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Identification of a stress-sensitive anorexigenic neurocircuit from medial prefrontal cortex to lateral hypothalamus.

      Abstract

      Background

      A greater understanding of how the brain controls appetite is fundamental to develop new approaches to treat disease characterized by dysfunctional feeding behavior, such as obesity and anorexia nervosa.

      Methods

      By modeling neural network dynamics related to homeostatic state and BMI, we identified a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans (n=53). We then assessed the physiological role and dissected the function of this mPFC-LH circuit in mice.

      Results

      In vivo recordings of population calcium activity revealed that this glutamatergic mPFC-LH pathway is activated in response to acute stressors and inhibited during food consumption, suggesting a role in stress-related control over food intake. Consistent with this role, inhibition of this circuit increased feeding and sucrose seeking during mild stressors, but not under non-stressful conditions. Finally, chemogenetic or optogenetic activation of the mPFC-LH pathway is sufficient to suppress food intake and sucrose-seeking in mice.

      Conclusions

      These studies identify a glutamatergic mPFC-LH circuit as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake.

      Keywords

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      References

        • Locke A.E.
        • Kahali B.
        • Berndt S.I.
        • Justice A.E.
        • Pers T.H.
        • Felix R.
        • et al.
        Genetic studies of body mass index yield new insights for obesity biology.
        Nature. 2015; 518: 197-U401
        • O'Rahilly S.
        • Farooqi I.S.
        Human obesity as a heritable disorder of the central control of energy balance.
        Int J Obes (Lond). 2008; 32: S55-61
        • Andermann M.L.
        • Lowell B.B.
        Toward a Wiring Diagram Understanding of Appetite Control.
        Neuron. 2017; 95: 757-778
        • Boswell R.G.
        • Kober H.
        Food cue reactivity and craving predict eating and weight gain: a meta-analytic review.
        Obesity Reviews. 2016; 17: 159-177
        • Kanoski S.E.
        Cognitive and neuronal systems underlying obesity.
        Physiology & Behavior. 2012; 106: 337-344
        • Harding I.H.
        • Andrews Z.B.
        • Mata F.
        • Orlandea S.
        • Martinez-Zalacain I.
        • Soriano-Mas C.
        • et al.
        Brain substrates of unhealthy versus healthy food choices: influence of homeostatic status and body mass index.
        Int J Obes (Lond). 2018; 42: 448-454
        • Hare T.A.
        • Camerer C.F.
        • Rangel A.
        Self-Control in Decision-Making Involves Modulation of the vmPFC Valuation System.
        Science. 2009; 324: 646-648
        • Brooks S.J.
        • Cedernaes J.
        • Schioth H.B.
        Increased Prefrontal and Parahippocampal Activation with Reduced Dorsolateral Prefrontal and Insular Cortex Activation to Food Images in Obesity: A Meta-Analysis of fMRI Studies.
        PLoS One. 2013; 8
        • Kennedy J.
        • Dimitropoulos A.
        Influence of feeding state on neurofunctional differences between individuals who are obese and normal weight: A meta-analysis of neuroimaging studies.
        Appetite. 2014; 75: 103-109
        • Stoeckel L.E.
        • Weller R.E.
        • Cook 3rd, E.W.
        • Twieg D.B.
        • Knowlton R.C.
        • Cox J.E.
        Widespread reward-system activation in obese women in response to pictures of high-calorie foods.
        NeuroImage. 2008; 41: 636-647
        • Uher R.
        • Murphy T.
        • Brammer M.J.
        • Dalgleish T.
        • Phillips M.L.
        • Ng V.W.
        • et al.
        Medial prefrontal cortex activity associated with symptom provocation in eating disorders.
        Am J Psychiat. 2004; 161: 1238-1246
        • Misic B.
        • Sporns O.
        From regions to connections and networks: new bridges between brain and behavior.
        Current opinion in neurobiology. 2016; 40: 1-7
        • Contreras-Rodriguez O.
        • Vilar-Lopez R.
        • Andrews Z.B.
        • Navas J.F.
        • Soriano-Mas C.
        • Verdejo-Garcia A.
        Altered cross-talk between the hypothalamus and non-homeostatic regions linked to obesity and difficulty to lose weight.
        Scientific reports. 2017; 7: 9951
        • Kullmann S.
        • Heni M.
        • Linder K.
        • Zipfel S.
        • Haring H.U.
        • Veit R.
        • et al.
        Resting-State Functional Connectivity of the Human Hypothalamus.
        Human brain mapping. 2014; 35: 6088-6096
        • Jennings J.H.
        • Ung R.L.
        • Resendez S.L.
        • Stamatakis A.M.
        • Taylor J.G.
        • Huang J.
        • et al.
        Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors.
        Cell. 2015; 160: 516-527
        • Buckner R.L.
        • Krienen F.M.
        • Yeo B.T.T.
        Opportunities and limitations of intrinsic functional connectivity MRI.
        Nature Neuroscience. 2013; 16: 832-837
        • Barone F.C.
        • Wayner M.J.
