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Dissecting the hypothalamic pathways that underlie innate behaviors

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Abstract

Many complex behaviors that do not require learning are displayed and are termed innate. Although traditionally the subject matter of ethology, innate behaviors offer a unique entry point for neuroscientists to dissect the physiological mechanisms governing complex behaviors. Since the last century, converging evidence has implicated the hypothalamus as the central brain area that controls innate behaviors. Recent studies using cutting-edge tools have revealed that genetically-defined populations of neurons residing in distinct hypothalamic nuclei and their associated neural pathways regulate the initiation and maintenance of diverse behaviors including feeding, sleep, aggression, and parental care. Here, we review the newly-defined hypothalamic pathways that regulate each innate behavior. In addition, emerging general principles of the neural control of complex behaviors are discussed.

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References

  1. Alcock J. Animal behavior: An evolutionary approach. Sinauer Associates, 1993.

    Google Scholar 

  2. Tinbergen N. The study of instinct. London and New York: Oxford University Press, 1951.

    Google Scholar 

  3. Akert K. Walter Rudolf Hess (1881-1973) and His Contribution to Neuroscience. J Hist Neurosci 1999, 8: 248–263.

    Article  CAS  PubMed  Google Scholar 

  4. Altman J, Bayer SA. Development of the rat hypothalamus. Springer-Verlag, 1986.

    Google Scholar 

  5. Saper CB, Lowell BB. The hypothalamus. Curr Biol 2014, 24: R1111–R1116.

    Article  CAS  PubMed  Google Scholar 

  6. Baumann CR, Bassetti CL, Scammell TE. Narcolepsy: Pathophysiology, Diagnosis, and Treatment. Springer Science & Business Media, 2011.

    Google Scholar 

  7. Nakai J, Ohkura M, Imoto K. A highly signal-to-noise Ca(2+) probe composed of a single green flurorescent protein. Nat Biotechnol 2001, 19: 137–41.

    Article  CAS  PubMed  Google Scholar 

  8. St-Pierre F, Marshall JD, Yang Y, Gong Y, Schnitzer MJ, Lin MZ. High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor. Nat Neurosci 2014, 17: 884–889.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Palmiter RD, Behringer RR, Quaife CJ, Maxwell F, Maxwell IH, Brinster RL. Cell lineage ablation in transgenic mice by cell-specific expression of a toxin gene. Cell 1987, 50: 435–443.

    Article  CAS  PubMed  Google Scholar 

  10. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 2005, 8: 1263–1268.

    Article  CAS  PubMed  Google Scholar 

  11. Buch T, Heppner FL, Tertilt C, Heinen TJAJ, Kremer M, Wunderlich FT, et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat Methods 2005, 2: 419–426.

    Article  CAS  PubMed  Google Scholar 

  12. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. Evolving the lock to fit the key to create a family of G proteincoupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A 2007, 104: 5163–5168.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Lerchner W, Xiao C, Nashmi R, Slimko EM, van Trigt L, Lester HA, et al. Reversible silencing of neuronal excitability in behaving mice by a genetically targeted, ivermectin-gated Cl-channel. Neuron 2007, 54: 35–49.

    Article  CAS  PubMed  Google Scholar 

  14. Airan RD, Thompson KR, Fenno LE, Bernstein H, Deisseroth K. Temporally precise in vivo control of intracellular signalling. Nature 2009, 458: 1025–1029.

    Article  CAS  PubMed  Google Scholar 

  15. Gradinaru V, Zhang F, Ramakrishnan C, Mattis J, Prakash R, Diester I, et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 2010, 141: 154–165.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Magnus CJ, Lee PH, Atasoy D, Su HH, Looger LL, Sternson SM. Chemical and Genetic Engineering of Selective Ion Channel–Ligand Interactions. Science 2011, 333: 1292–1296.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Yang CF, Chiang MC, Gray DC, Prabhakaran M, Alvarado M, Juntti SA, et al. Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 2013, 153: 896–909.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Dittgen T, Nimmerjahn A, Komai S, Licznerski P, Waters J, Margrie TW, et al. Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo. Proc Natl Acad Sci U S A 2004, 101: 18206–18211.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Fields RL, Ponzio TA, Kawasaki M, Gainer H. Cell-type specific oxytocin gene expression from AAV delivered promoter deletion constructs into the rat supraoptic Nucleus in vivo. PLoS One 2012, 7: e32085.

