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Article ; Online: Organization of neural systems expressing melanocortin-3 receptors in the mouse brain: Evidence for sexual dimorphism.

Bedenbaugh, Michelle N / Brener, Samantha C / Maldonado, Jose / Lippert, Rachel N / Sweeney, Patrick / Cone, Roger D / Simerly, Richard B

The Journal of comparative neurology

2022 Volume 530, Issue 16, Page(s) 2835–2851

Abstract: The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well- ... ...

Abstract	The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well-characterized melanocortin-4 receptor (MC4R), little is known regarding the organization of MC3R-expressing neural circuits. To increase our understanding of the intrinsic organization of MC3R neural circuits, identify specific differences between males and females, and gain a neural systems level perspective of this circuitry, we conducted a brain-wide mapping of neurons labeled for MC3R and characterized the distribution of their projections. Analysis revealed MC3R neuronal and terminal labeling in multiple brain regions that control a diverse range of physiological functions and behavioral processes. Notably, dense labeling was observed in the hypothalamus, as well as areas that share considerable connections with the hypothalamus, including the cortex, amygdala, thalamus, and brainstem. Additionally, MC3R neuronal labeling was sexually dimorphic in several areas, including the anteroventral periventricular area, arcuate nucleus, principal nucleus of the bed nucleus of the stria terminalis, and ventral premammillary region. Altogether, anatomical evidence reported here suggests that MC3R has the potential to influence several different classes of motivated behavior that are essential for survival, including ingestive, reproductive, defensive, and arousal behaviors, and is likely to modulate these behaviors differently in males and females.
MeSH term(s)	Animals ; Brain/metabolism ; Female ; Hypothalamus/metabolism ; Male ; Melanocortins ; Mice ; Receptor, Melanocortin, Type 3/genetics ; Receptor, Melanocortin, Type 3/metabolism ; Sex Characteristics
Chemical Substances	Mc3r protein, mouse ; Melanocortins ; Receptor, Melanocortin, Type 3
Language	English
Publishing date	2022-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.25379
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Article ; Online: Developmental specification of metabolic circuitry.

Elson, Amanda E / Simerly, Richard B

Frontiers in neuroendocrinology

2015 Volume 39, Page(s) 38–51

Abstract: The hypothalamus contains a core circuitry that communicates with the brainstem and spinal cord to regulate energy balance. Because metabolic phenotype is influenced by environmental variables during perinatal development, it is important to understand ... ...

Abstract	The hypothalamus contains a core circuitry that communicates with the brainstem and spinal cord to regulate energy balance. Because metabolic phenotype is influenced by environmental variables during perinatal development, it is important to understand how these neural pathways form in order to identify key signaling pathways that are responsible for metabolic programming. Recent progress in defining gene expression events that direct early patterning and cellular specification of the hypothalamus, as well as advances in our understanding of hormonal control of central neuroendocrine pathways, suggest several key regulatory nodes that may represent targets for metabolic programming of brain structure and function. This review focuses on components of central circuitry known to regulate various aspects of energy balance and summarizes what is known about their developmental neurobiology within the context of metabolic programming.
MeSH term(s)	Animals ; Energy Metabolism/physiology ; Female ; Humans ; Hypothalamus/growth & development ; Hypothalamus/physiology ; Neural Pathways/physiology ; Neurosecretory Systems/physiology ; Obesity/physiopathology ; Pregnancy
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	390985-2
ISSN	1095-6808 ; 0532-7466 ; 0091-3022
ISSN (online)	1095-6808
ISSN	0532-7466 ; 0091-3022
DOI	10.1016/j.yfrne.2015.09.003
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Zs.A 3423: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 443: Show issues

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Article: Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence.

Geben, Laura C / Brockman, Asa A / Chalkley, Mary Bronwen L / Sweet, Serena R / Gallagher, Julia E / Scheuing, Alexandra L / Simerly, Richard B / Ess, Kevin C / Irish, Jonathan M / Ihrie, Rebecca A

bioRxiv : the preprint server for biology

2023

Abstract: A limiting factor in the regenerative capacity of the adult brain is the abundance and proliferative ability of neural stem cells (NSCs). Adult NSCs are derived from a subpopulation of embryonic NSCs that temporarily enter quiescence during mid-gestation ...

