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Sex differences in activation of extra-hypothalamic forebrain areas during hedonic eating

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Abstract

Palatable foods can stimulate appetite without hunger, and unconstrained overeating underlies obesity and binge eating disorder. Women are more prone to obesity and binge eating than men but the neural causes of individual differences are unknown. In an animal model of hedonic eating, a prior study found that females were more susceptible than males to eat palatable food when sated and that the neuropeptide orexin/hypocretin (ORX) was crucial in both sexes. The current study examined potential extra-hypothalamic forebrain targets of ORX signaling during hedonic eating. We measured Fos induction in the cortical, thalamic, striatal, and amygdalar areas that receive substantial ORX inputs and contain their receptors in hungry and sated male and female rats during palatable (high-sucrose) food consumption. During the test, hungry rats of both sexes ate substantial amounts, and while sated males ate much less than hungry rats, sated females ate as much as hungry rats. The Fos induction analysis identified sex differences in recruitment of specific areas of the medial prefrontal cortex, paraventricular nucleus of the thalamus (PVT), nucleus accumbens (ACB), and central nucleus of the amygdala (CEA), and similar patterns across sexes in the insular cortex. There was a striking activation of the infralimbic cortex in sated males, who consumed the least amount food and unique correlations between the insular cortex, PVT, and CEA, as well as the prelimbic cortex, ACB, and CEA in sated females but not sated males. The study identified key functional circuits that may drive hedonic eating in a sex-specific manner.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  • Baldo BA, Daniel RA, Berridge CW, Kelley AE (2003) Overlaping distribution of orexin/hypocretin- and dopamine-β-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464:220–237

    Article  PubMed  Google Scholar 

  • Barson JR, Leibowitz SF (2015) GABA-induced activation of dorsal midline thalamic subregions has distinct effects on emotional behaviors. Neurosci Lett 609:92–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baumgartner HM, Schulkin J, Berridge KC (2021) Activating corticotropin-releasing factor systems in the nucleus accumbens, amygdala, and bed nucleus of stria terminalis: Incentive motivation or aversive motivation? Biol Psychiatry 89:1162–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boughter JD Jr, Fletcher M (2021) Rethinking the role of taste processing in insular cortex and forebrain circuits. Curr Opin Physio 20:52–56

    Article  Google Scholar 

  • Buczek L, Migliaccio J, Petrovich GD (2020) Hedonic eating: sex differences and characterization of orexin activation and signaling. Neuroscience 436:34–45

    Article  CAS  PubMed  Google Scholar 

  • Cai H, Haubensak W, Anthony TE, Anderson DJ (2014) Central amygdala PKC-δ+ neurons mediate the influence of multiple anorexigenic signals. Nat Neurosci 17(17):1240–1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Capuzzo G, Floresco SB (2020) Prelimbic and infralimbic prefrontal regulation of active and inhibitory avoidance and reward-seeking. J Neurosci 40:4773–4787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carr KD (2011) Food scarcity, neuroadaptations, and the pathogenic potential of dieting in an unnatural ecology: binge eating and drug abuse. Physiol Behav 104:162–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castro DC, Terry RA, Berridge KC (2016) Orexin in rostral hotspot of nucleus accumbens enhances sucrose ‘liking’ and intake but scopolamine in caudal shell shifts ‘liking’ toward ‘disgust’ and ‘fear.’ Neuropsychopharmacology 41:2101–2111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi DL, Davis JF, Fitzerald ME, Benoit SC (2010) The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats. Neuroscience 167:11–20

    Article  CAS  PubMed  Google Scholar 

  • Choi DL, Davis JF, Magrisso IJ, Fitzerald ME, Lipton JW, Benoit SC (2012) Orexin signaling in the paraventricular thalamic nucleus modulates mesolimbic dopamine and hedonic feeding in the rat. Neuroscience 210:243–248

    Article  CAS  PubMed  Google Scholar 

  • Christoffel DJ, Walsh JJ, Heifets BD, Hoerbelt P, Neuner S, Sun G, Ravikumar VK, Wu H, Halpern CH, Malenka RC (2021) Input-specific modulation of murine nucleus accumbens differentially regulates hedonic feeding. Nature Comunications 12:2135

