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references.txt
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[#Horton:2005]: Horton, J. C. and Adams, D. L. (2005). The cortical column: a structure without a function, Philos Trans R Soc Lond B Biol Sci, 360(1456), 837-62
<!-- Technical references -->
[#Lucas:1981]: B.D. Lucas and T. Kanade, “An Iterative image registration technique with an application to stereo vision”, in International Joint Conference on Artificial Intelligence, pp. 674-697, 1981.
[#Dollar]: P. Dollár, Piotr’s Image and Video Matlab Toolbox,
http://vision.ucsd.edu/~pdollar/toolbox/doc/index.html
<!-- 2014-07-11 09:25:18 -->
[#Kobayashi:1963]: Kobayashi, T. (1963). Brain-to-body ratios and time of maturation of the mouse brain, Am J Physiol, 204(), 343-6

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wholeBrain_main.md
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# Introduction
Brain development requires neural activity and calcium dynamics for establishing proper circuit structure and function. The importance of neural activity in the prenatal and neonatal period can be easily recognized in children exposed to chemical agents affecting neurotransmission during the fetal period that result in severe brain malformations, epilepsy, and mental retardation. Indeed, embryonic limb movements in species ranging from chick to human are thought to be initiated by spontaneous motor neuron activity in the spinal cord and thought to be crucial for activity-dependent development of motor synapses [Schoenberg:2003] [Marder,Lichtmann]. However it is only recently that we have begun to appreciate the underlying patterns of persistent neural activity that exist in the developing brain in vivo. For example, sensori-motor feedback associated with spontaneous movement generated by spinal motor neurons triggers synchronized 'spindle-burst' potentials among cells in somatosensory cortex [Yang:2009][Khazipov:2004a] before the start of locomotion and tactile behavior. Correlated bursts of activity occur in the developing rat hippocampus in vivo [#Leinekugel:2002] [Mohns&Blumberg]. Spontaneous retinal waves drive patterned activation of circuits throughout the immature visual system before the onset of vision [#Ackman:2012] [Hanganu,Colonnese?]. Furthermore, prenatal EEG recordings have demonstrated spindle burst oscillations and slow activity transients in the human infant somatosensory and occipital cortices before birth [#Vanhatalo:2005][#Tolonen:2007]. However, a comprehensive account of the dynamical patterns of persistent activity across the developing isocortex in vivo has not been undertaken, largely because a method to assess neural activity between most cortical areas simultaneously and non-invasively has not been available.
Brain development requires neural activity and calcium dynamics for establishing proper circuit structure and function. The importance of neural activity in the prenatal and postnatal period can be easily recognized in children exposed to chemical agents affecting neurotransmission during the fetal period that result in severe brain malformations, epilepsy, and mental retardation. Indeed, embryonic limb movements in species ranging from chick to human are thought to be initiated by spontaneous motor neuron activity in the spinal cord and thought to be crucial for activity-dependent development of motor synapses [Schoenberg:2003] [Marder,Lichtmann]. However it is only recently that we have begun to appreciate the underlying patterns of persistent neural activity that exist in the developing brain in vivo. For example, sensori-motor feedback associated with spontaneous movement generated by spinal motor neurons triggers synchronized 'spindle-burst' potentials among cells in somatosensory cortex [Yang:2009][Khazipov:2004a] before the start of locomotion and tactile behavior. Correlated bursts of activity occur in the developing rat hippocampus in vivo [#Leinekugel:2002] [Mohns&Blumberg]. Spontaneous retinal waves drive patterned activation of circuits throughout the immature visual system before the onset of vision [#Ackman:2012] [Hanganu,Colonnese?]. Furthermore, prenatal EEG recordings have demonstrated spindle burst oscillations and slow activity transients in the human infant somatosensory and occipital cortices before birth [#Vanhatalo:2005][#Tolonen:2007]. However, a comprehensive account of the dynamical patterns of persistent activity across the developing isocortex in vivo has not been undertaken, largely because a method to assess neural activity between most cortical areas simultaneously and non-invasively has not been available.
# Results
## Ongoing activity in developing neocortex is characterized by discrete domains
We performed transcranial optical recordings from mice expressing the genetic calcium reporter GCaMP (GCaMP3 or GCaMP6) throughout cortical neurons to assess neural population activity patterns with high spatial resolution and at macroscopic scale. We performed our recordings in three age groups: P2-P5, P8-P9, and P12-13. Functional mesoscale optical imaging (fMOI) revealed that supracellular cortical activity patterns were characterized by discrete domains of activation (Fig. 1) [Supplementary Movie 1](../wholeBrain_blob/ackmanWholeBrainGcampP3.mov) during the first two postnatal weeks. These activity domains ranged from 200-800 µm in diameter (*Ns*, *fig*), with larger sized domains of activation in the visual cortex and motor cortex (*Ns*, *fig*). In the second postnatal week the size of cortical activity domains became larger in the frontal-motor and S1-limb/body regions [Supplementary Movie 2](../wholeBrain_blob/ackmanWholeBrainImaging-lo.mov).
