Neurobiology of Learning and Memory xxx (2014) xxx–xxx

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Neurobiology of Learning and Memory journal homepage: www.elsevier.com/locate/ynlme

Review

Stress modulation of hippocampal activity – Spotlight on the dentate gyrus MingXin Fa a,1, Li Xia a,1, Rachel Anunu a, Orli Kehat d, Martin Kriebel c, Hansjürgen Volkmer c, Gal Richter-Levin a,b,d,⇑ a

‘‘Sagol’’ Department of Neurobiology, University of Haifa, Mount Carmel, 31095 Haifa, Israel Department of Psychology, University of Haifa, Mount Carmel, 31905 Haifa, Israel Department of Molecular Neurobiology, Natural and Medical Sciences Institute (NMI), Universität Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany d The Institute for the Study of Affective Neuroscience (ISAN), University of Haifa, Mount Carmel, 31905 Haifa, Israel b c

a r t i c l e

i n f o

Article history: Received 8 November 2013 Revised 17 March 2014 Accepted 8 April 2014 Available online xxxx Keywords: Hippocampus Dentate gyrus Stress LTP Neurogenesis

a b s t r a c t The effects of stress on learning and memory are diverse, ranging from impairment to facilitation. Many studies emphasize the major role of the hippocampus, mainly its CA1 and CA3 areas, in the process of memory formation under emotional and stressful conditions. In the current review, we summarize work which suggests that the dentate gyrus (DG) of the hippocampus is likely to play a pivotal role in defining the impact of stress on hippocampal functioning. We describe the effects of stress on long term potentiation (LTP) and local circuit activity in the DG and the role of the amygdala in mediating these effects. As one of the brain regions known to have a high rate of adult neurogenesis, the effects of stress on DG neurogenesis will also be reviewed. Finally, we discuss exposure to stress during juvenility and its influence on the adult DG. The DG is a dynamic structure which is susceptible to stress. Under stressful conditions, its response is variable and complex, much like the behavioral outcomes of such circumstances. It is likely to significantly contribute to the diverse effects of stress on memory formation. Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction Stress is not yet a well-defined concept (Koolhaas et al., 2011), but it has long been established that when facing a stressful challenge an organism will make the corresponding physiological/psychological responses in attempting to cope (Chrousos, 2009). Stress may be helpful and prepare an individual for the acute consequences of dangerous or threatening situations but it may also induce long-term negative outcomes (Habib, Gold, & Chrousos, 2001). Altered cardiovascular tone, immune-system suppression and changes of brain functions are often reported as adverse physiological effects of stress in humans and animals. Stress-induced alterations in learning and memory processes are also involved in the pathophysiology of stress-related disorders (de Kloet, Oitzl, & Joels, 1999; McEwen & Sapolsky, 1995). The hippocampus is a medial temporal lobe structure that is thought to take on various roles: it is crucial for the formation of stable ‘declarative’ memory (Squire, 1992), it specializes in ⇑ Corresponding author at: Department of Psychology, University of Haifa, Mount Carmel, 31905 Haifa, Israel. Fax: +972 48288578. E-mail address: [email protected] (G. Richter-Levin). 1 Authors with equal contributions.

encoding spatial information (Eichenbaum, Dudchenko, Wood, Shapiro, & Tanila, 1999) and it is an important regulator of emotion and particularly of the stress response (Herman, Ostrander, Mueller, & Figueiredo, 2005). The hippocampus contains an extremely high level of corticosteroid receptors (Chao, Choo, & McEwen, 1989; Van Eekelen, Jiang, De Kloet, & Bohn, 1988) and it is therefore particularly susceptible to stress hormones, which typically impair its function (Joels, Krugers, & Karst, 2008). Exposure to stress or stress hormones was shown to affect hippocampal synaptic plasticity, neurochemistry, neurogenesis, neural morphology and cell apoptosis (reviewed in Conrad, 2006, 2008; Herman & Seroogy, 2006; Joëls & Krugers, 2007; Joëls et al., 2004; Lucassen et al., 2006) as well as disrupt hippocampus-dependent memory performance (Conrad, 2009). Although most studies dealing with the effects of stress on hippocampal functioning describe impairments, it should be noted that some studies raise the possibility that under certain conditions stress may positively affect hippocampal functioning (for example, Kirby et al., 2013; Lyons et al., 2010). For instance, intermittent social separations and new pair formations increased hippocampal neurogenesis in squirrel monkey and enhanced hippocampal-dependent spatial learning performance (Lyons et al., 2010).

http://dx.doi.org/10.1016/j.nlm.2014.04.008 1074-7427/Ó 2014 Elsevier Inc. All rights reserved.