Abstract	A limiting factor in the regenerative capacity of the adult brain is the abundance and proliferative ability of neural stem cells (NSCs). Adult NSCs are derived from a subpopulation of embryonic NSCs that temporarily enter quiescence during mid-gestation and remain quiescent until postnatal reactivation. Here we present evidence that the mechanistic/mammalian target of rapamycin (mTOR) pathway regulates quiescence entry in embryonic NSCs of the developing forebrain. Throughout embryogenesis, two downstream effectors of mTOR, p-4EBP1/2 T37/46 and p-S6 S240/244, were mutually exclusive in NSCs, rarely occurring in the same cell. While 4EBP1/2 was phosphorylated in stem cells undergoing mitosis at the ventricular surface, S6 was phosphorylated in more differentiated cells migrating away from the ventricle. Phosphorylation of 4EBP1/2, but not S6, was responsive to quiescence induction in cultured embryonic NSCs. Further, inhibition of p-4EBP1/2, but not p-S6, was sufficient to induce quiescence. Collectively, this work offers new insight into the regulation of quiescence entry in embryonic NSCs and, thereby, correct patterning of the adult brain. These data suggest unique biological functions of specific posttranslational modifications and indicate that the preferential inhibition of such modifications may be a useful therapeutic approach in neurodevelopmental diseases where NSC numbers, proliferation, and differentiation are altered.
Language	English
Publishing date	2023-02-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.14.528513
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Article ; Online: An ensemble recruited by α

Brown, Jordan A / Petersen, Nicholas / Centanni, Samuel W / Jin, Allie Y / Yoon, Hye Jean / Cajigas, Stephanie A / Bedenbaugh, Michelle N / Luchsinger, Joseph R / Patel, Sachin / Calipari, Erin S / Simerly, Richard B / Winder, Danny G

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2022 Volume 48, Issue 8, Page(s) 1133–1143

Abstract: ... ...

Abstract	α
MeSH term(s)	Mice ; Animals ; Guanfacine/pharmacology ; Norepinephrine/pharmacology ; Neurons ; Substance-Related Disorders ; Signal Transduction ; Septal Nuclei
Chemical Substances	Guanfacine (30OMY4G3MK) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2022-09-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-022-01442-x
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Article ; Online: BNST PKCδ neurons are activated by specific aversive conditions to promote anxiety-like behavior.

Williford, Kellie M / Taylor, Anne / Melchior, James R / Yoon, Hye Jean / Sale, Eryn / Negasi, Milen D / Adank, Danielle N / Brown, Jordan A / Bedenbaugh, Michelle N / Luchsinger, Joseph R / Centanni, Samuel W / Patel, Sachin / Calipari, Erin S / Simerly, Richard B / Winder, Danny G

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2023 Volume 48, Issue 7, Page(s) 1031–1041

Abstract: The bed nucleus of the stria terminalis (BNST) is a critical mediator of stress responses and anxiety-like behaviors. Neurons expressing protein kinase C delta ( ... ...

Abstract	The bed nucleus of the stria terminalis (BNST) is a critical mediator of stress responses and anxiety-like behaviors. Neurons expressing protein kinase C delta (BNST
MeSH term(s)	Septal Nuclei/metabolism ; Anxiety ; Central Amygdaloid Nucleus/metabolism ; Neurons/physiology ; Affect
Language	English
Publishing date	2023-03-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-023-01569-5
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Article: Hypothalamic substrates of metabolic imprinting.

Simerly, Richard B

Physiology & behavior

2007 Volume 94, Issue 1, Page(s) 79–89

Abstract: The mammalian brain develops according to intrinsic genetic programs that are influenced by a variety of environmental factors. Developing neural circuits take shape in two major environments: one in utero and a second during postnatal life. Although an ... ...

Abstract	The mammalian brain develops according to intrinsic genetic programs that are influenced by a variety of environmental factors. Developing neural circuits take shape in two major environments: one in utero and a second during postnatal life. Although an abundance of epidemiological and experimental evidence indicates that nutritional variables during perinatal life have a lasting effect on metabolic phenotype, the underlying mechanisms remain unclear. Peripheral hormones are widely regarded as effective signals that reflect the state of peripheral environments and can directly influence the development of a variety of functional neural systems. Recent findings suggest that the adipocyte-derived hormone leptin may play an important role in directing formation of hypothalamic neural pathways that control body weight. The arcuate nucleus of the hypothalamus (ARH) is a key site for the regulatory actions of leptin in adults, and this same hormone is required for the normal development of ARH projections to other parts of the hypothalamus. In this review, the neurobiological role of leptin is considered within the context of hypothalamic development and the possibility that variations in both prenatal and postnatal nutritional environments may impact development of neural circuits that control energy metabolism through an indirect action on leptin secretion, or signaling, during key developmental critical periods.
MeSH term(s)	Animals ; Energy Metabolism/physiology ; Humans ; Hypothalamus/growth & development ; Hypothalamus/physiology ; Leptin/physiology ; Metabolism/physiology ; Nerve Net/physiology ; Nervous System/growth & development ; Signal Transduction/physiology
Chemical Substances	Leptin
Language	English
Publishing date	2007-11-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2007.11.023
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Zs.A 747: Show issues

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Article ; Online: Neonatal leptin exposure specifies innervation of presympathetic hypothalamic neurons and improves the metabolic status of leptin-deficient mice.