    Article  CAS  Google Scholar 

  20. Sauer B, Henderson N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A 1988, 85: 5166–5170.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Schlake T, Bode J. Use of mutated FLP recognition target (FRT) sites for the exchange of expression cassettes at defined chromosomal loci. Biochemistry 1994, 33: 12746–12751.

    Article  CAS  PubMed  Google Scholar 

  22. Callaway EM. Transneuronal circuit tracing with neurotropic viruses. Curr Opin Neurobiol 2008, 18: 617–623.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Soudais C, Laplace-Builhe C, Kissa K, Kremer EJ. Preferential transduction of neurons by canine adenovirus vectors and their efficient retrograde transport in vivo. FASEB J 2001, 15: 2283–2285.

    CAS  PubMed  Google Scholar 

  24. Bak IJ, Markham CH, Cook ML, Stevens JG. Intraaxonal transport of Herpes simplex virus in the rat central nervous system. Brain Res 1977, 136: 415–429.

    Article  CAS  PubMed  Google Scholar 

  25. Norgren RB, Jr., Lehman MN. Herpes simplex virus as a transneuronal tracer. Neurosci Biobehav Rev 1998, 22: 695–708.

    Article  PubMed  Google Scholar 

  26. Jennings JH, Ung RL, Resendez SL, Stamatakis AM, Taylor JG, Huang J, et al. Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 2015, 160: 516–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nieh EH, Matthews GA, Allsop SA, Presbrey KN, Leppla CA, Wichmann R, et al. Decoding neural circuits that control compulsive sucrose seeking. Cell 2015, 160: 528–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 2014, 507: 238–242.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Betley JN, Cao ZF, Ritola KD, Sternson SM. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 2013, 155: 1337–1350.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Atasoy D, Betley JN, Su HH, Sternson SM. Deconstruction of a neural circuit for hunger. Nature 2012, 488: 172–177.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Wickersham IR, Lyon DC, Barnard RJO, Mori T, Finke S, Conzelmann K-K, et al. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 2007, 53: 639–647.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Sternson SM, Nicholas Betley J, Cao ZF. Neural circuits and motivational processes for hunger. Curr Opin Neurobiol 2013, 23: 353–360.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Sternson SM. Hypothalamic survival circuits: blueprints for purposive behaviors. Neuron 2013, 77: 810–824.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. de Lecea L, Carter ME, Adamantidis A. Shining light on wakefulness and arousal. Biol Psychiatry 2012, 71: 1046–1052.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron 2010, 68: 1023–1042.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Anderson DJ. Optogenetics, sex, and violence in the brain: implications for psychiatry. Biol Psychiatry 2012, 71: 1081–1089.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Dulac C, O’Connell LA, Wu Z. Neural control of maternal and paternal behaviors. Science 2014, 345: 765–770.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. de Lecea L. Optogenetic Control of Hypocretin (Orexin) Neurons and Arousal Circuits. Curr Top Behav Neurosci 2014.

    Google Scholar 

  39. Falkner AL, Lin D. Recent advances in understanding the role of the hypothalamic circuit during aggression. Front Syst Neurosci 2014, 8.

    Google Scholar 

  40. Kennedy A, Asahina K, Hoopfer E, Inagaki H, Jung Y, Lee H, et al. Internal states and behavioral decision-making: toward an integration of emotion and cognition. Cold Spring Harb Symp Quant Biol 2014, 79: 199–210.

    Article  PubMed  Google Scholar 

  41. Mohr B. Neuropathology Communication from Dr. Mohr, Privat Docent in Würzburg. Obesity Res 1993, 1: 334–335.

    Article  CAS  Google Scholar 

  42. Hetherington A, Ranson S. Hypothalamic lesions and adiposity in the rat. Anat Rec 1940, 78: 149–172.

    Article  Google Scholar 

  43. Brobeck JR, Tepperman J, Long C. Experimental hypothalamic hyperphagia in the albino rat. Yale J Biol Med 1943, 15: 831.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Anand BK, Brobeck JR. Hypothalamic control of food intake in rats and cats. Yale J Biol Med 1951, 24: 123.