Please cite this article in press as: Fa, M., et al. Stress modulation of hippocampal activity – Spotlight on the dentate gyrus. Neurobiology of Learning and Memory (2014), http://dx.doi.org/10.1016/j.nlm.2014.04.008

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While most studies concerned with the effects of stress on hippocampal functioning focused on the CA1 and CA3 fields of the hippocampus proper, the DG received much less attention with regards to this subject. The DG is typically considered to have a key role in the encoding of spatial and contextual information, particularly in pattern separation and novelty detection (Kesner, 2007, 2013; Xavier & Costa, 2009). In recent years, the DG is also increasingly associated with affective regulation and pathophysiology of mood disorders. For instance, in a recent study Kheirbek et al. (2013) showed that elevating the activity in granule cells in the ventral DG (but not the dorsal DG) suppresses innate anxiety. In addition, abundant evidence points to a link between neurogenesis in the DG and exposure to stress and stress hormones. Acute and chronic stress as well as corticosterone treatment typically suppress neurogenesis of DG granule neurons (reviewed in Schoenfeld & Gould, 2012) while treatment with antidepressants can increase the level of granular cells in the DG under certain conditions (David et al., 2009). While evidence for functions of the DG gradually accumulates, many of the findings are still under active debate, particularly those concerning the DG’s function in emotional processing. In this review we summarize studies concerning the effects of stress on DG functioning. We evaluate the effects of stress on neural activity and plasticity, focusing on local circuit activity of DG interneurons and on long term potentiation (LTP). Since the amygdala has a central role in mediating the effects of stress on the DG, we also address the way in which it alters DG functioning under stressful conditions. Next, we address the effects of stress on neurogenesis and speculate their function in regulating the stress response. Finally, we discuss the effects of stress exposure in juvenility and its effects on DG functioning in adulthood. The review focuses on the DG as an important brain region affected by and involved in response to stress. The focus on the DG is important because its contribution to stress and emotional responses has so far been underestimated. However, it is also important to note that stress affects many brain regions and that in the end it is the circuitry and network activity that is altered by stress and that affects the phenotype. While a spotlight on the special role of the DG in this respect is important, it should be stated that in order to understand the effects of stress on an individual it would be important to ‘‘zoom out’’ again and study the connectivity and function of different brain networks as a whole, but with the DG as an important part of that network view.

receive input from the entorhinal cortex which represents the majority of excitatory synapses on granule cell dendritic arbors. The output of granule cells is formed by distinctive unmyelinated axons called mossy fibers. They pass through the mossy cells of the polymorphic layer to their final target, the CA3 pyramidal cells of the hippocampus (Amaral et al., 2007). Another type of excitatory hippocampal cell is the mossy cells which reside in the polymorphic layer. These glutamatergic cells have extensive dendritic arbors within the polymorphic layer and could be activated by granular cells (Scharfman, Kunkel, & Schwartzkroin, 1990), but occasionally their dendrites can also be found in the molecular layer, which suggests that they also receive inputs from the peforant path. The vast majority of mossy cells target DG granular cell dendrites. The axons of mossy cells are also sent to contralateral DG to form commissural projection while some synaptic contacts of mossy cells are also found on dendrites of interneurons in the polymorphoc layer (Ribak, Seress, & Amaral, 1985). Various interneurons have been identified in the rat hippocampal formation (a detailed overview of the characteristics of the various hippocampal interneurons can be found in Freund & Buzsaki, 1996), most of which are gamma-aminobutyric acid-ergic (GABAergic). These interneurons can further be divided into subtypes according to neuropeptide biomarkers that coexist with GABA, such as parvalbumin, somatostatin, neuropeptide Y and cholecystokinin. Another way to subdivide these interneurons is according to their morphology (basket cell, stellate cell, fusiform cell) and physiological properties (fast or slow-spiking). These interneurons innervate principal cells or other interneurons inside and outside of the DG. In addition, these interneurons also have axon terminals associated with the perforant pathway or the DG commissural pathway (Buckmaster & Schwartzkroin, 1995; Ribak & Seress, 1983; Sik, Penttonen, & Buzsaki, 1997). There is also evidence that commissural fibers from contralateral DG directly activate interneurons of the DG and form feed-forward inhibitory modulation on granule cells (Ribak et al., 1986). The effects of stress on inhibitory interneuron activity and on the interaction between interneurons and principle neurons will be further discussed in Sections 3.2 and 6 of this review.

