Reorganization of Synaptic Inputs to the Hypothalamic Paraventricular Nucleus During Chronic Psychogenic Stress in Rats

Published:December 05, 2011DOI:


      Chronic stress in humans precipitates hyper-reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis and triggers symptoms associated with certain forms of depression. Reorganization of neuronal networks has been implicated in development of depression, however it remained unknown how chronic exposure to psychogenic challenges affects excitatory and inhibitory inputs to corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus that govern neuroendocrine stress response.


      Rats (n = 32) were exposed for 21 days to chronic variable stress and their behavioral (sucrose preference) and hormonal (corticosterone) responses were followed together with electron microscopic stereologic analysis of excitatory and gamma-aminobutyric acid (GABA)-containing, inhibitory synapses on the CRH synthesizing neurons.


      Chronic stress in rats resulted in weight loss, anhedonia, and hyperactivity of hypothalamic-pituitary-adrenocortical axis. Following 3 weeks' exposure to variable psychologic stressors the number of synapses has been doubled in the paraventricular nucleus. Asymmetrical excitatory as well as GABAergic inhibitory synaptic contacts were increased on CRH neurons; however, the excitatory/inhibitory input ratio remained constant. In response to chronic stress, we found rearrangement of inhibitory GABA-containing inputs with the increase of contacts on dendrites and decrease at the soma region of CRH neurons.


      Significant remodeling of synaptic contacts was found on CRH neurons in response to chronic stress. This morphologic plasticity might be related to the hyperactivity of the HPA axis and to development of stress-related psychopathologies such as depression.

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        • Vale W.
        • Spiess J.
        • Rivier C.
        • Rivier J.
        Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.
        Science. 1981; 213: 1394-1397
        • Sawchenko P.E.
        • Brown E.R.
        • Chan R.K.
        • Ericsson A.
        • Li H.Y.
        • Roland B.L.
        • Kovacs K.J.
        The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress.
        Prog Brain Res. 1996; 107: 201-222
        • McEwen B.S.
        The neurobiology of stress: From serendipity to clinical relevance.
        Brain Res. 2000; 886: 172-189
        • Nemeroff C.B.
        • Krishnan K.R.
        • Reed D.
        • Leder R.
        • Beam C.
        • Dunnick N.R.
        Adrenal gland enlargement in major depression.
        Arch Gen Psychiatry. 1992; 49: 384-387
        • Schmider J.
        • Lammers C.H.
        • Gotthardt U.
        • Dettling M.
        • Holsboer F.
        • Heuser I.J.
        Combined dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I.
        Biol Psychiatry. 1995; 38: 797-802
        • Banasr M.
        • Valentine G.W.
        • Li X.Y.
        • Gourley S.L.
        • Taylor J.R.
        • Duman R.S.
        Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat.
        Bio Psychiatry. 2007; 62: 496-504
        • Tannenbaum B.
        • Tannenbaum G.S.
        • Sudom K.
        • Anisman H.
        Neurochemical and behavioral alterations elicited by a chronic intermittent stressor regimen: Implications for allostatic load.
        Brain Res. 2002; 953: 82-92
        • Herman J.P.
        • Adams D.
        • Prewitt C.
        Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm.
        Neuroendocrinology. 1995; 61: 180-190
        • Dallman M.F.
        • Akana S.F.
        • Cascio C.S.
        • Darlington D.N.
        • Jacobson L.
        • Levin N.
        Regulation of ACTH secretion: Variations on a theme of B.
        Recent Prog Horm Res. 1987; 43: 113-173
        • Herman J.P.
        • Cullinan W.E.
        Neurocircuitry of stress: Central control of the hypothalamo-pituitary-adrenocortical axis.
        Trends Neurosci. 1997; 20: 78-84
        • Roland B.L.
        • Sawchenko P.E.
        Local origins of some GABAergic projections to the paraventricular and supraoptic nuclei of the hypothalamus in the rat.
