Abstract
Regardless of its particular nature, emotional stressors appear to elicit a widespread and roughly similar brain activation pattern as evaluated by c-fos expression. However, their behavioral and physiological consequences may strongly differ. Here we addressed in adult male rats the contribution of the intensity and the particular nature of stressors by comparing, in a set of brain areas, the number of c-fos expressing neurons in response to open-field, cat odor or immobilization on boards (IMO). These are qualitatively different stressors that are known to differ in terms of intensity, as evaluated by biological markers. In the present study, plasma levels of the adrenocorticotropic hormone (ACTH) demonstrated that intensity increases in the following order: open-field, cat odor and IMO. Four different c-fos activation patterns emerged among all areas studied: (i) positive relationship with intensity (posterior-dorsal medial amygdala, dorsomedial hypothalamus, lateral septum ventral and paraventricular nucleus of the hypothalamus), (ii) negative relationship with intensity (cingulate cortex 1, posterior insular cortex, dorsal striatum, nucleus accumbens and some subdivisions of the hippocampal formation); (iii) activation not dependent on the intensity of the stressor (prelimbic and infralimbic cortex and lateral and basolateral amygdala); and (iv) activation specifically associated with cat odor (ventromedial amygdala and ventromedial hypothalamus). Histone 3 phosphorylation at serine 10, another neuronal activation marker, corroborated c-fos results. Summarizing, deepest analysis of the brain activation pattern elicit by emotional stressor indicated that, in spite of activating similar areas, each stressor possess their own brain activation signature, mediated mainly by qualitative aspects but also by intensity.
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Al-Hasani R, McCall JG, Shin G, Gomez AM, Schmitz GP, Bernardi JM, Pyo CO, Park SI, Marcinkiewcz CM, Crowley NA, Krashes MJ, Lowell BB, Kash TL, Rogers JA, Bruchas MR (2015) Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron 87:1063–1077
Amat J, Christianson JP, Aleksejev RM, Kim J, Richeson KR, Watkins LR, Maier SF (2014) Control over a stressor involves the posterior dorsal striatum and the act/outcome circuit. Eur J Neurosci 40:2352–2358
Anthony TE, Dee N, Bernard A, Lerchner W, Heintz N, Anderson DJ (2014) Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156:522–536
Armario A (2006a) The contribution of immediate early genes to the understanding of brain processing of stressors. In: Pinaud R, Tremere L (eds) Immediate early genes in sensory processing, cognitive performance and neurological disorders. Springer Science + Business Media, LLC, New York, pp 199–221
Armario A (2006b) The hypothalamic-pituitary-adrenal axis: what can it tell us about stressors? CNS Neurol Disord Drug Targets 5:485–501
Armario A, López-Calderon A, Jolín T, Castellanos JM (1986a) Sensitivity of anterior pituitary hormones to graded levels of psychological stress. Life Sci 39:471–475
Armario A, Montero JL, Balasch J (1986b) Sensitivity of corticosterone and some metabolic variables to graded levels of low intensity stresses in adult male rats. Physiol Behav 37:559–561
Armario A, Daviu N, Muñoz-Abellán C, Rabasa C, Fuentes S, Belda X, Gagliano H, Nadal R (2012) What can we know from pituitary-adrenal hormones about the nature and consequences of exposure to emotional stressors? Cell Mol Neurobiol 32:749–758
Bassareo V, De Luca MA, Di Chiara G (2002) Differential expression of motivational stimulus properties by dopamine in nucleus accumbens shell versus core and prefrontal cortex. J Neurosci 22:4709–4719
Beck CH (1995) Acute treatment with antidepressant drugs selectively increases the expression of c-fos in the rat brain. J Psychiatry Neurosci 20:25–32
Beck CH, Fibiger HC (1995) Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment. J Neurosci 15:709–720
Belda X, Márquez C, Armario A (2004) Long-term effects of a single exposure to stress in adult rats on behavior and hypothalamic-pituitary-adrenal responsiveness: comparison of two outbred rat strains. Behav Brain Res 154:399–408
Briski K, Gillen E (2001) Differential distribution of Fos expression within the male rat preoptic area and hypothalamus in response to physical vs. psychological stress. Brain Res Bull 55:401–408
Burow A, Day HE, Campeau S (2005) A detailed characterization of loud noise stress: intensity analysis of hypothalamo–pituitary–adrenocortical axis and brain activation. Brain Res 1062:63–73
