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Activation of a ventral hippocampus–medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine

Molecular Psychiatry volume 21, pages 1298–1308 (2016)Cite this article

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Abstract

A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine’s antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp–mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine’s antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine’s sustained antidepressant response. These data demonstrate that activity in the vHipp–mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine.

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References

  1. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905–1917.

    Article  Google Scholar 

  2. Katz MM, Bowden CL, Frazer A . Rethinking depression and the actions of antidepressants: uncovering the links between the neural and behavioral elements. J Affect Disord 2010; 120: 16–23.

    Article  CAS  Google Scholar 

  3. Pilc A, Wieronska JM, Skolnick P . Glutamate-based antidepressants: preclinical psychopharmacology. Biol Psychiatry 2013; 73: 1125–1132.

    Article  CAS  Google Scholar 

  4. Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG et al. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1155–1159.

    Article  CAS  Google Scholar 

  5. DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 2010; 71: 1605–1611.

    Article  CAS  Google Scholar 

  6. Zarate CA Jr, Brutsche N, Laje G, Luckenbaugh DA, Venkata SL, Ramamoorthy A et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry 2012; 72: 331–338.

    Article  CAS  Google Scholar 

  7. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013; 74: 250–256.

    Article  CAS  Google Scholar 

  8. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ . Ketamine for depression: where do we go from here? Biol Psychiatry 2012; 72: 537–547.

    Article  CAS  Google Scholar 

  9. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.

    Article  CAS  Google Scholar 

  10. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475: 91–95.

    Article  CAS  Google Scholar 

  11. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69: 754–761.

    Article  CAS  Google Scholar 

  12. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008; 63: 349–352.

    Article  CAS  Google Scholar 

  13. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G . Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012; 62: 35–41.

    Article  CAS  Google Scholar 

  14. Cook SC, Wellman CL . Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol 2004; 60: 236–248.

    Article  Google Scholar 

  15. Frodl T, Reinhold E, Koutsouleris N, Reiser M, Meisenzahl EM . Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. J Psychiatr Res 2010; 44: 799–807.

    Article  Google Scholar 

  16. Garrett JE, Wellman CL . Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence. Neuroscience 2009; 162: 195–207.

    Article  CAS  Google Scholar 

  17. Squire LR, Stark CE, Clark RE . The medial temporal lobe. Annu Rev Neurosci 2004; 27: 279–306.

    Article  CAS  Google Scholar 

  18. Videbech P, Ravnkilde B . Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004; 161: 1957–1966.

    Google Scholar 

  19. Ishikawa A, Nakamura S . Ventral hippocampal neurons project axons simultaneously to the medial prefrontal cortex and amygdala in the rat. J Neurophysiol 2006; 96: 2134–2138.

    Article  Google Scholar 

  20. Jay TM, Witter MP . Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J Comp Neurol 1991; 313: 574–586.

    Article  CAS  Google Scholar 

  21. French SJ, Totterdell S . Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats. Neuroscience 2003; 119: 19–31.

    Article  CAS  Google Scholar 

  22. Friedman DP, Aggleton JP, Saunders RC . Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: combined anterograde and retrograde tracing study in the Macaque brain. J Comp Neurol 2002; 450: 345–365.

    Article  Google Scholar 

  23. Miller EJ, Saint Marie LR, Breier MR, Swerdlow NR . Pathways from the ventral hippocampus and caudal amygdala to forebrain regions that regulate sensorimotor gating in the rat. Neuroscience 2010; 165: 601–611.

    Article  CAS  Google Scholar 

  24. Duman RS, Malberg J, Thome J . Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 1999; 46: 1181–1191.

    Article  CAS  Google Scholar 

  25. Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000; 48: 830–843.

    Article  CAS  Google Scholar 

  26. Nibuya M, Nestler EJ, Duman RS . Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16: 2365–2372.

    Article  CAS  Google Scholar 

  27. Cryan JF, Page ME, Lucki I . Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology 2005; 182: 335–344.

    Article  CAS  Google Scholar 

  28. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF . Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 2005; 8: 365–371.