        J Comp Neurol. 1993; 332: 123-143
        • Kovacs K.J.
        • Miklos I.H.
        • Bali B.
        GABAergic mechanisms constraining the activity of the hypothalamo-pituitary-adrenocortical axis.
        Ann N Y Acad Sci. 2004; 1018: 466-476
        • Verkuyl J.M.
        • Karst H.
        • Joels M.
        GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress.
        EurJ Neurosci. 2005; 21: 113-121
        • Miklos I.H.
        • Kovacs K.J.
        GABAergic innervation of corticotropin-releasing hormone (CRH)-secreting parvocellular neurons and its plasticity as demonstrated by quantitative immunoelectron microscopy.
        Neuroscience. 2002; 113: 581-592
        • Verkuyl J.M.
        • Joels M.
        Effect of adrenalectomy on miniature inhibitory postsynaptic currents in the paraventricular nucleus of the hypothalamus.
        J Neurophysiol. 2003; 89: 237-245
        • Verkuyl J.M.
        • Hemby S.E.
        • Joels M.
        Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus.
        Eur J Neusci. 2004; 20: 1665-1673
        • Castren E.
        Is mood chemistry?.
        Nat Rev Neurosci. 2005; 6: 241-246
        • Videbech P.
        • Ravnkilde B.
        Hippocampal volume and depression: A meta-analysis of MRI studies.
        Am J Psychiatry. 2004; 161: 1957-1966
        • Vythilingam M.
        • Vermetten E.
        • Anderson G.M.
        • Luckenbaugh D.
        • Anderson E.R.
        • Snow J.
        • Staib L.H.
        • et al.
        Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment.
        Biol Psychiatry. 2004; 56: 101-112
        • Vythilingam M.
        • Heim C.
        • Newport J.
        • Miller A.H.
        • Anderson E.
        • Bronen R.
        • et al.
        Childhood trauma associated with smaller hippocampal volume in women with major depression.
        Am J Psychiatry. 2002; 159: 2072-2080
        • Gianaros P.J.
        • Horenstein J.A.
        • Cohen S.
        • Matthews K.A.
        • Brown S.M.
        • Flory J.D.
        • et al.
        Perigenual anterior cingulate morphology covaries with perceived social standing.
        Soc Cogn Affect Neurosci. 2007; 2: 161-173
        • Perez-Cruz C.
        • Muller-Keuker J.I.
        • Heilbronner U.
        • Fuchs E.
        • Flugge G.
        Morphology of pyramidal neurons in the rat prefrontal cortex: Lateralized dendritic remodeling by chronic stress.
        Neural Plast. 2007; 2007: 46276
        • Pego J.M.
        • Morgado P.
        • Pinto L.G.
        • Cerqueira J.J.
        • Almeida O.F.
        • Sousa N.
        Dissociation of the morphological correlates of stress-induced anxiety and fear.
        Eur J Neurosci. 2008; 27: 1503-1516
        • Mitra R.
        • Adamec R.
        • Sapolsky R.
        Resilience against predator stress and dendritic morphology of amygdala neurons.
        Behav Brain Res. 2009; 205: 535-543
        • Hajszan T.
        • Dow A.
        • Warner-Schmidt J.L.
        • Szigeti-Buck K.
        • Sallam N.L.
        • Parducz A.
        • et al.
        Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression.
        Biol Psychiatry. 2009; 65: 392-400
        • Kovacs K.J.
        • Makara G.B.
        Corticosterone and dexamethasone act at different brain sites to inhibit adrenalectomy-induced adrenocorticotropin hypersecretion.
        Brain Res. 1988; 474: 205-210
        • Somogyi P.
        • Soltesz I.
        Immunogold demonstration of GABA in synaptic terminals of intracellularly recorded, horseradish peroxidase-filled basket cells and clutch cells in the cat's visual cortex.
