Diversity in the lateral hypothalamic input to the ventral tegmental area

Godfrey, Nathan; Borgland, Stephanie L.

doi:10.1016/j.neuropharm.2019.05.014

Cited by 29 publications

(17 citation statements)

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“…the LHA because this neuronal population directly regulates dopamine (DA) neurons in the VTA (Moorman and Aston-Jones, 2010;Leinninger et al, 2011;Muschamp et al, 2014;Godfrey and Borgland, 2019). Although these cells do not express the LepRb, they are regulated by leptin-sensitive afferent regions (Louis et al, 2010;Goforth et al, 2014) and accordingly modulate DA reward.…”

Section: Discussionmentioning

confidence: 99%

“…Homeostatic hypothalamic nuclei such as the arcuate nucleus (ARC), ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and hypothalamic paraventricular nucleus (PVN) project either directly or indirectly to the LHA (Hahn and Swanson, 2015) and together with multiple cortical, subcortical and brain stem inputs, regulate LHA activity (Bonnavion et al, 2016). In the LHA, multiple cell types are known to project to the VTA where they control dopamine and GABA interneuron firing activity and among these, several harbor functional leptin receptors (LeptR b ), including Neurotensin (Nts), Cocaine and Amphetamine Regulated Transcript (CART) neurons as well as different populations of GABA-containing neurons projecting to VTA GABA neurons (Nieh et al, 2016;Stuber and Wise, 2016;Godfrey and Borgland, 2019). Orexin-A (ORX-A) containing neurons in the LHA directly project to VTA dopamine neurons and stimulation of these cells has been shown to increase VTA DA firing activity and increase food intake (Tyree and de Lecea, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Increased Hypothalamic Projections to the Lateral Hypothalamus and Responses to Leptin in Rat Neonates From High Fat Fed Mothers

et al. 2020

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The lateral hypothalamus (LHA) is a central hub in the regulation of food intake and metabolism, as it integrates homeostatic and hedonic circuits. During early development, maturing input to and output from the LHA might be particularly sensitive to environmental dietary changes. We examined the effects of a maternal high fat diet (HFD, 60% Kcal in fat) on the density of hypothalamic projections to the orexin (ORX-A) field of the LHA in 10 day-old (PND10) rat pups using retrograde labeling with fluorescent microspheres. We also compared responsiveness of phenotypically identified LHA neurons to leptin administration (3 mg/kg, bw) between pups from control (CD) or high fat (HFD) fed mothers on PND10 and 15-16, at the onset of independent feeding. HFD pups exhibited a higher density of LHA projections (p = 0.05) from the ventromedial hypothalamus (VMH) compared to CD pups and these originated from both SF-1 and BDNF-positive neurons in the VMH. Increased circulating leptin levels in HFD pups, particularly on PND15-16 was consistent with enhanced pSTAT3 responses to leptin in the orexin (ORX-A) field of the LHA, with some of the activated neurons expressing a GABA, but not CART phenotype. ORX-A neurons colocalizing with pERK were significantly higher in PND15-16 HFD pups compared to CD pups, and leptininduced increase in pERK signaling was only observed in CD pups. There was no significant effect of leptin on pERK in HFD pups. These results suggest that perinatal maternal high fat feeding increases hypothalamic projections to the ORX-A field of the LHA, increases basal activation of ORX-A neurons and direct responsiveness of LHA neurons to leptin. Since these various LHA neuronal populations project quite heavily to Dopamine (DA) neurons in the ventral tegmental area, they might participate in the early dietary programming of mesocorticolimbic reward circuits and food intake.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased Hypothalamic Projections to the Lateral Hypothalamus and Responses to Leptin in Rat Neonates From High Fat Fed Mothers

et al. 2020

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“…For example, motivation will not accumulate before accessibility is granted 49 ( a = 0) . Motivation will also change according to factors such as satiety, valence, and memory 5, 12, 49, 52, 53 . Therefore, motivation at a certain time point ( M(t r ) ) can be written as the product of the integrated affecting factor and the integral of the following: When sufficient motivation is accumulated to pass a certain threshold (K ≥ 0), behaviour begins to appear.…”

Section: Supplementary Methodsmentioning

confidence: 99%

“…The AAV5.EF1⍺.DIO.hChR2(H134R).EYFP (Addgene; titre: 2.4×10 13 genome copies per ml) or AAV5.EF1⍺.DIO.eNpHR3.0.EYFP (Addgene; titre: 1.1×10 13 genome copies per ml) was utilised for optogenetic experiments. AAV8.hSyn.DIO.hM3D(Gq).mCherry (Addgene; titer 4.8x10 12 genome copies per ml) was used for chemogenetic experiments.…”

