Thyroid hormone regulation of adult hippocampal neurogenesis: Putative molecular and cellular mechanisms.

Adult hippocampal neurogenesis is sensitive to perturbations in thyroid hormone signaling, with evidence supporting a key role for thyroid hormone and thyroid hormone receptors (TRs) in the regulation of postmitotic progenitor survival and neuronal differentiation. In this book chapter we summarize the current understanding of the effects of thyroid hormone signaling on adult hippocampal progenitor development, and also critically address the role of TRs in regulation of distinct aspects of stage-specific hippocampal progenitor progression. We highlight actions of thyroid hormone on thyroid hormone responsive target genes, and the implications for hippocampal progenitor regulation. Given the influence of thyroid hormone on both mitochondrial and lipid metabolism, we discuss a putative role for regulation of metabolism in the effects of thyroid hormone on adult hippocampal neurogenesis. Finally, we highlight specific ideas that require detailed experimental investigation, and the need for future studies to obtain a deeper mechanistic insight into the influence of thyroid hormone and TRs in the developmental progression of adult hippocampal progenitors.

GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders.

Early adversity is a key risk factor for the development of several psychiatric disorders, including anxiety and depression. During early life, neurocircuits that regulate emotionality undergo substantial structural remodeling and functional maturation, and are thus particularly susceptible to modification by environmental experience. Preclinical evidence indicates that early stress enhances adult anxio-depressive behaviors. A commonality noted across diverse early stress models is life-long alterations in neuroendocrine stress responses and monoaminergic neurotransmission in key limbic circuits. Dysregulation of G protein-coupled receptor (GPCR) signaling is noted across multiple early stress models and is hypothesized to be an important player in the programming of aberrant emotionality. This raises the possibility that disruption of GPCR signaling in key limbic regions during critical temporal windows could establish a substrate for enhanced risk of adult psychopathology. Here, we review literature, predominantly from preclinical models, which supports the building hypothesis that a disruption of GPCR signaling could play a central role in programming persistent molecular, cellular, functional, and behavioral changes as a consequence of early adversity.

Altered Membrane Mechanics Provides a Receptor-Independent Pathway for Serotonin Action.

Serotonin, an important signaling molecule in humans, has an unexpectedly high lipid membrane affinity. The significance of this finding has evoked considerable speculation. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, providing an activity pathway completely independent of serotonin receptors. Atomic force microscopy shows that serotonin makes artificial lipid bilayers softer, and induces nucleation of liquid disordered domains inside the raft-like liquid-ordered domains. Solid-state NMR spectroscopy corroborates this data at the atomic level, revealing a homogeneous decrease in the order parameter of the lipid chains in the presence of serotonin. In the RN46A immortalized serotonergic neuronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, even in the presence of broad-spectrum serotonin receptor and transporter inhibitors. Similarly, it increases the membrane binding and internalization of oligomeric peptides. Our results uncover a mode of serotonin-membrane interaction that can potentiate key cellular processes in a receptor-independent fashion.

The Hallucinogenic Serotonin2A Receptor Agonist, 2,5-Dimethoxy-4-Iodoamphetamine, Promotes cAMP Response Element Binding Protein-Dependent Gene Expression of Specific Plasticity-Associated Genes in the Rodent Neocortex.

Psychedelic compounds that target the 5-HT2A receptor are reported to evoke psychoplastogenic effects, including enhanced dendritic arborization and synaptogenesis. Transcriptional regulation of neuronal plasticity-associated genes is implicated in the cytoarchitectural effects of serotonergic psychedelics, however, the transcription factors that drive this regulation are poorly elucidated. Here, we addressed the contribution of the transcription factor cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) in the regulation of neuronal plasticity-associated genes by the hallucinogenic 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). In vitro studies with rat cortical neurons indicated that DOI enhances the phosphorylation of CREB (pCREB) through mitogen-activated protein (MAP) kinase and calcium/calmodulin dependent kinase II (CaMKII) pathways, with both cascades contributing to the DOI-evoked upregulation of Arc, Bdnf1, Cebpb, and Egr2 expression, whilst the upregulation of Egr1 and cFos mRNA involved the MAP kinase and CaMKII pathway respectively. We observed a robust DOI-evoked increase in the expression of several neuronal plasticity-associated genes in the rat neocortex in vivo. This DOI-evoked upregulation of neuronal plasticity-associated genes was completely blocked by the 5-HT2A receptor antagonist MDL100,907 in vitro and was also abrogated in the neocortex of 5-HT2A receptor deficient mice. Further, 5-HT2A receptor stimulation enhanced pCREB enrichment at putative cAMP response element (CRE) binding sites in the Arc, Bdnf1, Cebpb, cFos, but not Egr1 and Egr2, promoters in the rodent neocortex. The DOI-mediated transcriptional induction of Arc, cFos and Cebpb was significantly attenuated in the neocortex of CREB deficient/knockout (CREBαδ KO) mice. Collectively, these results indicate that the hallucinogenic 5-HT2A receptor agonist DOI leads to a rapid transcriptional upregulation of several neuronal plasticity-associated genes, with a subset of them exhibiting a CREB-dependent regulation. Our findings raise the intriguing possibility that similar to slow-acting classical antidepressants, rapid-action serotonergic psychedelics that target the 5-HT2A receptor may also recruit the transcription factor CREB to enhance the expression of neuronal plasticity-associated genes in the neocortex, which could in turn contribute to the rapid psychoplastogenic changes evoked by these compounds.

