Hormone Neurons Research Articles

Elucidating the role of Rgs2 expression in the PVN for metabolic homeostasis in mice

ObjectiveRGS2 is a GTPase activating protein that modulates GPCR-Gα signaling and mice lacking RGS2 globally exhibit metabolic alterations. While RGS2 is known to be broadly expressed throughout the body including the brain, the relative contribution of brain RGS2 to metabolic homeostasis remains unknown. The purpose of this study was to characterize RGS2 expression in the paraventricular nucleus of hypothalamus (PVN) and test its role in metabolic homeostasis. MethodsWe used a combination of RNAscope in situ hybridization (ISH), immunohistochemistry, and bioinformatic analyses to characterize the pattern of Rgs2 expression in the PVN. We then created mice lacking Rgs2 either prenatally or postnatally in the PVN and evaluated their metabolic consequences. ResultsRNAscope ISH analysis revealed a broad but regionally enriched Rgs2 mRNA expression throughout the mouse brain, with the highest expression being observed in the PVN along with several other brain regions, such as the arcuate nucleus of hypothalamus and the dorsal raphe nucleus. Within the PVN, we found that Rgs2 is specifically enriched in CRH+ endocrine neurons and is further increased by calorie restriction. Functionally, although Sim1-Cre-mediated prenatal deletion of Rgs2 in PVN neurons had no major effects on metabolic homeostasis, AAV-mediated adult deletion of Rgs2 in the PVN led to significantly increased food intake, body weight (both fat and fat-free masses), body length, and blood glucose levels in both male and female mice. Strikingly, we found that prolonged postnatal loss of Rgs2 leads to neuronal cell death in the PVN, while rapid body weight gain in the early phase of viral-mediated PVN Rgs2 deletion is independent of PVN neuronal loss. ConclusionsOur results provide the first evidence to show that PVN Rgs2 expression is not only sensitive to metabolic challenge but also critically required for PVN endocrine neurons to function and maintain metabolic homeostasis.

Signaling pathways involved in NMDA-induced suppression of M-channels in corticotropin-releasing hormone neurons in central amygdala.

Glutamate N-methyl-d-aspartate (NMDA) receptors (NMDARs) and Kv7/M channels are importantly involved in regulating neuronal activity involved in various physiological and pathological functions. Corticotropin-releasing hormone (CRH)-expressing neurons in the central nucleus of the amygdala (CeA) critically mediate autonomic response during stress. However, the interaction between NMDA receptors and Kv7/M channels in the CRHCeA neurons remains unclear. In this study, we identified rat CRHCeA neurons through the expression of an AAV viral vector-mediated enhanced green fluorescent protein (eGFP) driven by the rat CRH promoter. M-currents carried by Kv7/M channels were recorded using the whole-cell patch-clamp approach in eGFP-tagged CRHCeA neurons in brain slices. Acute exposure to NMDA significantly reduced M-currents recorded from the CRHCeA neurons. NMDA-induced suppression of M-currents was eliminated by chelating intracellular Ca2+ , supplying phosphatidylinositol 4,5-bisphosphate (PIP2) intracellularly, or blocking phosphoinositide3-kinase (PI3K). In contrast, inhibiting protein kinase C (PKC) or calmodulin did not alter NMDA-induced suppression of M-currents. Sustained exposure of NMDA decreased Kv7.3 membrane protein levels and suppressed M-currents, while the Kv7.2 expression levels remained unaltered. Pre-treatment of brain slices with PKC inhibitors alleviated the decreases in Kv7.3 and reduction of M-currents in CRHCeA neurons induced by NMDA. PKC inhibitors did not alter Kv7.2 and Kv7.3 membrane protein levels and M-currents in CRHCeA neurons. These data suggest that transient activation of NMDARs suppresses M-currents through the Ca2+ -dependent PI3K-PIP2 signaling pathway. In contrast, sustained activation of NMDARs reduces Kv7.3 protein expression and suppresses M-currents through a PKC-dependent pathway.

Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development.

