Could Neurogenesis and Navigating Change Be Key to Cognitive Flexibility?

Summary: Researchers are closing in on the relationship between cognitive adaptability and adult neurogenesis. They developed a novel animal model to test cognitive flexibility by adding layers of complexity to a maze challenge. This revealed that gamma-radiation hindered cognitive adaptability and specific newly-generated neurons responded distinctively to the task. Aging and neurogenesis in the hippocampus, it seems, are deeply connected to cognitive flexibility.

Key Facts:

  1. The study utilized an innovative maze test, wherein mice had to adapt to changing cues to locate a submerged platform.
  2. Gamma-radiation exposure impacted cognitive flexibility without affecting the primary task learning, leading mice to search for the platform in its old location.
  3. The relationship between cognitive flexibility and neurogenesis was further underscored with aging, indicating potential areas for therapeutic interventions.

Source: Stony Brook University

The ability to shift from one type of cognitive problem-solving strategy to another when the circumstances change, called cognitive adaptability or flexibility, is an essential function for humans. When this ability is diminished—whether by aging, disease, trauma, or environmental exposure—mental behavior becomes more inflexible and a person has difficulty adapting to new cognitive demands and remains stuck in the previous way of thinking.

The same adverse conditions—disease and aging—also affect the process of creating new neurons long after birth (called adult neurogenesis). However, the link between the two conditions remains elusive. A team of researchers led by Stony Brook University scientists believe they have a new understanding of cognitive adaptability and the role of adult neurogenesis.

This shows neurons.
Remarkably, the older mice showed improvement and narrowed the performance gap with the younger mice after additional training—an indication of the older brains’ accommodation capacity. Credit: Neuroscience News

Their work and findings are highlighted in two recent papers, one in the Journal of Neuroscience, and one in Frontiers in Neuroscience.

According to Grigori Enikolopov Ph.D., Professor in the Department of Anesthesiology in the Renaissance School of Medicine at Stony Brook University and the Center for Developmental Genetics of the University, and a lead author of both papers, the full range of consequences impacting cognitive flexibility remains elusive to scientists largely because of a lack of effective research models.

He and colleagues developed a new animal model centered around behavioral tasks which were designed to challenge mice to respond to various cues to get around a maze.

The common version of this task requires the mouse to find a platform submerged in a water pool, remember the platform’s position relative to various cues surrounding the pool (for instance circles and crosses affixed to the walls of the area), and then use these cues to navigate to the platform (as one would learn the location of a local bike shop relative to other shop signs on the same block).

The authors designed a new behavioral assay by adding other variables in the common task, such as alternating daily the color of the pool, having children’s toys dangling above the pool, and changing the position of the platform (as if changing the store and building colors around the bike shop).

In The Journal of Neuroscience article, which was selected as the cover feature for the edition, the team focused on how an exposure to radiation affects cognitive flexibility and neurogenesis in the hippocampus, a brain region involved in learning and memory.

By using the test model, the team found that exposure to gamma-radiation did not affect how the mice learn the common version of the task but diminished the cognitive flexibility of the animals, as they stuck to the routine and kept searching for the platform in the old location.

“We also found that in animals exposed to this complex new task, newly generated neurons became activated by the selected features of the task, for instance by the local cues (the toys) hanging above,” says Evgeny Amelchenko, Ph.D., a Research Scientist in the lab and the first author in both papers.

“Intriguingly, the response was specific to those adult-generated neurons that were born three months before the test took place, but not to the younger neurons,” he adds.

Since aging is associated with impairments of cognitive flexibility and other brain functions, the researchers also tested adult (6 months) and mature adult mice (14 months) using the same intricate maze task—specifically crafted to invoke cognitive flexibility.

This work, described in the Frontiers in Neuroscience paper, led to the finding that age-related decline in cognitive adaptability is strongly associated with the levels of neurogenesis in the hippocampus.

According to Enikolopov, the team found a striking correlation between an animal’s performance in the task and the quantities of neurons that were generated in the animal several weeks or even months before completing the task.

“Animals exposed to artificial (exposure to radiation) or natural (aging) conditions show diminished neurogenesis, delayed learning, deficient memory, and reduced use of efficient navigation strategies when confronting scenarios that require the adjustments of previously learned search strategies,” explains Dr. Amelchenko.

