A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis

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A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis Olivia F. O’Leary1,2 and John F. Cryan1,2 1 2

Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

Adult hippocampal neurogenesis is implicated in antidepressant action, stress responses, and cognitive functioning. The hippocampus is functionally segregated along its longitudinal axis into dorsal (dHi) and ventral (vHi) regions in rodents, and analogous posterior and anterior regions in primates, whereby the vHi preferentially regulates stress and anxiety, while the dHi preferentially regulates spatial learning and memory. Given the role of neurogenesis in functions preferentially regulated by the dHi or vHi, it is plausible that neurogenesis is preferentially regulated in either the dHi or vHi depending upon the stimulus. We appraise here the literature on the effects of stress and antidepressants on neurogenesis along the hippocampal longitudinal axis and explore whether preferential regulation of neurogenesis in the vHi/anterior hippocampus contributes to stress resilience and antidepressant action. The hippocampus and adult hippocampal neurogenesis The hippocampus is heterogeneous in function, playing central roles in learning and memory, emotional processes, and the regulation of glucocorticoid release (see Glossary) by the hypothalamic–pituitary–adrenal (HPA) axis [1]. In the mammalian brain, the hippocampus is one of only a few brain areas where neurogenesis (Box 1), the birth of new neurons, takes place throughout postnatal life [2]. Adult hippocampal neurogenesis has been shown to contribute to the behavioural effects of antidepressant drugs, restoration of glucocorticoid concentrations following stress and antidepressant treatment, as well as to some hippocampus-dependent cognitive processes including spatial learning and memory [3–5]. Recent attention has focused on distinct separation of hippocampal function along its longitudinal axis (Figure 1). In rodents, the vHi (analogous to human anterior hippocampus) plays a preferential role in the stress response and anxiety, whereas the dHi (analogous Corresponding author: O’Leary, O.F. ([email protected]). Keywords: antidepressant; stress; depression; neurogenesis; hippocampus; ventral hippocampus. 0165-6147/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2014.09.011

to human posterior hippocampus) is preferentially involved in spatial learning and memory. Given that adult hippocampal neurogenesis is important in processes preferentially regulated by the dHi or the vHi, it is possible that neurogenesis is also preferentially regulated in these specific subregions depending upon the stimulus. Moreover, because adult hippocampal neurogenesis is implicated in the mechanism of antidepressant action [6–8], and that the vHi is connected to structures that regulate key processes that are dysfunctional in depression (Figure 2), it is plausible that neurogenesis in the vHi rather than in the dHi might be a crucial component in the treatment of depression. Furthermore, differential regulation of neurogenesis along the longitudinal axis of the hippocampus could potentially allow adult hippocampal neurogenesis to be selectively harnessed as a therapeutic strategy for either stress-related psychiatric disorders such as depression, or for particular cognitive dysfunctions. Thus, the purpose of the present review is to critically appraise the current literature on the effects of stress, depression, and antidepressant action on adult neurogenesis along the longitudinal axis of the rodent and human hippocampus, and to offer insight into how this relationship should be explored further using animal models and clinical neuroimaging. Segregation of the hippocampus along its longitudinal axis: anatomical and genomic clues Studies demonstrating that the rodent hippocampus has distinct anatomical connections along its dorsoventral axis provided the first hint that the hippocampus might be functionally segregated along its longitudinal axis ([1,9,10] for review). In rodents, the dHi and vHi exhibit distinct afferent and efferent connectivity (Figure 2). The dorsal CA1 sends projections to structures primarily involved in the processing of visuospatial information, spatial memory, and spatial exploration and navigation, whereas the vHi is anatomically connected to structures that regulate neuroendocrine and behavioural responses to stress, anxiety, reward processing, motivation, and executive function, processes that are frequently disrupted in depression (Figure 2). Functional neuroimaging studies suggest that a similar dichotomy in anatomical connectivity occurs Trends in Pharmacological Sciences xx (2014) 1–13

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Review Glossary Agomelatine: a recently developed antidepressant drug that acts as a melatonin receptor agonist and a 5-HT2C receptor antagonist. Amygdala: a brain structure that plays a key role in fear learning and anxiety. Anterior cingulate cortex (ACC): an area of cortex that receives projections from the dorsal CA1 and the dorsal subiculum of the hippocampal formation, and plays a role in visuospatial memory. Through connections with other brain areas, the ACC also plays an important role in determining the salience of emotion and motivational information, and in the emotional reaction to pain. Bed nucleus of the stria terminalis (BST): an area of the brain that serves as a relay and integration centre between nuclei involved in the regulation of reward, stress, and anxiety. It is a major output pathway of the amygdala to the hypothalamus, and it also serves as a relay centre for hippocampal regulation of the HPA axis in response to stress. BrdU/NeuN-positive cells: dual immunolabelling of BrdU (bromodeoxyuridine) and NeuN (neuronal nuclear antigen) is used to identify recently generated cells that have developed into mature neurons. BrdU is an exogenous chemical that is administered to label dividing cells. It acts as a thymidine analogue that becomes incorporated into the DNA of dividing cells. Depending upon the timing of its administration, BrdU can be used to measure rates of proliferation or survival of newlyborn cells. The phenotype of BrdUlabelled cells can be determined by coupling BrdU immunohistochemistry with immunohistochemistry of other cell markers such as NeuN. NeuN is a marker of mature neurons, and its expression becomes apparent as the expression of doublecortin begins to decline. Thus, BrdU/NeuN immunohistochemistry can be used to identify newly generated cells that have developed into mature neurons. Corticosterone: the glucocorticoid in rodents that regulates the stress response. In humans, cortisol is the glucocorticoid that plays this same role. Cytogenesis: the proliferation of new cells. Doublecortin-positive cells: doublecortin protein is used as a marker of immature neurons. Maturing neuronal cells express doublecortin for 2 or 3 weeks following their birth. Neuronal precursor cells also express doublecortin while dividing. Hypothalamus: a brain structure comprised of a group of smaller nuclei which secrete hormones and thus link the central nervous system with the endocrine system. It regulates the neuroendocrine response to stress via the HPA axis, and is also involved in the regulation of other processes such as feeding and sexual behaviour as well as body temperature. Hypothalamic–pituitary–adrenal axis (HPA axis): the neuroendocrine system that regulates the response to stress. It involves the release of corticotropinreleasing hormone (CRH) and vasopressin from the paraventricular nucleus of the hypothalamus, which in turn stimulate the secretion from the pituitary gland of adrenocorticotropic hormone (ACTH), which then acts on the adrenal cortex to produce the glucocorticoid hormones, cortisol in humans and corticosterone in rodents. Glucocorticoids exert negative feedback on the hypothalamus and pituitary (as well as the hippocampus) thus reducing further glucocorticoid release. A subset of depressed patients exhibit overactivity of the HPA axis and impairment of its negative feedback control mechanism. In vivo amperometry: a technique in which an electrode is inserted into the brain of a freely behaving animal for the purposes of measuring changes in extracellular fluid concentrations of neurotransmitters and other substances such as glucose and oxygen in real time. Optogenetics: a technique which uses a combination of light and gene technology to turn specific neurons on and off with millisecond precision in the brain of freely behaving animals. Long-term depression (LTD): a form of synaptic plasticity that decreases the strength between synapses. Long-term potentiation (LTP): a form of synaptic plasticity involving long-term strengthening of synapses between neurons when they have been activated simultaneously. Magnetoencephalography (MEG): a clinical neuroimaging technique that allows mapping of neural activity by measuring small magnetic fields associated with electrical activity in the brain. Mammillary nuclei: brain structures mainly concerned with spatial direction. Medial prefrontal cortex (mPFC): a brain region which plays an important role in processing convergent cognitive and emotionally relevant information, and makes decisions as to how to appropriately respond to this information. Within this role, it regulates the HPA axis response to psychological stress and is involved in fear information processing. The infralimbic cortex area of the mPFC plays an important role in extinguishing a learned fear memory (fear extinction). Disrupted fear extinction is associated with the anxiety disorder, post-traumatic stress disorder. By contrast, the prelimbic cortex area of the mPFC plays a role in fear expression. Nucleus accumbens: a brain area that plays a key role in reward processing and in the motivation of feeding behaviour. It plays an important role in drug addiction, and recent small clinical studies suggest that electrode stimulation of this brain area has antidepressant effects. Place field: when an animal enters a specific place in its environment, one or more neurons in the hippocampus become activated. Specific neurons