The impairment of development/migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons is the main cause of Kallmann's syndrome (KS), an inherited disorder characterized by hypogonadism, anosmia, and other developmental defects. Olfactorin is an extracellular matrix protein encoded by the UMODL1 (uromodulin-like 1) gene expressed in the mouse olfactory region along the migratory route of GnRH neurons. It shares a combination of WAP and FNIII repeats, expressed in complementary domains, with anosmin-1, the product of the ANOS1 gene, identified as the causative of KS. In the present study, we have investigated the effects of olfactorin in vitro and in vivo models. The results show that olfactorin exerts an anosmin-1-like strong chemoattractant effect on mouse-immortalized GnRH neurons (GN11 cells) through the activation of the FGFR and MAPK pathways. In silico analysis of olfactorin and anosmin-1 reveals a satisfactory similarity at the N-terminal region for the overall arrangement of corresponding WAP and FNIII domains and marked similarities between WAP domains’ binding modes of interaction with the resolved FGFR1–FGF2 complex. Finally, in vivo experiments show that the down-modulation of the zebrafish z-umodl1 gene (orthologous of UMODL1) in both GnRH3:GFP and omp 2k :gap-CFP rw034 transgenic zebrafish strains leads to a clear disorganization and altered fasciculation of the neurites of GnRH3:GFP neurons crossing at the anterior commissure and a significant increase in olfactory CFP + fibers with altered trajectory. Thus, our study shows olfactorin as an additional factor involved in the development of olfactory and GnRH systems and proposes UMODL1 as a gene worthy of diagnostic investigation in KS.

Regulation of the gonadotropin-releasing hormone neuron during stress.

The effect of stress on reproduction and gonadal function has captivated investigators for almost 100years. Following the identification of gonadotropin-releasing hormone (GnRH) 50years ago, a niche research field emerged fixated on how stress impairs this central node controlling downstream pituitary and gonadal function. It is now clear that both episodic GnRH secretion in males and females and surge GnRH secretion in females are inhibited during a variety of stress types. There has been considerable advancement in our understanding of numerous stress-related signaling molecules and their ability to impair reproductive neuroendocrine activity during stress. Recently, much attention has turned to the effects of stress on two populations of kisspeptin neurons: the stimulatory afferents to GnRH neurons that regulate pulsatile and surge-type gonadotropin secretion. Indeed, future work is still required to fully construct the neuroanatomical framework underlying stress effects, directly or indirectly, on GnRH neuron function. The present review evaluates and synthesizes evidence related to stress-related signaling molecules acting directly on GnRH neurons. Here, we review the evidence for and against the action of a handful of signaling molecules as inhibitors of GnRH neuron function, including corticotropin-releasing hormone, urocortins, norepinephrine, cortisol/corticosterone, calcitonin gene-related peptide and arginine-phenylalanine-amide-related peptide-3.

The role of gonadotropin-releasing hormone neurons in polycystic ovary syndrome.

Given the critical central role of gonadotropin‐releasing hormone (GnRH) neurons in fertility, it is not surprising that the GnRH neural network is implicated in the pathology of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility. Although many symptoms of PCOS relate most proximately to ovarian dysfunction, the central reproductive neuroendocrine system ultimately drives ovarian function through its regulation of anterior pituitary gonadotropin release. The typical cyclical changes in frequency of GnRH release are often absent in women with PCOS, resulting in a persistent high‐frequency drive promoting gonadotropin changes (i.e., relatively high luteinizing hormone and relatively low follicle‐stimulating hormone concentrations) that contribute to ovarian hyperandrogenemia and ovulatory dysfunction. However, the specific mechanisms underpinning GnRH neuron dysfunction in PCOS remain unclear. Here, we summarize several preclinical and clinical studies that explore the causes of aberrant GnRH secretion in PCOS and the role of disordered GnRH secretion in PCOS pathophysiology.

