Compensatory Plasticity Research Articles

The Gigantocellular Reticular Nucleus Plays a Significant Role in Locomotor Recovery after Incomplete Spinal Cord Injury.

Traditionally, the brainstem has been seen as hardwired and poorly capable of plastic adaptations following spinal cord injury (SCI). Data acquired over the past decades, however, suggest differently: following SCI in various animal models (lamprey, chick, rodents, nonhuman primates), different forms of spontaneous anatomic plasticity of reticulospinal projections, many of them originating from the gigantocellular reticular nucleus (NRG), have been observed. In line with these anatomic observations, animals and humans with incomplete SCI often show various degrees of spontaneous motor recovery of hindlimb/leg function. Here, we investigated the functional relevance of two different modes of reticulospinal fiber growth after cervical hemisection, local rewiring of axotomized projections at the lesion site versus compensatory outgrowth of spared axons, using projection-specific, adeno-associated virus-mediated chemogenetic neuronal silencing. Detailed assessment of joint movements and limb kinetics during overground locomotion in female adult rats showed that locally rewired as well as compensatory NRG fibers were responsible for different aspects of recovered forelimb and hindlimb functions (i.e., stability, strength, coordination, speed, or timing). During walking and swimming, both locally rewired as well as compensatory NRG plasticity were crucial for recovered function, while the contribution of locally rewired NRG plasticity to wading performance was limited. Our data demonstrate comprehensively that locally rewired as well as compensatory plasticity of reticulospinal axons functionally contribute to the observed spontaneous improvement of stepping performance after incomplete SCI and are at least partially causative to the observed recovery of function, which can also be observed in human patients with spinal hemisection lesions.SIGNIFICANCE STATEMENT Following unilateral hemisection of the spinal cord, reticulospinal projections are destroyed on the injured side, resulting in impaired locomotion. Over time, a high degree of recovery can be observed in lesioned animals, like in human hemicord patients. In the rat, recovery is accompanied by pronounced spontaneous plasticity of axotomized and spared reticulospinal axons. We demonstrate the causative relevance of locally rewired as well as compensatory reticulospinal plasticity for the recovery of locomotor functions following spinal hemisection, using chemogenetic tools to selectively silence newly formed connections in behaviorally recovered animals. Moving from a correlative to a causative understanding of the role of neuroanatomical plasticity for functional recovery is fundamental for successful translation of treatment approaches from experimental studies to the clinics.

Electrophysiological Dynamics of Visual-Tactile Temporal Order Perception in Early Deaf Adults.

Studies of compensatory plasticity in early deaf (ED) individuals have mainly focused on unisensory processing, and on spatial rather than temporal coding. However, precise discrimination of the temporal relationship between stimuli is imperative for successful perception of and interaction with the complex, multimodal environment. Although the properties of cross-modal temporal processing have been extensively studied in neurotypical populations, remarkably little is known about how the loss of one sense impacts the integrity of temporal interactions among the remaining senses. To understand how auditory deprivation affects multisensory temporal interactions, ED and age-matched normal hearing (NH) controls performed a visual-tactile temporal order judgment task in which visual and tactile stimuli were separated by varying stimulus onset asynchronies (SOAs) and subjects had to discern the leading stimulus. Participants performed the task while EEG data were recorded. Group averaged event-related potential waveforms were compared between groups in occipital and fronto-central electrodes. Despite similar temporal order sensitivities and performance accuracy, ED had larger visual P100 amplitudes for all SOA levels and larger tactile N140 amplitudes for the shortest asynchronous (± 30 ms) and synchronous SOA levels. The enhanced signal strength reflected in these components from ED adults are discussed in terms of compensatory recruitment of cortical areas for visual-tactile processing. In addition, ED adults had similar tactile P200 amplitudes as NH but longer P200 latencies suggesting reduced efficiency in later processing of tactile information. Overall, these results suggest that greater responses by ED for early processing of visual and tactile signals are likely critical for maintained performance in visual-tactile temporal order discrimination.

Increased Right Posterior STS Recruitment Without Enhanced Directional-Tuning During Tactile Motion Processing in Early Deaf Individuals.

