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You Wan - One of the best experts on this subject based on the ideXlab platform.
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spontaneous pain disrupts ventral hippocampal ca1 Infralimbic Cortex connectivity and modulates pain progression in rats with peripheral inflammation
2019Co-Authors: Lupeng Yue, Yuqi Zhang, Yue Wang, Bingxuan Han, Shuang Cui, Fengyu Liu, You WanAbstract:Pain involves an intrinsically dynamic connectome characterized by fluctuating spontaneous brain activity and continuous neuroplastic changes of relevant circuits. Activity in the hippocampus-medial prefrontal Cortex (mPFC) pathway has been suggested to correlate with spontaneous pain and pain chronicity, but causal evidence is lacking. Here we combine longitudinal in vivo electrophysiological recording with behavioral testing and show that persistent spontaneous pain disrupts ventral hippocampal CA1-Infralimbic Cortex (vCA1-IL) connectivity and hippocampal modulation of IL neuronal activity in rats with peripheral inflammation. Chemo- and optogenetic rescue of vCA1-IL dysfunction relieves spontaneous pain. Circuit-specific overexpression of brain-derived neurotrophic factor (BDNF) in vCA1-IL reverses electrophysiological changes, relieves spontaneous pain, and accelerates overall recovery from inflammatory pain. Our work identifies a neural pathway that specifically correlates with spontaneous pain and supports the significance of using a circuit dynamics-based strategy for more comprehensive understanding of circuitry mechanisms underlying chronic pain.
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spontaneous pain disrupts ventral hippocampal ca1 Infralimbic Cortex connectivity and modulates pain progression in rats with peripheral inflammation
2019Co-Authors: Lupeng Yue, Yuqi Zhang, Yue Wang, Bingxuan Han, Shuang Cui, Fengyu Liu, You WanAbstract:Pain is an intrinsically dynamic connectome characterized by fluctuating spontaneous activity and continuous neuroplastic changes of relevant circuits. With its strong impact on resting brain activity, persistent spontaneous pain may induce hypersensitivity to noxious stimuli and negative emotion, thus affecting overall progression of chronic pain. Hippocampus-medial prefrontal Cortex (mPFC) pathway has recently been suggested to correlate with spontaneous pain behaviors and pain chronicity. However, causal evidence for this relationship is lacking. We adopted a circuit dynamics-based strategy with combined longitudinal in vivo multichannel recording and behavioral testing, and revealed that persistent spontaneous pain disrupted ventral hippocampal CA1-Infralimbic Cortex (vCA1-IL) connectivity and hippocampal modulation of IL neuronal activity in rats with inflammatory pain. Transient chemo- and opto-genetic activation of vCA1-IL pathway specifically relieved spontaneous pain in inflammatory rats, and long-term chemogenetic rescue of vCA1-IL dysfunction produced additional relief from other behavioral dimensions including evoked pain and anxiety-like behaviors. Spontaneous pain in inflammatory rats was accompanied by decreased level of brain-derived neurotrophic factor (BDNF) in vCA1 and IL. Circuit-specific overexpression of BDNF in vCA1-IL reversed electrophysiological changes, relieved spontaneous pain, and accelerated overall recovery from inflammatory pain. The present study identifies a novel neural pathway that specifically correlates spontaneous pain behaviors and modulates overall pain progression in rats with peripheral inflammation, and supports the significance of circuit dynamics-based strategy for more comprehensive understanding of central mechanisms underlying chronic pain.
Mouna Maroun - One of the best experts on this subject based on the ideXlab platform.
