The mammalian central circadian clock integrates timing cues to synchronize physiological and behavioral functions


DA metab SCN pathways

Biological processes ranging from gene transcription to behavior oscillate and are synchronized to the 24-hour day/night cycle. Mammalian circadian rhythms, orchestrated by the hypothalamic suprachiasmatic nucleus (SCN) allow appropriately timed physiological and behavioral responses to daily recurring external cues (i.e. sunrise or timed meal availability). The resulting synchrony of physiology to the astronomical day maximizes metabolic efficiency and good health. However, many of the stresses of modern society (i.e. artificial lighting and omnipresence of food) weaken and desynchronize circadian rhythms. This in turn increases the prevalence of many pathologies including metabolic disorders (i.e. obesity, type 2 diabetes and cardiovascular diseases), neurodegenerative diseases (i.e. Alzheimer’s and Parkinson’s) and many types of cancer. The aim of my laboratory is to determine how circadian rhythms are synchronized (entrained) to external cues and how desynchronization impacts health. Although the neuronal pathways of light-driven entrainment are well-established, how other external cues, such as food availability, social interactions or exercise, influence the workings of the SCN remains unknown. In a recent breakthrough, we identified a neuronal connection between midbrain dopaminergic neurons that are activated in response to salient rewarding events and SCN neurons that express the dopamine receptor. We showed that this pathway accelerates entrainment and drives snacking. In parallel, we identified a novel molecular player that is necessary for anticipation of time-restricted food access. Now, we are leveraging our expertise in disentangling circadian entrainment neurocircuitry to determine whether strengthening circadian rhythmicity ameliorates symptoms of metabolic disorders or Alzheimer’s disease. Our work is aimed at understanding the relationship between entrainment cues, physiology and behavior while providing tangible strategies against the adverse consequences of circadian misalignment.

Dopamine Signaling in the Suprachiasmatic Nucleus Enables Weight Gain Associated with Hedonic Feeding. Grippo RM, Tang Q, Zhang Q, Chadwick SR, Gao Y, Altherr EB, Sipe L, Purohit AM, Purohit NM, Sunkara MD, Cios KJ, Sidikpramana M, Spano AJ, Campbell JN, Steele AD, Hirsh J, Deppmann CD, Wu M, Scott MM, Güler AD. Current Biology. 2020 Apr 6;30(7):1352-1355. doi: 10.1016/j.cub.2020.03.034. PMID: 32259494

The p75 neurotrophin receptor in AgRP neurons is necessary for homeostatic feeding and food anticipation. Podyma B, Johnson DA, Sipe L, Remcho TP, Battin K, Liu Y, Yoon SO, Deppmann CD, Güler AD. Elife. 2020 Jan 29;9:e52623. doi: 10.7554/eLife.52623.PMID: 31995032

Direct Midbrain Dopamine Input to the Suprachiasmatic Nucleus Accelerates Circadian Entrainment. Grippo RM, Purohit AM, Zhang Q, Zweifel LS, Güler AD. Current Biology. 2017 Aug 21;27(16):2465-2475.e3. doi: 10.1016/j.cub.2017.06.084. Epub 2017 Aug 3.PMID: 28781050

Palatability Can Drive Feeding Independent of AgRP Neurons. Denis RG, Joly-Amado A, Webber E, Langlet F, Schaeffer M, Padilla SL, Cansell C, Dehouck B, Castel J, Delbès AS, Martinez S, Lacombe A, Rouch C, Kassis N, Fehrentz JA, Martinez J, Verdié P, Hnasko TS, Palmiter RD, Krashes MJ, Güler AD, Magnan C, Luquet S. Cell Metabolism. 2015 Oct 6;22(4):646-57. doi: 10.1016/j.cmet.2015.07.011. Epub 2015 Aug 13.PMID: 26278050

Transient activation of specific neurons in mice by selective expression of the capsaicin receptor. Güler AD, Rainwater A, Parker JG, Jones GL, Argilli E, Arenkiel BR, Ehlers MD, Bonci A, Zweifel LS, Palmiter RD. Nature Communications. 2012 Mar 20;3:746. doi: 10.1038/ncomms1749.PMID: 22434189

Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Güler AD, Ecker JL, Lall GS, Haq S, Altimus CM, Liao HW, Barnard AR, Cahill H, Badea TC, Zhao H, Hankins MW, Berson DM, Lucas RJ, Yau KW, Hattar S. Nature. 2008 May 1;453(7191):102-5. doi: 10.1038/nature06829. Epub 2008 Apr 23.PMID: 18432195