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Brobeck JR. Mechanism of the development of obesity in animals with hypothalamic lesions. Physiol Rev 1946, 26: 541–559.

    CAS  PubMed  Google Scholar 

  46. Winn P. The physiology of motivation by Eliot Stellar. Brain Res Bull 1999, 50: 451–452.

    Article  CAS  PubMed  Google Scholar 

  47. Horvath TL, Diano S. The floating blueprint of hypothalamic feeding circuits. Nat Rev Neurosci 2004, 5: 662–667.

    Article  CAS  PubMed  Google Scholar 

  48. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997, 278: 135–138.

    Article  CAS  PubMed  Google Scholar 

  49. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997, 88: 131–141.

    Article  CAS  PubMed  Google Scholar 

  50. 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: 683–685.

    Article  CAS  PubMed  Google Scholar 

  51. Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 2011, 14: 351–355.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Investig 2011, 121: 1424.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Krashes MJ, Shah BP, Koda S, Lowell BB. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab 2013, 18: 588–595.

    Article  CAS  PubMed  Google Scholar 

  54. Sternson SM, Atasoy D. Agouti-related protein neuron circuits that regulate appetite. Neuroendocrinology 2014, 100: 95–102.

    Article  CAS  PubMed  Google Scholar 

  55. Chen Y, Lin YC, Kuo TW, Knight ZA. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 2015, 160: 829–841.

    Article  CAS  PubMed  Google Scholar 

  56. Betley JN, Xu S, Cao ZFH, Gong R, Magnus CJ, Yu Y, et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 2015.

    Google Scholar 

  57. King BM. The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol Behav 2006, 87: 221–244.

    Article  CAS  PubMed  Google Scholar 

  58. Jennings JH, Rizzi G, Stamatakis AM, Ung RL, Stuber GD. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 2013, 341: 1517–1521.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Garfield AS, Li C, Madara JC, Shah BP, Webber E, Steger JS, et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 2015, 18: 863–871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wu Q, Boyle MP, Palmiter RD. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to Starvation. Cell 2009, 137: 1225–1234.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Carter ME, Soden ME, Zweifel LS, Palmiter RD. Genetic identification of a neural circuit that suppresses appetite. Nature 2013, 503: 111–114.

    Article  CAS  PubMed  Google Scholar 

  63. Wu Q, Clark MS, Palmiter RD. Deciphering a neuronal circuit that mediates appetite. Nature 2012, 483: 594–597.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. von ECONOMO C. Some new methods of studing the brains of exceptional persons (Encephalometry and Brain Casts). J Nerv Ment Dis 1930, 71: 300–302.

    Article  Google Scholar 

  65. Nauta WJ. Hypothalamic regulation of sleep in rats; an experimental study. J Neurophysiol 1946, 9: 285–316.

    CAS  PubMed  Google Scholar 

  66. Sherin J, Shiromani P, McCarley R, Saper C. Activation of ventrolateral preoptic neurons during sleep. Science 1996, 271: 216–219.

    Article  CAS  PubMed  Google Scholar 

  67. Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB. Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep. J Neurosci 2002, 22: 4568–4576.

    CAS  PubMed  Google Scholar 

  68. Lu J, Greco MA, Shiromani P, Saper CB. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J Neurosci 2000, 20: 3830–3842.

    CAS  PubMed  Google Scholar 

  69. Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 1998, 18: 4705–4721.

    CAS  PubMed  Google Scholar 

  70. Gallopin T, Fort P, Eggermann E, Cauli B, Luppi P-H, Rossier J, et al. Identification of sleep-promoting neurons in vitro. Nature 2000, 404: 992–995.

    Article  CAS  PubMed  Google Scholar 

  71. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001, 24: 726–731.

    Article  CAS  PubMed  Google Scholar 

  72. Szymusiak R, Alam N, Steininger TL, McGinty D. Sleep–waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res 1998, 803: 178–188.

    Article  CAS  PubMed  Google Scholar 

  73. Takahashi K, Lin JS, Sakai K. Characterization and mapping of sleep–waking specific neurons in the basal forebrain and preoptic hypothalamus in mice. Neuroscience 2009, 161: 269–292.