Reduced Numbers of Corticotropin‐Releasing Hormone Neurons in Narcolepsy Type 1

Narcolepsy type 1 (NT1) is a chronic sleep disorder correlated with loss of hypocretin(orexin). In NT1 post‐mortem brains, we observed 88% reduction in corticotropin‐releasing hormone (CRH)‐positive neurons in the paraventricular nucleus (PVN) and significantly less CRH‐positive fibers in the median eminence, whereas CRH‐neurons in the locus coeruleus and thalamus, and other PVN neuronal populations were spared: that is, vasopressin, oxytocin, tyrosine hydroxylase, and thyrotropin releasing hormone‐expressing neurons. Other hypothalamic cell groups, that is, the suprachiasmatic, ventrolateral preoptic, infundibular, and supraoptic nuclei and nucleus basalis of Meynert, were unaffected. The surprising selective decrease in CRH‐neurons provide novel targets for diagnostics and therapeutic interventions. ANN NEUROL 2022;91:282–288

The electrophysiologic properties of gonadotropin-releasing hormone neurons.

For about two decades, recordings of identified gonadotropin-releasing hormone (GnRH) neurons have provided a wealth of information on their properties. We describe areas of consensus and debate the intrinsic electrophysiologic properties of these cells, their response to fast synaptic and neuromodulatory input, Ca2+ imaging correlates of action potential firing, and signaling pathways regulating these aspects. How steroid feedback and development change these properties, functions of GnRH neuron subcompartments and local networks, as revealed by chemo- and optogenetic approaches, are also considered.

A post‐mortem study of melanin‐concentrating hormone (MCH) neurons in Alzheimer’s disease and progressive supranuclear palsy: The complex degeneration pattern of the lateral hypothalamic area

AbstractBackgroundMelanin‐concentrating hormone neurons (MCH) are a key component of the subcortical brain circuits controlling sleep and wake states, and integrating them with other vital functions like motivated and feeding behavior into a 24‐hour circadian rhythm. Together with orexinergic neurons (OX), they represent the major neuronal population of the lateral hypothalamic area (LHA). Our group previously reported a profound degeneration of OX neurons in Alzheimer's disease (AD), and a reduction of OX production in progressive supranuclear palsy (PSP). In this report we provide for the first time a comprehensive and quantitative morphological study of MCH neurons in patients with AD, PSP and normal controls.MethodPost‐mortem human brain tissue of subjects with AD, PSP and controls was examined using unbiased stereology. Double immunohistochemistry with MCH‐ and tau‐antibodies on formalin‐fixed, celloidin embedded tissue was performed.ResultThere was no significant difference in the total number of MCH neurons between AD, PSP and controls, but a significant loss of non‐MCH neurons in AD patients (p=0.019). The proportion of MCH neurons was significantly higher in AD (p=0.0047). No such a difference was found in PSP. In PSP, but not AD, the proportion of tau+ MCH neurons was lower than the proportion of tau+ non‐MCH neurons (p=0.002). When comparing AD to PSP, the proportion of tau+MCH neurons was higher in AD (p<0.001).ConclusionHigh burden of tau‐inclusions, but comparably milder loss of MCH neurons in AD, together with previously reported orexinergic neuronal loss may lead to a hyperexcitability of the MCH system in AD. This may contribute to the well‐known impairment of vigilance, reduction of NREM sleep and REM sleep disruption in AD. In contrast, we found virtually no involvement of MCH neurons in PSP, which reflects a specific vulnerability of these neurons to AD pathology. Clinically, PSP features a hyperarousal state, indicating that the activity of the arousal system prevails over a deficient sleep promoting system. We conclude that the involvement of other sleep promoting nuclei contributes to the insomnia in PSP. Further experimental research is needed to understand the molecular pathways involved in the specific vulnerability of MCH neurons in AD.

Neural circuitry underlying REM sleep: A review of the literature and current concepts.

