bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different Brain Circuitries Mediating Controllable and Uncontrollable Pain
Authors: Bräscher Anne-Kathrin , Becker Susanne , Hoeppli Marie-Eve , Schweinhardt Petra 
Published: May 2016

Uncontrollable, compared with controllable, painful stimulation can lead to increased pain perception and activation in pain-processing brain regions, but it is currently unknown which brain areas mediate this effect. When pain is controllable, the lateral prefrontal cortex (PFC) seems to inhibit pain processing, although it is unclear how this is achieved. Using fMRI in healthy volunteers, we examined brain activation during controllable and uncontrollable stimulation to answer these questions. In the controllable task, participants self-adjusted temperatures applied to their hand of pain or warm intensities to provoke a constant sensation. In the uncontrollable task, the temperature time courses of the controllable task were replayed (yoked control) and participants rated their sensation continuously. During controllable pain trials, participants significantly downregulated the temperature to keep their sensation constant. Despite receiving the identical nociceptive input, intensity ratings increased during the uncontrollable pain trials. This additional sensitization was mirrored in increased activation of pain-processing regions such as insula, anterior cingulate cortex, and thalamus. Further, increased connectivity between the anterior insula and medial PFC (mPFC) in the uncontrollable and increased negative connectivity between dorsolateral PFC (dlPFC) and insula in the controllable task were observed. This suggests a pain-facilitating role of the mPFC during uncontrollable pain and a pain-inhibiting role of the dlPFC during controllable pain, both exerting their respective effects via the anterior insula. These results elucidate neural mechanisms of context-dependent pain modulation and their relation to subjective perception.SIGNIFICANCE STATEMENTPain control is of uttermost importance and stimulus controllability is an important way to achieve endogenous pain modulation. Here, we show differential effects of controllability and uncontrollability on pain perception and cerebral pain processing. When pain was controllable, the dorsolateral prefrontal cortex downregulated pain-evoked activation in important pain-processing regions. In contrast, sensitization during uncontrollable pain was mediated by increased connectivity of the medial prefrontal cortex with the anterior insula and other pain-processing regions. These novel insights into cerebral pain modulation by stimulus controllability have the potential to improve treatment approaches in pain patients.
Striatopallidal Neuron NMDA Receptors Control Synaptic Connectivity, Locomotor, and Goal-Directed Behaviors
Authors: Lambot Laurie , Chaves Rodriguez Elena , Houtteman Delphine , Li Yuquing , Schiffmann Serge N. , Gall David , de Kerchove d'Exaerde Alban 
Published: May 2016

The basal ganglia (BG) control action selection, motor programs, habits, and goal-directed learning. The striatum, the principal input structure of BG, is predominantly composed of medium-sized spiny neurons (MSNs). Arising from these spatially intermixed MSNs, two inhibitory outputs form two main efferent pathways, the direct and indirect pathways. Striatonigral MSNs give rise to the activating, direct pathway MSNs and striatopallidal MSNs to the inhibitory, indirect pathway (iMSNs). BG output nuclei integrate information from both pathways to fine-tune motor procedures and to acquire complex habits and skills. Therefore, balanced activity between both pathways is crucial for harmonious functions of the BG. Despite the increase in knowledge concerning the role of glutamate NMDA receptors (NMDA-Rs) in the striatum, understanding of the specific functions of NMDA-R iMSNs is still lacking. For this purpose, we generated a conditional knock-out mouse to address the functions of the NMDA-R in the indirect pathway. At the cellular level, deletion of GluN1 in iMSNs leads to a reduction in the number and strength of the excitatory corticostriatopallidal synapses. The subsequent scaling down in input integration leads to dysfunctional changes in BG output, which is seen as reduced habituation, delay in goal-directed learning, lack of associative behavior, and impairment in action selection or skill learning. The NMDA-R deletion in iMSNs causes a decrease in the synaptic strength of striatopallidal neurons, which in turn might lead to a imbalanced integration between direct and indirect MSN pathways, making mice less sensitive to environmental change. Therefore, their ability to learn and adapt to the environment-based experience was significantly affected.SIGNIFICANCE STATEMENTThe striatum controls habits, locomotion, and goal-directed behaviors by coordinated activation of two antagonistic pathways. Insofar as NMDA receptors (NMDA-Rs) play a key role in synaptic plasticity essential for sustaining these behaviors, we generated a mouse model lacking NMDA-Rs specifically in striatopallidal neurons. To our knowledge, this is the first time that a specific deletion of inhibitory, indirect pathway medium-sized spiny neuron (iMSN) NMDA-Rs has been used to address the role of these receptors in the inhibitory pathway. Importantly, we found that this specific deletion led to a significant reduction in the number and strength of the cortico–iMSN synapses, which resulted in the significant impairments of behaviors orchestrated by the basal ganglia. Our findings indicate that the NMDA-Rs of the indirect pathway are essential for habituation, action selection, and goal-directed learning.
Optogenetic Stimulation of Prefrontal Glutamatergic Neurons Enhances Recognition Memory
Authors: Benn Abigail , Barker Gareth R. I. , Stuart Sarah A. , Roloff Eva v. L. , Teschemacher Anja G. , Warburton E. Clea , Robinson Emma S. J. 
Published: May 2016

