Recovery of Evoked Potentials, Metabolic Activity and Behavior in a Mouse Model of Somatosensory Cortex Lesion: Role of the Neural Cell Adhesion Molecule (NCAM)

Abstract

Understanding the processes that underlie functional recovery after cortical injury is a major challenge for neurobiology and clinical neurology. The aim of the present study was to establish a mouse model of functional recovery that would facilitate the investigation of the molecular and cellular events involved in cortical dynamics. We show that a focal injury of approximately 0.5 mm of diameter and 1 mm depth made in the barrel cortex of adult mice induced a transitory deficit that could be characterized using somatosensory evoked potential (SEP), metabolic mapping and a behavioral test. SEP recordings of short latency responses using an epicranial multi-array system showed a decreased cortical activity in the peri-lesion regions 2 weeks after the injury and a partial recovery to normal pattern 6 weeks after the lesion. Delayed SEP signals over the motor cortex were not altered by the injury. Metabolic mapping with [14C]deoxyglucose uptake in the surround of the injury reproduced the time course of deficit and recovery. Finally, a deficit in vibrissae related performance in a gap-crossing test 1 week after injury was followed by a functional recovery in the following 2 weeks. We show in addition that the recovery process is deficient and significantly delayed in NCAM knockout mice lacking all isoforms of NCAM (neural cell adhesion molecule)and PSA-NCAM. These results support the hypothesis that impairment and recovery of functions after focal cortical lesion involves remodeling of intact circuits surrounding the lesion and that the NCAM molecule participate in this process. The model opens new possibilities for investigating the role of candidate molecules in functional recovery using genetically modified mice.

Long-Term Plasticity in Mouse Sensorimotor Circuits after Rhythmic Whisker Stimulation

“…As detailed previously (Troncoso et al, 2000(Troncoso et al, , 2004Mégevand et al, 2008), a custom-designed electromechanical device was used for stimulating whiskers. Stimuli consisted of 300 m back-and-forth deflections with 1 ms rise time, applied to all whiskers on one side of the snout, 1 cm away from the face [30 -100 stimuli per somatosensory-evoked potential (SEP), 2-3 s interstimulus interval].…”

“…To verify the proper positioning of the intracortical probe, a lesion was made in the barrel or motor cortex at the end of the recordings by passing current (20 A for 8 s) through a glass microelectrode filled with Chicago Sky Blue dye and inserted at 400 m depth. Mice were then killed with pentobarbital, perfused with 4% paraformaldehyde, and the brains were extracted and processed for cytochrome oxidase histochemistry on tangential sections of the barrel cortex or for cresyl violet staining on coronal sections of the motor cortex using previously detailed protocols (Troncoso et al, 2004).…”

“…For this purpose, we recorded the electrical response of the barrel cortex to mechanical deflection of contralateral whiskers (SEP) using minimally invasive epicranial electrodes applied to the surface of the skull bones under pentobarbital anesthesia ( Fig. 1 A) (Troncoso et al, 2000(Troncoso et al, , 2004. The SEP mainly reflects synchronized postsynaptic events evoked by somatosensory stimuli in populations of cortical neurons; the successive voltage peaks of the SEP waveform (traditionally described by their amplitude and latency) are generated by partly distinct neuronal populations and reflect stages in the processing of sensory information (Allison et al, 1989a,b;Di and Barth, 1991;Peterson et al, 1995;Jellema et al, 2004).…”

“…Whether similar mechanisms could be related to whisking activity and whether such changes could be behaviorally relevant is not known. To address these issues, we used multichannel epicranial recordings of somatosensoryevoked potentials and laminar intracortical recordings (Troncoso et al, 2000(Troncoso et al, , 2004Mégevand et al, 2008) to test in anesthetized mice whether a period of passive rhythmical whisker stimulation at 8 Hz, the dominant frequency during exploratory whisking behavior , could induce long-lasting changes of evoked sensory responses in the barrel and motor cortices. Furthermore, to explore the behavioral relevance of these effects, we compared them with changes possibly evoked by exposure of the animals to environmental enrichment.…”

PSA-NCAM in postnatally generated immature neurons of the olfactory bulb:a crucial role in regulating p75 expression and cell survival

“…Both PSA and p75 are known to be reexpressed in lesion contexts, such as in mechanical damage, focal ischemia, axotomy, stroke and epileptic seizures (Gage et al, 1989;Giehl et al, 2001;Kokaia et al, 1998;Rende et al, 1993;Roux et al, 1999). Remarkably, blockade or enzymatic disruption of PSA leads to an impaired repair process (Bonfanti et al, 1996; Daniloff et al, 1986) and the NCAM-knockout mice exhibit deficient recovery after cortical lesions (Troncoso et al, 2004). It has been reported that, in a mice model of amyotrophic lateral sclerosis, surviving motoneurons in transgenic animals express PSA-NCAM (Warita et al, 2001), raising the possibility that PSA re-expression protects undamaged and functional neurons from p75-mediated apoptosis.…”