“This underscores the importance of hippocampal neurogenesis in supporting cognitive flexibility.”

Remarkably, the older mice showed improvement and narrowed the performance gap with the younger mice after additional training—an indication of the older brains’ accommodation capacity.

Enikolopov adds that the entire body of work detailed in both papers “points to a close-knit relationship between the extent of adult neurogenesis and cognitive flexibility, rather than conventional learning and memory processes.

This connection raises the exciting prospects that augmenting neurogenesis levels could serve as a strategy for mitigating the effects of the aging- or disease-related cognitive decline.”

The researchers will continue testing cognitive flexibility and neurogenesis in their model with a closer look at the cohorts of neurons born at different times before the test, and to see if their assay can be used to screen in mice for compounds that might increase cognitive flexibility.

Eventually, they hope to advance the work to use fMRI in humans to understand how aging or disease affect cognitive flexibility.

About this cognitive flexibility and neurogenesis research news

Author: Grigori Enikolopov
Source: Stony Brook University
Contact: Grigori Enikolopov – Stony Brook University
Image: The image is credited to Neuroscience News

Original Research: Open access.
Age-related decline in cognitive flexibility is associated with the levels of hippocampal neurogenesis” by Evgeny M. Amelchenko et al. Frontiers in Neuroscience

Closed access.
Cognitive Flexibility Is Selectively Impaired by Radiation and Is Associated with Differential Recruitment of Adult-Born Neurons” by Evgeny M. Amelchenko et al. Journal of Neuroscience


Age-related decline in cognitive flexibility is associated with the levels of hippocampal neurogenesis

Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis.

We investigated the performance of 6-and 14-month-old mice (considered mature adult and late middle age, respectively) in learning and memory tasks based on the Morris water maze (MWM) and determined their levels of preceding and current neurogenesis.

While both age groups successfully performed in the spatial version of MWM (sMWM), the older mice were less efficient compared to the younger mice when presented with modified versions of the MWM that required a reassessment of the previously acquired experience.

This was detected in the reversal version of MWM (rMWM) and was particularly evident in the context discrimination MWM (cdMWM), a novel task that required integrating various distal cues, local cues, and altered contexts and adjusting previously used search strategies.

Older mice were impaired in several metrics that characterize rMWM and cdMWM, however, they showed improvement and narrowed the performance gap with the younger mice after additional training.

Furthermore, we analyzed the adult-born mature and immature neurons in the hippocampal dentate gyrus and found a significant correlation between neurogenesis levels in individual mice and their performance in the tasks demanding cognitive flexibility.

These results provide a detailed description of the age-related changes in learning and memory and underscore the importance of hippocampal neurogenesis in supporting cognitive flexibility.


Cognitive Flexibility Is Selectively Impaired by Radiation and Is Associated with Differential Recruitment of Adult-Born Neurons

Exposure to elevated doses of ionizing radiation, such as those in therapeutic procedures, catastrophic accidents, or space exploration, increases the risk of cognitive dysfunction.

The full range of radiation-induced cognitive deficits is unknown, partly because commonly used tests may be insufficiently sensitive or may not be adequately tuned for assessing the fine behavioral features affected by radiation.

Here, we asked whether γ-radiation might affect learning, memory, and the overall ability to adapt behavior to cope with a challenging environment (cognitive/behavioral flexibility).

We developed a new behavioral assay, the context discrimination Morris water maze (cdMWM) task, which is hippocampus-dependent and requires the integration of various contextual cues and the adjustment of search strategies.

We exposed male mice to 1 or 5 Gy of γ rays and, at different time points after irradiation, trained them consecutively in spatial MWM, reversal MWM, and cdMWM tasks, and assessed their learning, navigational search strategies, and memory.

Mice exposed to 5 Gy performed successfully in the spatial and reversal MWM tasks; however, in the cdMWM task 6 or 8 weeks (but not 3 weeks) after irradiation, they demonstrated transient learning deficit, decreased use of efficient spatially precise search strategies during learning, and, 6 weeks after irradiation, memory deficit.

We also observed impaired neurogenesis after irradiation and selective activation of 12-week-old newborn neurons by specific components of cdMWM training paradigm.

Thus, our new behavioral paradigm reveals the effects of γ-radiation on cognitive flexibility and indicates an extended timeframe for the functional maturation of new hippocampal neurons.

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