Abstract

This paper summarizes a series of studies aimed at characterizing the effects of stress-related changes in synaptic inputs to the hypothalamic paraventricular nucleus (PVN). This structure generates an integrated physiological stress response by activating the hypothalamus-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH)-synthesizing parvocellular neuroendocrine neurons of the PVN play a key role in this process. They receive extensive excitatory and inhibitory innervation conveying information about interoceptive and exteroceptive stressful stimuli from a variety of sources within the brain. These synaptic inputs modulate the activity of PVN neurons, which regulates the amount of CRH released into the portal circulation of the anterior pituitary. It has been demonstrated that with either single or repeated stress sessions, the efficacy of excitatory and inhibitory synapses on parvocellular neuroendocrine neurons changes considerably, which may be related to repeated stress-induced sensitization of the HPA axis. The nature of these changes depends on the type of stress and its duration. Changes in synaptic inputs and the excitability of parvocellular neuroendocrine neurons are thought to be responsible for dysfunctions of the HPA axis observed in affective disorders. Assessing how this controlling function of PVN neurons is modulated in response to stress is crucial to our understanding of the pathophysiology of affective disorders.

References

• 1. Antoni F.A.: Hypothalamic control of adrenocorticotropin secretion: advances since the discovery of 41-residue corticotropin-releasing factor. Endocr. Rev., 1986; 7: 351-378
  Google Scholar
• 2. Arborelius L., Owens M.J., Plotsky P.M., Nemeroff C.B.: The role of corticotropin-releasing factor in depression and anxiety disorders. J. Endocrinol., 1999; 160: 1-12
  Google Scholar
• 3. Avishai-Eliner S., Eghbal-Ahmadi M., Tabachnik E., Brunson K.L., Baram T.Z.: Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA. Endocrinology, 2001; 142: 89-97
  Google Scholar
• 4. Bains J.S., Wamsteeker Cusulin J.I., Inoue W.: Stress-related synaptic plasticity in the hypothalamus. Nat. Rev. Neurosci., 2015; 16: 377-388
  Google Scholar
• 5. Bartanusz V., Aubry J.M., Pagliusi S., Jezova D., Baffi J., Kiss J.Z.: Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscience, 1995; 66: 247-252
  Google Scholar
• 6. Binder E.B., Nemeroff C.B.: The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol. Psychiatry, 2010; 15: 574 -588
  Google Scholar
• 7. Bito H., Deisseroth K., Tsien R.W.: CREB phosphorylation and dephosphorylation: a Ca2+- and stimulus duration-dependent switch for hippocampal gene expression. Cell, 1996; 87: 1203-1214
  Google Scholar
• 8. Blatt G.J., Fatemi S.H.: Alterations in GABAergic biomarkers in the autism brain: research findings and clinical implications. Anat. Rec., 2011; 294: 1646-1652
  Google Scholar
• 9. Bochenek A., Reicher M.: Anatomia człowieka. Tom IV: Układ nerwowy ośrodkowy, wyd. III, Państwowy Zakład Wydawnictw Lekarskich, Warszawa 1993
  Google Scholar
• 10. Bonaventure P., Nepomuceno D., Hein L., Sutcliffe J.G., Lovenberg T., Hedlund P.B.: Radioligand binding analysis of knockout mice reveals 5-hydroxytryptamine7 receptor distribution and uncovers 8-hydroxy-2-(di-n-propylamino) tetralin interaction with α2 adrenergic receptors. Neuroscience, 2004; 124: 901-911
