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date: 18 November 2019

Mediators of Glucocorticoid-Regulated Adaptive Plasticity

Abstract and Keywords

The hippocampus has provided a gateway for understanding of how stress, as well as sex hormones, affect cognitive process and has revealed adaptive plasticity in neuronal structure and function throughout the brain and also contributes to damage. This involves direct and indirect epigenomic transcriptional regulation, as well as rapid, non-genomic signaling pathways initiated by membrane-bound glucocorticoid and mineralocorticoid receptors. Downstream of glucocorticoids, multiple mediators—including secreted factors as well as intracellular processes—play critical roles in driving stress-induced remodeling of dendritic arborization and postsynaptic dendritic spines. To understand how these processes act to maintain synaptic homeostasis; prevent permanent, excitotoxic damage; and adaptively regulate learning and decision making, and how we might go about intervening to promote resilience in stress-related neuropsychiatric conditions, new technologies for visualizing and manipulating dendritic spine remodeling and neuronal activity in specific neural circuits are being used to establish causal mechanisms and define new therapeutic strategies.

Keywords: glucocorticoids, adaptive plasticity, stress, resilience, dendrites, dendritic spines

Introduction

The adult as well as developing brain is capable of considerable structural and functional plasticity in which systemic hormones play a key role along with other mediators. This realization grew, at least in part, out of the field of neuroendocrinology, which began with the fundamental discovery of the communication between hypothalamus and pituitary by Geoffrey Harris, establishing a basis for understanding brain-body communication via the neuroendocrine system (Harris, 1970). This led to the discovery of releasing factors in the hypothalamus for pituitary hormones [e.g., (Guillemin, 1978; Schally et al., 1973; Vale et al., 1981)] as well as the feedback of hormones on the hypothalamus and pituitary for the purpose of regulating hormone secretion (Meites, 1992). During the same time period, steroid hormones were shown to bind to intracellular receptors that regulate gene expression in tissues such as liver, and in the case of sex hormones, the prostate and uterus (Jensen & Jacobson, 1962). Subsequently, tritium-labeled steroid hormones were used as probes to detect these receptors using cell fractionation (Toft & Gorski, 1966) as well as steroid autoradiography (Pfaff & Keiner, 1973; Stumpf, 1971).

The McEwen laboratory entered this field using tritium labeled steroids by serendipitously discovering adrenal steroid receptors, and, later, estrogen receptors, in the hippocampal formation of the rat using both steroid autoradiography, cell fractionation methods, and immunocytochemical methods at the electron microscopic, as well as light microscopic levels (Gerlach & McEwen, 1972; Loy et al., 1988; McEwen & Plapinger, 1970; McEwen et al., 1968; Milner et al., 2001; Zigmond & McEwen, 1970).

The hippocampus has provided the gateway into much of what we and other laboratories have learned about stress, sex hormones and brain plasticity; and the initial focus on hippocampus has expanded to other interconnected brain regions, such as the amygdala and prefrontal cortex (PFC). These findings have catalyzed studies that look at actions of hormonal feedback on the brain, not only to regulate hypothalamic functions, but also to influence neurological, cognitive, and emotional functions throughout the entire brain, including structural plasticity of synapses, dendrites and limited neurogenesis, with translation to the human brain in relation to aging, mood disorders and the impact of the social environment.

Using electron microscopic immunocytochemistry, steroid receptors were discovered outside of the cell nucleus, and recognition of “non-genomic” signaling mechanisms of steroid hormones in brain and other tissues is now a growing field (Kelly & Levin, 2001; McEwen & Milner, 2007; Levin & Hammes, 2016). This has, in turn, led to the recognition of other mediators and cellular processes that work with steroid hormones to mediate adaptive structural and functional plasticity in the adult and developing brain. This plasticity and the mediators for it will be the focus of our review.

Neural Structural Remodeling in the Adult Brain

Long regarded as a rather static and unchanging organ, except for electrophysiological responsivity, such as long-term potentiation (Bliss & Lomo, 1973), the brain has gradually been recognized as capable of substantial structural plasticity even in adulthood. The adult brain undergoes rewiring after brain damage (Parnavelas et al., 1974) and is also able to grow and change independent of injury, as seen by dendritic branching, angiogenesis and glial cell proliferation during cumulated experience (Bennett et al., 1964; Greenough & Volkmar, 1973). More specific physiological changes in synaptic connectivity were also recognized in relation to hormone action in the spinal cord (Arnold & Breedlove, 1985), and in environmentally directed plasticity of the adult songbird brain (DeVoogd & Nottebohm, 1981). Seasonally varying neurogenesis in restricted areas of the adult songbird brain is recognized as part of this plasticity (Nottebohm, 2002). Indeed, adult neurogenesis in the adult mammalian brain was initially described (Altman & Das, 1965; Kaplan & Bell, 1983) and then suppressed (Kaplan, 2001), only to be rediscovered in the dentate gyrus of the hippocampus (Cameron & Gould, 1994; Gould & McEwen, 1993) in the context of studies of neuron cell death and actions of adrenal steroids and excitatory amino acids in relation to stress. Neurogenesis in the dentate gyrus has gone on to become a huge topic related to effects of stress (Gould et al., 1997), exercise (van Praag et al., 1999), enriched environment (Kempermann et al., 1997), antidepressants (Duman et al., 1997) and learning and memory (Gould et al., 1999).

