Elsevier

Neuroscience

Volume 239, 3 June 2013, Pages 214-227
Neuroscience

Review
Dynamic plasticity: The role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors

https://doi.org/10.1016/j.neuroscience.2012.08.034Get rights and content

Abstract

Brain-derived neurotrophic factor (BDNF) is a secreted protein that has been linked to numerous aspects of plasticity in the central nervous system (CNS). Stress-induced remodeling of the hippocampus, prefrontal cortex and amygdala is coincident with changes in the levels of BDNF, which has been shown to act as a trophic factor facilitating the survival of existing and newly born neurons. Initially, hippocampal atrophy after chronic stress was associated with reduced BDNF, leading to the hypothesis that stress-related learning deficits resulted from suppressed hippocampal neurogenesis. However, recent evidence suggests that BDNF also plays a rapid and essential role in regulating synaptic plasticity, providing another mechanism through which BDNF can modulate learning and memory after a stressful event. Numerous reports have shown BDNF levels are highly dynamic in response to stress, and not only vary across brain regions but also fluctuate rapidly, both immediately after a stressor and over the course of a chronic stress paradigm. Yet, BDNF alone is not sufficient to effect many of the changes observed after stress. Glucocorticoids and other molecules have been shown to act in conjunction with BDNF to facilitate both the morphological and molecular changes that occur, particularly changes in spine density and gene expression. This review briefly summarizes the evidence supporting BDNF’s role as a trophic factor modulating neuronal survival, and will primarily focus on the interactions between BDNF and other systems within the brain to facilitate synaptic plasticity. This growing body of evidence suggests a more nuanced role for BDNF in stress-related learning and memory, where it acts primarily as a facilitator of plasticity and is dependent upon the coactivation of glucocorticoids and other factors as the determinants of the final cellular response.

Highlights

► This review summarizes the effects of glucocorticoids and BDNF on neural plasticity. ► BDNF localization and activation of its receptors are described. ► Trophic effects of glucocorticoids are compared in hippocampus and amygdala. ► Interactions with neurotransmitters and other signaling molecules are covered.

Introduction

The identification of brain-derived neurotrophic factor (BDNF), a protein isolated from the brain that supports neuronal survival both in vitro (Lindsay et al., 1985) and in vivo (Hofer and Barde, 1988), was a breakthrough whose impact is continuing to expand. Since it was first purified (Barde et al., 1982), BDNF has accumulated over 10,000 publications as new functions continue to be discovered. This review will focus on the role of BDNF in neuroplasticity in response to stress, and how glucocorticoids (GC) as well as other molecules work in conjunction with BDNF to facilitate changes in neural connectivity.

Chronic stress has numerous pathological effects in males that can vary by brain region, but have been most well-documented in the hippocampus, prefrontal cortex (PFC), and amygdala. In the hippocampus, stress has been associated with decreases in overall size, reduced numbers of new neurons (Gould et al., 1997), such as GABAergic parvalbumin-containing interneurons (Czeh et al., 2005, Hu et al., 2010), reduced dendritic branching, and decreases in spine density [reviewed (McEwen, 1999)]. Similar changes in dendritic branching and spine density have been observed in the PFC [reviewed (Holmes and Wellman, 2009)], whereas in the amygdala, opposite effects are observed, resulting in increases in dendritic length and spine density (Vyas et al., 2002, Mitra et al., 2005). In the hippocampus and amygdala, stress-induced changes can be replicated by the chronic administration of GCs, which mimic the elevation of cortisol that occurs during activation of the hypothalamic/pituitary/adrenal axis in response to stress (McEwen, 1999, Mitra and Sapolsky, 2008). However, recent work has also suggested that elevation of cortisol prior to an acute stress can be protective of stress-induced changes in the amygdala (Rao et al., 2012). Together these results show that the effects of GC elevation can vary depending on brain region, duration of treatment, and relation to other stressors, suggesting that other factors in the brain help to mediate the effects of GCs.