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alterations in neuronal morphology in Infralimbic Cortex predict resistance to fear extinction following acute stress
2016Co-Authors: Kelly M Moench, Mouna Maroun, Alexandra Kavushansky, Cara L WellmanAbstract:Dysfunction in corticolimbic circuits that mediate the extinction of learned fear responses is thought to underlie the perseveration of fear in stress-related psychopathologies, including post-traumatic stress disorder. Chronic stress produces dendritic hypertrophy in basolateral amygdala (BLA) and dendritic hypotrophy in medial prefrontal Cortex, whereas acute stress leads to hypotrophy in both BLA and prelimbic Cortex. Additionally, both chronic and acute stress impair extinction retrieval. Here, we examined the effects of a single elevated platform stress on extinction learning and dendritic morphology in Infralimbic Cortex, a region considered to be critical for extinction. Acute stress produced resistance to extinction, as well as dendritic retraction in Infralimbic Cortex. Spine density on apical and basilar terminal branches was unaffected by stress. However, animals that underwent conditioning and extinction had decreased spine density on apical terminal branches. Thus, whereas dendritic morphology in Infralimbic Cortex appears to be particularly sensitive to stress, changes in spines may more sensitively reflect learning. Further, in stressed rats that underwent conditioning and extinction, the level of extinction learning was correlated with spine densities, in that rats with poorer extinction retrieval had more immature spines and fewer thin spines than rats with better extinction retrieval, suggesting that stress may have impaired learning-related spine plasticity. These results may have implications for understanding the role of medial prefrontal Cortex in learning deficits associated with stress-related pathologies.
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Dissociation of the role of Infralimbic Cortex in learning and consolidation of extinction of recent and remote aversion memory
2015Co-Authors: Walaa Awad, Guillaume Ferreira, Mouna MarounAbstract:Medial prefrontal circuits have been reported to undergo a major reorganization over time and gradually take a more important role for remote emotional memories such as contextual fear memory or food aversion memory. The medial prefrontal Cortex, and specifically its ventral subregion, the Infralimbic Cortex (IL), was also reported to be critical for recent memory extinction of contextual fear conditioning and conditioned odor aversion. However, its exact role in the extinction of remotely acquired information is still not clear. Using postretrieval blockade of protein synthesis or inactivation of the IL, we showed that the IL is similarly required for extinction consolidation of recent and remote fear memory. However, in odor aversion memory, the IL was only involved in extinction consolidation of recent, but not remote, memory. In contrast, only remote retrieval of aversion memory induced c-Fos activation in the IL and preretrieval inactivation of the IL with lidocaine impaired subsequent extinction of remote but not recent memory, indicating IL is necessary for extinction learning of remote aversion memory. In contrast to the effects in odor aversion, our data show that the involvement of the IL in the consolidation of fear extinction does not depend on the memory age. More importantly, our data indicate that the IL is implicated in the extinction of fear and nonfear-based associations and suggest dissociation in the engagement of the IL in the learning and consolidation of food aversion extinction over time.
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enhanced extinction of aversive memories by high frequency stimulation of the rat Infralimbic Cortex
2012Co-Authors: Mouna Maroun, Alexandra Kavushansky, Cara L Wellman, Andrew Holmes, Helen MotanisAbstract:Electrical stimulation of the rodent medial prefrontal Cortex (mPFC), including the Infralimbic Cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion.
Filipa Pintoribeiro - One of the best experts on this subject based on the ideXlab platform.
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the medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mglur5 in the rat Infralimbic Cortex
2017Co-Authors: Ana Davidpereira, Antti Pertovaara, Armando Almeida, Boriss Sagalajev, Hong Wei, Filipa PintoribeiroAbstract:Metabotropic glutamate receptor 5 (mGluR5) activation in the Infralimbic Cortex (IL) induces pronociceptive behavior in healthy and monoarthritic rats. Here we studied whether the medullary dorsal reticular nucleus (DRt) and the spinal TRPV1 are mediating the IL/mGluR5-induced spinal pronociception and whether the facilitation of pain behavior is correlated with changes in spinal dorsal horn neuron activity. For drug administrations, all animals had a cannula in the IL as well as a cannula in the DRt or an intrathecal catheter. Heat-evoked paw withdrawal was used to assess pain behavior in awake animals. Spontaneous and heat-evoked discharge rates of single DRt neurons or spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons were evaluated in lightly anesthetized animals. Activation of the IL/mGluR5 facilitated nociceptive behavior in both healthy and monoarthritic animals, and this effect was blocked by lidocaine or GABA receptor agonists in the DRt. IL/mGluR5 activation increased spontaneous and heat-evoked DRt discharge rates in healthy but not monoarthritic rats. In the spinal dorsal horn, IL/mGluR5 activation increased spontaneous activity of WDR neurons in healthy animals only, whereas heat-evoked responses of WDR and NS neurons were increased in both experimental groups. Intrathecally administered TRPV1 antagonist prevented the IL/mGluR5-induced pronociception in both healthy and monoarthritic rats. The results suggest that the DRt is involved in relaying the IL/mGluR5-induced spinal pronociception in healthy control but not monoarthritic animals. Spinally, the IL/mGluR5-induced behavioral heat hyperalgesia is mediated by TRPV1 and associated with facilitated heat-evoked responses of WDR and NS neurons.