Upon early sensory deprivation, the remaining modalities often exhibit cross-modal reorganization, such as primary auditory cortex (PAC) recruitment for visual motion processing in early deafness (ED). Previous studies of compensatory plasticity in ED individuals have given less attention to tactile motion processing. In the current study, we aimed to examine the effects of early auditory deprivation on tactile motion processing. We simulated four directions of tactile motion on each participant’s right index finger and characterized their tactile motion responses and directional-tuning profiles using population receptive field analysis. Similar tactile motion responses were found within primary (SI) and secondary (SII) somatosensory cortices between ED and hearing control groups, whereas ED individuals showed a reduced proportion of voxels with directionally tuned responses in SI contralateral to stimulation. There were also significant but minimal responses to tactile motion within PAC for both groups. While early deaf individuals show significantly larger recruitment of right posterior superior temporal sulcus (pSTS) region upon tactile motion stimulation, there was no evidence of enhanced directional tuning. Greater recruitment of right pSTS region is consistent with prior studies reporting reorganization of multimodal areas due to sensory deprivation. The absence of increased directional tuning within the right pSTS region may suggest a more distributed population of neurons dedicated to processing tactile spatial information as a consequence of early auditory deprivation.

Dysregulation of external globus pallidus-subthalamic nucleus network dynamics in parkinsonian mice during cortical slow-wave activity and activation.

Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Using cell class-specific optogenetic identification and inhibition during cortical slow-wave activity and activation, we report that, in dopamine-depleted mice, (1) D2 dopamine receptor expressing striatal projection neurons (D2-SPNs) discharge at higher rates, especially during cortical activation, (2) prototypic parvalbumin-expressing GPe neurons are excessively patterned by D2-SPNs even though their autonomous activity is upregulated, (3) despite being disinhibited, STN neurons are not hyperactive, and (4) STN activity opposes striatopallidal patterning. These data argue that in parkinsonian mice abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment. Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally positioned network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Following the loss of dopamine, the activities of GPe and STN neurons become more temporally offset and strongly correlated with cortical oscillations below 40Hz. Previous studies utilized cortical slow-wave activity and/or cortical activation (ACT) under anaesthesia to probe the mechanisms underlying the normal and pathological patterning of basal ganglia activity. Here, we combined this approach with in vivo optogenetic inhibition to identify and interrupt the activity of D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs), parvalbumin-expressing prototypic GPe (PV GPe) neurons, and STN neurons. We found that, in dopamine-depleted mice, (1) the firing rate of D2-SPNs was elevated, especially during cortical ACT, (2) abnormal phasic suppression of PV GPe neuron activity was ameliorated by optogenetic inhibition of coincident D2-SPN activity, (3) autonomous PV GPe neuron firing ex vivo was upregulated, presumably through homeostatic mechanisms, (4) STN neurons were not hyperactive, despite being disinhibited, (5) optogenetic inhibition of the STN exacerbated abnormal GPe activity, and (6) exaggerated beta band activity was not present in the cortex or GPe-STN network. Together with recent studies, these data suggest that in dopamine-depleted mice abnormally correlated and temporally offset PV GPe and STN neuron activity is generated in part by elevated striatopallidal transmission, while compensatory plasticity prevents STN hyperactivity and limits cortical entrainment.

Compensatory Plasticity of Breathing in Patients with Neuromuscular Disease

Neuromuscular diseases are comprised of variable, often inherited conditions and characterized by muscular (e.g. Duchenne muscular dystrophy), neural (e.g. amyotrophic lateral sclerosis) or a mixed neuromuscular (e.g. Pompe disease) dysfunction. While individual neuromuscular disorders differ in the underlying mechanism and exhibit a unique disease presentation, the consistently leading cause of morbidity and mortality is respiratory failure. Loss of breathing function is literally a “life‐or‐death" issue for patients. Clinical management of breathing relies upon pulmonary function tests to estimate the degree of respiratory involvement in patients, but standard pulmonary function test results can be biased by learning, cognition, or poor effort. This presentation will discuss compensatory neuromuscular adaptations to preserve breathing in the face of worsening disease, including changes in neural drive, neuromuscular junction plasticity, and a greater reliance on less‐affected respiratory motor pools. Detection of these adaptations is needed for prescribing supportive therapies with greater precision and identifying clinically meaningful changes in response to treatments. Citing natural history studies from our team and others, this presentation will feature clinical approaches to objectively evaluate respiratory motor control and gain mechanistic insights into neuromuscular disease. The control of breathing will then be discussed in the context of clinical trials, with an emphasis on current and emerging treatments directed toward improvements in ventilation. Examples will highlight basic‐clinical collaborations that promote new therapeutic frontiers for patients with neuromuscular disease.Support or Funding InformationThis work is supported by National Institutes of Health awards R21 HD090752 and U01 HL121842.

