Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of FK506 can result in adverse side effects. The localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side effects. This study investigates the utility of a novel FK506-impregnated polyester urethane urea (PEUU) nerve wrap to treat PNI in a previously validated rat infraorbital nerve (ION) transection and repair model. ION function was assessed by microelectrode recordings of trigeminal ganglion cells responding to controlled vibrissae deflections in ION-transected and -repaired animals, with and without the nerve wrap. Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker-evoked response. Compared to no-wrap controls, rats with PEUU-FK506 wraps functionally recovered earlier, displaying larger response magnitudes. With nerve wrap treatment, FK506 blood levels up to six weeks were measured nearly at the limit of quantification (LOQ ≥ 2.0 ng/mL); whereas the drug concentrations within the ION and muscle were much higher, demonstrating the local delivery of FK506 to treat PNI. An immunohistological assessment of ION showed increased myelin expression for animals assigned to neurorrhaphy with PEUU-FK506 treatment compared to untreated or systemic-FK506-treated animals, suggesting that improved PNI outcomes using PEUU-FK506 is mediated by the modulation of Schwann cell activity.

Robust rodent hemifacial transplant model was used to record functional changes in somatosensory cortex after transplantation. Neurons in the somatosensory cortex of face transplant recipients had decreased sensitivity to stimulation of whiskers with increased directional sensitivity vs. naive rats. Transplant recipient cortical unit response was more dispersed in temporary vs. naive rats. Despite histological similarities to naive cortices, transplant recipient cortices had a mix of topographically appropriate and inappropriate whiskered at barrel cortex relationships.

RESULTS: Favorable outcome have been achieved in all cases. In the first group complete healing was observed in 98% (43 out of 44 patients). From one to three procedures was performed to get final result. Average healing time depended on size and depth of the wound and ranged from 8 to 14 weeks. Only in one case only VRAM flap was performed due to progressive osteoradionecrosis of the ribs. In the second group decreasing of LENT-SOMA grade was observed in all patients. Density of fibrotic tissues measured with elastosonography decreased from 220–650 kPa to 30–50 kPa. In the third group from 2 to 4 procedures were necessary to restore soft tissue flexibility. As far as density level becomes less than 60 kPa, additional 2–6 fat grafting sessions were performed to attain necessary volume and shape.

PURPOSE: Peripheral nerve injuries can be devastating, leading to permanent functional disabilities. Systemic FK506 administration has been shown to hasten recovery and improve functional outcomes after nerve injury repair. However, high systemic levels of FK506 can result in adverse side-effects. Localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side-effects. The purpose of this study is to infestigate the utility of a novel FK506-impregnated nerve wrap in treating peripheral nerve injuries in a previously validated rat infraorbital nerve transection and repair model. METHODS: Infraorbital nerve transection surgeries were performed on two groups (n=5 per group) of adult Lewis rats. In both groups, the infraorbital branch of the trigeminal nerve was transected. The transected nerve was then repaired primarily with 10-0 nylon suture with (treatment group) or without (no treatment group) the addition of a Poly(ester urethane) urea (PEUU) wrap impregnated with 20 mg of FK506. To evaluate neuroregeneration, trigeminal ganglion cell recordings, objective sensory testing, directional sensitivity, maximal response, and receptor compositions were analyzed from five rats in each group at four and six weeks postoperatively. Recordings from the trigeminal ganglion in naïve rats were taken for comparison. To assess local FK506 administration, blood and tissue samples (infraorbital nerve, muscle) were analyzed for FK506 concentration using liquid chromatography-mass spectrometry at four and six weeks postoperatively in the treatment group. RESULTS: Data were analyzed using custom software written in Excel Visual Basic and the Excel add-on statistical package, Analyze-it (Analyse-it Software, LTD). Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker evoked response. Rats within the treatment group (FK506 wraps) were found to have increased response magnitude at 4 weeks after implantation in the infraorbital cut and repair model in comparison to no treatment group (p<.013). FK506 blood levels at 4 and 6 weeks were close to the limit of quantification (<2ng/ml), whereas concentration within the tissues of interest, the infraorbital nerve and muscle, were much higher. CONCLUSION: This study investigates the use of an FK506-impregnated PEUU nerve wrap to improve functional recovery following peripheral nerve injury. Sensory testing provides objective data on the effects of these wraps in the treatment of peripheral nerve injuries and the FK wraps appear to accelerate nerve recovery at 4 weeks, with minimal systemic drug exposure. The findings from this study may translate into novel treatment systems and protocols to treat nerve injuries. J.M. Barnett: None. B. Xiao: None. Y. van der Merwe: None. X. Gu: None. F. Feturi: None. E. Katzel: None. R. Venkataramanan: None. M. Solari: None. W. Wagner: None. D. Simons: None. M.B. Steketee: None. K.M. Washington: None.