Structural Plasticity in Hippocampus, Amygdala, and Prefrontal Cortex

The hippocampus is one of the most sensitive and malleable regions of the brain and is also very important in cognitive function and mood regulation (McEwen et al., 2016). The dentate gyrus-CA3 system, which is delicately balanced anatomically and thus vulnerable to over-stimulation, as in seizures, is believed to play a role in the memory of sequences of events, although long-term storage of memory occurs in other brain regions (Lisman, 1999). Moreover, the anterior part of the hippocampus has strong connections to the amygdala and prefrontal cortex and is a nexus of vulnerability to depression. But, because the DG-CA3 system is so delicately balanced in its function and vulnerability to damage, there is also adaptive structural plasticity, in that new neurons continue to be produced in the dentate gyrus throughout adult life (Cameron et al., 1998), and CA3 pyramidal cells undergo a reversible remodeling of their dendrites in conditions such as hibernation and chronic stress (Magarinos et al., 2006b; McEwen, 1999). The role of this plasticity may be to protect against permanent damage. As a result, the hippocampus undergoes a number of adaptive changes in response to acute and chronic stress via a host of cellular and molecular mechanisms (McEwen et al., 2015), and also shows positive effects of regular physical activity on hippocampal volume and memory (Erickson et al., 2011).

Contrasting Effects.

Repeated stress also causes changes in other brain regions, including the amygdala, prefrontal cortex, orbitofrontal cortex, and striatum. As in the hippocampus, repeated stress causes dendritic atrophy in the medial prefrontal cortex, medial orbitofrontal cortex, and in medium spiny neurons of the dorsomedial striatum (Dias-Ferreira et al., 2009; Gourley et al., 2013b; Radley et al., 2004; Wellman, 2001; McEwen & Morrison, 2013). In contrast, chronic stress produces dendritic growth in neurons in the amygdala, lateral orbitofrontal cortex, and dorsolateral striatum (Dias-Ferreira et al., 2009; Liston et al., 2006; Radley et al., 2004; Vyas et al., 2002). Excitatory amino acids and BDNF are involved (Chattarji et al., 2015; Lakshminarasimhan & Chattarji, 2012; McEwen & Morrison, 2013).

Behavioral Correlates.

Chronic stress for 21 days or longer impairs hippocampal-dependent cognitive function and enhances amygdala-dependent unlearned fear and fear conditioning, which are consistent with the opposite effects of stress on hippocampal and amygdala structure (Chattarji et al., 2015). Chronic stress also increases aggression between animals living in the same cage, and this is likely to reflect another aspect of hyperactivity of the amygdala (Wood et al., 2008). Behavioral correlates of remodeling in the prefrontal cortex include impairment in attention set shifting (Liston et al., 2006), possibly reflecting structural remodeling in the medial prefrontal cortex (McEwen & Morrison, 2013). Chronic stress also reduces behavioral flexibility and biases decision making in favor of habit-driven responding, effects which have been linked to dendritic remodeling and reorganization of frontostriatal and orbitofrontal circuits (Dias-Ferreira et al., 2009; Gourley et al., 2013a; Gourley et al., 2013b).

Sex Differences.

Subtle sex differences exist for many of these functions that are developmentally programmed by hormones and by not-yet-precisely-defined genetic factors including the mitochondrial genome (McEwen & Milner 2017). These sex differences and responses to sex hormones in brain regions, and upon functions not previously regarded as subject to such differences, indicates that we are entering a new era of our ability to understand and appreciate the diversity of gender-related behaviors and brain functions.

Indeed, animal models of stress effects on the brain show that female and males respond differently to acute and chronic stressors because of developmental factors involving both epigenetic effects of hormones, along with genes in the sex chromosomes themselves (McCarthy & Arnold, 2011). Sex differences in the brain are subtle but widespread (McEwen & Milner, 2017) and yet males and females do many things equally well: e.g., In human subjects, taking tests on empathy, men and women do equally well but the brain activation patterns during the tests show different brain regions are activated (Derntl et al., 2010). This is reminiscent of an animal model study in which, despite no overall sex differences in fear conditioning freezing behavior, the neural processes underlying successful or failed extinction maintenance are sex-specific (Gruene et al., 2015). Given other work showing sex differences in stress-induced structural plasticity in prefrontal cortex projections to amygdala and other cortical areas (Shansky et al., 2010), these findings are relevant not only to sex differences in fear conditioning and extinction but, according to Gruene et al “also to exposure-based clinical therapies, which are similar in premise to fear extinction and which are primarily used to treat disorders that are more common in women than in men” (Gruene et al., 2015).

Glucocorticoid and Mineralocorticoid Receptor Signaling in Stress and Neuroprotection

Genomic Regulation.

The discovery of stress hormone receptors in actions in hippocampus has been the gateway to the investigation of other brain regions as well as mechanisms of stress and adrenal steroid action. Work by Reul and de Kloet demonstrated that there are two types of adrenal steroid receptors (Figure 1), mineralocorticoid (Type 1 or MR) and glucocorticoid (Type 2 or GR), in hippocampus and other brain regions (Reul & DeKloet, 1985), which was further elaborated by immunocytochemical mapping of the receptors (Ahima et al., 1991; Ahima & Harlan. 1990). Adrenal steroids produce biphasic effects mediated by MR and GR on long-term potentiation and long-term depression (Diamond et al., 1992; Joels, 2006; Pavlides et al., 1995) that are reflected in memory (Okuda et al., 2004). These effects depend on the state of behavioral arousal in a novel environment, which also implies a synergistic role of adrenaline and the fact that the hippocampus and amygdala work together (Roozendaal et al., 1996), which brings up the recurrent theme of synergistic interactions between multiple mediators along with adrenal steroids. The glucocorticoid receptor is involved in hippocampal dependent spatial memory via a genomic mechanism as shown in the dimerization-deficient GR mouse, which is compromised in its ability to bind to glucocorticoid response elements (GRE; Oitzl et al., 1997). GR’s act on cognitive processes throughout the brain: Ru486 blocks contextual fear memory mediated by hippocampus as well as amygdala (Pugh et al., 1997).

Mediators of Glucocorticoid-Regulated Adaptive PlasticityClick to view larger

Figure 1. Multiple mediators of glucocorticoid-induced adaptive plasticity.