Finding effective cognitive enhancers is a major health challenge; however, modulating glutamatergic neurotransmission has the potential to enhance performance in recognition memory tasks. Previous studies using glutamate receptor antagonists have revealed that the medial prefrontal cortex (mPFC) plays a central role in associative recognition memory. The present study investigates short-term recognition memory using optogenetics to target glutamatergic neurons within the rodent mPFC specifically. Selective stimulation of glutamatergic neurons during the online maintenance of information enhanced associative recognition memory in normal animals. This cognitive enhancing effect was replicated by local infusions of the AMPAkine CX516, but not CX546, which differ in their effects on EPSPs. This suggests that enhancing the amplitude, but not the duration, of excitatory synaptic currents improves memory performance. Increasing glutamate release through infusions of the mGluR7 presynaptic receptor antagonist MMPIP had no effect on performance.SIGNIFICANCE STATEMENTThese results provide new mechanistic information that could guide the targeting of future cognitive enhancers. Our work suggests that improved associative-recognition memory can be achieved by enhancing endogenous glutamatergic neuronal activity selectively using an optogenetic approach. We build on these observations to recapitulate this effect using drug treatments that enhance the amplitude of EPSPs; however, drugs that alter the duration of the EPSP or increase glutamate release lack efficacy. This suggests that both neural and temporal specificity are needed to achieve cognitive enhancement.
The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling That Requires NGF and TRPV1
Authors: Shutov Leonid P. , Warwick Charles A. , Shi Xiaoyu , Gnanasekaran Aswini , Shepherd Andrew J. , Mohapatra Durga P. , Woodruff Trent M. , Clark J. David , Usachev Yuriy M. 
Published: May 2016

The complement cascade is a principal component of innate immunity. Recent studies have underscored the importance of C5a and other components of the complement system in inflammatory and neuropathic pain, although the underlying mechanisms are largely unknown. In particular, it is unclear how the complement system communicates with nociceptors and which ion channels and receptors are involved. Here we demonstrate that inflammatory thermal and mechanical hyperalgesia induced by complete Freund's adjuvant was accompanied by C5a upregulation and was markedly reduced by C5a receptor (C5aR1) knock-out or treatment with the C5aR1 antagonist PMX53. Direct administration of C5a into the mouse hindpaw produced strong thermal hyperalgesia, an effect that was absent in TRPV1 knock-out mice, and was blocked by the TRPV1 antagonist AMG9810. Immunohistochemistry of mouse plantar skin showed prominent expression of C5aR1 in macrophages. Additionally, C5a evoked strong Ca2+mobilization in macrophages. Macrophage depletion in transgenic macrophage Fas-induced apoptosis mice abolished C5a-dependent thermal hyperalgesia. Examination of inflammatory mediators following C5a injection revealed a rapid upregulation of NGF, a mediator known to sensitize TRPV1. Preinjection of an NGF-neutralizing antibody or Trk inhibitor GNF-5837 prevented C5a-induced thermal hyperalgesia. Notably, NGF-induced thermal hyperalgesia was unaffected by macrophage depletion. Collectively, these results suggest that complement fragment C5a induces thermal hyperalgesia by triggering macrophage-dependent signaling that involves mobilization of NGF and NGF-dependent sensitization of TRPV1. Our findings highlight the importance of macrophage-to-neuron signaling in pain processing and identify C5a, NGF, and TRPV1 as key players in this cross-cellular communication.SIGNIFICANCE STATEMENTThis study provides mechanistic insight into how the complement system, a key component of innate immunity, regulates the development of pain hypersensitivity. We demonstrate a crucial role of the C5a receptor, C5aR1, in the development of inflammatory thermal and mechanical sensitization. By focusing on the mechanisms of C5a-induced thermal hyperalgesia, we show that this process requires recruitment of macrophages and initiation of macrophage-to-nociceptor signaling. At the molecular level, we demonstrate that this signaling depends on NGF and is mediated by the heat-sensitive nociceptive channel TRPV1. This deeper understanding of how immune cells and neurons interact to regulate pain processing is expected to facilitate mechanism-based approaches in the development of new analgesics.
Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway through a Novel mTOR/p70S6 Kinase Signaling Pathway
Authors: Renard Justine , Loureiro Michael , Rosen Laura G. , Zunder Jordan , de Oliveira Cleusa , Schmid Susanne , Rushlow Walter J. , Laviolette Steven R. 
Published: May 2016