3. The effects of stress on DG LTP induction and local circuit activity 3.1. The effects of stress on LTP induction

2. An overview of DG The DG region of the hippocampal formation receives the hippocampus’s major excitatory input from the cortex and subcortical areas, such as the amygdala. Cortical and subcortical projections converge within the entorhinal cortex which then projects to the DG, thus establishing it as the main gateway of information into the hippocampus. The DG is composed of three layers: molecular, granular, and polymorphic. The molecular layer is the outermost layer and is relatively cell free. It mainly contains the dendrites from the principal dentate neurons and axons that originate from the perforant path, arising from the entorhinal cortex. The second and main cell layer is the granule cell layer, which is made up largely of densely packed granule cells. The third layer is the polymorphic cell layer or the hilus which contains a number of cell types, in which the most prominent are the mossy cells (Amaral, Scharfman, & Lavenex, 2007). The principal cells of the hippocampus, the granule cells, are excitatory cells that extend their dendrites through the molecular layer and are covered with spines. The dendrites of granule cells

Exposure to stress causes modifications of plasticity in the hippocampus (Diamond, Fleshner, Ingersoll, & Rose, 1996; Foy, Stanton, Levine, & Thompson, 1987; Garcia, 2002; Kim, Foy, & Thompson, 1996). One such form of plasticity, repeatedly shown to be affected by stress and widely associated with learning and memory processes, is long-term potentiation (LTP) of reactivity to afferent stimulation (Bliss & Lomo, 1973). Many studies have shown that stress affects hippocampal subregions differentially. While Exposure to stress was constantly shown to impair LTP in CA1 field of the hippocampus (Foy et al., 1987; Kavushansky, Vouimba, Cohen, & Richter-Levin, 2006; Kim & Diamond, 2002; Pavlides, Ogawa, Kimura, & McEwen, 1996; Shors, Seib, Levine, & Thompson, 1989), reports about stress effects on LTP in the DG are much less consistent. Much like CA1 LTP, several studies have shown impairment in DG LTP induction following exposure to both acute and chronic stress (Alfarez et al., 2003; Shors & Dryver, 1994; Wang, Akirav, & Richter-Levin, 2000) or corticosterone (CORT) administration (Pavlides, Watanabe, & McEwen, 1993). For example, by using an unpredictable stress paradigm for 21 days, including immobilization,

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cold immobilization, vibration, isolation, crowding, swim and cold water swim, impairment of LTP in both CA1 and DG was observed (Alfarez, Joels, & Krugers, 2003). Applying acute severe stress was also reported to have similar effects: a brief traumatic stress in the form of underwater trauma was shown to reduce the induction of DG-LTP (Wang et al., 2000). In contrast, other studies have shown DG-LTP to be unaffected (Bramham, Southard, Ahlers, & Sarvey, 1998; Gerges, Stringer, & Alkadhi, 2001) or even enhanced by stress (Kavushansky et al., 2006). Kavushansky et al. (2006) studied the effects of controllable vs. uncontrollable mild stress on synaptic plasticity in the hippocampus and amygdala. While in CA1 both conditions impaired LTP induction, DG LTP remained unchanged in the controllable stress condition and was enhanced in the uncontrollable condition. Other studies show that stress can reinforce the maintenance of DG LTP and prolong its duration (Korz & Frey, 2003; Seidenbecher, Reymann, & Balschun, 1997). The variable effects stress may have on LTP in the DG demonstrate how vulnerable this region is to factors such as the type of stressor, the severity of the stressor, plasma levels of CORT and the timing of the stress exposure (Joëls & Krugers, 2007; Korz & Frey, 2003; Yamada, McEwen, & Pavlides, 2003).

3.2. Effects of stress on DG interneurons and local circuitry activity While it is widely accepted that LTP and long term depression (LTD) of synaptic transmission are important neurophysiological models for learning and memory processes, local circuit activity within DG is another level of activity that is also suggested to be involved in memory formation (Freund & Antal, 1988; Freund & Buzsaki, 1988; Maroun & Richter-Levin, 2002). Different from LTP which mainly reflects the enhancement in activity of excitatory synapses, local circuit activity highlights the interactions between principal cells and local GABAergic inhibitory interneurons. The function of the GABAergic system in the DG depends on the type, number and distribution of GABAergic interneurons in the DG, GABA synthesis, the expression of GABA receptors and the efficacy of the GABAergic synapse. Although GABAB and GABAC receptors might also be involved in regulation of DG local circuit activity, our main focus will be on the abundantly expressed GABAA receptor which is thought to be distributed mainly in synaptic contacts (reviewed in Farrant & Nusser, 2005). As a pentameric assembly of subunits that form a central ion channel, GABAA receptors in DG are composed of 2a, 2b and 1c subunit, with a substantial expression of a1, a2, a4, b1, b2, b3 and c2 subunits (Wisden, Laurie, Monyer, & Seeburg, 1992). The effects of stress on DG local circuit have been reported on all aspects of GABAergic system indicated above. Chronic stress was reported to significantly decrease the Calbindin-D28k-immunoreactive neuron densities (in granule cell layer) and parvalbumin-positive neurons in molecular layer of DG in rodents (Seidel, Helmeke, Poeggel, & Braun, 2008), while the increase of neuropeptide Y (NPY) mRNA in DG was found in acutely stressed rats (Conrad & McEwen, 2000). Glutamic acid decarboxylase (GAD), the enzyme that converts glutamate to GABA, was shown to be increased in DG after CORT treatment on postnatal days 48 and 60. The expression of the GAD isoforms GAD65 and GAD67 was differently affected, with increased expression of GAD65 24 h after CORT treatment but increased GAD67 expression only 5 days later (Stone et al., 2001). Since GAD65 and GAD67 are allocated in nerve terminal and cell body respectively (Esclapez, Tillakaratne, Kaufman, Tobin, & Houser, 1994), alterations of GAD expression caused by CORT treatment might have different short-term and long-term outcomes on DG activity.