As one of the fundamental sleep states, rapid eye movement (REM) sleep is believed to be associated with dreaming and is characterized by low-voltage, fast electroencephalographic activity and loss of muscle tone. However, the mechanisms of REM sleep generation have remained unclear despite decades of research. Several models of REM sleep have been established, including a reciprocal interaction model, limit-cycle model, flip-flop model, and a model involving γ-aminobutyric acid, glutamate, and aminergic/orexin/melanin-concentrating hormone neurons. In the present review, we discuss these models and summarize two typical disorders related to REM sleep, namely REM sleep behavior disorder and narcolepsy. REM sleep behavior disorder is a sleep muscle-tone-related disorder and can be treated with clonazepam and melatonin. Narcolepsy, with core symptoms of excessive daytime sleepiness and cataplexy, is strongly connected with orexin in early adulthood.

Plasticity of intrinsic excitability across the estrous cycle in hypothalamic CRH neurons

Stress responses are highly plastic and vary across physiological states. The female estrous cycle is associated with a number of physiological changes including changes in stress responses, however, the mechanisms driving these changes are poorly understood. Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic–pituitary–adrenal (HPA) axis and stress-evoked corticosterone secretion. Here we show that CRH neuron intrinsic excitability is regulated over the estrous cycle with a peak in proestrus and a nadir in estrus. Fast inactivating voltage-gated potassium channel (IA) currents showed the opposite relationship, with current density being lowest in proestrus compared to other cycle stages. Blocking IA currents equalized excitability across cycle stages revealing a role for IA in mediating plasticity in stress circuit function over the female estrous cycle.

Expression of type one cannabinoid receptor in different subpopulation of kisspeptin neurons and kisspeptin afferents to GnRH neurons in female mice

The endocannabinoids have been shown to target the afferents of hypothalamic neurons via cannabinoid 1 receptor (CB1) and thereby to influence their excitability at various physiological and/or pathological processes. Kisspeptin (KP) neurons form afferents of multiple neuroendocrine cells and influence their activity via signaling through a variation of co-expressed classical neurotransmitters and neuropeptides. The differential potency of endocannabinoids to influence the release of classical transmitters or neuropeptides, and the ovarian cycle-dependent functioning of the endocannabinoid signaling in the gonadotropin-releasing hormone (GnRH) neurons initiated us to study whether (a) the different subpopulations of KP neurons express CB1 mRNAs, (b) the expression is influenced by estrogen, and (c) CB1-immunoreactivity is present in the KP afferents to GnRH neurons. The aim of the study was to investigate the site- and cell-specific expression of CB1 in female mice using multiple labeling in situ hybridization and immunofluorescent histochemical techniques. The results support that CB1 mRNAs are expressed by both the GABAergic and glutamatergic subpopulations of KP neurons, the receptor protein is detectable in two-thirds of the KP afferents to GnRH neurons, and the expression of CB1 mRNA shows an estrogen-dependency. The applied estrogen-treatment, known to induce proestrus, reduced the level of CB1 transcripts in the rostral periventricular area of the third ventricle and arcuate nucleus, and differently influenced its co-localization with vesicular GABA transporter or vesicular glutamate transporter-2 in KP neurons. This indicates a gonadal cycle-dependent role of endocannabinoid signaling in the neuronal circuits involving KP neurons.

Activation of Corticotropin‐Releasing Hormone Neurons in the Central Nucleus of Amygdala is required for Chronic Stress‐Induced Hypertension

