Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model.

Posttraumatic stress disorder (PTSD) is a complex disorder that involves physiological, emotional, and cognitive dysregulation that may occur after exposure to a life-threatening event. In contrast with the condition of learned fear with resilience to extinction, abnormal fear with impaired fear extinction and exaggeration are considered crucial factors for the pathological development of PTSD. The prefrontal cortex (mPFC) is considered a critical region of top-down control in fear regulation, which involves the modulation of fear expression and extinction. The pathological course of PTSD is usually chronic and persistent; a number of studies have indicated temporal progression in gene expression and phenotypes may be involved in PTSD pathology. In the current study, we use a well-established modified single-prolonged stress (SPS&FS) rat model to feature PTSD-like phenotypes and compared it with a footshock fear conditioning model (FS model); we collected the frontal tissue after extreme stress exposure or fear conditioning and extracted RNA for transcriptome-level gene sequencing. We compared the genetic profiling of the mPFC at early (<2 h after solely FS or SPS&FS exposure) and late (7 days after solely FS or SPS&FS exposure) stages in these two models. First, we identified temporal differences in the expressional patterns between these two models and found pathways such as protein synthesis factor eukaryotic initiation factor 2 (EIF2), transcription factor NF-E2-related factor 2 (NRF2)-mediated oxidative stress response, and acute phase responding signaling enriched in the early stage in both models with significant p-values. Furthermore, in the late stage, the sirtuin signaling pathway was enriched in both models; other pathways such as STAT3, cAMP, lipid metabolism, Gα signaling, and increased fear were especially enriched in the late stage of the SPS&FS model. However, pathways such as VDR/RXR, GP6, and PPAR signaling were activated significantly in the FS model's late stage. Last, the network analysis revealed the temporal dynamics of psychological disorder, the endocrine system, and also genes related to increased fear in the two models. This study could help elucidate the genetic temporal alteration and stage-specific pathways in these two models, as well as a better understanding of the transcriptome-level differences between them.

Early- and late-phase changes of brain activity and early-phase neuromodulation in the posttraumatic stress disorder rat model.

Posttraumatic stress disorder (PTSD) is a complex syndrome that may occur after life-threatening events. Fear memory abnormalities may play vital roles in the pathogenesis of PTSD. Previous work has found that fear memories are not rigid; the retrieval of fear memories may change over time. Furthermore, prior studies suggest that theta wave (4 Hz) activity is highly correlated with fear expression in an animal model. However, the relationship between pathological fear memory and potential brain wave features in PTSD remains largely uncharacterized. Here, we hypothesized that after traumatic stress exposure, the longitudinal dynamics of abnormal fears in PTSD animal models could be reflected by the measurement of local field potentials (LFPs). Using a well-established modified single-prolonged stress and footshock (SPS & FS) PTSD rat model, animals were restrained for 2 h and subsequently subjected to 20 min of forced swimming, then exposed to diethyl ether until they lost consciousness and placed in a conditioning chamber for fear conditioning. To characterize the temporal changes, we characterized freezing behavior brain wave features during the conditioning chamber re-exposure in the early (10 and 30 min; 2, 4, and 6 h) and late (day 1, 3, 7, and 14) phases after traumatic stress exposure. Our results indicate that SPS & FS rats showed co-morbid PTSD phenotypes including significantly higher levels of anxiety-, depression-, and anhedonia-like behaviors, and impaired fear extinction. Delta wave (0.5-4 Hz) suppression in the medial prefrontal cortex, amygdala, and ventral hippocampus occurred 10 and 30 min after traumatic stress, followed by continuous delta wave activity from 2 h to day 14, correlating with fear levels. tDCS reduced delta activity and alleviated PTSD-like phenotypes in the SPS & FS group. In this study, profiling abnormal fears with brain wave correlates may improve our understanding of time-dependent pathological fear memory retrieval in PTSD and facilitate the development of effective intervention strategies.

Novel Pulsed Ultrahigh-frequency Spinal Cord Stimulation Inhibits Mechanical Hypersensitivity and Brain Neuronal Activity in Rats after Nerve Injury.