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The level of expression of different GABAA receptor subunits was also found to be affected by stress or CORT. Chronic treatment with CORT decreased a1 and a2, as well as b1 subunit expression but increased the expression of b2 and b3 subunits (Orchinik, Weiland, & McEwen, 1995). Acute application of CORT on brain slices of stressed rats increased a1 and decreased c1 subunit expression compared with control rats (Qin, Karst, & Joels, 2004). The pattern of GABAA receptor subunit expression after stress or CORT treatment makes it difficult to capture the overall impact on GABAergic functioning; measuring DG local activity by electrophysiological method is a feasible way to address this question. To measure the activity of this complex local circuit formed by interneurons with principal cells and with other interneurons, frequency-dependent inhibition (FDI), paired-pulse inhibiton and commissural inhibition are frequently used indexes (Buzsaki & Eidelberg, 1981; Richter-Levin, Greenberger, & Segal, 1994; Rosenblum, Maroun, & Richter-Levin, 1999; Sloviter, 1991). The application of GABAA receptor antagonist (bicuculin) was shown to cause a long lasting reduction in these forms of inhibition, indicating that they indeed reflect effects associated with GABAergic transmission (Rosenblum, Maroun, & Richter-Levin, 1999). We were able to demonstrate that 15-min forced swim stress did not alter FDI in DG but induced enhancement of commissural inhibition (Yarom, Maroun, & Richter-Levin, 2008). In another study exposure to severe stress caused an enhancement of paired-pulse inhibition, while exposure to a reminding cue of the trauma 24 h later resulted in the enhancement of both FDI and paired-pulse inhibition (Ardi, Ritov, Lucas, & Richter-Levin, 2013). Since it is suggested that FDI and commissural inhibition reflect feedforward inhibition while paired pulse inhibition reflects feedback inhibition (Buzsaki & Eidelberg, 1981; Ribak et al., 1986; Sloviter, 1991), it can be speculated that different aspects of encoding and retrieval of trauma-related memories involve differential subpopulations of interneurons in the DG. Theta burst stimulation (TBS) to the perforant path, used to induce LTP, was found to also affect FDI. FDI was significantly reduced by TBS, independently of the induction of LTP. This form of local circuit plasticity in the DG was impaired in spatial learning-impaired aged rats, even when LTP remained intact, supporting the notion that this form of plasticity in the DG might also contribute to hippocampal learning and memory (Maroun & RichterLevin, 2002). More recently differences in sensitivity of DG local circuit activity to stress were found between male and female rats (Zitman & Richter-Levin, 2013), which are in agreement with reported differences for the sensitivity of male and female rats in performing hippocampus-dependent tasks under stress, such as the active avoidance task (Dalla & Shors, 2009; Horovitz, Tsoory, Yovell, & Richter-Levin, 2014).

4. Effects of stress on DG neurogenesis Neurogenesis in the mammalian brain was previously thought to occur only during development and terminate before puberty. However, extensive evidence from many mammalian species revealed that certain brain areas preserve the ability to generate new neurons in the adult brain (Fuchs, Flugge, & Czeh, 2006; Gould & Tanapat, 1999). The sub-granular zone of the DG is an important brain area where adult spontaneous neurogenesis takes place (Altman & Das, 1965). In the sub-granular zone, through several developmental stages with distinctive physiological and morphological properties, most of neural progenitors differentiate into neurons and become incorporated into the granule cell layer (Cameron, Woolley, McEwen, & Gould, 1993), extend axons to their appropriate targets in CA3 and become functionally integrated into the hippocampal network. These newborn cells have distinct morphological and