Inhibition of Spinal Inflammation Restores Compensatory Plasticity Induced by Recurrent Reductions in Respiratory Neural Activity in Offspring Exposed to Gestational Intermittent Hypoxia

Sleep disordered breathing (SDB) during pregnancy is increasing in parallel with the obesity epidemic, yet the long‐term effects on the adult offspring are unknown. In our animal model of SDB during pregnancy, pregnant rats are exposed to chronic intermittent hypoxia (8 hrs/day, 2 min 10.5% O2 separated by 2 min of 21% O2) or intermittent normoxia from gestational days 10–21. Preliminary data show that adult male (but not female) offspring exposed to gestational intermittent hypoxia (GIH) show deficits in respiratory control that manifest as increased spontaneous central apneas during presumptive sleep and impaired compensatory responses to recurrent reductions in respiratory neural activity, a form of plasticity known as inactivity‐induced inspiratory motor facilitation (iMF). Preliminary data also show that microglia isolated from male GIH offspring show primed inflammatory responses in respiratory control regions. Since neuroinflammation impairs respiratory plasticity, we tested the hypothesis that inhibiting NF‐kappaB and STAT3 inflammatory transcription factor activation restores the capacity to elicit iMF in GIH offspring. Phrenic inspiratory output was measured in urethane‐anesthetized, vagotomized, mechanically ventilated GIH or gestational intermittent normoxia (GNX) offspring. Vehicle or 2‐[(aminocarbonyl)amino]‐5 ‐(4‐fluorophenyl)‐3‐ thiophenecarboxamide (TPCA‐1) was delivered intrathecally over the phrenic motor pool ~1 hour before exposure to recurrent reductions in neural activity (5, ~1 min neural apnea episodes, separated by 5 min). As expected, recurrent neural apnea elicited a significant increase in phrenic inspiratory output in vehicle‐ and TPCA‐treated GNX offspring (54±17% and 62±12% baseline, n=6, 5, respectively, p<0.05) when compared to time controls not receiving activity deprivation (11±4% baseline, n=4). By contrast, recurrent neural apnea did not elicit iMF in vehicle‐treated GIH offspring (25±3%, n=7, p>0.05). However, in GIH offspring receiving intrathecal TPCA‐1, recurrent neural apnea induced a significant increase in phrenic inspiratory output (75+/−10% baseline, n=7, p<0.05), indicating that NF‐kappaB and STAT3 inflammatory transcription factor inhibition rescues the capacity to elicit iMF in GIH offspring. These data indicate that increased neuroinflammation in male GIH offspring impairs the capacity for recurrent reductions in respiratory neural activity to trigger compensatory forms of neuroplasticity.Support or Funding InformationSupported by R01HL142752 (JJW and TLB)

Perspective-Taking in Blindness: An Event- Related Brain Potentials Study With the Continuous Wavelet Transform

This study presents brain electrophysiological characteristics of perspective-taking for blind individuals ver. sighted ones, aiming to extend our knowledge on social concept formation with visual sensory modality loss. A blind and a sighted group instructed to consider the moral dilemmas therein from a neutral (observer), a morally positive or a negative stance, after the auditory presentation of Aesop’s fables. We recorded the basic emotions evoked by every stance in each fable, and the late positive potentials (LPP) component of Event-Related Potential detected with Continuous Wavelet Transform, believed to reflect the sustained attention and stimuli encoding processes. Blind participants demonstrated: i) significantly attenuated LPP amplitudes at distributed brain areas, particularly at leads T3, P4, O2, T6, Cz, Pz, CPz and CP4 (p values 0.026-0.003), ii) prolonged LPP latencies at parietal areas, at leads CP4 (p=0.009), Pz (p=0.019), and P4 (p=0.023), iii) shorter latencies at the frontal area (lead FPz, p=0.026) and iv) significantly shorter latencies at the right posterior centrotemporal area under the negative than the positive condition (lead C4, p=0.009). Both groups exhibited higher LPP amplitudes under the morally positive, and lower under the negative condition located at the parietal areas (P3, p=0.001 and CPz, p=0.013). The relationships between behavior and LPP activation conform to the proposed generation and modulation of LPP. Our findings suggest that the visually deprived cortex may become more responsive to processes associated with perspective-taking, possibly through compensatory plasticity enabling cross-modal reorganization. Thus, the study introduces a novel model for accessing the sustained attention and stimulus-encoding processes underlying perspective-taking.