    CAS  Google Scholar 

  • Cole S, Hobin MP, Petrovich GD (2015a) Appetitive associative learning recruits a distinct network with cortical, striatal, and hypothalamic regions. Neuroscience 286:187–202

    Article  CAS  PubMed  Google Scholar 

  • Cole S, Mayer HS, Petrovich GD (2015b) Orexin/hypocretin-1 receptor antagonism selectively reduces cue-induced feeding in sated rats and recruits medial prefrontal cortex and thalamus. Sci Rep 5:16143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cole S, Keefer SE, Anderson LC, Petrovich GD (2020) Medial prefrontal cortex neural plasticity, orexin receptor 1 signaling, and connectivity with the lateral hypothalamus are necessary in cue-potentiated feeding. J Neurosci 40:1744–1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327

    Article  PubMed  PubMed Central  Google Scholar 

  • Dong X, Li S, Kirouac GJ (2017) Collateralization of projections from the paraventricular nucleus of the thalamus to the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain Struct Funct 222:3927–3943

    Article  PubMed  Google Scholar 

  • Douglass AM, Kucukdereli H, Ponserre M, Markovic M, Gründemann J, Strobel C, Morales PLA, Conzelmann KK, Lüthi A, Klein R (2017) Central amygdala circuits modulate food consumption through a positive-valence mechanism. Nat Neurosci 20:1384–1394

    Article  CAS  PubMed  Google Scholar 

  • Gao C, Leng Y, Ma J, Rooke V, Rodriguez-Gonzalez S, Ramakrishnan C, Deisseroth K, Penzo MA (2020) Two genetically, anatomically and functionally distinct cell types segregate across anteroposterior axis of paraventricular thalamus. Nat Neurosci 23:217–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giacomini JL, Sadeghian K, Baldo BA (2022) Eating driven by the gustatory insula: contrasting regulation by infralimbic vs. prelimbic cortices. Neuropsychopharmacology 47:1358–1366

    Article  CAS  PubMed  Google Scholar 

  • Hardaway JA, Halladay LR, Mazzone CM, Pati D, Bloodgood DW, Kim M, Jensen J, DiBerto J, Boyt KM, Shiddapur A, Erfani A, Hon OJ, Neira S, Stanhope CM, Sugam JA, Saddoris MP, Tipton G, McElligott Z, Jhou TC, Stuber GD, Bruchas MR, Bulik CM, Holmes A, Kash TL (2019) Central amygdala prepronociceptin-expressing neurons mediate palatable food consumption and reward. Neuron 102:1037–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hartogsveld B, Quaedflieg CWEM, van Ruitenbeek P, Smeets T (2022) Volume and connectivity differences in brain networks associated with cognitive constructs of binge eating. eNeuro 9:1–31

    Article  Google Scholar 

  • Hudson JI, Hiripi E, Harrison GP, Kessler RC (2007) The prevalence and correlates of eating disorders in the national comorbidity survey replication. Biol Psychiatry 61:348–358

    Article  PubMed  Google Scholar 

  • Kelley AE (2004) Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci Biobehav Rev 27:765–776

    Article  PubMed  Google Scholar 

  • Labouèbe G, Boutrel B, Tarussio D, Thorens B (2016) Glucose-responsive neurons of the paraventricular thalamus control sucrose-seeking behavior. Nat Neurosci 8:999–1002

    Article  Google Scholar 

  • Lee EY, Lee HS (2016) Dual projections of single orexin-or CART-immunoreactive, lateral hypothalamic neurons to the paraventricular thalamic nucleus and nucleus accumbens shell in the rat: Light microscopic study. Brain Res 1634:104–118

    Article  CAS  PubMed  Google Scholar 

  • Li S, Kirouac GJ (2012) Sources of inputs to the anterior and posterior aspects of the paraventricular nucleus of the thalamus. Brain Struct Funct 217:257–273

    Article  PubMed  Google Scholar 

  • Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17:1298–1303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maldonado-Irizarry CS, Swanson CJ, Kelley AE (1995) Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus. J Neurosci 15:6779–6788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25

    Article  CAS  PubMed  Google Scholar 

  • Mitchell S, Shaw D (2015) The worldwide epidemic of female obesity. Best Pract Res Clin Obstet Gynaecol 29:289–299

    Article  PubMed  Google Scholar 

  • Peciña S, Schulkin J, Berridge KC (2006) Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress? BMC Biol 4:8

