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wholeBrain_main.md

@@ -26,7 +26,7 @@ We performed transcranial optical recordings from mice expressing the genetic ca
 
 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 250 - 976 µm in diameter and 0.4 - 2.6 s in duration <!--(10-90th percentiles)-->(Fig. 1e-h) (Table 1.) . The duration of cortical 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). There was a significant effect of age on the diameter of cortical domain activations (F = 25.788, p = 0.000188, r^2 = 0.1277), but not hemisphere (F = 0.192, p = 0.671808) (Fig. 1g,h). The frequency with which cortical domain activations occurred 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. i,j) (Table 1).
 
-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]. Its intriguing that we found the size of cortical domains to be centered on this range at early ages, because this is in agreement with previous work showing that population activity in neonatal rat barrel cortex maps onto ontogenetic modules centered on each barrel column [#Yang:2012a] and barrels are an archetypical model for columnar cortical function in rodent. Indeed, we found a cortical area in primary somatosensory cortex at P2-5 where cortical domain activations group into rows and individual modules that match primary barrel cortex structure (Fig. 1c) (Supplementary Fig.). This indicates that early cortical activity in some cortical areas is matched to the size the functional cortical modules that are thought to be the fundamental procdessing unit of the cerebral cortex. 
+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 suggests that cortical columns range from 300-600µm diameter, even between species whose brain volumes differ by a factor of 10^3 [#Mountcastle:1997]. Its intriguing that we found the size of cortical domains to be centered on this range at early ages, because this is in agreement with previous work showing that population activity in neonatal rat barrel cortex maps onto ontogenetic modules centered on each barrel column [#Yang:2012a] and barrels are an archetypical model for columnar cortical function in rodent. Indeed, we found a cortical area in primary somatosensory cortex at P2-5 where cortical domain activations group into rows and individual modules that match primary barrel cortex structure (Fig. 1c) (Supplementary Fig.). This indicates that early cortical activity in some cortical areas is matched to the size the functional cortical modules that are thought to be the fundamental procdessing unit of the cerebral cortex. 
 
 
 ![ **Figure 1.** Calcium domains throughout neonatal mouse neocortex. **a** Experimental schematic. **b** Single image frame showing calcium domains in both hemispheres at postnatal day 3 (P3) and automatically detected domain masks. **c** Centroid positions for segmented domain masks from a 10 min recording. Points are overlaid on a reference map of primary sensory areas determined by thalamocortical inputs (red outlines). Notice rows of whisker barrels are evident in the structure of domain centroid positions. **d** Functional activity map at P3. Based on pixel activation frequency from all detected domains in a single 10 min recording. Map is overlaid on cortical areal parcellations. Notice localized maxima and minima of functional activity between areas that approximate known anatomical cortical area boundaries and the mirroring of map structure bilaterally. **e** Mean domain duration maps from 3 SNAP25-Ai103 mice. **f** Histograms showing domain durations distributions in the P2-5, P8-9, and P12-13 age groups and by cortical hemisphere (L, R). **g** Mean domain diameter maps from same 3 mice in e. **h** Histograms showing the distributions of domain diameters. **i** Mean domain frequency maps from same 3 mice in e. **j** Boxplot distributions of hemispheric domain frequencies.](figure1.png)
@@ -43,20 +43,16 @@ The neocortex exhibits a characteristic modular organization across the cortical
 
 We examined how the spatiotemporal properties of cortical domains vary among different cortical regions by parcellating the brain into distinct anatomical boundaries using reference coordinates from a mouse line that expressed a tdtomato reporter in thalamocortical afferents at P7 (Fig. 1c,d) (Supplementary Fig.). Patterns of thalamocortical axon terminals can be used to map 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 cortical area reference boundaries for each animal to maps containing functional boundaries for barrel cortex and visual cortex where spontaneous retinal waves functionally map out developing visual areas [#Ackman:2012]  (Fig. 1c-e,g,i). 
 