Background Chronic stress is a well-known risk factor for the etiology of hypertension. However, the underlying neural mechanisms remain largely unknown. Corticotropin-releasing hormone (CRH) neuroendocrine cells in central nucleus of the amygdala (CeA) are critical in mediating autonomic response to chronic stress. Therefore, we determined the role of CeA-CRH neurons in hypertension induced by chronic stress. Methods Broadline hypertensive rats (BHRs) were subjected to chronic unpredictable stress (CUS). Identified CeA-CRH neuron firing activity and M-currents were recorded by whole-cell patch-clamp technique in brain slice preparation. A CRH-Cre-directed chemogenetic approach was used to suppress CeA-CRH neurons. Kv7 channel protein and mRNA level were determined by western-blot and quantitative RT-PCR methods, respectively. Results CUS treatment induced a sustained elevation of blood pressure in BHRs and a significant increase in c-Fos expression CeA-CRH neurons. Identified CeA-CRH neurons displayed significantly higher spontaneous firing activities in BHRs subjected to CUS than in unstressed BHRs. Specifically suppressing CeA-CRH neurons activity by using CRH-Cre-directed chemogenetic approach restrained CUS-induced sustained hypertension in BHRs. Both mRNA and protein levels of Kv7.2 and Kv7.3 channels were decreased in CeA of BHRs subjected to CUS. M-currents recorded from CeA-CRH neurons were significantly decreased in CUS BHRs compared with unstressed BHRs. Blocking Kv7 channel with its specific antagonist increased excitability of CeA-CRH neurons in unstressed BHRs whereas did not alter their excitability in BHRs subjected to CUS. Conclusions These data suggest that CeA-CRH neurons are required for the development of chronic stress-induced hypertension. The hyperactivity of CeA-CRH neurons is due to impaired Kv7 channel activity induced by chronic stress. These findings revealed a novel mechanism involved in chronic stress-induced hypertension.

Activation of NMDA receptors suppresses Kv7 channel activity in corticotropin‐releasing hormone neurons in Amygdala

Corticotropin-releasing hormone (CRH)-expressing neurons in the central nucleus of the amygdala (CeA) are critically involved in autonomic response during stress. Glutamate N-methyl-D-aspartate (NMDA) receptors and Kv7 channels regulate the neuronal activity. However, the interaction between NMDA receptors and Kv7 channels remains unclear. CeA-CRH neurons were identified by an AAV virus-mediated expressing enhanced green fluorescent protein (eGFP) driven by the rat CRH promoter. M-currents carried by Kv7 channels were recorded by whole-cell patch-clamp approach in eGFP-tagged CeA-CRH neurons and Kv7 proteins were measured by western-blot. Acute application of NMDA significantly reduced M-currents recorded from CeA-CRH neurons. NMDA-induced suppression of M-currents was eliminated by chelating intracellular Ca2+ or supplying phosphatidylinositol 4,5-bisphosphate (PIP2) intracellularly but not by inhibiting protein kinase C (PKC), calmodulin, or phosphoinositide3-kinase (PI3K). Incubation of brain slices with NMDA decreased Kv7.3 membrane protein levels and M-currents, while the Kv7.2 expression levels was not altered. Treatment brain slice with PKC inhibitor alleviated the decreases in surface Kv7.3 levels and M-currents in CeA-CRH neurons induced by NMDA incubation. PKC inhibitor alone did not alter surface Kv7 levels and M-currents in CeA-CRH neurons. These data suggest that activation of NMDA receptors suppresses Kv7 channel activity through Ca2+-dependent PIP2 signaling in acute phase and PKC-dependent pathway in chronic phase.

Firing patterns and bifurcation analysis of neurons under electromagnetic induction

<p style='text-indent:20px;'>Based on the three-dimensional endocrine neuron model, a four-dimensional endocrine neuron model was constructed by introducing the magnetic flux variable and induced current according to the law of electromagnetic induction. Firstly, the codimension-one bifurcation and Interspike Intervals (ISIs) analysis were applied to study the bifurcation structure with respect to external stimuli and parameter <inline-formula><tex-math id="M1">$ k_0 $</tex-math></inline-formula>, and two dynamical behaviors were found: period-adding and period-doubling bifurcation leading to chaos. Besides, Hopf bifurcation was specially discussed corresponding to the transformation of the state. Secondly, the different firing patterns such as regular bursting, subthreshold oscillations, fast spiking, mixed-mode oscillations (MMOs) etc. can be observed by changing the external stimuli and the induced current. The neuron model presented more firing activities under strong coupling strength. Finally, the codimension-two bifurcation analysis shown more details of bifurcation. At the same time, the Bogdanov-Takens bifurcation point was also analyzed and three bifurcation curves were derived.</p>

Neural circuits of anxiolytic and antidepressant pherine molecules.

