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Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats

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Abstract

The dorsolateral striatum (DLS) processes motor and non-motor functions and undergoes extensive dopaminergic degeneration in Parkinson’s disease (PD). The nigrostriatal dopaminergic degeneration also affects other brain areas including the pre-frontal cortex (PFC), which has been associated with the appearance of anhedonia and depression at pre-motor phases of PD. Using behavioral, neurochemical, and electrophysiological approaches, we investigated the temporal dissociation between the role of the DLS and PFC in the appearance of anhedonia and defense behaviors relevant to depression in rats submitted to bilateral DLS lesions with 6-hydroxydopamine (6-OHDA; 10 μg/hemisphere). 6-OHDA induced partial dopaminergic nigrostriatal damage with no gross motor impairments. Anhedonic-like behaviors were observed in the splash and sucrose consumption tests only 7 days after 6-OHDA lesion. By contrast, defense behaviors relevant to depression evaluated in the forced swimming test and social withdrawal only emerged 21 days after 6-OHDA lesion when anhedonia was no longer present. These temporally dissociated behavioral alterations were coupled to temporal- and structure-dependent alterations in dopaminergic markers such as dopamine D1 and D2 receptors and dopamine transporter, leading to altered dopamine sensitivity in DLS and PFC circuits, evaluated electrophysiologically. These results provide the first demonstration of a dissociated involvement of the DLS and PFC in anhedonic-like and defense behaviors relevant to depression in 6-OHDA-lesioned rats, which was linked with temporal fluctuations in dopaminergic receptor density, leading to altered dopaminergic system sensitivity in these two brain structures. This sheds new light to the duality between depressive and anhedonic symptoms in PD.

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References

  1. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 318:121–134

    Article  PubMed  Google Scholar 

  2. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, NMSS Validation Group (2011) The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease. Mov Disord 3:399–406

    Article  Google Scholar 

  3. Chaudhuri KR, Healy DG, Schapira AH, National Institute for Clinical Excellence (2006) Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 5:235–245

    Article  PubMed  Google Scholar 

  4. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC

  5. Benazzi F (2006) Various forms of depression. Dialogues Clin Neurosci 8:151–161

    PubMed  PubMed Central  Google Scholar 

  6. Schrag A (2006) Quality of life and depression in Parkinson’s disease. J Neurol Sci 248:151–157

    Article  PubMed  Google Scholar 

  7. Martínez-Horta S, Riba J, de Bobadilla RF, Pagonabarraga J, Pascual-Sedano B, Antonijoan RM et al (2014) Apathy in Parkinson's disease: neurophysiological evidence of impaired incentive processing. J Neurosci 17:5918–5926

    Article  Google Scholar 

  8. Kehagia AA, Barker RA, Robbins TW (2010) Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease. Lancet Neurol 12:1200–1213

    Article  Google Scholar 

  9. Rieger JW, Schoenfeld MA, Heinze HJ, Bodis-Wollner I (2008) Different spatial organizations of saccade related BOLD activation in parietal and striate cortex. Brain Res 1233:89–97

    Article  CAS  PubMed  Google Scholar 

  10. Syed EC, Sharott A, Moll CK, Engel AK, Kral A (2011) Effect of sensory stimulation in rat barrel cortex, dorsolateral striatum and on corticostriatal functional connectivity. Eur J Neurosci 3:461–470

    Article  Google Scholar 

  11. Tops M, Koole SL, IJzerman H, Buisman-Pijlman FT (2014) Why social attachment and oxytocin protect against addiction and stress: insights from the dynamics between ventral and dorsal corticostriatal systems. Pharmacol Biochem Behav 119:39–48

    Article  CAS  PubMed  Google Scholar 

  12. Cryan JF, Lucki I (2000) Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine(2C) receptors. J Pharmacol Exp Ther 295:1120–1126

    CAS  PubMed  Google Scholar 

  13. Lopez-Rubalcava C, Lucki I (2000) Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology 22:191–199

    Article  CAS  PubMed  Google Scholar 

  14. Rial D, Castro AA, Machado N, Garção P, Gonçalves FQ, Silva HB et al (2014) Behavioral phenotyping of parkin-deficient mice: looking for early preclinical features of Parkinson's disease. PLoS One 9:e114216

    Article  PubMed  PubMed Central  Google Scholar 

  15. Craft TK, DeVries AC (2006) Role of IL-1 in poststroke depressive-like behavior in mice. Biol Psychiatry 60:812–818

    Article  CAS  PubMed  Google Scholar 

  16. Slattery DA, Markou A, Cryan JF (2007) Evaluation of reward processes in an animal model of depression. Psychopharmacology 190:555–568