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respond to specific locations. Neurons that are activated in response to a specific location are termed place cells. The area in which the neuron is activated the most is the place field of that neuron. Prenatal restraint stress: a model of early-life stress whereby pregnant mice or rats are restrained in a transparent cylinder several times per day for much of their pregnancy. The offspring of these dams exhibit depression-related neurobiological and behavioural alterations that persist into adulthood, including impaired feedback mechanisms of the HPA axis, increased stress sensitivity, disruption of circadian rhythms, and altered neuroplasticity. Retrosplenial cortex (RSP): an area of cortex that receives projections from the dorsal CA1 and the dorsal subiculum; the RSP processes visuospatial information and is involved in visuospatial memory. Social defeat stress: a model of psychosocial stress wherein an intruder mouse is periodically subordinated or defeated by an aggressive resident mouse. The test mouse is also forced to spend the remainder of a 24 h period in the same cage as the aggressor but is separated from the aggressor by a partition that allows olfactory, visual, and auditory contact but offers physical protection. Chronic social defeat stress results in social withdrawal behaviour in nonthreatening situations as well as several other behavioural and physiological changes characteristic of depression. Subiculum: the most inferior component of the hippocampal formation and the main output station of the hippocampus. Unpredictable chronic mild stress (UCMS): an animal model of chronic stress involving long-term exposure to a series of mild but unpredictable stressors which results in several behavioural and physiological changes that are also observed in depression, such as anhedonia. Ventral tegmental area (VTA): a brain structure that contains the dopamine neurons which form the mesocorticolimbic dopamine system which plays an important role in the reward circuitry of the brain. Disruption of the mesocorticolimbic dopamine system is thought to contribute to the inability to experience pleasure (termed anhedonia), a characteristic of depression. The VTA has also been shown to play an important role in locomotion and may contribute to visuospatial processes.

in the anterior and posterior regions of the hippocampus in humans, areas that are analogous to the rodent vHi and dHi, respectively [9]. In addition to this segregation in anatomical connectivity, recent transcriptomic studies have demonstrated genomic heterogeneity along the dorsoventral axis of the CA1, CA3, and dentate gyrus areas of the mouse hippocampus [1,11–14], and the granule cell layer of the rat hippocampus [15]. For example, in the mouse dentate gyrus, the gene encoding lactase, Lct, is preferentially expressed in the dorsal region, whereas the thyrotropin releasing hormone receptor gene, Trhr, is expressed specifically in the ventral region, and the expression of both genes is relatively limited in the intermediate portion of the hippocampus. Thus, it has been suggested that the rodent hippocampus is composed of three distinct molecular domains – dorsal, intermediate, and ventral [1]. Whether such genomic heterogeneity is directly related to the dichotomy in function of the dHi and vHi, and whether similar genomic variations occur along the longitudinal axis of the hippocampus of primates and humans, has yet to be determined, although a recent study suggests that there are differences in gene expression between the hippocampus of mice and humans [10,16]. Segregation of the hippocampus along its longitudinal axis: functional evidence The hypothesis that the hippocampus is functionally segregated along its longitudinal axis was first proposed by Moser and Moser, who also provided direct evidence for this phenomenon in rodents [17]. This functional segregation of the hippocampus along its longitudinal axis has since been supported by lesion, optogenetic, and electrophysiological studies in rodents (Figure 2), and more

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Box 1. Adult hippocampal neurogenesis: functions and regulation by extrinsic factors The hippocampus is one of only a few areas in the healthy brain where neurogenesis, the birth of new neurons, takes place throughout postnatal life [2,88,107] (Figure I). In the subgranular zone (SGZ) of the dentate gyrus of the hippocampus, activated quiescent radial glialike neural stem cells/neuroprogenitors (QNPs) self-renew and divide, giving rise to transient amplifying neuroprogenitors (ANPs) which proliferate and differentiate into neuronal committed neuroblasts. Neuroblasts develop into immature granule cells in the inner granule cell layer (GCL). These immature granule cells extend dendrites into the molecular layer (ML) of the dentate gyrus and axons through the hilus to the CA3 region, eventually becoming mature granule cells that are fully integrated with the hippocampal circuitry [2,108]. However, only a small proportion of adult-born cells actually survive to become mature granule neurons. The proliferation, differentiation, maturation, and survival of adult-born neurons is increased (green part of arrow) or decreased (red part of arrow) by extrinsic factors including stress, antidepressants, physical exercise, environmental enrichment, and learning; and by intrinsic factors such as transcription factors, growth factors, neurotransmitters, hormones, cytokines, morphogens, epigenetic factors, and ageing [8,63,108– 112]. The precise functional roles of adult-born neurons is not fully understood but ablation of neurogenesis in rodents impairs the HPA axis response to stress [5] and antidepressant drugs [4], as well as some of the behavioural responses to chronic antidepressant drug treatment in rodents and non-human primates [7,80]. Inhibiting neurogenesis in rodents also impairs performance in some tests of spatial learning and memory [3,113], and pattern separation (the evolution of neural activity patterns that allow discrimination between overlapping or similar but not identical events) [113,114]. Impairments in pattern separation might be associated with anxiety disorders such as post-traumatic stress disorder [115], although innate anxiety is generally not increased in neurogenesisimpaired rodents [6,116]. Ablating neurogenesis impairs cognitive flexibility [117], a process disrupted in depression [118]. More recently, a role for adult hippocampal neurogenesis in the encoding of new memories and the clearance of older memories has been demonstrated, thus perhaps reducing the likelihood that a given set of cues would re-invoke the same pattern of neural activity [119]. Despite