Ultradian fluctuations of glucocorticoids drive GR activation and reactivation, while MR occupancy for nuclear activation is more constant and promotes excitability (Stavreva et al., 2009). This has implications for genomic as well as non-genomic activity of adrenal steroids, as will be discussed below. Moreover, circadian alterations in glucocorticoids are also important for neural function and disruption in this due to shift work, jet lag and sleep deprivation (McEwen & Karatsoreos, 2015) can have serious consequences for brain function and behavior as will be discussed.

Epigenetics and Retrotransposons.

Epigenetics refers to the regulation of gene expression via modifications of histones, CpG methylation and demethylation, non-coding regulatory RNA’s, RNA editing, and retrotransposons (Mehler. 2008). Acetylation of lysine residues of histones in hippocampus occurs as a result of the actions of a rapidly acting putative antidepressant, acetyl-L-carnitine (LAC), that epigenetically up-regulates the metabotropic presynaptic glutamate receptor, mGlu2 (Nasca et al., 2013). In contrast, methylation of lysine residues in histones in hippocampus results from acute stress and represses the activity of retrotransposons that produce non-coding regulatory RNA’s among other functions (Hunter et al., 2012). This action appears to be specific for hippocampus and is lost after repeated stress (Hunter et al., 2012). These results are a unique demonstration of the regulatory effect of environmental stress, via an epigenetic mark, on the vast genomic terra incognita represented by transposable elements (Hunter, Gagnidze, McEwen, & Pfaff, 2015).

Mitochondria.

Mitochondria have their own DNA and transcription and translation machinery (Luck & Reich, 1964; Moutsatsou et al., 2001; Rifkin et al., 1967) and glucocorticoid receptors translocate to mitochondria and regulate expression of mitochondrial genes, particularly those associated with Complex I that is critical for ATP generation (Hunter et al., 2016; Roosevelt et al., 1973). Acute stress represses Complex I genes, an effect abolished by adrenalectomy, whereas chronic stress up-regulates at least one Complex I gene, ND6, and exogenous glucocorticoid treatment, without applied stress, up regulates 10 of 13 mitochondrial genes, apparently through a GRE on the mitochondrial DNA. This highlights not only the interactions with other mediators but also the biphasic nature of adrenal steroid actions. Indeed, three independent measures of mitochondrial function—mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity—were found to be regulated by long-term corticosterone (CORT) treatment in an inverted “U”-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection in that treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons (Du et al., 2009). Protective actions of CORT at physiological levels were associated with glucocorticoid receptors (GRs) forming a complex with the anti-apoptotic protein Bcl-2 and translocating with it into mitochondria where GR and Bcl-2 remained after protective doses but left within 3 days after damaging high CORT doses (Du et al., 2009).

Non-genomic Effects.

Immunocytochemistry at the electron microscopic level revealed specific immunolabeling for epitopes of glucocorticoid and estrogen receptors near the cell surface, in mitochondria, dendrites and presynaptic terminals and post-synaptic densities (Johnson et al., 2005; Liposits & Bohn, 1993; McEwen & Milner, 2007; Milner et al., 2001); (Milner et al., 2008). Along with evidence that steroid receptors work via non-genomic, rapid signaling mechanisms along with their epigenetic actions to regulate gene expression (Kelly & Levin, 2001), this has led to a new view of steroid hormone action via both direct and indirect genomic stimulation as well as a variety of other rapid signaling non-genomic mechanisms (Popoli et al., 2012) involving other mediators.

A powerful example of non-genomic functions of steroid receptors was the finding that the knock-out of the mineralocorticoid receptor (MR) abolished the ability of corticosterone to rapidly stimulate EAA release, implying a dual role for MR in both genomic and rapid non-genomic signaling (Karst et al., 2005). Again, this finding began with studies on hippocampus and it helped explain the adrenal-dependency of acute restraint stress induced increases in extracellular glutamate in hippocampus (Lowy et al., 1993) that are likely to underlie the ability of chronic restraint stress to cause dendritic remodeling in hippocampus (McEwen, 1999).

Cellular Processes in Dendritic Remodeling

The neuronal surface, cytoskeleton and nuclear envelope are each implicated in the mechanisms of stress-induced retraction and expansion of dendrites and synapse turnover. There are multiple secreted mediators for this plasticity that are summarized in BOX 1. Regarding intracellular processes in dendritic remodeling, the polysialated form of neural cell adhesion molecule (PSA-NCAM) is expressed in the CA3 and DG region of the hippocampus and is believed to denote the capacity for adaptive structural plasticity in many parts of the CNS (Rutishauser, 2008; Seki & Arai, 1999; Theodosis et al., 1999). Repeated stress causes retraction of CA3 hippocampal dendrites accompanied by a modest increase in PSA-NCAM expression, possibly the result of glucocorticoid mediation (Pham et al., 2003). Using EndoN to remove PSA from NCAM, Sandi reported impairment of consolidation of contextual fear conditioning (Sandi, 2004). Using the same treatment, we reported considerable expansion of the dendritic tree in both CA3 and CA1 and a marked increase in excitotoxicity and damage to CA3 neurons; repeated stress still caused some dendrite retraction after PSA removal (McCall et al., 2013). Thus, while PSA-NCAM is a facilitator of plasticity, the PSA moiety appears to also limit the extent of dendritic growth and yet is not necessary for dendritic retraction under stress.

Hibernation in European hamsters and ground squirrels results in rapid retraction of dendrites of CA3 pyramidal neurons and equally rapid expansion when hibernation torpor is reversed (Magarinos et al., 2006a; Popov et al., 1992) The retraction of dendrites is accompanied by increases in a soluble phosphorylated form of tau that may indicate disruption of the cytoskeleton, which permits the dendrite shortening and possible protection from excitotoxicity; at the same time, PSA-NCAM expression is lost during hibernation torpor reducing the capacity for plasticity (Arendt et al., 2003). This model highlights the important role that tau plays in normal cytoskeletal function, a fact that should be emphasized when attempting to understand its role in pathology (Morris et al., 2011).

