Afferent Input Research Articles

Repetitive Passive Movement Modulates Corticospinal Excitability: Effect of Movement and Rest Cycles and Subject Attention.

Repetitive passive movement (PM) affects corticospinal excitability; however, it is unknown whether a duty cycle which repeats movement and rest, or subjects’ conscious attention to movements, affects corticospinal excitability. We aimed to clarify the effect of the presence or absence of a duty cycle and subjects’ attention on corticospinal excitability. Three experiments were conducted. In Experiment 1, PM of the right index finger was performed for 10 min. Three conditions were used: (1) continuous PM (cPM) at a rate of 40°/s; (2) intermittent PM (iPM) with a duty cycle at 40°/s; and (3) iPM at 100°/s. In conditions 1 and 3, motor evoked potential (MEP) amplitude was significantly reduced. In Experiment 2, PM was performed for 30 min: condition 1 comprised cPM at a rate of 40°/s and Condition 2 comprised iPM at 40°/s. MEP amplitude significantly decreased in both conditions. In Experiment 3, PM was performed for 10 min: condition 1 comprised paying attention to the moving finger during iPM and Condition 2 was similar to Condition 1 but while counting images on a monitor without looking at the movement finger, and Condition 3 comprised counting images on a monitor without performing PM. MEP amplitude significantly increased only under Condition 1. Thus, afferent input from movements above a certain threshold may affect corticospinal excitability reduction. Furthermore, corticospinal excitability increases when paying attention to passive finger movement.

Vagal afferents contribute to sympathoexcitation-driven metabolic dysfunctions.

Multiple crosstalk between peripheral organs and the nervous system are required to maintain physiological and metabolic homeostasis. Using Vav3-deficient mice as a model for chronic sympathoexcitation-associated disorders, we report here that afferent fibers of the hepatic branch of the vagus nerve are needed for the development of the peripheral sympathoexcitation, tachycardia, tachypnea, insulin resistance, liver steatosis and adipose tissue thermogenesis present in those mice. This neuronal pathway contributes to proper activity of the rostral ventrolateral medulla, a sympathoregulatory brainstem center hyperactive in Vav3-/- mice. Vagal afferent inputs are also required for the development of additional pathophysiological conditions associated with deregulated rostral ventrolateral medulla activity. By contrast, they are dispensable for other peripheral sympathoexcitation-associated disorders sparing metabolic alterations in liver.

Synchronicity: The Role of Midbrain Dopamine in Whole-Brain Coordination.

Midbrain dopamine seems to play an outsized role in motivated behavior and learning. Widely associated with mediating reward-related behavior, decision making, and learning, dopamine continues to generate controversies in the field. While many studies and theories focus on what dopamine cells encode, the question of how the midbrain derives the information it encodes is poorly understood and comparatively less addressed. Recent anatomical studies suggest greater diversity and complexity of afferent inputs than previously appreciated, requiring rethinking of prior models. Here, we elaborate a hypothesis that construes midbrain dopamine as implementing a Bayesian selector in which individual dopamine cells sample afferent activity across distributed brain substrates, comprising evidence to be evaluated on the extent to which stimuli in the on-going sensorimotor stream organizes distributed, parallel processing, reflecting implicit value. To effectively generate a temporally resolved phasic signal, a population of dopamine cells must exhibit synchronous activity. We argue that synchronous activity across a population of dopamine cells signals consensus across distributed afferent substrates, invigorating responding to recognized opportunities and facilitating further learning. In framing our hypothesis, we shift from the question of how value is computed to the broader question of how the brain achieves coordination across distributed, parallel processing. We posit the midbrain is part of an “axis of agency” in which the prefrontal cortex (PFC), basal ganglia (BGS), and midbrain form an axis mediating control, coordination, and consensus, respectively.

