Welcome
Our research aims to understand the concepts and mechanisms which underly the complexities of fear and anxiety disorders. We use advanced research techniques and technologies to explore the brain molecules, cells, and circuits that underlie responses to threat in health and disease. Our research is generously supported by funding from NIH and a number of foundations.
Research
The Sears Lab investigates how the central nervous system orchestrates behavioral responses to threat. Our primary approach is Signaled Active Avoidance (SAA), a paradigm in which animals learn to perform a specific action to avoid an impending threat.
Our work shows that the amygdala, long associated with passive defensive responses like freezing, also contributes to active threat responding. We’ve further found that the circuits supporting SAA overlap substantially with those governing reward-seeking behaviors. For instance, we identified amygdala–nucleus accumbens interactions as critical for SAA, as are striatal regions, and found that the orexin system plays a key role in motivating this behavior.
Our overall goal is to characterize the neural circuits and neuromodulatory mechanisms underlying adaptive versus maladaptive threat coping, building a foundation for improved therapies for stress- and anxiety-related disorders.
Explore our current projects below.
Precise examination to unravel the role of the Orexin System in Proactive Coping Behaviors
We still have only a very limited understanding of most aspects of how different brain regions are connected and communicate with each other. Answering questions about this is essential for understanding the mechanistic role they play in fear and anxiety disorders, and for developing tools to further explore this research avenue with more sensitive measurements and improved data collection. Specifically, we are examining how the orexin system controls processes that may underlie fear and anxiety disorders in humans. We are currently using advanced molecular, chemogenetic, optogenetic and behavioral techniques to characterize the orexin system’s role in coping with threats. We propose that the molecular-genetic and neural activity of orexin neurons underlie individual differences in coping behaviors.
Novel tools to study the Neural Circuitry of Signaled Active Avoidance (SAA)
We are currently running SAA experiments in combination with cell-spicific photometic, chemogenetic and optogenetic tools we have developed to investigate the organization and functionality of the diverse parts of our experimental model.
Cover Story on Molecular Psychiatry March, 2020
Virally-targeted hemagglutinin-tagged (HA) hM3Dq receptors (red) are restricted to dopamine β hydroxylase (DBH)-expressing neurons (green) in locus coeruleus of the rat brain. Lower panels are magnified images of a single neuron from the upper panels. From left to right: HA, DBH, and merged (yellow). For more information, see the article by Gu et al. on pages 640-654.
Contact us for more information about what’s going on in the lab!
Recent Work
Reducing shock imminence eliminates poor avoidance in rats. Lindsay C Laughlin, Danielle M Moloney, Shanna B Samels, Robert M Sears, Christopher K Cain. Learn Mem. 2020 Jun 15;27(7):270-274. doi: 10.1101/lm.051557.120. PMID: 32540916; PMCID: PMC7301752.
A brainstem-central amygdala circuit underlies defensive responses to learned threats. Gu Y, Piper WT, Branigan LA, Vazey EM, Aston-Jones G, Lin L, LeDoux JE, Sears RM Mol Psychiatry. 2020 Mar;25(3):640-654. doi: 10.1038/s41380-019-0599-6. Epub 2019 Nov 22. PubMed PMID: 31758092; PubMed Central PMCID: PMC7042728.
Noradrenergic Regulation of Central Amygdala in Aversive Pavlovian-to-Instrumental Transfer. Campese VD, Soroeta JM, Vazey EM, Aston-Jones G, LeDoux JE, Sears RM.2017 Sep-Oct;4(5). eNeuro. doi: 10.1523/ENEURO.0224-17.2017. eCollection 2017 Sep-Oct. PubMed PMID: 29071299; PubMed Central PMCID: PMC5654237.
Primary auditory cortex regulates threat memory specificity. Wigestrand MB, Schiff HC, Fyhn M, LeDoux JE, Sears RM. Learn Mem. 2017 Jan;24(1):55-58. doi: 10.1101/lm.044362.116. Print 2017 Jan. PubMed PMID: 27980076; PubMed Central PMCID: PMC5159661.