Even though dendrite retraction and regrowth would appear to involve a reversible depolymerization and repolymerization of the cytoskeleton, there are other processes that point to the importance of nuclear factors. A recent example is the unexpected role of a cell nuclear pore complex protein, NUP-62, in the stress-induced dendritic remodeling in the CA3 region of hippocampus (Kinoshita et al., 2014). First identified as a gene that was down regulated in the prefrontal cortex of depressed patients (Tochigi et al., 2008), NUP-62 was also found to be reduced in response to chronic stress in CA3 neurons of rodents (Kinoshita et al., 2014). Importantly, the levels of other nuclear pore complex genes were unchanged with chronic stress, supporting the specificity of its role in stress remodeling. Subsequent in vitro studies confirmed that the down-regulation of NUP-62 is associated with dendritic retraction and this effect is regulated at the molecular level by NUP-62 phosphorylation at a PYK2 site, which results in its retention in the cytoplasm (Kinoshita et al., 2014). A role of NUP-62 in maintaining chromatin structure for transcription is suggested as well as in nucleo-cytoplasmic transport (Kinoshita et al., 2014).

Spine Synapse Turnover and Its Functional Significance for Learning and Memory

For years, it was generally assumed that synaptic connections defining the neocortical wiring diagram are essentially fixed in the adult brain, and that learning and memory are supported by changes in synaptic strength. This view evolved with the advent of two-photon microscopy (Figure 2) and related methods for quantifying structural remodeling in the living brain through longitudinal imaging of postsynaptic dendritic spine plasticity (Bhatt et al., 2009; Chklovskii et al., 2004; Holtmaat & Svoboda. 2009). Pioneering early studies showed that while a majority of dendritic spines are highly stable, the adult brain retains a remarkable capacity for spine remodeling (Grutzendler et al., 2002, Trachtenberg et al., 2002). New spine formation occurs on an on-going basis, and although most new spines do not persist for more than a few days, a subset will stabilize and form functional synapses (Grutzendler et al., 2002, Knott et al., 2006, Trachtenberg et al., 2002, Zuo et al., 2005). Subsequent studies showed that experience-dependent plasticity of cortical receptive fields, motor skill training, and other forms of learning modulate the formation and pruning of dendritic spines (Holtmaat et al., 2006; Trachtenberg et al., 2002; Xu et al., 2009; Yang et al., 2009). Furthermore, memory retention is highly correlated with the maintenance of a small subset of learning-related spines and the pruning of pre-existing synapses (Xu et al., 2009; Yang et al., 2009), processes that tend to occur at spatially clustered and branch-specific sites on the apical dendritic arbors of pyramidal cells (Fu et al., 2012; Yang et al., 2014). More recently, using a novel genetic tool for selectively shrinking and deleting recently formed spines, investigators showed that spinogenesis plays a necessary role in motor skill learning and memory storage (Hayashi-Takagi et al., 2015). Together, these findings show that the pruning and formation of new spines—and not merely the potentiation and depression of existing synapses—play important roles in encoding and storing memories in adulthood.

Mediators of Glucocorticoid-Regulated Adaptive PlasticityClick to view larger

Figure 2. Two-photon laser scanning microscopy, in combination with methods for obtaining optical access to brain tissue through a chronically implanted cranial window (or thinned skull preparation) or microprism (a), enables the visualization and quantification of postsynaptic dendritic spine remodeling in the living brain (b). In these images, arrows denote spines that were eliminated after chronic corticosterone exposure between P30 and P40 (Liston & Gan, 2011), with blue arrows denoting spines formed early in life (prior to postnatal day 23 [P23]) and red arrows denoting spines that formed after P23. The white arrowheads denote spines that formed between P30 and P40.

Figure adapted from Liston & Gan, 2011.

Importantly, experience-dependent spine remodeling is strongly influenced by steroid hormones and related molecular mediators of adaptive plasticity. Stereologic quantification of dendritic spine density in fixed tissue using Golgi staining or iontophoretic injection of fluorescent dyes anticipated this conclusion, showing that chronic stress and chronic corticosterone exposure decrease dendritic spine density in the hippocampus, medial orbitofrontal cortex, and medial prefrontal cortex and increase spine density in the amygdala (Gourley et al., 2013b; Mitra et al., 2005; Radley et al., 2006; Shors et al., 2001). Longitudinal imaging experiments in culture (Chen et al., 2008) and in vivo (Liston & Gan, 2011) showed that dendritic spines are in fact exquisitely sensitive to both corticosterone and corticotropin-releasing hormone (CRH). See BOX 1. Using transgenic mice expressing yellow fluorescent protein (Thy1/YFP) in a subset of pyramidal cells, Chen and colleagues showed that CRH drives spine loss in CA3 pyramidal cells within hours after acute stress by destabilizing actin polymers within spines and accelerating spine retraction in hippocampal organotypic slice cultures (Chen et al., 2008).

