Hypothalamic agouti-related peptide and neuropeptide Y-expressing (AgRP) neurons have a critical role in both feeding and non-feeding behaviors of newborn, adolescent, and adult mice, suggesting their broad modulatory impact on brain functions. Here we show that constitutive impairment of AgRP neurons or their peripubertal chemogenetic inhibition resulted in both a numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice. These changes were accompanied by alteration of oscillatory network activity in mPFC, impaired sensorimotor gating, and altered ambulatory behavior that could be reversed by the administration of clozapine, a non-selective dopamine receptor antagonist. The observed AgRP effects are transduced to mPFC in part via dopaminergic neurons in the ventral tegmental area and may also be conveyed by medial thalamic neurons. Our results unmasked a previously unsuspected role for hypothalamic AgRP neurons in control of neuronal pathways that regulate higher-order brain functions during development and in adulthood.
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Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005;310:683–5.
Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. 2005;8:1289–91.
Miletta MC, Iyilikci O, Shanabrough M, Sestan-Pesa M, Cammisa A, Zeiss CJ, et al. AgRP neurons control compulsive exercise and survival in an activity-based anorexia model. Nat Metab. 2020;2:1204–11.
Dietrich MO, Bober J, Ferreira JG, Tellez LA, Mineur YS, Souza DO, et al. AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors. Nat Neurosci. 2012;15:1108–10.
Dietrich MO, Zimmer MR, Bober J, Horvath TL. Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell. 2015;160:1222–32.
Zimmer MR, Fonseca AHO, Iyilikci O, Pra RD, Dietrich MO. Functional Ontogeny of Hypothalamic Agrp Neurons in Neonatal Mouse Behaviors. Cell. 2019;178:44–59.e7.
Zeltser LM. Feeding circuit development and early-life influences on future feeding behaviour. Nat Rev Neurosci. 2018;19:302–16.
Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, et al. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiological Rev. 2012;92:1479–514.
Dietrich MO, Antunes C, Geliang G, Liu ZW, Borok E, Nie Y, et al. Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J Neurosci. 2010;30:11815–25.
Brust V, Schindler PM, Lewejohann L. Lifetime development of behavioural phenotype in the house mouse (Mus musculus). Front Zool. 2015;12 Suppl 1:S17.
Herculano-Houzel S, Lent R. Isotropic fractionator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain. J Neurosci. 2005;25:2518–21.
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.
Gao XB, van den Pol AN. Melanin concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus. J Physiol. 2001;533:237–52.
Liu ZW, Gao XB. Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol. 2007;97:837–48.
Liu ZW, Gan G, Suyama S, Gao XB. Intracellular energy status regulates activity in hypocretin/orexin neurones: a link between energy and behavioural states. J Physiol. 2011;589:4157–66.
Stutz B, da Conceicao FS, Santos LE, Cadilhe DV, Fleming RL, Acquarone M, et al. Murine dopaminergic Muller cells restore motor function in a model of Parkinson’s disease. J Neurochem. 2014;128:829–40.
Miller EK. The prefrontal cortex: complex neural properties for complex behavior. Neuron. 1999;22:15–7.
Ongur D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb cortex. 2000;10:206–19.
Seamans JK, Lapish CC, Durstewitz D. Comparing the prefrontal cortex of rats and primates: insights from electrophysiology. Neurotox Res. 2008;14:249–62.
Williams MR, Chaudhry R, Perera S, Pearce RK, Hirsch SR, Ansorge O, et al. Changes in cortical thickness in the frontal lobes in schizophrenia are a result of thinning of pyramidal cell layers. Eur Arch Psychiatry Clin Neurosci. 2013;263:25–39.
Vardy E, Robinson JE, Li C, Olsen RHJ, DiBerto JF, Giguere PM, et al. A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior. Neuron. 2015;86:936–46.
Rowland AA, Voeltz GK. Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol. 2012;13:607–25.
Hayashi T, Rizzuto R, Hajnoczky G, Su TP. MAM: more than just a housekeeper. Trends cell Biol. 2009;19:81–8.
Dietrich MO, Liu ZW, Horvath TL. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell. 2013;155:188–99.
Schneeberger M, Dietrich MO, Sebastian D, Imbernon M, Castano C, Garcia A, et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell. 2013;155:172–87.
Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491:212–7.
Beier KT, Steinberg EE, DeLoach KE, Xie S, Miyamichi K, Schwarz L, et al. Circuit architecture of VTA dopamine neurons revealed by systematic input-output mapping. Cell. 2015;162:622–34.