  Google Scholar
• 11. Brunton P.J., Sausbier M., Wietzorrek G., Sausbier U., Knaus H.G., Russell J.A., Ruth P., Shipston M.J.: Hypothalamic-pituitary-adrenal axis hyporesponsiveness to restraint stress in mice deficient for large-conductance calcium- and voltage-activated potassium (BK) channels. Endocrinology, 2007; 148: 5496-5506
  Google Scholar
• 12. Budziszewska B.: Stres a zmiany neurodegeneracyjne w hipokampie. W: Mózg a stres. Red. J.B. Strosznajder, E. Przegaliński, Wydawnictwo Platan, Kraków 2008, 151-173
  Google Scholar
• 13. Burrone J., O’Byrne M., Murthy V.N.: Multiple forms of synaptic plasticity triggered by selective suppression of activity in individual neurons. Nature, 2002; 420: 414-418
  Google Scholar
• 14. Contesse V., Lenglet S., Grumolato L., Anouar Y., Lihrmann I., Lefebvre H., Delarue C., Vaudry H.: Pharmacological and molecular characterization of 5-hydroxytryptamine7 receptors in the rat adrenal gland. Mol. Pharmacol., 1999; 56: 552-561
  Google Scholar
• 15. Ferguson A.V., Latchford K.J., Samson W.K.: The paraventricular nucleus of the hypothalamus – a potential target for integrative treatment of autonomic dysfunction. Expert Opin. Ther. Targets, 2008; 12: 717-727
  Google Scholar
• 16. Flak J.N., Ostrander M.M., Tasker J.G., Herman J.P.: Chronic stress-induced neurotransmitter plasticity in the PVN. J. Comp. Neurol., 2009; 517: 156-165
  Google Scholar
• 17. Franco A.J., Chen C., Scullen T., Zsombok A., Salahudeen A.A., Di S., Herman J.P., Tasker J.G.: Sensitization of the hypothalamic-pituitary-adrenal axis in a male rat chronic stress model. Endocrinology, 2016; 157: 2346-2355
  Google Scholar
• 18. Gaetz W., Bloy L., Wang D.J., Port R.G., Blaskey L., Levy S.E., Roberts T.P.: GABA estimation in the brains of children on the autism spectrum: measurement precision and regional cortical variation. Neuroimage, 2014; 86: 1-9
  Google Scholar
• 19. Gregus A., Wintink A.J., Davis A.C., Kalynchuk L.E.: Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav. Brain. Res., 2005; 156: 105-114
  Google Scholar
• 20. Gunn B.G., Cunningham L., Cooper M.A., Corteen N.L., Seifi M., Swinny J.D., Lambert J.J., Belelli D.: Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: Relevance to neurosteroids and programming of the stress response. J. Neurosci., 2013; 33: 19534-19554
  Google Scholar
• 21. Herman J.P., Cullinan W.E.: Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci., 1997; 20: 78-84
  Google Scholar
• 22. Herman J.P, Figueiredo H., Mueller N.K., Ulrich-Lai Y., Ostrander M.M., Choi D.C., Cullinan W.E.: Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front. Neuroendocrinol., 2003; 24: 151-180
  Google Scholar
• 23. Herman J.P., Tasker J.G., Ziegler D.R., Cullinan W.E.: Local circuit regulation of paraventricular nucleus stress integration: Glutamate-GABA connections. Pharmacol. Biochem. Behav., 2002; 71: 457-468
  Google Scholar
• 24. Hewitt S.A., Wamsteeker J.I., Kurz E.U., Bains J.S.: Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis. Nat. Neurosci., 2009; 12: 438-443
  Google Scholar
• 25. Ho N., Liauw J.A., Blaeser F., Wei F., Hanissian S., Muglia L.M., Wozniak D.F., Nardi A., Arvin K.L., Holtzman D.M., Linden D.J., Zhuo M., Muglia L.J., Chatila T.A.: Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J. Neurosci., 2000; 20: 6459-6472
  Google Scholar