        • Scharoun S.L.
        • Guevaraaguilar R.
        • Aguilarbaturoni H.U.
        Afferent Connections to the Lateral Hypothalamus - a Horseradish-Peroxidase Study in the Rat.
        Brain research bulletin. 1981; 7: 75-88
        • Hahn J.D.
        • Swanson L.W.
        Distinct patterns of neuronal inputs and outputs of the juxtaparaventricular and suprafornical regions of the lateral hypothalamic area in the male rat.
        Brain Res Rev. 2010; 64: 14-103
        • Biro L.
        • Sipos E.
        • Bruzsik B.
        • Farkas I.
        • Zelena D.
        • Balazsfi D.
        • et al.
        Task Division within the Prefrontal Cortex: Distinct Neuron Populations Selectively Control Different Aspects of Aggressive Behavior via the Hypothalamus.
        Journal of Neuroscience. 2018; 38: 4065-4075
        • Liu L.
        • Zhang L.
        • Wang T.
        • Chen L.
        Dopamine D1 receptor in the medial prefrontal cortex mediates anxiety-like behaviors induced by blocking glutamatergic activity of the ventral hippocampus in rats.
        Brain Res. 2019; 1704: 59-67
        • Padilla-Coreano N.
        • Batra K.
        • Patarino M.
        • Chen Z.X.
        • Rock R.R.
        • Zhang R.H.
        • et al.
        Cortical ensembles orchestrate social competition through hypothalamic outputs.
        Nature. 2022; 603: 667
        • Matikainen-Ankney B.A.
        • Earnest T.
        • Ali M.
        • Casey E.
        • Sutton A.K.
        • Legaria A.
        • et al.
        Feeding Experimentation Device version 3 (FED3): An open-source home-cage compatible device for measuring food intake and operant behavior.
        eLife. 2021; https://doi.org/10.7554/eLife.66173
        • Friston K.J.
        • Mattout J.
        • Trujillo-Barreto N.
        • Ashburner J.
        • Penny W.
        Variational free energy and the Laplace approximation.
        NeuroImage. 2007; 34: 220-234
        • Kim C.K.
        • Ye L.
        • Jennings J.H.
        • Pichamoorthy N.
        • Tang D.D.
        • Yoo A.C.W.
        • et al.
        Molecular and Circuit-Dynamical Identification of Top-Down Neural Mechanisms for Restraint of Reward Seeking.
        Cell. 2017; 170 (-+): 1013
        • Laubach M.
        • Amarante L.M.
        • Swanson K.
        • White S.R.
        What, If Anything, Is Rodent Prefrontal Cortex?.
        Eneuro. 2018; 5
        • Wu Y.
        • Chen C.W.
        • Chen M.
        • Qian K.
        • Lv X.Y.
        • Wang H.T.
        • et al.
        The anterior insular cortex unilaterally controls feeding in response to aversive visceral stimuli in mice.
        Nature communications. 2020; 11
        • Daviu N.
        • Fuzesi T.
        • Rosenegger D.G.
        • Rasiah N.P.
        • Sterley T.L.
        • Peringod G.
        • et al.
        Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection.
        Nat Neurosci. 2020; 23: 398-410
        • Merali Z.
        • Levac C.
        • Anisman H.
        Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice.
        Biol Psychiatry. 2003; 54: 552-565
        • Francois M.
        • Canal Delgado I.
        • Shargorodsky N.
        • Leu C.S.
        • Zeltser L.
        Assessing the effects of stress on feeding behaviors in laboratory mice.
        eLife. 2022; 11
        • Lever C.
        • Burton S.
        • O'Keefe J.
        Rearing on hind legs, environmental novelty, and the hippocampal formation.
        Rev Neurosci. 2006; 17: 111-133
        • Zeisel A.
        • Hochgerner H.
        • Lonnerberg P.
        • Johnsson A.
        • Memic F.
        • van der Zwan J.
        • et al.
        Molecular Architecture of the Mouse Nervous System.
        Cell. 2018; 174 (-+): 999
        • Shin G.
        • Gomez A.M.
        • Al-Hasani R.
        • Jeong Y.R.
        • Kim J.
        • Xie Z.Q.
        • et al.
        Flexible Near-Field Wireless Optoelectronics as Subdermal Implants for Broad Applications in Optogenetics.
        Neuron. 2017; 93 (-+): 509
        • Schur E.A.
        • Kleinhans N.M.
        • Goldberg J.
        • Buchwald D.
        • Schwartz M.W.
        • Maravilla K.
        Activation in brain energy regulation and reward centers by food cues varies with choice of visual stimulus.
        Int J Obes (Lond). 2009; 33: 653-661
        • Land B.B.
        • Narayanan N.S.
        • Liu R.J.
        • Gianessi C.A.
        • Brayton C.E.
        • Grimaldi D.M.
        • et al.
        Medial prefrontal D1 dopamine neurons control food intake.
        Nat Neurosci. 2014; 17: 248-253
        • Otis J.M.
        • Namboodiri V.M.K.
        • Matan A.M.
        • Voets E.S.
        • Mohorn E.P.
        • Kosyk O.
        • et al.
        Prefrontal cortex output circuits guide reward seeking through divergent cue encoding.
        Nature. 2017; 543 (-+): 103
        • Li B.
        • Nguyen T.P.
        • Ma C.
        • Dan Y.
        Inhibition of impulsive action by projection-defined prefrontal pyramidal neurons.
        Proc Natl Acad Sci U S A. 2020; 117: 17278-17287
        • Alexander W.H.
        • Brown J.W.
        A general role for medial prefrontal cortex in event prediction.