Using transcranial two-photon microscopy, we have observed similar effects in vivo after intraperitoneal injection of corticosterone: just five hours after injection, we observed a ten-fold increase in spine elimination and formation in barrel cortex and primary motor cortex in mice at postnatal day 30 and similar effects of a smaller magnitude in adults (Liston & Gan, 2011). Co-injection with an MR antagonist (spironolactone) was sufficient to block effects on both formation and elimination, whereas a GR antagonist (mifepristone) interfered selectively with spine formation. These rapid and potent effects raised the interesting possibility that physiological spine remodeling in the developing brain may require glucocorticoid signaling. To test this prediction, we used low-dose (0.1 mg/kg) dexamethasone to induce a state of glucocorticoid deprivation in the brain by suppressing endogenous synthesis in the adrenal gland (dexamethasone does not penetrate the blood brain barrier at this dose). We found that central glucocorticoid deprivation suppressed physiological spine remodeling at postnatal day 30 (typically 7–8% over three days) and postnatal day 21 (typically ~15% over one day) to nearly undetectable levels. These findings show that dendritic spines are highly sensitive to stress-related CRH and glucocorticoid activity on an unexpectedly rapid timescale, yet physiological glucocorticoid activity also plays an important role in the maturation of neocortical circuits by facilitating spine remodeling during development.

These findings have raised interesting questions about the effects of physiological oscillations in glucocorticoid activity on dendritic spine remodeling and memory. Even in the absence of external stressors, glucocorticoid levels oscillate in synchrony with other circadian rhythms (Figure 3), with high levels during the active phase of an animal’s day and low levels during the inactive phase (De Kloet et al., 1998). Superimposed on this circadian rhythm are ultradian oscillations occurring with a period of 1–2 hours (Stavreva et al., 2009), considered in more detail below. Rapid glucocorticoid effects on spine formation and pruning suggest that circadian glucocorticoid oscillations could potentially modulate experience-dependent plasticity in dendritic spines. By training Thy1/YFP-expressing transgenic mice on a rotarod motor skill learning paradigm at different times during the circadian cycle, we found that circadian glucocorticoid peaks and troughs facilitate complementary aspects of learning-related remodeling (Liston et al., 2013). Circadian peaks are critical for generating new spines in the first few hours after motor skill learning. A small proportion (typically 20–30%) of these newly formed spines will go on to form functional synapses (Trachtenberg et al., 2002; Grutzendler et al., 2002; Zuo et al., 2005; Knott et al., 2006), a process that is strongly correlated with long-term memory retention (Xu et al., 2009; Yang et al., 2009). Accordingly, when learning occurs during a period of low glucocorticoid activity, learning-related spine formation and memory retention are reduced (Liston et al., 2013).

Mediators of Glucocorticoid-Regulated Adaptive PlasticityClick to view larger

Figure 3. Circadian glucocorticoid oscillations regulate learning-related spine plasticity (elements adapted from Liston et al., 2013). (a) Hypothalamic-pituitary-adrenal axis regulation of stress-induced glucocorticoid (cortisol) release. (b) Schematic. Glucocorticoid activity also oscillates in synchrony with circadian rhythms, with elevated glucocorticoid activity tending to coincide with the active period of an animal’s day. Superimposed on these circadian cycles are ultradian oscillations with a period of 1–2 hours. (c) Schematic of experiments for investigating how circadian glucocorticoid oscillations influence learning-induced plasticity in a RotaRod motor skill learning paradigm, adapted from Liston et al., 2013. Two photon imaging of the forelimb area of motor cortex was performed before and immediately after 2 days of RotaRod learning during the circadian peak to identify spines that formed during learning, and again 5 days later (Day 7) to quantify learning-related spine survival rates. On Days 4, 5, and 6, intraperitoneal injections of corticosterone or vehicle were administered during the circadian trough or circadian peak. (d) Circadian glucocorticoid troughs were critical for stabilizing and preserving spines that formed in association with learning. In other experiments not shown here, circadian peaks were critical for facilitating the formation of these new spines shortly after learning. (e) Across subjects, the survival of learning-related spines was correlated with memory retention. (f) Circadian glucocorticoid oscillations balanced the formation, pruning, and maintenance of postsynaptic dendritic spines, such that across many different experimental conditions, the survival of newly formed spines was tightly coupled with the pruning of a corresponding subset of preexisting connections. (g) Chronic corticosterone exposure, a model of chronic stress, disrupted this balance such that spine elimination rates exceeded formation and stabilization, leading to widespread spine loss.

However, circadian glucocorticoid troughs are also important for learning-induced spine remodeling: they are necessary for stabilizing a subset of newly formed spines and pruning a corresponding subset of pre-existing synapses, processes that are highly correlated such that in adults, the total number of spines is relatively stable (Liston et al., 2013). Other studies have shown that in humans, the retention of learned motor skills in both laboratory (Miller et al., 2012) and naturalistic settings (Atkinson & Reilly, 1996) depends on the time of day when training occurs. It is unknown whether circadian glucocorticoid rhythms also regulate spine remodeling after other forms of learning, it is well established that working memory, associative learning, fear conditioning, and declarative memory all show substantial circadian variations (Chaudhury & Colwell, 2002; Ruby et al., 2008,; Wright et al., 2006). Coupled with evidence that spine formation is not only correlated with memory retention (Xu et al., 2009,; Yang et al., 2009) but also required for normal memory storage (Hayashi-Takagi et al., 2015), these data indicate that circadian glucocorticoid oscillations play important roles in motor skill learning—and potentially in other forms of memory—by balancing the formation and pruning of postsynaptic dendritic spines after training.

Chronic stress disrupts this balance. In accord with a large body of work showing reductions in spine density after chronic stress in multiple brain regions (Gourley et al., 2013b; Radley et al., 2006, Shors et al., 2001) repeated injections of corticosterone during the circadian trough cause widespread spine loss through accelerated elimination of spines formed progressively earlier in life (Liston et al., 2013; Liston & Gan, 2011); and the correlation between new spine formation and the pruning of preexisting spines is lost (Liston et al., 2013). In this way, tightly regulated, physiological glucocorticoid oscillations promote learning and memory, but chronic, excessive exposure to glucocorticoids interferes with these processes.

Molecular Mechanisms.

