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Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction

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Ramanathan, Karthik R., Jin, Jingji, Giustino, Thomas F., Payne, Martin R., Maren, Stephen·2018·Nature Communications
DOI 10.1038/s41467-018-06970-zPMC PMC6207683
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Abstract

The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Here we show that the RE and its mPFC afferents are critical for the extinction of Pavlovian fear memories in rats. Pharmacological inactivation of the RE during extinction learning or retrieval increases freezing to an extinguished conditioned stimulus (CS); renewal of fear outside the extinction context was unaffected. Suppression of fear in the extinction context is associated with an increase in c-fos expression and spike firing in RE neurons to the extinguished CS. The role for the RE in suppressing extinguished fear requires the mPFC, insofar as pharmacogenetically silencing mPFC to RE projections impairs the expression of extinction memory. These results reveal that mPFC-RE circuits inhibit the expression of fear, a function that is essential for adaptive emotional regulation.

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  • The mPFC appears to suppress expression of erroneous contexts in a top-down manner through a disynaptic pathway through the reuniens nucleus of the thalamus.

    “the mPFC appears to suppress expression of erroneous contexts in a “top-down” manner through a disynaptic pathway through the reuniens nucleus of the thalamus [46].”

    From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [46]

    The Discussion (page unavailable) proposes that mPFC projections through the reuniens nucleus to the hippocampus may suppress retrieval of fear memories in safe contexts. It does not say that the pathway suppresses the expression of erroneous contexts themselves; the proposed mechanism concerns fear-memory retrieval, and the hippocampal route is not established as the mechanism in this study. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The reuniens nucleus of the thalamus coordinates oscillatory synchrony between the mPFC and the vHPC, which is necessary for proper contextual representation of threat memories.

    “The reuniens nucleus of the thalamus coordinates oscillatory synchrony between the mPFC and the vHPC, which is necessary for proper contextual representation of threat memories [46, 53].”

    From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [46]

    The Discussion (page not available) says the reuniens nucleus is important for synchronizing local field potentials in the mPFC–hippocampus circuit and reports that disrupting mPFC inputs to reuniens impairs fear extinction in safe contexts. It does not establish that oscillatory synchrony specifically between mPFC and ventral hippocampus is necessary for contextual representation of threat memories. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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References 44 · Cited by 140