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metabotropic glutamate 5 receptor in the Infralimbic Cortex contributes to descending pain facilitation in healthy and arthritic animals
2016Co-Authors: Ana Davidpereira, Sonia Puga, S Goncalves, Diana Amorim, C Silva, Antti Pertovaara, Armando Almeida, Filipa PintoribeiroAbstract:The involvement of the prefrontal Cortex in pain processing has been recently addressed. We studied the role of the Infralimbic Cortex (IL) and group I metabotropic glutamate receptors (mGluRs) in descending modulation of nociception in control and monoarthritic (ARTH) conditions. Nociception was assessed using heat-induced paw withdrawal while drugs were microinjected in the IL of rats. Local anesthesia of the IL or the adjacent prelimbic Cortex (PL) facilitated nociception, indicating that IL and PL are tonically promoting spinal antinociception. Phasic activation with glutamate (GLU) revealed opposing roles of the PL and IL; GLU in the PL had a fast antinociceptive action, while in the IL it had a slow onset pronociceptive action. IL administration of a local anesthetic or GLU produced identical results in ARTH and control animals. An mGluR5 agonist in the IL induced a pronociceptive effect in both groups, while mGluR5 antagonists had no effect in controls but induced antinociception in ARTH rats. Activation of the IL mGluR1 (through co-administration of mGluR1/5 agonist and mGluR5 antagonist) did not alter nociception in controls but induced antinociception in ARTH animals. IL administration of an mGluR1 antagonist failed to alter nociception in either experimental group. Finally, mGluR5 but not mGluR1 antagonists blocked the pronociceptive action of GLU in both groups. The results indicate that IL contributes to descending modulation of nociception. mGluR5 in the IL enhance nociception in healthy control and monoarthritic animals, an effect that is tonic in ARTH. Moreover, activation of IL mGluR1s attenuates nociception following the development of monoarthritis.
Peter W Kalivas - One of the best experts on this subject based on the ideXlab platform.
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neural circuit competition in cocaine seeking roles of the Infralimbic Cortex and nucleus accumbens shell
2012Co-Authors: Ryan T Lalumiere, Kyle C Smith, Peter W KalivasAbstract:Following cocaine self-administration and extinction training, activity in the Infralimbic Cortex (IL) suppresses cocaine-seeking behavior. IL inactivation induces cocaine-seeking whereas activation suppresses cocaine-reinstated drug-seeking. We asked how the suppression of cocaine-seeking induced by IL activation integrates with the circuitry promoting reinstated cocaine-seeking. Following cocaine self-administration and extinction training, rats underwent cue-induced reinstatement. In order to activate IL projections, microinjections of PEPA, a positive allosteric modulator of AMPA receptors, were made into the IL in combination with microinjections into a variety of nuclei known to regulate cocaine-seeking. Intra-IL PEPA administration suppressed cue-induced reinstatement without affecting locomotor activity. The suppression of cocaine-seeking was reversed by activating dopamine neurons in the ventral tegmental area with microinjections of the μ-opioid receptor agonist DAMGO, and was partially reversed by dopamine microinjections into the prelimbic Cortex or basolateral amygdala. Previous evidence suggests that the nucleus accumbens shell both promotes and suppresses cocaine-seeking. The suppression of cue-induced cocaine seeking by PEPA in the IL was reversed by intra-shell microinjections of either dopamine or the AMPA receptor antagonist CNQX, suggesting that the accumbens shell bidirectionally regulates cocaine-seeking depending on whether dopamine input is mimicked or glutamate input is inhibited. Together, these findings indicate that the IL acts 'upstream' from structures promoting cocaine-seeking, including from the mesolimbic dopamine projections to the prelimbic Cortex and basolateral amygdala, and that the accumbens shell may be a crucial point of integration between the circuits that promote (ventral tegmental area) and inhibit (IL) reinstated cocaine-seeking.
