Joan M C Blom

Università degli Studi di Modena e Reggio Emilia, Modène, Emilia-Romagna, Italy

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Publications (30)141.08 Total impact

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    ABSTRACT: The study of depression is facing major challenges: firstly, the need to develop new drugs with a faster onset of action and secondly, fulfilling the unmet needs of treatment resistant patients with more effective compounds. The chronic escape deficit (CED) is a valid and useful model of depression and is based on the induction of an escape deficit after exposure of rats to unavoidable stress. This behavioural model provides a method for evaluating the capacity of a treatment to revert the escape deficit. The majority of antidepressant drugs need to be administered for at least 3-4 weeks in order to revert the escape deficit. A 7-day treatment with escitalopram reverted the stress-induced escape deficit in approximately 50% of the animals. Escitalopram treatment decreased anxiety-related behaviours in stressed animals, by increasing the time spent in the central part of the arena with respect to saline treated stressed animals, without affecting exploratory related behaviours. Gene expression profiling was carried out in the hippocampus to identify new targets associated with the effects of stress or with the different response to escitalopram. By combining a well-validated animal model with gene expression analysis we demonstrated that the CED model may represent a perfect tool for studying treatment-resistant depression.
    Behavioural Brain Research 06/2014; 272. DOI:10.1016/j.bbr.2014.06.040 · 3.39 Impact Factor
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    ABSTRACT: Interleukin (IL)- 18 is a cytokine previously demonstrated to participate in neuroinflammatory processes. Since the components of the IL-18 receptor complex are expressed in neurons throughout the brain, IL-18 is also believed to directly influence neuronal function. Here we tested this hypothesis on mouse hippocampal neurons by measuring the effects of IL-18 on three pathways previously shown to be regulated by this cytokine in non-neuronal cells: the MAPK pathways, p38 and ERK1/2 MAPKs, STAT3 and NF-κB. Experiments were carried out in vitro using the immortalized hippocampal neuronal line HT-22 or in vivo following i.c.v. injection with recombinant mouse IL-18. We showed that IL-18 did not activate NF-κB in HT-22 cells whereas it induced a rapid (within 15 minutes) activation of the MAPK pathways. Moreover, we demonstrated that IL-18 treatment enhanced P-STAT3 (Tyr705)/ STAT3 ratio in the nucleus of HT-22 cells after 30- 60 minutes of exposure. A similar increase in P-STAT3 (Tyr705)/ STAT3 ratio was observed in the whole hippocampus one hour after i.c.v. injection. These data demonstrate that IL-18 can act directly on neuronal cells affecting the STAT3 pathway; therefore, possibly regulating the expression of specific genes within the hippocampus. This effect may help to explain some of the IL-18- induced effects on synaptic plasticity and functionality within the hippocampal system.
    Brain Behavior and Immunity 03/2014; DOI:10.1016/j.bbi.2014.02.015 · 6.13 Impact Factor
  • European Neuropsychopharmacology 03/2014; 24:S22–S23. DOI:10.1016/S0924-977X(14)70025-2 · 5.40 Impact Factor
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    ABSTRACT: Interleukin (IL)- 18 is a cytokine previously demonstrated to participate in neuroinflammatory processes. Since the components of the IL-18 receptor complex are expressed in neurons throughout the brain, IL-18 is also believed to directly influence neuronal function. Here we tested this hypothesis on mouse hippocampal neurons by measuring the effects of IL-18 on three pathways previously shown to be regulated by this cytokine in non-neuronal cells: the MAPK pathways, p38 and ERK1/2 MAPKs, STAT3 and NF-κB. Experiments were carried out in vitro using the immortalized hippocampal neuronal line HT-22 or in vivo following i.c.v. injection with recombinant mouse IL-18. We showed that IL-18 did not activate NF-κB in HT-22 cells whereas it induced a rapid (within 15 minutes) activation of the MAPK pathways. Moreover, we demonstrated that IL-18 treatment enhanced P-STAT3 (Tyr705)/ STAT3 ratio in the nucleus of HT-22 cells after 30- 60 minutes of exposure. A similar increase in P-STAT3 (Tyr705)/ STAT3 ratio was observed in the whole hippocampus one hour after i.c.v. injection. These data demonstrate that IL-18 can act directly on neuronal cells affecting the STAT3 pathway; therefore, possibly regulating the expression of specific genes within the hippocampus. This effect may help to explain some of the IL-18- induced effects on synaptic plasticity and functionality within the hippocampal system.
    Brain Behavior and Immunity 01/2014; · 6.13 Impact Factor