Research works printed but not linked: 37

  1. [1]Rosen JB Schulkin J From normal fear to pathological anxiety Psychol. Rev. 1998 105 325 350 10.1037/0033-295X.105.2.325 9577241 · DOI
  2. [2]Maren S Phan KL Liberzon I The contextual brain: implications for fear conditioning, extinction and psychopathology Nat. Rev. Neurosci. 2013 14 417 428 10.1038/nrn3492 23635870 PMC5072129 · DOI · Paper page
  3. [3]Goode TD Maren S Animal models of fear relapse Ilar. J. 2014 55 246 258 10.1093/ilar/ilu008 25225304 PMC4197897 · DOI
  4. [4]Milad MR Rosenbaum BL Simon NM Neuroscience of fear extinction: implications for assessment and treatment of fear-based and anxiety related disorders Behav. Res. Ther. 2014 62 17 23 10.1016/j.brat.2014.08.006 25204715 · DOI
  5. [6]Maren S Neurobiology of Pavlovian fear conditioning Annu. Rev. Neurosci. 2001 24 897 931 10.1146/annurev.neuro.24.1.897 11520922 · DOI
  6. [7]VanElzakker MB Dahlgren MK Davis FC Dubois S Shin LM From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders Neurobiol. Learn. Mem. 2014 113 3 18 10.1016/j.nlm.2013.11.014 24321650 PMC4156287 · DOI · Paper page
  7. [9]Bouton ME Context and behavioral processes in extinction Learn. Mem. 2004 11 485 494 10.1101/lm.78804 15466298 · DOI · Paper page
  8. [11]Wang Q Jin J Maren S Renewal of extinguished fear activates ventral hippocampal neurons projecting to the prelimbic and infralimbic cortices in rats Neurobiol. Learn. Mem. 2016 134 Pt A 38 43 10.1016/j.nlm.2016.04.002 27060752 PMC5018421 · DOI
  9. [12]Orsini CA Kim JH Knapska E Maren S Hippocampal and prefrontal projections to the basal amygdala mediate contextual regulation of fear after extinction J. Neurosci. 2011 31 17269 17277 10.1523/JNEUROSCI.4095-11.2011 22114293 PMC3241946 · DOI · Paper page
  10. [13]Jin J Maren S Fear renewal preferentially activates ventral hippocampal neurons projecting to both amygdala and prefrontal cortex in rats Sci. Rep. 2015 5 8388 10.1038/srep08388 25669753 PMC4323647 · DOI
  11. [14]Anderson MC Bunce JG Barbas H Prefrontal-hippocampal pathways underlying inhibitory control over memory Neurobiol. Learn. Mem. 2016 134 Pt A 145 161 10.1016/j.nlm.2015.11.008 26642918 PMC5106245 · DOI
  12. [15]McKenna JT Vertes RP Afferent projections to nucleus reuniens of the thalamus J. Comp. Neurol. 2004 480 115 142 10.1002/cne.20342 15514932 · DOI
  13. [16]Vertes RP Hoover WB Szigeti-Buck K Leranth C Nucleus reuniens of the midline thalamus: link between the medial prefrontal cortex and the hippocampus Brain Res. Bull. 2007 71 601 609 10.1016/j.brainresbull.2006.12.002 17292803 PMC4997812 · DOI
  14. [17]Padilla-Coreano N Do-Monte FH Quirk GJ A time-dependent role of midline thalamic nuclei in the retrieval of fear memory Neuropharmacology 2012 62 457 463 10.1016/j.neuropharm.2011.08.037 21903111 PMC3195904 · DOI · Paper page
  15. [18]Do-Monte FH Quiñones-Laracuente K Quirk GJ A temporal shift in the circuits mediating retrieval of fear memory Nature 2015 519 460 463 10.1038/nature14030 25600268 PMC4376623 · DOI · Paper page
  16. [19]Griffin AL Role of the thalamic nucleus reuniens in mediating interactions between the hippocampus and medial prefrontal cortex during spatial working memory Front. Syst. Neurosci. 2015 9 29 10.3389/fnsys.2015.00029 25805977 PMC4354269 · DOI
  17. [21]Layfield DM Patel M Hallock H Griffin AL Inactivation of the nucleus reuniens/rhomboid causes a delay-dependent impairment of spatial working memory Neurobiol. Learn. Mem. 2015 125 163 167 10.1016/j.nlm.2015.09.007 26391450 PMC4648689 · DOI
  18. [22]Hembrook JR Onos KD Mair RG Inactivation of ventral midline thalamus produces selective spatial delayed conditional discrimination impairment in the rat Hippocampus 2012 22 853 860 10.1002/hipo.20945 21542055 · DOI
  19. [23]Hallock HL Wang A Griffin AL Ventral midline thalamus is critical for hippocampal-prefrontal synchrony and spatial working memory J. Neurosci. 2016 36 8372 8389 10.1523/JNEUROSCI.0991-16.2016 27511010 PMC4978800 · DOI
  20. [24]Ito HT Zhang SJ Witter MP Moser EI Moser MB A prefrontal-thalamo-hippocampal circuit for goal-directed spatial navigation Nature 2015 522 50 55 10.1038/nature14396 26017312 · DOI
  21. [25]Xu W Südhof TC A neural circuit for memory specificity and generalization Science 2013 339 1290 1295 10.1126/science.1229534 23493706 PMC3651700 · DOI · Paper page
  22. [26]Vetere G Chemogenetic interrogation of a brain-wide fear memory network in mice Neuron 2017 94 363 374.e4 10.1016/j.neuron.2017.03.037 28426969 · DOI · Paper page
  23. [28]Bouton ME Kenney FA Rosengard C State-dependent fear extinction with two benzodiazepine tranquilizers Behav. Neurosci. 1990 104 44 55 10.1037/0735-7044.104.1.44 2317285 · DOI
  24. [29]Bouton ME García-Gutiérrez A Zilski J Moody EW Extinction in multiple contexts does not necessarily make extinction less vulnerable to relapse Behav. Res. Ther. 2006 44 983 994 10.1016/j.brat.2005.07.007 16198302 · DOI
  25. [30]Cornwall J Phillipson OT Mediodorsal and reticular thalamic nuclei receive collateral axons from prefrontal cortex and laterodorsal tegmental nucleus in the rat Neurosci. Lett. 1988 88 121 126 10.1016/0304-3940(88)90111-5 3380351 · DOI
  26. [32]Linley SB Gallo MM Vertes RP Lesions of the ventral midline thalamus produce deficits in reversal learning and attention on an odor texture set shifting task Brain Res. 2016 1649 110 122 10.1016/j.brainres.2016.08.022 27544424 PMC5796786 · DOI
  27. [33]Davoodi FG Motamedi F Akbari E Ghanbarian E Jila B Effect of reversible inactivation of reuniens nucleus on memory processing in passive avoidance task Behav. Brain Res. 2011 221 1 6 10.1016/j.bbr.2011.02.020 21354215 · DOI
  28. [34]Pereira de Vasconcelos A Cassel JC The nonspecific thalamus: a place in a wedding bed for making memories last? Neurosci. Biobehav. Rev. 2015 54 175 196 10.1016/j.neubiorev.2014.10.021 25451763 · DOI
  29. [35]Cassel JC The reuniens and rhomboid nuclei: neuroanatomy, electrophysiological characteristics and behavioral implications Prog. Neurobiol. 2013 111 34 52 10.1016/j.pneurobio.2013.08.006 24025745 PMC4975011 · DOI
  30. [36]Hobin JA Ji J Maren S Ventral hippocampal muscimol disrupts context-specific fear memory retrieval after extinction in rats Hippocampus 2006 16 174 182 10.1002/hipo.20144 16358312 · DOI
  31. [37]Zimmerman EC Grace AA The nucleus reuniens of the midline thalamus gates prefrontal-hippocampal modulation of ventral tegmental area dopamine neuron activity J. Neurosci. 2016 36 8977 8984 10.1523/JNEUROSCI.1402-16.2016 27559178 PMC4995308 · DOI
  32. [39]Roy A Svensson FP Mazeh A Kocsis B Prefrontal-hippocampal coupling by theta rhythm and by 2-5 Hz oscillation in the delta band: The role of the nucleus reuniens of the thalamus Brain Struct. Funct. 2017 222 2819 2830 10.1007/s00429-017-1374-6 28210848 PMC5542875 · DOI · Paper page
  33. [40]Adhikari A Topiwala MA Gordon JA Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety Neuron 2010 65 257 269 10.1016/j.neuron.2009.12.002 20152131 PMC2822726 · DOI · Paper page
  34. [41]Bukalo O Pinard CR Holmes A Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders Br. J. Pharmacol. 2014 171 4690 4718 10.1111/bph.12779 24835117 PMC4209938 · DOI
  35. [42]Milad MR Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert Biol. Psychiatry 2007 62 446 454 10.1016/j.biopsych.2006.10.011 17217927 · DOI · Paper page
  36. [43]Vertes RP Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat Neuroscience 2006 142 1 20 10.1016/j.neuroscience.2006.06.027 16887277 · DOI
  37. [44]Swanson, L. R. Brain maps 4.0—structure of the rat brain: an open access atlas with global nervous system nomenclature ontology and flatmaps. J. Comp. Neurol. 526, 935–943 (2017). PMC5851017 29277900