V2 Trigeminal Referred Pain from Chronic Occipital Neuralgia Caused by Entrapment of the Greater Occipital Nerve

AbstractAlthough entrapment of the greater occipital nerve (GON) is a well-known cause of occipital neuralgia, occurrence of referred hemifacial trigeminal pain involving V2 distribution from chronic occipital neuralgia is rare. A 67-year-old female patient with intermittent left-sided occipital neuralgia of 10-year duration presented with a new onset of left-sided hemifacial pain of 5-month duration. With aggravation of left-sided occipital neuralgia, continuous burning pain and paresthesia gradually developed in her left malar and periorbital area. They also spread to her left upper lip. Severe compression of the left GON by tendinous aponeurotic attachment of the trapezius was found intraoperatively. Decompression of the left GON from chronic entrapment resulted in immediate relief for her hemifacial pain and chronic occipital neuralgia. These findings provide clinical affirmation of the existence of trigeminal/cervical convergence and hypersensitivity. Chronic irritating afferent input of occipital neuralgia caused by entrapment of the GON seems to be associated with sensitization and hypersensitivity of the second-order neurons in the trigeminocervical complex receiving convergent input from dural and cervical structures. Referred trigeminal pain from chronic occipital neuralgia may extend to V2 in addition to V1 trigeminal distribution.

Temporal relationship between perceptual and physiological events triggered by nociceptive heat stimuli

A combined assessment tool for the perceptual-motor aspects of pain processing will be valuable to clinicians. Fifteen healthy subjects were exposed to contact-heat stimulation (Pathway, Medoc, Israel) to assess perception through a simple task (motor response or conscious appraisal of the time the stimulus was felt) or with a dual task (both responses). The outcome measure was the temporal relationship between contact heat evoked potentials (CHEPS), reaction time (RT) and conscious awareness (AW). There were different temporal profiles for CHEPs, RT and AW to changes in stimulus intensity, AW being the least affected. Performing the dual task led to a significantly more pronounced effect on RT than on AW, while CHEPS were not influenced by task performance. Our results support the dissociation between physiological, behavioral and cognitive events elicited by nociceptive stimuli. The time of conscious appraisal of stimulus occurrence is a complementary information to other responses such as evoked potentials or behavioral tasks. The combined assessment of physiological and behavioral aspects of pain processing may provide clinicians with information on the different paths followed by nociceptive afferent inputs in the central nervous system.

Development of Local Circuit Connections to Hilar Mossy Cells in the Mouse Dentate Gyrus.

Hilar mossy cells in the dentate gyrus (DG) shape the firing and function of the hippocampal circuit. However, the neural circuitry providing afferent input to mossy cells is incompletely understood, and little is known about the development of these inputs. Thus, we used whole-cell recording and laser scanning photostimulation (LSPS) to characterize the developmental trajectory of local excitatory and inhibitory synaptic inputs to mossy cells in the mouse hippocampus. Hilar mossy cells were targeted by visualizing non-red fluorescent cells in the dentate hilus of GAD2-Cre; Ai9 mice that expressed tdTomato in GAD+ neurons, and were confirmed by post hoc morphological characterization. Our results show that at postnatal day (P)6–P7, mossy cells received more excitatory input from neurons in the proximal CA3 versus those in the DG. In contrast, at P13–P14 and P21–P28, the largest source of excitatory input originated in DG cells, while the strength of CA3 and hilar inputs declined. A developmental trend was also evident for inhibitory inputs. Overall inhibitory input at P6–P7 was weak, while inhibitory inputs from the DG cell layer and the hilus predominated at P13–P14 and P21–P28. The strength of local DG excitation and inhibition to mossy cells peaked at P13–P14 and decreased slightly in older P21–P28 mice. Together, these data provide new detailed information on the development of local synaptic connectivity of mossy cells, and suggests mechanisms through which developmental changes in local circuit inputs to hilar mossy cells shape their physiology and vulnerability to injury during postnatal periods.