    Article  CAS  PubMed  Google Scholar 

  74. Modirrousta M, Mainville L, Jones B. Gabaergic neurons with a2-adrenergic receptors in basal forebrain and preoptic area express c-Fos during sleep. Neuroscience 2004, 129: 803–810.

    Article  CAS  PubMed  Google Scholar 

  75. de Lecea L, Kilduff T, Peyron C, Gao X-B, Foye P, Danielson P, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998, 95: 322–327.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92: 573–585.

    Article  CAS  PubMed  Google Scholar 

  77. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K. Distribution of orexin neurons in the adult rat brain. Brain Res 1999, 827: 243–260.

    Article  CAS  PubMed  Google Scholar 

  78. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999, 98: 365–376.

    Article  CAS  PubMed  Google Scholar 

  79. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999, 98: 437–451.

    Article  CAS  PubMed  Google Scholar 

  80. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000, 355: 39–40.

    Article  CAS  PubMed  Google Scholar 

  81. Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 2005, 46: 787–798.

    Article  CAS  PubMed  Google Scholar 

  82. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007, 450: 420–424.

    Article  CAS  PubMed  Google Scholar 

  83. Rolls A, Colas D, Adamantidis A, Carter M, Lanre-Amos T, Heller HC, et al. Optogenetic disruption of sleep continuity impairs memory consolidation. Proc Natl Acad Sci U S A 2011, 108: 13305–13310.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Tsunematsu T, Kilduff TS, Boyden ES, Takahashi S, Tominaga M, Yamanaka A. Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. J Neurosci 2011, 31: 10529–10539.

    Article  CAS  PubMed  Google Scholar 

  85. Tsunematsu T, Tabuchi S, Tanaka KF, Boyden ES, Tominaga M, Yamanaka A. Long-lasting silencing of orexin/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice. Behav Brain Res 2013, 255: 64–74.

    Article  CAS  PubMed  Google Scholar 

  86. Sasaki K, Suzuki M, Mieda M, Tsujino N, Roth B, Sakurai T. Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice. PLoS One 2011, 6: e20360.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  88. Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 2001, 98: 9965–9970.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Carter ME, Brill J, Bonnavion P, Huguenard JR, Huerta R, de Lecea L. Mechanism for hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci U S A 2012, 109: e2635–2644.

    Article  Google Scholar 

  90. Carter ME, Yizhar O, Chikahisa S, Nguyen H, Adamantidis A, Nishino S, et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci 2010, 13: 1526–1533.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Blanco-Centurion C, Gerashchenko D, Shiromani PJ. Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake. J Neurosci 2007, 27: 14041–14048.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001, 30: 345–354.

    Article  CAS  PubMed  Google Scholar 

  93. Sorooshyari S, Huerta R, de Lecea L. A framework for quantitative modeling of neural circuits involved in sleep-towake transition. Front Neurol 2015, 6: 32.

    Article  PubMed Central  PubMed  Google Scholar 

  94. Kosse C, Burdakov D. A unifying computational framework for stability and flexibility of arousal. Front Syst Neurosci 2014, 8: 192.

    Article  PubMed Central  PubMed  Google Scholar 

  95. Alexandre C, Andermann ML, Scammell TE. Control of arousal by the orexin neurons. Curr Opin Neurobiol 2013, 23: 752–759.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Tsujino N, Sakurai T. Role of orexin in modulating arousal, feeding, and motivation. Front Behav Neurosci 2013, 7: 28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Sakurai T. The role of orexin in motivated behaviours. Nat Rev Neurosci 2014, 15: 719–731.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996, 380: 243–247.

    Article  CAS  PubMed  Google Scholar 

  100. Adamantidis A, de Lecea L. Sleep and metabolism: shared circuits, new connections. Trends Endocrinol Metab 2008, 19: 362–370.

    Article  CAS  PubMed  Google Scholar 

  101. Apergis-Schoute J, Iordanidou P, Faure C, Jego S, Schone C, Aitta-Aho T, et al. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J Neurosci 2015, 35: 5435–5441.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Konadhode RR, Pelluru D, Shiromani PJ. Neurons containing orexin or melanin concentrating hormone reciprocally regulate wake and sleep. Front Syst Neurosci 2014, 8: 244.

