Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended central amygdala.
Leptin acts via its receptor (LepRb) to regulate neural circuits in concert with body energy stores. In addition to acting on a number of hypothalamic structures, leptin modulates the mesolimbic dopamine (DA) system. To determine the sites at which LepRb neurons might directly influence the mesolimbic DA system, we examined the distribution of LepRb neurons and their projections within mesolimbic brain regions. Although the ventral tegmental area (VTA) contains DA LepRb neurons, LepRb neurons are absent from the amygdala and striatum. Also, LepRb-EGFPf mice (which label projections from LepRb neurons throughout the brain) reveal that few LepRb neurons project to the nucleus accumbens (NAc). In contrast, the central amygdala (CeA) and its rostral extension receive copious projections from LepRb neurons. Indeed, LepRb-specific anterograde tracing demonstrates (and retrograde tracing confirms) that VTA LepRb neurons project to the extended CeA (extCeA) but not the NAc. Consistently, leptin promotes cAMP response element-binding protein phosphorylation in the extCeA, but not NAc, of leptin-deficient animals. Furthermore, transgenic mice expressing the trans-synaptic tracer wheat germ agglutinin in LepRb neurons reveal the innervation of CeA cocaine- and amphetamine-regulated transcript (CART) neurons by LepRb neurons, and leptin suppresses the increased CeA CART expression of leptin-deficient animals. Thus, LepRb VTA neurons represent a subclass of VTA DA neurons that specifically innervates and controls the extCeA; we hypothesize that these neurons primarily modulate CeA-directed behaviors.
Leshan
Rebecca L
RL
Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Opland
Darren M
DM
Louis
Gwendolyn W
GW
Leinninger
Gina M
GM
Patterson
Christa M
CM
Rhodes
Christopher J
CJ
Münzberg
Heike
H
Myers
Martin G
MG
D000661:Amphetamine / Q000032:analysis; D000679:Amygdala / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D003042:Cocaine / Q000032:analysis; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000737:chemistry / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D054411:Receptors, Leptin / Q000032:analysis / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D017557:Ventral Tegmental Area / Q000737:chemistry / Q000502:physiology*
D054411:Receptors, Leptin; D000661:Amphetamine; D003042:Cocaine
J Comp Neurol. 1998 Jun 15;395(4):535-47
9619505
J Comp Neurol. 2005 Dec 5;493(1):72-85
16255002
J Neurosci. 2008 Sep 3;28(36):8908-13
18768684
Cell Metab. 2009 Aug;10(2):89-98
19656487
Neuron. 2006 Jan 19;49(2):191-203
16423694
Nat Neurosci. 2005 Nov;8(11):1445-9
16251986
Obesity (Silver Spring). 2006 Aug;14 Suppl 5:216S-221S
17021370
Brain Res Rev. 2007 Nov;56(1):27-78
17574681
Brain Res. 2007 Jun 4;1152:234-40
17434149
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1593-8
16423896
Cell. 2009 Sep 4;138(5):976-89
19737523
J Comp Neurol. 2005 Dec 5;493(1):63-71
16254991
Cell Metab. 2009 Jun;9(6):537-47
19490908
Physiol Behav. 2007 Aug 15;91(5):486-98
17307205
J Neurosci. 2009 Mar 11;29(10):3138-47
19279251
Neuropsychopharmacology. 2009 Apr;34(5):1288-300
19005467
Neuroreport. 1999 Nov 8;10(16):3449-52
10599860
Science. 2000 Jan 7;287(5450):125-8
10615045
Nutr Rev. 2002 Oct;60(10 Pt 2):S1-14; discussion S68-84, 85-7
12403078
J Comp Neurol. 2009 Jun 10;514(5):518-32
19350671
Neuron. 2005 Jan 6;45(1):17-25
15629699
Cell Metab. 2010 Jan;11(1):77-83
20074530
J Androl. 2005 Sep-Oct;26(5):568-77
16088032
J Gerontol A Biol Sci Med Sci. 2001 Aug;56(8):B340-9
11487592
Neuron. 2004 Jun 24;42(6):983-91
15207242
Obesity (Silver Spring). 2006 Aug;14 Suppl 5:208S-212S
17021368
J Clin Invest. 2005 Dec;115(12):3484-93
16284652
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15148-53
12391304
J Clin Invest. 2001 Oct;108(8):1113-21
11602618
Neuron. 2006 Sep 21;51(6):811-22
16982425
J Neurosci. 2007 Jun 27;27(26):7021-7
17596451
Brain Res. 2008 Nov 13;1240:119-31
18823957
Cell Metab. 2009 Feb;9(2):117-23
19187770
Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R47-63
16959861
Nature. 2009 Jun 11;459(7248):837-41
19448610
Neuropsychopharmacology. 2008 Apr;33(5):1127-36
17637604
Psychopharmacology (Berl). 2010 Jan;207(4):535-45
19823809
Nature. 2006 Sep 21;443(7109):289-95
16988703
Endocrinology. 2003 May;144(5):2016-24
12697710
Cancer Res. 2006 Feb 1;66(3):1294-301
16452182
Life Sci. 2003 Jun 27;73(6):759-68
12801597
J Neurosci. 2007 Jan 3;27(1):69-74
17202473
Neuron. 2008 Mar 13;57(5):760-73
18341995
Annu Rev Neurosci. 2007;30:367-98
17506645
Physiol Behav. 2007 Aug 15;91(5):473-8
17137609
Neuron. 2006 Sep 21;51(6):801-10
16982424