    Article  CAS  PubMed  Google Scholar 

  17. Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110

    Article  CAS  PubMed  Google Scholar 

  18. Machado DG, Cunha MP, Neis VB, Balen GO, Colla AR, Grando J et al (2012) Rosmarinus officinalis L. hydroalcoholic extract, similar to fluoxetine, reverses depressive-like behavior without altering learning deficit in olfactory bulbectomized mice. J Ethnopharmacol 143:158–169

    Article  CAS  PubMed  Google Scholar 

  19. Koros E, Rosenbrock H, Birk G, Weiss C, Sams-Dodd F (2007) The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Neuropsychopharmacology 32:562–576

    Article  CAS  PubMed  Google Scholar 

  20. O’Shea M, McGregor IS, Mallet PE (2006) Repeated cannabinoid exposure during perinatal, adolescent or early adult ages produces similar long-lasting deficits in object recognition and reduced social interaction in rats. J Psychopharmacol 20:611–621

    Article  PubMed  Google Scholar 

  21. Matheus FC, Aguiar AS Jr, Castro AA, Villarinho JG, Ferreira J, Figueiredo CP et al (2012) Neuroprotective effects of agmatine in mice infused with a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behav Brain Res 235:263–272

    Article  CAS  PubMed  Google Scholar 

  22. Pandolfo P, Machado NJ, Köfalvi A, Takahashi RN, Cunha RA (2013) Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder. Eur Neuropsychopharmacol 23:317–328

    Article  CAS  PubMed  Google Scholar 

  23. Costenla AR, Diógenes MJ, Canas PM, Rodrigues RJ, Nogueira C, Maroco J et al (2011) Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing. Eur J Neurosci 34:12–21

    Article  PubMed  Google Scholar 

  24. Tadaiesky MT, Dombrowski PA, Figueiredo CP, Cargnin-Ferreira E, Da Cunha C, Takahashi RN (2008) Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson’s disease. Neuroscience 156:830–840

  25. Santiago RM, Barbieiro J, Lima MM, Dombrowski PA, Andreatini R, Vital MA (2010) Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine. Prog Neuropsychopharmacol Biol Psychiatry 34:1104–1114

    Article  CAS  PubMed  Google Scholar 

  26. Rampersaud N, Harkavyi A, Giordano G, Lever R, Whitton J, Whitton PS (2012) Exendin-4 reverses biochemical and behavioral deficits in a pre-motor 5 rodent model of Parkinson's disease with combined noradrenergic and serotonergic 6 lesions. Neuropeptides 46:183–193

    Article  CAS  PubMed  Google Scholar 

  27. Ferrer I, Martinez A, Blanco R, Dalfó E, Carmona M (2011) Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease. J Neural Transm 118:821–839

    Article  PubMed  Google Scholar 

  28. Schapira AH, Tolosa E (2013) Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat Rev Neurol 6:309–317

    Article  Google Scholar 

  29. Connolly B, Fox SH (2014) Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease. Neurotherapeutics 11:78–91

    Article  CAS  PubMed  Google Scholar 

  30. Lemke MR (2008) Depressive symptoms in Parkinson's disease. Eur J Neurol 15(Suppl 1):21–25

    Article  PubMed  Google Scholar 

  31. Loas G, Krystkowiak P, Godefroy O (2012) Anhedonia in Parkinson's disease: an overview. J Neuropsychiatry Clin Neurosci 24:444–451

    Article  PubMed  Google Scholar 

  32. Starkstein S, Dragovic M, Jorge R, Brockman S, Merello M, Robinson RG et al (2011) Diagnostic criteria for depression in Parkinson's disease: a study of symptom patterns using latent class analysis. Mov Disord 26:2239–2245

    Article  PubMed  Google Scholar 

  33. Agrawal AK, Husain R, Raghubir R, Kumar A, Seth PK (1995) Neurobehavioral, neurochemical and electrophysiological studies in 6-hydroxydopamine lesioned and neural transplanted rats. Int J Dev Neurosci 13:105–111

    Article  CAS  PubMed  Google Scholar 

  34. Deumens R, Blokland A, Prickaerts J (2002) Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 175:303–317

    Article  CAS  PubMed  Google Scholar 

  35. Gui ZH, Zhang QJ, Liu J, Zhang L, Ali U, Hou C et al (2011) Unilateral lesion ofthe nigrostriatal pathway decreases the response of fast-spiking interneurons in the medialprefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat. Neurochem Int 59:618–627

    Article  CAS  PubMed  Google Scholar 

  36. Zhang QJ, Li LB, Niu XL, Liu J, Gui ZH, Feng JJ et al (2011) The pyramidal neurons in the medial prefrontal cortex show decreased response to 5-hydroxytryptamine-3 receptor stimulation in a rodent model of Parkinson's disease. Brain Res 1384:69–79

