In this paper, I will discuss and critically analyze how newly born neurons contribute to adult brain function in humans and why their continuous renewal throughout life hints at a functional role for these neurons. Supporting an analysis of newly born neurons and their contribution to adult brain function, I will start by drawing on the study by Spalding et al. (2013), and subsequent developments in this area.
The existence of adult neurogenesis in sufficient numbers to contribute to brain function has been a hotly debated topic, up until advancements in the ability to birth-date hippocampal cells and prove that significant neurogenesis takes place in that area of the brain throughout life comparable with similar historical studies in adult mice’ supporting the notion that it is a contributing factor to human brain function. As far as the limitations of neurogenesis are concerned, this is restricted to the dentate gyrus in humans, as evidenced by Altman and Das (1965) and others, along with the ventricular-subventricular zone of the olfactory bulb (Lois and Alvarez-Buylla, 1994; Lois et al., 1996; Doetsch et al., 1999). Relevant to this essay, I will focus attention mainly on the former, adult hippocampal neurogenesis (AHN), due its apparent involvement in memory, learning, and mood regulation.
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As Spalding suggests, a large number of hippocampal neurons are subject to turnover, which are divided into two distinct populations, those that are replaced, and those non-renewing at the median adult neuronal turnover rate of 1.75% per year or 700 new neurons per day in the hippocampus, also evidencing significant neurogenesis throughout life and only modest decline in neurogenesis during ageing.
Relevant to the subject of brain function, computational models have indicated that the process of older redundant cells being replaced with new neutrons and improved synaptic plasticity, would optimize the effect of new neurons as opposed to an isolated exchange, that would have less influence (Appleby et al., 2011). Due to the localization of neurogenesis to the dentate gyrus, the generation of adult neurons then therefore supports a group that have functionally specific properties as opposed to replacing neurons on a generalized basis.
Certainly a few comparisons are offered by Spalding drawing on neurogenesis in humans and other species. Spalding hypothesizes this is possible by looking at the ratio of old to newborn neurons, concluding that 0.004% of the dentate gyrus neurons are exchanged every day in humans, 0.003-0.006% in two months old mice and 0.004-0.02% per day in 5-16-year-old macaque monkeys. Significantly, Spalding proposes that the proportion of relative adult-born neurons with functions that are unique in the human hippocampus may not be smaller than a middle-aged mouse. Therefore, passing the assumption that the human adult hippocampus may be required to possess the same cognitive adaptability dependent neurogenic quantities well documented in mice. A remarkable difference was also brought to light by Kohler et al. (2012), which showed a slower maturation of newly generated cells in non-human primates than rodents, which had overwhelming physiological implications due to the fact the higher excitability of these cells may be extended in long-living organisms, which has been proposed to express an important evolutionary advantage by permitting increased conflictive flexibility.
Beyond that, further development in this research showed that environmental enrichment, learning and physical exercise also regulate AHN by enhancing the survival and maturation rates of newly generated cells of in rodents (Van Praag et al., 1999; Kempermann et al., 2000; van Praag et al., 2000; Revest et al., 2008; Snyder et al., 2011; Hill et al., 2015; Anacker et al., 2018; Sahay et al., 2011; Strokes et al., 2015; Ishikawa et al., 2016).
All of that said, it should be noted that this deeply refined research in the world of AHN have not (for ethical technical reasons) been achieved yet in humans, so comparability has been limited. Also given only wild specimens were examined in some instances, and therefore diversity of results in studies may increase due to unknown age history of the animal along with capture potentially impacting AHN (Chawana et al., 2014; Wiget et al., 2017). It has also been suggested that the inclusion of greater numbers of specimens along with more detailed descriptions of tissue processing techniques for qualitative-quantitative comparisons of AHN data between the documented mammalian species and humans.
Over the years that followed Spalding, immunohistochemistry techniques have since supported the evidence of AHN in humans, however this was more recently challenged by Dennis et al. (2016), Sorrels et al. (2018) and Cipriani et al. (2018) that reported absent of scarce staining with markets of ANH in humans. Most notably, Seki et al. (2019) showed lower numbers of immature neurons and proliferative cells in the adult human. Conversely, it was showed in separate studies that AHN remains consistent throughout our lifetime (Bolderini et al., 2018; Moreno-Jimenez et al., 2019; Tobin et al., 2019), which raised technical concerns in this field. It’s been speculated the conflicting data relates to histologic methodology or tissue processing limit the detection of markers for AHN to the extent they may become unidentifiable. Conversely, high quality tissues subjected to appropriate histologic pretreatments and short fixation times, thousands of immature neurons can be observed in the dentate gyrus until the 10th decade of human life, indicating AHN occurs prevalently during pathological and physiological ageing.
Worth mentioning here also however that the bulk of work to date on AHN has been limited to post-mortem studies, which while effective, has been of limited therapeutic use. Recent advancements in the field of pattern separation as a proxy for human AHN may pave the way for noninvasive ways to turn AHN into a biomarker for neurodegenerative conditions to aid diagnosis and treatment.
Beyond the variations that manifest physiologically to AHN in human life, more recent exciting studies on animals has supported the dynamic form AHN takes in patients with a number of diseases, most notably neurodegenerative conditions like Alzheimer’s disease (AD), dementia, as well as, stroke, epilepsy, major depression, schizophrenia, cancer and a range of other conditions. Data obtained in patients with AD in particular, the decline in AHN associated with ageing there are additional mechanisms that influence the decrease in AHN (Moreno-Jimenez et al., 2019).
Undeniably based on the afore-mentioned rodent studies, AHN is a source of plasticity in rodents. With the number of new neurons that has been documented in patients with Alzheimer’s disease declining, it is exciting to see what research efforts in the space of protecting cells prior to neurodegeneration. Most notably, uncovering the mechanisms that control synaptic integration and newborn neutron maturation to hopefully find effective regenerative treatments in the human brain.
Ge et al., 2007 and Schmidt-Hieber et al., 2004 suggests hippocampal neurons that are adult-born possess increased synaptic plasticity for a period after their differentiation, looked at in concern with the fact that the dentate gyrus is effectively a ‘bottleneck’ in the neural network and have a profound impact on hippocampal function. In addition, there is the matter of pattern separation associated with the new neurons which acts to store experiences as distinct memories versus the legacy cells, required for ‘pattern completion’ and connect memories with one another. Generalization be caused by the failure of pattern separation, a feature common in depression and anxiety (Kherbek et al., 2012). While this has been challenging to explore in humans, certainly indications that reduced AHN may result in psychiatric disease.
In summary, further research is needed to determine whether reduced neurogenesis is associated with psychiatric disease in humans.
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