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01 October 2005

Consideration of adult neurogenesis from physiological and patho-physiologicalaspects.

Toshiyuki Saito

Med Sci Monit 2005; 11(10): LE16-17 :: ID: 430346


Dear Editor,
As Dr Taupin mentioned in the article, many papers have been published supporting the view that neural stem cells are present especially in two regions of the adult brain, the hippocampus and the subventricular zone (SVZ), and that neurogenesis occurs in these two regions.
The author comprehensively summarized in Table 1, modulation of neurogenesis in both regions under physiological and pathological conditions. However, the description may need further considerations to be well understood.
Among factors that may influence on neurogenesis in the dentate gyrus, adrenal steroids are reported to be potent regulators [1,2]. It is clearly demonstrated that repeated stress causes deleterious effects in the hippocampus of rodents and primates, and that stress and excess glucocorticoids suppress neurogenesis in the dentate gyrus [3]. The stress action of glucocorticoid is probably exerted through GR receptors [2,4,5]. In the studies for learning tasks, the animals are thought to receive training for accomplishing the task and getting a reward as well as to be exposed to novel stimuli. In these cases, dopaminergic, noradrenergic and other neuronal systems are possibly activated as well as glucocorticoids secretion. However, it is not definite whether or to what extent, neurons in the dentate gyrus are affected or exposed to stressful conditions, until the animals learn to carry the task out. The interactions remain also unclear between glucocorticoids and the dopaminergic, noradrenergic and other neurons in the dentate gyrus. If there is any factor in the experimental design and apparatus that strongly stimulates the GR receptors in the dentate gyrus, the results might be reverse, namely, decrease in neurogenesis.
In another study [6], chronic corticosterone treatment that flattens its rhythm is shown to attenuate the 5-HT[sub]1A[/sub] autoreceptor function in the hippocampus of rats, suggesting that disruption of the diurnal corticosterone rhythm may inhibit the 5-HT receptor function of the hippocampus. The authors pointed out this chronic treatment has been without raising the total daily amount of circulating corticosterone, and the possibility that GR activation varies widely over the normal diurnal variation in corticosterone levels [5,6]. This finding strongly suggests that disruption of the diurnal rhythm in the corticosterone level may be the first incident to cause functional loss in neurons of the dentate gyrus.
From a functional aspect, only a few data has been provided how neuronal properties may change by exposure to acute and chronic stress, how properties in newly generated neurons differ from those in old ones, and how new neurons make network connections with other neurons.
In the in vitro experiment [7], synaptic excitation of granule cells in the dentate gyrus may be enhanced following chronic stress exposure. This enhanced synaptic excitation may be correlated with rise in corticosterone levels. However, it is unclear whether the enhanced synaptic excitation may be a sign of pathological changes or lead to deneneration of the dentate granule cells following chronic stress exposure.
On the other hands, the properties in newly generated neurons have been examined and reported by the previous studies [8,9], indicating that young granule cells in the dentate are of the adult rat seems to exhibit robust LTP than mature granule cells, that cannot be inhibited by GABA. It is considered that young granule cells initially form few connections with other neurons, but later, they can make more new connections following certain period. Acquisition and retention of memory may be linked to formation of newly interconnection with other neurons. However, to our knowledge, few data have been issued showing clear correlation of synapse formation by newly generated granule cells with acquisition and retention of memory in the dentate cells of animals.
Adult neurogenesis is considered to be involved in physiological and pathological processes as Dr. Taupin described in the article. Newly generated neuronal cells may elicit any early sign in their properties, which leads to patho-physiological cell activities and to neuronal diseases. If such sign can be detected, development of therapeutic drugs and cell therapeutic techniques may be accelerated for inhibiting early patho-physiological neuronal activities, and for therapy to some of injured brain.

Toshiyuki Saito
Animal Neurophysiology Laboratory,
National Institute of Agrobiological Sciences,
Tsukuba 305-0901, Japan,
e-mail: [email protected]

1.Cameron HA, Gould E: Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neurosci, 1994; 61: 203–9
2.Ron de Kloet E, Joels M, Holsboer F: Stress and the brain: from adaptation to disease. Nat Rev Neurosci, 2005; 6: 463–75
3.Sandi C: Stress, cognitive impairment and cell adhesion molecules. Nat Rev Neurosci, 2004; 5: 917–30
4.Sapolsky RM, Romeo LM, Munck AU: How do glucocorticoids influence stress responses ? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine Rev, 2000; 21: 55–89
5.Reul JM, de Kloet ER: Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinol, 1985; 117: 2505–11
6.Leitch MM, Ingram CD, Young AH et al: Flattening the corticosterone rhythm attenuates 5-HT[sub]1A[/sub] autoreceptor function in the rat: relevance for depression. Neuropsychopharmacol, 2003; 28: 119–25
7.Karst H, Joels M: Effect of chronic stress on synaptic currents in rat hippocampal dentate gyrus neurons. J Neurophysiol, 2003; 89: 625–33
8.Wang S, Scott BW, Wojitowicz JM: Heterogenous properties of dentate granule neurons in the adult rat. J Neurobiol, 2000; 42: 248–57
9.Snyder JS, Kee N, Wojtowicz JM: Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J Neurophysiol, 2001; 85: 2423–31

Keywords: Brain - physiopathology, Glucocorticoids - secretion, Nervous System Physiological Phenomena, Receptor, Serotonin, 5-HT1A - physiology, Receptors, Glucocorticoid - physiology, Stem Cells - cytology

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750