• 26. Hofmann T., Weibert E., Ahnis A., Elbelt U., Rose M., Klapp B.F., Stengel A.: Phoenixin is negatively associated with anxiety in obese men. Peptides., 2017; 88: 32-36
  Google Scholar
• 27. Holmes M.C., Di Renzo G., Beckford U., Gillham B., Jones M.T.: Role of serotonin in the control of secretion of corticotrophin releasing factor. J. Endocrinol., 1982; 93: 151-160
  Google Scholar
• 28. Hrabovszky E., Liposits Z.: Novel aspects of glutamatergic signalling in the neuroendocrine system. J. Neuroendocrinol., 2008; 20: 743-751
  Google Scholar
• 29. Huang M.H., So E.C., Liu Y.C., Wu S.N.: Glucocorticoids stimulate the activity of large-conductance Ca2+-activated K+ channels in pituitary GH3 and AtT-20 cells via a non-genomic mechanism. Steroids, 2006; 71: 129-140
  Google Scholar
• 30. Ibata K., Sun Q., Turrigiano G.G.: Rapid synaptic scaling induced by changes in postsynaptic firing. Neuron, 2008; 57: 819-826
  Google Scholar
• 31. Inoue W., Baimoukhametova D.V., Füzesi T., Wamsteeker Cusulin J.I., Koblinger K., Whelan P.J., Pittman Q.J., Bains J.S.: Noradrenaline is a stress-associated metaplastic signal at GABA synapses. Nat. Neurosci., 2013; 16: 605-612
  Google Scholar
• 32. Inoue W., Bains J.S.: Beyond inhibition: GABA synapses tune the neuroendocrine stress axis. Bioessays, 2014; 36: 561-569
  Google Scholar
• 33. Jedema H.P., Grace A.A: Corticotropin-releasing hormone directly activates noradrenergic neurons of the locus coeruleus recorded in vitro. J. Neurosci., 2004; 24: 9703-9713
  Google Scholar
• 34. Jeffcoate W.J., Silverstone J.T., Edwards C.R., Besser G.M.: Psychiatric manifestations of Cushing’s syndrome: Response to lowering of plasma cortisol. Q. J. Med., 1979; 48: 465-472
  Google Scholar
• 35. Jørgensen H., Knigge U., Kjaer A., Møller M., Warberg J.: Serotonergic stimulation of corticotropin-releasing hormone and pro-opiomelanocortin gene expression. J. Neuroendocrinol., 2002; 14; 788-795
  Google Scholar
• 36. Jørgensen H., Knigge U., Kjaer A., Warberg J.: Adrenocorticotropic hormone secretion in rats induced by stimulation with serotonergic compounds. J. Neuroendocrinol., 1999; 11: 283-290
  Google Scholar
• 37. Kageyama K., Tozawa F., Horiba N., Watanobe H., Suda T.: Serotonin stimulates corticotropin-releasing factor gene expression in the hypothalamic paraventricular nucleus of conscious rats. Neurosci. Lett., 1998; 243: 17-20
  Google Scholar
• 38. Kang H., Sun L.D., Atkins C.M., Soderling T.R., Wilson M.A., Tonegawa S.: An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell, 2001; 106: 771-783
  Google Scholar
• 39. Kawai F.: Ca2+-activated K+ currents regulate odor adaptation by modulating spike encoding of olfactory receptor cells. Biophys. J., 2002; 82: 2005-2015
  Google Scholar
• 40. King J.T., Lovell P.V., Rishniw M., Kotlikoff M.I., Zeeman M.L., McCobb D.P.: β2 and β4 subunits of BK channels confer differential sensitivity to acute modulation by steroid hormones. J. Neurophysiol., 2006; 95: 2878-2888
  Google Scholar
• 41. Kling M.A., Rubinow D.R., Doran A.R., Roy A., Davis C.L., Calabrese J.R., Nieman L.K., Post R.M., Chrousos G.P., Gold P.W.: Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing’s disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion. Neuroendocrinology, 1993; 57: 79-88
  Google Scholar
