This is a follow-up to my previous article wherein the neurogenesis of neurones in hippocampus was briefly described. For making a better view on this, I summarise a few characteristics of other cell types, which are derived from neural progenitor cells.
Neural progenitor cells that did not develop into neurones can become glioblasts, which are precursors of astrocytes or oligodendrocytes. These two types of cells are quite different morphologically and functionally; a common factor between the two is primarily to help neurones to function, and to facilitate neurotransmissions.
Astrocytes support neuronal survival and synaptic transmissions
Astrocytes are relatively large cells with sponge-like appearance, extending multiple dendritic protrusions which display finely intricate branching patterns. Astrocytes can be found between blood vessels and neurones, or by synapses.
Basic Role 1: Astrocytes As a Crucial Supplier to Neurones
At blood vessels, astrocytes participate in forming the blood-brain barrier, which selectively takes necessary substances from the circulation into the brain. It sieves out larger and charged molecules sufficiently, but lipophilic substances (e.g. alcohol, synthetic lipid-soluble compounds) that permeate through the cell membranes cannot be excluded by this mechanism; hence such substances elicit central effects.
The blood also carries glutamate, an excitatory neurotransmitter, to the brain. In order to avoid neurones to get excited unnecessarily, neurones do not make a direct contact with the blood vessels. Astrocytes can collect glutamate via glutamate transporters (EAAT1-3) and convert that to a less excitable glutamine.
Glucose, the energy source, is also carried in the blood. Astrocytes collect glucose from the blood using their glucose transporter (GLUT1), and give much of that to energy-intensive neurones after converting it to lactate, which is readily utilisable in ATP synthesis.
Basic Role 2: The Synapses Are Protected by Astrocytes
At synapses, glutamate needs to be removed soon after the transmission, for not only a prolonged excitation cause seizures and paralysis by hyper-activating neurones, an excessive excitation could destroy neurones. The availability of glutamate at synapses therefore needs a close monitoring: astrocytes do this by collecting excess glutamate.
Q&A: G-Protein Couple Receptors and Calcium Oscillation in Astrocytes
The roles of astrocytes mentioned above are important for neurones to function, but the story does not stop there. Astrocytes in fact express various receptors for neurotransmitters including: adenosine triphosphate (ATP), serotonin (5-HT), acetylcholine (ACh), noradrenaline, histamine, dopamine and glutamate. Why do astrocytes have them, and what are they for? These receptors (GPCRs) raise intracellular calcium concentration by releasing calcium stored within the cells.
Then, do astrocytes release transmitters via synaptic vesicles like neurones, responding to the raised intracellular calcium concentration?
- They do, though such events may not be as major as in neurones; they don’t seem to have an obvious active zone at which dense vesicles accumulate as typically seen in the terminal of pre-synaptic neurones.
- They certainly do: there have been several evidences (1) indicating astrocytes release glutamate in calcium-dependent manner.
Release to where? How would that be useful?
- Astrocytes and neurones are known to form altogether a tripartite synapse comprising pre- and post-synaptic neurones, and peri-synaptic astrocytes. Astrocytes thereto release “gliotransmitter” in support of neurones, as well as protecting them by collecting excess excitatory neurotransmitters.
What on earth is gliotransmitter?
- In the tripartite synapse, astrocytes respond to presynaptic neurones, and release transmitters including glutamate, ATP, prostaglandin E2, and D-serine, in facilitating neuronal activity and synaptic transmission. The term gliotransmitter is used to distinguish the cellular origin of these chemical transmitters at the synapse.
Right, pre-synaptic neurones send signals to astrocytes: is that why the astrocytes have various GPCRs for neurotransmitters?
- I should think so. There is an evidence that exogenous ATP or ACh can increase the astrocytes interconnecting, but not via glutamate (1). Let us move onto see how their interconnection is important, in the next subsection.
Q&A: Gap Junctions and Calcium Oscillation in Astrocytes
Astrocytes can communicate with neighbouring cells by exchanging chemical substances through small gaps between them, known as gap junction. Astrocytes send inter-cellular calcium signalling via gap junctions; by doing that, the signal of calcium oscillation can spread widely across the cells.
Yes, they say that calcium ions propagate waves inside cells and make oscillatory changes. Can you tell us what’s behind the oscillation with a few numbers?