The Ministry of Fear: 'The Conjuring' of Fright in the Amygdala by the Raphe.

In this issue of Neuron, Sengupta and Holmes (2019) characterize a distinct serotonergic circuit from the dorsal raphe nucleus to the basal amygdala that facilitates fear conditioning and memory.

Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis.

Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.

Thyroid Hormone Regulation of Adult Neurogenesis.

Thyroid hormone is classically known to play a crucial role in neurodevelopment. The potent effects that thyroid hormone exerts on the adult mammalian brain have been uncovered relatively recently, including an important role in the modulation of progenitor development in adult neurogenic niches. This chapter extensively reviews the current understanding of the influence of thyroid hormone on distinct stages of adult progenitor development in the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) that lines the lateral ventricles. We discuss the role of specific thyroid hormone receptor isoforms, in particular TRα1, which modulates cell cycle exit in neural stem cells, progenitor survival, and cell fate choice, with both a discrete and overlapping nature of regulation noted in SGZ and SVZ progenitors. The balance between liganded and unliganded TRα1 can evoke differing consequences for adult progenitor development, and the relevance of this to conditions such as adult-onset hypothyroidism, wherein unliganded thyroid hormone receptors (TRs) dominate, is also a focus of discussion. Although a detailed molecular understanding of the specific thyroid hormone target genes that contribute to the neurogenic actions of thyroid hormone is currently lacking, we highlight the current state of knowledge and discuss avenues for future investigation. The goal of this chapter is to provide a comprehensive and detailed analysis of the effects of thyroid hormone on adult neurogenesis, to discuss putative molecular mechanisms that mediate these effects, and the behavioral, functional, and clinical implications of the neurogenic actions of thyroid hormone.

Perspectives on thyroid hormone action in adult neurogenesis.

Thyroid hormone exhibits profound effects on neural progenitor turnover, survival, maturation, and differentiation during perinatal development. Studies over the past decade have revealed that thyroid hormone continues to retain an important influence on progenitors within the neurogenic niches of the adult mammalian brain. The focus of the current review is to critically examine and summarize the current state of understanding of the role of thyroid hormone in regulating adult neurogenesis within the major neurogenic niches of the subgranular zone in the hippocampus and the subventricular zone lining the lateral ventricles. We review in depth the studies that highlight a role for thyroid hormone, in particular the TRα1 receptor isoform, in regulating progenitor survival and commitment to a neuronal fate. We also discuss putative models for the mechanism of action of thyroid hormone/TRα1 on specific stages of subgranular zone and subventricular zone progenitor development, and highlight potential thyroid hormone responsive target genes that may contribute to the neurogenic effects of thyroid hormone. The effects of thyroid hormone on adult neurogenesis are discussed in the context of a potential role of these effects in the cognitive- and mood-related consequences of thyroid hormone dysfunction. Finally, we detail hitherto unexplored aspects of the effects of thyroid hormone on adult neurogenesis that provide impetus for future studies to gain a deeper mechanistic insight into the neurogenic effects of thyroid hormone. Thyroid hormone regulation of adult neurogenesis in the mammalian brain exhibits both unique and overlapping effects within distinct neurogenic niches. Thyroid hormone regulates hippocampal subgranular zone (SGZ) progenitor survival and neuronal cell fate acquisition and influences subventricular zone (SVZ) progenitor cell turnover, cell cycle exit, and neuronal cell fate acquisition. In this review, we summarize, critically discuss and highlight open questions in regard to thyroid hormone regulation of adult neurogenesis.

