A little stress can be good for you. Just over 100 years ago, psychologists Robert Yerkes and John Dodson suggested that cognitive performance improves as stress increases, although it falls off again if stress levels continue to rise. The hippocampus is a key brain region for both memory and the regulation of emotion, and is highly sensitive to the main class of stress hormones, glucocorticoids. One particular subregion of the hippocampus, the dentate gyrus, contains a high density of glucocorticoid receptors, and is also notable for being one of only two regions in the adult mammalian brain that can give rise to new neurons via a process called neurogenesis.

Chronic stress is known to impair memory and to reduce neurogenesis. However, the effects of acute stress are less clear-cut: early studies suggested that it suppressed the generation of new neurons, whereas several recent studies have observed no effect. Other work has shown that acute stress increases the expression of growth factors—substances that stimulate cellular growth and proliferation—which would seem to suggest that stress could enhance neurogenesis.

Now Kirby et al. have obtained further insights into the effects of acute stress on the proliferation of cells in the dentate gyrus. Exposing rats to a moderate acute stressor, namely being restrained for a few hours, led to increased neurogenesis in the dorsal, but not ventral, hippocampus. Injecting rats with the stress hormone corticosterone had the same effect. In both cases, the enhanced neurogenesis was accompanied by increased expression of a growth factor called FGF2, which is produced by glial cells called astrocytes.

Intriguingly, Kirby and co-workers found that the stressed rats performed better than control animals in a memory test. Moreover, the beneficial effects were seen if the rats performed the task 2 weeks after their stressful experience, but not if they performed the task 2 days after being stressed. This is pertinent because new neurons in the dentate gyrus become functional 2 weeks after being generated, which suggests that the stress-induced increase in neurogenesis could account for the rats' improved memory.

The work of Kirby and co-workers has thus identified a mechanism by which moderate acute stress could have beneficial effects on cognition. Given that acute stress can be harmful in other instances—leading, for example, to post-traumatic stress disorder—further work is required to identify the factors that determine whether a response to stress is adaptive or pathological.

Stress is a powerful and essential mediator of mammalian behavior. Proper response to a perceived stressor facilitates survival at the individual level and species propagation at the population level. Despite this necessity, stress responses can become maladaptive. Chronic stress, for example, leads to a host of adverse health consequences, including cardiovascular disease, obesity, depression, and exacerbation of neurodegeneration (McEwen, 2004). Acute stress, defined as a single exposure on the scale of minutes to hours without cycles of recovery and re-exposure, has proven more enigmatic.

One model of stress effects on the brain, an inverted U function, explains the variable consequences of acute stress for brain health (Lupien and McEwen, 1997). In this model, while severe or prolonged stressors are detrimental, brief or moderate stressors actually enhance neural function. Behavioral studies focusing on the memory functions of the hippocampus have demonstrated such a relationship in rodents, where moderate stress enhances memory performance yet more severe stress impairs it (Conrad et al., 1999).

The hippocampus is exquisitely sensitive to stress and the primary stress hormone class, glucocorticoids (GCs). Within the dentate gyrus (DG) sub-region, in particular, there exists a high density of GC receptors that respond to elevated circulating GCs (De Kloet et al., 1998). In addition, the DG is strongly connected via the entorhinal cortex and medial septum to the basolateral amygdala (BLA), a brain region involved in emotional processing and an important mediator of many stress effects on the hippocampus (McGaugh, 2004). Both of these mediators of stress (GCs and BLA input) have been shown to regulate the unique population of neural progenitor cells (NPCs) that reside in the adult DG (Kirby and Kaufer, 2009; Kirby et al., 2012b).

Dentate NPCs proliferate and give rise to new neurons throughout the lifespan in several mammalian species, including rats, mice and primates (Abrous et al., 2005; Kirby and Kaufer, 2009). They become electrophysiologically active, integrate into local circuitry, play important modulatory roles in hippocampal memory function (Abrous et al., 2005) and can respond to stress and stress hormones at multiple phases of development (Kirby and Kaufer, 2009). Moreover, recent work indicates that newborn, immature neurons integrate multiple signals more readily than mature neurons and that they have enhanced excitability, possibly contributing to a disproportionately large role in new memory formation (Marín-Burgin et al., 2012).