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the Infralimbic Cortex regulates the consolidation of extinction after cocaine self administration
2010Co-Authors: Ryan T Lalumiere, Kate E Niehoff, Peter W KalivasAbstract:The Infralimbic Cortex (IL) regulates the consolidation of extinction learning for fear conditioning. Whether the IL influences the consolidation of extinction learning for cocaine self-administration is unknown. To address this issue, male Sprague-Dawley rats underwent 2 wk of cocaine self-administration followed by extinction training. On the first 5 d of extinction, rats underwent brief (15- or 30-min) extinction sessions and received intra-IL microinjections immediately after each extinction session. On days 6-12 of extinction, rats underwent full-length (2-h) extinction sessions that were used to assess the retention of the extinction learning from the short sessions. IL inactivation via microinjections of the GABA agonists baclofen and muscimol (BM) immediately after the extinction sessions (days 1-5) impaired the retention of extinction learning. Control experiments demonstrated that this effect was not due to inactivation of the prelimbic Cortex or due to effects of the drugs on the subsequent day's behavior. In contrast, post-training intra-IL microinjections of the allosteric AMPA receptor potentiator 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (PEPA) enhanced retention of the extinction learning. As evidence suggests a role for the beta-adrenergic receptors in memory consolidation, other rats received microinjections of the beta(2)-adrenergic receptor agonist clenbuterol or antagonist ICI-118,551 (ICI). Post-training intra-IL administration of clenbuterol or pre-training administration of ICI enhanced or impaired, respectively, the retention of extinction learning. These data indicate that the IL, and specifically the glutamatergic and beta-adrenergic systems in the IL, regulates the consolidation of extinction of cocaine self-administration and that the IL can be manipulated to influence the retention of extinction.
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Infralimbic prefrontal Cortex is responsible for inhibiting cocaine seeking in extinguished rats
2008Co-Authors: Jamie Peters, Ryan T Lalumiere, Peter W KalivasAbstract:The rat prelimbic prefrontal Cortex and nucleus accumbens core are critical for initiating cocaine seeking. In contrast, the neural circuitry responsible for inhibiting cocaine seeking during extinction is unknown. The present findings using inhibition of selected brain nuclei with GABA agonists show that the suppression of cocaine seeking produced by previous extinction training required activity in the rat Infralimbic Cortex. Conversely, the reinstatement of drug seeking by a cocaine injection in extinguished animals was suppressed by increasing neuronal activity in Infralimbic Cortex with the glutamate agonist AMPA. The cocaine seeking induced by inactivating Infralimbic Cortex resembled other forms of reinstated drug seeking by depending on activity in prelimbic Cortex and the basolateral amygdala. A primary efferent projection from the Infralimbic Cortex is to the nucleus accumbens shell. Akin to Infralimbic Cortex, inhibition of the accumbens shell induced cocaine seeking in extinguished rats. However, bilateral inhibition of the shell also elicited increased locomotor activity. Nonetheless, unilateral inhibition of the accumbens shell did not increase motor activity, and simultaneous unilateral inactivation of the Infralimbic Cortex and shell induced cocaine seeking, suggesting that an interaction between these two structures is necessary for extinction training to inhibit cocaine seeking. The Infralimbic Cortex and accumbens shell appear to be recruited by extinction learning because inactivation of these structures before extinction training did not alter cocaine seeking. Together, these findings suggest that a neuronal network involving the Infralimbic Cortex and accumbens shell is recruited by extinction training to suppress cocaine seeking.