Rats and mice are able to perform a variety of subtle tactile discriminations with their mystacial vibrissae. Increasingly, the design and interpretation of neurophysiological and behavioral studies are inspired by and linked to a more precise understanding of the detailed physical properties of the whiskers and their associated hair follicles. Here we used a piezoelectric sensor (bimorph) to examine how contact forces are influenced by the geometry of individual whisker hairs. For a given point along a whisker, bimorph signals are linearly related to whisker movement velocity. The slope of this linear function, called velocity sensitivity (VS), diminishes nonlinearly as whisker diameter decreases. Whiskers differ in overall length, thickness, and proximal-distal taper. Thus VS varies along an individual whisker and among different whiskers on the mystacial pad. Thinner, shorter whiskers, such as those located rostrally in rats and those in mice, have lower overall VSs, rendering them potentially less effective for mediating discriminations that rely on subtle velocity cues. The nonlinear effect of diameter combined with the linear effect of arc length produces radial distance tuning curves wherein small differences in the proximal-distal location of impacts yields larger differences in signal magnitude. Such position-dependent cues could contribute to the localization of objects near the face. Proximal-to-distal changes in contact location during whisking sweeps could also provide signals that aid texture discrimination.NEW & NOTEWORTHY This study describes the geometry of facial whiskers distributed across the mystacial pad with emphasis on velocity encoding of object strikes. Findings indicate how the shapes, lengths, and thicknesses of individual hairs can contribute to sophisticated vibrissa-based tactile discrimination.

Cardiac arrest is a common cause of global hypoxic-ischemic brain injury. Poor neurologic outcome among cardiac arrest survivors results not only from direct cellular injury but also from subsequent long-term dysfunction of neuronal circuits. Here, we investigated the long-term impact of cardiac arrest during development on the function of cortical layer IV (L4) barrel circuits in the rat primary somatosensory cortex. We used multielectrode single-neuron recordings to examine responses of presumed excitatory L4 barrel neurons to controlled whisker stimuli in adult (8 ± 2-mo-old) rats that had undergone 9 min of asphyxial cardiac arrest and resuscitation during the third postnatal week. Results indicate that responses to deflections of the topographically appropriate principal whisker (PW) are smaller in magnitude in cardiac arrest survivors than in control rats. Responses to adjacent whisker (AW) deflections are similar in magnitude between the two groups. Because of a disproportionate decrease in PW-evoked responses, receptive fields of L4 barrel neurons are less spatially focused in cardiac arrest survivors than in control rats. In addition, spiking activity among L4 barrel neurons is more correlated in cardiac arrest survivors than in controls. Computational modeling demonstrates that experimentally observed disruptions in barrel circuit function after cardiac arrest can emerge from a balanced increase in background excitatory and inhibitory conductances in L4 neurons. Experimental and modeling data together suggest that after a hypoxic-ischemic insult, cortical sensory circuits are less responsive and less spatially tuned. Modulation of these deficits may represent a therapeutic approach to improving neurologic outcome after cardiac arrest.

The functional role of input from the primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke AK, Simons DJ, Fanselow EE. Cereb Cortex 24: 2237-2248, 2014), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We found that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the postsynaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs, whereas ventral posterior medial nucleus-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. The results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures.

The rodent whisker/trigeminal system, characterized by high spatial and temporal resolution, provides an experimental model for developing new therapies for improving sensory functions of damaged peripheral nerves. Here, we use controlled whisker stimulation and single-unit recordings of trigeminal ganglion cells to examine in detail the nature and time course of functional recovery of mechanoreceptive afferents following nerve transection with microsurgical repair of the infraorbital nerve (ION) branch of the trigeminal nerve in adult rats. Response measures include rapid vs. slow adaptation, firing rate, interspike intervals, latency, and angular (directional) tuning. Whisker-evoked responses, readily observable by 3 wk post-transection, recover progressively for at least the next 5 wk. All cells in transected animals, as in control cases, responded to deflections of single whiskers only, but topography within the ganglion was clearly disrupted. The time course and extent of recovery of quantitative response measures were receptor dependent. Cells displaying slowly adapting (SA) properties recovered more quickly than rapidly adapting (RA) populations, and for some response measures-notably evoked firing rates-closely approached or attained control levels by 8 wk post-transection. Angular tuning of RA cells was slightly better than control units, whereas SA tuning did not differ from control values. Nerve conduction times and refractory periods, examined separately using electrical stimulation of the ION, were slower than normal in all transected animals and poorly reflected recovery of whisker-evoked response latencies and interspike intervals. Results underscore the need for multiple therapeutic strategies that target different aspects of functional restitution following peripheral nerve injury.

