scholarly journals Leptin Receptor Expressing Neurons in the Substantia Nigra Regulate Locomotion, and in The Ventral Tegmental Area Motivation and Feeding

2021 ◽  
Vol 12 ◽  
Author(s):  
Véronne A. J. de Vrind ◽  
Lisanne J. van ‘t Sant ◽  
Annemieke Rozeboom ◽  
Mieneke C. M. Luijendijk-Berg ◽  
Azar Omrani ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Food Reward ◽  
Leptin Receptor ◽  
Ventral Tegmental ◽  
Motivational Behavior ◽  
Lepr Expression

Leptin is an anorexigenic hormone, important in the regulation of body weight. Leptin plays a role in food reward, feeding, locomotion and anxiety. Leptin receptors (LepR) are expressed in many brain areas, including the midbrain. In most studies that target the midbrain, either all LepR neurons of the midbrain or those of the ventral tegmental area (VTA) were targeted, but the role of substantia nigra (SN) LepR neurons has not been investigated. These studies have reported contradicting results regarding motivational behavior for food reward, feeding and locomotion. Since not all midbrain LepR mediated behaviors can be explained by LepR neurons in the VTA alone, we hypothesized that SN LepR neurons may provide further insight. We first characterized SN LepR and VTA LepR expression, which revealed LepR expression mainly on DA neurons. To further understand the role of midbrain LepR neurons in body weight regulation, we chemogenetically activated VTA LepR or SN LepR neurons in LepR-cre mice and tested for motivational behavior, feeding and locomotion. Activation of VTA LepR neurons in food restricted mice decreased motivation for food reward (p=0.032) and food intake (p=0.020), but not locomotion. In contrast, activation of SN LepR neurons in food restricted mice decreased locomotion (p=0.025), but not motivation for food reward or food intake. Our results provide evidence that VTA LepR and SN LepR neurons serve different functions, i.e. activation of VTA LepR neurons modulated motivation for food reward and feeding, while SN LepR neurons modulated locomotor activity.

scholarly journals Targeted leptin receptor blockade: role of ventral tegmental area and nucleus of the solitary tract leptin receptors in body weight homeostasis

2014 ◽  
Vol 222 (1) ◽  
pp. 27-41 ◽  
Author(s):  
M Matheny ◽  
K Y E Strehler ◽  
M King ◽  
N Tümer ◽  
P J Scarpace
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Ventral Tegmental Area ◽  
Food Consumption ◽  
Leptin Receptor ◽  
Body Weight Gain ◽  
Solitary Tract ◽  
Leptin Receptors ◽  
Ventral Tegmental

The present investigation examined whether leptin stimulation of ventral tegmental area (VTA) or nucleus of the solitary tract (NTS) has a role in body weight homeostasis independent of the medial basal hypothalamus (MBH). To this end, recombinant adeno-associated viral techniques were employed to target leptin overexpression or overexpression of a dominant negative leptin mutant (leptin antagonist). Leptin antagonist overexpression in MBH or VTA increased food intake and body weight to similar extents over 14 days in rats. Simultaneous overexpression of leptin in VTA with antagonist in MBH resulted in food intake and body weight gain that were less than with control treatment but greater than with leptin alone in VTA. Notably, leptin overexpression in VTA increased P-STAT3 in MBH along with VTA, and leptin antagonist overexpression in the VTA partially attenuated P-STAT3 levels in MBH. Interestingly, leptin antagonist overexpression elevated body weight gain, but leptin overexpression in the NTS failed to modulate either food intake or body weight despite increased P-STAT3. These data suggest that leptin function in the VTA participates in the chronic regulation of food consumption and body weight in response to stimulation or blockade of VTA leptin receptors. Moreover, one component of VTA-leptin action appears to be independent of the MBH, and another component appears to be related to leptin receptor-mediated P-STAT3 activation in the MBH. Finally, leptin receptors in the NTS are necessary for normal energy homeostasis, but mostly they appear to have a permissive role. Direct leptin activation of NTS slightly increases UCP1 levels, but has little effect on food consumption or body weight.

scholarly journals Cooperative interaction between leptin and amylin signaling in the ventral tegmental area for the control of food intake

2015 ◽  
Vol 308 (12) ◽  
pp. E1116-E1122 ◽  
Author(s):  
Elizabeth G. Mietlicki-Baase ◽  
Diana R. Olivos ◽  
Brianne A. Jeffrey ◽  
Matthew R. Hayes
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Ventral Tegmental Area ◽  
Balance Control ◽  
Body Weight Gain ◽  
Body Weight Loss ◽  
Cooperative Interaction ◽  
Cooperative Effects ◽  
Ventral Tegmental