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    ABSTRACT: In human and rodents, the transcriptional response of neurons to stress is related to epigenetic modifications of both DNA and histone proteins. To assess the suitability of simple invertebrate models in studying the basic mechanisms of stress-related epigenetic modifications, we analyzed epigenetic modifications in neurons of the freshwater snail Pomacea canaliculata after the injection of Escherichia coli-derived lipopolysaccharide (LPS). The phospho-acetylation of histone H3, together with the induction of stress-related factors, c-Fos and HSP70, were evaluated in large and small neurons of the pedal ganglia of sham- and LPS-injected snails. Immunocytochemical investigations showed that after LPS injection, the immunopositivity towards phospho (Ser10)-acetyl (Lys14)-histone H3 and c-Fos increases in the nuclei of small gangliar neurons. Western blot analysis confirmed a significant increase of phospho (Ser10)-acetyl (Lys14)-histone H3 in nuclear extracts from 2h LPS-injected animals. c-Fos protein levels were significantly augmented 6h after LPS injection. Immunocytochemistry and western blot indicated that no changes occurred in HSP70 distribution and protein levels. To our knowledge this is the first demonstration of epigenetic changes in molluscan neurons after an immune challenge and indicate the gastropod P. canaliculata as a suitable model for evolutionary and translational studies on stress-related epigenetic modifications.
    Brain research 09/2013; 1537. DOI:10.1016/j.brainres.2013.09.009 · 2.83 Impact Factor
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    ABSTRACT: A complex interplay between gene and environment influences the vulnerability or the resilience to stressful events. In the acute escape deficit (AED) paradigm, rats exposed to an acute unavoidable stress (AUS) develop impaired reactivity to noxious stimuli. Here we assessed the behavioral and molecular changes in rats exposed to AUS. A genome-wide microarray experiment generated a comprehensive picture of changes in gene expression in the hippocampus and the frontal cortex of animals exposed or not to AUS. Exposure to AUS resulted in two distinct groups of rats with opposite behavioral profiles: one developing an AED, called "stress vulnerable," and one that did not develop an AED, called "stress resilient." Genome-wide profiling revealed a low percentage of overlapping mechanisms in the two areas, suggesting that, in the presence of stress, resilience or vulnerability to AUS is sustained by specific changes in gene expression that can either buffer or promote the behavioral and molecular adverse consequences of stress. Specifically, we observed in the frontal cortex a downregulation of the transcript coding for interferon-β and leukemia inhibitory factor in resilient rats and an upregulation of neuroendocrine related genes, growth hormone and prolactin, in vulnerable rats. In the hippocampus, the muscarinic M2 receptor was downregulated in vulnerable but upregulated in resilient rats. Our findings demonstrate that opposite behavioral responses did not correspond to opposite regulatory changes of the same genes, but resilience rather than vulnerability to stress was associated with specific changes, with little overlap, in the expression of patterns of genes. © Wiley Periodicals, Inc.
    Journal of Neuroscience Research 11/2012; 90(11):2103-15. DOI:10.1002/jnr.23100 · 2.73 Impact Factor
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    ABSTRACT: As in humans, genetic background in rodents may influence a peculiar set of behavioural traits such as sensitivity to pain and stressors or anxiety-related behaviours. Therefore, we tested the hypothesis that mice with different genetic backgrounds [outbred (CD1), inbred (C57BL/6J) and hybrid (B6C3F1) adult male mice] display altered reactivity to pain, stress and anxiety related behaviours. We demonstrated that B6C3F1 mice displayed the more anxious phenotype with respect to C57BL/6J or CD1 animals, with the latter being the less anxious strain when tested in an open field and on an elevated plus maze. No difference was observed across strains in thermal sensitivity to a radiant heat source. Mice were then treated with a sub-plantar injection of the inflammatory agent Complete Freund's Adjuvant (CFA), 24h later they were hyperalgesic with respect to saline exposed animals, irrespective of strain. We then measured intra-strain differences and CFA-induced inter-strain effects on the expression of various genes with a recognized role in pain and anxiety: BDNF, IL-6, IL-1β, IL-18 and NMDA receptor subunits in the mouse thalamus, hippocampus and hypothalamus. The more anxious phenotype observed in B6C3F1 hybrid mice displayed lower levels of BDNF mRNA in the hippocampus and hypothalamus when compared to outbred CD1 and C57BL/6J inbred mice. CFA led to a general decrease in central gene expression of the evaluated targets especially in CD1 mice, while BDNF hypothalamic downregulation stands out as a common effect of CFA in all three strains evaluated.
