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Section on Neuroadaptation
and Protein Metabolism

Brain Imaging

Functional brain imaging methods that employ quantitative autoradiography or positron emission tomography (PET) can be used to map absolute rates of well-defined physiological or biochemical processes simultaneously in all regions of the brain of the living organism. The ability to measure absolute rates is important when different individuals or groups need to be compared. This contrasts quantitative autoradiography and PET with other functional imaging methods, such as functional magnetic resonance imaging (fMRI) and laser doppler flowmetry, that determine rates relative to baseline values in each individual.

brain image

Quantitative autoradiographic methods for measuring regional cerebral blood flow (rCBF) [1] and regional cerebral glucose metabolism (rCMRglc)[2] in experimental animals map short-term changes in excitability in the nervous system. Measurements of rCBF and rCMRglc are also possible in man with PET by use of the tracers H215O [3] and the fluorine-18 labeled glucose analogue [18F]fluorodeoxyglucose [4].

14C]Deoxyglucose autoradiograms from brains of control (left) and ketamine-treated (right) rats illustrating acute changes in functional activity in regions of the limbic system in response to ketamine treatment [5].

The nervous system also responds to chronic conditions in the environment by modifying synaptic connections imbuing nervous tissue with the properties of plasticity and adaptation. Long-lasting changes in synaptic connections are dependent on protein synthesis and can be mapped by measuring rates of protein synthesis. We have developed a quantitative autoradiographic method for the measurement of regional rates of cerebral protein synthesis (rCPS) in experimental animals in vivo [6]. The method uses L [1 14C]leucine as the tracer.

brain imaging of older monkeys

[14C]Leucine autoradiograms of lateral geniculate nuclei from 25-day old monkeys illustrating effects of chronic monocular deprivation on protein synthesis rates in deprived-eye laminae [9].

We have shown that under conditions such as neural regeneration [7,8], developmental plasticity [9], normal development [10] and aging [11,12], slow-wave sleep [13], hibernation in ground squirrels [14], fragile X syndrome 15], and phenylketonurnia [16] we can measure significant effects on rCPS in experimental animals. Recently we have developed the first fully quantitative method for measurement of rCPS with PET and L-[111C]leucine [17,18,19]. This method can now be used in the study of normal human brain and in clinical medicine, where it may prove useful in the investigation of disorders of brain development, recovery from brain injury, and neurodegenerative diseases.

brain imaging

Regional rates of cerebral protein synthesis (rCPS) in awake 21 year old male (adapted from Bishu et al., 2008.) [19].

References

[1] Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L. Measurement of local cerebral blood flow with iodo[14C]antipyrine. Am J Physiol 1978, 234(1):H59-H66.

[2] Sokoloff L, Reivich M, Kennedy C, DesRosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977, 28:897-916.  

[3] Raichle ME, Martin WRW, Herscovitch P, Mintun MA, Markham J. Brain blood flow measured with intravenous H215O. II. Implementation and validation. J Nucl Med 1983, 24:790-798. 

[4] Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Casella V, Fowler J, Hoffman E, Alavi A, Som P, Sokoloff L. The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ Res 1979, 44:127-137. (return to text) 

[5] Eintrei C, Sokoloff L, Smith CB. The effects of diazepam and ketamine administered individually or in combination on regional rates of cerebral glucose utilization in rat. Brit J Anaesth 1999, 82:596-602.  

[6] Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L. Measurement of local cerebral protein synthesis in vivo: Influence of recycling of amino acids derived from protein degradation. Proc Natl Acad Sci USA 1988, 85:9341-9345.  

[7] Smith CB, Crane AM, Kadekaro M, Agranoff BW, Sokoloff L. Stimulation of protein synthesis and glucose utilization in the hypoglossal nucleus induced by axotomy. J Neurosci 1984:4:2489-2496.  

[8] Sun Y, Deibler GE, Smith CB. Effects of Axotomy of protein synthesis in the rat hypoglossal nucleus - examination of the influence of local recycling of leucine derived from protein degradation into the precursor pool. J Cereb Blood Flow Metab 1993, 13:1006-1012.  

[9] Kennedy C, Suda S, Smith CB, Miyaoka M, Ito M, Sokoloff L. Changes in protein synthesis underlying functional plasticity in immature monkey visual system. Proc Natl Acad Sci USA 1981, 78:3950-3953.  

[10] Ingvar MC, Maeder P, Sokoloff L, Smith CB. Effects of aging on local rates of cerebral protein synthesis in Sprague-Dawley rats. Brain 1985, 108:155-170.  

[11] Sun Y, Deibler GE, Jehle J, Macedonia J, Dumont I, Dang T, Smith, CB. Rates of local cerebral protein synthesis in the rat during normal postnatal development. Am J Physiol 1995, 268:R549-R561.  

[12] Smith CB, Sun Y, Sokoloff L. Effects of aging on regional rates of cerebral protein synthesis in the Sprague-Dawley rat - examination of the influence of recycling of amino-acids derived from protein degradation into the precursor pool. Neurochem Internl 1995, 27:407-416 [pdf].  

[13] Nakanishi H, Sun Y, Nakamura RK, Mori K, Ito M, Suda S, Namba H, Storch FI, Dang TP, Mendelson W, Mishkin M, Kennedy C, Gillin JC, Smith CB, Sokoloff L. Positive correlations between cerebral protein synthesis rates and deep sleep in Macaca mulatta Eur J Neurosci 1997, 9:271-279.  

[14] Frerichs KU, Smith CB, Brenner M, DeGracia DJ, Krause GS, Marrone L, Dever TE, Hallenbeck JM. Suppression of protein synthesis in brain during hibernation involves inhibition of protein initiation and elongation. Proc Natl Acad Sci USA 1998, 95:14511-14516.  

[15] Qin M, Kang J, Burlin TV, Jiang C, Smith CB. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse. J Neuroscience 2005, 25(20):5087-5095. 

[16] Smith CB, Kang J. Cerebral protein synthesis in a genetic mouse model of phenylketonuria. Proc Natl Acad Sci USA 2000, 97:11014-11019. 

[17] Schmidt KC, Cook MP, Qin M, Kang J, Burlin TV, Smith CB. Measurement of regional rates of cerebral protein synthesis with L-[1-C11]leucine and PET with correction for recycling of tissue amino acids: I. Kinetic modeling approach. .J Cereb Blood Flow Metab 2005, 25:617-628.  

[18] Smith CB, Schmidt KC, Qin M, Burlin TV, Cook MP, Kang J, Saunders RC, Bacher JD, Carson RE, Channing MA, Eckelman WC, Herscovitch P, Laverman P, Vuong B-K. Measurement of regional rates of cerebral protein synthesis with L-[1-C11]leucine and PET with correction for recycling of tissue amino acids: II. Validation in rhesus monkeys. J Cereb Blood Flow Metab 2005, 25:629-640. 

[19] Bishu S, Schmidt KC, Burlin TV, Channing MA, Conant S, Huang T-J, Liu Z-H, Qin M, Unterman A, Xia Z, Zametkin A, Herscovitch P, Smith CB. Regional rates of cerebral protein synthesis measured with L-[1-11C]leucine and PET in conscious, young adult men: normal values, variability, and reproducibility. J Cereb Blood Flow Metab 2008, 28:1502-1513.