Ultra-sparse Connectivity within the Lateral Hypothalamus

Abstract

The lateral hypothalamic area (LH) is a vital controller of arousal, feeding, and metabolism [1Bernardis L.L. Bellinger L.L. The lateral hypothalamic area revisited: ingestive behavior.Neurosci. Biobehav. Rev. 1996; 20: 189-287Crossref PubMed Scopus (358) Google Scholar, 2Bonnavion P. Mickelsen L.E. Fujita A. de Lecea L. Jackson A.C. Hubs and spokes of the lateral hypothalamus: cell types, circuits and behaviour.J. Physiol. 2016; 594: 6443-6462Crossref PubMed Scopus (116) Google Scholar], which integrates external and internal sensory information. Whereas sensory and whole-body output properties of LH cell populations have received much interest, their intrinsic synaptic organization has remained largely unstudied. Local inhibitory and excitatory connections could help integrate and filter sensory information and mutually inhibitory connections [3Tinbergen N. The Study of Instinct. Clarendon Press, 1951Google Scholar] could allow coordinating activity between LH cell types, some of which have mutually exclusive behavioral effects, such as LH VGLUT2 and VGAT neurons [4Jennings J.H. Rizzi G. Stamatakis A.M. Ung R.L. Stuber G.D. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding.Science. 2013; 341: 1517-1521Crossref PubMed Scopus (314) Google Scholar, 5Jennings J.H. Ung R.L. Resendez S.L. Stamatakis A.M. Taylor J.G. Huang J. Veleta K. Kantak P.A. Aita M. Shilling-Scrivo K. et al.Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors.Cell. 2015; 160: 516-527Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 6Li Y. Zeng J. Zhang J. Yue C. Zhong W. Liu Z. Feng Q. Luo M. Hypothalamic circuits for predation and evasion.Neuron. 2018; 97: 911-924.e5Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 7Stamatakis 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.J. Neurosci. 2016; 36: 302-311Crossref PubMed Scopus (185) Google Scholar] and orexin- (ORX) and melanin-concentrating hormone (MCH) neurons [8Adamantidis A.R. Zhang F. Aravanis A.M. Deisseroth K. de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons.Nature. 2007; 450: 420-424Crossref PubMed Scopus (952) Google Scholar, 9Jego S. Glasgow S.D. Herrera C.G. Ekstrand M. Reed S.J. Boyce R. Friedman J. Burdakov D. Adamantidis A.R. Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.Nat. Neurosci. 2013; 16: 1637-1643Crossref PubMed Scopus (298) Google Scholar, 10Konadhode R.R. Pelluru D. Blanco-Centurion C. Zayachkivsky A. Liu M. Uhde T. Glen Jr., W.B. van den Pol A.N. Mulholland P.J. Shiromani P.J. Optogenetic stimulation of MCH neurons increases sleep.J. 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Studies with optogenetic circuit mapping within the LH have demonstrated only a minority of connections when a large pool of presynaptic neurons was activated [15Apergis-Schoute J. Iordanidou P. Faure C. Jego S. Schöne C. Aitta-Aho T. Adamantidis A. Burdakov D. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits.J. Neurosci. 2015; 35: 5435-5441Crossref PubMed Scopus (90) Google Scholar, 16Ferrari L.L. Park D. Zhu L. Palmer M.R. Broadhurst R.Y. Arrigoni E. Regulation of lateral hypothalamic orexin activity by local GABAergic neurons.J. Neurosci. 2018; 38: 1588-1599Crossref PubMed Scopus (33) Google Scholar, 17Kosse C. Burdakov D. Natural hypothalamic circuit dynamics underlying object memorization.Nat. Commun. 2019; 10: 2505Crossref PubMed Scopus (36) Google Scholar, 18Kosse C. Schöne C. Bracey E. Burdakov D. Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice.Proc. Natl. Acad. Sci. USA. 2017; 114: 4525-4530Crossref PubMed Scopus (49) Google Scholar, 19Bonnavion P. Jackson A.C. Carter M.E. de Lecea L. Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses.Nat. Commun. 2015; 6: 6266Crossref PubMed Scopus (111) Google Scholar]. Because multiple patch clamp has not been used to study LH connectivity, aside from a limited dataset of MCH neurons where no connections were discovered [15Apergis-Schoute J. Iordanidou P. Faure C. Jego S. Schöne C. Aitta-Aho T. Adamantidis A. Burdakov D. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits.J. Neurosci. 2015; 35: 5435-5441Crossref PubMed Scopus (90) Google Scholar], we used quadruple whole-cell recordings to screen connectivity within the LH with standard methodology we previously used in the neocortex [20Jackson J. Karnani M.M. Zemelman B.V. Burdakov D. Lee A.K. Inhibitory control of prefrontal cortex by the claustrum.Neuron. 2018; 99: 1029-1039.e4Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 21Karnani M.M. Jackson J. Ayzenshtat I. Hamzehei Sichani A. Manoocheri K. Kim S. Yuste R. Opening holes in the blanket of inhibition: localized lateral disinhibition by VIP interneurons.J. Neurosci. 2016; 36: 3471-3480Crossref PubMed Scopus (111) Google Scholar, 22Karnani M.M. Jackson J. Ayzenshtat I. Tucciarone J. Manoocheri K. Snider W.G. Yuste R. Cooperative subnetworks of molecularly similar interneurons in mouse neocortex.Neuron. 2016; 90: 86-100Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Finding a lack of local connectivity, we used optogenetic circuit mapping to study the strength of LH optogenetic responses and network oscillations, which were consistent with ultra-sparse intrinsic connectivity within the LH. These results suggest that input from other brain structures is decisive for selecting active populations in the LH.

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