    Behavioural brain research 05/2011; 224(1):23-34. DOI:10.1016/j.bbr.2011.05.011 · 3.39 Impact Factor
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    ABSTRACT: The gene coding for the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is a stress-responsive gene. Changes in its expression may underlie some of the pathological effects of stress-related disorders like depression. Data on the stress-induced regulation of the expression of BDNF in pathological conditions are rare because often research is conducted using healthy animals. In our experiments, we used transgenic mice with glucocorticoid receptor impaired (GR-i) expression in the hypothalamus created as a tool to study the neuroendocrine changes occurring in stress-related disorders. First, under basal condition, GR-i mice displayed lower levels of BDNF exons IX and IV and decreased CRE(BDNF) binding activity with respect to wild-type (WT) mice in the hippocampus. Then, we exposed GR-i and WT mice to an acute restraint stress (ARS) to test the hypothesis that GR-i mice display: 1] different ARS induced expression of BDNF, and 2] altered activation of signaling pathways implicated in regulating BDNF gene expression in the hippocampus with respect to WT mice. Results indicate that ARS enhanced BDNF mRNA expression mainly in the CA3 hippocampal sub-region of GR-i mice in the presence of enhanced levels of pro-BDNF protein, while no effect was observed in WT mice. Moreover, ARS reduced CREB signaling and binding to the BDNF promoter in GR-i mice but enhanced signaling and binding, possibly through ERK1/2 activation, in WT mice. Thus, life-long central GR dysfunction resulted in an altered sensitivity at the transcriptional level that may underlie an impaired response to an acute psycho-physical stress. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
    Neuropharmacology 02/2011; 60(7-8):1337-46. DOI:10.1016/j.neuropharm.2011.01.050 · 4.82 Impact Factor
  • European Psychiatry 01/2010; 25:1408-1408. DOI:10.1016/S0924-9338(10)71394-8 · 3.21 Impact Factor
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    ABSTRACT: Protracted or recurrent pain and inflammation in the early neonatal period may cause long-lasting changes in central neural function. However, more research is necessary to better characterize the long-term behavioral sequelae of such exposure in the neonatal period. Objectives: (1) to study whether timing of postnatal exposure to persistent inflammation alters responsiveness to thermal pain in the adult animal; (2) to assess whether animals experiencing early postnatal chronic inflammation display altered anxiety related behavior; (3) to study the importance of genetic background. Newborn mice (outbred strain, CD1 and F1 hybrid strain, B6C3F1) received an injection of Complete Freund's Adjuvant (CFA) or saline on either postnatal day 1 or 14 (PND1; PND14) into the left hind paw. Pain to radiant heat and anxiety were examined in 12-week-old adult animals. Adult baseline PWL was significantly decreased in CD1 mice exposed to CFA on PND 1 and 14 as compared to their saline treated counterparts. B6C3F1 mice exposed to CFA on PND14 showed markedly reduced baseline PWL compared to the PND14 saline group. Persistent inflammation experienced by B6C3F1 mice on PND1 failed to affect baseline adult thermal responsiveness. Adult mice, CD1 and B6C3F1, displayed low anxiety traits only if they had been exposed to persistent inflammation on PND1 and not on PND14. Our research suggests a role for genetic background in modulating long-term behavioral consequences of neonatal persistent inflammation: the data support the hypothesis that pain experienced very early in life differentially affects adult behavioral and emotional responsiveness in outbred (CD1) and hybrid mice (B6C3F1).
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 09/2009; 27(7):661-8. DOI:10.1016/j.ijdevneu.2009.07.009 · 2.92 Impact Factor
  • European Neuropsychopharmacology 09/2009; 19. DOI:10.1016/S0924-977X(09)70526-7 · 5.40 Impact Factor
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    ABSTRACT: The cytokine IL-18 acts on the CNS both in physiological and pathological conditions. Its action occurs through the heterodimeric receptor IL-18Ralpha\beta. To better understand IL-18 central effects, we investigated in the mouse brain the distribution of two IL-18Ralpha transcripts, a full length and an isoform lacking the intracellular domain hypothesized to be a decoy receptor. Both isoforms were expressed in neurons throughout the brain primarily with overlapping distribution but also with some unique pattern. These data suggest that IL-18 may modulate neuronal functions and that its action may be regulated through expression of a decoy receptor.
    Journal of neuroimmunology 08/2009; 214(1-2):43-54. DOI:10.1016/j.jneuroim.2009.06.016 · 2.79 Impact Factor