Authors
Ramanathan, K. R., Jin, J., Giustino, T. F., Payne, M. R., & Maren, S.
Affiliations
Texas A&M University (US)
Corresponding author
Maren, Stephen
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-10-30
Volume
9
Issue
1
Pages
4527-4527
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-06970-z
PMC
PMC6207683
OpenAlex
W2898444937
Cited by
140
References
44
Citations by year
2026: 8 · 2025: 22 · 2024: 26 · 2023: 20 · 2022: 13 · 2021: 24 · 2020: 18 · 2019: 8 · 2018: 1
FWCI
7.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (F31MH112208, R01MH117852, R01MH065961)
  • McKnight Foundation (Memory and Cognitive Disorders Award)
  • Brain and Behavior Research Foundation (Distinguished Investigator Grant)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
medial prefrontal cortex, fear extinction, fear renewal, Fos expression, neuronal firing, emotion regulation
MeSH terms
Afferent Pathways, Animals, Behavior, Animal, Conditioning, Classical, Extinction, Psychological, Fear, Learning, Male, Memory, Muscimol, Neurons, Proto-Oncogene Proteins c-fos, Prefrontal Cortex, Rats, Long-Evans, Midline Thalamic Nuclei, Freezing Reaction, Cataleptic, Rats, GABA-A Receptor Agonists

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