Fight Aging!

Neurogenesis is the process by which new neurons are created by neural stem cells, thereafter maturing and integrating into existing neural circuits. This is most studied in the hippocampus, where continual change in the circuits of the brain is essential to memory. With age, the pace of neurogenesis declines, as one might expect given what is known of the progressive loss of stem cell activity in later life. This is thought to contribute to cognitive decline in general, and to loss of memory function specifically.

In today's open access paper, researchers report on a study in which they disabled neurogenesis in mice to observe the resulting loss of memory function. Along the way they found evidence for a compensatory process that operates when neurogenesis falters, but operates poorly. The process can be dramatically improved by provoking a greater secretion of stored acetylcholine. This prevents loss of memory function, despite the continued lack of neurogenesis. As the researchers point out, success in restoring memory in mice via this approach is unexpected, given that efforts to increase levels of acetylcholine, via acetylcholinesterase inhibitor drugs that block the degradation of acetylcholine, failed to produce meaningful gains in memory function. Clearly the underlying biochemistry is complex.

Baby Neurons in Adult Brains Are Needed to Maintain Memory

Researchers estimate that the brain's hippocampus - which plays a key role in memory, learning, and emotion - makes about a thousand new neurons each day throughout adulthood. "Considering that the brain contains about 100 billion neurons, it's reasonable to question whether this level of neurogenesis could have any impact on brain function. But over the life of the animal, the effects of these new cells can add up as they make connections with other neurons and other parts of the brain."

To test whether adult neurogenesis is vital to brain health over the long term, the team stopped the process in adult mice by irradiating the birthplace of new neurons or with genetic engineering. Over time, the mice produced less and less of the neurotransmitter acetylcholine in the hippocampus, leading to a profound rewiring of a brain circuit critical for memory. The mice also experienced a slow but progressive decline in working memory (temporary "sticky notes" for carrying out mental tasks). Remarkably, while neurogenesis was suppressed immediately after treatment, the memory, anatomic, and biochemical changes took five months (about a quarter of the mouse life span) to emerge.

Even though the brain circuit changed in a way that impaired memory, the circuit did form new, but dysfunctional, connections that could be recruited to improve memory."It was as if existing neurons were trying, but failing, to compensate for the loss of neurogenesis and what started out as a subtle defect in acetylcholine, and they just needed a little nudge." The researchers suspected that the remodeled circuit had sufficient reserves of acetylcholine but couldn't release it when needed. Using a drug, the researchers nudged the circuit to release more acetylcholine and completely rescued the memory deficits even in aged mice.

"The results suggest that we have to revisit old notions about the aging brain. It seems to be more plastic than we've thought." Cholinesterase inhibitors have been used to treat patients with Alzheimer's disease, with little success. "We think this drug, and many others, have failed because they're focused on one type of cell or molecule. What our findings tell us is that we probably need to address the fact that the whole memory circuit is compromised in aging and dementia."

Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits.

These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.