Section: Dmentioning

confidence: 99%

“…Heterogenous GABAergic neurons are widely distributed in the lateral hypothalamus (LH) and are involved in various motivated behaviours, including feeding 9, 10, 11, 12, 13 . Among LH GABA neurons, leptin receptor (LepR) neurons are reported to be associated with feeding behaviour, although the results of previous studies remain controversial 14, 15, 16, 17, 18 .…”

Section: Introductionmentioning

confidence: 99%

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Neural Mechanism of Hunger-gated Food-seeking and Evaluating

Lee

Song

Kim

et al. 2020

Preprint

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Agouti-related protein (AgRP) has been believed to be the main driver of feeding behaviors ever since its discovery. However, recent studies using fiber photometry and optogenetics proved that feeding behaviors are not directly driven by AgRP neurons (temporal discrepancy between neuronal activity and behavior). To resolve this paradox, we conducted novel multi-phase feeding experiments to scrutinize the dynamics of AgRP. Fiber photometry study showed that AgRP neurons start to deactivate even before the initiation of the food search phase. Using optogenetics, we could prove that the feeding behavior induced by AgRP neuron activation had substantial temporal delay and the feeding behavior was sustained for substantial time even after cessation of optogenetic activation. These results indicate that AgRP neurons are not the direct driver of feeding behavior and another downstream neuron is the driver of feeding behavior. Leptin receptor (LepR) neurons in the lateral hypothalamus (LH). LH LepR neurons were activated before voluntary food search behavior initiation and showed robust increase after food approach behavior. Artificial activation of LH LepR neurons drives food search and food approach behavior. In accordance, chemogenetic activation of LepR neurons increased food search and food approach behaviors. Lastly, slice calcium imaging results showed the possibility that NPY from the AgRP neurons could be the downstream neuromodulator of AgRP neuron, driving LH LepR neuron activation. Overall, our study shows that AgRP neurons are not the direct drivers of feeding behavior, whereas LH LepR neurons directly drive sustained food seeking behavior.

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Top-down projections of the prefrontal cortex to the ventral tegmental area, laterodorsal tegmental nucleus, and median raphe nucleus

et al. 2022

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Anatomical and functional evidence suggests that the PFC is fairly unique among all cortical regions, as it not only receives input from, but also robustly projects back to mesopontine monoaminergic and cholinergic cell groups. Thus the PFC is in a position to exert a powerful top-down control over several state setting modulatory transmitter systems that are critically involved in the domains of arousal, motivation, reward/aversion, working memory, mood regulation, and stress processing. Regarding this scenario, the origin of cortical afferents to the ventral tegmental area (VTA), laterodorsal tegmental nucleus (LDTg), and median raphe nucleus (MnR) was here compared, by using the retrograde tracer cholera toxin subunit b (CTb). CTb injections into VTA, LDTg, or MnR produced retrograde labeling in the cortical mantle, which was mostly confined to medial, orbital, and lateral PFC subdivisions, along with rostral and mid-cingulate areas. Remarkably, in all of the three groups, retrograde labeling was densest in layer V pyramidal neurons of the infralimbic, prelimbic, medial orbital and frontal polar cortex. Moreover, a conspicuous lambda-shaped region around the apex of the rostral pole of the nucleus accumbens stood consistently out as heavily labeled. At almost all rostrocaudal levels through the PFC analyzed, retrograde labeling was strongest following injections into MnR and weakest following injections into VTA. Altogether, our findings reveal a broadly similar set of prefrontal afferents to VTA, LDTg, and MnR, further supporting an eminent functional role of the PFC as a controller of all major state setting mesopontine modulatory transmitter systems.

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Diversity in the lateral hypothalamic input to the ventral tegmental area

Cited by 29 publications

References 133 publications

Increased Hypothalamic Projections to the Lateral Hypothalamus and Responses to Leptin in Rat Neonates From High Fat Fed Mothers

Increased Hypothalamic Projections to the Lateral Hypothalamus and Responses to Leptin in Rat Neonates From High Fat Fed Mothers

Neural Mechanism of Hunger-gated Food-seeking and Evaluating

Top-down projections of the prefrontal cortex to the ventral tegmental area, laterodorsal tegmental nucleus, and median raphe nucleus

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