Cabib S, Pulgisi-Allegra S (2012) The mesoaccumbens dopamine in coping with stress. Neurosci Biobehav Rev 36:79–89
Campeau S, Watson SJ (1997) Neuroendocrine and behavioral responses and brain pattern of c-fos induction associated with audiogenic stress. J Neuroendocrinol 9:577–588
Campeau S, Falls WA, Cullinan WE, Helmreich DL, Davis M, Watson SJ (1997) Elicitation and reduction of fear: behavioural and neuroendocrine indices and brain induction of the immediate-early gene c-fos. Neuroscience 78:1087–1104
Chawla MK, Guzowski JF, Ramirez-Amaya V, Lipa P, Hoffman KL, Marriott LK, Worley PF, McNaughton BL, Barnes CA (2005) Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience. Hippocampus 15:579–586
Chowdhury GM, Fujioka T, Nakamura S (2000) Induction and adaptation of Fos expression in the rat brain by two types of acute restraint stress. Brain Res Bull 52:171–182
Christianson JP, Benison AM, Jennings J, Sandsmark EK, Amat J, Kaufman RD, Baratta MV, Paul ED, Campeau S, Watkins LR, Barth DS, Maier SF (2008) The sensory insular cortex mediates the stress-buffering effects of safety signals but not behavioral control. J Neurosci 28:13703–13711
Christianson JP, Jennings JH, Ragole T, Flyer JG, Benison AM, Barth DS, Watkins LR, Maier SF (2011) Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. Biol Psychiatry 70:458–464
Crane JW, French KR, Buller KM (2005) Patterns of neuronal activation in the rat brain and spinal cord in response to increasing durations of restraint stress. Stress 8:199–211
Cullinan WE, Herman JP, Battaglia DF, Akil H, Watson SJ (1995) Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64:477–505
Day HE, Akil H (1996) Differential pattern of c-fos mRNA in rat brain following central and systemic administration of interleukin-1-beta: implications for mechanism of action. Neuroendocrinology 63:207–218
Day HE, Badiani A, Uslaner JM, Oates MM, Vittoz NM, Robinson TE, Watson SJ Jr, Akil H (2001) Environmental novelty differentially affects c-fos mRNA expression induced by amphetamine or cocaine in subregions of the bed nucleus of the stria terminalis and amygdala. J Neurosci 21:732–740
Day HE, Nebel S, Sasse S, Campeau S (2005) Inhibition of the central extended amygdala by loud noise and restraint stress. Eur J Neurosci 21:441–454
Dayas CV, Buller KM, Day TA (1999) Neuroendocrine responses to an emotional stressor: evidence for involvement of the medial but not the central amygdala. Eur J Neurosci 11:2312–2322
Dayas CV, Buller KM, Crane JW, Xu Y, Day TA (2001) Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci 14:1143–1152
Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR (2007) The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes–Dodson law. Neural Plast 2007:60803
Dielenberg RA, Hunt GE, McGregor IS (2001) “When a rat smells a cat”: the distribution of Fos immunoreactivity in rat brain following exposure to a predatory odor. Neuroscience 104:1085–1097
Dielenberg RA, Leman S, Carrive P (2004) Effect of dorsal periaqueductal gray lesions on cardiovascular and behavioral responses to cat odor exposure in rats. Behav Brain Res 153:487–496
Elmquist JK, Scammell TE, Jacobson CD, Saper CB (1996) Distribution of fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration. J Comp Neurol 371:85–103
Emmert MH, Herman JP (1999) Differential forebrain c-fos mRNA induction by ether inhalation and novelty: evidence for distinctive stress pathways. Brain Res 845:60–67
Engeland WC, Miller P, Gann DS (1989) Dissociation between changes in plasma bioactive and immunoreactive adrenocorticotropin after hemorrhage in awake dogs. Endocrinology 124:2978–2985
Fevurly RD, Spencer RL (2004) Fos expression is selectively and differentially regulated by endogenous glucocorticoids in the paraventricular nucleus of the hypothalamus and the dentate gyrus. J Neuroendocrinol 16:970–979
Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, Brooks JM, Iniguez SD, O’Donnell P, Kravitz A, Lobo MK (2015) Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry 77:212–222
Funk D, Li Z, Le AD (2006) Effects of environmental and pharmacological stressors on c-fos and corticotropin-releasing factor mRNA in rat brain: Relationship to the reinstatement of alcohol seeking. Neuroscience 138:235–243
Gallitano AL, Satvat E, Gil M, Marrone DF (2016) Distinct dendritic morphology across the blades of the rodent dentate gyrus. Synapse 70:277–282