In this review, we describe proposed circuits mediating the mechanism of action of pherines, a new class of synthetic neuroactive steroids with demonstrated antianxiety and antidepressant properties, that engage nasal chemosensory receptors. We hypothesize that afferent signals triggered by activation of these peripheral receptors could reach subgroups of olfactory bulb neurons broadcasting information to gamma-aminobutyric acid (GABAergic) and corticotropin-releasing hormone (CRH) neurons in the limbic amygdala. We propose that chemosensory inputs triggered by pherines project to centrolateral (CeL) and centromedial (CeM) amygdala neurons, with downstream effects mediating behavioral actions. Anxiolytic pherines could activate the forward inhibitory GABAergic neurons that facilitate the release of neuropeptide S (NPS) in the locus coeruleus (LC) and GABA in the bed nucleus of the stria terminalis (BNST) and inhibit catecholamine release in the LC and ventral tegmental area (VTA) leading to rapid anxiolytic effect. Alternatively, antidepressant pherines could facilitate the CRH and GABAergic neurons that inhibit the release of NPS from the LC, increase glutamate release from the BNST, and increase norepinephrine (NE), dopamine (DA), and serotonin release from the LC, VTA, and raphe nucleus, respectively. Activation of these neural circuits leads to rapid antidepressant effect. The information provided is consistent with this model, but it should be noted that some steps on these pathways have not been demonstrated conclusively in the human brain.

Identifying Isl1 Genetic Lineage in the Developing Olfactory System and in GnRH-1 Neurons.

During embryonic development, symmetric ectodermal thickenings [olfactory placodes (OP)] give rise to several cell types that comprise the olfactory system, such as those that form the terminal nerve ganglion (TN), gonadotropin releasing hormone-1 neurons (GnRH-1ns), and other migratory neurons in rodents. Even though the genetic heterogeneity among these cell types is documented, unidentified cell populations arising from the OP remain. One candidate to identify placodal derived neurons in the developing nasal area is the transcription factor Isl1, which was recently identified in GnRH-3 neurons of the terminal nerve in fish, as well as expression in neurons of the nasal migratory mass (MM). Here, we analyzed the Isl1 genetic lineage in chemosensory neuronal populations in the nasal area and migratory GnRH-1ns in mice using in situ hybridization, immunolabeling a Tamoxifen inducible Isl1CreERT and a constitutive Isl1Cre knock-in mouse lines. In addition, we also performed conditional Isl1 ablation in developing GnRH neurons. We found Isl1 lineage across non-sensory cells of the respiratory epithelium and sustentacular cells of OE and VNO. We identified a population of transient embryonic Isl1 + neurons in the olfactory epithelium and sparse Isl1 + neurons in postnatal VNO. Isl1 is expressed in almost all GnRH neurons and in approximately half of the other neuron populations in the MM. However, Isl1 conditional ablation alone does not significantly compromise GnRH-1 neuronal migration or GnRH-1 expression, suggesting compensatory mechanisms. Further studies will elucidate the functional and mechanistic role of Isl1 in development of migratory endocrine neurons.

Prolonged exposure therapy: hypothalamic corticotropin-releasing hormone neurons might have a say in its success.

Prolonged exposure therapy: hypothalamic corticotropin-releasing hormone neurons might have a say in its success.

Endogenous oxytocin inhibits hypothalamic corticotrophin-releasing hormone neurones following acute hypernatraemia.