RARE-14. STRUCTURAL BRAIN PLASTICITY OF THE GRAY MATTER IN PATIENTS WITH BASAL GANGLIA GERM CELL TUMORS: A VBM STUDY

Abstract OBJECTIVE To assess the whole brain structural plasticity in case of unilateral basal ganglia germ cell tumors (BGGCTs). METHODS To detect changes in gray matter volume of the whole brain from structural Magnetic Resonance Imaging (MRI), we used voxel-based morphometry (VBM) in a sample of 41 patients with BGGCTs invading the left basal ganglia (BasalG_L group; n = 22) or the right basal ganglia (BasalG_R group; n = 19) and a sample of 16 patients with GCTs arising in pineal or suprasellar regions, comparing these groups with 16 age-matched normal controls (NCs) by two-sample t test after that. RESULTS To left BGGCTs patients, the regions of whole brain VBM analysis emphasized a large cluster of voxels with gray matter volume increase in left para hippocampal (k = 529 voxels, T=4.18, p< 0.01) and decrease in left thalamus (k = 527 voxels, T=-4.88, p< 0.01). At the same time, the cluster of voxels with gray matter volume increase in right middle cingulate cortex (rMCC) (k = 172 voxels, T=3.96, p< 0.01), and decrease in right inferior frontal gyrus (rIFG), pars opercular (k = 495 voxels, T= -4.29, p< 0.01) in right BGGCTs patients. Furthermore, gray matter volume showed no significant difference between groups of patients with GCTs arising in pineal or suprasellar regions and NCs by two-sample t test. And the results were corrected by family-wise-error correction. CONCLUSIONS The revealed results demonstrate that slow-growing but destructive lesion of the BGGCTs markedly and asymmetrically atrophies the gray matter volume in specific brain regions and shows compensatory plasticity in each side of cerebral hemisphere. Our findings direct focus on the whole cerebral adaptation that perhaps be a physiologic basis for the high level of functional compensation and partially explain the relationships between gray matter remodeling and cognitive disturbances observed in patients with BGGCTs.

Increased Gain in the Auditory Pathway, Alzheimer's Disease Continuum, and Air Pollution: Peripheral and Central Auditory System Dysfunction Evolves Across Pediatric and Adult Urbanites.

A major impediment in early diagnosis of Alzheimer's disease (AD) is the lack of robust non-invasive biomarkers of early brain dysfunction. Metropolitan Mexico City (MMC) children and young adults show hyperphosphorylated tau, amyloid-β, and α-synuclein within auditory and vestibular nuclei and marked dysmorphology in the ventral cochlear nucleus and superior olivary complex. Based on early involvement of auditory brainstem centers, we believe brainstem auditory evoked potentials can provide early AD biomarkers in MMC young residents. We measured brainstem auditory evoked potentials in MMC clinically healthy children (8.52±3.3 years) and adults (21.08±3.0 years, 42.48±8.5 years, and 71.2±6.4 years) compared to clean air controls (6.5±0.7 years) and used multivariate analysis adjusting for age, gender, and residency. MMC children had decreased latency to wave I, delays in waves III and V, and longer latencies for interwave intervals, consistent with delayed central conduction time of brainstem neural transmission. In sharp contrast, young adults have significantly shortened interwave intervals I-III and I-V. By the 5th decade, wave V and interval I-V were significantly shorter, while the elderly cohort had significant delay in mean latencies and interwave intervals. Compensatory plasticity, increased auditory gain, cochlear synaptopathy, neuroinflammation, and AD continuum likely play a role in the evolving distinct auditory pathology in megacity urbanites. Understanding auditory central and peripheral dysfunction in the AD continuum evolving and progressing in pediatric and young adult populations may shed light on the complex mechanisms of AD development and help identify strong noninvasive biomarkers. AD evolving from childhood in air pollution environments ought to be preventable.

Competing mechanisms of plasticity impair compensatory responses to repetitive apnoea.

Intermittent reductions in respiratory neural activity, a characteristic of many ventilatory disorders, leads to inadequate ventilation and arterial hypoxia. Both intermittent reductions in respiratory neural activity and intermittent hypoxia trigger compensatory enhancements in inspiratory output when experienced separately, forms of plasticity called inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. Reductions in respiratory neural activity that lead to moderate, but not mild, arterial hypoxia occludes plasticity expression, indicating that concurrent induction of iMF and LTF impairs plasticity through cross-talk inhibition of their respective signalling pathways. Moderate hypoxia undermines iMF by enhancing NR2B-containing NMDA receptor signalling, which can be rescued by exogenous retinoic acid, a molecule necessary for iMF. These data suggest that in ventilatory disorders characterized by reduced inspiratory motor output, such as sleep apnoea, endogenous mechanisms of compensatory plasticity may be impaired, and that exogenously activating respiratory plasticity may be a novel strategy to improve breathing. Many forms of sleep apnoea are characterized by recurrent reductions in respiratory neural activity, which leads to inadequate ventilation and arterial hypoxia. Both recurrent reductions in respiratory neural activity and hypoxia activate mechanisms of compensatory plasticity that augment inspiratory output and lower the threshold for apnoea, inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. However, despite frequent concurrence of reduced respiratory neural activity and hypoxia, mechanisms that induce and regulate iMF and LTF have only been studied separately. Here, we demonstrate that recurrent reductions in respiratory neural activity ('neural apnoea') accompanied by cessations in ventilation that result in moderate (but not mild) hypoxaemia do not elicit increased inspiratory output, suggesting that concurrent induction of iMF and LTF occludes plasticity. A key role for NMDA receptor activation in impairing plasticity following concurrent neural apnoea and hypoxia is indicated since recurrent hypoxic neural apnoeas triggered increased phrenic inspiratory output in rats in which spinal NR2B-containing NMDA receptors were inhibited. Spinal application of retinoic acid, a key molecule necessary for iMF, bypasses NMDA receptor-mediated constraints, thereby rescuing plasticity following hypoxic neural apnoeas. These studies raise the intriguing possibility that endogenous mechanisms of compensatory plasticity may be impaired in some individuals with sleep apnoea, and that exogenously activating pathways giving rise to respiratory plasticity may be a novel pharmacological strategy to improve breathing.