• 42. Kubas B., Kułak W., Sobaniec W., Tarasow E., Lebkowska U., Walecki J.: Metabolite alterations in autistic children: a 1H MR spectroscopy study. Adv. Med. Sci, 2012; 57: 152-156
  Google Scholar
• 43. Kumar P., Kalonia H., Kumar A.: Huntington’s disease: pathogenesis to animal models. Pharmacol. Rep., 2010; 62: 1-14
  Google Scholar
• 44. Kusek M., Tokarski K., Hess G.: Repeated restraint stress enhances glutamatergic transmission in the paraventricular nucleus of the rat hypothalamus. J. Physiol. Pharmacol., 2013; 64: 565-570
  Google Scholar
• 45. Kuzmiski J.B, Marty V., Baimoukhametova D.V., Bains J.S.: Stress-induced priming of glutamate synapses unmasks associative short-term plasticity. Nat. Neurosci., 2010; 13: 1257-1264
  Google Scholar
• 46. Larsen P.J., Hay-Schmidt A., Vrang N., Mikkelsen J.D.: Origin of projections from the midbrain raphe nuclei to the hypothalamic paraventricular nucleus in the rat: A combined retrograde and anterograde tracing study. Neuroscience, 1996; 70: 963-988
  Google Scholar
• 47. Levine S.: Maternal and environmental influences on the adrenocortical response to stress in weanling rats. Science, 1967; 156: 258-260
  Google Scholar
• 48. Linkowski P., Van Cauter E., Leclercq R., Desmedt D., Brasseur M., Golstein J., Copinschi G., Mendlewicz J.: ACTH, cortisol and growth hormone 24-hour profiles in major depressive illness. Acta Psychiatr. Belg., 1985; 85: 615-623
  Google Scholar
• 49. Liposits Z., Paull W.K., Jackson I.M., Lechan R.M.: Hypophysiotrophic thyrotropin releasing hormone (TRH) synthesizing neurons. Ultrastructure, adrenergic innervation and putative transmitter action. Histochemistry, 1987; 88: 1-10
  Google Scholar
• 50. Lovell P.V., King J.T., McCobb D.P.: Acute modulation of adrenal chromaffin cell BK channel gating and cell excitability by glucocorticoids. J. Neurophysiol., 2004; 91: 561-570
  Google Scholar
• 51. Magariños A.M., McEwen B.S.: Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience, 1995; 69: 89-98
  Google Scholar
• 52. Matthews E.A., Weible A.P., Shah S., Disterhoft J.F.: The BK-mediated fAHP is modulated by learning a hippocampus-dependent task. Proc. Natl. Acad. Sci. USA, 2008; 105: 15154-15159
  Google Scholar
• 53. Meredith A.L., Wiler S.W., Miller B.H., Takahashi J.S., Fodor A.A., Ruby N.F., Aldrich R.W.: BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output. Nat. Neurosci., 2006; 9: 1041-1049
  Google Scholar
• 54. Miklós I.H., Kovács K.J.: Reorganization of synaptic inputs to the hypothalamic paraventricular nucleus during chronic psychogenic stress in rats. Biol. Psychiatry, 2012; 71: 301-308
  Google Scholar
• 55. Muneoka K.T., Takigawa M.: 5-Hydroxytryptamine7 (5-HT7) receptor immunoreactivity-positive ‘stigmoid body’-like structure in developing rat brains. Int. J. Dev. Neurosci., 2003; 21: 133-143
  Google Scholar
• 56. Murphy B.E.: Antiglucocorticoid therapies in major depression: A review. Psychoneuroendocrinology, 1997; 22: S125-S132
  Google Scholar
• 57. Nelson A.B., Krispel C.M., Sekirnjak C., du Lac S.: Long-lasting increases in intrinsic excitability triggered by inhibition. Neuron, 2003; 40: 609-620
  Google Scholar
• 58. Nemeroff C.B., Widerlöv E., Bissette G., Walléus H., Karlsson I., Eklund K., Kilts C.D., Loosen P.T., Vale W.: Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science, 1984; 226: 1342-1344
  Google Scholar
