and, to date, the resulting consequences of ghrelin release for stress coping remain poorly understood. Indeed, ghrelin has been proposed to act as a stress hormone that reduces fear, anxiety- and depression-like behaviors in rodents but some studies suggest that ghrelin may - in contrast - promote such behaviors. In this review, we aim to provide a comprehensive overview of the literature on the role of the ghrelin system in stress coping. We discuss whether ghrelin release is more than a byproduct of disrupted energy homeostasis following stress exposure. Furthermore, we explore the notion that ghrelin receptor signaling in the brain may have effects independent of circulating ghrelin and in what way this might influence stress coping in rodents. Finally, we examine how the ghrelin system could be utilized as a therapeutic avenue in stress-related psychiatric disorders (with a focus on anxiety- and trauma-related disorders), for example to develop novel biomarkers for a better diagnosis or new interventions to tackle relapse or treatment resistance in patients.
The striatum projection neurons are striatonigral and striatopallidal medium-sized spiny neurons (MSNs) that preferentially express D1 (D1R) and D2 (D2R) dopamine receptors, respectively. It is ...generally assumed that these neurons are physically intermingled, without cytoarchitectural organization although this has not been tested. To address this question we used BAC transgenic mice expressing enhanced green fluorescence (EGFP) under the control of Drd1a or Drd2 promoter and spatial point pattern statistics. We demonstrate that D1R- and D2R-expressing MSNs are randomly distributed in most of the dorsal striatum, whereas a specific region in the caudal striatum, adjacent to the GPe, lacks neurons expressing markers for indirect pathway neurons. This area comprises almost exclusively D1R-expressing MSNs. These neurons receive excitatory inputs from the primary auditory cortex and the medial geniculate thalamic nucleus and a rich dopamine innervation. This area contains cholinergic and GABAergic interneurons but apparently no D2R/A2aR modulation because no fluorescence was detected in the neuropil of Drd2-EGFP or Drd2-Cre, and Adora-Cre BAC transgenic mice crossed with reporter mice. This striatal area that expresses calbindin D28k, VGluT1 and 2, is poor in μ opiate receptors and preproenkephalin. Altogether, the differences observed in D1R-MSNs, D2R-MSNs, and interneurons densities, as well as the anatomical segregation of D1R- and D2R/A2aR-expressing MSNs suggest that there are regional differences in the organization of the striatum.
The hunger hormone ghrelin has been implicated in the modulation of anxiety- and fear-related behaviors in rodents and humans, while its dysregulation may be associated with psychiatric illness. ...Along these lines, the ghrelin system has been suggested as a potential target to facilitate fear extinction, which is the main mechanism underlying cognitive behavioral therapy. So far, this hypothesis has not been tested in individuals that have difficulties to extinguish fear. Thus, we investigated pharmacological (ghrelin receptor agonist MK0677) and non-pharmacological (overnight fasting) strategies to target the ghrelin system in the 129S1/SvImJ (S1) mouse strain, which models the endophenotype of impaired fear extinction that has been associated with treatment resistance in anxiety and PTSD patients. MK0677 induced food intake and overnight fasting increased plasma ghrelin levels in S1 mice, suggesting that the ghrelin system is responsive in the S1 strain. However, neither systemic administration of MK0677 nor overnight fasting had an effect on fear extinction in S1 mice. Similarly, our groups previously reported that both interventions did not attenuate fear in extinction-competent C57BL/6J mice. In summary, our findings are in contrast to several studies reporting beneficial effects of GHSR agonism and overnight fasting on fear- and anxiety-related behaviors in rodents. Rather, our data agree with accumulating evidence of divergent behavioral effects of ghrelin system activation and underscore the hypothesis that potential benefits of targeting the ghrelin system in fear extinction may be dependent on factors (e.g., previous stress exposure) that are not yet fully understood.
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