Hale MW, Bouwknecht JA, Spiga F, Shekhar A, Lowry CA (2006) Exposure to high- and low-light conditions in an open-field test of anxiety increases c-Fos expression in specific subdivisions of the rat basolateral amygdaloid complex. Brain Res Bull 71:174–182
Hardin JW, Hilbe JM (2003) Generalized linear models and extension. Stata Press, College station
Hennessy MB, Levine S (1978) Sensitive pituitary-adrenal responsiveness to varying intensities of psychological stimulation. Physiol Behav 21:295–297
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Front Neuroendocrinol 24:151–180
Hitzemann B, Hitzemann R (1999) Chlordiazepoxide-induced expression of c-Fos in the central extended amygdala and other brain regions of the C57BL/6J and DBA/2J inbred mouse strains: relationships to mechanisms of ethanol action. Alcohol Clin Exp Res 23:1158–1172
Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70
Honkaniemi J, Fuxe K, Rechard L, Koistinaho J, Isola J, Gustafsson JA, Okret S, Pelto-Huikko M (1992) Colocalization of fos- and glucocorticoid receptor-like immunoreactivities in the rat amygdaloid complex after immobilization stress. J Neuroendocrinol 4:547–555
Inoue T, Tsuchiya K, Koyama T (1994) Regional changes in dopamine and serotonin activation with various intensity of physical and psychological stress in the rat brain. Pharmacol Biochem Behav 49:911–920
Kovacs KJ (1998) c-Fos as a transcription factor: a stressful (re)view from a functional map. Neurochem Int 33:287–297
Lacroix S, Rivest S (1997) Functional circuitry in the brain of immune-challenged rats: partial involvement of prostaglandins. J Comp Neurol 387:307–324
Lammel S, Lim BK, Malenka RC (2014) Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76 Pt B:351–359
Li HY, Ericsson A, Sawchenko PE (1996) Distinct mechanisms underlie activation of hypothalamic neurosecretory neurons and their medullary catecholaminergic afferents in categorically different stress paradigms. Proc Natl Acad Sci USA 93:2359–2364
Maier SF (2015) Behavioral control blunts reactions to contemporaneous and future adverse events: medial prefrontal cortex plasticity and a corticostriatal network. Neurobiol Stress 1:12–22
Marin-Blasco I, Munoz-Abellan C, Andero R, Nadal R, Armario A (2017) Neuronal activation after prolonged immobilization: do the same or different neurons respond to a novel stressor? Cereb Cortex 16:1–12
Márquez C, Belda X, Armario A (2002) Post-stress recovery of pituitary-adrenal hormones and glucose, but not the response during exposure to the stressor, is a marker of stress intensity in highly stressful situations. Brain Res 926:181–185
Mason J (1974) Specificity in the organization of neuroendocrine response profiles. In: Seeman P, Brown G (eds) Frontiers in neurology and neuroscience research. University of Toronto Press, Toronto, pp 68–80
McCulloch C, Searle S (2001) Generalized, linear and mixed models. Wiley, New York
McGregor IS, Dielenberg RA (1999) Differential anxiolytic efficacy of a benzodiazepine on first versus second exposure to a predatory odor in rats. Psychopharmacology 147:174–181
McGregor IS, Hargreaves GA, Apfelbach R, Hunt GE (2004) Neural correlates of cat odor-induced anxiety in rats: region-specific effects of the benzodiazepine midazolam. J Neurosci 24:4134–4144
Muñoz-Abellán C, Andero R, Nadal R, Armario A (2008) Marked dissociation between hypothalamic–pituitary–adrenal activation and long-term behavioral effects in rats exposed to immobilization or cat odor. Psychoneuroendocrinology 33:1139–1150
Muñoz-Abellán C, Armario A, Nadal R (2010) Do odors from different cats induce equivalent unconditioned and conditioned responses in rats? Physiol Behav 99:388–394
Muñoz-Abellán C, Rabasa C, Daviu N, Nadal R, Armario A (2011) Behavioral and endocrine consequences of simultaneous exposure to two different stressors in rats: interaction or independence? PLoS One 6:e21426
Natelson BH, Tapp WN, Adamus JE, Mittler JC, Levin BE (1981) Humoral indices of stress in rats. Physiol Behav 26:1049–1054
Ons S, Martí O, Armario A (2004) Stress-induced activation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) is restricted to telencephalic areas in the rat brain: relationship to c-fos mRNA. J Neurochem 89:1111–1118
Pacak K, Palkovits M (2001) Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 22:502–548
Pacak K, Palkovits M, Yadid G, Kvetnansky R, Kopin IJ, Goldstein DS (1998) Heterogeneous neurochemical responses to different stressors: a test of Selye’s doctrine of nonspecificity. Am J Physiol 275:R1247-1255
