The Development of Circadian Rhythms in Human Infants

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The Development of Circadian Rhythms in Human Infants Desaline Veronica Joseph Abstract Introduction The first four postnatal months, for a newborn infant, is a period of rapid adaptation and change. Infants undergo a series of integrated physiological changes that culminate in mature physiological diurnal rhythms by which they establish equilibrium with the new environment, all of which are under the genetic control of the biological clock. This is a longitudinal study of 35 infants in which the age related changes in physiology, are assessed during night time sleep and related to circadian genes, melatonin and cortisol. Aim The aim of the study is to monitor the physiological development of normal full-term human infants concomitantly assessing the expression of circadian genes. Method Full term healthy infants were selected. Infants were recruited into the study from 6 weeks until 18 weeks of age. Fortnightly home visits were conducted in which the overnight deep body temperature of infants was monitored. On each night of study, actigraphy was used to study infant and maternal sleep. Longitudinal measurements of melatonin and cortisol secretion by paired day-night urine collection and peripheral gene expression using buccal swabs were taken by mothers. Results There is evidence of a sequential and ordered development of circadian rhythms in human infant physiology. There was a temporal relationship demonstrated in the maturation of the infant circadian rhythms. Core body temperature demonstrated a robust rhythm, characterised by an abrupt change, the timing of which varied from infant to infant. Night time melatonin secretion increased with age. Cortisol played a key role. Infant sleep improved with physiological maturation. A number of complex relationships between aspects of the physiology and circadian gene expression were elucidated. Conclusion There is a demonstrable integration of genetic and physiological changes, during the immediate postnatal period when infants are most vulnerable to illnesses and particularly to sudden and unexpected death.
Table of Contents LIST OF FIGURES ...................................................................................................................................... ii LIST OF TABLES ........................................................................................................................................ iv 1 INTRODUCTION ...................................................................................... 1 1.1 Introduction ..................................................................................................... 1 1.2 Physiological Development in Humans .......................................................... 4 1.3 Circadian Rhythms .......................................................................................... 8 1.3.1 Detection of Rhythm .............................................................................. 12 1.3.2 Exogenous and Endogenous Rhythm .................................................... 12 1.4 Ontogeny in Human Infants .......................................................................... 13 1.5 Temperature .................................................................................................. 13 1.5.1 The Mechanism of Thermal Regulation ................................................ 14 1.5.2 Circadian Rhythms in Temperature ....................................................... 15 1.5.3 Ontogeny of Temperature Control ......................................................... 16 1.5.4 Factors affecting Temperature Control .................................................. 17 1.6 Melatonin ...................................................................................................... 19 1.6.1 Production and Regulation of Melatonin Secretion ............................... 19 1.6.2 Actions of Melatonin ............................................................................. 20 1.6.3 Circadian Pattern of Melatonin Production ........................................... 21 1.6.4 Ontogeny of Melatonin Secretion .......................................................... 22 1.6.5 Factors affecting Melatonin Secretion ................................................... 23 1.7 Cortisol .......................................................................................................... 25 1.7.1 Production and Regulation of Cortisol Secretion .................................. 25 1.7.2 Actions of Cortisol ................................................................................. 26 1.7.3 Circadian pattern of Cortisol Secretion .................................................. 27 1.7.4 Ontogeny of Cortisol Secretion ............................................................. 27 1.7.5 Factors Affecting Cortisol Secretion ..................................................... 30 1.8 Sleep .............................................................................................................. 32 1.8.1 Functions of Sleep .................................................................................. 35 1.8.2 Regulation of Sleep ................................................................................ 36 1.8.3 Ontogeny of Sleep in Infants ................................................................. 37 1.8.4 Measurement of Sleep ............................................................................ 39 1.9 Central clock genes ....................................................................................... 44 1.9.1 The Master Clock – The Suprachiasmatic nucleus ................................ 44 1.9.2 Peripheral Clock ..................................................................................... 45 1.9.3 Molecular Components of the Clock ..................................................... 49 1.9.4 Clock Input ............................................................................................. 52 1.9.5 Clock Output .......................................................................................... 52 1.9.6 Cortisol and the Clock ........................................................................... 52 1.9.7 Melatonin and Clock .............................................................................. 53 1.9.8 Temperature and the Clock .................................................................... 54 2 METHODS ............................................................................................58 2.1 Overview of recruitment for study ................................................................ 58 I
Page 1: The Development of Circadian Rhythm
Page 5 and 6: 7.1 Analysis of infant sleep measur
Page 7 and 8: List of Figures Figure 1.1 - Diagra
Page 9 and 10: List of Tables Table 3.1 - Descript
Page 11 and 12: 1 Introduction Happiness is not a m
Page 13 and 14: Each of these independently is impo
Page 15 and 16: There is general agreement, that al
Page 17 and 18: Summary 1. Development encompasses
Page 19 and 20: Figure 1.1 - Diagram illustrating c
Page 21 and 22: A phase shift is used to describe a
Page 23 and 24: 1.4 Ontogeny in Human Infants Well
Page 25 and 26: 1.5.2 Circadian Rhythms in Temperat
Page 27 and 28: 1.5.4 Factors affecting Temperature
Page 29 and 30: 1.6 Melatonin (Reviewed in Cardinal
Page 31 and 32: mechanism by which this occurs is n
Page 33 and 34: It is at this time that infant slee
Page 35 and 36: 1.7 Cortisol Cortisol is a hormone,
Page 37 and 38: 1.7.3 Circadian pattern of Cortisol
Page 39 and 40: In a separate study, Weerth et al u
Page 41 and 42: Summary 1. Cortisol is crucial to a
Page 43 and 44: NREM sleep has 4 stages. It occupie
Page 45 and 46: 1.8.1 Functions of Sleep The functi
Page 47 and 48: 1.8.3 Ontogeny of Sleep in Infants
Page 49 and 50: Sleep can clearly be used as marker
Page 51 and 52: For the purpose of this study, the
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Summary 1. Sleep is defined by lack
Page 55 and 56:
Overall the SCN generates signals (
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Figure 1.2 - The mammalian circadia
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1.9.3 Molecular Components of the C
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Figure 1.3 - Mechanisms from SCN to
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1.9.7 Melatonin and Clock Melatonin
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The links between the central clock
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Chapter 2 Methods