- At resting conditions, intracellular calcium concentration is kept very low, about the ratio of 1:10,000 relative to the extracellular concentration. Upon stimulation, the intracellular concentration is raised by: the release of intracellular storage via certain GPCRs of which action opens IP3 receptors (IP3R) on the endoplasmic reticulum (ER) that stores calcium; and/or by calcium influx via ionotropic channels. The ER also has ryanodine receptor (RyR) which opens at higher calcium concentration. The intracellular calcium concentration is increased from ≈ 0.3 μM until it reaches about 1μM. The activity of phospholiapase C (PLC), which generates IP3, is up-regulated by calcium at its concentration over 100 nM; PLC also activates protein kinase C (PKC) that down regulates PLC. The numbers mentioned here refer to studies on smooth muscle cells (2). The phenomena is IMPOSSIBLE to be described satisfactory in a paragraph….
Let’s not neglect our subject, astrocytes. Is there anything identified to participate in mediating calcium waves in astrocytes?
- Astrocytes need to release ATP when propagating long-range calcium signals. PLC activation causes ATP release from astrocytes (3) and the released ATP to neighbouring cells activates their P2Y receptors (4) which activates PLC, and so it carries on. ATP is an important gliotransmitter between astrocytes through gap junction, as well as at the synaptic cleft between them and neurones.
Let’s carry on talking about another gliotransmitter.
- I’ll mention another one briefly in the next section, with a reference to learning process.
In Learning and Memories: Astrocytes facilitate neuronal transduction
Astrocytes can convert natural L-serine to unnatural D-serine, which is released as a gliotransmitter. D-serine increases calcium permeability of ionotropic glutamate NMDA receptors upon glutamate activation. As mentioned in my previous post (9th.Mar.11), young neurones start responding to glutamate excitatory signal via NMDA receptors with a pronounced responsiveness of long-term potentiation (LTP). These events initiated by calcium propagations do not readily cease, for various intracellular events leading to cellular changes and reorganisation are then processed; calcium signals are thereby crucial in synaptic plasticity, responsible in memory formation.
Oligodendrocytes increases the rate of neuronal conductances
The another type of glial cells, oligodendrocytes are large cells with several elongated protrusions, which can wrap around axon fibres to insulate them with regular intervals: this increases the late of axonal conductance enormously, as well as providing physical protection to the fine axon fibres. A single oligodendrocyte can wrap around (i.e. myelinate) separately each axon extended from a set of neurones that propagate simultaneously; this keeps the integrity of the neuronal activity as this allows neurones to be stay closer as a set of bundles. In this way, oligodendrocytes participate in maintaining coordinated brain networks.
It has been said that learning certain tasks, such as playing a musical instrument, could increase the thickness of the sheath extended from oligodendrocytes; but this might need more verification.
Recently, GPR17, which is a dual receptor for uracil nucleotides and cysteinyl-leukotrienes, was shown to be crucial in the maturation of myelinating oligodendrocytes, and the ligands to the receptor are potential regulators upon them under the normal condition and during myelin repair (5). Oligodendrocytes can also communicate with neurones by means of ATP (6).
Concluding remarks
Glial cells have been underestimated unsung heroes for a very long time. They deserve to be studied more.
R e f e r e n c e s
(1) Several research articles have been published over years by Dr. Philip G. Haydon and co-workers, regarding the function of metabotropic glutamate receptors in astrocytes.
(2) Summarised in a review article by Iino M, 2010. Spatiotemporal dynamics of Ca2+ signaling and its physiological roles. doi:10.2183/pjab.86.244.
(3) Wang Z, Haydon PG, Yeung ES. 2000. Direct observation of calcium-independent intercellular ATP signaling in astrocytes. Analytical Chemistry 72:2001–2007.
(4) Fam SR, Gallagher CJ, Salter MW. 2000. P2Y(1) purinoceptor-mediated Ca(2+) signaling and Ca(2+) wave propagation in dorsal spinal cord astrocytes. The Journal of Neuroscience 20:2800–2808.
(5) Fumagalli M. et al., 2011. J. Biol. Chem. http://www.jbc.org/cgi/doi/10.1074/jbc.M110.162867
(6) Please find several papers published by a group of Dr. R. Douglas Fields.
F u r t h e r R e a d i n g s
Neuroglia, 2nd Ed. Eds. Kettenmann H., Ransom B.R., Oxford Press. 2005.
A lovely book on my wish list. Expensive, but it definitely worths the cost. Beautiful.
The Root of Thought. Koob A. FT Press. 2009.
An affordable popular science book for casual read.
Thursday, 17 March 2011
Friday, 4 March 2011
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
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.
