ReviewDynamic plasticity: The role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors
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)
- et al.
Co-localization of caldesmon and calponin with cortical afferents, metabotropic glutamate and neurotrophic receptors in the lateral and central nuclei of the amygdala
Brain Res
(2008) - et al.
Neurotrophic factors in the central nucleus of amygdala may be organized to provide substrates for associative learning
Brain Res
(2006) - et al.
Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway
Neuron
(1998) - et al.
Variant brain derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice
Biol Psychiatry
(2012) - et al.
Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator
Neuroscience
(2007) - et al.
Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication
Biol Psychiatry
(2001) - et al.
Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial
Lancet Neurol
(2011) - et al.
Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior
Brain Res Mol Brain Res
(2004) - et al.
Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains
J Psychiatr Res
(2009) - et al.
The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function
Cell
(2003)
Chronic administration of selective serotonin reuptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects
Neuroimage
Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice
Neuroscience
Activation of the type 2 adrenal steroid receptor can rescue granule cells from death during development
Brain Res Dev Brain Res
Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus
Neuroscience
Acute hippocampal brain-derived neurotrophic factor restores motivational and forced swim performance after corticosterone
Biol Psychiatry
Analysis of pyramidal neuron morphology in an inducible knockout of brain-derived neurotrophic factor
Biol Psychiatry
Stress-induced prefrontal reorganization and executive dysfunction in rodents
Neurosci Biobehav Rev
BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex
Cell
Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala
Neuroscience
Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs
Brain Res Mol Brain Res
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
P75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping
Neuron
Placode and neural crest-derived sensory neurons are responsive at early developmental stages to brain-derived neurotrophic factor
Dev Biol
Identification of a new acute phase protein
J Biol Chem
Pro-region of neurotrophins: role in synaptic modulation
Neuron
Repeated stress causes reversible impairments of spatial memory performance
Brain Res
Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly
Neurosci Res
Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress
Mol Cell Neurosci
Prenatal stress differentially alters brain-derived neurotrophic factor expression and signaling across rat strains
Neuroscience
Neurobiology of depression
Neuron
CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period
Neuron
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
Glucocorticoids protect against the delayed behavioral and cellular effects of acute stress on the amygdala
Biol Psychiatry
A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients
J Neurol
Gender differences in the enhanced vulnerability of BDNF+/− mice to mild stress
Int J Neuropsychopharmacol
The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death
J Cell Biol
Purification of a new neurotrophic factor from mammalian brain
EMBO J
BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity
Neuropsychopharmacology
Modulation of semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon patterning
J Neurosci
Brain-derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons
Eur J Neurosci
Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75
Nature
The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex
Eur J Neurosci
Lipocalin comes callin’ on the hippocampus
Proc Natl Acad Sci USA
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
Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport
J Neurosci
Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist
Neuropsychopharmacology
Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy
Stroke
Brain corticosteroid receptor balance in health and disease
Endocr Rev
Neuronal growth cone retraction relies on proneurotrophin receptor signaling through Rac
Sci Signal
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
Cited by (188)
Hair brain-derived neurotrophic factor (BDNF) as predictor of developing psychopathological symptoms in childhood
2023, Journal of Affective DisordersAssociation between plasma levels of BDNF and GDNF and the diagnosis, treatment response in first-episode MDD
2022, Journal of Affective DisordersInteraction of lithium and sleep deprivation on memory performance and anxiety-like behavior in male Wistar rats
2022, Behavioural Brain Research