        Neuroscience. 1986; 19: 1051-1065
        • Bileviciute I.
        • Ahmed M.
        • Bergstrom J.
        • Ericsson-Dahlstrand A.
        • Kreicbergs A.
        • Lundeberg T.
        Expression of corticotropin-releasing factor in the peripheral nervous system of the rat.
        Neuroreport. 1997; 8: 3127-3130
        • Geinisman Y.
        • Gundersen H.J.
        • van der Zee E.
        • West M.J.
        Unbiased stereological estimation of the total number of synapses in a brain region.
        J Neurocytol. 1996; 25: 805-819
        • West M.J.
        • Gundersen H.J.
        Unbiased stereological estimation of the number of neurons in the human hippocampus.
        J Comp Neurol. 1990; 296: 1-22
        • Beaulieu C.
        Numerical data on neocortical neurons in adult rat, with special reference to the GABA population.
        Brain Res. 1993; 609: 284-292
        • Beaulieu C.
        • Campistron G.
        • Crevier C.
        Quantitative aspects of the GABA circuitry in the primary visual cortex of the adult rat.
        J Comp Neurol. 1994; 339: 559-572
        • De Groot D.M.
        • Bierman E.P.
        The complex-shaped “perforated” synapse, a problem in quantitative stereology of the brain.
        J Microsc. 1983; 131: 355-360
        • Sterio D.C.
        The unbiased estimation of number and sizes of arbitrary particles using the disector.
        J Microsc. 1984; 134: 127-136
        • 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
        • Whitnall M.H.
        Stress selectively activates the vasopressin-containing subset of corticotropin-releasing hormone neurons.
        Neuroendocrinology. 1989; 50: 702-707
        • Ceccatelli S.
        • Cortes R.
        • Hokfelt T.
        Effect of reserpine and colchicine on neuropeptide mRNA levels in the rat hypothalamic paraventricular nucleus.
        Brain Res Mol Brain Res. 1991; 9: 57-69
        • Ostrander M.M.
        • Ulrich-Lai Y.M.
        • Choi D.C.
        • Flak J.N.
        • Richtand N.M.
        • Herman J.P.
        Chronic stress produces enduring decreases in novel stress-evoked c-fos mRNA expression in discrete brain regions of the rat.
        Stress. 2009; 12: 469-477
        • Decavel C.
        • Van den Pol A.N.
        GABA: A dominant neurotransmitter in the hypothalamus.
        J Comp Neurol. 1990; 302: 1019-1037
        • Dallman M.F.
        Stress update: Adaptation of the hypothalamic-pituitary-adrenal axis to chronic stress.
        Trends Endocrinol Metab. 1993; 4: 62-69
        • Herman J.P.
        • Flak J.
        • Jankord R.
        Chronic stress plasticity in the hypothalamic paraventricular nucleus.
        Prog Brain Res. 2008; 170: 353-364
        • Luscher C.
        • Nicoll R.A.
        • Malenka R.C.
        • Muller D.
        Synaptic plasticity and dynamic modulation of the postsynaptic membrane.
        Nat Neurosci. 2000; 3: 545-550
        • Sawchenko P.E.
        • Swanson L.W.
        Central noradrenergic pathways for the integration of hypothalamic neuroendocrine and autonomic responses.
        Science. 1981; 214: 685-687
        • Pacak K.
        • Palkovits M.
        • Kopin I.J.
        • Goldstein D.S.
        Stress-induced norepinephrine release in the hypothalamic paraventricular nucleus and pituitary-adrenocortical and sympathoadrenal activity: In vivo microdialysis studies.
        Front Neuroendocrinol. 1995; 16: 89-150
        • Cole R.L.
        • Sawchenko P.E.
        Neurotransmitter regulation of cellular activation and neuropeptide gene expression in the paraventricular nucleus of the hypothalamus.
        J Neurosci. 2002; 22: 959-969
        • Follwell M.J.
        • Ferguson A.V.