The underlying molecular signaling mechanisms that mediate glucocorticoid effects on dendritic spine remodeling are incompletely understood. Glucocorticoids administered through a microscopic craniotomy promote spine formation rapidly, within minutes, through direct (cell-autonomous) effects on neurons mediated by a membrane-bound glucocorticoid receptor and a non-genomic, transcription-independent signaling mechanism (Liston et al., 2013). Undoubtedly, many factors are involved, but it appears that the LIM kinase 1 (LIMK1) signaling pathway is an important one. Corticosterone causes a rapid increase in the phosphorylated forms of LIMK1 and its substrate cofilin (Liston et al., 2013), which in turn stabilizes actin polymers and promotes spine growth (Gu et al., 2010). These effects are required for glucocorticoid-induced spine formation, and interestingly, corticosterone has no effect on spine formation in Limk1-/- knockout mice (Liston et al., 2013), a transgenic model of Williams Syndrome, which is a neuro-developmental disorder featuring learning disabilities and reduced LIMK1 expression (Bellugi et al., 1999; Meng et al., 2002). LIMK1 phosphoryaltion is also implicated in the spine synapse formation induced by estrogens in the hippocampus (Yuen et al., 2011).

In contrast, glucocorticoid effects on spine pruning involve a genomic, transcription-dependent signaling mechanism that occurs on a slower timescale, beginning 3–5 hours after exposure and peaking ~24 hours later (Liston et al., 2013). Intracellular mineralocorticoid (MR) receptors are required but the glucocorticoid receptor is not, indicating that at least in neocortical pyramidal cells, this mechanism is initiated by MR/MR dimers and not MR/GR dimeriziation. It is unclear which specific downstream targets of transcription regulation are responsible for glucocorticoid-induced spine pruning. Interactions with myocyte enhancer factor 2 (MEF2) transcription factors could be important, given their established roles in activity-dependent pruning of excitatory synapses by increasing the transcription of Arc, Syngap1, and other plasticity-related genes (Flavell et al., 2006; Shalizi et al., 2006), but that remains to be tested. Class II histone deacetylases (HDACs) may also be involved: they bind MEF2 transcription factors as co-repressors; their activity is sensitive to stress; and they play established roles in mediating learning- and stress-induced plasticity and associated behaviors (Guan et al., 2009; Pulipparacharuvil et al., 2008; Renthal et al., 2007; Tsankova et al., 2006; Zhang et al., 2002).

The mechanisms mediating stress effects on spine elimination are likely still more complex, involving multiple mediators in addition to glucocorticoids, including CRH, NMDAR-signaling driven by excessive glutamate release, tissue plasminogen activator (tPA), serotonin, and the transmembrane glycoprotein M6a (Alfonso et al., 2005; Chen et al., 2008, Chen et al., 2010, Christian et al., 2011, Magarinos & McEwen, 1995, Magarinos et al., 1996, McKittrick et al., 1995, McKittrick et al., 2000, Pawlak et al., 2005b). See BOX 1. Furthermore, in chronic stress states, excessive protein kinase C (PKC) activity is another critical mediator of spine loss. Increased noradrenergic tone activates PKC signaling (Birnbaum et al., 2004), which is sufficient to cause spine collapse in vitro (Calabrese & Halpain, 2005), and inhibition of PKC blocks the effects of chronic stress on prefrontal cortical spine loss and working memory (Hains et al., 2009). How signaling by these diverse mediators of stress-induced spine remodeling interact with circadian glucocorticoid rhythms is another important unanswered question.

Spine synapse turnover also involves a number of cellular processes in which the mediators noted above and in BOX 1 are also involved. Two classes of cell adhesion molecules are reported to change with chronic stress, with behavioral consequences, mediated in part by spine synapse turnover. Neuroligins (NLGNs) are important for proper synaptic formation and functioning, and are critical regulators of the balance between neural excitation/inhibition (E/I), and chronic restraint stress reduced hippocampal NLGN-2 levels, in association with reduced sociability and increased aggression (van der Kooij et al., 2014a); (Wood et al., 2003). This occurred along with a reduction of NLGN-2 expression throughout the hippocampus, detectable in different layers of the CA1, CA3, and DG subfields. Intra-hippocampal administration of neurolide-2 that interferes with the interaction between NLGN-2 and neurexin led to reduced sociability and increased aggression, thus mimicking effects of chronic stress (van der Kooij et al., 2014a).

Chronic restraint stress also increases activity of matrix metalloproteinase-9 (MMP-9) in the CA1. MMP-9 carries out proteolytic processing of another cell adhesion molecule, nectin-3. Chronic stress reduced nectin-3 in the perisynaptic CA1, but not in the CA3, with consequences for social exploration, social recognition and for a CA1-dependent cognitive task. Implicated in this is a stress-related increase in extracellular glutamate and NMDA receptor mediation of MMP-9 (van der Kooij et al., 2014b). These findings are reminiscent of the CA1-specific effects of tissue plasminogen activator mediating stress effects on spine density in CA1 (Pawlak et al., 2005a). Actin polymerization plays a key role in filopodial extension and spine synapse formation as well as plasticity within the synapse itself (Matus et al., 2000), and cytoskeletal remodeling is an important factor in the effects of stress and other environmental manipulations.

Ultradian Glucocorticoid Oscillations.

Superimposed on circadian glucocorticoid oscillations are ultradian oscillations in glucocorticoid release that occur with a period of 1–2 hours (Conway-Campbell et al., 2012; Stavreva et al., 2009). Rapid chaperone-mediated recycling of nuclear GRs enable temporally precise pulses in gene expression in response to ultradian fluctuations in glucocorticoid levels (Stavreva et al., 2009). We are only just beginning to understand how ultradian glucocorticoid pulses influence synaptic plasticity and dendritic spines. However, we now know that ultradian pulses do in fact penetrate the blood/brain barrier (Droste et al., 2008), and neuroendocrine and behavioral measures of responsiveness to an acute noise stressor vary with the ultradian cycle, such that the stress response is magnified when a stressor occurs during the ascending phase of the ultradian oscillation (Sarabdjitsingh et al., 2010a). Interestingly, the relationship between stress responsiveness and ultradian phase also varied by brain region in this study, with differing patterns of cFos activation in the amygdala, hippocampus, pituitary, and paraventricular nucleus.