Neonatal whisker trimming followed by adult whisker regrowth leads to higher responsiveness and altered receptive field properties of cortical neurons in corresponding layer 4 barrels. Studies of functional thalamocortical (TC) connectivity in normally reared adult rats have provided insights into how experience-dependent TC synaptic plasticity could impact the establishment of feedforward excitatory and inhibitory receptive fields. The present study employed cross-correlation analyses to investigate lasting effects of neonatal whisker trimming on functional connections between simultaneously recorded thalamic neurons and regular-spike (RS), presumed excitatory, and fast-spike (FS), presumed inhibitory, barrel neurons. We find that, as reported previously, RS and FS cells in whisker-trimmed animals fire more during the earliest phase of their whisker-evoked responses, corresponding to the arrival of TC inputs, despite a lack of change or even a slight decrease in the firing of thalamic cells that contact them. Functional connections from thalamus to cortex are stronger. The probability of finding TC-RS connections was twofold greater in trimmed animals and similar to the frequency of TC-FS connections in control and trimmed animals, the latter being unaffected by whisker trimming. Unlike control cases, trimmed RS units are more likely to receive inputs from TC units (TCUs) and have mismatched angular tuning and even weakly responsive TCUs make strong functional connections on them. Results indicate that developmentally appropriate tactile experience early in life promotes the differential thalamic engagement of excitatory and inhibitory cortical neurons that underlies normal barrel function.

Feedforward inhibition is a common motif of thalamocortical circuits. Strong engagement of inhibitory neurons by thalamic inputs enhances response differentials between preferred and nonpreferred stimuli. In rat whisker-barrel cortex, robustly driven inhibitory barrel neurons establish a brief epoch during which synchronous or near-synchronous thalamic firing produces larger responses to preferred stimuli, such as high-velocity deflections of the principal whisker in a preferred direction. Present experiments in mice show that barrel neuron responses to preferred vs. nonpreferred stimuli differ less than in rats. In addition, fast-spike units, thought to be inhibitory barrel neurons, fire less robustly to whisker stimuli in mice than in rats. Analyses of real and simulated data indicate that mouse barrel circuitry integrates thalamic inputs over a broad temporal window, and that, as a consequence, responses of barrel neurons are largely similar to those of thalamic neurons. Results are consistent with weaker feedforward inhibition in mouse barrels. Differences in thalamocortical circuitry between mice and rats may reflect mechanical properties of the whiskers themselves.

Anatomical studies have shown that primary somatosensory (S1) and primary motor (M1) cortices are reciprocally connected. The M1 to S1 projection is thought to represent a modulatory signal that conveys motor-related information to S1. Here, we investigated M1 synaptic inputs to S1 by injecting an AAV virus containing channelrhodopsin-2 and a fluorescent tag into M1. Consistent with previous results, we found labeling of M1 axons within S1 that was most robust in the deep layers and in L1. Labeling was sparse in L4 and was concentrated in the interbarrel septa, largely avoiding barrel centers. In S1, we recorded in vitro from regular-spiking excitatory neurons and fast-spiking and somatostatin-expressing inhibitory interneurons. All 3 cell types had a high probability of receiving direct excitatory M1 input. Both excitatory and inhibitory cells within L4 were the least likely to receive such input from M1. Disynaptic inhibition was observed frequently, indicating that M1 recruits substantial inhibition within S1. Additionally, a subpopulation of L6 regular-spiking excitatory neurons received exceptionally strong M1 input. Overall, our results suggest that activation of M1 evokes within S1 a bombardment of excitatory and inhibitory synaptic activity that could contribute in a layer-specific manner to state-dependent changes in S1.

Correlated variability of neural spiking activity has important consequences for signal processing. How incoming sensory signals shape correlations of population responses remains unclear. Cross-correlations between spiking of different neurons may be particularly consequential in sparsely firing neural populations such as those found in layer 2/3 of sensory cortex. In rat whisker barrel cortex, we found that pairs of excitatory layer 2/3 neurons exhibit similarly low levels of spike count correlation during both spontaneous and sensory-evoked states. The spontaneous activity of excitatory–inhibitory neuron pairs is positively correlated, while sensory stimuli actively decorrelate joint responses. Computational modeling shows how threshold nonlinearities and local inhibition form the basis of a general decorrelating mechanism. We show that inhibitory population activity maintains low correlations in excitatory populations, especially during periods of sensory-evoked coactivation. The role of feedforward inhibition has been previously described in the context of trial-averaged phenomena. Our findings reveal a novel role for inhibition to shape correlations of neural variability and thereby prevent excessive correlations in the face of feedforward sensory-evoked activation.