Van Eden CG, Hoorneman EM, Buijs RM, Matthijssen MA, Geffard M, Uylings HB. Immunocytochemical localization of dopamine in the prefrontal cortex of the rat at the light and electron microscopical level. Neuroscience. 1987;22:849–62.
Otani S, Daniel H, Roisin MP, Crepel F. Dopaminergic modulation of long-term synaptic plasticity in rat prefrontal neurons. Cereb cortex. 2003;13:1251–6.
Wang M, Vijayraghavan S, Goldman-Rakic PS. Selective D2 receptor actions on the functional circuitry of working memory. Science. 2004;303:853–6.
Slifstein M, van de Giessen E, Van Snellenberg J, Thompson JL, Narendran R, Gil R, et al. Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry. 2015;72:316–24.
Bubser M, Koch M. Prepulse inhibition of the acoustic startle response of rats is reduced by 6-hydroxydopamine lesions of the medial prefrontal cortex. Psychopharmacology. 1994;113:487–92.
Ellenbroek BA, Budde S, Cools AR. Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex. Neuroscience. 1996;75:535–42.
Balla A, Sershen H, Serra M, Koneru R, Javitt DC. Subchronic continuous phencyclidine administration potentiates amphetamine-induced frontal cortex dopamine release. Neuropsychopharmacology. 2003;28:34–44.
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K, et al. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron. 2010;65:480–9.
Kumari V, Fannon D, Geyer MA, Premkumar P, Antonova E, Simmons A, et al. Cortical grey matter volume and sensorimotor gating in schizophrenia. Cortex. 2008;44:1206–14.
Rohleder C, Wiedermann D, Neumaier B, Drzezga A, Timmermann L, Graf R, et al. The functional networks of prepulse inhibition: neuronal connectivity analysis based on FDG-PET in awake and unrestrained rats. Front Behav Neurosci. 2016;10:148.
Sebban C, Zhang XQ, Tesolin-Decros B, Millan MJ, Spedding M. Changes in EEG spectral power in the prefrontal cortex of conscious rats elicited by drugs interacting with dopaminergic and noradrenergic transmission. Br J Pharm. 1999;128:1045–54.
Lohani S, Martig AK, Deisseroth K, Witten IB, Moghaddam B. Dopamine modulation of prefrontal cortex activity is manifold and operates at multiple temporal and spatial scales. Cell Rep. 2019;27:99–114.e116.
Schmidt R, Herrojo Ruiz M, Kilavik BE, Lundqvist M, Starr PA, Aron AR. Beta oscillations in working memory, executive control of movement and thought, and sensorimotor function. J Neurosci. 2019;39:8231–8.
Tapias-Espinosa C, Rio-Alamos C, Sanchez-Gonzalez A, Oliveras I, Sampedro-Viana D, Castillo-Ruiz MDM, et al. Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume. Neuropsychopharmacology. 2019;44:1975–84.
Goldman-Rakic PS, Muly EC 3rd, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000;31:295–301.
Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004;74:1–58.
Lammel S, Hetzel A, Hackel O, Jones I, Liss B, Roeper J. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron. 2008;57:760–73.
Weele CMV, Siciliano CA, Tye KM. Dopamine tunes prefrontal outputs to orchestrate aversive processing. Brain Res. 2019;1713:16–31.
Broberger C, Johansen J, Johansson C, Schalling M, Hokfelt T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci USA. 1998;95:15043–8.
Wang D, He X, Zhao Z, Feng Q, Lin R, Sun Y, et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat. 2015;9:40.
Matyas F, Komlosi G, Babiczky A, Kocsis K, Bartho P, Barsy B, et al. A highly collateralized thalamic cell type with arousal-predicting activity serves as a key hub for graded state transitions in the forebrain. Nat Neurosci. 2018;21:1551–62.
Radhu N, Ravindran LN, Levinson AJ, Daskalakis ZJ. Inhibition of the cortex using transcranial magnetic stimulation in psychiatric populations: current and future directions. J Psychiatry Neurosci. 2012;37:369–78.
Arime Y, Kasahara Y, Hall FS, Uhl GR, Sora I. Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice. Neuropsychopharmacology. 2012;37:2522–30.
Manitt C, Mimee A, Eng C, Pokinko M, Stroh T, Cooper HM, et al. The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. J Neurosci. 2011;31:8381–94.
Benes FM, Taylor JB, Cunningham MC. Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology. Cereb cortex. 2000;10:1014–27.