β-Adrenergic Receptors Regulate the Acquisition and Consolidation Phases of Aversive Memory Formation Through Distinct, Temporally Regulated Signaling Pathways. Schiff HC, Johansen JP, Hou M, Bush DE, Smith EK, Klein JE, LeDoux JE, Sears RM. Neuropsychopharmacology. 2017 Mar;42(4):895-903. doi: 10.1038/npp.2016.238. Epub 2016 Oct 20. PubMed PMID: 27762270; PubMed Central PMCID: PMC5312069.
Active avoidance requires a serial basal amygdala to nucleus accumbens shell circuit. Ramirez F, Moscarello JM, LeDoux JE, Sears RM. J Neurosci. 2015 Feb 25;35(8):3470-7. doi: 10.1523/JNEUROSCI.1331-14.2015. PubMed PMID: 25716846; PubMed Central PMCID: PMC4339356.
Other Relevant Publications
Axon TRAP reveals learning-associated alterations in cortical axonal mRNAs in the lateral amgydala. Ostroff LE, Santini E, Sears R, Deane Z, Kanadia RN, LeDoux JE, Lhakhang T, Tsirigos A, Heguy A, Klann E. Elife. 2019 Dec 11;8. doi: 10.7554/eLife.51607. PubMed PMID: 31825308; PubMed Central PMCID: PMC6924958.
A principled method to identify individual differences and behavioral shifts in signaled active avoidance. Krypotos AM, Moscarello JM, Sears RM, LeDoux JE, Galatzer-Levy I. Learn Mem. 2018 Nov;25(11):564-568. doi: 10.1101/lm.047399.118. Print 2018 Nov. PubMed PMID: 30322888; PubMed Central PMCID: PMC6191017.
Characterization of the amplificatory effect of norepinephrine in the acquisition of Pavlovian threat associations. Díaz-Mataix L, Piper WT, Schiff HC, Roberts CH, Campese VD, Sears RM, LeDoux JE. Learn Mem. 2017 Sep;24(9):432-439. doi: 10.1101/lm.044412.116. Print 2017 Sep. PubMed PMID: 28814469; PubMed Central PMCID: PMC5580522.
The birth, death, and resurrection of avoidance: a reconceptualization of a troubled paradigm. LeDoux JE, Moscarello J, Sears R, Campese V. Mol Psychiatry. 2017 Jan;22(1):24-36. doi: 10.1038/mp.2016.166. Epub 2016 Oct 18. Review. PubMed PMID: 27752080; PubMed Central PMCID: PMC5173426.
Stimulation-induced transient changes in neuronal activity, blood flow and N-acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS-BOLD study. Baslow MH, Cain CK, Sears R, Wilson DA, Bachman A, Gerum S, Guilfoyle DN. NMR Biomed. 2016 Dec;29(12):1678-1687. doi: 10.1002/nbm.3629. Epub 2016 Oct 3. PubMed PMID: 27696530; PubMed Central PMCID: PMC5123928.
The Neural Foundations of Reaction and Action in Aversive Motivation. Campese VD, Sears RM, Moscarello JM, Diaz-Mataix L, Cain CK, LeDoux JE. Curr Top Behav Neurosci. 2016;27:171-95. doi: 10.1007/7854_2015_401. Review. PubMed PMID: 26643998.
Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity. Anastasio NC, Stutz SJ, Fink LH, Swinford-Jackson SE, Sears RM, DiLeone RJ, Rice KC, Moeller FG, Cunningham KA. ACS Chem Neurosci. 2015 Jul 15;6(7):1248-58. doi: 10.1021/acschemneuro.5b00094. Epub 2015 Jul 7. PubMed PMID: 26120876; PubMed Central PMCID: PMC4811199.
Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. Anastasio NC, Stutz SJ, Fox RG, Sears RM, Emeson RB, DiLeone RJ, O'Neil RT, Fink LH, Li D, Green TA, Moeller FG, Cunningham KA. Neuropsychopharmacology. 2014 Jan;39(2):370-82. doi: 10.1038/npp.2013.199. Epub 2013 Aug 13. PubMed PMID: 23939424; PubMed Central PMCID: PMC3970795.
Molecular mechanisms of threat learning in the lateral nucleus of the amygdala. Sears RM, Schiff HC, LeDoux JE. Prog Mol Biol Transl Sci. 2014;122:263-304. doi: 10.1016/B978-0-12-420170-5.00010-6. Review. PubMed PMID: 24484705.
Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Sears RM, Fink AE, Wigestrand MB, Farb CR, de Lecea L, Ledoux JE. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20260-5. doi: 10.1073/pnas.1320325110. Epub 2013 Nov 25. PubMed PMID: 24277819; PubMed Central PMCID: PMC3864341.
Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex. Martinez RC, Gupta N, Lázaro-Muñoz G, Sears RM, Kim S, Moscarello JM, LeDoux JE, Cain CK. Learn Mem. 2013 Jul 18;20(8):446-52. doi: 10.1101/lm.031047.113. PubMed PMID: 23869027; PubMed Central PMCID: PMC3718200.
The orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Sears RM, Fink AE, Wigestrand MB, Farb CR, deLecea L, LeDoux JE.Proc Natl Acad Sci USA. 2013 Dec 10;110(50):20260-5. PMID: 24277819; PMCID: PMC3864341.
Erk1/2 mediates leptin receptor signaling in the ventral tegmental area. Trinko R, Gan G, Gao XB, Sears RM, Guarnieri DJ, DiLeone RJ. PLoS One. 2011;6(11):e27180. doi: 10.1371/journal.pone.0027180. Epub 2011 Nov 4. PubMed PMID: 22076135; PubMed Central PMCID: PMC3208604.
Chronic loss of melanin-concentrating hormone affects motivational aspects of feeding in the rat. Mul JD, la Fleur SE, Toonen PW, Afrasiab-Middelman A, Binnekade R, Schetters D, Verheij MM, Sears RM, Homberg JR, Schoffelmeer AN, Adan RA, DiLeone RJ, De Vries TJ, Cuppen E. PLoS One. 2011 May 5;6(5):e19600. doi: 10.1371/journal.pone.0019600. PubMed PMID: 21573180; PubMed Central PMCID: PMC3088702.
Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone. Sears RM, Liu RJ, Narayanan NS, Sharf R, Yeckel MF, Laubach M, Aghajanian GK, DiLeone RJ. J Neurosci. 2010 Jun 16;30(24):8263-73. doi: 10.1523/JNEUROSCI.5858-09.2010. PubMed PMID: 20554878; PubMed Central PMCID: PMC2907886.
Neural mechanisms underlying obesity and drug addiction. Trinko R, Sears RM, Guarnieri DJ, DiLeone RJ. Physiol Behav. 2007 Aug 15;91(5):499-505. doi: 10.1016/j.physbeh.2007.01.001. Epub 2007 Jan 16. Review. PubMed PMID: 17292426.
Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M, DiLeone RJ. Neuron. 2006 Sep 21;51(6):801-10. doi: 10.1016/j.neuron.2006.08.023. PubMed PMID: 16982424.
The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolaños CA, Marsh DJ, Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ. J Neurosci. 2005 Mar 16;25(11):2933-40. doi: 10.1523/JNEUROSCI.1714-04.2005. PubMed PMID: 15772353; PubMed Central PMCID: PMC6725126.
Local gene knockdown in the brain using viral-mediated RNA interference. Hommel JD, Sears RM, Georgescu D, Simmons DL, DiLeone RJ. Nat Med. 2003 Dec;9(12):1539-44. doi: 10.1038/nm964. Epub 2003 Nov 23. PubMed PMID: 14634645.
Current Lab Members
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Rob Sears, PhD
Principle Investigator
Cristina Siller-Perez, PhD
Post-Doc
​
I study the role of the orexin peptides in learned safety. I am interested in dissecting the neuromodulatory dynamics of orexin in active avoidance using fiber photometry and optogenetics. Looking forward to what we discover next in the lab!
Outside the lab, I enjoy reading, photography, and sciency embroidery.
Mason Hochstetler, PhD
Post-Doc
​
I study the role of norepinephrine in active avoidance behavior, using a circuit-focused chemogenetic approach. I'm interested in how neural circuits communicate to drive and shape behavior. Always curious to see where the data takes us.
Outside the lab, I enjoy gaming, photography and board games.
Lab Alumni
Research Assistant
Shanna Samels, BA
PhD Student in the Espana Lab, Drexel Universty
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