Schizophrenia-related psychosis is associated with disturbances in mesolimbic dopamine (DA) transmission, characterized by hyperdopaminergic activity in the mesolimbic pathway. Currently, the only clinically effective treatment for schizophrenia involves the use of antipsychotic medications that block DA receptor transmission. However, these medications produce serious side effects leading to poor compliance and treatment outcomes. Emerging evidence points to the involvement of a specific phytochemical component of marijuana called cannabidiol (CBD), which possesses promising therapeutic properties for the treatment of schizophrenia-related psychoses. However, the neuronal and molecular mechanisms through which CBD may exert these effects are entirely unknown. We used amphetamine (AMPH)-induced sensitization and sensorimotor gating in rats, two preclinical procedures relevant to schizophrenia-related psychopathology, combined within vivosingle-unit neuronal electrophysiology recordings in the ventral tegmental area, and molecular analyses to characterize the actions of CBD directly in the nucleus accumbens shell (NASh), a brain region that is the current target of most effective antipsychotics. We demonstrate that Intra-NASh CBD attenuates AMPH-induced sensitization, both in terms of DAergic neuronal activity measured in the ventral tegmental area and psychotomimetic behavioral analyses. We further report that CBD controls downstream phosphorylation of the mTOR/p70S6 kinase signaling pathways directly within the NASh. Our findings demonstrate a novel mechanism for the putative antipsychotic-like properties of CBD in the mesolimbic circuitry. We identify the molecular signaling pathways through which CBD may functionally reduce schizophrenia-like neuropsychopathology.SIGNIFICANCE STATEMENTThe cannabis-derived phytochemical, cannabidiol (CBD), has been shown to have pharmacotherapeutic efficacy for the treatment of schizophrenia. However, the mechanisms by which CBD may produce antipsychotic effects are entirely unknown. Using preclinical behavioral procedures combined with molecular analyses andin vivoneuronal electrophysiology, our findings identify a functional role for the nucleus accumbens as a critical brain region whereby CBD can produce effects similar to antipsychotic medications by triggering molecular signaling pathways associated with the effects of classic antipsychotic medications. Specifically, we report that CBD can attenuate both behavioral and dopaminergic neuronal correlates of mesolimbic dopaminergic sensitization, via a direct interaction with mTOR/p70S6 kinase signaling within the mesolimbic pathway.
Effects of Electrical Stimulation in the Inferior Colliculus on Frequency Discrimination by Rhesus Monkeys and Implications for the Auditory Midbrain Implant
Authors: Pages Daniel S. , Ross Deborah A. , Puñal Vanessa M. , Agashe Shruti , Dweck Isaac , Mueller Jerel , Grill Warren M. , Wilson Blake S. , Groh Jennifer M. 
Published: May 2016

Understanding the relationship between the auditory selectivity of neurons and their contribution to perception is critical to the design of effective auditory brain prosthetics. These prosthetics seek to mimic natural activity patterns to achieve desired perceptual outcomes. We measured the contribution of inferior colliculus (IC) sites to perception using combined recording and electrical stimulation. Monkeys performed a frequency-based discrimination task, reporting whether a probe sound was higher or lower in frequency than a reference sound. Stimulation pulses were paired with the probe sound on 50% of trials (0.5–80 μA, 100–300 Hz,n= 172 IC locations in 3 rhesus monkeys). Electrical stimulation tended to bias the animals' judgments in a fashion that was coarsely but significantly correlated with the best frequency of the stimulation site compared with the reference frequency used in the task. Although there was considerable variability in the effects of stimulation (including impairments in performance and shifts in performance away from the direction predicted based on the site's response properties), the results indicate that stimulation of the IC can evoke percepts correlated with the frequency-tuning properties of the IC. Consistent with the implications of recent human studies, the main avenue for improvement for the auditory midbrain implant suggested by our findings is to increase the number and spatial extent of electrodes, to increase the size of the region that can be electrically activated, and to provide a greater range of evoked percepts.SIGNIFICANCE STATEMENTPatients with hearing loss stemming from causes that interrupt the auditory pathway after the cochlea need a brain prosthetic to restore hearing. Recently, prosthetic stimulation in the human inferior colliculus (IC) was evaluated in a clinical trial. Thus far, speech understanding was limited for the subjects and this limitation is thought to be partly due to challenges in harnessing the sound frequency representation in the IC. Here, we tested the effects of IC stimulation in monkeys trained to report the sound frequencies they heard. Our results indicate that the IC can be used to introduce a range of frequency percepts and suggest that placement of a greater number of electrode contacts may improve the effectiveness of such implants.
The Proinflammatory Cytokine Interleukin 18 Regulates Feeding by Acting on the Bed Nucleus of the Stria Terminalis
Authors: Francesconi Walter , Sánchez-Alavez Manuel , Berton Fulvia , Alboni Silvia , Benatti Cristina , Mori Simone , Nguyen William , Zorrilla Eric , Moroncini Gianluca , Tascedda Fabio , Conti Bruno 
Published: May 2016