Tonotopic Differentiation of Coupling between Ca2+ and Kv1.1 Expression in Brainstem Auditory Circuit

SummaryTonotopic differentiations of ion channels ensure sound processing across frequencies. Afferent input plays a critical role in differentiations. We demonstrate here in organotypic culture of chicken cochlear nucleus that expression of Kv1.1 was coupled with Ca2+ to a different degree depending on tonotopic regions, thereby differentiating the level of expression within the nucleus. In the culture, Kv1.1 was down-regulated and not differentiated tonotopically. Chronic depolarization increased Kv1.1 expression in a level-dependent manner. Moreover, the dependence was steeper at higher-frequency regions, which restored the differentiation. The depolarization increased Kv1.1 via activation of Cav1 channels, whereas basal Ca2+ level elevated similarly irrespective of tonotopic regions. Thus, the efficiency of Ca2+-dependent Kv1.1 expression would be fine-tuned in a tonotopic-region-specific manner, emphasizing the importance of neuronal tonotopic identity as well as pattern of afferent input in the tonotopic differentiation of the channel in the auditory circuit.

Effects of lactate ions on the cardiorespiratory system in rainbow trout (Oncorhynchus mykiss).

Lactate ions are involved in several physiological processes, including a direct stimulation of the carotid body, causing increased ventilation in mammals. A similar mechanism eliciting ventilatory stimulation in other vertebrate classes has been demonstrated, but it remains to be thoroughly investigated. Here, we investigated the effects of lactate ions on the cardiorespiratory system in swimming rainbow trout by manipulating the blood lactate concentration. Lactate elicited a vigorous, dose-dependent elevation of ventilation and bradycardia at physiologically relevant concentrations at constant pH. After this initial confirmation, we examined the chiral specificity of the response and found that only l-lactate induced these effects. By removal of the afferent inputs from the first gill arch, the response was greatly attenuated, and a comparison of the responses to injections up- and downstream of the gills collectively demonstrated that the lactate response was initiated by branchial cells. Injection of specific receptor antagonists revealed that a blockade of serotonergic receptors, which are involved in the hypoxic ventilatory response, significantly reduced the lactate response. Finally, we identified two putative lactate receptors based on sequence homology and found that both were expressed at substantially higher levels in the gills. We propose that lactate ions modulate ventilation by stimulating branchial oxygen-sensing cells, thus eliciting a cardiorespiratory response through receptors likely to have originated early in vertebrate evolution.

The role of afferent input in postamputation pain: a randomized, double-blind, placebo-controlled crossover study.

In this randomized, double-blind, placebo-controlled crossover study, we investigated whether a peripheral nerve block could temporarily eliminate phantom and stump pain after amputation. Amputees with constant postamputation pain were included and randomized to receive a nerve block with lidocaine 2% with adrenaline or saline in a crossover design. Spontaneous phantom and stump pain and evoked responses were assessed at baseline and at fixed time-points until 120 minutes after lidocaine or saline injection. The primary outcome was the difference in absolute change between worst pain intensity, either phantom or stump pain, at baseline and at 30 minutes after lidocaine or saline injection. Twelve amputees were randomized and 9 patients were included in the analysis. The absolute change in median worst pain intensity between lidocaine and saline injection was -2.0 (interquartile range, -4.0 to 0.0) (n = 9, P = 0.12). Nine of 9 patients reported at least some pain relief after lidocaine injection compared with only 2 of 9 patients after saline injection (P = 0.02). Phantom pain intensity was significantly reduced after lidocaine compared with saline injection (P = 0.04), whereas there was no significant change in stump pain intensity between the 2 interventions (P = 0.17). In all 9 amputees, evoked responses were eliminated after lidocaine injection. Thus, our findings suggest that afferent input from the peripheral nervous system plays an important role in postamputation pain.

Brainstem reflex excitability after high-frequency repetitive transcranial magnetic stimulation in healthy and spinal cord injury subjects

