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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

Unlocking the complexity and immense interconnectedness of the central nervous system which dictates the properties and processes of the behavioral mechanisms underlying active responding to a threat is a major goal of the Sears Lab. To this end, we use Signaled Active Avoidance (SAA) behavioral paradigm in which animals can learn to perform an action to avoid imminent threats. We find that the amygdala, a brain area important for passive reactions, i.e. freezing is also important for active responding to threats. We also find that brain regions and neural circuits important for SAA may overlap with those required for seeking food, sex, drugs, etc. For example, we recently found that interactions between  the amygdala and the nucleus accumbens are important for SAA. We have also found the orexin system plays an integral role in motivating SAA behavior. We seek to acquire a detailed understanding of the neural circuits and the molecular and cellular mechanisms of coping, both passive and active. The ultimate goal of our work is to lay the groundwork to develop better therapies for individuals suffering from stress and anxiety-related disorders. Have a look at some of our 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.

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Novel tools to study the Neural Circuitry of Signaled Active Avoidance (SAA)

 We are currently running SAA experiments in combination with chemogenetics and optogenetic tools we have developed to investigate the organization and functionality of the diverse parts of our experimental model.

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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.

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Contact us for more information about what’s going on in the lab.

 

Recent Work

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. Proceedings of the National Academy of Sciences of the United States of America. 2013;

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.

 

People

Scientific Minds

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Rob Sears, PhD

Principle Investigator

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Cristina Siller-Perez, PhD

Post-Doc

 

Lab Alumni

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Shanna Samels, BA

Research Assistant

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Chicora Oliver, PhD

Post-Doc

 
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CV

Full curriculum vitae

 

Contact Us

140 Old Orangeburg Rd, Orangeburg, NY 10962

845-398-6633

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