    PubMed Central  PubMed  Google Scholar 

  103. Tsunematsu T, Ueno T, Tabuchi S, Inutsuka A, Tanaka KF, Hasuwa H, et al. Optogenetic manipulation of activity and temporally controlled cell-specific ablation reveal a role for MCH neurons in sleep/wake regulation. J Neurosci 2014, 34: 6896–6909.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Konadhode RR, Pelluru D, Blanco-Centurion C, Zayachkivsky A, Liu M, Uhde T, et al. Optogenetic stimulation of MCH neurons increases sleep. J Neurosci 2013, 33: 10257–10263.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Jego S, Glasgow SD, Herrera CG, Ekstrand M, Reed SJ, Boyce R, et al. Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nat Neurosci 2013, 16: 1637–1643.

    Article  CAS  PubMed  Google Scholar 

  106. Irmak SO, de Lecea L. Basal forebrain cholinergic modulation of sleep transitions. Sleep 2014, 37: 1941–1951.

    PubMed  Google Scholar 

  107. van Dort CJ, Zachs DP, Kenny JD, Zheng S, Goldblum RR, Gelwan NA, et al. Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc Natl Acad Sci U S A 2015, 112: 584–589.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  108. Williams RH, Chee MJ, Kroeger D, Ferrari LL, Maratos-Flier E, Scammell TE, et al. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J Neurosci 2014, 34: 6023–6029.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  109. Scott JP. Agonistic behavior of mice and rats: a review. Am Zool 1966, 6: 683–701.

    Article  CAS  PubMed  Google Scholar 

  110. Blanchard DC, Blanchard RJ. Ethoexperimental approaches to the biology of emotion. Annu Rev Psychol 1988, 39: 43–68.

    Article  CAS  PubMed  Google Scholar 

  111. Bard P. A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system. Am J Physiol 1928.

    Google Scholar 

  112. Bard P. On emotional expression after decortication with some remarks on certain theoretical views: Part I. Psychol Revi 1934, 41: 309.

    Article  Google Scholar 

  113. Putkonen PT. Attack elicited by forebrain and hypothalamic stimulation in the chicken. Experientia 1966, 22: 405–407.

    Article  CAS  PubMed  Google Scholar 

  114. Kruk MR, van der Poel AM, de Vos-Frerichs TP. The induction of aggressive behaviour by electrical stimulation in the hypothalamus of male rats. Behaviour 1979, 70: 292–322.

    Article  CAS  PubMed  Google Scholar 

  115. Lipp HP, Hunsperger RW. Threat, attack and flight elicited by electrical stimulation of the ventromedial hypothalamus of the marmoset monkey Callithrix jacchus. Brain Behav Evol 1978, 15: 260–293.

    Article  CAS  PubMed  Google Scholar 

  116. Bejjani BP, Houeto JL, Hariz M, Yelnik J, Mesnage V, Bonnet AM, et al. Aggressive behavior induced by intraoperative stimulation in the triangle of Sano. Neurology 2002, 59: 1425–1427.

    Article  CAS  PubMed  Google Scholar 

  117. Haller J. The neurobiology of abnormal manifestations of aggression—a review of hypothalamic mechanisms in cats, rodents, and humans. Brain Res Bull 2013, 93: 97–109.

    Article  CAS  PubMed  Google Scholar 

  118. Kruk MR, van der Poel AM, Meelis W, Hermans J, Mostert PG, Mos J, et al. Discriminant analysis of the localization of aggression-inducing electrode placements in the hypothalamus of male rats. Brain Res 1983, 260: 61–79.

    Article  CAS  PubMed  Google Scholar 

  119. Kruk MR. Hypothalamic attack: a wonderful artifact or a useful perspective on escalation and pathology in aggression? A viewpoint. Curr Top Behav Neurosci 2014, 17: 143–188.

