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

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Highlights

  • The hippocampus (Hi) is functionally segregated along its longitudinal axis.

  • The ventral hippocampus (vHi) preferentially regulates stress and anxiety responses.

  • Stress affects neurogenesis preferentially in the vHi.

  • Neurogenesis in vHi but not dHi is required for a behavioural effect of fluoxetine.

  • Antidepressants increase neurogenesis in anterior but not posterior Hi in primates.

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.

Section snippets

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

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

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 recently by neuroimaging and postmortem brain studies in humans.

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

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 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

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

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).

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

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