recently by neuroimaging and postmortem brain studies in humans. Functional segregation of the hippocampus into dorsal and ventral regions in rodents In rodents, lesions of the dHi but not the vHi impair spatial memory (Figure 2) [18–21]. In agreement with this preferential role of the dHi in spatial learning and memory, electrophysiology studies demonstrate a greater density of place fields in the dHi than the vHi; although there are place fields in the vHi, they are less selective for specific locations than those of the dHi [22]. By contrast, lesions of the vHi but not the dHi attenuate innate anxiety behaviours [21,23–26] and prevent the physiological response of increased defecation in response to an anxiogenic environment [23,25] (Figure 2). More recently, an in vivo optogenetic study revealed that increasing the activity of granule cells in the dentate gyrus of the vHi, but not in the dHi, suppresses innate anxiety, and that manipulation of granule cell activity in the dHi but not vHi impairs contextual encoding of a footshock [27]. In parallel, using in vivo amperometry it has been demonstrated that oxygen demand is greater in the rat vHi than the dHi during behavioural tests of innate anxiety [28]. In addition to regulating innate anxiety, the vHi has also been shown to regulate physiological responses to

all this knowledge on the functional roles of adult hippocampal neurogenesis, the precise mechanisms through which adult-born neurons can contribute to such diverse processes are not clear, but might be a function of differential activity along the dorsoventral axis of the hippocampus.

Learning Environmental enrichment Physical exercise Andepressants

Stress Inflammaon Aging

ML

GCL SGZ QNP

ANPs

Neuroblast Young immature neurons Mature granule (3 days old) neuron (>4 weeks old)

HPA axis response to stress and andepressants Behavioural response to chronic andepressant treatment Spaal learning and memory Paern separaon Memory erasure TRENDS in Pharmacological Sciences

Figure I. The birth of new neurons in the hippocampus takes place throughout the lifespan.

stress. Accordingly, vHi but not dHi lesions have been reported to attenuate stress-induced increases in plasma corticosterone [25], an effect likely mediated by the ventral subiculum through which the hippocampus exerts much of its influence on the hypothalamus [29]. However, it is also important to note that others have reported that lesions of the vHi or ventral subiculum do not significantly affect plasma corticosterone [30]. The vHi can also play an important role in social interaction via afferents from the amygdala ([31]; but also see [21]) and, because social withdrawal is a key feature of the depressive state, this circuit may be particularly important in depression. Intriguingly, synaptic plasticity in the dHi and vHi is differentially regulated by stress and glucocorticoids. Under baseline conditions, long-term potentiation (LTP) is suppressed in the CA1 of the vHi compared to the dHi [32–34]. However, exposure to an acute stressor or the stress hormone corticosterone enhances LTP in the vHi while suppressing it in the dHi, and this effect in the vHi is mediated by mineralocorticoid (MR) but not glucocorticoid (GR) receptors [32]. Acute stress also exerts divergent effects on long-term depression (LTD) in the dHi and vHi, enhancing it in the dHi while converting it to LTP in the vHi [35]. This dHi/vHi disparity in the ability to express LTP and LTD in response to an acute stressor in adulthood is sustained for at least 2 months in rats that 3

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Mouse Anterior dHi (septal)

vHi (temporal) Dorsal

Rostral

Caudal Ventral

Human Anterior

Posterior

Posterior Hi Anterior Hi

TRENDS in Pharmacological Sciences

Figure 1. The longitudinal axis of the hippocampus in rodents and humans. A longitudinal axis of the hippocampus has been described in both rodents and humans. In mice and rats the hippocampus can be described as extending along a rostrocaudal axis as well as a dorsoventral axis, such that the dorsal hippocampus (dHi) is in the septal pole (in red) of the hippocampus while the ventral hippocampus (vHi) is in the temporal pole (in blue) of the hippocampus. The most rostral coronal sections of the mouse hippocampus contain dHi only. By contrast, more caudal coronal sections contain not only the vHi but also parts of the dHi and the intermediate hippocampus. In humans the septal pole (in red) is located posteriorly while the temporal pole (in blue) is located anteriorly; the anterior hippocampus in humans is analogous to the vHi in rodents while the posterior hippocampus of primates is analogous to the rodent dHi [9,120].

had already been exposed to a stressful experience while they were juveniles [36]. Taken together, this suggests that during acute stress there is an engagement of the vHi and a suppression of dHi activity, and that prior exposure to stress during early life can also influence this process. Finally, it is interesting to note that a recent magnetic resonance imaging (MRI) study demonstrated morphometric differences in the right vHi of rats resilient or susceptible to stress-induced anhedonia [37]. Functional segregation of the hippocampus into anterior and posterior regions in primates Compared to rodents, discrete roles of the anterior and posterior regions of the hippocampus in primates including humans are less well-characterised and not as clear. However, one of the first clues that the human hippocampus is functionally segregated along its longitudinal axis came from studies reporting increased volume of the posterior hippocampus (analogous to the dHi in rodents) in London 4