More recently, studies have shown that ultradian glucocorticoid pulses also modulate synaptic plasticity. In accord with prior work, a single pulse of corticosterone increased responses to spontaneous glutamate release by increasing the expression of postsynaptic glutamate receptors, impairing the capacity for long-term potentiation (Sarabdjitsingh et al., 2014). In contrast, a second corticosterone pulse reversed these effects, restoring the capacity for LTP, but only when it was administered one hour later, mimicking the ultradian period, indicating that ultradian glucocorticoid oscillations probably play important roles in regulating the stress responsiveness of hippocampal synapses. Other studies have shown that chronic stress disrupts these ultradian oscillations, with correlated effects on gene expression, locomotor activity, and risk assessment behavior (Sarabdjitsingh et al., 2010b; Sarabdjitsingh et al., 2010c). Additional studies are needed to determine whether ultradian oscillations—and disrupted oscillations in chronic stress states—have corresponding effects on dendritic spine remodeling.

Functional Connectivity Correlates of Stress-Related Plasticity in the Human Brain

The results reviewed above indicate that stress has potent effects on dendritic arborization and postsynaptic dendritic spines in neocortical and hippocampal pyramidal cells, which in turn imply corresponding effects on connectivity within cortical microcircuits and in the corticocortical projections that give rise to functional brain networks. Although dendritic arborization and spine plasticity cannot be measured non-invasively in the living human brain, an exponentially growing body of work established the utility of fMRI for quantifying functional connectivity between cortical regions—a potential indirect proxy for synaptic connectivity. Much of this work builds on the observation that the fMRI blood-oxygenation-level-dependent (BOLD) signal exhibits spontaneous, low frequency fluctuations, and that these fluctuations are correlated over time in brain regions comprising distinct functional networks (Biswal et al., 1995; Fox & Raichle, 2007; Fox et al., 2005; Greicius et al., 2003). Although resting state functional connectivity measures are not completely determined by monosynaptic connections, they do reflect structural connectivity as indexed by diffusion tractography in humans (Greicius et al., 2009) and synaptic tracer studies in non-human primates (Carmichael & Price, 1996; Kobayashi & Amaral, 2003; Lavenex et al., 2002; Parvizi et al., 2006; Petrides & Pandya, 1999; Suzuki & Amaral, 1994).

In this way, neuroimaging studies have begun to elucidate how acute and chronic stressors influence functional connectivity in human brain networks. Acutely, stress (in this case, viewing aversive, emotionally arousing films) increases functional connectivity between frontoinsula cortex, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, temporoparietal cortex, and the amygdala, thalamus, hypothalamus, and midbrain (Hermans et al., 2011), including multiple components of a salience network and a ventral attention network, which have been implicated in integrating affective information with externally generated sensory information (Seeley et al., 2007) and in reorienting attention and maintaining alertness (Dosenbach et al., 2008), respectively. However, these effects were evident within minutes of exposure to the acute stressor, a timescale that is probably too fast to be mediated by the remodeling of dendrites or spines. Accordingly, they were blocked by treatment with a beta adrenergic receptor antagonist but not by metyrapone, which interferes with cortisol synthesis, indicating that they are driven in part by noradrenergic signaling but most likely not by glucocorticoids. Another study employed a different stressor (a “socially evaluated cold pressor test”) and a self-control task in which subjects were asked to choose between images of a healthy and unhealthy food option during scanning. As in the earlier study, an acute stressor increased functional connectivity between ventromedial prefrontal cortex and amygdala (and striatum), as well as a reduction in functional connectivity between ventromedial prefrontal cortex and dorsolateral prefrontal cortical areas correlated with self-control success (Maier et al., 2015). These studies show that acute stress triggers a rapid reorganization of functional connectivity mediated in part by noradrenergic signaling mechanisms and potentially compromising self-control abilities by suppressing the influence of prefrontal control networks on subcortical reward processing.

Chronic stress also has potent effects on functional connectivity within resting state networks in the human brain. In accord with rodent studies demonstrating dendritic spine loss and apical dendritic atrophy in prefrontal cortical layer 2/3 pyramidal cells—the primary targets of long-range corticocortical projections—chronic stress in humans (in this case, medical students preparing for 3-4 weeks for a high-stakes exam) was associated with a loss of functional connectivity between the dorsolateral prefrontal cortex and multiple components of a frontoparietal executive control network and correlated impairments in attention regulation on a perceptual attentional set-shifting task (Liston et al., 2009). In contrast, chronic stress increased functional connectivity between primary sensory areas, ventral prefrontal cortex, and orbitofrontal areas and did not interfere response inhibition. Importantly, stress effects on fMRI measures of functional connectivity and behavioral measures of attention regulation were fully reversible four weeks after cessation of the stressor in these chronically stressed but otherwise healthy human subjects without any history of stress-related psychiatric conditions. This capacity for resilience and recovery is consistent with previous reports showing that chronic stress effects on prefrontal cortical dendritic arborization were also reversible after a three-week recovery period (Radley et al., 2005). Interestingly, a different pattern was seen after recovery from depression: when actively depressed, patients exhibited deficits in functional connectivity within a frontoparietal control network that were strikingly similar to those observed in chronically stressed subjects but when these same patients were re-scanned one month later in a clinically euthymic state, these functional connectivity deficits persisted (Liston et al., 2014). Although it is unknown whether these deficits might improve given a longer recovery period, these findings raise the intriguing possibility that a reduced capacity for resilience and recovery from stress effects on network connectivity, dendritic atrophy, and spine remodeling could be an important mechanism of pathophysiology in individual vulnerable to depression.

