A closer look into the function of adult-born neurons based on a recent paper by McAvoy et al.

Activity Matters

Judith M. Reichel

Adult-born neurons are intricately linked to cognitive performance. Here, McAvoy and colleagues could show that the successful incorporation of these neurons into the hippocampus hinges on a delicate balance of neuronal activity between mature and new-born neurons.

original paper can be found here: http://dx.doi.org/10.1016/j.neuron.2016.08.009

Age-related cognitive decline is a troubling reality for many aged individuals – even in the absence of overt neurodegenerative diseases such as Alzheimer’s1. The hippocampal formation in the brain is the main structure involved in memory formation and storage. It is also one of the few areas in the adult mammalian brain presenting with neurogenesis; meaning within in the Hippocampus (HPC) – specifically at the sub granular zone (SGZ) of the Dentate Gyrus (DG) – new neurons are “born” throughout life.

This generation of adult-born neurons is called “neurogenesis”, and much has been reported about its importance regarding cognitive abilities. In fact, increased neurogenesis has been linked to infantile amnesia2, while the declining numbers of adult-born neurons in age have been implicated in age-related cognitive decline3. Although it is know that life-style choices4 can modify the proliferation and survival of adult-born neurons, many aspects of the specific molecular and cellular mechanisms guiding the incorporation of the newly generated neurons into the existing HPC formation remain elusive.

Now, McAvoy and colleagues5 have deciphered a specific mechanism through which the integration of  adult-born neurons into the existing network can be improved; and by enhancing that very mechanism, the authors were able to diminish age-related cognitive deficits.

The authors of this study employed elegant and complementary genetic approaches, which explore the importance of functional balance between mature Dentate Granular Cells (DGCs) and adult-born DGCs. McAvoy et al. transiently overexpressed the transcription factor Klf9, which resulted in a reduced number of spines on mature DGCs and thus reduced activity of these cells, which in turn enhanced the activity and successful integration of 2-3 weeks old adult-born DGCs. In a separate but complementary genetic approach the authors overexpressed Rac1, which caused the same effects regarding integration and survival of adult-born DGCs, but without the confounding changes of increased neural stem cells or progenitor cells. Thus the authors were able to show through a straight-forward approach that decreased spine density and subsequent decreased activity in mature DGCs leads to an increased rate of survival and integration of adult-born DGCs in the adult HPC.

In addition to identifying this pathway, McAvoy et al. could also show that an increased integration of 5-to 8-week-old adult-born DGCs in 12- and 17-month-old mice has beneficial physiological effects. More specifically they could show that in aged mice an increased incorporation of adult-born DGCs resulted in better retention of previously established memories, as well as improved discriminatory abilities between similar contexts, a mechanism known as pattern separation6.

Impaired pattern separation has not only been linked to age-related cognitive decline, but is also well documented in the context of anxiety disorders, such as Posttraumatic Stress Disorder (PTSD), where impaired pattern separation can lead to generalized fear7, confining patients to a shrinking environment they feel safe in. In turn, PTSD and Depression have also been linked to decreased neurogenesis, which implies that the mechanisms here described by McAvoy et al. could not only diminish age-related cognitive decline, but indeed could be a targeted approach for many neuropsychiatric disorders as well.

In conclusion, McAvoy et al. elegantly and succinctly demonstrate a specific mechanism whereby reduced spine density on mature DGCs leads to a decrease in their activity, which in turn increases the neuronal activity of adult-born DGCs. This increased activity then enhances the successful and functional integration of adult-born DGCs into the HPC; which in turn results in improved cognition in aged mice. In addition to the cognitive benefits in aged individuals, this specific mechanism also has the potential to aid in the treatment of several neuropsychiatric disorders.

 

The original article is by McAvoy et al.: Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits. Neuron 91, 1356-1373, doi:http://dx.doi.org/10.1016/j.neuron.2016.08.009  (2016).

 

Cited literature:

  1. Morrison, J.H. & Baxter, M.G. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nature reviews. Neuroscience 13, 240-250 (2012).
  2. Josselyn, S.A. & Frankland, P.W. Infantile amnesia: a neurogenic hypothesis. Learning & memory 19, 423-433 (2012).
  3. Villeda, S.A., et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90-94 (2011).
  4. Kempermann, G. Activity Dependency and Aging in the Regulation of Adult Neurogenesis. Cold Spring Harb Perspect Biol 7 (2015).
  5. McAvoy, Kathleen M., et al. Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits. Neuron 91, 1356-1373 (2016).
  6. Deng, W., Aimone, J.B. & Gage, F.H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature reviews. Neuroscience 11, 339-350 (2010).
  7. Besnard, A. & Sahay, A. Adult Hippocampal Neurogenesis, Fear Generalization, and Stress. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 41, 24-44 (2016).

 

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