Brain Structure and Function

, Volume 224, Issue 5, pp 1831–1843 | Cite as

Controllable stress elicits circuit-specific patterns of prefrontal plasticity in males, but not females

  • Michael V. Baratta
  • Tina M. Gruene
  • Samuel D. Dolzani
  • Lauren E. Chun
  • Steven F. Maier
  • Rebecca M. ShanskyEmail author
Original Article


Actual or perceived behavioral control during a traumatic event can promote resilience against future adversity, but the long-term cellular and circuit mechanisms by which this protection is conferred have not been identified. Clinical outcomes following trauma exposure differ in men and women, and, therefore, it is especially important in preclinical research to dissect these processes in both males and females. In male adult rats, an experience with behavioral control over tail shock (“escapable stress”, ES) has been shown to block the neurochemical and behavioral outcomes produced by later uncontrollable tail shock (“inescapable stress”, IS), a phenomenon termed “behavioral immunization”. Here, we determined whether behavioral immunization is present in females. Unlike males, the stress-buffering effects of behavioral control were absent in female rats. We next examined the effects of ES and IS on spine morphology of dorsal raphe nucleus (DRN)–projecting prelimbic (PL) neurons, a circuit critical to the immunizing effects of ES in males. In males, IS elicited broad, non-specific alterations in PL spine size, while ES elicited PL–DRN circuit-specific spine changes. In contrast, females exhibited broad, non-specific spine enlargement after ES but only minor alterations after IS. These data provide evidence for a circuit-specific mechanism of structural plasticity that could underlie sexual divergence in the protective effects of behavioral control.


Coping Medial prefrontal cortex Dorsal raphe nucleus Dendritic spines Structural plasticity Learned helplessness 



This work was supported by NIH Grants R01 MH050479 (SFM), R21 MH106817 (MVB), T32 MH016880 (SDD), a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (MVB), and a Dissertation Research Grant from Northeastern University (TMG). The authors thank Alexis Stefano for spine illustrations (Figs. 1 and 6) and Nathan Leslie and Isabella Fallon for technical assistance.

Compliance with ethical standards

Conflict of Interest

The authors declare no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

429_2019_1875_MOESM1_ESM.docx (2.9 mb)
Supplementary material 1 (docx 2937 kb)