Pace TW, Gaylord R, Topczewski F, Girotti M, Rubin B, Spencer RL (2005) Immediate-early gene induction in hippocampus and cortex as a result of novel experience is not directly related to the stressfulness of that experience. Eur J Neurosci 22:1679–1690
Paxinos G, Watson C (2014) Paxinos and Watson’s the rat brain in stereotaxic coordinates, 7th edn. Academic, San Diego
Perez-Gomez A, Bleymehl K, Stein B, Pyrski M, Birnbaumer L, Munger SD, Leinders-Zufall T, Zufall F, Chamero P (2015) Innate predator odor aversion driven by parallel olfactory subsystems that converge in the ventromedial hypothalamus. Curr Biol 25:1340–1346
Rabasa C, Muñoz-Abellán C, Daviu N, Nadal R, Armario A (2011) Repeated exposure to immobilization or two different footshock intensities reveals differential adaptation of the hypothalamic-pituitary-adrenal axis. Physiol Behav 103:125–133
Rotllant D, Pastor-Ciurana J, Armario A (2013) Stress-induced brain histone H3 phosphorylation: contribution of the intensity of stressors and length of exposure. J Neurochem 125:599–609
Salchner P, Singewald N (2002) Neuroanatomical substrates involved in the anxiogenic-like effect of acute fluoxetine treatment. Neuropharmacology 43:1238–1248
Sandi C, Pinelo-Nava MT (2007) Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast 2007:78970
Sawchenko PE, Li HY, Ericsson A (2000) Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms. Prog Brain Res 122:61–78
Schwabe L, Wolf OT, Oitzl MS (2009) Memory formation under stress: quantity and quality. Neurosci Biobehav Rev 34:584–591
Scicli AP, Petrovich GD, Swanson LW, Thompson RF (2004) Contextual fear conditioning is associated with lateralized expression of the immediate early gene c-fos in the central and basolateral amygdalar nuclei. Behav Neurosci 118:5–14
Simmons D, Arriza JL, Swanson LW (1989) A complete protocol for in situ hybridization of messenger RNAs in brain and other tissues with radio-labeled single-stranded RNA probes. J Histotechnol 12(3):169–181
Staples LG, McGregor IS, Apfelbach R, Hunt GE (2008) Cat odor, but not trimethylthiazoline (fox odor), activates accessory olfactory and defense-related brain regions in rats. Neuroscience 151:937–947
Trnecková L, Rotllant D, Klenerová V, Hynie S, Armario A (2007) Dynamics of immediate early gene and neuropeptide gene response to prolonged immobilization stress: evidence against a critical role of the termination of exposure to the stressor. J Neurochem 100:905–914
Ungless MA, Argilli E, Bonci A (2010) Effects of stress and aversion on dopamine neurons: implications for addiction. Neurosci Biobehav Rev 35:151–156
Vahl TP, Ulrich-Lai YM, Ostrander MM, Dolgas CM, Elfers EE, Seeley RJ, D’Alessio DA, Herman JP (2005) Comparative analysis of ACTH and corticosterone sampling methods in rats. Am J Physiol Endocrinol Metab 289:E823-828
Vigas M (1984) Problems of definition of stress stimulus and specificity of stress response. In: Usdin E, Kvetňanský R, Axelrod J (eds) Stress, the role of catecholamines and other neurotransmitters: proceedings of the third international symposium on catecholamines and other neurotransmitters in stress. Gordon and Breach Science Publishers, New York, pp 27–35
Voorn P, Vanderschuren LJ, Groenewegen HJ, Robbins TW, Pennartz CM (2004) Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci 27:468–474
Wilson YM, Murphy M (2009) A discrete population of neurons in the lateral amygdala is specifically activated by contextual fear conditioning. Learn Mem 16:357–361
Acknowledgements
This work was supported by grants from the Spanish government to AA and RN: “Ministerio de Economía y Competitividad” (Grant number SAF2014-53876R) and “Generalitat de Catalunya” (SGR 2014−1020). JU-C is the recipient of predoctoral fellowship from “Ministerio de Economía y Competitividad” (Grant number BES-2015-071464). RN is the recipient of an ICREA-ACADEMIA award (2015–2019) from “Generalitat de Catalunya”. IM-B was a recipient of a predoctoral fellowship from the Basque Government (Grant number 2008-AE). The UAB animal facility received funding from 2015FEDER7S-20IU16-001945.
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Úbeda-Contreras, J., Marín-Blasco, I., Nadal, R. et al. Brain c-fos expression patterns induced by emotional stressors differing in nature and intensity. Brain Struct Funct 223, 2213–2227 (2018). https://doi.org/10.1007/s00429-018-1624-2
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DOI: https://doi.org/10.1007/s00429-018-1624-2