HIV gp120 induced gene expression signatures in vaginal epithelial cells.

Gp120 is the envelope protein of HIV which binds to CD4 independent proteins on vaginal epithelial cells. HIV-gp120 has been reported to modulate gene expression in several cell types. How this interaction may alter the physiologic vaginal milieu during the earliest stages of vaginal transmission of HIV, is currently unknown. Vaginal epithelial cells were treated with HIV-gp120, and a global snapshot of changes in gene expression profiles, were unraveled by microarray analysis. The differentially expressed genes were involved in diverse cellular functions. Genes of immunomodulatory processes and induction of proteases were highly enriched. We propose that the induction of inflammation and proteases may act in concert to weaken the vaginal epithelium, making it more permeable to viral entry. Identification of the gene signatures involved in vaginal-HIV dialogue would aid in understanding the environ induced by HIV itself, as the virus invades and gains entry into its host.

HIV gp120 binds to mannose receptor on vaginal epithelial cells and induces production of matrix metalloproteinases.

BACKGROUND: During sexual transmission of HIV in women, the virus breaches the multi-layered CD4 negative stratified squamous epithelial barrier of the vagina, to infect the sub-epithelial CD4 positive immune cells. However the mechanisms by which HIV gains entry into the sub-epithelial zone is hitherto unknown. We have previously reported human mannose receptor (hMR) as a CD4 independent receptor playing a role in HIV transmission on human spermatozoa. The current study was undertaken to investigate the expression of hMR in vaginal epithelial cells, its HIV gp120 binding potential, affinity constants and the induction of matrix metalloproteinases (MMPs) downstream of HIV gp120 binding to hMR. PRINCIPAL FINDINGS: Human vaginal epithelial cells and the immortalized vaginal epithelial cell line Vk2/E6E7 were used in this study. hMR mRNA and protein were expressed in vaginal epithelial cells and cell line, with a molecular weight of 155 kDa. HIV gp120 bound to vaginal proteins with high affinity, (Kd = 1.2±0.2 nM for vaginal cells, 1.4±0.2 nM for cell line) and the hMR antagonist mannan dose dependently inhibited this binding. Both HIV gp120 binding and hMR exhibited identical patterns of localization in the epithelial cells by immunofluorescence. HIV gp120 bound to immunopurified hMR and affinity constants were 2.9±0.4 nM and 3.2±0.6 nM for vaginal cells and Vk2/E6E7 cell line respectively. HIV gp120 induced an increase in MMP-9 mRNA expression and activity by zymography, which could be inhibited by an anti-hMR antibody. CONCLUSION: hMR expressed by vaginal epithelial cells has high affinity for HIV gp120 and this binding induces production of MMPs. We propose that the induction of MMPs in response to HIV gp120 may lead to degradation of tight junction proteins and the extracellular matrix proteins in the vaginal epithelium and basement membrane, leading to weakening of the epithelial barrier; thereby facilitating transport of HIV across the vaginal epithelium.

CD4 independent binding of HIV gp120 to mannose receptor on human spermatozoa.

OBJECTIVE: To characterize the CD4-independent HIV-binding protein of 160 kDa on human spermatozoa. METHODS: The N-terminal amino acid sequence of the 160 kDa protein and its peptide obtained by tryptic digestion were determined. Polymerase chain reaction amplification of human testicular cDNA was performed using degenerate primers corresponding to peptide sequences of the 160 kDa protein. Localization of 160 kDa protein on sperm was performed using fluorescently labeled gp120, followed by inhibition experiments using antagonists to determine the specificity. RESULTS: The partial cDNA sequence of the 160 kDa protein demonstrated 99% identity with human macrophage mannose receptor. Sequence of testicular mannose receptor was obtained and exhibited 99% identity with that of macrophage mannose receptor. Furthermore, mannose receptor protein from sperm extract was found to have a molecular weight of 160 kDa, congruent with that of 160 kDa HIV-binding protein. gp120 binding and mannose receptor expression were localized to the equatorial segment in 10% of ejaculated sperm, which increased after capacitation. Mannan at molar excess concentrations completely inhibited gp120 binding to sperm. CONCLUSIONS: The 160 kDa, CD4-independent HIV-binding sperm protein has been identified as the human mannose receptor protein. The role of mannose receptor in HIV transmission and association with risk of sexual transmission merit further investigation.