Trends in Pharmacological Sciences
ReviewA ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis
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
References (128)
- et al.
Are the dorsal and ventral hippocampus functionally distinct structures?
Neuron
(2010) - et al.
Adult neurogenesis in the mammalian brain: significant answers and significant questions
Neuron
(2011) - et al.
Requirement of adult-born neurons for hippocampus-dependent learning
Behav. Brain Res.
(2012) Long-axis specialization of the human hippocampus
Trends Cogn. Sci.
(2013)Genomic anatomy of the hippocampus
Neuron
(2008)Molecular heterogeneity along the dorsal–ventral axis of the murine hippocampal CA1 field: a microarray analysis of gene expression
Neuroscience
(2006)Transcriptome differentiation along the dorso-ventral axis in laser-captured microdissected rat hippocampal granular cell layer
Neuroscience
(2010)Ventral hippocampal lesions affect anxiety but not spatial learning
Behav. Brain Res.
(2003)Regional dissociations within the hippocampus – memory and anxiety
Neurosci. Biobehav. Rev.
(2004)Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus
Neuron
(2013)