Compensatory Plasticity in the Lateral Extrastriate Visual Cortex Preserves Audiovisual Temporal Processing following Adult-Onset Hearing Loss

Partial hearing loss can cause neurons in the auditory and audiovisual cortices to increase their responsiveness to visual stimuli; however, behavioral studies in hearing-impaired humans and rats have found that the perceptual ability to accurately judge the relative timing of auditory and visual stimuli is largely unaffected. To investigate the neurophysiological basis of how audiovisual temporal acuity may be preserved in the presence of hearing loss-induced crossmodal plasticity, we exposed adult rats to loud noise and two weeks later performed in vivo electrophysiological recordings in two neighboring regions within the lateral extrastriate visual (V2L) cortex—a multisensory zone known to be responsive to audiovisual stimuli (V2L-Mz) and a predominantly auditory zone (V2L-Az). To examine the cortical layer-specific effects at the level of postsynaptic potentials, a current source density (CSD) analysis was applied to the local field potential (LFP) data recorded in response to auditory and visual stimuli presented at various stimulus onset asynchronies (SOAs). As predicted, differential effects were observed in the neighboring cortical regions' postnoise exposure. Most notably, an analysis of the strength of multisensory response interactions revealed that V2L-Mz lost its sensitivity to the relative timing of the auditory and visual stimuli, due to an increased responsiveness to visual stimulation that produced a prominent audiovisual response irrespective of the SOA. In contrast, not only did the V2L-Az in noise-exposed rats become more responsive to visual stimuli but neurons in this region also inherited the capacity to process audiovisual stimuli with the temporal precision and specificity that was previously restricted to the V2L-Mz. Thus, the present study provides the first demonstration that audiovisual temporal processing can be preserved following moderate hearing loss via compensatory plasticity in the higher-order sensory cortices that is ultimately characterized by a functional transition in the cortical region capable of temporal sensitivity.

Early Blindness Shapes Cortical Representations of Auditory Frequency within Auditory Cortex.

Early loss of vision is classically linked to large-scale cross-modal plasticity within occipital cortex. Much less is known about the effects of early blindness on auditory cortex. Here, we examine the effects of early blindness on the cortical representation of auditory frequency within human primary and secondary auditory areas using fMRI. We observe that 4 individuals with early blindness (2 females), and a group of 5 individuals with anophthalmia (1 female), a condition in which both eyes fail to develop, have lower response amplitudes and narrower voxelwise tuning bandwidths compared with a group of typically sighted individuals. These results provide some of the first evidence in human participants for compensatory plasticity within nondeprived sensory areas as a result of sensory loss.SIGNIFICANCE STATEMENT Early blindness has been linked to enhanced perception of the auditory world, including auditory localization and pitch perception. Here we used fMRI to compare neural responses with auditory stimuli within auditory cortex across sighted, early blind, and anophthalmic individuals, in whom both eyes fail to develop. We find more refined frequency tuning in blind subjects, providing some of the first evidence in human subjects for compensation within nondeprived primary sensory areas as a result of blindness early in life.

Microglial depletion rescues deficits in compensatory respiratory plasticity in adult offspring exposed to gestational intermittent hypoxia