Peripheral coadministration of amylin and leptin produces enhanced suppression of food intake and body weight, but the central nuclei mediating these effects remain unclear. Because each of these peptides controls feeding via actions at the ventral tegmental area (VTA), we tested the hypothesis that the VTA is a site of action for the cooperative effects of leptin and amylin on energy balance control. First, we show that intra-VTA injection of amylin and leptin at doses of each peptide that are effective in reducing food intake and body weight when administered separately produces an enhanced suppression of feeding when administered in combination. We also demonstrate that subthreshold doses of both amylin and leptin cause significant hypophagia and body weight loss when coadministered into the VTA. Additionally, we provide evidence that VTA amylin receptor blockade significantly attenuates the ability of intra-VTA leptin to reduce feeding and body weight gain. Together, these data provide the first evidence that the VTA mediates the interaction of amylin and leptin to cooperatively promote negative energy balance.

scholarly journals GLP-1 Neurons in the Nucleus of the Solitary Tract Project Directly to the Ventral Tegmental Area and Nucleus Accumbens to Control for Food Intake

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 647-658 ◽  
Author(s):  
Amber L. Alhadeff ◽  
Laura E. Rupprecht ◽  
Matthew R. Hayes
Keyword(s):  
Body Weight ◽  
Nucleus Accumbens ◽  
Food Intake ◽  
Ventral Tegmental Area ◽  
Nucleus Tractus Solitarius ◽  
Receptor Activation ◽  
Current Data ◽  
Solitary Tract ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

Central glucagon-like-peptide-1 (GLP-1) receptor activation reduces food intake; however, brain nuclei and mechanism(s) mediating this effect remain poorly understood. Although central nervous system GLP-1 is produced almost exclusively in the nucleus of the solitary tract in the hindbrain, GLP-1 receptors (GLP-1R) are expressed throughout the brain, including nuclei in the mesolimbic reward system (MRS), e.g. the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Here, we examine the MRS as a potential site of action for GLP-1-mediated control of food intake and body weight. Double immunohistochemistry for Fluorogold (monosynaptic retrograde tracer) and GLP-1 neuron immunoreactivity indicated that GLP-1-producing nucleus tractus solitarius neurons project directly to the VTA, the NAc core, and the NAc shell. Pharmacological data showed that GLP-1R activation in the VTA, NAc core, and NAc shell decreased food intake, especially of highly-palatable foods, and body weight. Moreover, blockade of endogenous GLP-1R signaling in the VTA and NAc core resulted in a significant increase in food intake, establishing a physiological relevance for GLP-1 signaling in the MRS. Current data highlight these nuclei within the MRS as novel sites for GLP-1R-mediated control of food intake and body weight.

scholarly journals Role of GABA Release From Leptin Receptor-Expressing Neurons in Body Weight Regulation

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2223-2233 ◽  
Author(s):  
Yuanzhong Xu ◽  
William G. O'Brien ◽  
Cheng-Chi Lee ◽  
Martin G. Myers ◽  
Qingchun Tong
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Leptin Receptor ◽  
Gaba Release ◽  
Neuron Activity ◽  
Chow Diet ◽  
Weight Regulation ◽  
Body Weight Regulation ◽  
The Brain

It is well established that leptin regulates energy balance largely through isoform B leptin receptor-expressing neurons (LepR neurons) in the brain and that leptin activates one subset of LepR neurons (leptin-excited neurons) while inhibiting the other (leptin-inhibited neurons). However, the neurotransmitters released from LepR neurons that mediate leptin action in the brain are not well understood. Previous results demonstrate that leptin mainly acts on γ-aminobutyric acid (GABA)ergic neurons to reduce body weight, and that leptin activates proopiomelanocortin neuron activity by reducing GABA release onto these neurons, suggesting a body weight-promoting role for GABA released from leptin-inhibited neurons. To directly examine the role of GABA release from LepR neurons in body weight regulation, mice with disruption of GABA release specifically from LepR neurons were generated by deletion of vesicular GABA transporter in LepR neurons. Interestingly, these mice developed mild obesity on chow diet and were sensitive to diet-induced obesity, which were associated with higher food intake and lower energy expenditure. Moreover, these mice showed blunted responses in both food intake and body weight to acute leptin administration. These results demonstrate that GABA plays an important role in mediating leptin action. In combination with the previous studies that leptin reduces GABA release onto proopiomelanocortin neurons through leptin-inhibited neurons and that disruption of GABA release from agouti gene-related protein neurons, one subset of LepR-inhibited neurons, leads to a lean phenotype, our results suggest that, under our experimental conditions, GABA release from leptin-excited neuron dominates over leptin-inhibited ones.

scholarly journals Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain

2018 ◽  
Author(s):  
Tatiana V Tarasova ◽  
Olga A Lytkina ◽  
Valeria V Goloborshcheva ◽  
Larisa N Skuratovskaya ◽  
Alexandr I Antohin ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Embryonic Development ◽  
Ventral Tegmental Area ◽  
Knockout Mice ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Nigrostriatal System ◽  
Ventral Tegmental

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson's disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in PD brain, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

scholarly journals Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain

2018 ◽  
Author(s):  
Tatiana V Tarasova ◽  
Olga A Lytkina ◽  
Valeria V Goloborshcheva ◽  
Larisa N Skuratovskaya ◽  
Alexandr I Antohin ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Embryonic Development ◽  
Ventral Tegmental Area ◽  
Knockout Mice ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Nigrostriatal System ◽  
Ventral Tegmental

