Exercise and Cognitive Deficits

Neurodegenerative diseases, such as aging-related neurodegenerative diseases and brain injuries result in severe cognitive deficits that are associated with atrophy of the hippocampus, a brain structure involved in short-term and long-term memories, and in the processing of spatial memory that controls navigation [1].

Exercise and physical activity have been shown to reduce or slow down these cognitive deficits by promoting the production of new neurons in the hippocampus, a process known as hippocampal neurogenesis.

I. How Does Hippocampal Neurogenesis Work?

The hippocampus is a niche of a population of adult neural stem cells that can self-renew and make intermediate proliferating progenitors (IPCs) cells and neuroblasts to generate hippocampal neurons known as granule neurons of the dentate gyrus (DG) [2] [3] [4].

Intermediate proliferating progenitors (IPCs) cells and neuroblasts are adult stem cells that specialize in producing hippocampal neurons. They are specifically found in the part of the hippocampus known as the dentate gyrus.

These highly specialized cells are essential to memory their function in decorrelating pattern separation [5].

Therefore, upon cognitive impairment due to hippocampal atrophy, these adult stem cells can be stimulated to potentially improve recovery.

II. Exercise and Hippocampal Neurogenesis

Several studies showed that physical exercise can induce hippocampal neurogenesis and suggested that physical exercise could be used as therapy or as an adjunctive therapeutic strategy for cognitive decline.

In human adults, exercise has been shown to increase the size of the hippocampus in human adults [6] and in rodent models.

Exercise increases the proliferation and survival of Intermediate proliferating progenitors (IPCs) cells and neuroblasts which increase the number of granule neurons in the dentate gyrus (DG) [7] [8].

III. How Exercise Stimulates Hippocampal Neurogenesis?

To investigate the link between exercise and neurogenesis, studies investigated the expression of a key regulator of neurogenesis known as BDNF.

Several studies showed that treadmill exercise in mice and aerobic exercise in humans increase BDNF expression by regulating its gene expression in the hippocampus [9] [10].

1- What is BDNF?

The Brain-Derived Neurotrophic Factor or BDNF is a growth factor that belongs to the neurotrophin family that is highly expressed in the brain and throughout the rest of the central nervous system [11].

The neurotrophin family is a group of proteins that promotes the survival of neurons by preventing their death through a natural process known as programmed cell death.

BDNF is involved in the proliferation (division and self-renewal), differentiation, maturation, survival, and plasticity of neurons.

The plasticity of neurons is associated with the connection that neurons make between them, named synapses, to increase their activities in neurotransmission, and therefore, transfer of information.

BDNF is specifically expressed by glutaminergic neurons that are involved in neurotransmission that involves the neurotransmitter, glutamate.

BDNF is mainly expressed in the hippocampus, cortex, basal forebrain, and cerebellum which are important brain structures involved in memory, learning, and thinking.

2- What Does BDNF in the Hippocampus?

As a member of the neurotrophin family, BDNF ensures that Intermediate proliferating progenitors (IPCs) cells and neuroblasts proliferate (divide and self-renew), differentiate, and mature into hippocampal neurons.

It also ensures the survival of hippocampal neurons by preventing their death.

Another role is to increase the connection between the hippocampal neurons to enhance neurotransmission of information related to learning and memory in the hippocampus.

3- How Is BDNF Stimulated?

Unlike aging, Alzheimer’s disease, chronic stress, exercise, enriched environment, and antidepressants have been shown to stimulate the expression of BDNF [12].

• How Is BDNF Stimulated by Exercise?

Although the mechanism by which exercise induces an increase in BDNF levels is not well known, a study proposed that this increase is due to the muscles secreting a factor known as exercise factor (EF) during exercise.

EF is secreted in the circulation and transported to neurons where it binds to their membranes through a receptor known as exercise factor receptors.

This binding results in a cascade of reactions within the neurons that leads to the transcriptional activation of BDNF expression [13].

• How Is BDNF Stimulated by Enriched Environment

An enriched environment is associated with conditions that provide major sensory, cognitive, motor, and social stimulations when compared with a standard environment.

An enriched environment has been shown to increases synaptic connectivity between neurons in the hippocampus through the induction of BDNF which plays an important role in this process.

This effect of an enriched environment reduces the level of stress, improves the performance of memory and spatial learning tasks [14]

• How Is BDNF Stimulated by Antidepressants

Antidepressant drugs have been shown to increase neuronal plasticity through a mechanism that involves, at least partly, BDNF [15]. This mechanism has been reported to involve the induction of TrKB by BDNF.

TrKB (Tropomyosin receptor Kinase B) is a receptor for BDNF and is involved in the survival and activity of neurons. Therefore, the activation of BDNF by antidepressants promotes the activity of TrKB.

4- What Reduces BDNF?

• How Is BDNF Reduced During Aging?

During aging, a decrease in the brain volume, including the hippocampus volume, is observed and which starts at middle age and continues afterward.

This decrease in the volume of the brain also results in a reduction of the levels of BDNF.

Interestingly, the injection of the drug ampakine, which enhances glutamate neurotransmission, reverted the decrease of BDNF levels in the brain and hippocampus and improved memory in rodents [16].

Whether ampakine has the same effect on the human brain and hippocampus is not known.

• Why is BDNF Reduced During Alzheimer’s disease?

Several studies implicated BDNF as one of the causes of Alzheimer’s disease as reflected by reduced levels of BDNF in post-mortem brains of AD patients.

Although the mechanism is well known, it was suggested that the accumulation of beta-amyloid (Aβ) plaques in the hippocampus of patients with Alzheimer’s disease, reduces the levels of BDNF [17].

• How Chronic Stress Reduces BDNF?

During chronic stress, the hypothalamus secretes CRH (corticotropin-releasing hormone) to stimulate the secretion of ACTH (Adrenocorticotropic hormone) by the pituitary gland leading to the secretion of glucocorticoids (e.g., cortisol) by the adrenal glands as part of the “Fight-or-Flight” mechanism.

Glucocorticoids have been shown to reduce the levels of BDNF in the hippocampus [18].

Conclusion

Physical exercise could be used as therapy or as an adjunctive therapeutic strategy for cognitive decline that is associated with aging-related neurodegenerative diseases and brain injuries.