Positive Influences on Adult Neurogenesis

Process of Neurogenesis
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New born neurons start off as neuronal stem cells and transform
through various stages of development before becoming granular neuron.
Source: <http://www.richardsmrt.com/research?replytocom=9>

It is often assumed that the formation of new neurons in the brain is ceased in adulthood. However, starting from birth, neurons are generated in our brains and they continue to generate throughout adulthood [1]. There are many factors that contribute to the survival of the neurons at both pre and post natal stages and that assist in further neuronal proliferation. These factors include learning, exercise, diet, and sleep. All of these things contribute to forming new neurons in the brain which in turn increases brain plasticity. Neurogenesis occurs in the dentate gyrus (DG) of the hippocampus and in the subventricular zone of the brain [2]. More specifically, neuronal cell proliferation starts in the granule cells of the dentate gyrus, then proceeds to the mossy fibres in the CA3 pyramidal neurons, before travelling through the Schaffer collaterals, and ultimately leading to the CA1 neurons [1]. The dentate gyrus is one of the only areas of the brain where neurogenesis continues to occur throughout life [3].
Neurogenesis occurs mostly in the subventricular zone (SVZ) of the brain [2]. These new born cells migrate to the olfactory bulb (sensory receptor) before developing into granule cells and integrating into the brain circuit [2]. At this time, it is unknown why this migration process occurs in humans, but the process is deemed to play a role in learning and memory [2]. Neurogenesis also heavily occurs in the dentate gyrus (DG) of the hippocampus [2]. However, these neurons from the dentate gyrus do not migrate and remain within the granule cells, even though they also play an important role in learning and memory [2]. Astrocytes are also involved in the migration of new neurons as astrocytes promote the differentiation of adult progenitor cells from the hippocampus and assist in their integration [2]. The progenitor cells that result from neurogenesis are often labelled with bromodeoxyuridine (BrdU) molecular marker to measure the level of proliferation in research studies [2].

1.0 Learning and Memory

Learning Promotes Cell Survival
Dr. Tracey Shors, a world renowned neuroscientist, talks about how learning
and memory are involved in neurogenesis and how it can prolong cell survival.
source: youtube.com <www.youtube.com/watch?v=Im1qnPM3Y7w>

Not only does learning help increase neuronal cell proliferation, but neurogenesis also enhances learning.

1.1 Mechanism

New neurons in the dentate gyrus can survive longer than average as a result of associative and hippocampal-dependent learning [1][4]. The lives of adult neurons in the dentate gyrus are unaffected by hippocampal-independent learning [1]. The integration of new information in the hippocampus requires conscious or intentional sensory perceptions [1]. The critical period of new neurons is around 1-2 weeks after birth [1]. At this time, these neurons would have integrated in the granule cell layer and be in the middle of forming neuronal dendrites and reaching out towards CA3 neurons with their axons [1]. Learning and memory can be defined by the level of strength in the synapses or long term potentiation (LTP) [4]. Though, it is known that both NMDA and AMPA receptors are involved in the excitatory response of healthy neurons, LTP in new neurons occurs because of the NR2B units in NMDA receptors [4]. This is a critical step in the pathway for retaining long-term memories [4]. Neurons of 4-6 weeks of age experience greater LTP than older neurons and this activity may be controlled by the NR2B subunit in the NMDA receptor [2].
The development of critical neurons from the subventricular zone is influenced by the organisms' life experiences such as spatial learning and interacting with the environment [2].
The key process of learning in the hippocampus involves the activity if granule cells from the dentate gyrus [5]. The activation of CA3 pyramidal cells also occurs during the encoding of information [4]. CA3 neurons are stimulated by the mossy fibres that extend from the granule cells in the dentate gyrus [4]. However, while retrieving information, the perforant pathway and the entorhinal cortex drive the activation of CA3 neurons[5]. The perforant pathway and the entorhinal cortex are involved in activating CA1 neurons during the encoding phase of learning [5]. The perforant pathway, entorhinal cortex, and Schaffer collaterals all assist in the activation of CA1 neurons, but drive the CA3 neurons for information retrieval [5]. All of these structures are important in the consolidation of learning process.