  1. Adrian M, Kusters R, Storm C, Hoogenraad CC, Kapitein LC (2017) Probing the interplay between dendritic spine morphology and membrane-bound diffusion. Biophys J 113:2261–2270CrossRefGoogle Scholar
  2. Amat J, Sparks PD, Matus-Amat P, Griggs J, Watkins LR, Maier SF (2001) The role of the habenular complex in the elevation of dorsal raphe nucleus serotonin and the changes in the behavioral responses produced by uncontrollable stress. Brain Res 917:118–126CrossRefGoogle Scholar
  3. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 8:365–371CrossRefGoogle Scholar
  4. Amat J, Paul E, Zarza C, Watkins LR, Maier SF (2006a) Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex. J Neurosci 26:13264–13272CrossRefGoogle Scholar
  5. Amat J, Paul E, Zarza C, Watkins LR, Maier SF (2006b) Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex. J Neurosci 26:13264–13272CrossRefGoogle Scholar
  6. Amat J, Aleksejev RM, Paul E, Watkins LR, Maier SF (2010) Behavioral control over shock blocks behavioral neurochemical effects of later social defeat. Neuroscience 165:1031–1038CrossRefGoogle Scholar
  7. Bangasser DA, Wicks B (2017) Sex-specific mechanisms for responding to stress. J Neurosci Res 95:75–82CrossRefGoogle Scholar
  8. Baratta MV, Christianson JP, Gomez DM, Zarza CM, Amat J, Masini CV, Watkins LR, Maier SF (2007) Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear. Neuroscience 146:1495–1503CrossRefGoogle Scholar
  9. Baratta MV, Zarza CM, Gomez DM, Campeau S, Watkins LR, Maier SF (2009) Selective activation of dorsal raphe nucleus-projecting neurons in the ventral medial prefrontal cortex by controllable stress. Eur J Neurosci 30:1111–1116CrossRefGoogle Scholar
  10. Baratta MV, Leslie NR, Fallon IP, Dolzani SD, Chun LE, Tamalunas AM, Watkins LR, Maier SF (2018) Behavioural neural sequelae of stressor exposure are not modulated by controllability in females. Eur J Neurosci 47:959–967CrossRefGoogle Scholar
  11. Breslau N, Kessler RC (2001) The stressor criterion in DSM-IV posttraumatic stress disorder: an empirical investigation. Biol Psychiatry 50:699–704CrossRefGoogle Scholar
  12. Charney DS (2004) Psychobiological mechanisms of resilience vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 161:195–216CrossRefGoogle Scholar
  13. Chen Y, Molet J, Lauterborn JC, Trieu BH, Bolton JL, Patterson KP, Gall CM, Lynch G, Baram TZ (2016) Converging, synergistic actions of multiple stress hormones mediate enduring memory impairments after acute simultaneous stresses. J Neurosci 36:11295–11307CrossRefGoogle Scholar
  14. Christianson JP, Paul ED, Irani M, Thompson BM, Kubala KH, Yirmiya R, Watkins LR, Maier SF (2008) The role of prior stressor controllability the dorsal raphé nucleus in sucrose preference social exploration. Behav Brain Res 193:87–93CrossRefGoogle Scholar
  15. Christianson JP, Thompson BM, Watkins LR, Maier SF (2009) Medial prefrontal cortical activation modulates the impact of controllable uncontrollable stressor exposure on a social exploration test of anxiety in the rat. Stress 12:445–450CrossRefGoogle Scholar
  16. Christianson JP, Ragole T, Amat J, Greenwood BN, Strong PV, Paul ED, Fleshner M, Watkins LR, Maier SF (2010) 5-Hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67:339–345CrossRefGoogle Scholar
  17. Christianson JP, Flyer-Adams JG, Drugan RC, Amat J, Daut RA, Foilb AR, Watkins LR, Maier SF (2014) Learned stressor resistance requires extracellular signal-regulated kinase in the prefrontal cortex. Front Behav Neurosci 8:348CrossRefGoogle Scholar
  18. Dalla C, Edgecomb C, Whetstone AS, Shors TJ (2008) Females do not express learned helplessness like males do. Neuropsychopharmacology 33:1559–1569CrossRefGoogle Scholar
  19. Dolzani SD, Baratta MV, Moss JM, Leslie NL, Tilden SG, Sørensen AT, Watkins LR, Lin Y, Maier SF (2018) Inhibition of a descending prefrontal circuit prevents ketamine-induced stress resilience in females. Eneuro 5, ENEURO.0025-18.2018Google Scholar
  20. Farrell MR, Gruene TM, Shansky RM (2015) The influence of stress gonadal hormones on neuronal structure function. Horm Behav 76:118–124CrossRefGoogle Scholar
  21. Frank AC, Huang S, Zhou M, Gdalyahu A, Kastellakis G, Silva TK, Lu E, Wen X, Poirazi P, Trachtenberg JT et al (2018) Hotspots of dendritic spine turnover facilitate clustered spine addition learning memory. Nat Commun 9:422CrossRefGoogle Scholar
  22. Fu M, Yu X, Lu J, Zuo Y (2012) Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature 483:92–95CrossRefGoogle Scholar
  23. Garrett JE, Wellman CL (2009) Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences estrogen dependence. Neuroscience 162:195–207CrossRefGoogle Scholar
  24. Gruene TM, Roberts E, Thomas V, Ronzio A, Shansky RM (2015) Sex-specific neuroanatomical correlates of fear expression in prefrontal-amygdala circuits. Biol Psychiatry 78:186–193CrossRefGoogle Scholar
  25. Gruene T, Flick K, Rendall S, Cho JH, Gray J, Shansky R (2016) Activity-dependent structural plasticity after aversive experiences in amygdala auditory cortex pyramidal neurons. Neuroscience 328:157–164CrossRefGoogle Scholar
  26. Hayashi-Takagi A, Yagishita S, Nakamura M, Shirai F, Wu YI, Loshbaugh AL, Kuhlman B, Hahn KM, Kasai H (2015) Labelling optical erasure of synaptic memory traces in the motor cortex. Nature 525:333–338CrossRefGoogle Scholar
  27. Heinsbroek RP, Van Haaren F, Van de Poll NE, Steenbergen HL (1991) Sex differences in the behavioral consequences of inescapable footshocks depend on time since shock. Physiol Behav 49:1257–1263CrossRefGoogle Scholar