Numerous studies show that chronic stress, in addition to impairing memory function, suppresses proliferation, survival and differentiation of new neurons in the adult DG (Wong and Herbert, 2004; Mirescu and Gould, 2006; Kirby and Kaufer, 2009). The effect of acute stress on neurogenesis, however, is unclear. While early work indicated suppression of proliferation following acute stress or GC injection (Cameron and Gould, 1994; Gould et al., 1997), subsequent studies have yielded mixed results, often reporting no change in proliferation following a variety of acute stressors (Thomas et al., 2006; Thomas et al., 2007; Dagyte et al., 2009; Hanson et al., 2011). In contrast, investigations of hippocampal growth factor secretion have shown that acute stress enhances expression of mitogenic growth factors such as basic fibroblast growth factor (FGF2) and nerve growth factor (NGF) (Mocchetti et al., 1996; Molteni et al., 2001), implying a potential for increased neurogenesis following acute stress. Indeed, a number of interventions that stimulate GC release such as acute exercise (Kronenberg et al., 2006) and acute sexual experience (Leuner et al., 2010) actually increase neurogenesis in the adult hippocampus. Combined, these studies suggest that adult hippocampal neurogenesis may follow an inverted U function similar to hippocampal memory—decreasing following chronic stress yet increasing in response to acute stressors.

We examined the effect of several forms of acute stress on adult hippocampal neurogenesis, seeking to resolve the contradictory evidence for enhanced vs impaired hippocampal plasticity. We found that acute stress or corticosterone (CORT, the primary rat GC) administration increased dorsal but not ventral hippocampus cell proliferation in adult rats. This increase was not dependent on input from the BLA and was accompanied by an increase in FGF2 expression in dorsal hippocampal astrocytes. Furthermore, we show that astrocyte-secreted FGF2 is necessary for CORT-induced enhancement in NPC proliferation in vitro. 2 weeks after acute stress, when newborn neurons are first becoming functional, we also find enhancement in hippocampus-dependent memory accompanied by enhanced activation of newborn neurons. These findings have important implications for understanding regulation of hippocampal plasticity in the face of environmental challenge and in distinguishing adaptive vs pathological stress responses. Moreover, they suggest that stress effects on adult neurogenesis may follow an inverted U function similar to that already demonstrated for hippocampal memory function (Lupien and McEwen, 1997).

The present study demonstrates that acute stress or exposure to the stress hormone CORT induces an increase in proliferation of hippocampal NPCs via increased secretion of astrocytic FGF2. This increase in proliferation is correlated with selective activation of the hyper-plastic newborn neurons and enhanced retention of fear extinction 2 weeks after the stressor. Taken together, these findings suggest a beneficial role for acute stress on hippocampal plasticity. Consistent with our findings, previous studies using similar stress paradigms show stress-induced enhancements in memory consolidation and growth factor expression (Roozendaal et al., 1999; Molteni et al., 2001; Roozendaal et al., 2009b). Acute stress may also support hippocampal LTP, another factor implicated in stimulating adult hippocampal neurogenesis (Korz and Frey, 2005). Notably, other manipulations that increase stress hormone secretion, such as exercise, sexual experience and mild immune challenge, similarly stimulate adult neurogenesis (Kronenberg et al., 2006; Wolf et al., 2009; Leuner et al., 2010; Buwalda et al., 2012). Recent work in adult squirrel monkeys also shows that coping with intermittent social stress through multiple pair separations and new pair formations both stimulates adult hippocampal neurogenesis and improves hippocampal memory (Lyons et al., 2010). These studies, along with our findings, evoke the interesting possibility that acute stress may be beneficial for brain health in general and hippocampal plasticity in particular.

