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Molecularly Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Retrieval

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Hallock, Henry L., Quillian, Henry M., Maynard, Kristen R., Mai, Yishan, Chen, Huei-Ying, Hamersky, Gregory R., Shin, Joo Heon, Maher, Brady J. +2 more·2020·Biological Psychiatry
DOI 10.1016/j.biopsych.2020.04.014PMC PMC7487039

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Abstract

Background Context fear memory dysregulation is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder and posttraumatic stress disorder. The hippocampus (HC) and prelimbic (PrL) subregion of the medial prefrontal cortex have been linked with context fear memory retrieval in rodents, but the mechanisms by which HC-PrL circuitry regulates this process remain poorly understood. Methods Spatial and genetic targeting of HC-PrL circuitry was used for RNA sequencing (n = 31), chemogenetic stimulation (n = 44), in vivo calcium imaging (n = 20), ex vivo electrophysiology (n = 8), and molecular regulation of plasticity cascades during fear behavior (context fear retrieval) (n = 16). Results We showed that ventral HC (vHC) neurons with projections to the PrL cortex (vHC-PrL projectors) are a transcriptomically distinct subpopulation compared with adjacent nonprojecting neurons, and we showed complementary enrichment for diverse neuronal processes and central nervous system-related clinical gene sets. We further showed that stimulation of this population of vHC-PrL projectors suppresses context fear memory retrieval and impairs the ability of PrL neurons to dynamically distinguish between distinct phases of fear learning. Using transgenic and circuit-specific molecular targeting approaches, we demonstrated that unique patterns of activity-dependent gene transcription associated with brain-derived neurotrophic factor signaling within vHC-PrL projectors causally regulated activity in excitatory and inhibitory PrL neurons during context fear memory retrieval. Conclusions Together, our data show that activity-dependent brain-derived neurotrophic factor release from molecularly distinct vHC-PrL projection neurons modulates postsynaptic signaling in both inhibitory and excitatory PrL neurons, modifying activity in discrete populations of PrL neurons to suppress freezing during context fear memory retrieval.

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  • Reversible inactivation of the dorsal hippocampus interferes with context-specific information of a threat memory.

    “Reversible inactivation of the dorsal hippocampus, through either pharmacologic or chemogenetic means, interferes with context-specific information of a threat memory [40, 41].”

    From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [41]

    The Discussion (page unavailable) says the ventral hippocampus is necessary for context fear retrieval and discusses ventral hippocampal inactivation. It does not establish that reversible inactivation of the dorsal hippocampus interferes with context-specific threat-memory information; the paper’s own manipulation activates ventral hippocampal inputs to the prelimbic cortex. (LLM, conf=0.78)

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Research works printed but not linked: 44