taxi drivers who acquire spatial and navigational information, although this appears to be at the expense of the anterior hippocampus [38]. This preferential role of the posterior hippocampus in spatial learning and memory is in agreement with an electrophysiological study in nonhuman primates that reported a higher proportion of active neurons in the posterior hippocampus following a spatial learning task [39], and is in congruence with findings from rodent studies. Studies investigating the relative contributions of the anterior and posterior regions of the primate hippocampus in the regulation of anxiety, stress, and depression are only recently emerging. In non-human primates, anxiety and elevated HPA axis activity has been associated with increased metabolism in the anterior hippocampus [40], and activity of the anterior hippocampus predicts the heritability of this anxious temperament [41]. By contrast, hypoactivation of an area bordering the anterior hippocampus and dorsal amygdala has been reported in a metaanalysis of neuroimaging studies of post-traumatic stress disorder [42]. However, state anxiety levels have also been correlated with activity of the anterior but not posterior hippocampus in humans [43]. Altered structure and activity of the hippocampus has long been implicated in depression. Clinical neuroimaging studies consistently report that hippocampal volume is reduced in depression and that this effect is particularly apparent in unmedicated depressed patients [44,45]. Recent postmortem studies in primates including humans have reported that histological changes in depressed individuals occur mainly in the anterior rather than the posterior hippocampus. Specifically, granule cell layer volume in the anterior hippocampus was reportedly smaller in unmedicated depressed subjects, and larger in depressed subjects treated with selective serotonin reuptake inhibitor (SSRI) antidepressant drugs compared to control subjects, while no differences were observed in the posterior hippocampus [46]. In parallel, reductions in neuropil and cell layer volumes have been reported in the CA1 and dentate gyrus of the anterior but not posterior hippocampus of depressed monkeys [47]. Furthermore, decreased expression of MR in the anterior but not the posterior hippocampus has been reported in depression, with no significant changes in GR [48]. This differential expression of MR in the anterior hippocampus of depressed patients parallels findings in rodents reporting that MR mediates corticosterone-induced alterations in synaptic plasticity in the vHi but not dHi [32,49]. In addition to histological changes, the activity of the anterior hippocampus has also been reported to be altered in depression. Accordingly, magnetoencephalography recordings have revealed reduced engagement of the right anterior hippocampus in depressed individuals during a spatial navigation task [50]. Several clinical neuroimaging studies have investigated whether volumetric reductions in the hippocampus in depression occur preferentially within specific subregions. However, there is no standardised method for regional segregation of the human hippocampus into anterior and posterior regions [9]. Most of these studies report that depression is associated with reductions in the body/tail region of the hippocampus, which includes

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Rostral

Caudal RSP

ACC Dorsal dHi (septal) mPFC vHi (temporal)

BST

key: VTA

vHi-related

AMY

Acb

dHi and vHi-related

Hyp

Ventral

dHi-related

MM LM

Neurogenesis-related

Funcons of dHi-connecng structures

Effects of dHi lesion

Spaal learning and memory Spaal exploraon and navigaon Visuospaal processing

Impairs spaal memory

Effects of VHi lesion

Funcons of vHi-connecng structures

Aenuates stress-induced corcosterone Suppresses innate anxiety behaviour: hyponeophagia; light-dark exploraon; open field; elevated plus maze; uncondioned defensive behaviours Reduced anxiety-associated defecaon

Corcosterone release Reward processing Execuve funcon Fear learning Anxiety Movaon of feeding behaviour

Neurogenesis in vHi versus dHi Slower maturaon of newborn cells in vHi Preferenal stress-induced decreases in vHi Preferenal increases in vHi by some AD Ablaon of NG in vHi prevents effects of FLX Preferenal AD-induced increases in NPCs in anterior human Hi TRENDS in Pharmacological Sciences

Figure 2. Segregation of the rodent hippocampus along its dorsoventral axis and its relationship with adult neurogenesis. The rodent hippocampus extends along rostrocaudal and dorsoventral axes, beginning at the septal nuclei forming a septal pole (pink) and ending in the temporal lobe to form a temporal pole (green). Along the dorsoventral axis, the rodent hippocampus exhibits distinct anatomical connections (see the Glossary for explanation of the functional roles of each connecting brain structure). Connecting structures of the dorsal hippocampus (dHi) are depicted in pink and play roles in spatial learning, memory, exploration, and navigation, as well as in visuospatial processing. By contrast, connecting structures of the ventral hippocampus (vHi) are depicted in green and are important regulators of stress hormone (corticosterone) release, reward processing, anxiety, motivation, and executive function. Selective lesions of the dorsal or ventral hippocampus have confirmed a preferential role for the dHi in spatial learning memory, and for the vHi in the regulation of innate anxiety and stress-induced corticosterone release. Adult hippocampal neurogenesis has been suggested to play a regulatory role in some functions that are preferentially regulated by the dorsal or ventral hippocampus and their connecting structures (denoted by ), and is differentially regulated along the dorsoventral axis. Abbreviations: ACC, anterior cingulate cortex; Acb, nucleus accumbens; AD, antidepressant; AMY, amygdala; BST, bed nucleus of the stria terminalis; FLX, fluoxetine; Hi, hippocampus; Hyp, hypothalamus; mPFC, medial prefrontal cortex (infralimbic and prelimbic cortex); LM, lateral mammillary nucleus; MM, medial mammillary nucleus; NG, neurogenesis; NPCs, neural progenitor cells; RSP, retrosplenial cortex; VTA, ventral tegmental area.

mainly the posterior and mid hippocampus, rather than in the head region which includes much of the anterior hippocampus ([51–55]; also see the discussion on clinical neuroimaging of neurogenesis). Segregation of neurogenesis along the longitudinal axis of the adult hippocampus The hippocampus is one of only a few areas of the adult mammalian brain where neurogenesis, the birth of new neurons, takes place (Box 1). Accumulating evidence demonstrates a reciprocal relationship between adult hippocampal neurogenesis, spatial learning and memory, and stress and antidepressant drug action, whereby these factors influence the rate of neurogenesis, and in turn neurogenesis can play a functional role in these processes (Box 1). Given the evidence from rodent studies that adult hippocampal neurogenesis plays a role in behaviours preferentially regulated by either the dHi (spatial learning and memory) or the vHi (stress and anxiety), it is possible

that adult neurogenesis might also be preferentially regulated in either the dHi or the vHi depending upon the stimulus presented. We review here the evidence for differential regulation of neurogenesis along the longitudinal axis of the human or rodent hippocampus, and discuss whether stress and antidepressant drugs exert preferential effects in the vHi of rodents or the anterior hippocampus of humans (Figure 2). Adult-born neurons have distinct features depending upon their location along the dorsoventral axis of the rodent hippocampus Emerging data suggest that newlyborn neurons have distinct features depending upon their location along the dorsoventral axis of the adult rodent hippocampus. Specifically, the density of newlyborn neurons is higher in the dHi than in the vHi of adult rodents [56,57], and newlyborn neurons in the dHi mature faster compared to those in the vHi [58,59]. During ageing, neurogenesis declines more 5

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Table 1. The ventral hippocampus (vHi): a locus for the effects of stress and antidepressants on adult hippocampal neurogenesis?a Stimulus

Proliferation

Survival

Neurogenesis DCX+ cells

Chronic stress Non-human primate studies Rodent studies

b c

Corticosterone Rodents Antidepressant-like treatments SSRIs and TCAs in humans with MDD Fluoxetine Non-human primates Rodents