  • European Neuropsychopharmacology 03/2009; 19. DOI:10.1016/S0924-977X(09)70036-7 · 5.40 Impact Factor
  • European Neuropsychopharmacology 03/2008; 18. DOI:10.1016/S0924-977X(08)70004-X · 5.40 Impact Factor
  • G. Petrilli, R. Rovelli, G. Barera, J. M. C. Blom
    European Neuropsychopharmacology 03/2007; 17. DOI:10.1016/S0924-977X(07)70059-7 · 5.40 Impact Factor
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    ABSTRACT: The objective of this study was to test whether postnatal chronic inflammation resulted in altered reactivity to pain later in life when reexposed to the same inflammatory agent and whether this alteration correlated with brain-region-specific patterns of N-methyl-D-aspartate (NMDA) receptor subtype gene expression. Neonatal mouse pups received a single injection of complete Freund's adjuvant (CFA) or saline into the left hind paw on postnatal day 1 or 14. At 12 weeks of age, both neonatal CFA- and saline-treated animals received a unilateral injection of CFA in the left hind paw. Adult behavioral responsiveness of the left paw to a radiant heat source was determined in mice treated neonatally with saline or CFA before and after receiving CFA as adults. Twenty-four hours later, brains were dissected and NMDA receptor subunit gene expression was determined in four different brain areas by using an RNase protection assay. The results indicated that NMDA receptor subtype gene expression in adult mice exposed to persistent neonatal peripheral inflammation was brain region specific and that NMDA gene expression and pain reactivity differed according to the day of neonatal CFA exposure. Similarly, adult behavioral responsiveness to a noxious radiant heat source differed according to the age of neonatal exposure to CFA. The data suggest a possible molecular basis for the hypothesis that chronic persistent inflammation experienced early during development may permanently alter the future behavior and the sensitivity to pain later in life, especially in response to subsequent or recurrent inflammatory events.
    Journal of Neuroscience Research 12/2006; 84(8):1789-98. DOI:10.1002/jnr.21077 · 2.73 Impact Factor
  • European Neuropsychopharmacology 09/2006; 16. DOI:10.1016/S0924-977X(06)70383-2 · 5.40 Impact Factor
  • G. Petrilli, J. M. C. Blom
    European Neuropsychopharmacology 09/2006; 16. DOI:10.1016/S0924-977X(06)70777-5 · 5.40 Impact Factor
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    ABSTRACT: Evidence has accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Moreover, antidepressants show an anti-inflammatory action possibly related to their clinical efficacy. An improvement in psychiatric symptoms has been recently reported in patients treated with anti-inflammatory drugs for other indications. These data imply that inflammation may be involved in the pathogenesis of depression and that anti-inflammatory drugs may be used as an adjunctive therapy. The aim of the present study was to evaluate the behavioural effect of the co-administration of acetylsalicylic acid (ASA, 45 mg/kg or 22.5 mg/kg) and fluoxetine (FLX, 5 mg/kg) in the chronic escape deficit model of depression. The chronic escape deficit model is based on the modified reactivity of rats to external stimuli induced by exposure to unavoidable stress and allows evaluation of the capacity of a treatment to revert the condition of escape deficit. In this model, FLX alone needs to be administered for at least 3 weeks to revert this condition. Our results show that combined treatment of fluoxetine and ASA completely reverted the condition of escape deficit by as early as 7 days, the effect being already partially present after 4 days. The effect was maintained after 14 and 21 days of treatment. ASA alone was ineffective at any time tested and the effect of fluoxetine was significant only at 21 days. These results, together with clinical data from preliminary results, suggest that ASA might accelerate the onset of action of selective serotonin reuptake inhibitor antidepressants.
    International Clinical Psychopharmacology 08/2006; 21(4):219-25. DOI:10.1097/00004850-200607000-00004 · 3.10 Impact Factor
  • European Neuropsychopharmacology 03/2006; 16. DOI:10.1016/S0924-977X(06)80074-X · 5.40 Impact Factor

Publication Stats

355 Citations
141.08 Total Impact Points

Institutions

  • 2001–2014
    • Università degli Studi di Modena e Reggio Emilia
      • • Department of Medical and Surgical Sciences for Children and Adults
      • • Department of Life Sciences
      Modène, Emilia-Romagna, Italy
  • 2006
    • Laval University
      Quebec City, Quebec, Canada
    • Vrije Universiteit Brussel
      • Department of Psychiatry
      Bruxelles, Brussels Capital, Belgium
  • 2002–2005
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
  • 1996
    • University of Milan
      • Center of Neuropharmacology
      Milano, Lombardy, Italy