1.2 Role of NT-3

Structure of NT-3
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The structure and positioning of NT-3 when
bound to its receptor p75 [7].

NT-3 is a neurotrophin that has been shown to regulate neurogenesis and also play a significant role in learning and memory [6]. Neurotrophins are also essential components involved in the survival, differentiation, and maintenance of new neurons [7]. The main receptors that neurotrophins bind to are either p75 neurotrophin receptor (p75 NTR) or tyrosine kinase receptors (Trks) [7]. However, Trk receptors bind to a more specific subset of neurotrophins while all neurotrophins can bind to p75 [7]. NT-3 binds to both p75 and Trk receptors and its expression remains confined to the dentate gyrus of the hippocampus [6]. NT-3 has been shown in culture to induce the differentiation of neural progenitor cells [6]. If NT-3 receptors are removed or binding with the substrate are inhibited, there are fewer synaptic connections in the dentate gyrus leading to a reduced capacity for memory [6]. Therefore, it is likely that NT-3 plays a significant role in synaptic long-term potentiation- an important component in the formation of memories [6]. The formation of strong synapses along the mechanistic pathway described in the previous section is what drives the consolidation of learned materials and memories.

1.3 Adult Hippocampal Role in Spatial Memory

There are a lot of research teams that have studied the effects of learning on neurogenesis, and thus there exists a lot of data proving that not only does learning promote neurogenesis at a young age, but also in adulthood. Mouse studies have demonstrated impaired spatial memory if there are lesions or tissue damage in the dentate gyrus [4]. A study conducted at the University of Toronto treated adult hippocampal neurons in mice with a small amount of irradiation (IRR) which significantly decreases neurogenesis in the hippocampus but does not affect other neurons in the central nervous system and trained the mice to perform the Morris water maze test (with visual cues) [4]. The goal was to understand the effect that neurons of various ages have in learning [4]. The neurons were labelled using the BrdU and CaBP molecular markers [4]. Their main findings were that neurons between 4-28 days of age are necessary at the time of training for the consolidation of learning into long term memory [4]. Irradiation of any neurons prior or posterior to the experiment did not affect the learning abilities of the mice [4]. This corresponds to the mechanism of memory consolidation as it is at age 4-10 days that the axons of these neurons extend and synapse with CA3 neurons [4]. During this critical period, synapses formed while learning targets the NMDA receptors on the post synaptic neuron which independently prolongs the life of the neuron [2].

2.0 Diet and Exercise

Both diet and exercise have been shown to improve neurogenesis and cell proliferation in the hippocampus [8][9].

Exercise improves neurogenesis and survival
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The increase in neurogenesis and cerebral blood volume in the dentate gyrus have a strong relationship
with exercise as demonstrated by BrdU labelling[3].

2.1 Exercise in Neurogenesis

It has been shown that exercise can improve the rates of neurogenesis and learning [8]. Mice that were provided a running wheel to run every day, learned faster and had better memory than mice of the same age that did not run [8]. What was once seen as a decrease in the neurogenesis as the mice were aging was reversed by up to 50% by exercise [8]. The side-effects of aging can be reversed and prevent by regular exercise[8]. Exercise can have positive and preventative effects in the development of diseases like Alzheimer's Disease and Dementia as well [8]. Exercise promotes neurogenesis in the hippocampus and improves cognition [8]. The earlier the mice started running and exercising, the greater the capacity for learning and cognitive functions the mice received [8].

2.2 BDNF and VEGF in Exercise

The two important neurotrophic factors involved in the promotion of neurogenesis with exercise are brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) [10].

2.2a Role BDNF

There is a powerful correlation between BDNF’s link to exercise and synaptic plasticity [10]. BDNF in the hippocampus controls the effects of exercise on learning and memory [10]. The results from a study conducted in China show that when BDNF was inhibited by irradiation in the hippocampus, rats were unable to effectively complete the Morris water maze test like they were previously capable of [10]. Irradiation can have devastating effects on cognitive abilities in both youth and adults [8]. As a result of BDNF activity, exercise can improve neurogenesis and plasticity in the hippocampus reversing the effects of cognitive decline [10].