Significant prior evidence indicates that centrally acting oxytocin robustly modulates stress responsiveness and anxiety-like behaviour, although the neural mechanisms behind these effects are not entirely understood. A plausible neural basis for oxytocin-mediated stress reduction is via inhibition of corticotrophin-releasing hormone (CRH) neurones in the paraventricular nucleus of the hypothalamus (PVN) that regulate activation of the hypothalamic-pituitary-adrenal axis. Previously, we have shown that, following s.c. injection of 2.0molL-1 NaCl, oxytocin synthesising neurones are activated in the rat PVN, an oxytocin receptor (Oxtr)-dependent inhibitory tone develops on a subset of parvocellular neurones and stress-mediated increases in plasma corticosterone levels are blunted. In the present study, we utilised transgenic male CRH-reporter mice to selectively target PVN CRH neurones for whole-cell recordings. These experiments reveal that acute salt loading produces tonic inhibition of PVN CRH neurones through a mechanism that is largely independent of synaptic activity. Further studies reveal that a subset of CRH neurones within the PVN synthesise mRNA for Oxtr(s). Salt induced Oxtr-dependent inhibitory tone was eliminated in individual PVN CRH neurones filled with GDP-β-S. Additional electrophysiological studies suggest that reduced excitability of PVN CRH neurones in salt-loaded animals is associated with increased activation of inwardly rectifying potassium channels. Nevertheless, substantial effort to recapitulate the core effects of salt loading by activating Oxtr(s) with an exogenous agonist produced mixed results. Collectively, these results enhance our understanding of how oxytocin receptor-mediated signalling modulates the function of CRH neurones in the PVN.

Heterogeneous Origin of Gonadotropin Releasing Hormone-1 Neurons in Mouse Embryos Detected by Islet-1/2 Expression.

In vertebrates, Gonadotropin releasing hormone-1 (GnRH) neuroendocrine cells originate in the olfactory placode and migrate into the forebrain where they regulate reproduction. However, the embryonic lineage of their progenitors remains controversial. Most GnRH neurons are derived from placodal ectodermal progenitor cells, but data from lineage tracing in zebrafish (Whitlock et al., 2003) and mouse (Forni and Wray, 2012) indicate that some GnRH progenitor cells have a neural crest (NC) origin. In contrast, a recent study in zebrafish (Aguillon et al., 2018), using Islet-1/2 expression, identified this LIM-homeodomain protein in all developing GnRH neuroendocrine cells, and the authors concluded a homogenous origin from progenitors within the preplacodal ectoderm. Evidence in different animal models and systems suggests that expression of Islet-1 plays a pivotal role in cell fate specification and differentiation. Thus, expression of Islet-1/2 in all GnRH cells in the nasal placode may not be lineage dependent but rather initiated locally in the placode as part of the program for GnRH cell specification and/or differentiation. This study addresses this issue and shows two populations of olfactory derived GnRH neurons in embryonic mouse: Islet-1/2(+) and Islet-1/2(−). Notably, triple-label immunofluorescence using the NC lineage tracer Wnt1, showed that GnRH neurons derived from Wnt1 progenitors are Islet-1/2(−). These results are consistent with two separate origins of GnRH neuroendocrine cells and suggest that either (1) NC-derived GnRH cells differentiate earlier than PE-derived GnRH cells or (2) different programs are used for cell specification in NC- vs. PE-derived GnRH cells.

Identification of VGF nerve growth factor inducible-producing cells in human spinal cords and expression change in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a serious disease characterized by the degeneration of motor neurons resulting in muscle weakness and paralysis. The neuroendocrine polypeptide VGF is localized in the central nervous system and peripheral endocrine neurons and is cleaved into several polypeptides with multiple functions. Previous studies revealed that VGF was decreased in the cerebrospinal fluid of ALS model mice and sporadic ALS patients. However, it is unknown which cells supply VGF in the spinal cord and a detailed localization is lacking. In this study, we evaluated the VGF-producing cells and protein localization using in situ hybridization and immunostaining in the spinal cords of ALS and control patients. VGF mRNA was localized both in the dorsal and anterior horns of the spinal cords. Moreover, in the anterior horn, VGF mRNA co-localized with a neurofilament heavy chain, which is a motor neuron marker, and VGF mRNA-positive motor neurons were decreased in the spinal cords of ALS patients. We revealed that VGF protein level was decreased in the anterior horn of ALS patients; however, the expression level of VGF protein was not changed in the posterior horn or white matter. Furthermore, the expression level of VGF protein was conserved in ALS patients with long-term survival. These results reveal that VGF is mainly supplied by human motor neurons, and suggest that VGF expression changes may be involved in ALS pathology.