BackgroundThe excitability of brainstem interneuronal circuits is partly under control from descending inputs. Since high frequency repetitive transcranial magnetic stimulation (rTMS) modulates cortical output, we hypothesized that it will also modulate brainstem functions. Such modulation may be different in healthy subjects than in subjects with spinal cord injury (SCI), submitted to an altered integration of body afferent inputs. MethodsIn this randomized, double-blind, sham-controlled trial, we recruited 22 subjects with SCI assigned to either real (n = 11) or sham (n = 11) rTMS and nine healthy subjects, who served as control group, receiving both real (at 20 Hz, with double cone coil over vertex) and sham rTMS separated by at least one week. We recorded the blink reflex (BR) to supraorbital nerve (SON) electrical stimulation and its modification by another conditioning SON, to study the BR excitability recovery (BRER), or a prepulse electrical stimulus to the right index finger, to study the BR inhibition by prepulse (BRIP). Subjects were examined immediately before and after either sham or real rTMS. ResultsReal but not sham rTMS significantly reduced the area of the BR R2 response in both SCI and healthy subjects. There were no changes in BRER and BRIP. ConclusionrTMS over the vertex modulates brainstem reflexes with no significant differences between SCI and healthy subjects.

Connectivity and Dynamics Underlying Synaptic Control of the Subthalamic Nucleus.

Adaptive motor control critically depends on the interconnected nuclei of the basal ganglia in the CNS. A pivotal element of the basal ganglia is the subthalamic nucleus (STN), which serves as a therapeutic target for deep brain stimulation (DBS) in movement disorders, such as Parkinson's disease. The functional connectivity of the STN at the microcircuit level, however, still requires rigorous investigation. Here we combine multiple simultaneous whole-cell recordings with extracellular stimulation and post hoc neuroanatomical analysis to investigate intrinsic and afferent connectivity and synaptic properties of the STN in acute brain slices obtained from rats of both sexes. Our data reveal an absence of intrinsic connectivity and an afferent innervation with low divergence, suggesting that STN neurons operate as independent processing elements driven by upstream structures. Hence, synchrony in the STN, a hallmark of motor processing, exclusively depends on the interactions and dynamics of GABAergic and glutamatergic afferents. Importantly, these inputs are subject to differential short-term depression when stimulated at high, DBS-like frequencies, shifting the balance of excitation and inhibition toward inhibition. Thus, we present a mechanism for fast yet transient decoupling of the STN from synchronizing afferent control. Together, our study provides new insights into the microcircuit organization of the STN by identifying its neurons as parallel processing units and thus sets new constraints for future computational models of the basal ganglia. The observed differential short-term plasticity of afferent inputs further offers a basis to better understand and optimize DBS algorithms.SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a pivotal element of the basal ganglia and serves as target for deep brain stimulation, but information on the functional connectivity of its neurons is limited. To investigate the STN microcircuitry, we combined multiple simultaneous patch-clamp recordings and neuroanatomical analysis. Our results provide new insights into the synaptic organization of the STN identifying its neurons as parallel processing units and thus set new constraints for future computational models of the basal ganglia. We further find that synaptic dynamics of afferent inputs result in a rapid yet transient decoupling of the STN when stimulated at high frequencies. These results offer a better understanding of deep brain stimulation mechanisms, promoting the development of optimized algorithms.

Efficacy of Kinesio Taping and McConnell Taping Techniques in the Management of Anterior Knee Pain

Anterior knee pain also known as patellofemoral pain syndrome is a frequently encountered musculoskeletal disorder that worsens with activity. The multifactorial etiology of patellofemoral pain syndrome alters lower-extremity mechanics, increasing patellofemoral joint stresses during weight-bearing tasks. Kinesio and McConnell tapings are often incorporated into the treatment, but their efficacy is still unclear. To test the efficacy of Kinesio taping, McConnell taping, and sham taping in improving knee mechanics and reducing pain during activity. Cross-sectional design. Clinical biomechanics laboratory. Ten participants (age: 20.3 [1.5]y, height: 169.9 [10.4]cm, and mass: 70.17 [13.1]kg) with anterior knee pain and no history of trauma. Three trials each of squat, drop jump, and step-down tasks with 3 taping conditions in a counterbalanced order. Two-dimensional motion capture data of lower-extremities in frontal and sagittal planes were recorded and analyzed using 3 iPads and Spark Motion® application. Pooled effect sizes (Hedges' g), 95% confidence intervals, and repeated-measures analysis of variance (P < .05) compared baseline and taping conditions during exercises for pain Visual Analog Scale and knee flexion in all exercises, hip abduction during step-down and drop jump, frontal plane projection during step-downs, and knee translation in sagittal plane during squats. Significant reductions in Visual Analog Scale were recorded during squats between tapes (F2.505,12.867 = 3.407, P = .04, Hedges' g = -0.70). Pairwise comparison showed a decrease in Visual Analog Scale for sham taping (mean difference = 1.14cm, P = .01) and Kinesio taping (mean difference = 1.54cm, P = .02) compared with baseline during squats. A variety of taping methods can potentially reduce perceived pain in individuals with patellofemoral pain syndrome, allowing clinicians to perform rehabilitation exercises. Sensory effects associated with short-term taping may be sufficient enough to modify knee pain acutely by afferent input blocking nocioceptive pain before the participants could adapt. Most interestingly, the sham taping technique demonstrated promise for enhancing functional outcomes, depending on the length of the tape and area covered.