References
Ben-Ari Y. et al., 2007. GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations. Physiol. Rev. 87: 1215-1284.
Bruel-Jungerman E. et al., 2006. Long-Term Potentiation Enhances Neurogenesis in the Adult Dentate Gyrus. The Journal of Neuroscience 26: 5888 –5893.
Deng W., Aimone J.B. & Gage F.H. 2010. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11: 339–350.
Koehl M. et al., 2008. Exercise-induced promotion of hippocampal cell proliferation requires β-endorphin. FASEB 22: 2253-2262.
Kotani S. et al., 2006. Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience 142: 505-514.
Mattson M.P. 2008. Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease. Ann. N. Y. Acad. Sci. 1144: 97–112.
Persson, A.I. et al., 2003. Opioid-induced proliferation through the MAPK pathway in cultures of adult hippocampal progenitors. Mol. Cell. Neurosci. 23: 360-372.
Rapanelli M., Frick L.R. & Zanutto B.S., 2011. Learning an Operant Conditioning Task Differentially Induces Gliogenesis in the Medial Prefrontal Cortex and Neurogenesis in the Hippocampus. PLoS ONE 6: e14713.
Resende P.R. & Adhikari A., 2009. Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation. Cell Communication and Signaling. 7: 20 BioMed Central.
Rizk P. et al., 2006. The alpha2-adrenoceptor antagonist dexefaroxan enhances hippocampal neurogenesis by increasing the survival and differentiation of new granule cells. Neuropsychopharmacology 31: 1146-1157.
Raynor K. et al., 1994. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol. Pharmacol. 45: 330-334.
Simonin F. et al., 1995. K-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc. Natl. Acad. Sci. U S A, 92: 7006-7010.
Toll L. et al., 1998. Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res. Monogr. 178: 440-466.
Yasuda K. et al., 1993. Cloning and functional comparison of κ and δ opioid receptors from mouse brain. Proc. Natl. Acad. Sci. USA, 90: 6736-6740.
Zhao C., Deng W., & Gage F.H. 2008. Mechanisms and functional implications of adult neurogenesis. Cell 132: 645–660.
Zhang H. et al., 2006. Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects. Eur. J. Neurosci. 23: 984–994.
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.
References
Ben-Ari Y. et al., 2007. GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations. Physiol. Rev. 87: 1215-1284.
Bruel-Jungerman E. et al., 2006. Long-Term Potentiation Enhances Neurogenesis in the Adult Dentate Gyrus. The Journal of Neuroscience 26: 5888 –5893.
Deng W., Aimone J.B. & Gage F.H. 2010. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11: 339–350.
Koehl M. et al., 2008. Exercise-induced promotion of hippocampal cell proliferation requires β-endorphin. FASEB 22: 2253-2262.
Kotani S. et al., 2006. Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience 142: 505-514.
Mattson M.P. 2008. Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease. Ann. N. Y. Acad. Sci. 1144: 97–112.
Persson, A.I. et al., 2003. Opioid-induced proliferation through the MAPK pathway in cultures of adult hippocampal progenitors. Mol. Cell. Neurosci. 23: 360-372.
Rapanelli M., Frick L.R. & Zanutto B.S., 2011. Learning an Operant Conditioning Task Differentially Induces Gliogenesis in the Medial Prefrontal Cortex and Neurogenesis in the Hippocampus. PLoS ONE 6: e14713.
Resende P.R. & Adhikari A., 2009. Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation. Cell Communication and Signaling. 7: 20 BioMed Central.
Rizk P. et al., 2006. The alpha2-adrenoceptor antagonist dexefaroxan enhances hippocampal neurogenesis by increasing the survival and differentiation of new granule cells. Neuropsychopharmacology 31: 1146-1157.
Raynor K. et al., 1994. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol. Pharmacol. 45: 330-334.
Simonin F. et al., 1995. K-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc. Natl. Acad. Sci. U S A, 92: 7006-7010.
Toll L. et al., 1998. Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res. Monogr. 178: 440-466.
Yasuda K. et al., 1993. Cloning and functional comparison of κ and δ opioid receptors from mouse brain. Proc. Natl. Acad. Sci. USA, 90: 6736-6740.
Zhao C., Deng W., & Gage F.H. 2008. Mechanisms and functional implications of adult neurogenesis. Cell 132: 645–660.
Zhang H. et al., 2006. Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects. Eur. J. Neurosci. 23: 984–994.
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