    Article  CAS  Google Scholar 

  29. Laviolette SR, Lipski WJ, Grace AA . A subpopulation of neurons in the medial prefrontal cortex encodes emotional learning with burst and frequency codes through a dopamine D4 receptor-dependent basolateral amygdala input. J Neurosci 2005; 25: 6066–6075.

    Article  CAS  Google Scholar 

  30. Furmaga H, Carreno FR, Frazer A . Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain. PLoS One 2012; 7: e34844.

    Article  CAS  Google Scholar 

  31. Kotermanski SE, Johnson JW, Thiels E . Comparison of behavioral effects of the NMDA receptor channel blockers memantine and ketamine in rats. Pharmacol Biochem Behav 2013; 109: 67–76.

    Article  CAS  Google Scholar 

  32. Floresco SB, Seamans JK, Phillips AG . Differential effects of lidocaine infusions into the ventral CA1/subiculum or the nucleus accumbens on the acquisition and retention of spatial information. Behav Brain Res 1996; 81: 163–171.

    Article  CAS  Google Scholar 

  33. Chudasama Y, Doobay VM, Liu Y . Hippocampal-prefrontal cortical circuit mediates inhibitory response control in the rat. J Neurosci 2012; 32: 10915–10924.

    Article  CAS  Google Scholar 

  34. Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F . Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 2001; 21: 9917–9929.

    Article  CAS  Google Scholar 

  35. Koponen E, Rantamaki T, Voikar V, Saarelainen T, MacDonald E, Castren E . Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. Cell Mol Neurobiol 2005; 25: 973–980.

    Article  Google Scholar 

  36. Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 2008; 59: 399–412.

    Article  CAS  Google Scholar 

  37. Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci USA 2004; 101: 10827–10832.

    Article  CAS  Google Scholar 

  38. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK . Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 2012; 71: 996–1005.

    Article  CAS  Google Scholar 

  39. Laje G, Lally N, Mathews D, Brutsche N, Chemerinski A, Akula N et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry 2012; 72: e27–e28.

    Article  CAS  Google Scholar 

  40. Rocher C, Spedding M, Munoz C, Jay TM . Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex 2004; 14: 224–229.

    Article  Google Scholar 

  41. Jodo E, Suzuki Y, Katayama T, Hoshino KY, Takeuchi S, Niwa S et al. Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway. Cereb Cortex 2005; 15: 663–669.

    Article  Google Scholar 

  42. Homayoun H, Moghaddam B . NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007; 27: 11496–11500.

    Article  CAS  Google Scholar 

  43. Moghaddam B, Adams B, Verma A, Daly D . Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921–2927.

    Article  CAS  Google Scholar 

  44. Dwyer JM, Duman RS . Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants. Biol Psychiatry 2013; 73: 1189–1198.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIMH grants MH082933 (AF) and MH090067 (DJL) and a NARSAD award from the Maltz Family Foundation (DJL).

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Authors and Affiliations

  1. Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA

    F R Carreno, J J Donegan, A M Boley, A Shah, M DeGuzman, A Frazer & D J Lodge

  2. Audie L. Murphy Division,, South Texas Veterans Health Care System, San Antonio,, TX, USA

    A Frazer

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  1. F R Carreno
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  2. J J Donegan
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Correspondence to F R Carreno.

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Competing interests

Dr Frazer has served on advisory boards for Lundbeck and for Takeda Pharmaceuticals International, Inc and Eli Lilly and Co., and as a consultant for Dey Pharmaceuticals. Dr Lodge reports receiving consulting fees from Dey Pharmaceuticals.

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Carreno, F., Donegan, J., Boley, A. et al. Activation of a ventral hippocampus–medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol Psychiatry 21, 1298–1308 (2016). https://doi.org/10.1038/mp.2015.176

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