Refs

BrdU+/NeuN+ cells [80] [65–67,69,72–76,78] [68,69,77,79] [71] [70,71]

NPC

[86,87] b

[80] [66] [68,70,73]

Escitalopram Non-stressed rats Rats that demonstrate behavioural recovery from stress Agomelatine (rodents)

[65] [65]

c

GABAB receptor blockade (rodents) CGP 52532 (antagonist) GABAB(1b)/ mice Lithium (rodents) Neuregulin-1b (rodents)

[70,73,81–83] [70,73,81,82] [84] [75] [75] [77] [85]

a

Studies reporting increased ("), decreased (#), or no preferential effect ($) on various stages of neurogenesis in the vHi of rodents or anterior hippocampus of primates. Bold arrows indicate that a study was conducted in stressed animals while grey arrows indicate that a study was conducted in corticosterone-treated or glucocorticoid receptor-impaired animals; all other arrows indicate non-pathophysiological conditions. Abbreviations: NPC, neural progenitor cells; MDD, major depressive disorder.

b

Stage 3 DCX+ cells.

c

Used PSA-NCAM-BrdU as a marker (71).

rapidly in the vHi compared to the dHi, and it has been suggested that this might contribute to the depressive symptoms that frequently precede dementia [60]. Importantly, the vHi has been identified as the embryonic origin for adult neural stem cells (NSCs) in the dentate gyrus [61]. This suggests that NSCs in the adult dHi and vHi likely share the same intrinsic properties, but are regulated by input to the specific brain area in which they reside. In this way, NSC activity along the longitudinal axis of the hippocampus might be differentially regulated by specific stimuli. Indeed, the faster maturation rate of newlyborn neurons in the dHi has been associated with higher levels of basal network activity [58]. In agreement, voluntary exercise which increased dendritic spine density on newlyborn neurons specifically in the vHi to near dHi levels was accompanied by enhanced network activity in the vHi but not in the dHi [58]. Given the role of adult hippocampal neurogenesis in behaviours preferentially regulated by either the dHi (spatial learning and memory) or the vHi (stress and anxiety), it is possible that adult neurogenesis might be preferentially regulated in the vHi by stress and antidepressant interventions [62] (summarised in Table 1). The effects of stress and antidepressant treatments on adult neurogenesis along the longitudinal axis of the rodent and primate hippocampus Effects of stress. Rodent studies have revealed that adult hippocampal neurogenesis is decreased by chronic stress and is also affected by the stress hormone, corticosterone 6

[63,64]. In turn, adult hippocampal neurogenesis is required for antidepressant-induced normalisation of HPA axis activity [4], and has also been shown to be involved in appropriate recovery of glucocorticoid levels following acute stress or a dexamethasone challenge [5]. However, whether this reciprocal relationship between stress and neurogenesis is restricted to the vHi is only beginning to be investigated [62]. Several rodent studies have reported that unpredictable chronic mild stress (UCMS) preferentially decreases cell proliferation in the vHi compared to the dHi [65–67], although stress-induced decreases in both the vHi and the dHi have also been reported following UCMS [68] or maternal deprivation [69] (Table 1). Because HPA axis overactivity occurs in a subset of depressed patients, chronic corticosterone treatment in rodents is sometimes used as a physiological model of chronic stress or depression. Evidence of a preferential effect of corticosterone on cell proliferation in the vHi versus dHi is lacking, however, with one study reporting equivalent decreases in both subregions [70] while another reports selective effects in the vHi [71]. The data for stress-induced decreases in the survival of newlyborn cells in the vHi is less equivocal than for reduced cell proliferation, with the majority of studies reporting preferential reductions in the vHi following UCMS [67,72], prenatal restraint stress [73,74], maternal deprivation [69,75], or social defeat stress [76]. However, equivalent effects in the dHi and vHi have also been reported following UCMS [68], as have selective effects

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Review in the dHi following chronic restraint stress [77]. Only some of the studies described above determined the impact of chronic stress on the differentiation and maturation of these adult-born cells into neurons (doublecortin-positive cells) and their survival as mature neurons (BrdU/NeuN-positive cells). Nevertheless, most report that chronic stressors including UCMS [66,67,78], prenatal restraint stress [73,74], and maternal deprivation [69] preferentially decrease neurogenesis in the vHi, although equivalent decreases in the vHi and dHi have also been reported [68,79]. Similarly, in non-human primates, the number of immature neurons that were at the threshold of complete maturation was reduced by chronic stress in the anterior but not posterior hippocampus, and this effect was correlated with stress-induced anhedonia [80]. Sex-dependent effects of chronic corticosterone treatment on neurogenesis have been reported, with preferential reductions in the vHi being reported in female [71] but not male rats [71]. Taken as a whole, the evidence suggests that stress-induced decreases in some phases of neurogenesis can occur preferentially in the rodent vHi rather than in the dHi. This preferential effect of stress in the vHi is most apparent when measuring both the survival of newlyborn cells and neurogenesis, with effects on cell proliferation being more equivocal (Table 1). Effects of antidepressant drugs under basal and stress conditions. Although it has been known for some time that antidepressants increase adult hippocampal neurogenesis [8,64], recently there has been a growing appreciation that this effect might occur at discrete locations along the longitudinal axis of the hippocampus. Several studies in rodents have now investigated whether drugs with antidepressantlike effects affect different stages of adult neurogenesis in the vHi and dHi [62]. Under basal conditions, agomelatine [81–83], the GABAB receptor antagonist CGP 52532 [84], and the neurotrophic factor neuregulin-1b [85] preferentially increase cell proliferation in the vHi. However, non-preferential increases in cell proliferation have also been reported with both fluoxetine [70] and escitalopram [65]. When investigating the mechanism of action of antidepressant treatments it is important to use them in the context of depression rather than under non-pathological conditions. As such, chronic stress and chronic corticosterone treatment have been used to model depression and to interrogate the effects of antidepressant drugs on different stages of neurogenesis along the longitudinal axis of the hippocampus. Chronic treatment with lithium [77], agomelatine [73], or fluoxetine [66] increased cell proliferation in the vHi but not in the dHi of stressed mice, although equivalent fluoxetine-induced increases in both the dHi and vHi have also been reported in mice undergoing stress [68] or with impaired glucocorticoid function [83]. In corticosterone-treated animals, equivalent increases in both regions have been reported following fluoxetine or agomelatine treatment [70]. Interestingly, when rats are stratified into non-responders and responders to escitalopram in the context of stress-induced anhedonia, escitalopram-induced increases in cytogenesis were only apparent in the vHi of responders, while there were no differences in cytogenesis in the dHi between non-responders and responders [65]. It is tempting to speculate that neurogenesis in the vHi rather than in the

