Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Dietrich, Marcelo O; Zimmer, Marcelo R.; Bober, Jeremy; Horváth, Tamas L.

doi:10.1016/j.cell.2017.04.006

Cited by 63 publications

(103 citation statements)

References 42 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests the possibility that different neural circuits controlling ghrelin-induced CPP or CPA exist. The description that different subpopulations of hunger-sensitive AgRP neurons drive feeding or non-feeding related behaviours (Betley et al, 2013) together with evidence that AgRP neurons drive repetitive stereotypic behaviour independent of hunger state (Dietrich et al, 2015) support this idea.…”

Section: Discussionmentioning

confidence: 81%

“…The increase in locomotor behaviour is interpreted as foodseeking behaviour and acute activation of AgRP neurons, the key neural target for ghrelin-induced food intake, increases locomotor behaviour in the absence but not presence of food. AgRP neurons convey the sense of hunger and recent evidence highlights that AgRP activation in the absence of food intake can lead to repetitive complex behaviours that are reversed by food consumption (Dietrich et al, 2015). Thus, the presence or absence of food after ghrelin injection elicits distinctive opposing behavioural patterns.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Diet-induced obesity causes ghrelin resistance in reward processing tasks

Lockie

Dinan

Lawrence

et al. 2015

Psychoneuroendocrinology

View full text Add to dashboard Cite

Diet-induced obesity (DIO) causes ghrelin resistance in hypothalamic Agouti-related peptide (AgRP) neurons. However, ghrelin promotes feeding through actions at both the hypothalamus and mesolimbic dopamine reward pathways. Therefore, we hypothesized that DIO would also establish ghrelin resistance in the ventral tegmental area (VTA), a major site of dopaminergic cell bodies important in reward processing. We observed reduced sucrose and saccharin consumption in Ghrelin KO vs Ghrelin WT mice. Moreover, DIO reduced saccharin consumption relative to chow-fed controls. These data suggest that the deletion of ghrelin and high fat diet both cause anhedonia. To assess if these are causally related, we tested whether DIO caused ghrelin resistance in a classic model of drug reward, conditioned place preference (CPP). Chow or high fat diet (HFD) mice were conditioned with ghrelin (1mg/kg in 10ml/kg ip) in the presence or absence of food in the conditioning chamber. We observed a CPP to ghrelin in chow-fed mice but not in HFD-fed mice. HFD-fed mice still showed a CPP for cocaine (20mg/kg), indicating that they maintained the ability to develop conditioned behaviour. The absence of food availability during ghrelin conditioning sessions induced a conditioned place aversion, an effect that was still present in both chow and HFD mice. Bilateral intra-VTA ghrelin injection (0.33μg/μl in 0.5μl) robustly increased feeding in both chow-fed and high fat diet (HFD)-fed mice; however, this was correlated with body weight only in the chow-fed mice. Our results suggest that DIO causes ghrelin resistance albeit not directly in the VTA. We suggest there is impaired ghrelin sensitivity in upstream pathways regulating reward pathways, highlighting a functional role for ghrelin linking appropriate metabolic sensing with reward processing.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Diet-induced obesity causes ghrelin resistance in reward processing tasks

Lockie

Dinan

Lawrence

et al. 2015

Psychoneuroendocrinology

View full text Add to dashboard Cite

show abstract

“…Metabolic status is one of the major determinants of healthy aging and life expectancy (61). In turn, metabolism is controlled by the activity of neuronal networks capable to integrate hormonal signals from peripheral organs and cognitive inputs from the central nervous system (62,63). Therefore, specific brain circuits can integrate sensory, cognitive and physiological inputs and affect the psychophysiological status of the body determining healthy aging trajectories.…”