Spinal Hyper-Excitability and Altered Muscle Structure Contribute to Muscle Hypertonia in Newborns After Antenatal Hypoxia-Ischemia in a Rabbit Cerebral Palsy Model.

Rabbit kits after global antenatal hypoxic-ischemic injury exhibit motor deficits similar to humans with cerebral palsy. We tested several mechanisms previously implicated in spinal hyper-excitability after perinatal brain injury that may explain muscle hypertonia in newborns. Stiffness of hind limb muscles during passive stretch, electromyogram, and spinal excitability by Hoffman reflex, were assessed in rabbit kits with muscle hypertonia after global hypoxic-ischemic brain injury and naïve controls. Affected muscle architecture, motoneuron morphology, primary afferents density, gliosis, and KCC2 expression transporter in the spinal cord were also examined. Decrease knee stiffness after anesthetic administration was larger, but residual stiffness was higher in hypertonic kits compared to controls. Hypertonic kits exhibited muscle shortening and atrophy, in both agonists and antagonists. Sarcomere length was longer in tibialis anterior in hypertonic kits than in controls. Hypertonic kits had decreased rate dependent depression and increased Hmax/Mmax in H-reflex. Motor neuron soma sizes, primary afferent density were not different between controls and hypertonic kits. Length of dendritic tree and ramification index were lower in hypertonic group. Gene expression of KCC2 was lower in hypertonic kits, but protein content was not different between the groups. In conclusion, while we found evidence of decreased supraspinal inhibitory control and increased excitability by H-reflex that may contribute to neuronal component in hypertonia, increased joint resistance to stretch was explained predominantly by changes in passive properties of muscles and joints. We did not find structural evidence of increased sensory afferent input or morphological changes in motoneurons that might explain increased excitability. Gliosis, observed in spinal gray matter, may contribute to muscle hypertonia.

Sensorimotor Cortical Activity in Acute Low Back Pain: A Cross-Sectional Study

Sensorimotor cortical activity is altered in both the immediate acute and chronic stages of musculoskeletal pain. However, these changes are opposite, with decreased cortical activity reported in experimentally induced acute pain (lasting minutes to hours), and increased cortical activity in chronic, clinical pain (lasting >6 months). It is unknown whether sensorimotor cortical activity is altered in acute, clinical musculoskeletal pain (lasting <4 weeks). In 36 individuals with acute, nonspecific, clinical low back pain (LBP) and 36 age- and sex-matched, pain-free controls, we investigated the processing of non-noxious afferent inputs using sensory evoked potentials (SEPs), as well as corticomotor excitability and organization of the primary motor cortex using transcranial magnetic stimulation. Processing of non-noxious sensory inputs was lower (smaller area of the N80–N150–P260 SEP complex) in acute LBP (F1,70 = 45.28, P < .01). The examination of specific SEP components revealed a smaller area of the N150 and P260 SEP components in acute LBP, although interindividual variability was high. Motor cortical map volume was lower in acute LBP (F1,70 = 5.61, P = .02). These findings demonstrate that acute LBP is characterized by lower sensorimotor cortical activity at the group level. However, individual variation was high, suggesting individual adaptation of cortical plasticity in acute pain. PerspectiveThis is the first study to examine sensorimotor cortical activity in the acute stage of clinical LBP. This information is critical for understanding the neurophysiology of acute LBP.