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson's disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in PD brain, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

scholarly journals The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling

2009 ◽  
Vol 297 (1) ◽  
pp. E202-E210 ◽  
Author(s):  
Gregory J. Morton ◽  
James E. Blevins ◽  
Francis Kim ◽  
Miles Matsen ◽  
Dianne P. Figlewicz
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Ventral Tegmental Area ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Janus Kinase ◽  
Leptin Signaling ◽  
Local Inhibition ◽  
Midbrain Region ◽  
Ventral Tegmental

Recent evidence suggests that leptin reduces food intake via actions in the brain circuitry of food reward, such as the ventral tegmental area (VTA), as leptin receptors are present in the VTA, and leptin injection in the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Janus kinase-signal transducer and activator of transcription (Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI 3-kinase), and mammalian target of rapamycin (mTOR). In this study, we determined whether leptin activates each of these signal transduction pathways in the VTA and whether these signaling pathways are required for VTA-leptin induced anorexia. Here, we show that pSTAT3-Tyr705, a marker of leptin activation, was induced in a midbrain region containing the VTA and substantia nigra following either intracerebroventricular leptin or direct administration of leptin to the VTA, but these interventions failed to increase levels of either pAKT-Ser473 or phospho-p70S6K-Thr389, markers of IRS-PI 3-kinase and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20-h food intake and 20-h body weight was blocked by an inhibitor of Jak-2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI 3-kinase (LY-294002) or mTOR (rapamycin) in this timeframe. Taken together, these data support the hypothesis that leptin signaling in the VTA is involved in the regulation of energy balance, but, in contrast to the leptin signaling in the hypothalamus, these effects are mediated predominantly via Jak-2 signaling rather than via the IRS-PI 3-kinase or mTOR signaling pathway.

scholarly journals Netrin 1-Mediated Role of the Substantia Nigra Pars Compacta and Ventral Tegmental Area in the Guidance of the Medial Habenular Axons

2021 ◽  
Vol 9 ◽  
Author(s):  
Verónica Company ◽  
Abraham Andreu-Cervera ◽  
M. Pilar Madrigal ◽  
Belén Andrés ◽  
Francisca Almagro-García ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Dopaminergic Neurons ◽  
Functional Organization ◽  
Substantia Nigra Pars Compacta ◽  
Fasciculus Retroflexus ◽  
Ventral Tegmental

The fasciculus retroflexus is an important fascicle that mediates reward-related behaviors and is associated with different psychiatric diseases. It is the main habenular efference and constitutes a link between forebrain regions, the midbrain, and the rostral hindbrain. The proper functional organization of habenular circuitry requires complex molecular programs to control the wiring of the habenula during development. However, the mechanisms guiding the habenular axons toward their targets remain mostly unknown. Here, we demonstrate the role of the mesodiencephalic dopaminergic neurons (substantia nigra pars compacta and ventral tegmental area) as an intermediate target for the correct medial habenular axons navigation along the anteroposterior axis. These neuronal populations are distributed along the anteroposterior trajectory of these axons in the mesodiencephalic basal plate. Using in vitro and in vivo experiments, we determined that this navigation is the result of netrin 1 attraction generated by the mesodiencephalic dopaminergic neurons. This attraction is mediated by the receptor deleted in colorectal cancer (DCC), which is strongly expressed in the medial habenular axons. The increment in our knowledge on the fasciculus retroflexus trajectory guidance mechanisms opens the possibility of analyzing if its alteration in mental health patients could account for some of their symptoms.

scholarly journals Distinct Alterations in Cerebellar Connectivity with Substantia Nigra and Ventral Tegmental Area in Parkinsons Disease

2021 ◽  
Author(s):  
Ian M O'Shea ◽  
Haroon Popal ◽  
Ingrid R Olson ◽  
Vishnu P Murty ◽  
David V Smith
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Occipital Cortex ◽  
Resting State Fmri ◽  
Healthy Adults ◽  
Anterior Cingulate ◽  
Functional Coupling ◽  
Parkinsons Disease ◽  
Ventral Tegmental

In Parkinsons disease (PD), neurodegeneration of dopaminergic neurons occurs in the midbrain, specifically targeting the substantia nigra (SN), while leaving the ventral tegmental area (VTA) relatively spared in early phases of the disease. Although the SN and VTA are known to be functionally dissociable in healthy adults, it remains unclear how this dissociation is altered in PD. To examine this issue, we performed a whole-brain analysis to compare functional coupling in PD to healthy adults using resting-state fMRI data compiled from three independent datasets. Our analysis showed that across the sample, the SN had greater coupling to the precuneus, anterior cingulate gyrus, and areas of the occipital cortex, partially replicating our previous work in healthy young adults. Notably, we also found that, in PD, VTA-right cerebellum coupling was higher than SN-right cerebellum coupling, whereas the opposite trend occurred in healthy controls. This double dissociation may reflect a compensatory role of the cerebellum in PD and could provide a potential target for future study and treatment.

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