Bouyer, Karine / Simerly, Richard B

The Journal of neuroscience : the official journal of the Society for Neuroscience

2013 Volume 33, Issue 2, Page(s) 840–851

Abstract: The paraventricular nucleus of the hypothalamus (PVH) consists of distinct functional compartments regulating neuroendocrine, behavioral, and autonomic activities that are involved in the homeostatic control of energy balance. These compartments receive ... ...

Abstract	The paraventricular nucleus of the hypothalamus (PVH) consists of distinct functional compartments regulating neuroendocrine, behavioral, and autonomic activities that are involved in the homeostatic control of energy balance. These compartments receive synaptic inputs from neurons of the arcuate nucleus of the hypothalamus (ARH) that contains orexigenic agouti-related peptide (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neuropeptides. The axon outgrowth from the ARH to PVH occurs during a critical postnatal period and is influenced by the adipocyte-derived hormone leptin, which promotes its development. However, little is known about leptin's role in specifying patterns of cellular connectivity in the different compartments of the PVH. To address this question, we used retrograde and immunohistochemical labeling to evaluate neuronal inputs onto sympathetic preautonomic and neuroendocrine neurons in PVH of leptin-deficient mice (Lep(ob)/Lep(ob)) exposed to a postnatal leptin treatment. In adult Lep(ob)/Lep(ob) mice, densities of AgRP- and α-melanocortin stimulating hormone (αMSH)-immunoreactive fibers were significantly reduced in neuroendocrine compartments of the PVH, but only AgRP were reduced in all regions containing preautonomic neurons. Moreover, postnatal leptin treatment significantly increased the density of AgRP-containing fibers and peptidergic inputs onto identified preautonomic, but not onto neuroendocrine cells. Neonatal leptin treatment neither rescued αMSH inputs onto neuroendocrine neurons, nor altered cellular ratios of inhibitory and excitatory inputs. These effects were associated with attenuated body weight gain, food intake and improved physiological response to sympathetic stimuli. Together, these results provide evidence that leptin directs cell type-specific patterns of ARH peptidergic inputs onto preautonomic neurons in the PVH, which contribute to normal energy balance regulation.
MeSH term(s)	Adipose Tissue, Brown/cytology ; Adipose Tissue, Brown/drug effects ; Adipose Tissue, White/cytology ; Adipose Tissue, White/drug effects ; Animals ; Animals, Newborn/physiology ; Body Temperature Regulation/drug effects ; Body Temperature Regulation/genetics ; Body Temperature Regulation/physiology ; Body Weight/physiology ; Eating/drug effects ; Energy Metabolism/drug effects ; Female ; Glucose Tolerance Test ; Glutamic Acid/physiology ; Hypothalamus/cytology ; Hypothalamus/drug effects ; Hypothalamus/growth & development ; Image Processing, Computer-Assisted ; Immunohistochemistry ; Leptin/deficiency ; Leptin/genetics ; Leptin/pharmacology ; Male ; Mice ; Mice, Knockout ; Neurons/drug effects ; Neurosecretory Systems/cytology ; Neurosecretory Systems/drug effects ; Neurosecretory Systems/growth & development ; Parasympathetic Nervous System/cytology ; Parasympathetic Nervous System/drug effects ; Parasympathetic Nervous System/growth & development ; Peptides/physiology ; gamma-Aminobutyric Acid/physiology
Chemical Substances	Leptin ; Peptides ; Glutamic Acid (3KX376GY7L) ; gamma-Aminobutyric Acid (56-12-2)
Language	English
Publishing date	2013-01-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.3215-12.2013
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Zs.A 1668: Show issues

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Article: Wired on hormones: endocrine regulation of hypothalamic development.

Simerly, Richard B

Current opinion in neurobiology

2005 Volume 15, Issue 1, Page(s) 81–85

Abstract: The hormones that regulate the hypothalamic circuits that control essential functions, such as reproduction and energy homeostasis, also specify brain architecture by regulating key developmental events. The cellular mechanisms underlying the ... ...