2.2b Role of VEGF

Like BDNF, the role of VEGF is also to regulate neurogenesis in the hippocampus and to improve cognitive function [11]. Running increased VEGF activity in the hippocampus to increase cell proliferation in the subventricular zone [11]. The effects of VEGF are more prominent on new neurons in the central nervous system than in peripheral nervous system [10]. As a result, there are other neuronal growth factors involved in the pathway of neurogenesis as a result of exercise especially in the PNS [11]. Researched data shows that after blocking VEGF in the PNS, neurogenesis activities decreased back to initial rates- the same amount was seen in animals that performed exercise and those that did not [11] The pathways of neurogenesis in the central and peripheral nervous systems are distinct and VEGF has a greater effect in the enhancement of neurogenesis in the CNS [11]

2.3 Diet in Neurogenesis

2.3a Omega-3 Fatty Acids

Similar to the results seen in exercise and neurogenesis, omega-3 fatty acids and docoahexaneoic acid (DHA) also promote neurogenesis and offer Neuroprotective effects to adult brains [9]. Increased omega-3 polyunsaturated fatty acid (PUFA) levels are also highly associated with greater results on hippocampus-dependent memory tasks [9]. Research also shows that solely increasing DHA levels can lead to reversal of age effects in the hippocampal and improve memory and cognition [9]. The increase of omega-3 PUFA and neurogenesis in the hippocampus in mouse brains are also highly correlated with levels of BDNF [9].
Both diet and exercise play an important role in hippocampal-dependent neurogenesis. Increasing omega-3 PUFA intake and time spent doing exercise can reverse tissue damage by increasing neurogenesis rates and even have Neuroprotective effects. These findings can soon help create therapies to treat neurodegenerative diseases like Alzheimer’s, Dementia, and Multiple Sclerosis and brain tumours. These treatments would employ similar effects in the brain as demonstrated by omega-3 PUFA and exercise.
Foods with the highest amount of omega-3 fatty acids are fish; therefore it is important to incorporate fish in our diet (in moderation) [12]. Other good sources of omega-3 and DHA are poultry, eggs, nuts, and berries [13]. Walnuts in particular have been shown increase neurogenesis and improve brain functions even through old age due to their high content of PUFA's [14].

2.3b Ketogenic Diet

It has also been shown that the Ketogenic Diet (high in fats, low in carbohydrates) can be beneficial in improving neurogenesis in epileptic patients [15]. In a study performed on mice, subjects on the ketogenic diet had increased neurogenesis after being induced with seizures than did healthy controls on the same diet [15]. The mice began eating the ketogenic food 21 days after birth [15]. The ketogenic food included a high amount of polyunsaturated fatty acids [15]. After 4 weeks on the diet, researchers induced seizures in the mice using kainic acid (KA) [15]. The mice were injected with a BrdU molecular marker to observe the effects of the diet on brain neurogenesis [15]. The results showed an increase in neurogenesis caused by the ketogenic diet. Though the exact influence of the ketogenic diet is unknown, it is thought that this diet is beneficial for treating epilepsy and seizures because it improves mitochondrial activity and decreases oxidation [16]. In addition, the fatty acids have also been shown to alter the activity ion channels, and neurotransmitters [16]. The promotion of neurogenesis after seizures can help reduce the amount of damages to the brain and protect the brain from harsh conditions [15]. In addition, a high fat diet such as ketogenic can help prevent seizures as the results also demonstrated that mice on the ketogenic diet had a delayed onset of seizures than the controls [15]. Diets high in fatty acids promote neurogenesis and offer neuroprotective effects.

3.0 Sleep

Sleep also has important implications on neurogenesis and learning and memory [17].

