scholarly journals Morpholino-mediated knockdown of the brain mineralocorticoid receptor affects glucocorticoid signaling and neuroplasticity in wild ocellated wrasse (Symphodus ocellatus)

2021 ◽  
Author(s):  
Bridget M. Nugent ◽  
Kelly A. Stiver ◽  
Jiawei Han ◽  
Holly K Kindsvater ◽  
Susan E. Marsh-Rollo ◽  
...  

Uncovering the genetic, physiological, and developmental mechanisms underlying phenotypic variation is necessary for understanding how genetic and genomic variation shape phenotypic variation and for discovering possible targets of selection. Although the neural and endocrine mechanisms underlying social behavior are evolutionarily ancient, we lack an understanding of the proximate causes and evolutionary consequences of variation in these mechanisms. Here, we examine in the natural environment the behavioral, neuromolecular, and fitness consequences of a morpholino-mediated knockdown of the mineralocorticoid receptor (MR) in the brain of nesting males of the ocellated wrasse, Symphodus ocellatus, a species with male alternative reproductive tactics. Even though MR knockdown did not significantly change male behavior directly, this experimental manipulation strongly altered glucocorticoid signaling and neuroplasticity in the preoptic area, the putative hippocampus homolog, and the putative basolateral amygdala homolog. We also found that individual variation in stress axis gene expression and neuroplasticity is strongly associated with variation in male behavior and fitness-related traits. The brain region-specific effects of MR knockdown on phenotypic integration in the wild reported here suggest specific neuroendocrine and neuroplasticity pathways that may be targets of selection.

2008 ◽  
Vol 198 (2) ◽  
pp. 403-417 ◽  
Author(s):  
Ellen H Stolte ◽  
Aurélia F de Mazon ◽  
Karen M Leon-Koosterziel ◽  
Maria Jesiak ◽  
Nic R Bury ◽  
...  

In higher vertebrates, mineralo- (aldosterone) and glucocorticoids (cortisol/corticosterone) exert their multiple actions via specific transcription factors, glucocorticoid (GR) and mineralocorticoid (MR) receptors. Teleostean fishes lack aldosterone and mineral regulatory processes seem under dominant control by cortisol. Despite the absence of the classical mineralocorticoid aldosterone, teleostean fishes do have an MR with cortisol and possibly 11-deoxycorticosterone (DOC) (as alternative for aldosterone) as predominant ligands. We studied corticoid receptors in common carp (Cyprinus carpio L). Through homology cloning and bioinformatic analysis, we found duplicated GR genes and a single MR gene. The GR genes likely result from a major genomic duplication event in the teleostean lineage; we propose that the gene for a second MR was lost. Transactivation studies show that the carp GRs and MR have comparable affinity for cortisol; the MR has significantly higher sensitivity to DOC, and this favours a role for DOC as MR ligand in fish physiology. mRNA of the GRs and the MR is expressed in forebrain (in pallial areas homologous to mammalian hippocampus), corticotrophin-releasing hormone (CRH) cells in the pre-optic nucleus (NPO) and pituitary pars distalis ACTH cells, three key neural/endocrine components of the stress axis. After exposure to prolonged and strong (not to mild acute) stressors, mRNA levels of both GRs and MR become down-regulated in the brain, but not in the NPO CRH cells or pituitary ACTH cells. Our data predicts a function in stress physiology for all CRs and suggest telencephalon as a first line cortisol target in stress.


2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Bianca S Bono ◽  
Persephone A Miller ◽  
Nikita K Koziel Ly ◽  
Melissa J Chee

Abstract Fibroblast growth factor 21 (FGF21) has emerged as a critical endocrine factor for understanding the neurobiology of obesity, such as by the regulation thermogenesis, food preference, and metabolism, as well as for neuroprotection in Alzheimer’s disease and traumatic brain injury. FGF21 is synthesized primarily by the liver and pancreas then crosses the blood brain barrier to exert its effects in the brain. However, the sites of FGF21 action in the brain is not well-defined. FGF21 action requires the activation of FGF receptor 1c as well as its obligate co-receptor beta klotho (KLB). In order to determine the sites of FGF21 action, we mapped the distribution of Klb mRNA by in situ hybridization using RNAscope technology. We labeled Klb distribution throughout the rostrocaudal axis of male wildtype mice by amplifying Klb hybridization using tyramine signal amplification and visualizing Klb hybridization using Cyanine 3 fluorescence. The resulting Klb signal appears as punctate red “dots,” and each Klb neuron may express low (1–4 dots), medium (5–9 dots), or high levels (10+ dots) of Klb hybridization. We then mapped individual Klb expressing neuron to the atlas plates provided by the Allen Brain Atlas in order to determine Klb distribution within the substructures of each brain region, which are defined by Nissl-based parcellations of cytoarchitectural boundaries. The distribution of Klb mRNA is widespread throughout the brain, and the brain regions analyzed thus far point to notable expression in the hypothalamus, amygdala, hippocampus, and the cerebral cortex. The highest expression of Klb was localized to the suprachiasmatic nucleus in the hypothalamus, which contained low and medium Klb-expressing neurons in the lateral hypothalamic area and ventromedial hypothalamic nucleus while low expressing Klb neurons were seen in the paraventricular and dorsmedial hypothalamic nucleus. Hippocampal Klb expression was limited to the dorsal region and largely restricted to the pyramidal cell layer of the dentate gyrus, CA3, CA2, and CA1 but at low levels only. In the amygdala, low and medium Klb expressing cells were seen in lateral amygdala nucleus while low levels were observed in the basolateral amygdala nucleus. Cortical Klb expression analyzed thus far included low Klb-expressing neurons in the olfactory areas, including layers 2 and 3 of piriform cortex and nucleus of the lateral olfactory tract. These findings are consistent with the known roles of FGF21 in the central regulation of energy balance, but also implicates potentially wide-ranging effects of FGF21 such as in executive functions.