    Article  PubMed  Google Scholar 

  120. Falkner AL, Dollar P, Perona P, Anderson DJ, Lin D. Decoding ventromedial hypothalamic neural activity during male mouse aggression. J Neurosci 2014, 34: 5971–5984.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Lin D, Boyle MP, Dollar P, Lee H, Lein ES, Perona P, et al. Functional identification of an aggression locus in the mouse hypothalamus. Nature 2011, 470: 221–226.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Lee H, Kim DW, Remedios R, Anthony TE, Chang A, Madisen L, et al. Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus. Nature 2014, 509: 627–632.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Sano K, Tsuda MC, Musatov S, Sakamoto T, Ogawa S. Differential effects of site-specific knockdown of estrogen receptor alpha in the medial amygdala, medial pre-optic area, and ventromedial nucleus of the hypothalamus on sexual and aggressive behavior of male mice. Eur J Neurosci 2013, 37: 1308–1319.

    Article  PubMed  Google Scholar 

  124. Yang CF, Shah NM. Representing sex in the brain, one module at a time. Neuron 2014, 82: 261–278.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Newman SW. The medial extended amygdala in male reproductive behavior. A node in the mammalian social behavior network. Ann N Y Acad Sci 1999, 877: 242–257.

    Article  CAS  PubMed  Google Scholar 

  126. Swanson LW. Cerebral hemisphere regulation of motivated behavior. Brain Res 2000, 886: 113–164.

    Article  CAS  PubMed  Google Scholar 

  127. Wu Z, Autry AE, Bergan JF, Watabe-Uchida M, Dulac CG. Galanin neurons in the medial preoptic area govern parental behaviour. Nature 2014, 509: 325–330.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Canteras NS, Simerly RB, Swanson LW. Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat. J Comp Neurol 1995, 360: 213–245.

    Article  CAS  PubMed  Google Scholar 

  129. Silva BA, Mattucci C, Krzywkowski P, Murana E, Illarionova A, Grinevich V, et al. Independent hypothalamic circuits for social and predator fear. Nat Neurosci 2013, 16: 1731–1733.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Martinez RC, Carvalho-Netto EF, Amaral VC, Nunes-de- Souza RL, Canteras NS. Investigation of the hypothalamic defensive system in the mouse. Behav Brain Res 2008, 192: 185–190.

    Article  PubMed  Google Scholar 

  131. Choi GB, Dong HW, Murphy AJ, Valenzuela DM, Yancopoulos GD, Swanson LW, et al. Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus. Neuron 2005, 46: 647–660.

    Article  CAS  PubMed  Google Scholar 

  132. Canteras NS, Simerly RB, Swanson LW. Connections of the posterior nucleus of the amygdala. J Comp Neurol 1992, 324: 143–179.

    Article  CAS  PubMed  Google Scholar 

  133. Wang L, Chen IZ, Lin D. Collateral pathways from the ventromedial hypothalamus mediate defensive behaviors. Neuron 2015, 85: 1344–1358.

    Article  CAS  PubMed  Google Scholar 

  134. Kunwar PS, Zelikowsky M, Remedios R, Cai H, Yilmaz M, Meister M, et al. Ventromedial hypothalamic neurons control a defensive emotion state. Elife 2015, 4.

    Google Scholar 

  135. Hong W, Kim DW, Anderson DJ. Antagonistic control of social versus repetitive self-grooming behaviors by separable amygdala neuronal subsets. Cell 2014, 158: 1348–1361.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Unger EK, Burke KJ, Yang CF, Bender KJ, Fuller PM, Shah NM. Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep 2015, 10: 453–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Numan M, Insel TR. The neurobiology of parental behavior. New York: Springer, 2003.

    Google Scholar 

  138. Champagne FA, Meaney MJ. Transgenerational effects of social environment on variations in maternal care and behavioral response to novelty. Behav Neurosci 2007, 121: 1353–1363.

    Article  PubMed  Google Scholar 

  139. Neuwald MF, Agranonik M, Portella AK, Fleming A, Wazana A, Steiner M, et al. Transgenerational effects of maternal care interact with fetal growth and influence attention skills at 18 months of age. Early Hum Dev 2014, 90: 241–246.

    Article  PubMed  Google Scholar 

  140. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004, 7: 847–854.

    Article  CAS  PubMed  Google Scholar 

  141. Kuroda KO, Tachikawa K, Yoshida S, Tsuneoka Y, Numan M. Neuromolecular basis of parental behavior in laboratory mice and rats: with special emphasis on technical issues of using mouse genetics. Prog Neuropsychopharmacol Biol Psychiatry 2011, 35: 1205–1231.