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dHi may be an important determinant of the antidepressant response and stress resilience. Similarly, we have recently observed that GABAB(1b)/ mice, which are resilient to stress-induced anhedonia, exhibit increased survival of newlyborn cells in the dHi under non-stress conditions; however, under stress conditions, this increased density of surviving newlyborn cells shifts from the dHi to the vHi [75]. The hypothesis that the vHi is associated with stress resilience is further supported by a neuroimaging study in rats reporting morphometric differences in the vHi between stress-susceptible anhedonic animals and stressresilient animals [37]. To date, relatively few studies have investigated whether antidepressant-like drugs affect the survival of newlyborn cells preferentially in the dHi or the vHi. These studies have generally reported equivalent increases in both regions following fluoxetine [68,73] treatment. The effects of agomelatine are more variable with vHi-selective [81,83] and non-selective increases [82] being reported, while neuregulin-1b increased survival of newlyborn cells in the vHi [85]. An important question is whether such newlyborn cells differentiate into neurons. Fluoxetine has been reported to increase neurogenesis in both the dHi and the vHi under both non-stress [68,70] and stress conditions [68,70], although one study reported a preferential increase in the vHi under stress conditions [66]. Equivalent effects in the dHi and vHi have also been reported following agomelatine treatment under non-stress conditions [70] and in prenatally stressed animals [73]. However, vHiselective increases have been reported in corticosteronetreated rats following agomelatine treatment [70]. Taken together, it appears that some but not all drugs with antidepressant-like properties increase cell proliferation preferentially in the vHi. Whether they exert preferential effects on the survival of newlyborn cells and their differentiation into mature neurons is less clear, which may in part be due to a limited number of studies being conducted (Table 1). Although many of the rodent studies suggest that fluoxetine does not exert preferential effects in the vHi [62], it is important to note that recent human postmortem studies have reported that the number of neural progenitor cells is increased in the anterior and intermediate hippocampus, but not in the posterior hippocampus, of subjects treated with antidepressants including SSRIs [86,87]. Given these findings in humans and the limited number of rodent studies to date, it is clear that a more systematic and thorough investigation of the effects of chronic antidepressant treatments on neurogenesis along the longitudinal axis of the hippocampus is warranted, particularly under conditions that model the depressive state. In addition, given the preliminary evidence in rodents that a successful response to escitalopram is correlated with increased cytogenesis in the vHi rather than dHi [65], future studies should consider stratifying animals according to their behavioural responses to stress (i.e., susceptible vs resilient) and antidepressant treatment (i.e., responders vs non-responders) before determining correlations between neurogenesis along the dorsoventral axis and antidepressant-related behaviour. Such an approach might reveal a potential role for neurogenesis in the vHi in stress resilience, behavioural recovery from stress, and a successful response 7

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Box 2. Potential mechanisms underlying preferential effects of stress and antidepressant treatments on adult neurogenesis in the vHi The mechanisms through which stress and antidepressant-like drugs could exert preferential effects in the vHi rather than the dHi are not clear [62] but, in terms of selective effects of stress in the vHi, the glucocorticoid (GR) and mineralocorticoid receptors (MR) are plausible candidates. Regional differences in stress-induced changes in the expression of these receptors along the rodent dorsoventral axis have been described, although conflicting patterns have been reported [121,122]. Interestingly, a human postmortem study reported decreased expression of MR in the anterior but not the posterior hippocampus in depressed subjects compared to controls, while there were no significant changes in GR expression in either brain region [48]. This differential expression of MR in the anterior hippocampus parallels findings in rodents reporting that MR mediates corticosterone-induced alterations in synaptic plasticity in the vHi but not dHi [32,49]. The loss of MR receptors in depression might thus interfere with the capacity of the anterior hippocampus to appropriately respond to stress. Whether this is directly related to neurogenesis remains to be investigated because, to the best of our knowledge, it is not yet known whether basal or stimulus-induced expression of GRs and MRs on neural precursor cells and immature

to antidepressant treatment. The mechanisms underlying the preferential effects of stress and some antidepressants in neurogenesis in the vHi are not clear, but may be a function of regional differences in the expression of glucocorticoid and serotonergic receptors (Box 2). Probing the effects of antidepressants on adult neurogenesis in the human hippocampus: of mice and men or lost in translation? A key outstanding question is whether findings in the animal studies described above translate to humans, and

neurons differs along the longitudinal axis of the rodent or human hippocampus. In terms of antidepressant action, preferential effects in the vHi might occur as a function of enhanced serotonergic innervation [123] and higher densities of certain serotonin receptors in the vHi relative to the dHi, including the 5-HT2C receptor [124,125] at which agomelatine acts as an antagonist. Interestingly, chronic treatment with 5-HT2C antagonists has been shown to increase cell proliferation in the vHi but not dHi [82]. The expression of the 5-HT1A receptor also changes along the dorsoventral axis of the mouse hippocampus, with higher densities being observed in the dentate gyrus and CA3 regions of the vHi [124], and 5-HT1A receptors are required for fluoxetine-induced increases in neurogenesis [7]. However, it is also important to note that evidence for a vHi-selective effect of fluoxetine-induced increases in neurogenesis is lacking (Table 1) [62]. Other neurotransmitter systems could also play role; for example, we have found that a GABAB receptor antagonist increases hippocampal cytogenesis preferentially in the vHi but not dHi [84], and that mice lacking the 1b subunit of this receptor are resilient to stress-induced anhedonia and stress-induced decreases in the survival of adult-born cells in the vHi [75].

thus are of clinical relevance. Immunohistochemistry techniques can be used to measure cell proliferation and neural precursor cell density in the postmortem human brain (Box 3). Although this strategy has shown that antidepressant-treated subjects exhibit increased neural progenitor cells in the anterior but not posterior hippocampus at the time of death, it does not allow dating or tracing of adult-born cells to assess neurogenesis per se. Measuring 14 C DNA content of neuronal cells (Box 3) has been used to estimate the relative numbers of adult-born neurons in the hippocampus at the time of death [88] but, like the