-Cortical domain frequency among different regions scaled as a function of net cortical area and this association became stronger during the course of development (Fig. 2a). The overall frequency of activity was remarkably uniform across cortical areas at eah age of devloepment (Supplementary Fig). The most frequently cortical regions at each age group when normalized to the amount of total amount of coritcal space was the limb/trunk representations in somatosensory cortex (Fig. 1i, Supplementary Fig.). The long tails in the domain duration and diameter distributions at P2-5 adn P8-9 (Fig. 1f,h) were dominated by retinal wave driven cortical activity in V1 that lasted on the order of seconds to tens of seconds (Fig. 1e, Fig. 2b,c), but also by long lasting wave-like activations occurring in motor cortex (Fig. 1e, Fig. 2b,c). 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) (Fig. 2d). 
+Cortical domain frequency among different regions scaled as a function of net cortical area and this association became stronger during the course of development (Fig. 2a). The most frequently cortical regions at each age group when normalized to the amount of total amount of cortical space was the limb/trunk representations in somatosensory cortex (Fig. 1i, Supplementary Fig.). Generally, the frequency of activity was remarkably uniform across cortical areas at each age of development (Supplementary Fig) indicating a homeostatic mechanism regulating global activity levels. The long tails in the domain duration and diameter distributions at P2-5 and P8-9 (Fig. 1f,h) were dominated by retinal wave driven cortical activity in V1 that lasted on the order of seconds to tens of seconds (Fig. 1e, Fig. 2b,c), but also by long lasting wave-like activations occurring in motor cortex (Fig. 1e, Fig. 2b,c). Indeed the cortical regions with the highest wave motion indices were V1 and M1 at P2-5, with V1 continuing to have the highest index at P8-9 and then dropping to mean motion idx level similar to other cortical regions at P12-13. The diameter of domain activation became larger among cortical regions during the second postnatal week including the S1-limb/body regions where at P13 a small subpopulation of events had mean diameters approaching that of the entire hemisphere and a higher wave motion index (Fig. 2d-f) (x% of all events, ~2/10min) [Supplementary Movie 2](../wholeBrain_blob/ackmanWholeBrainImaging-lo.mov) (Fig. 2d). These global population events synchronized activity across cortical areas and had centers of mass that were concentrated near the middle of each hemisphere in the S1-limb/body area.
 
 
 ![ **Figure 2.** Spatiotemporal characteristics of cortical domains. **a** Domain frequency as function of cortical area size. **b** Scatterplots of domain diameter and duration. **c** Time projection color maps of waves in visual cortex and motor cortex at P5. **d** Time projection color maps of interareal activations at P13. **e** Scatterplots of wave motion index as function of domain diameter. **f** Mean wave motion index over development.](figure2.png)
 
 
 
-## Cortical domain activity is state dependent
+## Cortical domain activity is coordinated with motor behavior
 
-* Previously demonstrated that general anesthesia abolishes spontaneous activity in visual system [#Ackman:2012]. 
-* During anesthesia induction, there is rapid (<30 s) knock down of discrete domain activity (P3 mouse <120518_09.tif>) at all ages. Cingulate, retrosplenial activations the last to go-- 
-* No population calcium activity found during gen'l anesthesia in neonates. Altered spontaneous patterns in older mice.
-default mode/resting state network areas last.
-<120518_09_mjpeg.mov>
+Next we assessed mesoscale cortical activity patterns as a function of physiological state and motor behavior. It has previously been demonstrated that general anesthesia abolishes spontaneous retinal wave activity in visual system [#Ackman:2012]. We found that during anesthesia induction, there is rapid (<60 s) knock down of cortical activity (Supplementary Movie) (Supplementary Fig) at all ages. While in neonates, no cortical activity was found during general anesthesia in neonates, at P12-13 we found altered spontaneous patterns, with short duration, large diameter population activities synchronizing multiple cortical areas. (Supplementary Movie)
 
 Variation in the strength of correlation between cortical areas and the motor movement signal depended on brain region (p < 2.2e-16, anova) and age (p = 1.627e-05, anova)  The first age group in which motor cortex exhibited signficant positive correlation with motor movements was at P12-13 (r=0.06±0.02, p-value = 0.001449, t-test).