    Article  CAS  PubMed  Google Scholar 

  142. Rosenblatt JS. Nonhormonal basis of maternal behavior in the rat. Science 1967, 156: 1512–1514.

    Article  CAS  PubMed  Google Scholar 

  143. Siegel HI, Rosenblatt JS. Estrogen-induced maternal behavior in hysterectomized-overiectomized virgin rats. Physiol Behav 1975, 14: 465–471.

    Article  CAS  PubMed  Google Scholar 

  144. vom Saal FS. Time-contingent change in infanticide and parental behavior induced by ejaculation in male mice. Physiol Behav 1985, 34: 7–15.

    Article  Google Scholar 

  145. Numan M, Numan MJ. Expression of Fos-like immunoreactivity in the preoptic area of maternally behaving virgin and postpartum rats. Behav Neurosci 1994, 108: 379–394.

    Article  CAS  PubMed  Google Scholar 

  146. Numan M, Numan MJ. Importance of pup-related sensory inputs and maternal performance for the expression of Foslike immunoreactivity in the preoptic area and ventral bed nucleus of the stria terminalis of postpartum rats. Behav Neurosci 1995, 109: 135–149.

    Article  CAS  PubMed  Google Scholar 

  147. Kalinichev M, Rosenblatt JS, Nakabeppu Y, Morrell JI. Induction of c-fos-like and fosB-like immunoreactivity reveals forebrain neuronal populations involved differentially in pupmediated maternal behavior in juvenile and adult rats. J Comp Neurol 2000, 416: 45–78.

    Article  CAS  PubMed  Google Scholar 

  148. Tsuneoka Y, Maruyama T, Yoshida S, Nishimori K, Kato T, Numan M, et al. Functional, anatomical, and neurochemical differentiation of medial preoptic area subregions in relation to maternal behavior in the mouse. J Comp Neurol 2013, 521: 1633–1663.

    Article  CAS  PubMed  Google Scholar 

  149. Numan M. Medial preoptic area and maternal behavior in the female rat. J Comp Physiol Psychol 1974, 87: 746–759.

    Article  CAS  PubMed  Google Scholar 

  150. Numan M, Corodimas KP, Numan MJ, Factor EM, Piers WD. Axon-sparing lesions of the preoptic region and substantia innominata disrupt maternal behavior in rats. Behav Neurosci 1988, 102: 381–396.

    Article  CAS  PubMed  Google Scholar 

  151. Slawski BA, Buntin JD. Preoptic area lesions disrupt prolactin-induced parental feeding behavior in ring doves. Horm Behav 1995, 29: 248–266.

    Article  CAS  PubMed  Google Scholar 

  152. Perrin G, Meurisse M, Levy F. Inactivation of the medial preoptic area or the bed nucleus of the stria terminalis differentially disrupts maternal behavior in sheep. Horm Behav 2007, 52: 461–473.

    Article  CAS  PubMed  Google Scholar 

  153. Numan M, Rosenblatt JS, Komisaruk BR. Medial preoptic area and onset of maternal behavior in the rat. J Comp Physiol Psychol 1977, 91: 146–164.

    Article  CAS  PubMed  Google Scholar 

  154. Bridges RS, Ronsheim PM. Prolactin (PRL) regulation of maternal behavior in rats: bromocriptine treatment delays and PRL promotes the rapid onset of behavior. Endocrinology 1990, 126: 837–848.

    Article  CAS  PubMed  Google Scholar 

  155. Bridges RS, Numan M, Ronsheim PM, Mann PE, Lupini CE. Central prolactin infusions stimulate maternal behavior in steroid-treated, nulliparous female rats. Proc Natl Acad Sci U S A 1990, 87: 8003–8007.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  156. Risold PY, Canteras NS, Swanson LW. Organization of projections from the anterior hypothalamic nucleus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J Comp Neurol 1994, 348: 1–40.

    Article  CAS  PubMed  Google Scholar 

  157. Canteras NS, Simerly RB, Swanson LW. Organization of projections from the ventromedial nucleus of the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J Comp Neurol 1994, 348: 41–79.