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There were strict inclusion and exc
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This personal contact on the postna
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2.1.3 Home monitoring visits The fi
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2.1.4 Further monitoring informatio
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Core body temperature was taken sim
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2.3 Collection of urine samples Pai
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were read against air at 429 nm aft
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allowed the display and comprehensi
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2.8.1 RNA preparation and cDNA synt
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In total three methods were trialle
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2.11 Statistical methods For compar
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test that each infant‟s height an
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Power calculation Sample size: Fift
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3 Results 3.1 Recruited subjects an
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predominantly affluent areas of the
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Birth history and past medical hist
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3.1.3 Socioeconomic demographics of
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her best friend losing her battle w
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Sleep environment of infants All mo
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Summary 1. This study had higher ra
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4 Results 4.1 Core body temperature
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Degrees Celsius 36.70 36.60 36.50 3
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11-13 weeks There is no significant
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Core body temperature (degrees Cels
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Number of infants 10 8 6 4 2 0 7 8
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Mean minimum rectal temperature in
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Mean minimum rectal temperature in
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Figure 4.7 shows the changes in the
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Chapter 5 Result
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4 or 6 hourly samples. Circadian rh
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Figure 5.1 - Distribution of mean n
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5.1.2 Emergence of diurnal rhythm f
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Figure 5.3 - Histogram showing dist
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Figure 5.4 - Changes in night time
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Night-day difference in melatonin s
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Summary 1. There is an increase in
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6 Results DESCRIPTION OF THE URINAR
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6.1.2 Emergence of diurnal rhythm f
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Figure 6.3 - Histogram showing dist
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Cortisol values were corrected to a
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6.1.4 Relationship between night an
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Chapter 7 Results
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Mean Length of Sleep/ Wake Bouts Th
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Sleep parameters were recorded as m
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7.3 Development of infant sleep rel
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Figure 7.2 - Changes in infant slee
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Figure 7.4 - Changes in percentage
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Figure 7.5 - Changes in infant frag
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Figure 7.7 - Changes in number of m
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Figure 7.9 - Changes in the percent
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Sleep efficiency (%) 100.0 90.0 80.
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Chapter 8 Results
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Considering only those weeks of mea
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8.2 Description of peripheral gene
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18:30 hours 0.9927; 01:00 ours 1.01
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The weeks after temperature maturat
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Further peripheral gene graphical r
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Raw data points are represented by
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H3f3b/Gap H3f3b/Gap H3f3b/Gap H3f3b
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8.3 Detailed gene expression analys
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Summary 1. H3f3b was selected as ge
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9 Results FACTORS AFFECTING SLEEP A
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Care and infant related factors �
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Table 9.3 - Effect of family occupa
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* Class 7 used as reference group
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Table 9.6 - Effect of measured infa
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Summary: 1. A mature physiological
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10 Results 10.1 Circadian rhythms -
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value of above 0.5 for R squared wa
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Table 10.1 - Temporal relationship
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Chapter 11 Discussion
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� What if any are the factors whi
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11.1 Physiological development - ag
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There are other proven factors whic
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drawbacks of the spread of data - a
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presented in table 6.1 do not have
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separate methods were applied to th
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significant. Sleep latency was cons
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The function of sleep in developmen
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Melatonin secretion was higher on n
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In this study sleeping in the same
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Timing of sleep maturation was diff
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systematic, ordered developmental p
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individual gene plots that provide
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temperature recording devices adapt
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Both melatonin and cortisol rhythms
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Extension of this period of monitor
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Second, we demonstrated the gene of
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Cortisol and melatonin Slope based
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Summary and Future work This study
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� Maximise technique for measurin
Page 255 and 256:
“There is a science of infant car
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References
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Bajanowski, T., Vege, Å., Byard, R
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Chamley, C.A., Carson P, Randall D,
Page 263 and 264:
Frank, M.G., Heller, H.C., 2003. Th
Page 265 and 266:
intrahypothalamic administration of
Page 267 and 268:
Mirmiran, M. & Ariagno, R.L., 2000.
Page 269 and 270:
Rawson, D., Petersen, S.A., Wailoo,
Page 271 and 272:
Stokkan, K.A., Yamazaki, S., Tei, H
Page 273 and 274:
Winter, J.S.D., 1985. The adrenal c
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