        Front Comput Neurosci. 2014; 8: 69
        • Fisher P.M.
        • Price J.C.
        • Meltzer C.C.
        • Moses-Kolko E.L.
        • Becker C.
        • Berga S.L.
        • et al.
        Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity.
        Biol Mood Anxiety Disord. 2011; 1: 2
        • Parfitt G.M.
        • Nguyen R.
        • Bang J.Y.
        • Aqrabawi A.J.
        • Tran M.M.
        • Seo D.K.
        • et al.
        Bidirectional Control of Anxiety-Related Behaviors in Mice: Role of Inputs Arising from the Ventral Hippocampus to the Lateral Septum and Medial Prefrontal Cortex.
        Neuropsychopharmacology. 2017; 42: 1715-1728
        • Pratt W.E.
        • Mizumori S.J.
        Neurons in rat medial prefrontal cortex show anticipatory rate changes to predictable differential rewards in a spatial memory task.
        Behav Brain Res. 2001; 123: 165-183
        • McKlveen J.M.
        • Myers B.
        • Herman J.P.
        The Medial Prefrontal Cortex: Coordinator of Autonomic, Neuroendocrine and Behavioural Responses to Stress.
        J Neuroendocrinol. 2015; 27: 446-456
        • Radley J.J.
        • Arias C.M.
        • Sawchenko P.E.
        Regional differentiation of the medial prefrontal cortex in regulating adaptive responses to acute emotional stress.
        Journal of Neuroscience. 2006; 26: 12967-12976
        • Uribe-Marino A.
        • Gassen N.C.
        • Wiesbeck M.F.
        • Balsevich G.
        • Santarelli S.
        • Solfrank B.
        • et al.
        Prefrontal Cortex Corticotropin-Releasing Factor Receptor 1 Conveys Acute Stress-Induced Executive Dysfunction.
        Biological Psychiatry. 2016; 80: 743-753
        • Kaplan R.
        • Schuck N.W.
        • Doeller C.F.
        The Role of Mental Maps in Decision-Making.
        Trends Neurosci. 2017; 40: 256-259
        • Luk C.H.
        • Wallis J.D.
        Dynamic encoding of responses and outcomes by neurons in medial prefrontal cortex.
        J Neurosci. 2009; 29: 7526-7539
        • Schmidt B.
        • Duin A.A.
        • Redish A.D.
        Disrupting the medial prefrontal cortex alters hippocampal sequences during deliberative decision making.
        J Neurophysiol. 2019; 121: 1981-2000
        • Kim J.S.
        • Han S.Y.
        • Iremonger K.J.
        Stress experience and hormone feedback tune distinct components of hypothalamic CRH neuron activity.
        Nature communications. 2019; 10: 5696
        • Chen Y.
        • Lin Y.C.
        • Kuo T.W.
        • Knight Z.A.
        Sensory detection of food rapidly modulates arcuate feeding circuits.
        Cell. 2015; 160: 829-841
        • Reichenbach A.
        • Clarke R.E.
        • Stark R.
        • Lockie S.H.
        • Mequinion M.
        • Dempsey H.
        • et al.
        Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum.
        eLife. 2022; 11
        • Sinclair E.B.
        • Klump K.L.
        • Sisk C.L.
        Reduced Medial Prefrontal Control of Palatable Food Consumption Is Associated With Binge Eating Proneness in Female Rats.
        Frontiers in behavioral neuroscience. 2019; 13: 252
        • Blasco-Serra A.
        • Gonzalez-Soler E.M.
        • Cervera-Ferri A.
        • Teruel-Marti V.
        • Valverde-Navarro A.A.
        A standardization of the Novelty-Suppressed Feeding Test protocol in rats.
        Neurosci Lett. 2017; 658: 73-78
        • Chen B.T.
        • Yau H.J.
        • Hatch C.
        • Kusumoto-Yoshida I.
        • Cho S.L.
        • Hopf F.W.
        • et al.
        Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking.
        Nature. 2013; 496 (-+): 359
        • Ferenczi E.A.
        • Zalocusky K.A.
        • Liston C.
        • Grosenick L.
        • Warden M.R.
        • Amatya D.
        • et al.
        Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior.
        Science. 2016; 351
        • Jonkman S.
        • Mar A.C.
        • Dickinson A.
        • Robbins T.W.
        • Everitt B.J.
        The Rat Prelimbic Cortex Mediates Inhibitory Response Control But Not the Consolidation of Instrumental Learning.
        Behavioral neuroscience. 2009; 123: 875-885
        • Pfarr S.
        • Meinhardt M.W.
        • Klee M.L.
        • Hansson A.C.
        • Vengeliene V.
        • Schonig K.
        • et al.
        Losing Control: Excessive Alcohol Seeking after Selective Inactivation of Cue-Responsive Neurons in the Infralimbic Cortex.
        Alcohol Alcoholism. 2015; 50
        • Bossert J.M.
        • Stern A.L.
        • Theberge F.R.M.
        • Marchant N.J.
        • Wang H.L.
        • Morales M.
        • et al.
        Role of Projections from Ventral Medial Prefrontal Cortex to Nucleus Accumbens Shell in Context-Induced Reinstatement of Heroin Seeking.
        Journal of Neuroscience. 2012; 32: 4982-4991
        • McFarland K.
        • Davidge S.B.
        • Lapish C.C.
        • Kalivas P.W.
        Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior.
        Journal of Neuroscience. 2004; 24: 1551-1560
      1. Ellinson Z, Foong J, Howard R, Bullmore E, Williams S, Treasure J (1998): Functional anatomy of calorie fear in anorexia nervosa. Lancet. 352:1192-1192.