        Cellular mechanisms of orexin actions on paraventricular nucleus neurones in rat hypothalamus.
        J Physiol. 2002; 545: 855-867
        • Zelena D.
        • Mergl Z.
        • Makara G.B.
        Glutamate agonists activate the hypothalamic-pituitary-adrenal axis through hypothalamic paraventricular nucleus but not through vasopressinerg neurons.
        Brain Res. 2005; 1031: 185-193
        • Mezey E.
        • Kiss J.Z.
        • Skirboll L.R.
        • Goldstein M.
        • Axelrod J.
        Increase of corticotropin-releasing factor staining in rat paraventricular nucleus neurones by depletion of hypothalamic adrenaline.
        Nature. 1984; 310: 140-141
        • Liposits Z.
        • Phelix C.
        • Paull W.K.
        Electron microscopic analysis of tyrosine hydroxylase, dopamine-beta-hydroxylase and phenylethanolamine-N-methyltransferase immunoreactive innervation of the hypothalamic paraventricular nucleus in the rat.
        Histochemistry. 1986; 84: 105-120
        • Liposits Z.
        • Phelix C.
        • Paull W.K.
        Synaptic interaction of serotonergic axons and corticotropin releasing factor (CRF) synthesizing neurons in the hypothalamic paraventricular nucleus of the rat.
        Histochemistry. 1987; 86: 541-549
        • Fuzesi T.
        • Wittmann G.
        • Liposits Z.
        • Lechan R.M.
        • Fekete C.
        Contribution of noradrenergic and adrenergic cell groups of the brainstem and agouti-related protein-synthesizing neurons of the arcuate nucleus to neuropeptide-y innervation of corticotropin-releasing hormone neurons in hypothalamic paraventricular nucleus of the rat.
        Endocrinology. 2007; 148: 5442-5450
        • Wittmann G.
        • Lechan R.M.
        • Liposits Z.
        • Fekete C.
        Glutamatergic innervation of corticotropin-releasing hormone- and thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus of the rat.
        Brain Res. 2005; 1039: 53-62
        • Kim H.
        • Whang W.W.
        • Kim H.T.
        • Pyun K.H.
        • Cho S.Y.
        • Hahm D.H.
        • et al.
        Expression of neuropeptide Y and cholecystokinin in the rat brain by chronic mild stress.
        Brain Res. 2003; 983: 201-208
        • Bowers G.
        • Cullinan W.E.
        • Herman J.P.
        Region-specific regulation of glutamic acid decarboxylase (GAD) mRNA expression in central stress circuits.
        J Neurosci. 1998; 18: 5938-5947
        • Cullinan W.E.
        • Ziegler D.R.
        • Herman J.P.
        Functional role of local GABAergic influences on the HPA axis.
        Brain Struct Funct. 2008; 213: 63-72
        • Bali B.
        • Kovacs K.J.
        GABAergic control of neuropeptide gene expression in parvocellular neurons of the hypothalamic paraventricular nucleus.
        Eur J Neurosci. 2003; 18: 1518-1526
        • Herman J.P.
        • Ostrander M.M.
        • Mueller N.K.
        • Figueiredo H.
        Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis.
        Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29: 1201-1213
        • McEwen B.S.
        Physiology and neurobiology of stress and adaptation: Central role of the brain.
        Physiol Rev. 2007; 87: 873-904
        • Duman R.S.
        • Malberg J.
        • Nakagawa S.
        • D'Sa C.
        Neuronal plasticity and survival in mood disorders.
        Biol Psychiatry. 2000; 48: 732-739
        • Calabrese F.
        • Molteni R.
        • Racagni G.
        • Riva M.A.
        Neuronal plasticity: A link between stress and mood disorders.
        Psychoneuroendocrinology. 2009; 34: S208-S216
        • Sandi C.
        Stress, cognitive impairment and cell adhesion molecules.
        Nat Rev Neurosci. 2004; 5: 917-930