Ana Davidpereira - One of the best experts on this subject based on the ideXlab platform.
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the medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mglur5 in the rat Infralimbic Cortex
2017Co-Authors: Ana Davidpereira, Antti Pertovaara, Armando Almeida, Boriss Sagalajev, Hong Wei, Filipa PintoribeiroAbstract:Metabotropic glutamate receptor 5 (mGluR5) activation in the Infralimbic Cortex (IL) induces pronociceptive behavior in healthy and monoarthritic rats. Here we studied whether the medullary dorsal reticular nucleus (DRt) and the spinal TRPV1 are mediating the IL/mGluR5-induced spinal pronociception and whether the facilitation of pain behavior is correlated with changes in spinal dorsal horn neuron activity. For drug administrations, all animals had a cannula in the IL as well as a cannula in the DRt or an intrathecal catheter. Heat-evoked paw withdrawal was used to assess pain behavior in awake animals. Spontaneous and heat-evoked discharge rates of single DRt neurons or spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons were evaluated in lightly anesthetized animals. Activation of the IL/mGluR5 facilitated nociceptive behavior in both healthy and monoarthritic animals, and this effect was blocked by lidocaine or GABA receptor agonists in the DRt. IL/mGluR5 activation increased spontaneous and heat-evoked DRt discharge rates in healthy but not monoarthritic rats. In the spinal dorsal horn, IL/mGluR5 activation increased spontaneous activity of WDR neurons in healthy animals only, whereas heat-evoked responses of WDR and NS neurons were increased in both experimental groups. Intrathecally administered TRPV1 antagonist prevented the IL/mGluR5-induced pronociception in both healthy and monoarthritic rats. The results suggest that the DRt is involved in relaying the IL/mGluR5-induced spinal pronociception in healthy control but not monoarthritic animals. Spinally, the IL/mGluR5-induced behavioral heat hyperalgesia is mediated by TRPV1 and associated with facilitated heat-evoked responses of WDR and NS neurons.
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metabotropic glutamate 5 receptor in the Infralimbic Cortex contributes to descending pain facilitation in healthy and arthritic animals
2016Co-Authors: Ana Davidpereira, Sonia Puga, S Goncalves, Diana Amorim, C Silva, Antti Pertovaara, Armando Almeida, Filipa PintoribeiroAbstract:The involvement of the prefrontal Cortex in pain processing has been recently addressed. We studied the role of the Infralimbic Cortex (IL) and group I metabotropic glutamate receptors (mGluRs) in descending modulation of nociception in control and monoarthritic (ARTH) conditions. Nociception was assessed using heat-induced paw withdrawal while drugs were microinjected in the IL of rats. Local anesthesia of the IL or the adjacent prelimbic Cortex (PL) facilitated nociception, indicating that IL and PL are tonically promoting spinal antinociception. Phasic activation with glutamate (GLU) revealed opposing roles of the PL and IL; GLU in the PL had a fast antinociceptive action, while in the IL it had a slow onset pronociceptive action. IL administration of a local anesthetic or GLU produced identical results in ARTH and control animals. An mGluR5 agonist in the IL induced a pronociceptive effect in both groups, while mGluR5 antagonists had no effect in controls but induced antinociception in ARTH rats. Activation of the IL mGluR1 (through co-administration of mGluR1/5 agonist and mGluR5 antagonist) did not alter nociception in controls but induced antinociception in ARTH animals. IL administration of an mGluR1 antagonist failed to alter nociception in either experimental group. Finally, mGluR5 but not mGluR1 antagonists blocked the pronociceptive action of GLU in both groups. The results indicate that IL contributes to descending modulation of nociception. mGluR5 in the IL enhance nociception in healthy control and monoarthritic animals, an effect that is tonic in ARTH. Moreover, activation of IL mGluR1s attenuates nociception following the development of monoarthritis.