  28. Jankowski MP, Sesack SR (2004) Prefrontal cortical projections to the rat dorsal raphe nucleus: ultrastructural features associations with serotonin?—aminobutyric acid neurons. J Comp Neurol 468:518–529CrossRefGoogle Scholar
  29. Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H (2003) Structure-stability-function relationships of dendritic spines. Trends Neurosci 26:360–368CrossRefGoogle Scholar
  30. Kirk RC, Blampied NM (1985) Activity during inescapable shock subsequent escape avoidance learning: female male rats compared. NZ J Psychol 14:9–14Google Scholar
  31. Maier SF (2015) Behavioral control blunts reactions to contemporaneous future adverse events: medial prefrontal cortex plasticity a corticostriatal network. Neurobiol Stress 1:12–22CrossRefGoogle Scholar
  32. Maier SF, Seligman ME (1976) Learned helplessness: theory evidence. J Exp Psychol Gen 105:3–46CrossRefGoogle Scholar
  33. Maier SF, Watkins LR (2005) Stressor controllability learned helplessness: the roles of the dorsal raphe nucleus, serotonin, corticotropin-releasing factor. Neurosci Biobehav Rev 29:829–841CrossRefGoogle Scholar
  34. Maier SF, Grahn RE, Watkins LR (1995) 8-OH-DPAT microinjected in the region of the dorsal raphe nucleus blocks reverses the enhancement of fear conditioning interference with escape produced by exposure to inescapable shock. Behav Neurosci 109:404–412CrossRefGoogle Scholar
  35. Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H (2001) Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci 4:1086–1092CrossRefGoogle Scholar
  36. Matsuzaki M, Honkura N, Ellis-Davies GCR, Kasai H (2004) Structural basis of long-term potentiation in single dendritic spines. Nature 429:761–766CrossRefGoogle Scholar
  37. McEwen BS, Morrison JH (2013) The brain on stress: vulnerability plasticity of the prefrontal cortex over the life course. Neuron 79:16–29CrossRefGoogle Scholar
  38. McEwen BS, Stellar E (1993) Stress the individual. Mechanisms leading to disease. Arch Intern Med 153:2093–2101CrossRefGoogle Scholar
  39. Musazzi L, Milanese M, Farisello P, Zappettini S, Tardito D, Barbiero VS, Bonifacino T, Mallei A, Baldelli P, Racagni G et al (2010) Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS One 5:e8566CrossRefGoogle Scholar
  40. Nava N, Treccani G, Alabsi A, Kaastrup Mueller H, Elfving B, Popoli M, Wegener G, Nyengaard JR (2015) Temporal dynamics of acute stress-induced dendritic remodeling in medial prefrontal cortex the protective effect of desipramine. Cereb Cortex 27:bhv254CrossRefGoogle Scholar
  41. Pereira AC, Lambert HK, Grossman YS, Dumitriu D, Waldman R, Jannetty SK, Calakos K, Janssen WG, McEwen BS, Morrison JH (2014) Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering. Proc Natl Acad Sci 111:18733–18738CrossRefGoogle Scholar
  42. Popoli M, Yan Z, McEwen BS, Sanacora G (2011) The stressed synapse: the impact of stress glucocorticoids on glutamate transmission. Nat Rev Neurosci 13:22CrossRefGoogle Scholar
  43. Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, Morrison JH, Wearne SL, Hof PR (2008) Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol 507:1141–1150CrossRefGoogle Scholar
  44. Radley JJ, Anderson RM, Hamilton BA, Alcock JA, Romig-Martin SA (2013) Chronic stress-induced alterations of dendritic spine subtypes predict functional decrements in an hypothalamo-pituitary-adrenal-inhibitory prefrontal circuit. J Neurosci 33:14379–14391CrossRefGoogle Scholar
  45. Shansky RM, Morrison JH (2009) Stress-induced dendritic remodeling in the medial prefrontal cortex: effects of circuit, hormones rest. Brain Res 1293:108–113CrossRefGoogle Scholar
  46. Shansky RM, Hamo C, Hof PR, McEwen BS, Morrison JH (2009) Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cereb Cortex 19:2479–2484CrossRefGoogle Scholar
  47. Shapiro DH, Schwartz CE, Astin JA (1996) Controlling ourselves, controlling our world. Am Psychol 51:1213–1230CrossRefGoogle Scholar
  48. Southwick SM, Charney DS (2012) The science of resilience: implications for the prevention treatment of depression. Science 338:79–82CrossRefGoogle Scholar
  49. Steenbergen HL, Heinsbroek RP, Van Hest A, Van de Poll NE (1990) Sex-dependent effects of inescapable shock administration on shuttlebox-escape performance elevated plus-maze behavior. Physiol Behav 48:571–576CrossRefGoogle Scholar
  50. Strong PV, Christianson JP, Loughridge AB, Amat J, Maier SF, Fleshner M, Greenwood BN (2011) 5-hydroxytryptamine 2C receptors in the dorsal striatum mediate stress-induced interference with negatively reinforced instrumental escape behavior. Neuroscience 197:132–144CrossRefGoogle Scholar
  51. Tanaka J-I, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GCR, Kasai H (2008) Protein synthesis neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683–1687CrossRefGoogle Scholar
  52. Varga V, Székely AD, Csillag A, Sharp T, Hajós M (2001) Evidence for a role of GABA interneurones in the cortical modulation of midbrain 5-hydroxytryptamine neurones. Neuroscience 106:783–792CrossRefGoogle Scholar
  53. Yehuda R, LeDoux J (2007) Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56:19–32CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Michael V. Baratta
    • 1
  • Tina M. Gruene
    • 2
  • Samuel D. Dolzani
    • 1
  • Lauren E. Chun
    • 1
  • Steven F. Maier
    • 1
  • Rebecca M. Shansky
    • 2
    Email author
  1. 1.Department of Psychology and NeuroscienceUniversity of Colorado BoulderBoulderUSA
  2. 2.Department of PsychologyNortheastern UniversityBostonUSA

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