15 KiB
Author: James B. Ackman
Date: 2013-09-04 10:54:02
Tags: paper, draft, manuscript, literature, research, #results, retinal waves, spontaneous activity, development, calcium domains
Structured population activity across developing isocortex
Structured neural activity across developing cerebral hemispheres
Mesoscale mapping of neural activity across developing cerebral hemispheres
Abstract
The cerebral cortex exhibits spontaneous and sensory evoked patterns of activity during fetal and postnatal development that are crucial for the activity-dependent formation and refinement of circuits [#Katz:1996]. Knowing the source and flow of these activity patterns locally and globally is crucial to understanding self-organization in the developing brain. Here we show that neural population activity within newborn mice in vivo is characterized by spatially discrete domains that are coordinated in a state dependent and areal dependent fashion throughout developing isocortex. Whole brain optical recordings from neonatal mice expressing a genetic calcium reporter showed that ongoing activity in the cerebral cortex was characterized by discrete and repetitively active domains measuring hundreds of microns in diameter. Cortical domain activity depended on brain state with periods of localized and global domain synchrony exhibiting positive and negative correlations to motor behavior respectively. Furthermore, domain activity exhibited mirror-symmetric patterns between the hemispheres, with strong correlations between cortical areas that correspond to the default-mode network in primates. This study provides the first comprehensive description of population activity in the developing isocortex at a scope and scale that bridges the microscopic or macroscopic spatiotemporal resolutions provided by traditional neurophysiological or neuroimaging techniques. Mesoscale maps of cortical population dynamics within animal models will be vital to engineering future repair strategies and brain-machine interfaces for neurodevelopmental disorders.
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 has been recognized in chick to human and is 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 in fact 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 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 structural dynamics of persistent activity throughout the developing isocortex in vivo has not been undertaken.
- Neural activity, drugs, and birth defects
- epilepsy
- autism
- What is the activity?
- instructive or permissive?
- leinekukel and khazipov work [#Leinekugel:2002][#Khazipov:2004a]
- ucla konnerth imaging work [#Golshani:2009][#Adelsberger:2005]
- human occipital cortex and retinal wave paper [#Vanhatalo:2005][#Tolonen:2007][#Ackman:2012]
- To understand the informational capacity of neural activty in the developing brain, the structural dynamics of persistent activity must be understood.
- completely random? Organized in space and time, and at what scale?
- previous work on interneuron migration, axon growth (olavarria work) synaptic formation, and anatomical studies indicates significant development decisions are being made in first postnatal week
Results
Ongoing activity in the developing cerebral cortex is characterized by discrete domains
- Cortical column (mini/meso/super columns) history (20th century anatomists-- sherrington, valverde, rakic, etc).
- Column physiology-- Hubel and Wiesel. Rodent V1?
- Developmental studies-- fetal monkey ODCs.
- Rodent barrels (early anatomical emergence from TC input, functional/physiological emergence?).
- What is known about columns/domains in secondary/association/non-primary sensory representations? Rest of rodent S1 (non-barrel cortex?).
- Calcium domains of Yuste, Science 1992 paper. [#Yuste:1992]
- Other slice calcium recordings, patch/gap junctions. In vivo physiology? (Not too many multisite electrode recordings in cortex, spatial resolution issue).
- Calcium imaging-- Konnerth 'waves' in Ent cortex [#Adelsberger:2005]. For visual cortex, domains activity in extrastriate cortex (Ackman Nature 2012). But S1-- [#Golshani:2009] work in later postnatal-- but activity not obeying domains in barrel cortex-- problem with spatial sampling in the xy and the z for this study?
| metric | mean | min | max | unit |
|---|---|---|---|---|
| diameter | 396.0 | 22.7 | 2383.5 | µm |
| duration | 0.6 | 0.2 | 14.6 | s |
| frequency | 2.9 | domains/sec/hemisphere | ||
| [Table 1: Domain statistics] |
Cortical domain activity is state dependent
- EEG slow oscillations not detectable until P10 in rodent.
- Previously demonstrated that general anesthesia abolishes spontaneous activity in visual system [#Ackman:2012].
- What about ongoing activity in other cortical areas during early brain development? Surgical procedure relevance.
- No population calcium activity found during gen'l anesthesia, only slow traveling waves.
- During anesthesia induction, rapid (<30 s) knock down of discrete domain activity (P3 mouse <120518_09.tif>). Cingulate, retrosplenial activations the last to go-- default mode/resting state network areas last. <120518_09_mjpeg.mov>
Conclusions: The two hemispheres seem to be mostly synchronized, though it’s possible the R hemispshere (which is also the slightly more ‘active’ hemisphere, see stats table below) leads the left by a bit. The asymmetric peak at –150–175frames is interesting. That would be about 30–35 sec.
The big secondary peaks around ±30 sec is present in both autocorrs and xcorrs and is far above the random normal xcorr baseline (blue trace). In fact there is a periodicity seen in the autocorrs and the xcorrs where there is a dampening oscillation about on this interval! (See ideal dampening frequency in random sine wave example above). This corresponds to a 1/30sec == 0.033 Hz ultra-slow oscillation.
Looking at the above plot showing lags from [–1000, 1000] frames which is ± 200 s, we can see about 5.5 cycles of this underlying dampening oscillation in both autocorr plots. This corresponds to (1000fr*0.2sec/fr)/5.5 => 36.36 sec/cycle => 0.0275 cycles/sec or ~0.03 Hz
Percentage of cortical activity which exhibits corr with motor signal?
| lenActvFraction>0 | fracCorr | timeCorr_s | fracCorrPos | timeCorrPos_s | fracCorrNeg | timeCorrNeg_s |
|---|---|---|---|---|---|---|
| 2161 | 0.30032 | 129.8 | 0.27441 | 118.6 | 0.025914 | 11.2 |
Cortical activity is mirrored between the hemispheres
- Inter hemispheric functional connectivity, importance for autism, schizophrenia. Maybe an activity-dependent mechanism for commisural connectivity.
- olavarria work, evidence for inter hemispheric activity dependence
- [#Hanganu:2006], 30% of spindle bursts correlated across hemispheres
- Activity correlated in anterior-posterior and medial-lateral directions
- Mirror symmetric and non-mirror symmetric patterns
- Regional effects, more corr anticorr in certain regions?
- State dependent corr?
| xy pearson corr coef ML | xy pearson corr coef AP |
|---|---|
| p = 1.1591e-28 | p = 7.0982e-07 |
| scatterplots in figure 3 |
Conclusions: So the activity in both hemispheres at postnatal day 3 (P3) clearly exhibits significant spatial correlations in both in the medial-lateral and anterior-extent. This is consistent with and complementary to the fact that the active pixel fraction in each hemisphere exhibits a strong temporal correlation as I found earlier in this report [Temporal correlation of activity][]. The medial-lateral positional correlation is stronger than the anterior-posterior (higher R and lower p value). The total number of coactive frames is numel(y1(~isnan(y1)&~isnan(y2))) == 1114 frames. This is accounts to 37.13% of the movie or 222.8 s. Cortex.L had 1635 actvFrames and cortex.R had 1677 actvFrames which means that each hemisphere was coactive with the other hemisphere 1114/1635 == 68.13% and 1114/1677 == 66.43% of the active time respectively.
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