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electrophysiological properties that differ from mature granule cells (Schmidt-Hieber, Jonas, & Bischofberger, 2004). In the past two decades, accumulating evidence gives emphasis to the role of neurogenesis in the DG in hippocampal functioning. Studies investigating the link between adult neurogenesis in the DG and hippocampal-dependent cognitive abilities have yielded contradictory findings (reviewed in Deng, Aimone, & Gage, 2010) and this issue is still under debate. On the other hand, findings regarding the high susceptibility of these newly-formed neurons to stress and stress hormones are particularly consistent. Overall, applying both acute and chronic stress tends to decrease adult neurogenesis by influencing cell proliferation, neuronal differentiation or cell survival (reviewed in Schoenfeld & Gould, 2012). Exposure to stressful stimuli such as chronic restraint (Pham, Nacher, Hof, & McEwen, 2003; Rosenbrock, Koros, Bloching, Podhorna, & Borsini, 2005), social isolation (Stranahan, Khalil, & Gould, 2006), chronic social stress (Ferragud et al., 2010; Kozorovitskiy & Gould, 2004; Lagace et al., 2010; Mitra, Sundlass, Parker, Schatzberg, & Lyons, 2006) and predator odor (Tanapat, Hastings, Rydel, Galea, & Gould, 2001) all reveal a reduction in neurogenesis. CORT is considered to have an important role in mediating the effects of stress on neurogenesis. Removal of the adrenal glands by adrenalectomy was shown to increase neurogenesis in the DG (Cameron & Gould, 1994) while administration of CORT reduced neurogenesis (Brummelte & Galea, 2010; Cameron & Gould, 1994; Wong & Herbert, 2006). In addition, treatment with the glucocorticoid receptor antagonist mifepristone normalized chronic stress-induced reductions in neurogenesis (Oomen, Mayer, de Kloet, Joels, & Lucassen, 2007). These results suggest that in general, elevated levels of CORT appear to reduce the rate of neurogenesis in the DG (but see Schoenfeld & Gould, 2013), although the mechanism by which they do so is not fully understood. Current studies link neurogenesis to regulation of stress responses. Given that the hippocampus is associated with HPA regulation (Herman et al., 1989), it can be speculated that new neurons take part in these processes. Indeed, several studies reveal that specific ablation of newborn neurons in the adult DG is associated with impaired HPA function and anxiety-related behavior (Bergami, Berninger, & Canossa, 2009; Bergami et al., 2008; Revest et al., 2009; Schloesser, Manji, & Martinowich, 2009). For instance, Schloesser et al. (2009) show that suppression of neurogenesis in the DG leads to potentiated HPA response following exposure to a stressor, thus suggesting that newly-formed neurons in the DG take part in HPA regulation. Revest et al. (2009) used transgenic animals, in which hippocampal neurogenesis has been specifically impaired, to show that decreasing adult-born neurons increases anxiety-related behaviors. Taken together, these findings show that neurogenesis plays an important role in the regulation of affective states and may be involved in the pathophysiology of stress disorders. The exact way the sensitivity of DG neurogenesis to stress is translated to contribute to psychopathologies such as mood disorders and post-traumatic stress disorder (PTSD) is far from being clear (DeCarolis & Eisch, 2010; Hanson, Owens, & Nemeroff, 2011; Petrik, Lagace, & Eisch, 2012). However, the relative specificity of adulthood neurogenesis to the DG, and the strong correlational evidence between stress, neurogenesis and psychopathological symptoms strongly support the notion that the DG holds a unique role associated with emotional modulation and with these pathologies.

5. Amygdala and the effects of stress on DG Considerable evidence indicates that the amygdala is critically involved in mediating stress-related modulation of hippocampal functioning (Roozendaal, 2003; Roozendaal, McReynolds, &