2019 ◽  
Vol 20 (7) ◽  
pp. 1575 ◽  
Author(s):  
Lisa van Weert ◽  
Jacobus Buurstede ◽  
Hetty Sips ◽  
Isabel Mol ◽  
Tanvi Puri ◽  
...  

Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding.


BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Alexandra B. Bentz ◽  
Douglas B. Rusch ◽  
Aaron Buechlein ◽  
Kimberly A. Rosvall

Abstract Background The brain plays a critical role in upstream regulation of processes central to mating effort, parental effort, and self-maintenance. For seasonally breeding animals, the brain is likely mediating trade-offs among these processes within a short breeding season, yet research thus far has only explored neurogenomic changes from non-breeding to breeding states or select pathways (e.g., steroids) in male and/or lab-reared animals. Here, we use RNA-seq to explore neural plasticity in three behaviorally relevant neural tissues (ventromedial telencephalon [VmT], hypothalamus [HYPO], and hindbrain [HB]), comparing free-living female tree swallows (Tachycineta bicolor) as they shift from territory establishment to incubation. We additionally highlight changes in aggression-related genes to explore the potential for a neurogenomic shift in the mechanisms regulating aggression, a critical behavior both in establishing and maintaining a territory and in defense of offspring. Results HB had few differentially expressed genes, but VmT and HYPO had hundreds. In particular, VmT had higher expression of genes related to neuroplasticity and processes beneficial for competition during territory establishment, but down-regulated immune processes. HYPO showed signs of high neuroplasticity during incubation, and a decreased potential for glucocorticoid signaling. Expression of aggression-related genes also shifted from steroidal to non-steroidal pathways across the breeding season. Conclusions These patterns suggest trade-offs between enhanced activity and immunity in the VmT and between stress responsiveness and parental care in the HYPO, along with a potential shift in the mechanisms regulating aggression. Collectively, these data highlight important gene regulatory pathways that may underlie behavioral plasticity in females.


2008 ◽  
Vol 100 (6) ◽  
pp. 3429-3436 ◽  
Author(s):  
Frank Z. Nagy ◽  
Denis Paré

The amygdala and bed nucleus of the stria terminalis (BNST) are thought to subserve distinct functions, with the former mediating rapid fear responses to discrete sensory cues and the latter longer “anxiety-like” states in response to diffuse environmental contingencies. However, these structures are reciprocally connected and their projection sites overlap extensively. To shed light on the significance of BNST–amygdala connections, we compared the antidromic response latencies of BNST and central amygdala (CE) neurons to brain stem stimulation. Whereas the frequency distribution of latencies was unimodal in BNST neurons (∼10-ms mode), that of CE neurons was bimodal (∼10- and ∼30-ms modes). However, after stria terminalis (ST) lesions, only short-latency antidromic responses were observed, suggesting that CE axons with long conduction times course through the ST. Compared with the direct route, the ST greatly lengthens the path of CE axons to the brain stem, an apparently disadvantageous arrangement. Because BNST and CE share major excitatory basolateral amygdala (BL) inputs, lengthening the path of CE axons might allow synchronization of BNST and CE impulses to brain stem when activated by BL. To test this, we applied electrical BL stimuli and compared orthodromic response latencies in CE and BNST neurons. The latency difference between CE and BNST neurons to BL stimuli approximated that seen between the antidromic responses of BNST cells and CE neurons with long conduction times. These results point to a hitherto unsuspected level of temporal coordination between the inputs and outputs of CE and BNST neurons, supporting the idea of shared functions.