Supplementary Motor Area and Superior Parietal Lobule Restore Sensory Facilitation Prior to Stepping When a Decrease of Afferent Inputs Occurs.

The weighting of the sensory inputs is not uniform during movement preparation and execution. For instance, a transient increase in the transmission to the cortical level of cutaneous input ~700 ms was observed before participants initiated a step forward. The sensory facilitation occurred at a time when feet cutaneous information is critical for setting the forces to be exerted onto the ground to shift the center of mass toward the supporting side prior to foot-off. Despite clear evidence of task-dependent modulation of the early somatosensory signal transmission, the neural mechanisms are mainly unknown. One hypothesis suggests that during movement preparation the premotor cortex and specifically the supplementary motor area (SMA) can be the source of an efferent signal that facilitates the somatosensory processes irrespectively of the amount of sensory inputs arriving at the somatosensory areas. Here, we depressed mechanically the plantar sole cutaneous transmission by increasing pressure under the feet by adding an extra body weight to test whether the task-dependent modulation is present during step preparation. Results showed upregulation of the neural response to tactile stimulation in the extra-weight condition during the stepping preparation whereas depressed neural response was still observed in standing condition. Source localization indicated the SMA and to a lesser extent the superior parietal lobule (SPL) areas as the likely origin of the response modulation. Upregulating cutaneous inputs (when mechanically depressed) at an early stage by efferent signals from the motor system could be an attempt to restore the level of sensory afferents to make it suitable for setting the anticipatory adjustments prior to step initiation.

The influence of High Dose Spinal Cord Stimulation on the descending pain modulatory system in patients with failed back surgery syndrome.

The descending pain modulatory system (DPMS) comprises a network of cortical and subcortical brain and brainstem regions that can inhibit nociceptive afferent brain input (Ossipov et al., 2010; Tracey, 2010; Zhuo and Gebhart, 1997). These pathways seem to be altered in several chronic pain syndromes such as knee osteoarthritis, fibromyalgia, painful diabetic neuropathy and low back pain (Brietzke et al., 2019; da Graca-Tarrago et al., 2019; Kong et al., 2018; Segerdahl et al., 2018). The DPMS network comprises the bilateral anterior insulae (AI), the anterior cingulate cortex (ACC), bilateral middle frontal gyri (mFG), both amygdalae (AMY), the rostral ventromedial medulla (RVM) and the periaqueductal gray (PAG) (Goksan et al., 2018; Schweinhardt and Bushnell, 2010). In the past, it has been suggested that traditional, paresthesia-generating Spinal Cord Stimulation (SCS) induces several changes in modulation circuits located in the cerebrum and brainstem. An inhibitory effect of traditional SCS on somatosensory evoked potentials, and potential mediators like the thalamus and the anterior cingulate cortex (ACC), could play a role in the mechanism of action (MOA) of SCS as well (Bentley et al., 2016; De Ridder and Vanneste, 2016; Moens et al., 2013, 2012). Several studies have provided evidence of the impact of SCS on the DPMS resulting in this inhibitory supraspinal effect (Sankarasubramanian et al., 2018; Schuh-Hofer et al., 2018). More recently, researchers have hypothesized similar influences on the DPMS by other paradigms of SCS such as high frequency SCS at 10 kHz and Burst SCS, as well as by other forms of neurostimulation e.g. occipital nerve field stimulation (Ahmed et al., 2018a, 2018c). Tonic SCS at sub-sensory threshold and at 500 Hz and pulse width 500μsec, so called high density or high dose SCS (HD-SCS), is a SCS form based on the impact of electrical charge delivery to the spinal cord (Chen et al., 2018; Linderoth and Foreman, 2017; Miller et al., 2016; Sweet et al., 2016; Wille et al., 2017). After some initial case series studies, researchers are still exploring the clinical effect and impact on chronic pain of HD-SCS (De Jaeger et al., 2017; Provenzano et al., 2017; Wille et al., 2017). In the past, several researchers have investigated the supraspinal effects of SCS by examining human cerebral circuits via different neuroimaging techniques (e.g. MR Spectroscopy (MRS), single photon emission computerized tomography (SPECT), positron emission tomography (PET), electroencephalography (EEG) and, functional magnetic resonance imaging (fMRI)) to capture alterations in modulation circuits (De Ridder and Vanneste, 2016; Kishima et al., 2010; Moens et al., 2013, 2012; Nagamachi et al., 2006). fMRI is especially interesting due to the robustness and test-retest reliability of the functional connectivity (FC) method in clinical applications (Apkarian, 2015; Shehzad et al., 2009). Additionally, the introduction of MRI-conditioned SCS devices enables further exploration of MOA of SCS, not only during trial period but also on long-term implanted devices. Based on this knowledge, we hypothesized, in this study, that HD-SCS may alter the DPMS and indirectly, might generate an inhibitory supraspinal effect. This hypothesis-driven pilot study aimed to investigate the influence of HD-SCS on FC within the DPMS, measured by resting state fMRI.