• 59. Neumaier J.F., Sexton T.J., Yracheta J., Diaz A.M., Brownfield M.: Localization of 5-HT7 receptors in rat brain by immunocytochemistry, in situ hybridization, and agonist stimulated cFos expression. J. Chem. Neuroanat., 2001; 21: 63-73
  Google Scholar
• 60. Nunn N., Womack M., Dart C., Barrett-Jolley R.: Function and pharmacology of spinally-projecting sympathetic pre-autonomic neurones in the paraventricular nucleus of the hypothalamus. Curr. Neuropharmacology, 2011; 9: 262-277
  Google Scholar
• 61. Pan L., Gilbert F.: Activation of 5-HT1A receptor subtype in the paraventricular nuclei of the hypothalamus induces CRH and ACTH release in the rat. Neuroendocrinol., 1992; 56: 797-802
  Google Scholar
• 62. Pariante C.M., Makoff A., Lovestone S., Feroli S., Heyden A., Miller A.H., Kerwin R.W.: Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters. Br. J. Pharmacol., 2001; 134: 1335-1343
  Google Scholar
• 63. Pérez-Otaño I., Ehlers M.D.: Homeostatic plasticity and NMDA receptor trafficking. Trends Neurosci., 2005; 28: 229-238
  Google Scholar
• 64. Pyner S., Coote J.H.: Identification of branching paraventricular neurons of the hypothalamus that project to the rostroventrolateral medulla and spinal cord. Neuroscience, 2000; 100: 549-556
  Google Scholar
• 65. Salter E.W., Sunstrum J.K., Matovic S., Inoue W.: Chronic stress dampens excitatory synaptic gain in the paraventricular nucleus of the hypothalamus. J. Physiol, 2018; 596: 4157-4172
  Google Scholar
• 66. Sapolsky R.M.: Stress, health and social behavior. W: Encyclopedia of Animal Behavior, red.: M.D. Breed, J. Moore. Academic Press, London 2010, 350-357
  Google Scholar
• 67. Sapolsky R.M., Krey L.C., McEwen B.S.: Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. Proc. Natl. Acad. Sci. USA, 1984; 81: 6174-6177
  Google Scholar
• 68. Sarkar J., Wakefield S., MacKenzie G., Moss S.J., Maguire J.: Neurosteroidogenesis is required for the physiological response to stress: role of neurosteroid-sensitive GABAA receptors. J. Neurosci. 2011; 31: 18198-18210
  Google Scholar
• 69. Sawchenko P.E., Swanson L.W., Stenbusch H.W., Verhofstad A.A.: The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat. Brain Res., 1983; 277: 355-360
  Google Scholar
• 70. Selye H.: Hypertension as adaptation disease. Med. Klin., 1950; 45: 1637
  Google Scholar
• 71. Shafton A.D., Ryan A., Badoer E.: Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat. Brain Res., 1998; 801: 239-243
  Google Scholar
• 72. Shipston M.J., Kelly J.S., Antoni F.A.: Glucocorticoids block protein kinase A inhibition of calcium-activated potassium channels. J. Biol. Chem., 1996; 271: 9197-9200
  Google Scholar
• 73. Soderling T.R.: The Ca2+-calmodulin-dependent protein kinase cascade. Trends Biochem Sci., 1999; 24: 232-236
  Google Scholar
• 74. Sousa N., Madeira M.D., Paula-Barbosa M.M.: Corticosterone replacement restores normal morphological features to the hippocampal dendrites, axons and synapses of adrenalectomized rats. J. Neurocytol., 1999; 28: 541-558
  Google Scholar
• 75. Stokes P.E., Sikes C.R.: Hypothalamic-pituitary-adrenal axis in psychiatric disorders. Annu. Rev. Med., 1991; 42: 519-531
  Google Scholar
• 76. Szlachcic A., Surmiak M., Majka J., Brzozowski T.: Nesfatyna 1 – nowy hormon uczestniczący w kontroli przyjmowania pokarmu oraz w mechanizmach uszkodzenia i ochrony błony śluzowej żołądka. Prz. Gastroenterol., 2012; 7: 339-350
  Google Scholar