Naneix F, Marchand AR, Di Scala G, Pape JR, Coutureau E. Parallel maturation of goal-directed behavior and dopaminergic systems during adolescence. J Neurosci. 2012;32:16223–32.
Rosenberg DR, Lewis DA. Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol. 1995;358:383–400.
Rothmond DA, Weickert CS, Webster MJ. Developmental changes in human dopamine neurotransmission: cortical receptors and terminators. BMC Neurosci. 2012;13:18.
Weickert CS, Webster MJ, Gondipalli P, Rothmond D, Fatula RJ, Herman MM, et al. Postnatal alterations in dopaminergic markers in the human prefrontal cortex. Neuroscience. 2007;144:1109–19.
Hoops D, Flores C. Making Dopamine Connections in Adolescence. Trends Neurosci. 2017;40:709–19.
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996;379:606–12.
Kozuka T, Omori Y, Watanabe S, Tarusawa E, Yamamoto H, Chaya T, et al. miR-124 dosage regulates prefrontal cortex function by dopaminergic modulation. Sci Rep. 2019;9:3445.
Arenas MC, Navarro-Frances CI, Montagud-Romero S, Minarro J, Manzanedo C. Baseline prepulse inhibition of the startle reflex predicts the sensitivity to the conditioned rewarding effects of cocaine in male and female mice. Psychopharmacology. 2018;235:2651–63.
Chang PK, Yu L, Chen JC. Dopamine D3 receptor blockade rescues hyper-dopamine activity-induced deficit in novel object recognition memory. Neuropharmacology. 2018;133:216–23.
Sathler MF, Stutz B, Martins RS, Dos Santos Pereira M, Pecinalli NR, Santos LE, et al. Single exposure to cocaine impairs aspartate uptake in the pre-frontal cortex via dopamine D1-receptor dependent mechanisms. Neuroscience. 2016;329:326–36.
Alagarsamy S, Phillips M, Pappas T, Johnson KM. Dopamine neurotoxicity in cortical neurons. Drug alcohol Depend. 1997;48:105–11.
Chang WL, Weber M, Breier MR, Saint Marie RL, Hines SR, Swerdlow NR. Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats. Brain Res. 2012;1437:69–76.
Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC. Optogenetic dissection of medial prefrontal cortex circuitry. Front Syst Neurosci. 2014;8:230.
LaLumiere RT, Kalivas PW. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci. 2008;28:3170–7.
Abela AR, Li Z, Le AD, Fletcher PJ. Clozapine reduces nicotine self-administration, blunts reinstatement of nicotine-seeking but increases responding for food. Addiction Biol. 2019;24:565–76.
Kouidrat Y, Amad A, Lalau JD, Loas G. Eating disorders in schizophrenia: implications for research and management. Schizophrenia Res Treat. 2014;2014:791573.
Pakpoor J, Agius M. A review of the adverse side effects associated with antipsychotics as related to their efficacy. Psychiatr Danubina. 2014;26 Suppl 1:273–84.
Goldstein JM, Seidman LJ, Makris N, Ahern T, O’Brien LM, Caviness VS Jr., et al. Hypothalamic abnormalities in schizophrenia: sex effects and genetic vulnerability. Biol psychiatry. 2007;61:935–45.
Vogt MC, Paeger L, Hess S, Steculorum SM, Awazawa M, Hampel B, et al. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell. 2014;156:495–509.
Koch M, Varela L, Kim JG, Kim JD, Hernandez-Nuno F, Simonds SE, et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 2015;519:45–50.
The authors thank Klara Szigeti-Buck and Alex Ralevski for technical assistance with electron microscopy preparation and imaging, Tamás Herczeg for immunohistochemistry and confocal imaging, Luis Varela for assistance in mitochondria quantification, and Naaman Mehta for assistance with behavioral experiments. This work was supported by the Yale University Neurobiology of Cortical Systems Training Grant [5-T32NS007224-30] to MJW, NIH grants AG052005, AG067329, DK045735, DK126447, DA046160, AG051459, funding from the Kavli Institute for Neuroscience at Yale University, and the Klarman Family Foundation to TLH, the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund (FK124434 and K138836 to FM; KKP126998 to BR, PS, FM), by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002 to FM) by the New National Excellence Program of the Ministry for Innovation and Technology (ÚNKP-21-5—ÁTE to FM). FM is a János Bolyai Research Fellow.
The authors declare no competing interests.
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Stutz, B., Waterson, M.J., Šestan-Peša, M. et al. AgRP neurons control structure and function of the medial prefrontal cortex. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01691-8