McGaugh, 2004). For example, amygdala lesions and/or pharmacological manipulations have been show to impair in vivo LTP in DG of the hippocampus (Kim, Lee, Han, & Packard, 2001; Koo, Han, & Kim, 2004). Anatomically, although there is no direct projection from the amygdala to the DG, widespread projections from the basal nucleus of the amygdala to the entorhinal cortex, parasubiculum and subsubiculum provide a potent indirect pathway from amygdala to the DG (Pikkarainen, Ronkko, Savander, Insausti, & Pitkanen, 1999), which may potentially influence DG functioning. Another potential way for the amygdala to influence the hippocampus is via its regulation of CORT: the activation of amygdala increases the level of CORT which may regulate DG activity (Vouimba & Richter-Levin, 2013). The amygdala has been implicated in emotional learning and in modulating attention mechanisms in several brain areas (McGaugh, Cahill, & Roozendaal, 1996), but our focus will be on the potential role of the amygdala in mediating effects of stress on DG activity. Electrophysiological studies show that the amygdala is involved in modulating DG activity in a biphasic way: there is a fast excitatory phase, which results in the enhancement of hippocampal plasticity, and a slow inhibitory phase, which suppresses hippocampal plasticity. Basolateral amygdala priming shortly before (30 s before perforant path TBS) high frequency stimulation significantly enhanced DG-LTP (Akirav & Richter-Levin, 1999), while LTP was significantly attenuated when basolateral amygdala priming was applied 1 h before the perforant path stimulation, similar to the effect of acute behavioral stress (such as exposure to an elevated platform). It was suggested that through the fast excitatory phase, the amygdala ‘‘marks’’ emotionally charged experiences as important by strengthening of synapses located on hippocampal neurons that have just been activated due to the learning experience (Richter-Levin & Akirav, 2000). We termed this enhancement of memories by amygdala modulation ‘‘emotional tagging’’ (Richter-Levin & Akirav, 2003). Together with the fact that amygdala activity during memory encoding was correlated with enhanced episodic recognition memory and the findings that the amygdala enhances episodic memory in part through modulation of hippocampal activity (Hamann & Adolphs, 1999), the early phase modulation of DG activity by amygdala may support memory formation while stress and delayed amygdala activation have a negative effect. Stress was demonstrated to activate the amygdala, and to induce lasting plasticity, but the level of activation may depend on the characteristics of the stress experience (Kogan & RichterLevin, 2008) both attenuation and enhancement of basolateral amygdala LTP have been induced by different stressors (Kavushansky et al., 2006). It is reasonable to assume that when the activity within the amygdala is modified, the impact of the amygdala on DG will also be modified. This idea is supported by electrophysiological results. Amygdala priming with weak stimulation (1 V, 50 ls pulse duration) was found to enhance DG-LTP while priming the amygdala with a strong stimulus (2 V, 100 ls pulse duration) impaired it (Li & Richter-Levin, 2012). Variable effects of amygdala priming on DG-LTP were also seen when different frequencies were applied to the amygdala, with 100 Hz significantly enhancing DG LTP, 400 Hz having no affect, while 25 Hz and 1 Hz stimulation dramatically reducing DG-LTP (Vouimba & Richter-Levin, 2013). Taken together, these results, which mirror findings with the effects of stress on DG LTP (Section 3.1 above), suggest that the amygdala is closely involved in the mechanisms leading to variable effects of stress on DG-LTP. Another mechanism by which the amygdala may modulate emotional processing in the hipppocampus is by regulating neurogenesis in the DG. As we described in the previous section, there is strong evidence for the role of adult neurogenesis in the DG in regulating the stress response. A recent study shows that neurogenesis can be

Please cite this article in press as: Fa, M., et al. Stress modulation of hippocampal activity – Spotlight on the dentate gyrus. Neurobiology of Learning and Memory (2014), http://dx.doi.org/10.1016/j.nlm.2014.04.008

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particularly sensitive to emotional input from the basolateral amygdala (Kirby et al., 2012). In their study, Kirby et al. (2012) show that lesions of the basolateral amygdala suppress hippocampal neurogenesis and that the activation of new neurons during exposure to a fearassociated context was blocked by basolateral amygdala lesions. These important findings propose a novel approach by which the amygdala can influence emotional processing in the DG, and emphasize the importance of amygdalar inputs under stress conditions. 6. Juvenile stress and DG activity It is known that differences in brain functionality/morphology, due to different developmental stage and/or sex in human or rodent, underlie different responses to stressors. In humans, there are overwhelming data indicating that adverse early-life stress and childhood emotional trauma represent major risk factors for the emergence of a variety of stress-related psychopathologies, particularly PTSD and depressive or anxiety symptoms (Brietzke et al., 2012; Gerson & Rappaport, 2013; Pratchett & Yehuda, 2011). In rodents, early life trauma, such as prolonged maternal separation, foot shock or restraint, was demonstrated to lead to heightened emotionality and anxiety or depression in the adult (Andersen & Teicher, 2004; Cirulli, Santucci, Laviola, Alleva, & Levine, 1994; Kehoe, Shoemaker, Triano, Callahan, & Rappolt, 1998; Kikusui & Mori, 2009; Plotsky & Meaney, 1993; Rosenfeld, Wetmore, & Levine, 1992; Schmidt, Wang, & Meijer, 2011; van Oers, de Kloet, Li, & Levine, 1998; Vazquez, Van Oers, Levine, & Akil, 1996). However, because the human literature emphasizes more childhood than infancy, we have initiated studies at a rodent developmental period more relevant to human childhood, the post weaning prepuberty, ‘juvenility’ or the early adolescence stage (Avital & Richter-Levin, 2005; Horovitz, Tsoory, Hall, Jacobson-Pick, & Richter-Levin, 2012; Tsoory & Richter-Levin, 2006). In the past decade our lab and others modeled juvenile or adolescent stress and studied the impact of exposure of rats to stressors during juvenility and the ability of these animals to cope with stressors later in adulthood (Avital & Richter-Levin, 2005; Chocyk et al., 2014; Eiland & Romeo, 2013; Horovitz et al., 2012; Moore, Gauchan, & Genovese, 2014; Negrón-Oyarzo, Pérez, Terreros, Muñoz, & Dagnino-Subiabre, 2014; Tsoory & Richter-Levin, 2006). We found that a brief exposure to forced swimming in juvenility could modulate the ability of coping with stress in adulthood(Avital & Richter-Levin, 2005). Adult rats that were exposed to stress during pre-puberty, displayed increased anxiety-like behavior, learning deficits, and impaired coping ability with stressors compared with control rats (Avital & Richter-Levin, 2005; Tsoory, Cohen, & Richter-Levin, 2007; Tsoory & Richter-Levin, 2006). Importantly, many of these studies demonstrated considerable individual and sex differences in responding to stress in juvenility (reviewed in Horovitz et al., 2012, 2014). It was also shown that exposing juvenile rats to variable chronic stress resulted in reduced volumes of CA3, CA1 and DG regions of the hippocampus as well as, impaired spatial learning and CORT response to an acute stressor in adulthood (Isgor, Kabbaj, Akil, & Watson, 2004). Ours and Others studies also demonstrated that during juvenility, significant adversities may permanently alter stress response mechanisms, which are involved in increasing the levels of circulating CORT and ACTH and upregulating the expression of cell adhesion molecules and CRH as well as altering GABAergic system or endocannabinoids-mediated neurotransmission and synaptic plasticity (Horovitz et al., 2012; Klein & Romeo, 2013; Reich, Mihalik, Iskander, Seckler, & Weiss, 2013). This implies that the developmental stage between weaning and puberty, i.e. ‘juvenile’ age, indeed represents a stress sensitive period. The effects of juvenile stress on DG activity and plasticity have also been studied. On the electrophysiological level, Zitman and