Previous studies of adult NPC response to acute stress have yielded mixed results. While some initial work suggested that acute stress causes a decrease in NPC proliferation (Cameron and Gould, 1994; Gould et al., 1997), more recent publications have not replicated these findings (Thomas et al., 2006; Thomas et al., 2007; Dagyte et al., 2009; Hanson et al., 2011). Notably, while we found that acute CORT enhanced proliferation in well-handled, habituated rats, we did not find any effect of acute CORT on neurogenesis in rats that were not habituated to injection. Our findings therefore demonstrate that factors present before the stressor begins may alter the effect of acute stress, perhaps by changing the susceptibility of controls or stressed animals to manipulation. Not surprisingly, a rich literature exists regarding the role of handling on altering the rodent stress response (Korosi and Baram, 2010). Such experimental differences could explain discrepancies in the literature.

Previous research concerning the long-term effects of acute stress in rodents focuses primarily on models of traumatic stress and the resultant PTSD-like symptoms. Most prominently, the single prolonged stress model of PTSD uses three acute stressors in series (restraint, forced swim and ether) and results in delayed deficits in fear extinction, as well as enhanced anxiety (Knox et al., 2012a, 2012b). However, if any one of the three components of this stressor protocol are eliminated, deficits are no longer evident (Knox et al., 2012a), suggesting that stressor effects depend on the severity and length of the stressor, perhaps following the inverted U function previously described (Lupien and McEwen, 1997).

Previous work in primates has provided additional evidence for an inverted U relationship between stress and neural function. In multiple non-human primate species, for example, mild early life stress can lead to resilience against stress later in life, a phenomenon referred to as stress inoculation (Lyons and Parker, 2007; Katz et al., 2009; Parker and Maestripiero, 2011). In contrast, more severe early life stress can have the opposite outcome, increasing stress vulnerability later in adulthood. When combined with our current findings, these studies fit well with the proposed inverted U function for stress effects on brain health (Lupien and McEwen, 1997; Salehi et al., 2010; Luksys and Sandi, 2011). At high, traumatic levels, acute stress may result in maladaptive pathology (e.g., PTSD-like symptoms in the single prolonged stress model). At more moderate levels, though, such as immobilization in well-handled rats, acute stress may actually enhance function. Future research will be needed to more precisely define the limits of stimulating vs detrimental acute stress.

Many acute-stress-induced changes in hippocampal plasticity rely on functional input from the BLA. For example, while stress enhances hippocampal memory consolidation and LTP, lesion of the BLA blocks these enhancements (Quirarte et al., 1997; Roozendaal et al., 2009a, 2009b). We have recently reported that hippocampal cell proliferation and the activation of the newborn neurons in a fear-conditioning paradigm both depend on BLA neural input (Kirby et al., 2012b). In the current study, we found that while BLA lesion suppressed hippocampal cell proliferation as we have shown before, it did not affect the acute stress-induced increase in neurogenesis. These findings imply that acute stress regulation of neurogenesis may not rely on the same systems-level in vivo circuitry that mediates acute stress regulation of memory consolidation and LTP. In support of this hypothesis, we were able to model CORT-induced NPC proliferation in isolated NPCs. We found that while NPCs did not respond to acute CORT treatment independently in vitro, they did proliferate more in response to conditioned media from CORT-treated primary astrocytes, suggesting a role for secreted factors from local astrocytes in mediating stress effects on NPCs.

