Thoughts on Dual Linguistic Processing and What Could Affect Neurogenesis in Ageing Brain

Learning to do a unfamiliar task may seem like a time-consuming process at first, taking much time away. As soon as taking a hold of it, however, we could be gripped by a feeling of excitement start rushing in. I presume it could be the moment at which the newly established neural connections have been recognised in one head.

To provide an example to illustrate, I describe my recent struggle with translating a few writings from one language to another. At first I did not enjoy the activity, mainly for overwhelming fuzzy uncertainty. Although it still bothers me when precisions in semantics are sought in detail, nevertheless I became less frustrated as I got faster at the task; the “fuzziness” also turned from mere messy confusions into compromises upon predicting applicability of logic.

The uncomfortableness I experienced is thought to be due to the fact that I had rarely attempted to use two languages simultaneously. One language often predominates another as one is used to receive, think and express, applying a set of rules at each occasion. Interchanging two sets of the rules is like travelling between two distinct entities processing same information differently. That is because the differences between languages often are not only lexical semantics and grammatical structures, there is a semi-subliminal differences in cultural norms underlining beneath at places. The separate entities could be kept apart in a brain. The distance though, appeared to have shrunk as I practiced more; the process gradually speeded up, until eventually the two sets became more like a two-sided card which could be turned around at ease.

With my irrepressible tendency to speculate, I could hardly resist to propose that there must have been some sort of structural changes occurring at the area governing language processing, possibly by means of:
1) establishing new connections associating the two sets for quicker access to each or both simultaneously;
2) extending existing neuronal connections between the two sets of information to allow direct comparisons and mirroring of information in the two sets; or
3) strengthening already existing connections between the two to increase the speed of communications.  

The first two possibilities above would involve neuroanatomical changes by synaptic re-configurations, and as for the third, it can be done by increasing glial cells (oligodendrocytes) which wrap around the axons to increase the electrical conductivity by insulating.           

Before I get carried away full blowing the speculations on multilingual processing in cerebrum, saving that to another occasion, I should better move on to focus on the process generating neuronal cells from progenitor cells (i.e. neurogenesis) in mature mammalian brains. Neural progenitor cells can divide into neurones or glial cells (astrocytes or oligodendrocytes). In the following section, the development of neurones in adult rodents is summarised.  
 

Neurogenesis in the dentate gyrus by the hippocampus contribute to the learning in adulthood

Leaning tasks and memory acquisition involve neural re-configuration. A study evaluated cell proliferation in the hippocampus and the medial prefrontal cortex during and after learning revealed that increased number of newborn neurones were observed during learning (Rapanelli, Frick and Zanutto, 2011). 

In a mature mammalian brain, neurones can be formed from neural progenitor cells in two regions: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus (DG). Newly made neurones in the former migrate to the olfactory bulb, and the newborns in the latter integrate locally into the neural circuitry of the DG (reviewed by Deng, Aimone and Gage, 2010). The following describes the latter event.

The newly born, small neurones (granule cells) in the DG often retain a high intracellular chloride concentration due to the activity of Na-K-2Cl cation-anion co-transporter, NKCC1, which imports chloride. The cells are under the influence of neighbouring cells releasing gamma-aminobutyric acid (GABA) (i.e. GABAergic neurones); the GABAergic input, which has an inhibitory effect on mature neurones, can exhibit a tonic excitatory effect on the granule cells, as the opening of ionotropic GABAA receptor causes chloride efflux by the concentration gradient (reviewed by Ben-Ari. et al. 2007).

Gradually, the granule cells start forming extended synapses with pyramidal neurones in cornu Ammonis 3 (CA3) area within the hippocampus; some connect with the perforant path of axons extended from the entorhinal cortex of rhinal cortical area, which functions as an interface between the hippocampus and the neocortex. The newly integrated connections involves glutamatergic output, and the granule cells start responding to it primarily via N-methyl-D-Aspartate (NMDA) receptors which flux calcium. At this stage, the action of GABAergic input becomes inhibitory as the expression of a K-Cl co-transporter KCC, which exports chloride, becomes more prominent. The inhibitory effect of GABA on maturing neurones is also increased by the action of metabotropic GABAB receptor, which contributes to hyperpolarisation by activating inward-rectifying potassium channel (Kir). For a while, these cells display stronger synaptic plasticity with lower threshold for inducing long-term potentiation (LTP) with higher amplitudes. LTP induced between the perforant path and granule cells was demonstrated to increase survival of newborn cells (Bruel-Jungerman et al., 2006). The developing period of the cells (up to 6 weeks in rodents) appear to contribute to memory formation in adult (reviewed by Deng, Aimone and Gage, 2010).



Not only mental, but physical exercises could also increase neurogenesis

There have been evidences indicating that physical exercises also improve the number of granule cells in the dentate gyrus in rodents, as well as improving cognition in humans. The induction of angiogenesis and expression of neurotrophic factors have been the likely reasons for the positive effect of exercises (reviewed by Deng, Aimone and Gage, 2010).

In addition to glutamate and GABA, a few neurotransmitters have been suggested to participate in the proliferation of neural progenitor cells upon exercises, as summarised below. However, the direct effects of these on adult neurogenesis remain yet largely uncertain.


Beta-endorphin

Physical exercises are known to stimulate the releases of β-endorphin, which elicits full effects at μ receptors and also at δ receptors (Raynor et al., 1994; Toll et al., 1998), or just partial effect at κ receptors (Simonin et al., 1995; Yasuda et al., 1993). Rat hippocampal progenitor cells are shown to proliferate more after β-endorphin treatment, and the proliferative effect was reversed by a μ antagonist naloxone (Persson et al., 2003). A knockout study wherein the effect of missing β-endorphin was investigated in mice showed that the proliferative effect, induced by physical exercise, decreased during the developing stage up to the 5th week of neurogenesis in the absence of β-endorphin (Koehl et al., 2008). Endogenous opioids including β-endorphin and enkephalins have been shown to up-regulate brain-derived neurotrophic factor (BDNF) notably in the DG (Zhang et al., 2006); this could be a reason contributing to the proliferative effect of β-endorphin on neural progenitor cells.

Acetylcholine

The four weeks treatment of adult rats with an acetylcholinesterase inhibitor donepezil was reported to increase proliferative cells in the dentate gyrus, and a same-length treatment with muscarinic acetylcholine receptor antagonist scopolamine showed the opposite effect. The study also revealed that the expression of phosphorylated cAMP response element binding protein (CREB) was enhanced by the former treatment whilst it was suppressed by the latter (Kotani et al., 2006). The positive actions of both muscarinic and nicotinic receptors on cell proliferation and neural differentiation, largely by increasing intracellular calcium concentration, have been documented (reviewed by Resende and Adhikari, 2009).          

Noradrenaline

A selective antagonist dexefaroxan inhibits alpha2-adrenoceptor, which is a presynaptic inhibitory autoreceptor for the noradrenaline release in the hippocampus. Although prolonged systemic treatment of rats with dexefaroxan did not affect neurogenesis in dentate gyrus, it was shown to promote survival of newborns (Rizk et al., 2006).

     

The loss of neurogenesis in neurological conditions
The process of neurogenesis is negatively affected in conditions with notable cognitive decline, including major depression and neurodegenerative diseases such as Alzheimer’s disease (reviewed by Zhao, Deng and Gage 2008; Mattson 2008). Approaches to restore neurogenesis might be beneficial for patients affected by these conditions, whilst efforts of sustaining neurogenesis may provide preventative measures.



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