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Richter-Levin (2013) compared DG activity and plasticity of stressed juvenile rats and stressed adult rats. Findings show that exposure to acute stress enhanced DG LTP only in juvenile male rats but not in adult male rats. In addition, marked differences between local inhibitory activities were found between the two groups (Zitman & Richter-Levin, 2013). Differences are also reflected at the molecular level. Exposure to juvenile stress by itself had no significant effects on the pattern of expression of the GABAa subunits a1 and a2 in juvenility, but it induced a form of metaplasticity that resulted in alterations in the expression of these subunits in the hippocampus of adult animals exposed to stress in adulthood, on the background of juvenile stress (Jacobson-Pick & Richter-Levin, 2012). In recent studies in our lab we assessed the impact of altering the expression of these GABAA receptor subunits by employing specific viral vectors to selectively knockdown either GABAA receptor a1 or a2 subunits in the DG of juvenile rats. When tested in adulthood, this manipulation significantly altered local inhibitory activity in the DG. At the behavioral level, selective knockdown of GABAA receptor a2 subunit in DG lead to no apparent change in anxiety levels but significantly improved the performance of rats in novel object recognition task (unpublished data). Because the modulation of GABA functioning in this way is mild and very local, these results clearly indicate that the GABAergic modulation of DG activity plays a critical role in mediating emotional and stress effects on hippocampal functioning. Some studies also demonstrate the short-term and long term effects of stress in juvenility on DG neurogenesis in rodents. King et al. (2004) showed that acute restraint and immobilization in juvenile rats significantly reduced the number of granule cells tagged in the fascia dentate, while chronic antidepressants were shown to increase adult neurogenesis in the DG (Malberg, Eisch, Nestler, & Duman, 2000; Malberg & Schechter, 2005; Navailles, Hof, & Schmauss, 2008). Isgor et al. (2004) also reported that juvenile rats subjected to random, variable physical or social stress regimens for 4 weeks led to inhibition of neural growth in the DG granular cell layer. Toth et al. (2008) found that chronic mild stress at the age of 4 weeks increased neurogenesis and levels of brain derived neurotrophic factor (BDNF), which is also suggested to be involved in the regulation of neurogenesis, in the DG of young animals and decreased these parameters in adult animals. In addition, some studies suggest that juvenile stress differentially influence neurogenesis in the DG of male and female rat. In females, it showed a reduced number of proliferating and surviving cells in the DG in adulthood compared to non-stressed female controls, while males showed a slight increase in adult neurogenesis (Barha, Brummelte, Lieblich, & Galea, 2011; McCormick et al., 2012). Furthermore, chronic forced swim stress in juvenility but not in adulthood significantly inhibits neurogenesis and decreases BDNF immunoreactivity in DG (Badowska-Szalewska, Spodnik, Klejbor, & Morys, 2010; Kikusui, Ichikawa, & Mori, 2009).

