In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration.

BACKGROUND: Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborisation and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons. RESULTS: To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that regulate WD within the mouse cerebral cortex. We combined single-axon-resolution multiphoton imaging with laser microsurgery through a cranial window and a fluorescent membrane reporter. Longitudinal imaging of > 150 individually injured excitatory cortical axons revealed a threshold length below which injured axons consistently underwent a rapid-onset form of WD (roWD). roWD started on average 20 times earlier and was executed 3 times slower than WD described in other regions of the nervous system. Cortical axon WD and roWD were dependent on synaptic density, but independent of axon complexity. Finally, pharmacological and genetic manipulations showed that a nicotinamide adenine dinucleotide (NAD+)-dependent pathway could delay cortical roWD independent of transcription in the damaged neurons, demonstrating further conservation of the molecular mechanisms controlling WD in different areas of the mammalian nervous system. CONCLUSIONS: Our data illustrate how in vivo time-lapse imaging can provide new insights into the spatiotemporal dynamics and synaptic mechanisms of axon loss and assess therapeutic interventions in the injured mammalian brain.

Revisiting horizontal connectivity rules in V1: from like-to-like towards like-to-all.

Horizontal connections in the primary visual cortex of carnivores, ungulates and primates organize on a near-regular lattice. Given the similar length scale for the regularity found in cortical orientation maps, the currently accepted theoretical standpoint is that these maps are underpinned by a like-to-like connectivity rule: horizontal axons connect preferentially to neurons with similar preferred orientation. However, there is reason to doubt the rule's explanatory power, since a growing number of quantitative studies show that the like-to-like connectivity preference and bias mostly observed at short-range scale, are highly variable on a neuron-to-neuron level and depend on the origin of the presynaptic neuron. Despite the wide availability of published data, the accepted model of visual processing has never been revised. Here, we review three lines of independent evidence supporting a much-needed revision of the like-to-like connectivity rule, ranging from anatomy to population functional measures, computational models and to theoretical approaches. We advocate an alternative, distance-dependent connectivity rule that is consistent with new structural and functional evidence: from like-to-like bias at short horizontal distance to like-to-all at long horizontal distance. This generic rule accounts for the observed high heterogeneity in interactions between the orientation and retinotopic domains, that we argue is necessary to process non-trivial stimuli in a task-dependent manner.

Layer 2/3 Pyramidal Neurons of the Mouse Granular Retrosplenial Cortex and Their Innervation by Cortico-Cortical Axons.

The retrosplenial cortex forms part of the cingulate cortex and is involved in memory and navigation. It is ventral region, the granular retrosplenial cortex, or GRSC is characterized by the presence, of small pyramidal neurons with a distinctive late-spiking (LS) firing pattern in layer 2/3. Using in vitro brain slices of the mouse GRSC we have studied the electrophysiological properties and synaptic responses of these LS neurons, comparing them with neighboring non-LS pyramidal neurons. LS and non-LS neurons showed different responses during cortical propagation of epileptiform discharges. All non-LS neurons generated large supra-threshold excitatory responses that generated bursts of action potentials. Contrastingly, the LS neurons showed small, and invariably subthreshold excitatory synaptic potentials. Although both types of pyramidal neurons were readily intermingled in the GRSC, we observed differences in their innervation by cortico-cortical axons. The application of glutamate to activate cortical neurons evoked synaptic responses in LS neurons only when applied at less than 250 µm, while in non-LS neurons we found synaptic responses when glutamate was applied at larger distances. Analysis of the synaptic responses evoked by long-range cortico-cortical axons (with the origin at 1200 µm from the recorded neurons or in the contralateral hemisphere) confirmed that non-LS neurons were strongly innervated by these axons, while they evoked only small responses or no response at all in the LS neurons (contralateral stimulation, non-LS: 194.0 ± 196.63 pA, n = 22; LS: 51.91 ± 35.26 pA, n = 10; p = 0.004). The excitatory/inhibitory balance was similar in both types of pyramidal neurons, but the latency of the EPSCs evoked by long-range cortico-cortical axons was longer in LS neurons (contralateral stimulation non-LS: 8.13 ± 1.23 ms, n = 17; LS: 10.76 ± 1.58 ms, n = 7; p = 0.004) suggesting a disynaptic mechanism. Our findings highlight the differential cortico-cortical axonal innervation of LS and non-LS pyramidal neurons, and that the two types of neurons are incorporated in different cortico-cortical neuronal circuits. This strongly suggests that the functional organization of the dorsal part of the GRSC is based on independent cortico-cortical circuits (among other elements).

EEG functional connectivity, axon delays and white matter disease.

OBJECTIVE: Both structural and functional brain connectivities are closely linked to white matter disease. We discuss several such links of potential interest to neurologists, neurosurgeons, radiologists, and non-clinical neuroscientists. METHODS: Treatment of brains as genuine complex systems suggests major emphasis on the multi-scale nature of brain connectivity and dynamic behavior. Cross-scale interactions of local, regional, and global networks are apparently responsible for much of EEG's oscillatory behaviors. Finite axon propagation speed, often assumed to be infinite in local network models, is central to our conceptual framework. RESULTS: Myelin controls axon speed, and the synchrony of impulse traffic between distant cortical regions appears to be critical for optimal mental performance and learning. Several experiments suggest that axon conduction speed is plastic, thereby altering the regional and global white matter connections that facilitate binding of remote local networks. CONCLUSIONS: Combined EEG and high resolution EEG can provide distinct multi-scale estimates of functional connectivity in both healthy and diseased brains with measures like frequency and phase spectra, covariance, and coherence. SIGNIFICANCE: White matter disease may profoundly disrupt normal EEG coherence patterns, but currently these kinds of studies are rare in scientific labs and essentially missing from clinical environments.