The function of chronic brain machine interfaces depends on stable electrical contact between neurons and electrodes. A key step in the development of interfaces is therefore to identify implant configurations that minimize adverse long-term tissue reactions. To this end, we here characterized the separate and combined effects of implant size and fixation mode at 6 and 12 weeks post implantation in rat (n = 24) cerebral cortex. Neurons and activated microglia and astrocytes were visualized using NeuN, ED1 and GFAP immunofluorescence microscopy, respectively. The contributions of individual experimental variables to the tissue response were quantified. Implants tethered to the skull caused larger tissue reactions than un-tethered implants. Small diameter (50 µm) implants elicited smaller tissue reactions and resulted in the survival of larger numbers of neurons than did large diameter (200 µm) implants. In addition, tethering resulted in an oval-shaped cavity, with a cross-section area larger than that of the implant itself, and in marked changes in morphology and organization of neurons in the region closest to the tissue interface. Most importantly, for implants that were both large diameter and tethered, glia activation was still ongoing 12 weeks after implantation, as indicated by an increase in GFAP staining between week 6 and 12, while this pattern was not observed for un-tethered, small diameter implants. Our findings therefore clearly indicate that the combined small diameter, un-tethered implants cause the smallest tissue reactions.
During development, information about the three-dimensional shape and mechanical properties of the body is laid down in the synaptic connectivity of sensorimotor systems through unknown adaptive mechanisms. In spinal reflex systems, this enables the fast transformation of complex sensory information into adequate correction of movements. Here we use a computer simulation to show that an unsupervised correlation-based learning mechanism, using spontaneous muscle twitches, can account for the functional adaptation of the withdrawal reflex system. We also show that tactile feedback resulting from spontaneous muscle twitches during sleep does indeed modify sensorimotor transformation in young rats in a predictable manner. The results indicate that these twitches, corresponding to human fetal movements, are important in spinal self-organization.
SUMMARY1. The cutaneous receptive fields of 225 climbing fibres projecting to the forelimb area of the C3 zone in the cerebellar anterior lobe were mapped in the pentobarbitoneanaesthetized cat. Responses in climbing fibres were recorded as complex spikes in Purkinje cells.2. A detailed topographical organization of the nociceptive climbing fibre input to the C3 zone was found. In the medial C3 zone climbing fibres with receptive fields covering proximal and/or lateral parts of the forelimb projected most medially. Climbing fibres with receptive fields located more medially on the forelimb projected successively more laterally. The sequence of receptive fields found in the lateral C3 zone was roughly the reverse of that in the medial C3 zone. Climbing fibres with receptive fields restricted to the digits projected preferentially to the caudal part of the forelimb area, whereas those with receptive fields covering both proximal and ventral areas of the forearm projected to more rostral parts.3. The representation of the forelimb was uneven. Receptive fields with a focus on the digits or along the lateral side of the forearm dominated.4. The proximal borders of the receptive fields were located close to joints. The area from which maximal responses were evoked was usually located eccentrically within the receptive field. Based on spatial characteristics the receptive fields could be divided into eight classes, which in turn were tentatively divided into subclasses. Similar subclasses of receptive fields were found in different cats. This classification was further supported by the results of a quantitative analysis of eighty-nine climbing fibres. The receptive fields of these climbing fibres were mapped with standardized noxious stimulation.5. Climbing fibres terminating within sagittal strips (width, 100-300 ,tm; length, > 1 mm) had receptive fields which belonged to the same subclass. There were commonly abrupt changes in receptive fields between such microzones. Most classes of receptive fields were found in both the medial and the lateral parts of the C3 zone. However, receptive fields with a focus on the ventral side of either the metacarpals, the wrist or the forearm were found only in the medial part of the C3 zone.
Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex.
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