Sleep disordered breathing during pregnancy is increasing at an alarming rate, but virtually nothing is known about long‐lasting effects on adult offspring physiology. Preliminary data suggest that adult rat offspring exposed to gestational intermittent hypoxia (GIH) exhibit increased spontaneous apneas during sleep. Preliminary data also suggest that microglia isolated from adult GIH offspring exhibit enhanced inflammatory gene expression and primed responses to inflammatory stimuli. Since neuroinflammation impairs some forms of respiratory plasticity, we tested the hypothesis that adult GIH offspring have impaired compensatory plasticity in response to recurrent apnea. Pregnant rat dams were exposed to chronic intermittent hypoxia (8 hrs/day, 2 min 10.5% O2 separated by 2 min of 21% O2) or intermittent normoxia from gestation days 10–21 (GIH and GNX, respectively). Respiratory plasticity was assessed by measuring the response to recurrent neural apnea in urethane‐anesthetized, mechanically ventilated GNX and GIH offspring. In GNX offspring, recurrent neural apnea (5, ~1 min neural apnea episodes, separated by 5 min) triggered a significant increase in phrenic burst amplitude (59±4% baseline, n=12, p<0.05), a form of plasticity known as inactivity‐induced inspiratory motor facilitation (iMF). By contrast, intermittent neural apnea did not trigger increased phrenic burst amplitude in GIH offspring (5±7% baseline, n=11, p>0.05), suggesting that in utero intermittent hypoxia impairs the capacity to elicit iMF. To determine if microglia participate in impairing iMF in GIH offspring, microglia were depleted with Pexidartinib (PLX3397; 80 mg/kg, 7 days po), a colony stimulating factor 1 receptor (CSFR1) inhibitor that results in microglial apoptosis. PLX3397 significantly reduced Iba1+ and CD11b+ cells throughout the brain and spinal cord (−82±8%, n=4, p<0.05), which were restored to control levels 7 days after PLX withdrawal (−6±17%, n=4, p>0.05). Preliminary data indicate that recurrent neural apnea triggered increased phrenic burst amplitude in GIH offspring receiving PLX (71±21 % baseline, n=5), suggesting that microglial depletion rescues the ability to trigger compensatory responses to recurrent neural apnea. iMF impairments in PLX‐treated GIH rats returned upon repopulation of microglia after PLX withdrawal (14±14 % baseline, n=5). PLX treatment had no impact on iMF in GNX offspring (75±11% baseline). Since iMF is hypothesized to be a compensatory form of plasticity that prevents recurrent apneas, the impact of restoring iMF on breathing stability during sleep in GIH offspring is currently being investigated.Support or Funding Information(Supported by NIH R01 HL105511 and NS085226).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Microglial Depletion Abolishes Compensatory Plasticity Induced by Prolonged Reductions in Respiratory Neural Activity

Reduced respiratory neural activity elicits a compensatory enhancement in inspiratory motor output to the diaphragm, a form of plasticity known as inactivity‐induced inspiratory motor facilitation (iMF). Mechanisms that induce iMF differ depending on the pattern of reduced respiratory neural activity; spinal TNF‐α and subsequent activation of TNFR2 on phrenic motor neurons is necessary to induce iMF following prolonged reductions in respiratory neural activity, whereas spinal retinoic acid synthesis and subsequent activation of RARa on phrenic motor neurons is necessary to induce iMF following intermittent reductions in respiratory neural activity. Little is known regarding the cell subtypes required for iMF induced by either stimulus. Since microglia are an important source of TNF‐α in the CNS, we tested the hypothesis that microglia are necessary for iMF following prolonged, but not intermittent, reductions in respiratory neural activity. Male and female rats received vehicle or pexidartinib (PLX3397; 80 mg/kg, 7 days po), a colony stimulating factor 1 receptor (CSFR1) inhibitor that results in microglial apoptosis. PLX3397 significantly reduced Iba1+ and CD11b+ cells throughout the brain and spinal cord (−82±8%, n=4, p<0.05). The capacity for prolonged (30 min) and intermittent (5, ~1 min) reductions in respiratory neural activity to elicit iMF was then assessed in urethane‐anesthetized, mechanically ventilated rats. In vehicle‐treated rats, both intermittent and prolonged reductions in respiratory neural activity triggered significant increases in phrenic inspiratory output (75 ± 16% and 99 ± 32% baseline, n=6 each, p<0.05), indicating iMF. By contrast, in PLX‐treated rats, only intermittent (63 ± 13% baseline, n=6, p<0.05), but not prolonged (21 ± 6% baseline, n=6, p>0.05) reductions in respiratory neural activity increased phrenic inspiratory output, suggesting that microglial depletion selectively impairs iMF activated by prolonged, but not intermittent, reductions in respiratory neural activity. These data suggest that in response to prolonged reductions in inspiratory‐related synaptic inputs to phrenic motor neurons, microglia may release TNF‐α to trigger compensatory enhancement in phrenic inspiratory output. Studies are underway to investigate this idea further.Support or Funding InformationNIH R01 HL105511 and NS085226This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Reduced Dynamic Interactions Within Intrinsic Functional Brain Networks in Early Blind Patients.