Clinical Implications of Dysregulated Circadian Plasticity Mechanisms

The mechanisms mediating functional connectivity differences in stress-related neuropsychiatric disorders are most likely multifactorial and complex, but converging findings from multiple sources underscore a potential role for dysfunctional circadian plasticity mechanisms. It is now well established that stress—an important trigger for depressive episodes, anxiety, and PTSD—disrupts circadian glucocorticoid oscillations. A meta-analysis of studies examining stress effects on hypothalamic-pituitary-adrenal (HPA) axis activity comprising 8,521 subjects in total revealed two well replicated conclusions (Miller et al., 2007). First, uncontrollable traumatic stressors like those that might cause PTSD in vulnerable individuals elicit an elevated, flattened diurnal profile. Second, chronic stress increased total daily glucocorticoid synthesis but it also tended to flatten the diurnal glucocorticoid rhythm and reduce the amplitude of the circadian peak. Based on the studies in animal models reviewed above, both effects could potentially compromise the ability to link salient experiences with postsynaptic spine formation and to stabilize newly formed spines by disrupting the circadian trough.

Other evidence comes from studies of HPA reactivity and circadian rhythms in stress-related clinical populations. Disrupted circadian glucocorticoid rhythms are an important feature of both depression and PTSD (Heim et al., 2000; Holsboer, 2000; Miller et al., 2007; Yehuda, 2002; Yehuda et al., 1996). In depression, increased glucocorticoid levels during the early morning circadian through is a consistent finding, especially in psychotic depression, and some but not all studies indicate that total daily glucocorticoid synthesis is also increased (Holsboer, 2000; Keller et al. 2006; Sachar et al. 1973). In PTSD, the amplitude of circadian glucocorticoid peaks is reduced, causing a reduction in total daily glucocorticoid synthesis (Yehuda et al., 1996), and blunted glucocorticoid oscillations are a prominent feature of both PTSD and depression (Yehuda et al., 1996).

Corresponding effects on direct measures of synaptic remodeling have been challenging to study, but neuroimaging and postmortem histopathological studies have revealed indirect evidence. In postmortem studies of depressed patients, there is a loss of neuropil volume without a reduction in cell number in the hippocampus and lateral prefrontal cortex (Pittenger & Duman, 2008; Rajkowska, 2000; Rajkowska et al., 1999; Stockmeier et al., 2004), potentially consistent with observations of stress-induced dendritic atrophy in rodents. Another recent report using electron microscopic stereology and microarray gene profiling showed that synapse number and the expression levels of multiple synapse-related genes are reduced in depression, findings that were linked to transcriptional repressor (GATA1), which was higher in depression and reduced dendritic branching and synapse number when expressed in PFC neurons in the rat (Kang et al., 2012). And multiple neuroimaging studies of depression and PTSD have revealed deficits in hippocampal volume and widespread functional connectivity differences in resting state brain networks (Bremner et al., 2000; Bremner et al;, 1995; Davidson et al., 2002; Greicius et al., 2007; Lanius et al., 2004; Qin et al., 2012; Sheline et al., 1996; Yin et al., 2011). Importantly, these findings do not occur uniformly in all depressed patients; instead, clustered patterns of dysfunctional connectivity in different brain circuits can be used to define subtypes of depression with differing clinical symptom profiles and differing antidepressant responses (Drysdale et al., 2017).

Dysfunctional circadian plasticity mechanisms may also contribute to cognitive impairments and psychiatric symptoms in circadian rhythm sleep disorders. In mouse models of circadian rhythm dysfunction induced by a 20-hour light/dark cycle or by corticosterone administration in the drinking water, mice develop apical dendritic atrophy in mPFC pyramidal cells and correlated deficits in PFC-related cognitive functions (Karatsoreos et al., 2011, Karatsoreos et al., 2010). Interestingly, they also become obese, insulin resistant, and have elevated leptin levels. Similar effects on cognition, mood, and metabolic function have been observed in circadian rhythm sleep disorders, shift workers, and after travel across multiple time zones (Jauhar & Weller, 1982; Lupien et al., 2009; McEwen, 2012; Sack et al., 2007a; Sack et al., 2007b), suggesting that strategies for rescuing circadian rhythm disturbances and associated plasticity mechanisms may be promising targets for developing new treatments.

Conclusions and Future Directions

Since the serendipitous discovery of adrenal steroid receptors in the hippocampal formation of the rat 49 years ago, the hippocampus has provided a gateway to insights that have transformed our understanding of how stress, as well as sex hormones, support adaptive plasticity in neuronal structure and function throughout the brain. Converging evidence now implicates both conventional genomic signaling mechanisms and epigenetic mechanisms for regulating transcription, as well as rapid, non-genomic signaling pathways initiated by membrane-bound glucocorticoid and mineralocorticoid receptors. Downstream of glucocorticoids, multiple mediators—including secreted factors (BDNF, endocannabinoids, CRF, and lipocalin) as well as intracellular processes (PSA-NCAM, LIMK1, cofilin, cytoskeletal reorganization)—play critical roles in driving stress-induced remodeling of dendritic arborization and postsynaptic dendritic spines. We are only just beginning to understand how these processes act to maintain synaptic homeostasis, prevent permanent, excitotoxic damage, and adaptively regulate learning, memory, and decision making in chronic stress states, and how we might go about intervening to rescue or prevent the deleterious consequences of this remodeling in stress-related neuropsychiatric conditions. To this end, new technologies for visualizing and manipulating dendritic spine remodeling and neuronal activity in specific neural circuits will be critical for establishing causal mechanisms and defining new therapeutic strategies.

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