    Article  CAS  PubMed  Google Scholar 

  158. Simerly RB, Swanson LW. Projections of the medial preoptic nucleus: a Phaseolus vulgaris leucoagglutinin anterograde tract-tracing study in the rat. J Comp Neurol 1988, 270: 209–242.

    Article  CAS  PubMed  Google Scholar 

  159. Sheehan T, Paul M, Amaral E, Numan MJ, Numan M. Evidence that the medial amygdala projects to the anterior/ventromedial hypothalamic nuclei to inhibit maternal behavior in rats. Neuroscience 2001, 106: 341–356.

    Article  CAS  PubMed  Google Scholar 

  160. Tachikawa KS, Yoshihara Y, Kuroda KO. Behavioral transition from attack to parenting in male mice: a crucial role of the vomeronasal system. J Neurosci 2013, 33: 5120–5126.

    Article  CAS  PubMed  Google Scholar 

  161. Fahrbach SE, Morrell JI, Pfaff DW. Identification of medial preoptic neurons that concentrate estradiol and project to the midbrain in the rat. J Comp Neurol 1986, 247: 364–382.

    Article  CAS  PubMed  Google Scholar 

  162. Champagne FA, Chretien P, Stevenson CW, Zhang TY, Gratton A, Meaney MJ. Variations in nucleus accumbens dopamine associated with individual differences in maternal behavior in the rat. J Neurosci 2004, 24: 4113–4123.

    Article  CAS  PubMed  Google Scholar 

  163. Afonso VM, Grella SL, Chatterjee D, Fleming AS. Previous maternal experience affects accumbal dopaminergic responses to pup-stimuli. Brain Res 2008, 1198: 115–123.

    Article  CAS  PubMed  Google Scholar 

  164. Afonso VM, King S, Chatterjee D, Fleming AS. Hormones that increase maternal responsiveness affect accumbal dopaminergic responses to pup- and food-stimuli in the female rat. Horm Behav 2009, 56: 11–23.

    Article  CAS  PubMed  Google Scholar 

  165. Afonso VM, Shams WM, Jin D, Fleming AS. Distal pup cues evoke dopamine responses in hormonally primed rats in the absence of pup experience or ongoing maternal behavior. J Neurosci 2013, 33: 2305–2312.

    Article  CAS  PubMed  Google Scholar 

  166. Gaffori O, Le Moal M. Disruption of maternal behavior and appearance of cannibalism after ventral mesencephalic tegmentum lesions. Physiol Behav 1979, 23: 317–323.

    Article  CAS  PubMed  Google Scholar 

  167. Numan M, Smith HG. Maternal behavior in rats: evidence for the involvement of preoptic projections to the ventral tegmental area. Behav Neurosci 1984, 98: 712–727.

    Article  CAS  PubMed  Google Scholar 

  168. Numan M, Stolzenberg DS, Dellevigne AA, Correnti CM, Numan MJ. Temporary inactivation of ventral tegmental area neurons with either muscimol or baclofen reversibly disrupts maternal behavior in rats through different underlying mechanisms. Behav Neurosci 2009, 123: 740–751.

    Article  CAS  PubMed  Google Scholar 

  169. Keer SE, Stern JM. Dopamine receptor blockade in the nucleus accumbens inhibits maternal retrieval and licking, but enhances nursing behavior in lactating rats. Physiol Behav 1999, 67: 659–669.

    Article  CAS  PubMed  Google Scholar 

  170. Madisen L, Garner AR, Shimaoka D, Chuong AS, Klapoetke NC, Li L, et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 2015, 85: 942–958.

    Article  CAS  PubMed  Google Scholar 

  171. Fenno LE, Mattis J, Ramakrishnan C, Hyun M, Lee SY, He M, et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat Methods 2014, 11: 763–772.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  172. Xiu J, Zhang Q, Zhou T, Zhou TT, Chen Y, Hu H. Visualizing an emotional valence map in the limbic forebrain by TAIFISH. Nat Neurosci 2014, 17: 1552–1559.

    Article  CAS  PubMed  Google Scholar 

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Zha, X., Xu, X. Dissecting the hypothalamic pathways that underlie innate behaviors. Neurosci. Bull. 31, 629–648 (2015). https://doi.org/10.1007/s12264-015-1564-2

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