Sex differences in the contributions of spinal atypical PKCs and downstream targets to the maintenance of nociceptive sensitization.

BackgroundChronic pain has been shown to depend on nociceptive sensitization in the spinal cord, and while multiple mechanisms involved in the initiation of plastic changes have been established, the molecular targets which maintain spinal nociceptive sensitization are still largely unknown. Building upon the established neurobiology underlying the maintenance of long-term potentiation in the hippocampus, this present study investigated the contributions of spinal atypical protein kinase C (PKC) isoforms PKCι/λ and PKMζ and their downstream targets (p62/GluA1 and NSF/GluA2 interactions, respectively) to the maintenance of spinal nociceptive sensitization in male and female rats.ResultsPharmacological inhibition of atypical PKCs by ZIP reversed established allodynia produced by repeated intramuscular acidic saline injections in male animals only, replicating previously demonstrated sex differences. Inhibition of both PKCι/λ and downstream substrates p62/GluA1 resulted in male-specific reversals of intramuscular acidic saline-induced allodynia, while female animals continued to display allodynia. Inhibition of NSF/GluA2, the downstream target to PKMζ, reversed allodynia induced by intramuscular acidic saline in both sexes. Neither PKCι/λ, p62/GluA1 or NSF/GluA2 inhibition had any effect on formalin response for either sex.ConclusionThis study provides novel behavioural evidence for the male-specific role of PKCι/λ and downstream target p62/GluA1, highlighting the potential influence of ongoing afferent input. The sexually divergent pathways underlying persistent pain are shown here to converge at the interaction between NSF and the GluA2 subunit of the AMPA receptor. Although this interaction is thought to be downstream of PKMζ in males, these findings and previous work suggest that females may rely on a factor independent of atypical PKCs for the maintenance of spinal nociceptive sensitization.

Defining a Spinal Microcircuit that Gates Myelinated Afferent Input: Implications for Tactile Allodynia

Chronic pain presents a major unmet clinical problem. One of the most common symptoms of chronic pain is tactile allodynia, where previously innocuous mechanical stimuli are perceived as painful. To help develop more effective analgesics to treat this condition, a better understanding of the neuronal circuits underlying sensory perception in necessary. We have shown that inhibitory interneurons in the spinal dorsal horn that express parvalbumin (PV) form axoaxonic synapses on to the central terminals of low threshold mechanoreceptive (LTMR) afferents. Here, we define a spinal microcircuit comprising of LTMR afferents, inhibitory PV interneurons, and glutamatergic vertical cells whose axons project to lamina I, that explains how LTMR input can activate pain circuits under pathological conditions. We show that these PV cells receive monosynaptic input from myelinated LTMR afferents from both hairy and glabrous skin. We also determine that these interneurons are the source of axoaxonic synapses on to the central terminals of LTMR afferents that appose vertical cells, forming triadic synaptic arrangements. Furthermore, we provide evidence that these interneurons generate both GABAergic presynaptic inhibition of myelinated LTMR afferents, and postsynaptic inhibition of vertical cells through the release of GABA and glycine. In neuropathic mice, PV cell excitability is reduced, but we find no evidence of structural plasticity. Taken together, these findings show that PV cell-mediated presynaptic inhibition of LTMR afferents and postsynaptic inhibition of vertical cells both play critical roles in the normal perception of mechanical stimuli, and identify this microcircuit as a target for therapeutic intervention to alleviate allodynia.

