Department of Neuroscience and Regenerative Medicinehttp://hdl.handle.net/10675.2/5831982024-03-28T09:26:26Z2024-03-28T09:26:26ZHypothalamic AgRP and POMC neurons modulate stress-induced depression-related behaviorsFang, Xinghttp://hdl.handle.net/10675.2/6233722020-06-09T19:25:52ZHypothalamic AgRP and POMC neurons modulate stress-induced depression-related behaviors
Fang, Xing
Depression is a common and debilitating mental disease. Currently available antidepressants are not effective for many individuals with depression and our understanding of the underlying mechanisms remain limited. Evidence suggests that hypothalamic arcuate nucleus (ARC) is highly responsive to acute stress. The ARC contains two distinct subpopulations of neurons—expressing orexigenic agouti-related peptide (AgRP) and anorexigenic pro-opiomelanocortin (POMC). AgRP and POMC neurons regulate food intake and the food reward system. It is unknown whether AgRP and POMC neurons are recruited by chronic stress and if their dysfunction may contribute to the development of chronic stress-induced depression-related behaviors. To address this, we have developed a mouse model of chronic unpredictable stress (CUS), which can induce anhedonia and despair behavior that mimic symptoms in human depression. Using this animal model, I investigated the roles of AgRP and POMC neurons in stress responses and stress-induced depression-related behaviors. I demonstrated that CUS decreases activity of AgRP neurons but increases activity of POMC neurons. A chemogenetic approach was used to selectively manipulate the activity of POMC and AgRP neurons, leading to opposite effects of stress-induced depression-related behaviors. These results suggest that AgRP and POMC neurons are differentially involved in stress maladaptation and related behaviors. It provides insight into the mechanisms underlying the development of depression and novel strategies for the treatment of this mental illness.
Record is embargoed until 06/04/2021
Neuron-derived estrogen and neural functionLu, Yujiaohttp://hdl.handle.net/10675.2/6232302021-04-01T14:32:33Z2020-05-01T00:00:00ZNeuron-derived estrogen and neural function
Lu, Yujiao
17β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. We created a forebrain neuron-specific aromatase knockout (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice. Under normal conditions, FBN-ARO-KO mice showed a 70-80% decrease in aromatase and forebrain E2 levels. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent cognitive functions. Reinstating forebrain E2 levels via exogenous in vivo E2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore, electrophysiological study suggested normal long-term potentiation (LTP) induction, but significantly decreased amplitude in FBN-ARO-KO mice which could be fully rescued by acute E2 treatment in vitro. Mechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. After global cerebral ischemia (GCI), ovariectomized female FBN-ARO-KO mice had significantly attenuated aromatase and hippocampal E2 levels. Intriguingly, FBN-ARO-KO mice exhibited a robust reduction in astrocyte activation, as well as exacerbated neuronal damage and worse cognitive dysfunction after GCI. Similar results were observed in intact male mice. RNA-seq analysis revealed alterations in pathways and genes associated with astrocyte activation, neuroinflammation and oxidative stress in FBN-ARO-KO mice. The compromised astrocyte activation in FBN-ARO-KO mice was associated with robust downregulation of the astrocyte-derived neurotrophic factors, BDNF and IGF-1, as well as the astrocytic glutamate transporter, GLT-1. In vivo E2 replacement rescued the compromised reactive astrogliosis and cognitive deficits. Moreover, neuronal FGF2, which acts in a paracrine manner to suppress astrocyte activation, was dramatically increased in FBN-ARO-KO neurons. Interestingly, blocking FGF2 signaling in astrocytes by central injection of an FGFR3 antibody was able to reverse the diminishment in neuroprotective astrocyte reactivity, and attenuate neuronal damage in FBN-ARO-KO mice. Collectively, our data provides novel genetic evidence for the roles of neuron-derived E2 in regulating synaptic plasticity, cognitive function in the non-injured brain, and astrocyte activation and neuroprotection in the injured brain.
This record is embargoed until 10/08/2020
2020-05-01T00:00:00ZRoles of Astrocyte-Derived Estrogen in the BrainMeyre, Pornjittra (Ja)http://hdl.handle.net/10675.2/6231252023-08-03T15:04:52Z2019-12-01T00:00:00ZRoles of Astrocyte-Derived Estrogen in the Brain
Meyre, Pornjittra (Ja)
The steroid hormone, 17β-estradiol (E2) is an important hormone that regulates many
functions in the body. Traditionally, E2 was believed to be produced primarily by the ovaries in
females, but a number of studies have shown that brain cells such as neurons and astrocytes can
also make significant quantities of E2. The study presented in this thesis examined the role of
astrocyte-derived E2 in exerting neuroprotection in the CA1 region of the hippocampus, as well
as its ability to regulate two specific pathways implicated in neuroprotection - the LIF and
STAT3 pathways. Since the hippocampal CA1 region is known to be highly vulnerable to global
cerebral ischemia (GCI), such as occurs after cardiac arrest, we used a mouse GCI model to
examine the neuroprotective role of astrocyte-derived E2 in the hippocampal CA1 region. The
results of the study indicate that mice that lack the enzyme aromatase in astrocytes and were
unable to produce astrocyte-derived E2, have decreased reactive astrocyte activation after GCI,
greater neuronal deficits after GCI in both genders, and they have significantly decreased LIFSTAT3 signaling in the hippocampus.
Record is embargoed until 03/04/2022
2019-12-01T00:00:00ZGenetic Modeling and Pathophysiological Analysis of FAM109A, a Putative Human Disease GeneAtes, Kristin Mariehttp://hdl.handle.net/10675.2/6224502020-05-20T16:27:42Z2019-05-01T00:00:00ZGenetic Modeling and Pathophysiological Analysis of FAM109A, a Putative Human Disease Gene
Ates, Kristin Marie
A critical barrier in the treatment of endocytic diseases is the lack of information and understanding of the in vivo mechanisms of endocytosis. Part of this is due to the diverse array of endocytic adaptor proteins that have not yet been studied. We address this by investigating a key endocytic adaptor protein, FAM109A, which interacts with OCRL1, a causative gene for Lowe syndrome. Previous in vitro studies have identified FAM109A as a regulator for endosomal trafficking, particularly in the recycling of receptors in endosomes and sorting of cargo to lysosomes, based on knock-down studies. Here we conduct the first study into the developmental and physiological functions of FAM109A in vivo, utilizing the zebrafish model. We find that depletion of both zebrafish orthologs, zFAM109A and zFAM109B, in our maternal-zygotic homozygous mutant models (AB mutant) disrupts fluid-phase endocytosis and ciliogenesis in the pronephros. Partial knockdown of OCRL1 in the AB mutants exacerbates the endocytosis deficit, confirming that OCRL1 and FAM109 proteins are linked in a common endocytic pathway.
In addition, we discover that zFAM109A/B mutant animals exhibit reduced jaw size and delay in chondrocyte maturation, indicating a novel role for zFAM109A and zFAM109B in craniofacial development. This is consistent with the phenotype in a patient within the NIH’s Undiagnosed Diseases Program (UDP). The UDP patient carries a de novo arginine (R) to cysteine (C) mutation (R6C) in FAM109A and presents with craniofacial abnormalities, developmental delay, auditory and vision impairments, and renal dysfunction. Expressing zFAM109A with the R6C mutation in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner.
Together, these results show that FAM109A is involved in fluid-phase endocytosis and ciliogenesis in vivo. Moreover, we provide further insight into the potential pathogenesis of a UDP patient’s disease in association with a de novo mutation in FAM109A.
2019-05-01T00:00:00Z