Section: Discussionmentioning

confidence: 99%

Dlx5andDlx6expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan

Lombares

Heude

Alfama

et al. 2019

Preprint

View full text Add to dashboard Cite

Dlx5 and Dlx6 encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development Dlx5/6 are important for the differentiation of Parvalbumin (Pvalb)-expressing neurons. Perinatal lethality of homozygous mice in which Dlx5/6 have been constitutively deleted has, so far, hindered the study of the function of these genes in adult neurons. We first show that Dlx5 and Dlx6 are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyse VgatΔDlx5-6 mice in which Dlx5 and Dlx6 are simultaneously inactivated in all GABAergic interneurons. VgatΔDlx5-6 mice present a behavioral pattern suggesting reduction of anxiety and obsessive-compulsive activities. They rapidly access and spend more time in the central region of an open field, bury few marbles in the marble burying test and show little interest in nest building. Male and female 20-month-old VgatΔDlx5-6 animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, both VgatΔDlx5-6/+ and VgatΔDlx5-6 mice present a 33% longer median survival than their control littermates. Hallmarks of biological aging such as motility, adipose deposition and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate mammalian healthspan and lifespan through Dlx5/6-dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.SIGNIFICANCE STATEMENTDlx5 and Dlx6 are transcription factors controlling several developmental processes, including GABAergic neuronal migration and differentiation. To study their function in adult brain, we selectively inactivated both genes in GABAergic interneurons (VgatΔDlx5-6 mice). Mutant mice have reduced anxiety-like and obsessive-compulsive behaviors. Interestingly, VgatΔDlx5-6 mice have a 25% body weight reduction and about 70% less white and brown adipose tissue; their general health status is excellent. VgatΔDlx5-6 mice have a median survival about 33% longer than their control littermates and hallmarks of biological aging are improved. Dlx5/6-dependent regulations in GABAergic neurons could be an entry point to understand how the brain determines the psychophysiological status of the body and, ultimately, longevity and healthy aging.

show abstract

“…VGLUT3 is also expressed in other brain regions than the striatum and the raphe, notably the hippocampus, the amygdala, the bed nucleus of the stria terminalis, the hypothalamus, the habenula, inner hear cells of the cochlea and in non-5HT neurons of the raphe (Herzog et al 2004;Ruel et al 2008;Seal et al 2008;Jackson et al 2009). Although largely unexplored, several studies suggest a role for some of the above-mentioned structures in repetitive and stereotypic behaviors (Al-Amin et al 2000;Bauman et al 2008;Singer 2013;Dietrich et al 2015). To date, we cannot exclude a potential involvement of these structures in phenotypes herein observed following acute and chronic administration of amphetamine in VGLUT3 À⁄À mice.…”

Section: Discussionmentioning

confidence: 76%

“…; Singer ; Dietrich et al . ). To date, we cannot exclude a potential involvement of these structures in phenotypes herein observed following acute and chronic administration of amphetamine in VGLUT3 −⁄− mice.…”

Section: Discussionmentioning

confidence: 97%

VGLUT3 gates psychomotor effects induced by amphetamine

Mansouri-Guilani

Bernard

Vigneault

et al. 2019

Journal of Neurochemistry

View full text Add to dashboard Cite

Several subtypes of modulatory neurons co‐express vesicular glutamate transporters (VGLUTs) in addition to their cognate vesicular transporters. These neurons are believed to establish new forms of neuronal communication. The atypical VGLUT3 is of particular interest since in the striatum this subtype is found in tonically active cholinergic interneurons (TANs) and in a subset of 5‐HT fibers. The striatum plays a major role in psychomotor effects induced by amphetamine. Whether and how VGLUT3‐operated glutamate/ACh or glutamate/5HT co‐transmissions modulates psychostimulants‐induced maladaptive behaviors is still unknown. Here, we investigate the involvement of VGLUT3 and glutamate co‐transmission in amphetamine‐induced psychomotor effects and stereotypies. Taking advantage of constitutive and cell‐type specific VGLUT3‐deficient mouse lines, we tackled the hypothesis that VGLUT3 could gate psychomotor effects (locomotor activity and stereotypies) induced by acute or chronic administration of amphetamine. Interestingly, VGLUT3‐null mice demonstrated blunted amphetamine‐induced stereotypies as well as reduced striatal ∆FosB expression. VGLUT3‐positive varicosities within the striatum arise in part from 5HT neurons. We tested the involvement of VGLUT3 deletion in serotoninergic neurons in amphetamine‐induced stereotypies. Mice lacking VGLUT3 specifically in 5HT fibers showed no alteration to amphetamine sensitivity. In contrast, specific deletion of VGLUT3 in cholinergic neurons partially phenocopied the effects observed in the constitutive knock‐out mice. Our results show that constitutive deletion of VGLUT3 modulates acute and chronic locomotor effects induced by amphetamine. They point to the fact that the expression of VGLUT3 in multiple brain areas is pivotal in gating amphetamine‐induced psychomotor adaptations. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

show abstract

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Cited by 63 publications

References 42 publications

Diet-induced obesity causes ghrelin resistance in reward processing tasks

Diet-induced obesity causes ghrelin resistance in reward processing tasks

Dlx5andDlx6expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan

VGLUT3 gates psychomotor effects induced by amphetamine

Contact Info

Product

Resources

About