Synaptic Reorganization Response in the Cochlear Nucleus Following Intense Noise Exposure

The cochlear nucleus, located in the brainstem, receives its afferent auditory input exclusively from the auditory nerve fibers of the ipsilateral cochlea. Noise-induced neurodegenerative changes occurring in the auditory nerve stimulate a cascade of neuroplastic changes in the cochlear nucleus resulting in major changes in synaptic structure and function. To identify some of the key molecular mechanisms mediating this synaptic reorganization, we unilaterally exposed rats to a high-intensity noise that caused significant hearing loss and then measured the resulting changes in a synaptic plasticity gene array targeting neurogenesis and synaptic reorganization. We compared the gene expression patterns in the dorsal cochlear nucleus (DCN) and ventral cochlear nucleus (VCN) on the noise-exposed side versus the unexposed side using a PCR gene array at 2 d (early) and 28 d (late) post-exposure. We discovered a number of differentially expressed genes, particularly those related to synaptogenesis and regeneration. Significant gene expression changes occurred more frequently in the VCN than the DCN and more changes were seen at 28 d versus 2 d post-exposure. We confirmed the PCR findings by in situ hybridization for Brain-derived neurotrophic factor (Bdnf), Homer-1, as well as the glutamate NMDA receptor Grin1, all involved in neurogenesis and plasticity. These results suggest that Bdnf, Homer-1 and Grin1 play important roles in synaptic remodeling and homeostasis in the cochlear nucleus following severe noise-induced afferent degeneration.

Disparate forms of heterogeneities and interactions among them drive channel decorrelation in the dentate gyrus: Degeneracy and dominance.

The ability of a neuronal population to effectuate channel decorrelation, which is one form of response decorrelation, has been identified as an essential prelude to efficient neural encoding. To what extent are diverse forms of local and afferent heterogeneities essential in accomplishing channel decorrelation in the dentate gyrus (DG)? Here, we incrementally incorporated four distinct forms of biological heterogeneities into conductance‐based network models of the DG and systematically delineate their relative contributions to channel decorrelation. First, to effectively incorporate intrinsic heterogeneities, we built physiologically validated heterogeneous populations of granule (GC) and basket cells (BC) through independent stochastic search algorithms spanning exhaustive parametric spaces. These stochastic search algorithms, which were independently constrained by experimentally determined ion channels and by neurophysiological signatures, revealed cellular‐scale degeneracy in the DG. Specifically, in GC and BC populations, disparate parametric combinations yielded similar physiological signatures, with underlying parameters exhibiting significant variability and weak pair‐wise correlations. Second, we introduced synaptic heterogeneities through randomization of local synaptic strengths. Third, in including adult neurogenesis, we subjected the valid model populations to randomized structural plasticity and matched neuronal excitability to electrophysiological data. We assessed networks comprising different combinations of these three local heterogeneities with identical or heterogeneous afferent inputs from the entorhinal cortex. We found that the three forms of local heterogeneities were independently and synergistically capable of mediating significant channel decorrelation when the network was driven by identical afferent inputs. However, when we incorporated afferent heterogeneities into the network to account for the divergence in DG afferent connectivity, the impact of all three forms of local heterogeneities was significantly suppressed by the dominant role of afferent heterogeneities in mediating channel decorrelation. Our results unveil a unique convergence of cellular‐ and network‐scale degeneracy in the emergence of channel decorrelation in the DG, whereby disparate forms of local and afferent heterogeneities could synergistically drive input discriminability.