These changes in the hippocampus in response to stress led to the formulation of the “neurotrophic hypothesis” of mood disorders, which postulated that depression and anxiety arose from a lack of trophic support in specific brain regions, and by reversing this deficit symptoms could be ameliorated (Duman et al., 1997, Nestler et al., 2002). Research into the neurotrophic hypothesis has focused on BDNF as a primary factor. Initial studies showed reductions in BDNF in the hippocampus after acute and chronic stress that, in the dentate, could be replicated by corticosterone (CORT) administration (Smith et al., 1995b). Studies of post-mortem brain have shown reductions in BDNF in the hippocampus (Dwivedi et al., 2003, Karege et al., 2005, Dunham et al., 2009) and PFC (Karege et al., 2005) of depressed patients. Alternatively, either no change or increases in BDNF have been observed in patients treated with antidepressants (Chen et al., 2001). In rodents, direct infusion of BDNF has been shown to increase neurogenesis in the hippocampus (Scharfman et al., 2005). Further, the administration of antidepressants to rodents can increase BDNF expression in the hippocampus (Nibuya et al., 1995) and prevent stress-induced changes (McEwen et al., 1997). However, work from this lab (Kuroda and McEwen, 1998) and others (Isgor et al., 2004) have not consistently identified reductions in BDNF mRNA after chronic stress, suggesting that the hippocampal atrophy observed cannot simply be explained as decreased neurogenesis resulting from decreased BDNF. These data, as well as more recent studies showing that BDNF levels in CA3 return to baseline after recovery from either an acute or chronic stressor (Lakshminarasimhan and Chattarji, 2012), suggest that hippocampal BDNF levels are highly dynamic. This review seeks to characterize the complex interplay between fluctuating GC and BDNF levels as they relate to structural and functional changes in the brain in response to stress.

Section snippets

Localization and activation of BDNF and its receptors

BDNF is initially translated as a precursor protein (proBDNF) that is proteolytically cleaved to form mature BDNF (Seidah et al., 1996, Lu, 2003). Mature BDNF functions by binding primarily to tropomyosin-related kinase B (TrkB) receptors to activate several intracellular signaling pathways, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), phospholipase Cγ (PLCγ), and phosphoinositide 3-kinase (PI3K)(Huang and Reichardt, 2003). ProBDNF

Trophic influence of GCs in brain

Coincident with the discovery of BDNF, GCs were also established as trophic factors in the hippocampus. Studies removing circulating GCs by adrenalectomy showed reduced dendritic branching and complexity as well as death of granule neurons of the dentate gyrus as early as three days after the procedure (Gould et al., 1990) and this loss persisted for three to four months in rats (Sloviter et al., 1989). However, cell death and changes in neuronal morphology could be prevented by CORT

In vivo regional and temporal variation in the BDNF response to elevated GCs resulting from stress

As research into the effects of stress on the brain expanded beyond the hippocampus, it became evident that elevated GC levels can have contrasting effects across brain regions. In the male rat basolateral amygdala (BLA), chronic restraint stress resulted in dendritic growth and increases in spine density, exactly opposite the changes observed in the hippocampus (Vyas et al., 2002). These changes in the BLA in response to stress are less plastic in comparison to the CA3 of the hippocampus,

Synaptic plasticity requires GC, BDNF and other modulators

Direct evidence has emerged demonstrating an essential role for GCs in spine remodeling and plasticity in vivo. Using transcranial two-photon live imaging of the cortex, Liston and Gan (2011), showed that CORT injections enhance spine turnover in multiple cortical regions and either dexamethasone suppression (Fig. 3A–C) or use of CORT antagonists (Fig. 3D, E) can block spine remodeling. However, while short-term CORT treatments enhanced spine dynamics, chronic CORT exposure disrupted

Future directions

The research described above demonstrates the importance of other molecules acting together with BDNF to modulate neural plasticity, yet the mechanisms underlying how they each orchestrate changes in the brain’s structure and function are far from fully described. Of particular importance going forward will be a more detailed analysis of the time-course and mechanisms of GC–BDNF actions, as recent work has suggested GCs are positioned to mediate rapid actions on TrkB (Johnson et al., 2005),

Summary

This review summarizes how neural plasticity in response to stress involves not only the elevation of GCs, but requires BDNF and other molecules to induce numerous physiological and morphological changes in neurons. BDNF and its receptors are localized to regions of the brain that are the most dynamic in response to stress, both at the gross anatomical level in the hippocampus and amygdala, and at the ultrastructural level in either presynaptic terminals or postsynaptic dendritic shafts and

Acknowledgements

This work was supported by the Gary R. Helman fellowship to JDG, NIH Grants MH41256 and AG016765 to BSM and NIH Grants HL098351, HL096571, DA08259 and AG039850 to TAM.

The authors thank: Drs. Barbara Hempstead and Jianmin Yang (Weill Cornell Medical College) for providing the BDNF-HA mice (Fig. 1), Ms. Andreina Gonzalez for preparing the BDNF-HA labeled light microscopic tissue (Fig. 1), Dr. Elizabeth M. Waters and Ms. Jolanta Gorecka (The Rockefeller University) for providing the ptrkB-labeled

References (130)

  • A. Gerdelat-Mas et al.

    Chronic administration of selective serotonin reuptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects

    Neuroimage

    (2005)
  • J.A. Gorski et al.

    Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice

    Neuroscience

    (2003)
  • E. Gould et al.