Box 3. Measuring adult hippocampal neurogenesis in humans Postmortem studies: immunohistochemistry of cell cycle markers (e.g., Ki67, MCM2, PCNA) or markers of neural progenitor cells (e.g., nestin) is used to obtain a snapshot of cell proliferation or neural precursor cell density, respectively, but does not allow dating or tracing of adult-born neurons to assess neurogenesis per se [89]. Adult-born cells can be labelled by administering BrdU, a thymidine analogue that incorporates into the DNA of newlyborn cells. Immunohistochemical detection of BrdU coupled with neuronal markers (e.g., NeuN) allows the identification of newlyborn neurons. This approach has shown that adult hippocampal neurogenesis takes place in cancer patients who had received BrdU for diagnostic purposes [107], but cannot be used routinely to measure neurogenesis. Nuclear weapons testing in the 1960s released large amounts of 14C into the atmosphere, and levels subsequently declined. Because 14C is readily incorporated into the DNA of newlyborn cells, the date a cell was generated can be determined from its genomic 14C DNA content. The measurement of 14 C in neurons in human brain can therefore be used to estimate the relative numbers of adult-born neurons in the hippocampus at the time of death [88]. However, like immunohistochemistry, this method cannot monitor dynamic changes in neurogenesis in response to specific stimuli over a longitudinal manner in the living human brain. Therefore, effort has been directed towards developing clinical neuroimaging techniques to measure adult neurogenesis in the human hippocampus [89]. Magnetic resonance spectroscopy: application of this technique suggested that a lipid metabolite resonating at 1.28 ppm could be a marker of neural precursor cells in rodents, and this metabolite was also detected in the human hippocampus [126]. However, the identity of this peak remains unknown, the specificity of the peak and the analytical methods used have been questioned [127], and the results have not yet been replicated or applied to depression. 8

Cerebral blood volume (CBV): measurements of CBV in the dentate gyrus (DG) using magnetic resonance imaging (MRI) might be useful as an indirect measure of neurogenesis in vivo because neurogenesis can be accompanied by angiogenesis [128]. However, thus far the relationship between CBV and neurogenesis has only been investigated using exercise as a proneurogenic stimulus and, although confirmed in animals [128], these findings cannot be validated in humans without appropriate postmortem analysis. Whether this correlation of CBV with neurogenesis extends to the proneurogenic effects of antidepressants is not yet clear. However, a recent human postmortem study reported that both angiogenesis and hippocampal neural precursor cells are increased selectively in the anterior and mid-DG [86], thus raising the possibility that antidepressant-induced increases in neurogenesis might be accompanied by increased angiogenesis, and thus might be detected using CBV measurements. MRI-based volumetric analysis: when applied to DG-containing subregions of the hippocampus, this technique might also be used to indirectly monitor neurogenesis in vivo. For example, when a particular protocol to segment the hippocampus into head, body, and tail regions [90] was coupled with high magnetic field strength [4.7 T] MRI, the tail and head had the greatest proportion of the CA, while the body contained a greater proportion of the DG relative to the CA [91]. Thus, volumetric changes occurring mainly in the body, rather than in the head and tail regions, might indirectly reflect changes in neurogenesis. However, it is important to note that measuring changes in neurogenesis with MRI-based tools is limited by voxel dimensions that are much larger than individual cells. Indeed, it has been suggested that the addition of 100 new cells within the same cluster would be required to produce increase volume in a single voxel [99], and thus detecting subtle volumetric changes in the DG as an index of neurogenesis remains a major challenge.

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Review immunohistochemistry approach, it cannot be used to monitor dynamic changes in neurogenesis in response to specific stimuli (such as successful responding to antidepressants) and over a longitudinal manner in the living human brain [89]. Although meeting this challenge requires significant advances in clinical neuroimaging technologies, there has been some effort to indirectly measure neurogenesis using current methods (Box 3). For example, one such indirect approach involves volumetric or shape analysis of hippocampal subregions. One group has demonstrated that when their protocol segmenting the hippocampus into head, body, and tail regions [90] is coupled with higher magnetic field strength (4.7 T), the hippocampal tail and head appear to have the greatest proportion of the CA, while the body of the hippocampus contained a greater proportion of DG relative to CA [91]. Using lower magnetic field strength (1.5 T) MRI, the same group reported that medicated major depressive disorder (MDD) patients showed increased hippocampal body volume compared to both healthy controls and unmedicated patients [55]. However, there were no differences in hippocampal body volume between unmedicated depressed and healthy controls, although significant reductions in the volume of the hippocampal tail, right hippocampal head, and right total hippocampus were observed in depressed patients compared to controls [55]. Others have also reported volumetric reductions [52,53,55] or shape deformations [92] in the tail or combined body/tail [54] in depressed subjects compared to controls, suggesting that structural changes in the body/tail rather than the head are a trait of depression. A recent study by the same group [55] using higher magnetic field strength (4.7 T) MRI investigated both subfield (dentate gyrus, CA1–3, subiculum) and subregion (head, body, tail) volumes and reported that the volume of the dentate gyrus was greater in medicated MDD patients than in unmedicated MDD patients, while there were no differences in the CA region. The same study also demonstrated that unmedicated MDD patients but not medicated MDD patients had smaller hippocampal body and tail volumes compared to controls [51]. Given the lack of volumetric changes in the CA regions, it is tempting to speculate that most of the changes in the hippocampal body and tail volumes in this study occurred in the dentate gyrus, the site of neurogenesis, although further studies will be required to verify this. It was also recently reported that MDD subjects who responded to chronic antidepressant treatment exhibit increased combined body/tail volume compared to control subjects [93] and that remission is associated with larger pretreatment hippocampal body/tail volumes [94]. Furthermore, a shape analysis study has reported differences in the mid-body of the left hippocampus and lateral side of the head between controls and unremitted depressives, a difference that was not apparent in remitted patients [95]. Taken together, these studies suggest that the body of the hippocampus which contains a high ratio of dentate gyrus to CA primarily undergoes structural changes in response to antidepressants, and that these changes might be associated with remission, while the volumetric reductions that are primarily observed in the tail or combined body/tail regions in depressed subjects may be a trait marker of depression. Although challenging, further segmentation of the body of the hippocampus into anterior and posterior regions might