Global hypoxia-ischemia interrupts oxygen delivery and blood flow to the entire brain. Previous studies of global brain hypoxia-ischemia have primarily focused on injury to the cerebral cortex and to the hippocampus. Susceptible neuronal populations also include inhibitory neurons in the thalamic reticular nucleus. We therefore investigated the impact of global brain hypoxia-ischemia on the thalamic circuit function in the somatosensory system of young rats. We used single neuron recordings and controlled whisker deflections to examine responses of thalamocortical neurons to sensory stimulation in rat survivors of 9 min of asphyxial cardiac arrest incurred on postnatal day 17. We found that 48–72 h after cardiac arrest, thalamocortical neurons demonstrate significantly elevated firing rates both during spontaneous activity and in response to whisker deflections. The elevated evoked firing rates persist for at least 6–8 weeks after injury. Despite the overall increase in firing, by 6 weeks, thalamocortical neurons display degraded receptive fields, with decreased responses to adjacent whiskers. Nine minutes of asphyxial cardiac arrest was associated with extensive degeneration of neurites in the somatosensory nucleus as well as activation of microglia in the reticular nucleus. Global brain hypoxia-ischemia during cardiac arrest has a long-term impact on processing and transfer of sensory information by thalamic circuitry. Thalamic circuitry and normalization of its function may represent a distinct therapeutic target after cardiac arrest.

Activity in thalamocortical circuits depends strongly on immediate past experience. When the successive activity is attenuated on short timescales, this phenomenon is known as adaptation. Adaptive processes may be effectively initiated by ongoing exposure to sensory stimuli and/or direct electrical stimulation of neural tissue. Ongoing high-frequency electrical stimulation is increasingly employed as a treatment for a variety of neurological disorders. Neural stimulation with similar parameters to therapeutic electrical stimulation may modulate the way in which cortical neurons respond and adapt to sensory stimuli. Here, we studied the effects of high-frequency stimulation of the somatosensory thalamus on the transmission of sensory signals in thalamocortical circuits. We examined how whisker-evoked sensory inputs in layer IV cortical barrels are affected by concurrent 100 Hz thalamic electrical stimulation and how the latter modulates sensory-evoked adaptation. Even in the presence of ongoing thalamic stimulation, sensory transmission in thalamocortical circuits is maintained. However, cortical responses to whisker deflections are reduced in an intensity-dependent fashion and can be nearly abolished with high intensity currents. The electrical stimulation-induced reduction in cortical responsiveness likely reflects engagement of circuit mechanisms that normally produce sensory adaptation.

Zanoun, RR; Afrooz, PN; Washington, KM; Kwegyir-Afful, EE; Simons, DJ; Lee, WP Author Information

Each region along the rat mystacial vibrissa pathway contains neurons that respond preferentially to vibrissa deflections in a particular direction, a property called angular tuning. Angular tuning is normally defined using responses to deflections of the principal vibrissa, which evokes the largest response magnitude. However, neurons in most brain regions respond to multiple vibrissae and do not necessarily respond to different vibrissae with the same angular tuning. We tested the consistency of angular tuning across the receptive field in several stations along the vibrissa-to-cortex pathway: primary somatosensory (barrel) cortex, ventroposterior medial nucleus of the thalamus (VPM), second somatosensory cortex, and superior colliculus. We found that when averaged across the population, neurons in all of these regions have low (superior colliculus and second somatosensory cortex) or statistically insignificant (barrel cortex and VPM) angular tuning consistencies across vibrissae. Nevertheless, in each region there are a small number of neurons that display consistent angular tuning for at least some vibrissae. We discuss the relevance of these findings for the transformation of inputs along the vibrissa trigeminal pathway and for the detection of sensory cues by whisking animals.

Complex spatial patterning, common in the brain as well as in other biological systems, can emerge as a result of dynamic interactions that occur locally within developing structures. In the rodent somatosensory cortex, groups of neurons called “barrels” correspond to individual whiskers on the contralateral face. Barrels themselves often contain subbarrels organized into one of a few characteristic patterns. Here we demonstrate that similar patterns can be simulated by means of local growth-promoting and growth-retarding interactions within the circular domains of single barrels. The model correctly predicts that larger barrels contain more spatially complex subbarrel patterns, suggesting that the development of barrels and of the patterns within them may be understood in terms of some relatively simple dynamic processes. We also simulate the full nonlinear equations to demonstrate the predictive value of our linear analysis. Finally, we show that the pattern formation is robust with respect to the geometry of the barrel by simulating patterns on a realistically shaped barrel domain. This work shows how simple pattern forming mechanisms can explain neural wiring both qualitatively and quantitatively even in complex and irregular domains.