    Article  PubMed  PubMed Central  Google Scholar 

  • Petrovich GD (2018) Feeding behavior survival circuit: anticipation & competition. Curr Opin Behav Sci 24:137–142

    Article  PubMed  PubMed Central  Google Scholar 

  • Petrovich GD (2019) Orexins and control of feeding by learned cues. In: Fadel JR, Burk JA (eds) The orexins/hypocretins system: functional roles and therapeutic potential, 1st edn. Academic Press, pp 85–98

    Chapter  Google Scholar 

  • Petrovich GD (2021) The function of paraventricular thalamic circuitry in the adaptive control of feeding behavior. Front Behav Neurosci 15:671096

    Article  PubMed  PubMed Central  Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raynolds SM, Berridge KC (2008) Emotional environments retune the valence of appetitive versus fearful functions in nucleus accumbens. Nat Neurosci 11:423–425

    Article  Google Scholar 

  • Reppucci CJ, Petrovich GD (2012) Learned food-cue stimulates persistent feeding in sated rats. Appetite 59:437–447

    Article  PubMed  PubMed Central  Google Scholar 

  • Reppucci CJ, Petrovich GD (2016) Organization of connections between the amygdala, medial prefrontal cortex, and lateral hypothalamus: a single and double retrograde tracing study in rats. Brain Struct Funct 221:2937–2962

    Article  PubMed  Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JRS, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    Article  CAS  PubMed  Google Scholar 

  • Small DM (2009) Individual differences in the neurophysiology of reward and the obesity epidemic. Int J Obes 33:S44–S48

    Article  Google Scholar 

  • Stratford TR, Kelley AE (1997) GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior. J Neurosci 17:4434–4440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun X, Kroemer NB, Veldhuizen M, Babbs AE, de Araujo IE, Gitelman DR, Sherwin RS, Sinha R, Small DM (2015) Basolateral amygdala response to food cues in the absence of hunger is associated with weight gain susceptibility. J Neurosci 35:7964–7976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swanson LW (2018) Brain maps 4.0—Structure of the rat brain: an open access atlas with global nervous system nomenclature ontology and flatmaps. J Comp Neurol 526:935–943

    Article  PubMed  PubMed Central  Google Scholar 

  • Terrill SJ, Subramanian KS, Lan R, Liu CM, Cortella AM, Noble E, Kanoski SE (2020) Nucleus accumbens melanin-concentrating hormone signaling promotes feeding in a sex-specific manner. Neuropharmacology 178:108270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thorpe AJ, Kotz CM (2005) Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res 1050:156–162

    Article  CAS  PubMed  Google Scholar 

  • Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438:71–75

    Article  CAS  PubMed  Google Scholar 

  • Zahm DS, Brog JS (1992) On the significance of subterritories in the “accumbens” part of the rat ventral striatum. Neuroscience 50:751–767

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Kelley AE (2000) Enhanced intake of high-fat food following striatal mu-opioid stimulation: microinjection mapping and Fos expression. Neuroscience 99:267–277

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health, NIDDK grant R01DK085721 to GDP. We thank Dr. Ehri Ryu for helpful advice regarding statistical analyses.

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Authors and Affiliations

  1. Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA, 02467, USA

    William Parsons, Eliza Greiner, Laura Buczek, Jennifer Migliaccio, Erin Corbett, Amanda M. K. Madden & Gorica D. Petrovich

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  1. William Parsons
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  2. Eliza Greiner
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  3. Laura Buczek
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  4. Jennifer Migliaccio
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  5. Erin Corbett
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  6. Amanda M. K. Madden
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  7. Gorica D. Petrovich
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Contributions

GDP conceptualized the study and supervised the experiments and directed the data analysis. GDP, LB and JM designed the experiments. LB and JM carried out the experiment. WP, EG, LB, JM, EC, AMKM conducted the histological preparation and analyses. WP and EG prepared the figures. WP and GDP wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Gorica D. Petrovich.

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Parsons, W., Greiner, E., Buczek, L. et al. Sex differences in activation of extra-hypothalamic forebrain areas during hedonic eating. Brain Struct Funct 227, 2857–2878 (2022). https://doi.org/10.1007/s00429-022-02580-0

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  • DOI: https://doi.org/10.1007/s00429-022-02580-0

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