  1. [1]Greenberg T, Carlson JM, Cha J, Hajcak G & Mujica-Parodi LR Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization. Depress. Anxiety 30, 242– 250 (2013). 23139148
  2. [2]Zubieta JK, Chinitz JA, Lombardi U, Fig LM, Cameron OG, & Liberzon I. Medial frontal cortex involvement in PTSD symptoms: a SPECT study. J. Psychiatr. Res. 33, 259– 264 (1999). 10367992
  3. [3]Lanius Ruth A., Frewen Paul A., Vermetten E, & Yehuda R. Fear conditioning and early life vulnerabilities: Two distinct pathways of emotional dysregulation and brain dysfunction in PTSD. Eur. J. Psychotraum, 1: 5467 (2010). PMC3401986 22893793
  4. [4]Parsons RG & Ressler KJ Implications of memory modulation for post-traumatic stress and fear disorders. Nat. Neurosci. 16, 146– 153 (2013). 23354388 PMC3752300
  5. [5]Liberzon I, & Abelson JL Context processing and the neurobiology of post-traumatic stress disorder. Neuron, 92, 14– 30 (2016). 27710783 PMC5113735
  6. [6]Maren S, Phan KL, & Liberzon I. The contextual brain: Implications for fear conditioning, extinction and psychopathology. Nat. Rev. Neurosci, 14, 417– 428 (2013). 23635870 PMC5072129
  7. [7]Corcoran KA & Quirk GJ Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J. Neurosci. 27, 840– 844 (2007). 17251424 PMC6672908
  8. [9]Marek R, Xu L, Sullivan RKP & Sah P. Excitatory connections between the prelimbic and infralimbic medial prefrontal cortex show a role for the prelimbic cortex in fear extinction. Nat. Neurosci. 21, 654– 658 (2018). 29686260
  9. [10]Giza JI, Kim J, Meyer HC, Anastasia A, Dincheva I, Zheng CI, The BDNF val66met prodomain disassembles dendritic spines altering fear extinction circuitry and behavior. Neuron 99, 163– 178. e6 (2018). 29909994 PMC6054457
  10. [11]Hobin JA, Ji J & Maren S. Ventral hippocampal muscimol disrupts context-specific fear memory retrieval after extinction in rats. Hippocampus 16, 174– 182 (2006). 16358312
  11. [12]Aster RS, St. Germain SA, Tolin D, Ford J, Russell D, & Stevens M. Hippocampus function predicts severity of post-traumatic stress disorder. CyberPsych. & Behav, 9: 234– 240 (2006) 16640486
  12. [13]Hayes JP, LaBar KS, McCarthy G, Selgrade E, Nasser J, Dolcos F, Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD. J. Psych. Res, 45: 660– 669 (2011). PMC3081889 21047644
  13. [14]Swanson LW A direct projection from Ammon’s horn to prefrontal cortex in the rat. Brain Res. 217, 150– 154 (1981). 7260612
  14. [15]Jay TM, Burette F & Laroche S. Plasticity of the hippocampal-prefrontal cortex synapses. J Physiol Paris 90, 361– 366 (1996). 9089514
  15. [16]Rouillard AD, Gundersen GW, Fernandez NF, Wang Z, Monteiro CD, McDermott MG, The harmonizome: A collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database, doi: 10.1093/database/baw100. PMC4930834 27374120 · DOI · Paper page
  16. [17]Peters J, Dieppa-Perea LM, Melendez LM, & Quirk GJ Induction of fear extinction with hippocampal-infralimbic BDNF. Science, 39, 2161– 2169 (2010). PMC3570764 20522777
  17. [18]Rosas-Vidal LE, Do-Monte FH, Sotres-Bayon F & Quirk GJ Hippocampal--prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology 39, 2161– 2169 (2014). 24625752 PMC4104333
  18. [19]Hixson KM, Cogswell M, Brooks-Kayal AR & Russek SJ Transcriptomic analysis of the BDNF- induced JAK/STAT pathway in neurons: a window into epilepsy-associated gene expression. BioRxiv (2019). doi: 10.1101/577627 · DOI
  19. [20]Maynard KR, Hill JL, Calcaterra NE, Palko ME, Kardian A, Paredes D, Functional role of bdnf production from unique promoters in aggression and serotonin signaling. Neuropsychopharmacology 41, 1943– 1955 (2016). 26585288 PMC4908631
  20. [21]Hill JL, Hardy NF, Jimenez DV, Maynard KR, Kardian AS, Pollock CJ, Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation. Transl. Psychiatry 6, e873 (2016). 27552586 PMC5022093
  21. [22]Lubin FD, Roth TL & Sweatt JD Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J. Neurosci. 28, 10576– 10586 (2008). 18923034 PMC3312036
  22. [23]Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, & Barad M. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn. Mem. 14, 268– 276 (2007). 17522015 PMC2216532
  23. [24]Harward SC, Hedrick NG, Hall CE, Parra-Bueno P, Milner TA, Pan E, Autocrine BDNF- TrkB signalling within a single dendritic spine. Nature 538, 99– 103 (2016). 27680698 PMC5398094
  24. [25]Bast T, Zhang W-N & Feldon J. The ventral hippocampus and fear conditioning in rats. Exp. Brain Res. 139, 39– 52 (2001). 11482842
  25. [26]Kjelstrup KG, Tuvnes FA, Steffenach HA, Murison R, Moser EI, & Moser MB Reduced fear expression after lesions of the ventral hippocampus. Proc. Natl. Acad. Sci. USA 99, 10825– 10830 (2002). 12149439 PMC125057