Neuroimaging studies in early blind (EB) patients have shown altered connections or brain networks. However, it remains unclear how the causal relationships are disrupted within intrinsic brain networks. In our study, we used spectral dynamic causal modeling (DCM) to estimate the causal interactions using resting-state data in a group of 20 EB patients and 20 healthy controls (HC). Coupling parameters in specific regions were estimated, including the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and inferior parietal lobule (IPC) in the default mode network (DMN); dorsal anterior cingulate cortex (dACC) and bilateral anterior insulae (AI) in the salience network (SN), and bilateral frontal eye fields (FEF) and superior parietal lobes (SPL) within the dorsal attention network (DAN). Statistical analyses found that all endogenous connections and the connections from the mPFC to bilateral IPCs in EB patients were significantly reduced within the DMN, and the effective connectivity from the PCC and lIPC to the mPFC, and from the mPFC to the PCC were enhanced. For the SN, all significant connections in EB patients were significantly decreased, except the intrinsic right AI connections. Within the DAN, more significant effective connections were observed to be reduced between the EB and HC groups, while only the connections from the right SPL to the left SPL and the intrinsic connection in the left SPL were significantly enhanced. Furthermore, discovery of more decreased effective connections in the EB subjects suggested that the disrupted causal interactions between specific regions are responsive to the compensatory brain plasticity in early deprivation.

Foraging guppies can compensate for low-light conditions, but not via a sensory switch

Animals can adapt to changes in their environment through behavioural or developmental plasticity, but studies of these responses tend to focus on either short-term exposure of adults to the changed conditions, or long-term exposure of juveniles. Juvenile guppies Poecilia reticulata reared in low-light environments have previously been shown to make a sensory switch to using olfactory, rather than visual, cues in foraging. It is not clear whether this compensatory sensory plasticity is limited to juveniles, or whether longer term exposure allows adults to similarly adapt. We investigated how adult guppies that were exposed to light or dark environments for 2 and 4 weeks responded to visual, olfactory and a combination of both food cues, in both dark- and light-test environments. We found that after 2 weeks of exposure, adult guppies were better able to locate a food cue in light test environments regardless of their exposure environment. After 4 weeks, however, guppies were more successful at locating the food cue in the environment they had been exposed to, suggesting that dark-exposed guppies adapted their behaviour in response to their environment. We found that foraging was most successful when both visual and olfactory cues were available and least successful in the presence of olfactory cues, suggesting that the mechanism behind the change in success for dark-exposed guppies was not due to increased reliance on, or sensory switch to olfactory cues.Significance statementHuman-induced environmental change often acts to disrupt an animal’s sensory environment. For example, turbidity can degrade the visual environment, resulting in reduced foraging rates in fish. Juvenile guppies (Poecilia reticulata) can compensate for the reduced visual information available in low-light environments through developmental changes that allow them to rely on an alternative sense, olfaction. This ability, however, may be limited to a critical developmental window, or possible throughout life. Here, we show that while adult guppies are generally better able to locate food resources in well-lit environments, after four (but not two) weeks living under low-light conditions, fish were better able to find food in dark environments than in the light. However, unlike juvenile fish, they did not seem to be relying more on olfactory cues to do so.

Repetitive verbal behaviors are not always harmful signs: Compensatory plasticity within the language network in aphasia

Repetitive verbal behaviors such as conduite d’approche (CdA) and mitigated echolalia (ME) are well-known phenomena since early descriptions of aphasia. Nevertheless, there is no substantial fresh knowledge on their clinical features, neural correlates and treatment interventions. In the present study we take advantage of three index cases of chronic fluent aphasia showing CdA, ME or both symptoms to dissect their clinical and neural signatures. Using multimodal neuroimaging (structural magnetic resonance imaging and [18]-fluorodeoxyglucose positron emission tomography during resting state), we found that despite of the heterogeneous lesions in terms of etiology (stroke, traumatic brain injury), volume and location, CdA was present when the lesion affected in greater extent the left dorsal language pathway, while ME resulted from preferential damage to the left ventral stream. The coexistence of CdA and ME was associated with involvement of areas overlapping with the structural lesions and metabolic derangements described in the subjects who showed one of these symptoms (CdA or ME). These findings suggest that CdA and ME represent the clinical expression of plastic changes that occur within the spared language network and its interconnected areas in order to compensate for the linguistic functions that previously relied on the activity of the damaged pathway. We discuss the results in the light of this idea and consider alternative undamaged neural networks that may support CdA and ME.