The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra−/−), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons.SIGNIFICANCE STATEMENTLoss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.
Ventromedial Prefrontal Cortex Damage Is Associated with Decreased Ventral Striatum Volume and Response to Reward
Authors: Pujara Maia S. , Philippi Carissa L. , Motzkin Julian C. , Baskaya Mustafa K. , Koenigs Michael 
Published: May 2016

The ventral striatum and ventromedial prefrontal cortex (vmPFC) are two central nodes of the “reward circuit” of the brain. Human neuroimaging studies have demonstrated coincident activation and functional connectivity between these brain regions, and animal studies have demonstrated that the vmPFC modulates ventral striatum activity. However, there have been no comparable data in humans to address whether the vmPFC may be critical for the reward-related response properties of the ventral striatum. In this study, we used fMRI in five neurosurgical patients with focal vmPFC lesions to test the hypothesis that the vmPFC is necessary for enhancing ventral striatum responses to the anticipation of reward. In support of this hypothesis, we found that, compared with age- and gender-matched neurologically healthy subjects, the vmPFC-lesioned patients had reduced ventral striatal activity during the anticipation of reward. Furthermore, we observed that the vmPFC-lesioned patients had decreased volumes of the accumbens subregion of the ventral striatum. Together, these functional and structural neuroimaging data provide novel evidence for a critical role for the vmPFC in contributing to reward-related activity of the ventral striatum. These results offer new insight into the functional and structural interactions between key components of the brain circuitry underlying human affective function and decision-making.SIGNIFICANCE STATEMENTMaladaptive decision-making is a common problem across multiple mental health disorders. Developing new pathophysiologically based strategies for diagnosis and treatment thus requires a better understanding of the brain circuits responsible for adaptive decision-making and related psychological subprocesses (e.g., reward valuation, anticipation, and motivation). Animal studies provide evidence that these functions are mediated through direct interactions between two key nodes of a posited “reward circuit,” the ventral striatum and the ventromedial prefrontal cortex (vmPFC). For the first time in humans, we demonstrate that damage to the vmPFC results in decreased ventral striatum activity during reward anticipation. These data provide unique evidence on the causal mechanisms by which the vmPFC and ventral striatum interact during the anticipation of rewards.
The Insula Mediates Access to Awareness of Visual Stimuli Presented Synchronously to the Heartbeat
Authors: Salomon Roy , Ronchi Roberta , Dönz Jonathan , Bello-Ruiz Javier , Herbelin Bruno , Martet Remi , Faivre Nathan , Schaller Karl , Blanke Olaf 
Published: May 2016

The processing of interoceptive signals in the insular cortex is thought to underlie self-awareness. However, the influence of interoception on visual awareness and the role of the insular cortex in this process remain unclear. Here, we show in a series of experiments that the relative timing of visual stimuli with respect to the heartbeat modulates visual awareness. We used two masking techniques and show that conscious access for visual stimuli synchronous to participants' heartbeat is suppressed compared with the same stimuli presented asynchronously to their heartbeat. Two independent brain imaging experiments using high-resolution fMRI revealed that the insular cortex was sensitive to both visible and invisible cardio–visual stimulation, showing reduced activation for visual stimuli presented synchronously to the heartbeat. Our results show that interoceptive insular processing affects visual awareness, demonstrating the role of the insula in integrating interoceptive and exteroceptive signals and in the processing of conscious signals beyond self-awareness.SIGNIFICANCE STATEMENTThere is growing evidence that interoceptive signals conveying information regarding the internal state of the body influence perception and self-awareness. The insular cortex, which receives sensory inputs from both interoceptive and exteroceptive sources, is thought to integrate these multimodal signals. This study shows that cardiac interoceptive signals modulate awareness for visual stimuli such that visual stimuli occurring at the cardiac frequency take longer to access visual awareness and are more difficult to discriminate. Two fMRI experiments show that the insular region is sensitive to this cardio–visual synchrony even when the visual stimuli are rendered invisible through interocular masking. The results indicate a perceptual and neural suppression for visual events coinciding with cardiac interoceptive signals.