    Activation of the type 2 adrenal steroid receptor can rescue granule cells from death during development

    Brain Res Dev Brain Res

    (1997)
  • E. Gould et al.

    Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus

    Neuroscience

    (1990)
  • S.L. Gourley et al.

    Acute hippocampal brain-derived neurotrophic factor restores motivational and forced swim performance after corticosterone

    Biol Psychiatry

    (2008)
  • J.J. Hill et al.

    Analysis of pyramidal neuron morphology in an inducible knockout of brain-derived neurotrophic factor

    Biol Psychiatry

    (2005)
  • A. Holmes et al.

    Stress-induced prefrontal reorganization and executive dysfunction in rodents

    Neurosci Biobehav Rev

    (2009)
  • Z.J. Huang et al.

    BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex

    Cell

    (1999)
  • L.R. Johnson et al.

    Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala

    Neuroscience

    (2005)
  • F. Karege et al.

    Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs

    Brain Res Mol Brain Res

    (2005)
  • Y. Kuroda et al.

    Effect of chronic restraint stress and tianeptine on growth factors, growth-associated protein-43 and microtubule-associated protein 2 mRNA expression in the rat hippocampus

    Brain Res Mol Brain Res

    (1998)
  • Y.S. Lim et al.

    P75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping

    Neuron

    (2008)
  • R.M. Lindsay et al.

    Placode and neural crest-derived sensory neurons are responsive at early developmental stages to brain-derived neurotrophic factor

    Dev Biol

    (1985)
  • Q. Liu et al.

    Identification of a new acute phase protein

    J Biol Chem

    (1995)
  • B. Lu

    Pro-region of neurotrophins: role in synaptic modulation

    Neuron

    (2003)
  • V. Luine et al.

    Repeated stress causes reversible impairments of spatial memory performance

    Brain Res

    (1994)
  • S. Murakami et al.

    Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly

    Neurosci Res

    (2005)
  • G. Naert et al.

    Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress

    Mol Cell Neurosci

    (2011)
  • E.W. Neeley et al.

    Prenatal stress differentially alters brain-derived neurotrophic factor expression and signaling across rat strains

    Neuroscience

    (2011)
  • E.J. Nestler et al.

    Neurobiology of depression

    Neuron

    (2002)
  • T.A. Pham et al.

    CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period

    Neuron

    (1999)
  • E.P. Pioro et al.

    Distribution of nerve growth factor receptor-like immunoreactivity in the adult rat central nervous system. Effect of colchicine and correlation with the cholinergic system-I. Forebrain

    Neuroscience

    (1990)
  • R.P. Rao et al.

    Glucocorticoids protect against the delayed behavioral and cellular effects of acute stress on the amygdala

    Biol Psychiatry

    (2012)
  • M. Acler et al.

    A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients

    J Neurol

    (2009)
  • T. Advani et al.

    Gender differences in the enhanced vulnerability of BDNF+/− mice to mild stress

    Int J Neuropsychopharmacol

    (2009)
  • S.X. Bamji et al.

    The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death

    J Cell Biol

    (1998)
  • Y.A. Barde et al.

    Purification of a new neurotrophic factor from mammalian brain

    EMBO J

    (1982)
  • K.G. Bath et al.

    BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity

    Neuropsychopharmacology

    (2012)
  • A. Ben-Zvi et al.

    Modulation of semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon patterning

    J Neurosci

    (2007)
  • P. Berghuis et al.

    Brain-derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons

    Eur J Neurosci

    (2004)
  • P. Casaccia-Bonnefil et al.

    Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75

    Nature

    (1996)
  • A. Cellerino et al.

    The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex

    Eur J Neurosci

    (1996)
  • S. Chattarji

    Lipocalin comes callin’ on the hippocampus

    Proc Natl Acad Sci USA

    (2011)
  • Z.Y. Chen et al.

    Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons

    J Neurosci

    (2004)
  • J.M. Conner et al.

    Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport

    J Neurosci

    (1997)
  • B. Czeh et al.

    Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist

    Neuropsychopharmacology

    (2005)
  • M. Dam et al.

    Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy

    Stroke

    (1996)
  • E.R. De Kloet et al.

    Brain corticosteroid receptor balance in health and disease

    Endocr Rev

    (1998)
  • K. Deinhardt et al.

    Neuronal growth cone retraction relies on proneurotrophin receptor signaling through Rac

    Sci Signal

    (2011)
  • K.D. Dougherty et al.

    P75NTR immunoreactivity in the rat dentate gyrus is mostly within presynaptic profiles but is also found in some astrocytic and postsynaptic profiles

    J Comp Neurol

    (1999)
  • Cited by (188)

    View all citing articles on Scopus
    View full text