We performed transcranial optical recordings from mice expressing the genetic calcium reporter GCaMP (GCaMP3 or GCaMP6) throughout cortical neurons to assess neural population activity patterns with mesoscopic spatial and temporal resolutions (10s of microns and 100s of milliseconds) at macroscopic scale (millimeters). We performed our recordings in three age groups during the first two postnatal weeks during which the mouse brain develops to >90% of its adult weight [#Kobayashi:1963]: P2-P5, P8-P9, and P12-13. Functional mesoscale optical imaging (fMOI) revealed that supracellular cortical activity patterns were characterized by discrete domains of activation (Fig. 1a-c) [Supplementary Movie 1](../wholeBrain_blob/ackmanWholeBrainGcampP3.mov). These activity domains ranged from 147 - 735 µm in diameter <!--(median ± 2MAD)--> (Table 1.) (*Ns*, *fig*) and , with larger sized domains of activation in the visual cortex and motor cortex (*Ns*, *fig*). In the second postnatal week the size of cortical activity domains became larger in the frontal-motor and S1-limb/body regions [Supplementary Movie 2](../wholeBrain_blob/ackmanWholeBrainImaging-lo.mov).
The duration of domain activations was not significantly affected by age (F = 0.933, p = 0.428, r^2 = 0.00567) or by hemisphere (F = 0.017, p = 0.900) (P2-5, N = 15653; P8-9, N = 70189; P12-13, N = 120214 domains) (Fig. 1e,f).
@@ -30,9 +30,9 @@ There was a significant effect of age on the diameter of cortical domain activat
Cortical calcium domain frequency significantly increased with age (F = 29.562, p = 8.86e-12, r^2 = 0.2535) and did not differ significantly between the hemispheres (F = 0.012, p = 0.911) (P2-5, N = 22; P8-9, N = 30; P12-13, N = 38 movies/hemi) (Fig. 1i,j).
The neocortex exhibits a characteristic columnar organization by cortical macrocolumns tiled across the cortical surface that reflects a such that vertical arrays of cells concerned with specific sensory features are grouped together as columns [#Mountcastle:1997] in a topographic fashion. Most evidence to date suggests that cortical macrocolumns are 300-800µm diameter across species [mountcastle ref].
The neocortex exhibits a characteristic modular organization across the cortical surface such that vertical arrays of cells concerned with specific sensory features are grouped together as columns in a topographic fashion [#Mountcastle:1997]. Most evidence to date suggests that cortical columns range from 300-600µm diameter, even between species whose brain volumes differ by a factor of 10^3 [#Mountcastle:1997].
We parcellated the brain into distinct anatomical boundaries by using reference coordinates from a mouse line that expressed the tdtomato reporter in thalamocortical afferents. The expression can be used to parcellate out areal boundaries of primary sensory cortical areas (wong riley 1979). We matched these parcellations to a Allen brain atlas adult mouse reference image and than linearly scaled the remaining parcellations in our FOV on to the images of our recordings that contain fucntional boundaries (like in the domain centroid activation plot and in the normalized domain frequency plots).
We parcellated the brain into distinct anatomical boundaries by using reference coordinates from a mouse line that expressed the tdtomato reporter in thalamocortical afferents (Fig. 1c,d). Patterns of thalamocortical axon terminal can be used to parcellate out areal boundaries of primary sensory cortical areas [wong riley 1979]. We matched these parcellations to a Allen brain atlas adult mouse reference image and than linearly scaled the remaining parcellations in our FOV on to the images of our recordings that contain functional boundaries (like in the domain centroid activation plot and in the domain frequency maps).
There were longer activations on the order of seconds to tens of seconds in visual cortex driven by retinal waves [#Ackman:2012]. Long lasting wave-like activations also occured in motor cortex P2-5 (Fig 2 montage).
@@ -40,11 +40,11 @@ There were longer activations on the order of seconds to tens of seconds in visu
| | duration (s) | diameter (µm) | frequency (hemisphere-min^-1) |
| ------ | ------------ | ----------------- | ----------------------------- |
| P2-5 | 0.8 ± 0.4 | 441.12 ± 147.04 | 30.90 ± 9.55 |
| P8-9 | 0.6 ± 0.2 | 569.78 ± 220.56 | 98.35 ± 27.60 |
| P12-13 | 0.4 ± 0.2 | 1047.66 ± 367.60 | 147.80 ± 78.65 |
| P2-5 | 0.8 (0.4) | 441.12 (147.04) | 30.90 (9.55) |
| P8-9 | 0.6 (0.2) | 569.78 (220.56) | 98.35 (27.60) |
| P12-13 | 0.4 (0.2) | 1047.66 (367.60) | 147.80 (78.65) |
| Notes: Values are reported as medians ± median absolute deviation ||||
| Notes: Values are reported as medians (median absolute deviation) ||||
[ **Table 1: Domain statistics**]
@@ -136,7 +136,7 @@ Anesthetized Rx-Cre:GCaMP3 or SNAP25-GCaMP6 mice between postnatal day 2 to 13 (
**Acknowledgements** We thank Y. Zhang for technical support. We would like to thank members of the Crair lab for valuable comments on the manuscript. This work was supported by NIH grants P30 EY000785, R01 EY015788 to M.C.C. M.C.C. also thanks the family of William Ziegler III for their support.
**Author Contributions** J.B.A. and M.C.C. designed the experiments. J.B.A. performed in vivo imaging experiments, wrote the movie and data analysis code, and analyzed the recordings. H.Z. created the GCaMP3 and GCaMP6 mouse lines. J.B.A. and M.C.C. wrote the manuscript.
**Author Contributions** J.B.A. and M.C.C. designed the experiments. J.B.A. performed in vivo imaging experiments, wrote the image processing and data analysis code, and analyzed the recordings. H.Z. created the GCaMP3 and GCaMP6 mouse lines. J.B.A. and M.C.C. wrote the manuscript.
**Author Information** Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to J.B.A. (james.ackman@gmail.com) or M.C.C. (michael.crair@yale.edu).