• 77. Thiagarajan T.C., Lindskog M., Tsien R.W.: Adaptation to synaptic inactivity in hippocampal neurons. Neuron, 2005; 47: 725-737
  Google Scholar
• 78. Tian L., Philp J.A., Shipston M.J.: Glucocorticoid block of protein kinase C signalling in mouse pituitary corticotroph AtT20 D16:16 cells. J. Physiol., 1999; 516: 757-768
  Google Scholar
• 79. Turrigiano G.: Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb. Perspect. Biol., 2012; 4: a005736
  Google Scholar
• 80. Turrigiano G.G., Leslie K.R., Desai N.S., Rutherford L.C., Nelson S.B.: Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature, 1998; 391: 892-896
  Google Scholar
• 81. Ulrich-Lai Y.M., Jones K.R., Ziegler D.R., Cullinan W.E., Herman J.P.: Forebrain origins of glutamatergic innervation to the rat paraventricular nucleus of the hypothalamus: Differential inputs to the anterior versus posterior subregions. J. Comp. Neurol., 2011; 519: 1301-1319
  Google Scholar
• 82. Valentino R.J., Foote S.L., Aston-Jones G.: Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Brain Res., 1983; 270: 363-367
  Google Scholar
• 83. Verkuyl J.M., Hemby S.E., Joëls M.: Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus. Eur. J. Neurosci., 2004; 20: 1665-1673
  Google Scholar
• 84. Verkuyl J.M., Karst H., Joëls M.: GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress. Eur. J. Neurosci., 2005; 21: 113-121
  Google Scholar
• 85. Vyas A., Mitra R., Shankaranarayana Rao B.S., Chattarji S.: Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci., 2002; 22: 6810-6818
  Google Scholar
• 86. Wamsteeker Cusulin J.I., Füzesi T., Watts A.G., Bains J.S.: Characterization of corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus of Crh-IRES-Cre mutant mice. PLoS One, 2013; 8: e64943
  Google Scholar
• 87. Watanabe Y., Gould E., Daniels D.C., Cameron H., McEwen B.S.: Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur. J. Pharmacol., 1992; 222: 157-162
  Google Scholar
• 88. Watt A.J., van Rossum M.C., MacLeod K.M., Nelson S.B., Turrigiano G.G.: Activity coregulates quantal AMPA and NMDA currents at neocortical synapses. Neuron, 2000; 26: 659-670
  Google Scholar
• 89. Wellman C.L.: Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J. Neurobiol., 2001; 49: 245-253
  Google Scholar
• 90. West A.E., Griffith E.C., Greenberg M.E.: Regulation of transcription factors by neuronal activity. Nat. Rev. Neurosci., 2002; 3: 921-931
  Google Scholar
• 91. Wiedemann K., Holsboer F.: Plasma dexamethasone kinetics during the DST after oral and intravenous administration of the test drug. Biol. Psychiatry, 1987; 22: 1340-1348
  Google Scholar
• 92. Wierońska J.M., Pilc A.: Depression and schizophrenia viewed from the perspective of amino acidergic neurotransmission: Antipodes of psychiatric disorders. Pharmacol. Ther., 2019; 193: 75-82
  Google Scholar
• 93. Yip J., Soghomonian J.J., Blatt G.J.: Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol., 2007; 113: 559-568
  Google Scholar
• 94. Ziegler D.R., Edwards M.R., Ulrich-Lai Y.M., Herman J.P., Cullinan W.E.: Brainstem origins of glutamatergic innervation of the rat hypothalamic paraventricular nucleus. J. Comp. Neurol., 2012; 520: 2369-2394
  Google Scholar
• 95. Zobel A.W., Nickel T., Künzel H.E., Ackl N., Sonntag A., Ising M., Holsboer F.: Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res., 2000; 34: 171-181
  Google Scholar

Full text