7. Conclusions Activity and plasticity in the DG are affected by exposure to stress, but in a complex way that only starts to reveal itself. Since the stress response is the basic strategy of an organism to cope with a changing environment, it is to be expected that under stress the vast energy consuming processes such as neurogenesis in DG are temporally shut down. Under some conditions, when the stressor leads to learning and memory formation (especially spatial memory), the activity of DG could be enhanced as is evident by the enhancement of LTP induction found following exposure mainly to mild stressors. The impact of amygdala on DG adds yet another level of complexity to this phenomenon. In addition, the history of the circuit, as is exemplified by exposure to juvenile

Please cite this article in press as: Fa, M., et al. Stress modulation of hippocampal activity – Spotlight on the dentate gyrus. Neurobiology of Learning and Memory (2014), http://dx.doi.org/10.1016/j.nlm.2014.04.008

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stress, certainly has profound consequences, as it exaggerates the effects of stress in adulthood. Clearly, the response to stress involves activation of a network of brain regions, with the DG being but one of those regions and a part of a network. Even within the scope of the current review we emphasize the importance of amygdala modulation of the DG. Other brain areas, such as the prefrontal cortex, or nucleus accumbens, are also part of that network and a full description of the impact of stress would require relating to the network effect (Segal, Richter-Levin, & Maggio, 2010). However, the current review focuses specifically on the role of the DG, because the effects of stress and of amygdala priming on the DG suggest that under emotional and stressful conditions the DG assumes a pivotal role in memory formation. The finding that modifying, by way of viral vectors, only a subset of local circuit activity specifically within the DG is sufficient to induce significant behavioral alterations, is a strong support for such a claim. Alterations of plasticity in the DG were observed at different levels including changes in LTP induction, inhibitory interneurons and neurogenesis. DG is definitely vulnerable to stress, but as a dynamic structure, its response to stress is variable, as can be observed in DG-LTP studies. Acknowledgments This research was funded by The Israel Science Foundation Grant No. 1403/07 to GRL, by The German Israeli Project Cooperation (DIP) RI 1922/1-1 HE 1128/16-1, to GRL, by German-Israeli Cooperation in Biotechnology (BIO-DISC) to GRL and 0315512B to HV, by Hope for Depression Research Foundation Grant No. 2011-0011 to GRL, and by a USAMRMC award (10071009) to GRL. References Akirav, I., & Richter-Levin, G. (1999). Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat. Journal of Neuroscience, 19(23), 10530–10535. Alfarez, D. N., Joels, M., & Krugers, H. J. (2003). Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. European Journal of Neuroscience, 17(9), 1928–1934. Altman, J., & Das, G. D. (1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. Journal of Comparative Neurology, 124(3), 319–335. Amaral, D. G., Scharfman, H. E., & Lavenex, P. (2007). The dentate gyrus: Fundamental neuroanatomical organization (dentate gyrus for dummies). Progress in Brain Research, 163, 3–22. Andersen, S. L., & Teicher, M. H. (2004). Delayed effects of early stress on hippocampal development. Neuropsychopharmacology, 29(11), 1988–1993. http://dx.doi.org/10.1038/sj.npp.1300528. Ardi, Z., Ritov, G., Lucas, M., & Richter-Levin, G. (2013). The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms. International Journal of Neuropsychopharmacology, 17(4), 571–580. http:// dx.doi.org/10.1017/S1461145713001272. Avital, A., & Richter-Levin, G. (2005). Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat. International Journal of Neuropsychopharmacology, 8(2), 163–173. http://dx.doi.org/10.1017/ S1461145704004808. Badowska-Szalewska, E., Spodnik, E., Klejbor, I., & Morys, J. (2010). Effects of chronic forced swim stress on hippocampal brain-derived neutrophic factor (BDNF) and its receptor (TrkB) immunoreactive cells in juvenile and aged rats. Acta Neurobiologiae Experimentalis (Wars), 70(4), 370–381. Barha, C. K., Brummelte, S., Lieblich, S. E., & Galea, L. A. (2011). Chronic restraint stress in adolescence differentially influences hypothalamic–pituitary–adrenal axis function and adult hippocampal neurogenesis in male and female rats. Hippocampus, 21(11), 1216–1227. Bergami, M., Berninger, B., & Canossa, M. (2009). Conditional deletion of TrkB alters adult hippocampal neurogenesis and anxiety-related behavior. Communicative & Integrative Biology, 2, 14–16. Bergami, M., Rimondini, R., Santi, S., Blum, R., Gotz, M., & Canossa, M. (2008). Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proceedings of the National Academy of Sciences of the United States of America, 105, 15570–15575. Bliss, T. V., & Lomo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. Journal of Physiology, 232(2), 331–356. Bramham, C. R., Southard, T., Ahlers, S. T., & Sarvey, J. M. (1998). Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor

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