Adult hippocampal neurogenesis

In 1913, Santiago Ramón y Cajal concluded that neurons are exclusively generated prenatally, and the notion that no further neurons are produced after birth has remained a central dogma within neuroscience. Within the past decade, this view has been challenged following the demonstration that new brain cells are generated within specific neurogenic sites throughout adulthood. These are the dentate gyrus of the hippocampus and the subventricular zone.Reference Gage¹ In humans, adult neurogenesis undoubtedly occurs in the hippocampus,Reference Spalding, Bergmann, Alkass, Bernard, Salehpour and Huttner² but its function and importance has yet to be convincingly demonstrated because of a paucity of clinical studies and lack of a validated measure of new neuron function. Nevertheless, valid methods to index neurogenesis are achievable,Reference Ho, Hooker, Sahay, Holt and Roffman³ and given the potential of an understanding of neurogenesis to advance treatments for mental health disorders, psychiatrists should explore this area.

What is adult hippocampal neurogenesis for?

A model for the function of adult-born neurons in the dentate gyrus is emerging as evidence from animal work accumulates.Reference Anacker and Hen⁴ With greater excitability and plasticity, new neurons in the dentate gyrus can modulate the activity of mature neurons, enhancing the ability to learn and discriminate between highly similar contexts in a neural process known as pattern separation. This involves successful recall of two distinct memories with overlapping features, for example, where you parked your car today v. the place you parked it yesterday. By preventing interference between novel and older memories, neurogenesis may also enhance the ability to adapt to new contexts where old rules are replaced with new associations, as in reversal learning.

Why might neurogenesis be important for psychiatry?

Impaired neurogenesis would reduce the ability to learn that a new context is safe once a stressful situation has finished. A consequent persisting negative emotion, such as fear or anxiety, could then plausibly contribute to psychopathology, for example in depression, anxiety or post-traumatic stress disorder. Hence, factors that impair neurogenesis in rodents and non-human primates, such as chronic stress with hypothalamic–pituitary–adrenal axis hyperactivity and elevated glucocorticoid levels, lead to animal models of depressive behaviours.Reference Murray, Smith and Hutson⁵ A recent study has demonstrated the neurogenesis inhibition that accompanies cancer chemotherapy and the emergence of depressive behaviours in mice,Reference Egeland, Guinaudie, Du Preez, Musaelyan, Zunszain and Fernandes⁶ thus, explaining the depressive and cognitive symptoms described in patients undergoing chemotherapy. Evidence that this may also apply to humans includes the neurogenesis-inhibiting effect of glucocorticoids on hippocampal stem cells in vitro,Reference Anacker, Cattaneo, Luoni, Musaelyan, Zunszain and Milanesi⁷ and the observation that patients with depression perform poorly on pattern-separation tasks,Reference Anacker and Hen⁴ have lower levels of circulating neurogenic factors (brain-derived neurotrophic factor) that correlate with symptom severityReference Brunoni, Lopes and Fregni⁸ and reduced newborn hippocampal neurons at post-mortem.Reference Lucassen, Stumpel, Wang and Aronica⁹

If impaired neurogenesis can lead to depressive and anxiety symptoms, could its recovery underlie antidepressant treatment effects? There is good evidence to suggest that this could be the case. Administration of antidepressants are associated with increased neurogenesis in rodents, non-human primates, human hippocampal stem cells in vitro and human post-mortem brain tissue, with some rodent studies finding that neurogenesis is necessary for some of the behavioural effects of selective serotonin reuptake inhibitors.Reference Anacker and Hen⁴ Intriguingly, the time course of maturation of newly generated neurons in the dentate gyrus generally coincides with the time to therapeutic action of antidepressants. Non-pharmacological treatments for depression such as electroconvulsive shock therapy and physical exercise have also been shown to restore neurogenesis in animals, and human performance on a pattern-separation task improves after an exercise intervention.Reference Déry, Pilgrim, Gibala, Gillen, Wojtowicz and Macqueen¹⁰

The observation that adult hippocampal neurogenesis declines with increasing age could explain some of the reduced cognitive flexibility and impaired memory performance associated with normal ageing, mild cognitive impairment and neurodegenerative conditions such as Alzheimer's disease. Many of the molecular players in Alzheimer's disease are also modulators of neurogenesisReference Mu and Gage¹¹ and performance on tasks designed to test pattern-separation ability show an age–mild cognitive impairment–Alzheimer's disease continuum.Reference Ally, Hussey, Ko and Molitor¹²

Although there is increasing evidence for the role of neurogenesis in mood and cognitive disorders, there are some caveats to consider. Any effects of impaired neurogenesis are likely to be context dependent. For example, chronic stress may be necessary if depressive behaviours are to arise through this mechanism. Further, neurogenesis is likely to be one of several potential mechanisms of antidepressant action and may not necessarily underlie all of the behavioural effects of treatment. Finally, findings from animals can never be wholly applied to humans, although the accumulated evidence provides testable hypotheses that can be translated to human studies.

How can neurogenesis be investigated in humans?

There is currently no method to directly detect and measure hippocampal neurogenesis in humans. One strategy to clarify the precise relationship between neurogenesis and cognition/mood could involve a combination of different correlates of neurogenesis to optimise convergent validity. For example, observing within a population whose impaired neurogenesis would be expected to recover that these correlates improve in accordance with the known maturation time of human hippocampal stem cells (4–8 weeks)Reference Yu, Di Giorgio, Yao, Marchetto, Brennand and Wright¹³ would have predictive validity. Demonstration of a temporal dissociation between the recovery of putative neurogenesis-dependent correlates and other non-neurogenesis-dependent measures would also be informative. These approaches could be nested within clinical trials, for example, in patients with cancer after receiving a discrete regimen of chemotherapy or patients with depression about to start antidepressant therapy. It can be expected that any improvement in mood will be temporally associated with improvements in neurogenesis correlates (described below).

A combination of neuropsychology, neuroimaging and biological correlates can indirectly measure neurogenesis. Pattern-separation tasks are convenient and easy to administer tests designed to probe the function of new neurons in different cognitive domains, for example emotional, spatial or temporal pattern separation. These can be combined and used in conjunction with non-neurogenesis-dependent cognitive tasks (for example episodic and working memory, attention, executive function) to reveal a performance dissociation compared with a control group and between two time points measured before and after presumed neural stem-cell maturation.

The validity of pattern-separation tasks as markers for neurogenesis can be tested by functioning magnetic resonance imaging to show that performance is associated with activity in the dentate gyrus.Reference Liu, Gould, Coulson, Ward and Howard¹⁴ The small size of individual hippocampal subfields makes them notoriously difficult to delineate and measure; however, the increasing availability of 7-Tesla magnetic resonance imaging scanners could provide insight into dentate gyrus volume changes that may be associated with neurogenesis.

Therapeutic implications

If human studies uncover a role for hippocampal neurogenesis in neuropsychiatric disorders, existing treatments and novel neurogenic agents could be prescribed to target this process in patients with depression, neurodegenerative conditions and those being treated with chemotherapy. Studies investigating neurogenesis can identify potentially targetable molecular mechanisms for future antidepressants.Reference Anacker, Cattaneo, Luoni, Musaelyan, Zunszain and Milanesi⁷ Increasingly, research is also revealing a possible role for neurogenesis in schizophrenia and drug addiction.Reference DeCarolis and Eisch¹⁵ Stem-cell based therapies are also on the horizon; impending clinical trials for Parkinson's diseaseReference Barker, Parmar, Kirkeby, Björklund, Thompson and Brundin¹⁶ may pave a way for future human hippocampal stem-cell transplants.