    Article  CAS  PubMed  Google Scholar 

  37. Ernst M, Fudge JL (2009) A developmental neurobiological model of motivated behavior: anatomy, connectivity and ontogeny of the triadic nodes. Neurosci Biobehav Rev 33:367–382

    Article  PubMed  Google Scholar 

  38. Morgane PJ, Galler JR, Mokler DJ (2005) A review of systems and networks of the limbic forebrain/limbic midbrain. Prog Neurobiol 75:143–160

    Article  PubMed  Google Scholar 

  39. Krishnan V, Nestler EJ (2010) Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 167:1305–1320

    Article  PubMed  PubMed Central  Google Scholar 

  40. Price JL, Drevets WC (2012) Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn Sci 16:61–71

    Article  PubMed  Google Scholar 

  41. Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC (2014) Optogenetic dissection of medial prefrontal cortex circuitry. Front Syst Neurosci 8:230

    Article  PubMed  PubMed Central  Google Scholar 

  42. Volman SF, Lammel S, Margolis EB, Kim Y, Richard JM, Roitman MF et al (2013) New insights into the specificity and plasticity of reward and aversion encoding in the mesolimbic system. J Neurosci 33:17569–71576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Drew MR, Simpson EH, Kellendonk C, Herzberg WG, Lipatova O, Fairhurst S et al (2007) Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing. J Neurosci 27:7731–7739

    Article  CAS  PubMed  Google Scholar 

  44. Der-Avakian A, Markou A (2012) The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci 35:68–77

    Article  CAS  PubMed  Google Scholar 

  45. Marchand WR (2012) Self-referential thinking, suicide, and function of the cortical midline structures and striatum in mood disorders: possible implications for treatment studies of mindfulness-based interventions for bipolar depression. Depress Res Treat 2012:246725

    PubMed  Google Scholar 

  46. Shepherd GM (2013) Corticostriatal connectivity and its role in disease. Nat Rev Neurosci 14:278–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Johnstone T, van Reekum CM, Urry HL, Kalin NH, Davidson RJ (2007) Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J Neurosci 27:8877–8884

    Article  CAS  PubMed  Google Scholar 

  48. Duman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338:68–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Downar J, Geraci J, Salomons TV, Dunlop K, Wheeler S, McAndrews MP et al (2014) Anhedonia and reward-circuit connectivity distinguish non-responders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry 76:176–185

    Article  PubMed  Google Scholar 

  50. Hamilton JP, Chen MC, Waugh CE, Joormann J, Gotlib IH (2014) Distinctive and common neural underpinnings of major depression, social anxiety, and their comorbidity. Soc Cogn Affect Neurosci (in press)

  51. Cools R, D'Esposito M (2011) Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 69:e113–e125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Floresco SB (2013) Prefrontal dopamine and behavioral flexibility: shifting from an "inverted-U" toward a family of functions. Front Neurosci 7:62

    Article  PubMed  PubMed Central  Google Scholar 

  53. Grace AA, Floresco SB, Goto Y, Lodge DJ (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 30:220–227

    Article  CAS  PubMed  Google Scholar 

  54. Yadid G, Friedman A (2008) Dynamics of the dopaminergic system as a key component to the understanding of depression. Prog Brain Res 172:265–286

    Article  CAS  PubMed  Google Scholar 

  55. Dreyer JK (2014) Three mechanisms by which striatal denervation causes breakdown of dopamine signaling. J Neurosci 37:12444–12456

    Article  Google Scholar 

  56. Lemke MR, Brecht HM, Koester J, Kraus PH, Reichmann H (2005) Anhedonia, depression, and motor functioning in Parkinson's disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci 17:214–220

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-FCT), Programa de Apoio aos Núcleos de Excelência (PRONEX - Project NENASC), Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), Ciência sem Fronteiras, DARPA (09-68-ESR-FP-010), NARSAD, QREN (09-68-ESR-FP-010), and Santa Casa da Misericórdia. F.C.M and D.R received scholarships from CNPq. R.N.T. and R.D.P. are supported by research fellowship from CNPq.

Conflict of interest

All authors reported no biomedical financial interests or potential conflicts of interest.

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Authors and Affiliations

  1. Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, 88049-900, Brazil

    Filipe C. Matheus, Daniel Rial, Reinaldo N. Takahashi, Leandro J. Bertoglio & Rui D. Prediger

  2. Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-517, Coimbra, Portugal

    Daniel Rial, Joana I. Real, Cristina Lemos & Rodrigo A. Cunha

  3. Faculty of Medicine, University of Coimbra, 3005-504, Coimbra, Portugal

    Rodrigo A. Cunha

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  1. Filipe C. Matheus
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Correspondence to Rui D. Prediger.

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Matheus, F.C., Rial, D., Real, J.I. et al. Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats. Mol Neurobiol 53, 3891–3899 (2016). https://doi.org/10.1007/s12035-015-9330-z

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