        • Malvaez M.
        • Shieh C.
        • Murphy M.D.
        • Greenfield V.Y.
        • Wassum K.M.
        Distinct cortical-amygdala projections drive reward value encoding and retrieval.
        Nat Neurosci. 2019; 22: 762-769
        • Stamatakis A.M.
        • Van Swieten M.
        • Basiri M.L.
        • Blair G.A.
        • Kantak P.
        • Stuber G.D.
        Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward.
        Journal of Neuroscience. 2016; 36: 302-311
        • Siemian J.N.
        • Arenivar M.A.
        • Sarsfield S.
        • Aponte Y.
        Hypothalamic control of interoceptive hunger.
        Curr Biol. 2021; 31
        • Berrios J.
        • Li C.
        • Madara J.C.
        • Garfield A.S.
        • Steger J.S.
        • Krashes M.J.
        • et al.
        Food cue regulation of AGRP hunger neurons guides learning.
        Nature. 2021; 595: 695-700
        • Gonzalez J.A.
        • Iordanidou P.
        • Strom M.
        • Adamantidis A.
        • Burdakov D.
        Awake dynamics and brain-wide direct inputs of hypothalamic MCH and orexin networks.
        Nature communications. 2016; 711395
        • Milton L.K.
        • Mirabella P.N.
        • Greaves E.
        • Spanswick D.C.
        • van den Buuse M.
        • Oldfield B.J.
        • et al.
        Suppression of Corticostriatal Circuit Activity Improves Cognitive Flexibility and Prevents Body Weight Loss in Activity-Based Anorexia in Rats.
        Biol Psychiatry. 2021; 90: 819-828