2018 ◽  
Vol 53 (4) ◽  
pp. 383-393
Author(s):  
Dallas W Henderson ◽  
Brian C Small

The turquoise killifish Nothobranchius furzeri is an increasingly popular model species for comparative vertebrate research, and the basic physiology including responses to stressful stimuli are of primary interest. We exposed adult killifish to a single or repeated periods of acute confinement followed by analysis of tissue cortisol and plasma cortisol concentrations. Individuals were also sampled for messenger RNA (mRNA) expression of corticotropin-releasing hormone ( CRH), mineralocorticoid receptor ( MR), and glucocorticoid receptor ( GR) in the brain to examine the effects of repeated stress events on constitutive expression of these important stress axis components. Following a single 30-minute confinement stress, male plasma cortisol significantly differed from baseline ( p = 0.04). Both male and female whole-body cortisol were significantly increased ( p = 0.004 and p = 0.04, respectively) at 15 and 30 minutes poststress. Despite obvious dimorphic behavior and morphology, cortisol concentrations did not differ between the sexes. Exposure to daily repeated confinement for one week altered the cortisol response in both sexes. Time 0, 15, and 60 minutes poststress cortisol concentrations were depressed in repeatedly stressed males ( p ≤ 0.05), and times 0, 30 and 120 minutes poststress cortisol concentrations were depressed in repeatedly stressed females ( p ≤ 0.05). Constitutive expression of CRH, MR, and GR mRNA in the brain following one week of repeated stress events did not differ among treatments or sexes. This study introduces the first description of hypothalamic-pituitary-interrenal axis activity in this important model species. Reduced cortisol production in repeatedly stressed adult killifish suggests acclimation to repeated stressors. Furthermore, acclimation was rapid, and plasma cortisol concentrations altered significantly in as little as one week.


2014 ◽  
Vol 306 (1) ◽  
pp. E75-E90 ◽  
Author(s):  
Emmanuelle Kuhn ◽  
Christine Bourgeois ◽  
Vixra Keo ◽  
Say Viengchareun ◽  
Adeline Muscat ◽  
...  

The mineralocorticoid receptor (MR) exerts proadipogenic and antithermogenic effects in vitro, yet its in vivo metabolic impact remains elusive. Wild type (WT) and transgenic (Tg) mice overexpressing human MR were subjected to standard chow (SC) or high-fat diet (HFD) for 16 wk. Tg mice had a lower body weight gain than WT animals and exhibited a relative resistance to HFD-induced obesity. This was associated with a decrease in fat mass, an increased population of smaller adipocytes, and an improved glucose tolerance compared with WT animals. Quantitative RT-PCR studies revealed decreased expression of PPARγ2, a master adipogenic gene, and of glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1, consistent with an impaired local glucocorticoid signaling in adipose tissues (AT). This paradoxical resistance to HFD-induced obesity was not related to an adipogenesis defect since differentiation capacity of Tg preadipocytes isolated from stroma-vascular fractions was unaltered, suggesting that other nonadipocyte factors might compromise AT development. Although AT macrophage infiltration was not different between genotypes, Tg mice exhibited a distinct macrophage polarization, as revealed by FACS analysis and CD11c/CD206 expression studies. We further demonstrated that Tg macrophage-conditioned medium partially impaired preadipocyte differentiation. Therefore, we propose that modification of M1/M2 polarization of hMR-overexpressing macrophages could account in part for the metabolic phenotype of Tg mice. Collectively, our results provide evidence that MR exerts a pivotal immunometabolic role by controlling adipocyte differentiation processes directly but also indirectly through macrophage polarization regulation. Our findings should be taken into account for the pharmacological treatment of metabolic disorders.


2017 ◽  
Vol 284 (1860) ◽  
pp. 20171018 ◽  
Author(s):  
Yinan Hu ◽  
R. Craig Albertson

Understanding the developmental processes that underlie the production of adaptive variation (i.e. the ‘arrival of the fittest’) is a major goal of evolutionary biology. While most evo-devo studies focus on the genetic underpinnings of adaptive phenotypic variation, factors beyond changes in nucleotide sequence can also play a major role in shaping developmental outcomes. Here, we document a vigorous but enigmatic gaping behaviour during the early development of Lake Malawi cichlid larvae. The onset of the behaviour precedes the formation of bone, and we predicted that it might influence craniofacial shape by affecting the mechanical environment in which bone develops. Consistent with this, we found that both natural variation and experimental manipulation of this behaviour induced differential skeletal development that foreshadows adaptive variation in adult trophic morphology. In fact, the magnitude of difference in skeletal morphology induced by these simple shifts in behaviour was similar to those predicted to be caused by genetic factors. Finally, we demonstrate that this mechanical-load-induced shift in skeletal development is associated with differences in ptch1 expression, a gene previously implicated in mediating between-species differences in skeletal shape. Our results underscore the complexity of development, and the importance of epigenetic ( sensu Waddington) mechanisms in determining adaptive phenotypic variation.


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