The dynamic role of astrocytes in facilitating neuronal function through secreted factors has gained much recognition (Eroglu and Barres, 2010). In addition to aiding in synaptic glutamate recycling, astrocytes secrete several factors such as thrombospondins (Eroglu and Barres, 2010), Hevin, SPARC (Kucukdereli et al., 2011) and glypicans (Allen et al., 2012) that regulate synaptic formation and function in mature neurons (Eroglu and Barres, 2010). Astrocytes express the glucocorticoid receptor, GR, and when they are exposed to high levels of GCs, GC-bound GR translocates to the nucleus and enhances FGF2 gene transcription (Molteni et al., 2001; Gubba et al., 2004; Unemura et al., 2012). FGF2 is a potent and necessary proliferative factor in adult NPCs (Chipperfield et al., 2002). We found that acute stress stimulated FGF2 expression in the dorsal hippocampus and in primary hippocampal astrocytes. We further showed that in the DG and hilus, the enhancement in FGF2 levels following stress is largely restricted to GFAP+ astrocytes. Notably, changes in FGF2 protein levels following acute stress closely paralleled the neurogenic response; that is, FGF2 levels were increased only in stress conditions that also stimulated neurogenesis. Neutralizing the astrocyte-secreted FGF2 prevented enhanced proliferation in cultured NPCs. These findings suggest a novel role for astrocytes in supporting hippocampal plasticity in response to an environmental stressor through secreted FGF2. Further research will be required to fully dissect the molecular mechanisms by which stress induces FGF2 secretion from astrocytes.

Newly-born neurons are implicated in numerous hippocampal memory functions (Aimone et al., 2010), particularly contextual fear conditioning. Contextual fear conditioning activates immature neurons (Kirby et al., 2012b) and when new neurons are selectively knocked down, fear extinction is impaired (Deng et al., 2009; Stone et al., 2010). Sahay et al. have further shown that prolonging survival of newly-born neurons through targeted knockdown of apoptotic pathways enhances discrimination between similar contexts in a fear conditioning task (Sahay et al., 2011). We found that 2 weeks, but not 2 days, after acute stress, immobilized rats showed enhanced contextual fear extinction retention compared to controls. We also found that immobilized rats had greater activation of newly born neurons in response to fear extinction recall. This time window coincides with the period in which the newborn cells are hyper-plastic and more likely to be recruited to active circuitry (Kee et al., 2007; Deng et al., 2009; Kirby et al., 2012b). Given that immobilized rats had a similar number of newborn neurons as controls, these data suggest that immobilized rats better utilize the pool of immature neurons, possibly contributing to their enhanced memory. However, this connection does not preclude the potential contribution of other aspects of hippocampal plasticity to the enhanced memory. Future research will be necessary to fully determine the role of immature neurons vs existing circuitry in enhancement of hippocampal memory.

A recent hypothesis posits that the dorsal and ventral hippocampus support different behavioral functions, with the dorsal region being important for spatial and declarative memory while the ventral region facilitates affective regulation (Fanselow and Dong, 2010). This division may also apply to neural stem cell regulation within the DG of each region where chronic stress preferentially effects the ventral over the dorsal hippocampus, perhaps reflecting the negative affective consequences of chronic stress (Tanti et al., 2012). In the present study, we found that acute stress or stress hormone exposure increased neurogenesis and FGF2 expression in the dorsal, but not in the ventral, hippocampus. Moreover, the memory benefits observed 2 weeks after stress were in contextual fear extinction, a task that relies on the kind of spatial memory hypothesized to depend on the dorsal DG (Fanselow and Dong, 2010). This selective involvement of the dorsal hippocampus implies that our acute stressor model functions as a cognitive stimulant for the declarative domains of hippocampal function rather than as a modulator of emotional responsivity.

The brain's response to acute stress can define the line between life-saving adaptation and long-term pathology. The current study suggests that moderate, acute stress may stimulate heightened brain plasticity via increased neurogenesis. These findings have important implications for understanding adaptive vs pathological responses to stress.

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Author details

1. Elizabeth D Kirby

   Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States

   Present address

   1. Neurology, Stanford University, Stanford, United States
   2. Neurology, Stanford University, Stanford, United States

   Contribution

   EDK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Sandra E Muroy

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   SEM, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. Wayne G Sun

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   WGS, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

4. David Covarrubias

   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   DC, Conception and design, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Megan J Leong

   Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States

   Contribution

   MJL, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Laurel A Barchas

   Department of Integrative Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   LAB, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

7. Daniela Kaufer

   1. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
   2. Department of Integrative Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   DK, Conception and design, Drafting or revising the article

   For correspondence

   danielak@berkeley.edu

   Competing interests

   The authors declare that no competing interests exist.

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