Analysis of recovering diaphragmatic neuromuscular junctions in a novel sublethal model of systemic botulism reveals multiple forms of compensatory neuromuscular plasticity

Analysis of recovering diaphragmatic neuromuscular junctions in a novel sublethal model of systemic botulism reveals multiple forms of compensatory neuromuscular plasticity

Effects of Transcranial Direct Current Stimulation on Knee Osteoarthritis Pain in Elderly Subjects With Defective Endogenous Pain-Inhibitory Systems: Protocol for a Randomized Controlled Trial.

BackgroundKnee osteoarthritis (OA) has been the main cause behind chronic pain and disabilities in the elderly population. The traditional treatment for knee OA pain currently concerns a number of combinations of pharmacological and nonpharmacological therapies. However, such combinations have displayed little effects on a significant group of subjects. In addition to this, pharmacological treatments often cause adverse effects, which limits their use on this population. Previous studies showed that chronic knee OA pain may be associated with maladaptive compensatory plasticity in pain-related neural central circuits indexed by a defective descending pain-inhibitory system. Transcranial direct current stimulation (tDCS) can revert some of these maladaptive changes, thus decreasing chronic pain sensation. Numerous studies have demonstrated that the use of anodal tDCS stimulation over the primary motor cortex (M1) has positive effects on chronic neuropathic pain. Yet, data on OA pain in elderly patients, including its effects on the endogenous pain-inhibitory system, remain limited.ObjectiveThe objective of this study is to evaluate the efficacy of tDCS in reducing pain intensity caused by knee OA in elderly subjects with defective endogenous pain-inhibitory systems.MethodsWe designed a randomized, sham-controlled, single-center, double-blinded clinical trial. Patients with knee OA who have maintained a chronic pain level during the previous 6 months and report a pain score of 4 or more on a 0-10 numeric rating scale (NRS) for pain in that period will undergo a conditioned pain modulation (CPM) task. Participants who present a reduced CPM response, defined as a decrease in NRS during the CPM task of less than 10%, and meet all of the inclusion criteria will be randomly assigned to receive 15 sessions of 2 mA active or sham tDCS for 20 minutes. A sample size of 94 subjects was calculated. The Brief Pain Inventory pain items will be used to assess pain intensity as our primary outcome. Secondary outcomes will include pain impact on functioning, mobility performance, quality of life, CPM, pressure pain threshold, touch-test sensory evaluation, and safety. Follow-up visits will be performed 2, 4, and 8 weeks following intervention. The data will be analyzed using the principle of intention-to-treat.ResultsThis study was approved by the institutional review board with the protocol number 1685/2016. The enrollment started in April 2018; at the time of publication of this protocol, 25 subjects have been enrolled. We estimate we will complete the enrollment process within 2 years.ConclusionsThis clinical trial will provide relevant data to evaluate if anodal tDCS stimulation over M1 can decrease chronic knee OA pain in elderly subjects with defective CPM. In addition, this trial will advance the investigation of the role of central sensitization in knee OA and evaluate how tDCS stimulation may affect it.Trial RegistrationClinicalTrials.gov NCT03117231; https://clinicaltrials.gov/ct2/show/NCT03117231 (Archived by WebCite at http://webcitation.org/73WM1LCdJ)International Registered Report Identifier (IRRID)RR1-10.2196/11660

Synergistic Transcriptional Changes in AMPA and GABAA Receptor Genes Support Compensatory Plasticity Following Unilateral Hearing Loss

Debilitating perceptual disorders including tinnitus, hyperacusis, phantom limb pain and visual release hallucinations may reflect aberrant patterns of neural activity in central sensory pathways following a loss of peripheral sensory input. Here, we explore short- and long-term changes in gene expression that may contribute to hyperexcitability following a sudden, profound loss of auditory input from one ear. We used fluorescence in situ hybridization to quantify mRNA levels for genes encoding AMPA and GABAA receptor subunits (Gria2 and Gabra1, respectively) in single neurons from the inferior colliculus (IC) and auditory cortex (ACtx). Thirty days after unilateral hearing loss, Gria2 levels were significantly increased while Gabra1 levels were significantly decreased. Transcriptional rebalancing was more pronounced in ACtx than IC and bore no obvious relationship to the degree of hearing loss. By contrast to the opposing, synergistic shifts in Gria2 and Gabra1 observed 30 days after hearing loss, we found that transcription levels for both genes were equivalently reduced after 5 days of hearing loss, producing no net change in the excitatory/inhibitory transcriptional balance. Opposing transcriptional shifts in AMPA and GABA receptor genes that emerge several weeks after a peripheral insult could promote both sensitization and disinhibition to support a homeostatic recovery of neural activity following auditory deprivation. Imprecise transcriptional changes could also drive the system toward perceptual hypersensitivity, degraded temporal processing and the irrepressible perception of non-existent environmental stimuli, a trio of perceptual impairments that often accompany chronic sensory deprivation.