New Hippocampal Neurons are Involved in Stress Resilience

What’s the science?

The hippocampus plays an important role in memory and cognition, but also in stress and anxiety. In many brain regions there is no neurogenesis (new neurons generated) in adulthood, however, neurogenesis does occur in the ventral dentate gyrus of the hippocampus. These adult-born neurons are known to play a role in mood regulation, but their role in protecting against stress-induced anxiety behaviours is not known. This week in Nature, Anacker and colleagues inhibited adult-born neurons in the ventral dentate gyrus to assess their role in resilience to chronic stress.

How did they do it?

The authors developed a new model to silence adult-born neurons (granule cells) of the ventral dentate gyrus in mice by expressing a ‘designer receptor exclusively activated by designer drugs’ (DREADD). Specifically, they crossed a tamoxifen-induced CreERT2 recombinase transgenic mouse line with mice expressing loxP-STOP-mCherry-loxP-hM4Di. Then, they could administer an agonist for the DREADD (clozapine-N-oxide) to decrease activity of adult-born neurons. Mice with DREADDs (Cre+ mice) underwent a short social-defeat paradigm (5 days) in which they fought and were defeated by an aggressive mouse. Then, the authors tested whether mice would change their social behaviour or exploration patterns (less exploring an open area indicates anxiety) after the social-defeat paradigm. In control mice, this social-defeat paradigm had been shown to be short enough not to change the mouse’s subsequent response to social interactions. To examine any effects of adult-born neuron silencing on neural activity of mature neurons of the ventral dentate gyrus, the authors examined Fos gene expression and performed electrophysiological recordings during perforant path stimulation (the main glutamatergic input into the ventral dentate gyrus) in vivo. To test whether neurogenesis could promote resilience to stress, they deleted the Bax gene (‘iBax mice’) to promote increased neurogenesis. Control mice and iBax mice were subjected to a 10 day chronic social-defeat paradigm, which usually increases anxiety and reduces social behaviours in control mice. They also assessed whether the activity of mature neurons (indicated by c-Fos+ neurons) increased in iBax mice. Finally, they performed cell selectivity analyses using calcium imaging to assess whether certain cells were selective for different neuronal events in control mice and iBax mice during the chronic social-defeat task.

What did they find?

After mice with activated DREADDs underwent the social-defeat paradigm, they explored an open area and approached novel mice less in a social interaction test. This indicates that the inhibition of young neurons increases stress responses/anxiety. Fos gene expression was increased in mature neurons following social-defeat in Cre+ mice (versus control mice), and increased mature neuronal activity was found following performant path stimulation. This indicates that mature neurons may be more activated by stress after silencing young neurons. In iBax mice (who had increased neurogenesis) compared with control mice, the authors found normal levels of social interaction following a chronic social defeat paradigm, suggesting that increased neurogenesis in iBax mice made them resilient to stress. After X-ray irradiation of the ventral dentate gyrus in iBax mice, these effects were no longer seen, providing further evidence that adult-born neurons are responsible for resilience to stress.

When the authors assessed activity of mature neurons (c-Fos+ levels) they found that iBax mice had less c-Fos+ cells after stress, indicating that new neurons can decrease the activity of the dentate gyrus. During attack periods, using cell selectivity analysis, they found 17% of ventral dentate gyrus cells to be selective for the attack periods during the chronic social defeat task. This population of attack-selective cells increased to over 30% after chronic stress. Interestingly, these cells were less active (lower calcium transient rates) during attacks in iBax mice. This indicates that neurogenesis could result in lower activity of attack-selective cells (i.e. inhibition). The authors then mimicked the effect of neurogenesis on inhibiting the dentate gyrus by directly expressing inhibitory DREADD receptors in mature granule cells. By doing this, they found that directly inhibiting the ventral dentate gyrus is sufficient to confer stress resilience.

What’s the impact?

This is the first study to demonstrate the role of new neurons in the ventral dentate gyrus of the hippocampus in response to stress and anxiety in mice. Neurogenesis in the ventral dentate gyrus appears to reduce the response to stress, and silencing new neurons in this region appears to increase the response to stress. Understanding the role of new neurons in this region is critical to understand vulnerability to stress and could be applicable in psychiatric disorders. The study also suggests that novel strategies aimed at inhibiting the ventral dentate gyrus could be used to treat or prevent stress-induced psychiatric disorders.

Anacker et al., Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature (2018). Access the original scientific publication here.