Abstract	The hormones that regulate the hypothalamic circuits that control essential functions, such as reproduction and energy homeostasis, also specify brain architecture by regulating key developmental events. The cellular mechanisms underlying the developmental actions of testosterone and estrogen to determine patterns of neuronal cell death, synaptogenesis and axon guidance are being identified. Recent neuroanatomical evidence indicates that the adipocyte-derived hormone leptin may direct the development of hypothalamic pathways involved in energy homeostasis by promoting axonal projections from the arcuate nucleus of the hypothalamus to other hypothalamic sites that mediate the effects of leptin on food intake and body weight. Understanding how sex steroids and leptin regulate hypothalamic development will enable us to identify hormonally directed signaling events essential to the specification of neural circuitry that is optimized for sustained homeostasis.
MeSH term(s)	Animals ; Endocrine System/physiology ; Gonadal Steroid Hormones/physiology ; Humans ; Hypothalamus/growth & development ; Nerve Net/growth & development ; Nerve Net/physiology
Chemical Substances	Gonadal Steroid Hormones
Language	English
Publishing date	2005-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1078046-4
ISSN	1873-6882 ; 0959-4388
ISSN (online)	1873-6882
ISSN	0959-4388
DOI	10.1016/j.conb.2005.01.013
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Zs.A 3260: Show issues

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Article ; Online: Leptin grows up and gets a neural network.

Cone, Roger D / Simerly, Richard B

Neuron

2011 Volume 71, Issue 1, Page(s) 4–6

Abstract: Studies seeking a dominant site of action for the hormone leptin have focused on leptin receptor-expressing neuropeptidergic neurons. In this issue, Vong et al. show that leptin regulates energy homeostasis predominantly via a distributed network of ... ...

Abstract	Studies seeking a dominant site of action for the hormone leptin have focused on leptin receptor-expressing neuropeptidergic neurons. In this issue, Vong et al. show that leptin regulates energy homeostasis predominantly via a distributed network of GABAergic neurons.
Language	English
Publishing date	2011-06-28
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2011.06.033
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 92: Show issues

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Article ; Online: Attenuation of diet-induced hypothalamic inflammation following bariatric surgery in female mice.

Herrick, Mary K / Favela, Kristin M / Simerly, Richard B / Abumrad, Naji N / Bingham, Nathan C

Molecular medicine (Cambridge, Mass.)

2018 Volume 24, Issue 1, Page(s) 56

Abstract: Background: Exposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus. Such hypothalamic inflammation is associated with metabolic dysfunction, ... ...

Abstract	Background: Exposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus. Such hypothalamic inflammation is associated with metabolic dysfunction, central leptin resistance, and maintenance of obesity. Bariatric surgeries result in long-term stable weight loss and improved metabolic function. However, the effects of such surgical procedures on HFD-induced hypothalamic inflammation are unknown. We sought to characterize the effects of two bariatric surgical procedures, Roux-en-Y gastric bypass (RYGB) and biliary diversion (BD-IL), in female mice with particular emphasis on HFD-induced hypothalamic inflammation and microgliosis. Methods: RYGB and BD-IL were performed on diet-induced obese (DIO) mice. Quantitative RT-PCR and fluorescent microscopy were used to evaluate hypothalamic inflammatory gene expression and microgliosis. Results were compared to lean (CD), DIO sham-surgerized mice (DIO-SHAM), and dietary weight loss (DIO-Rev) controls. Results: In female mice, RYGB and BD-IL result in normalization of hypothalamic inflammatory gene expression and microgliosis within 8 weeks of surgery, despite ongoing exposure to HFD. Paralleling these results, the hypothalamic expression levels of the orexigenic neuropeptide Agrp and the anorexic response of surgical mice to exogenous leptin were comparable to lean controls (CD). In contrast, results from DIO-Rev mice were comparable to DIO-SHAM mice, despite transition back to standard rodent show and normalization of weight. Conclusion: Bariatric surgery attenuates HFD-induced hypothalamic inflammation and microgliosis and restores leptin sensitivity, despite ongoing exposure to HFD.
MeSH term(s)	Animals ; Bariatric Surgery ; Diet, High-Fat ; Female ; Hypothalamus/pathology ; Inflammation/pathology ; Inflammation/surgery ; Mice, Inbred C57BL ; Obesity/surgery
Language	English
Publishing date	2018-10-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1283676-x
ISSN	1528-3658 ; 1076-1551
ISSN (online)	1528-3658
ISSN	1076-1551
DOI	10.1186/s10020-018-0057-y
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Zs.A 4456: Show issues

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