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give some insight as to whether antidepressant medications exert preferential effects along the longitudinal axis of the dentate gyrus in human subjects. Concluding remarks At present, the literature on whether antidepressants have selective effects on neurogenesis in the vHi or dHi of rodents is variable and possibly depends upon the treatment and pathophysiological state (e.g., unchallenged vs stress, depression, or anhedonic state). Interestingly, albeit a comparatively limited literature, studies in primates including humans suggest that antidepressants increase neurogenesis preferentially in the anterior hippocampus, particularly in the presence of a relevant pathophysiological state. The variability in the rodent literature may in part be due to inconsistent definitions of what constitutes the dHi versus vHi [62], despite the fact that these areas can be defined based on their segregated anatomical connectivity or, more recently, by genomic markers as demonstrated in a recent study [1,96–98] (Box 4). Similarly to the rodent studies, delineation and labelling of hippocampal subregions varies between clinical neuroimaging studies, with some segmenting the hippocampus into anterior and posterior regions, others dividing it into head, body and tail regions, some normalising whole-brain images into an atlas space while others do not, and some studies including CA3 within the same label as the dentate gyrus while others do not [9,99]. Furthermore, the majority of rodent studies, including our own, have used coronal sections through the rodent hippocampus; while the most rostral sections primarily contain only the dHi, caudal sections containing the vHi can also contain parts of the dorsal and much of the intermediate hippocampus [62]. The inclusion of the intermediate hippocampus in sections that also contain the vHi might interfere with data interpretation. A growing body of literature suggests that the intermediate zone of the hippocampus is distinct from both the dHi and vHi in terms of gene expression and anatomical connectivity [1,11]. Moreover, several studies have demonstrated that the intermediate hippocampus is functionally distinct from the anterior hippocampus in humans [100] and from the dHi and vHi in rodents [101–104]. Rats with lesions of the intermediate hippocampus, but not of both the dHi and vHi, exhibit impaired rapid place learning [101]. At the cellular level, novel spatial content facilitates a form of synaptic plasticity, LTD, in the dorsal but not intermediate hippocampus [102], and differences in the Box 4. Outstanding questions  Will the establishment of agreed definitions of what constitutes the anatomical boundaries of the dorsal/posterior and ventral/ anterior hippocampus result in more consistent findings?  Do stress and antidepressant-induced changes in cytogenesis result in similar changes in neurogenesis?  Will the findings in rodents translate to other studies in humans?  Does impairment of neurogenesis selectively in the vHi promote depression-like behaviour and increase stress susceptibility?  Can increasing neurogenesis selectively in the vHi promote stress resilience and antidepressant-like behavioural effects?  What are the molecular mechanisms underlying stimulus-specific effects on adult neurogenesis in the vHi? Can these mechanisms be harnessed for antidepressant drug development? 9

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Review persistence of LTP in the dHi and intermediate hippocampus have also been reported [103]. Similarly, differences in short-term plasticity have also been described between the intermediate and ventral routes of the hippocampus–prefrontal cortex pathway [104]. Thus, future studies should also focus on parsing the role of the intermediate hippocampus in the context of adult hippocampal neurogenesis. To circumvent the inclusion of the intermediate hippocampus in sections containing the vHi, the hippocampus could be sectioned perpendicular to the dorsoventral axis, thus yielding sections that are more representative of the dHi, vHi, and intermediate hippocampus. This would also offer the advantage of producing sections with a similar shape and volume [57]. Further, analysis along the entire long axis of the hippocampus will also be important in light of the very recent description of both graded and distinct levels of organisation along its longitudinal axis [10]. As detailed above, behavioural lesion, electrophysiological recording, and intrinsic-connectivity studies have suggested a functional distinction between the ventral and dorsal hippocampus. By contrast, other studies have revealed gradual changes along the hippocampus in terms of extrinsic connectivity, receptor expression, and placefield size, whereas transcriptomic studies indicate that there are various long axis gene expression patterns, including gradual changes as well as sharp transitions [10]. Strange and colleagues have thus suggested that superimposing all of these organizational patterns results in a new model of functional organization along the hippocampal long axis [10]. Thus, it will be important that future studies also investigate the relationship of this model to adult hippocampal neurogenesis. In addition to these anatomical boundary discrepancies, it is important to note that few studies investigated all stages of neurogenesis (proliferation, differentiation, maturation, survival) within the same experiment, thus making extrapolations of the effects on cytogenesis to neurogenesis difficult. Other discrepancies may be attributable to grouping individuals together by stimulus (stress or antidepressant) irrespective of whether or not the stimulus exerted a behavioural change in all individual subjects. Taken together, future studies investigating adult neurogenesis along the dorsoventral axis of the rodent hippocampus should investigate all stages of neurogenesis, use sections that are perpendicular to the axis and segregated according to anatomical connectivity or genomic profiles, as well as stratifying subjects according to their behavioural response to the stimulus. Despite the limitations of the studies described above, on the whole, the evidence suggests that stress-induced decreases in the survival of newlyborn cells and neurons occur preferentially in the vHi rather than the dHi in rodents, and this finding is supported by a study in nonhuman primates. However, a preferential effect of antidepressant drugs in the vHi is not as robust, with drugdependent effects being reported [62]. Nevertheless, recent human postmortem studies have reported that antidepressants increase the number of neural progenitor cells in the anterior and central parts of the hippocampus but not in the posterior hippocampus [86,87]. Moreover, a recent study in mice demonstrated that ablation of neurogenesis 10

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in the vHi but not in the dHi impacts the behavioural effects of fluoxetine, thus suggesting that the correlational relationship between antidepressants and neurogenesis described above might play a functional role in antidepressant action. In that study it was shown that ablation of neurogenesis by focal irradiation in the vHi, but not in the dHi, prevented the anxiolytic effects of fluoxetine in mice that had undergone chronic footshock stress [105]. Future studies should determine whether neurogenesis in the vHi but not in the dHi mediates behaviours associated with depression such as anhedonia, in addition to investigating the response to stress and antidepressant treatments. In this regard, optogenetic manipulation of the activity of newlyborn neurons of different ages would be informative [106]. Finally, it is also noteworthy that preferential effects on neurogenesis in the vHi are more consistent for recently identified antidepressant drug targets, and that cytogenesis in the vHi might be linked with stress resilience. Studies investigating whether such preferential increases in neurogenesis in the rodent vHi or primate anterior hippocampus transpire as a novel and selective way to modulate mood are eagerly awaited. Elucidation of the molecular mechanisms underlying such effects may lead to the identification of potential novel targets for antidepressant drug development. This is important because a large proportion of individuals fail to achieve remission with currently available antidepressant drugs, many of which do not appear to preferentially affect neurogenesis in the vHi of rodents, at least according to the current literature and methodological methods used. Finally, adult hippocampal neurogenesis is not only important in stress-related responses and the mechanism of antidepressant action but also plays a role in cognitive processes such as spatial learning and memory which are thought to be preferentially mediated by the dHi. Thus manipulating neurogenesis at specific locations in the hippocampus might also be a useful approach for treating particular cognitive impairments. Acknowledgements O.O.L. has received funding from the University College Cork (UCC) Strategic Research Fund. J.F.C. is supported by Science Foundation Ireland in the form of a centre grant (Alimentary Pharmabiotic Centre; Grant No. SFI/12/RC/2273) and by an Investigator Award (Grant No. 12/ IA/1537). J.F.C. also received funding from the the Health Research Board of Ireland (Grant number HRA_POR/2012/32).

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