3.1 Effects of Sleep on Neurogenesis

Sleep Deprivation
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The number of BrdU labelled cells in the subventricular zone of the dentate gyrus in rodents
after various hours of sleep deprivation compared to controls [18].

There exist several factors by which sleep can control neurogenesis [17]. Sleep disturbances inhibit neurogenesis, plasticity, learning, and memory[17]. Chronic stress which negatively affects sleep can also prevent neurogenesis [17]. The same idea applies for depression and aging. Since both of these concepts have a tendency to prevent proper sleep cycles, they in turn also negatively affect neurogenesis [17].

3.2 Short Term Sleep Deprivation

Short-term deprivation is considered to be less than 2 days of no rapid-eye movement (REM) [17]. After one night of no sleep, around 40-60% of people in the study showed an improvement in mood [17]. Productivity also increased after one night’s lack of sleep, but only if this is done once a week [17]. Sleep deficiency of 12 hours in rats increased of neurogenesis in the dentate gyrus of the hippocampus and promoted survival of neurons [17]. However, no change occurred in neurogenesis on the subventricular zone [18]. Therefore, only certain areas of the brain profit from [sleep deprivation [18]. There is also an increase in BDNF levels in response to sleep deprivation [18]. Sleep deprivation along with exercise and diet have positive effects on neurogenesis, learning and memory, and cell survival and the common factor involved in all of these processes is BDNF.

3.3 Long Term Sleep Deprivation

Long-term sleep deprivation is defined to be between 56 and 96 hours of no rapid-eye movement (REM) sleep [17]. Mice that underwent long term sleep deprivation showed 50% less cell proliferation in the dentate gyrus [17]. The activity of motor neurons also reduces by 36-54% [18]. In a separate study, mice were sleep deprived 20 hours a day for 8 days and only 4 hours a day was dedicated for sleep [17]. Ki67 molecular labelling decreased profoundly in the subgranular zone; however, BrdU levels showed no change [17]. This indicated that sleep restriction affected the development of neuroblasts in the earlier stages, but does not affect cell maturation of survival[17]. Many research groups have discovered a decrease in the size of the hippocampus in people, which is correlated with sleep apnea, and insomnia [17]. Reduction in proper sleep, leads to a decrease in hippocampal-dependent neurogenesis, which ultimately affects learning, memory, and cognition [17]. As a result, it is important to ensure that organisms achieve an adequate amount of sleep per day to prevent the harmful effects of long term sleep deprivation and promote the survival of neurons.

3.4 Peak Times of Day for Neurogenesis

Neurogenesis at Different Times of the Day
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The average data taken from 3 different studies of mice showing the rate of neurogenesis at
different times of the day using BrdU labelling. Cell proliferation occurs mostly at around 12 zeitgeber time (ZT) [17].

The duration of the cell cycle for the generation of new cells is around 24-25 hours; therefore, a complete cycle of cell proliferation requires a full day [17]. The circadian cycle of neurogenesis can easily be tracked by BrdU labelling [17]. Proliferation tends to peak at night when it is time to sleep which corresponds with the role of sleep in neurogenesis [17].
In a study conducted with mice, subjects were habituated to a 12 hour light and 12 hour dark daily cycle [19]. The mice were then sacrificed at various zeitgeber times throughout the day [19]. Neurogenesis was observed in the subgranular zone of the dentate gyrus using an immunostaining mechanism to mark M-phase cells [19]. The results show that the M-phase of cell proliferation is highest during nighttime compared to daytime [19]. Yet, the numbers of cells in S-phase were similar in both day and night times [19]. There is a large difference in the timing of mitosis in cell proliferation [19]. It is possible that M-phase in the hippocampus is prolonged at night leading to a greater appearance of cells in this phase during the dark [19]. M-phase could also be suppressed during the day and thus occurs only at night [19]. These variations are more prevalent in the ventricular zone of the dentate gyrus, the area of the brain known to regulate mood [19]. Thus these variations, may explain how changes in mood occur at different times of the day and may link mood changes with the amount of neurogenesis in this area [19].

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