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Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood

Key Points

  • The ventral hippocampus is a crucial brain region in the neural circuitry that regulates mood and anxiety.

  • Adult-born neurons in the dentate gyrus of the hippocampus have been proposed both to encode information as independent encoding units and to modulate the overall activity of the dentate gyrus by inhibiting mature granule cells.

  • Neurogenesis-mediated inhibition of mature cells may reduce memory interference and may enable reversal learning both in neutral and in fearful situations.

  • This improved capacity for reversal learning and cognitive flexibility may facilitate the switch from perceiving a safe environment as fearful in the absence of a persistent threat to no longer associating the safe environment with fear.

  • Treating dentate gyrus function and cognitive flexibility deficits may be promising new treatment strategies for mood and anxiety disorders.


Adult hippocampal neurogenesis has been implicated in cognitive processes, such as pattern separation, and in the behavioural effects of stress and antidepressants. Young adult-born neurons have been shown to inhibit the overall activity of the dentate gyrus by recruiting local interneurons, which may result in sparse contextual representations and improved pattern separation. We propose that neurogenesis-mediated inhibition also reduces memory interference and enables reversal learning both in neutral situations and in emotionally charged ones. Such improved cognitive flexibility may in turn help to decrease anxiety-like and depressive-like behaviour.

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Figure 1: The ventral hippocampus and the neural circuitry of mood and anxiety.
Figure 2: Neurogenesis facilitates cognitive flexibility by allowing the formation of new distinct memory traces.
Figure 3: Neurogenesis promotes efficient stress recovery.
Figure 4: Potential methods of harnessing the function of adult-born neurons to treat dentate gyrus-dependent mood and anxiety disorders.


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R.H. is supported by the Hope for Depression Research Foundation (HDRF, RGA-13-003), the US National Institutes of Health (R01 AG043688, R01 MH083862, R37 MH068542) and NYSTEM (C029157). C. A. is supported by a K99/R00 award from the US National Institutes of Health (K99 MH108719).

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Cognitive flexibility

A cognitive process of executive function by which previously learned behavioural strategies can be modified to adapt to changes in environmental contingencies. Enables adaptation to new situations by switching from previously held beliefs or thoughts to new response strategies.


A research technique that allows the control of the activity of live neurons that have been genetically modified to express light-sensitive ion channels. Cell type-specific expression of photosensitive cation or anion channels can be used to acutely depolarize or hyperpolarize neurons with light in a spatially and temporally defined manner.

Trisynaptic circuit

The flow of incoming information within the hippocampus generally occurs via three synapses: from entorhinal cortex to dentate gyrus, from dentate gyrus to CA3, and from CA3 to CA1.

Critical period

The first 2–6 weeks in the development of adult-born neurons during which they display heightened excitability and plasticity.

Input resistance

In a neuron, the ratio of the input voltage to the input current, as determined by the number of open membrane ion channels. Young adult-born neurons display high input resistance due to a low density of membrane K+ channels during early development.

GABAergic inhibition

Inhibitory interneurons primarily release GABA, which activates ionotropic GABA type A receptors (GABAARs), or metabotropic GABABRs. GABAARs are Cl channels that hyperpolarize mature neurons. In young adult-born neurons, GABAAR-mediated currents are depolarizing because of a reverse Cl gradient.

Immediate early genes

Genes the expression of which is rapidly and transiently increased following neuronal activation; for example, Fos, Arc and Zif268. Such genes are used as markers for neuronal activity or to indelibly label neurons that are active during a specific experience.

X-ray irradiation

Repeated exposure to 2.5–5 Gy of X-rays eliminates proliferating progenitor cells from the dentate gyrus and consequently ablates neurogenesis.

Entorhinal cortex

A medial temporal lobe area that is divided into lateral and medial entorhinal cortices and that provides the main excitatory input into the hippocampal dentate gyrus.

Hilar interneurons

Dentate gyrus interneurons are a diverse group of inhibitory neurons that are primarily located in the hilus and use GABA as their primary neurotransmitter.


Neuronal ensembles that are recruited during memory encoding to form a cellular representation of that memory (memory trace).

Proactive interference

A neurobiological process by which previously learned information hinders the acquisition and distinct encoding of a new memory trace.


Specific aspects of complex diseases that have a measurable biological foundation. Can be used to stratify heterogeneous (psychiatric) illnesses.

Negative affect

The experience of unpleasant emotions, poor self-confidence and lack of motivation.

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Anacker, C., Hen, R. Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood. Nat Rev Neurosci 18, 335–346 (2017).

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