  26. [27]Asok A, Schreiber WB, Jablonski SA, Rosen JB, & Stanton ME Egr-1 increases in the prefrontal cortex following training in the context preexposure facilitation effect (CPFE) paradigm. Neurobiol. Learn. Mem. 106: 145– 153 (2013). 23973447 PMC3852177
  27. [28]Wang ME, Fraize NP, Yin L, Yuan RK, Petsagourakis D, Wann EG, Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning. Hippocampus, 23: 451– 466 (2013). 23460388
  28. [29]Sotres-Bayon F, Sierra-Mercado D, Pardilla-Delgado E & Quirk GJ Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76, 804– 812 (2012). 23177964 PMC3508462
  29. [30]Vasquez JH, Leong KC, Gagliardi CM, Harland B, Apicella AJ, & Muzzio IA Pathway specific activation of ventral hippocampal cells projecting to the prelimbic cortex diminishes fear renewal. Neurobiol. Learn. Mem. 161, 63– 71 (2019). 30898692 PMC6736601
  30. [32]Padilla-Coreano N, Bolkan SS, Pierce GM, Blackman DR, Hardin WD, Garcia-Garcia AL, Direct ventral hippocampal-prefrontal input is required for anxiety-related neural activity and behavior. Neuron, 89: 857– 866 (2016). 26853301 PMC4760847
  31. [33]Kim EJ, Kim N, Kim HT & Choi J-S The prelimbic cortex is critical for context-dependent fear expression. Front. Behav. Neurosci. 7, 73 (2013). 23801949 PMC3689071
  32. [34]Vidal-Gonzalez I, Vidal-Gonzalez B, Rauch SL & Quirk GJ Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn. Mem. 13, 728– 733 (2006). 17142302 PMC1783626
  33. [35]Chudasama Y, Izquierdo A, & Murray EA Distinct contributions of the amygdala and hippocampus to fear expression. Eur. J. Neurosci, 30: 2327– 2337 (2009). 20092575 PMC2852103
  34. [37]Pare D & Duvarci S. Amygdala microcircuits mediating fear expression and extinction. Curr. Opin. Neurobiol, 22: 717– 723 (2012). 22424846 PMC3380167
  35. [38]Cembrowski MS, Bachman JL, Wang L, Sugino K, Shields BC, & Spruston N. Spatial gene- expression gradients underlie prominent heterogeneity of CA1 pyramidal neurons. Neuron 89, 351– 368 (2016). 26777276
  36. [39]Mukherjee D, Ignatowska-Jankowska BM, Itskovits E, Gonzales BJ, Turm H, Izakson L, Salient experiences are represented by unique transcriptional signatures in the mouse brain. eLife, 7: doi: 10.7554/eLife.31220. PMC5862526 29412137 · DOI
  37. [40]Sagar V & Kahnt T. Genetic signatures of memories. Elife 7, (2018). PMC5862524 29560859
  38. [41]Tekin S & Cummings JL Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J. Psychosom. Res. 53, 647– 654 (2002). 12169339
  39. [42]Li X, Zhao Q, Wei W, Lin Q, Magnan C, Emami MR, The DNA modification N6-methyl-2’- deoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction. Nat. Neurosci. 22, 534– 544 (2019). 30778148 PMC6462436
  40. [43]Hill JL & Martinowich K. Activity-dependent signaling: influence on plasticity in circuits controlling fear-related behavior. Curr. Opin. Neurobiol. 36, 59– 65 (2016). 26485574 PMC4738053
  41. [44]Hallock HL, Quillian HM, Mai Y, Maynard KR, Hill JL, & Martinowich K. Manipulation of a genetically and spatially defined sub-population of BDNF-expressing neurons potentiates learned fear and decreases hippocampal-prefrontal synchrony in mice. Neuropsychopharmacology (2019). doi: 10.1038/s41386-019-0429-1 PMC6898598 31170726 · DOI
  42. [45]Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257– 269 (2003). 12553913
  43. [46]Solimon F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science, 327, 863– 866 (2010). 20075215 PMC2829261
  44. [47]Hoover WB, & Vertes RP Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct. Func, 212: 149– 179 (2007). 17717690

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Authors
Hallock, H. L., Quillian, H. M., Maynard, K. R., Mai, Y., Chen, H.-Y., Hamersky, G. R., Shin, J. H., Maher, B. J., Jaffe, A. E., & Martinowich, K.
Affiliations
  • Lieber Institute for Brain Development (US)
  • Johns Hopkins University (US)
Corresponding author
Martinowich, Keri
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2020-10
Volume
88
Issue
7
Pages
554-565
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2020.04.014
PMC
PMC7487039
OpenAlex
W3023960886
Cited by
25
References
5
Citations by year
2026: 2 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 1 · 2020: 1
FWCI
1.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Lieber Institute for Brain Development
  • National Institutes of Health (R01MH105592, F32MH121052)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
hippocampus, prelimbic cortex, ventral hippocampus, neuronal subpopulations, fear extinction, freezing behavior, post-traumatic stress disorder, generalized anxiety disorder, postsynaptic signaling, excitatory and inhibitory neurons
MeSH terms
Fear, Hippocampus, Memory, Population Dynamics, Prefrontal Cortex

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