BACKGROUND: Spinal cord stimulation (SCS) is an important pain treatment modality. This study hypothesized that a novel pulsed ultrahigh-frequency spinal cord stimulation (pUHF-SCS) could safely and effectively inhibit spared nerve injury-induced neuropathic pain in rats. METHODS: Epidural pUHF-SCS (± 3V, 2-Hz pulses comprising 500-kHz biphasic sinewaves) was implanted at the thoracic vertebrae (T9 to T11). Local field brain potentials after hind paw stimulation were recorded. Analgesia was evaluated by von Frey-evoked allodynia and acetone-induced cold allodynia. RESULTS: The mechanical withdrawal threshold of the injured paw was 0.91 ± 0.28 g lower than that of the sham surgery (24.9 ± 1.2 g). Applying 5-, 10-, or 20-min pUHF-SCS five times every 2 days significantly increased the paw withdrawal threshold to 13.3 ± 6.5, 18.5 ± 3.6, and 21.0 ± 2.8 g at 5 h post-SCS, respectively (P = 0.0002, < 0.0001, and < 0.0001; n = 6 per group) and to 6.1 ± 2.5, 8.2 ± 2.7, and 14.3 ± 5.9 g on the second day, respectively (P = 0.123, 0.013, and < 0.0001). Acetone-induced paw response numbers decreased from pre-SCS (41 ± 12) to 24 ± 12 and 28 ± 10 (P = 0.006 and 0.027; n = 9) at 1 and 5 h after three rounds of 20-min pUHF-SCS, respectively. The areas under the curve from the C component of the evoked potentials at the left primary somatosensory and anterior cingulate cortices were significantly decreased from pre-SCS (101.3 ± 58.3 and 86.9 ± 25.5, respectively) to 39.7 ± 40.3 and 36.3 ± 20.7 (P = 0.021, and 0.003; n = 5) at 60 min post-SCS, respectively. The intensity thresholds for pUHF-SCS to induce brain and sciatic nerve activations were much higher than the therapeutic intensities and thresholds of conventional low-frequency SCS. CONCLUSIONS: Pulsed ultrahigh-frequency spinal cord stimulation inhibited neuropathic pain-related behavior and paw stimulation evoked brain activation through mechanisms distinct from low-frequency SCS.

Modulation of Thalamocingulate Nociceptive Transmission and Glutamate Secretion by Targeting P2×7 Receptor.

The complexity and diversity of pain signaling have led to obstacles for prominent treatments due to mechanisms that are not yet fully understood. Among adenosine triphosphate (ATP) receptors, P2×7 differs in many respects from P2×1-6, it plays a significant role in various inflammatory pain, but whether it plays a role in noninflammatory pain has not been widely discussed. In this study, we utilized major neuropharmacological methods to record the effects of manipulating P2×7 during nociceptive signal transmission in the thalamocingulate circuits. Our results show that regardless of the specific cell type distribution of P2×7 in the central nervous system (CNS), it participates directly in the generated nociceptive transmission, which indicates its apparent functional existence in the major pain transmission path, the thalamocingulate circuits. Activation of P2×7 may facilitate transmission velocity along the thalamocingulate projection as well as neuron firings and synaptic vesicle release in anterior cingulate cortical neurons. Targeting thalamic P2×7 affects glutamate and ATP secretion during nociceptive signal transmission. PERSPECTIVE: The observations in this study provide evidence that the ATP receptor P2×7 presents in the central ascending pain path and plays a modulatory role during nociceptive transmission, which could contribute new insights for many antinociceptive applications.

Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states.

Introduction: Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning. Methods: All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus. Results: The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning. Conclusion: Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.

Modulation of Melatonin in Pain Behaviors Associated with Oxidative Stress and Neuroinflammation Responses in an Animal Model of Central Post-Stroke Pain.

Central post-stroke pain is a severe persistent pain disease that affects 12% of stroke survivors (CPSP). These patients may have a cognitive impairment, depression, and sleep apnea, which leave them open to misdiagnosis and mistreatment. However, there has been little research on whether the neurohormone melatonin can effectively reduce pain in CPSP conditions. In the present study, we labeled melatonin receptors in various brain regions of rats. Later, we established a CPSP animal model by intra-thalamic collagenase lesions. After a rehabilitation period of three weeks, melatonin was administered using different doses (i.e., 30 mg/kg, 60 mg/kg, 120 mg/kg) for the following three weeks. Mechanical allodynia, thermal hyperalgesia, and cold allodynia behavioral tests were performed. Immediately after behavioral parameters were tested, animals were sacrificed, and the thalamus and cortex were isolated for biochemical (mitochondrial complexes/enzyme assays and LPO, GSH levels) and neuroinflammatory (TNF-α, IL-1ß, IL-6) assessments. The results show that melatonin receptors were abundant in VPM/VPL regions. The thalamic lesion significantly induced pain behaviors in the mechanical, thermal planters, and cold allodynia tests. A significant decrease in mitochondrial chain complexes (C-I, II, III, IV) and enzymes (SOD, CAT, Gpx, SDH) was observed after the thalamic lesion. While there were significant increases in reactive oxygen species levels, including increases in LPO, the levels of reduced GSH were decreased in both the cortex and thalamus. Proinflammatory infiltration was noticed after the thalamic lesion, as there was a significant elevation in levels of TNF-α, IL-1ß, and IL-6. Administration of melatonin has been shown to reverse the injury effect dose-dependently. Moreover, a significant increase in C-I, IV, SOD, CAT, and Gpx levels occurred in the CPSP group. Proinflammatory cytokines were significantly reduced by melatonin treatments. Melatonin seems to mediate its actions through MT1 receptors by preserving mitochondrial homeostasis, reducing free radical generation, enhancing mitochondrial glutathione levels, safeguarding the proton potential in the mitochondrial ETC by stimulating complex I and IV activities, and protecting the neuronal damage. In summary, exogenous melatonin can ameliorate pain behaviors in CPSP. The present findings may provide a novel neuromodulatory treatment in the clinical aspects of CPSP.

Modulation of melatonin to the thalamic lesion-induced pain and comorbid sleep disturbance in the animal model of the central post-stroke hemorrhage.

The devastating chronic central post stroke pain is associated with variety of comorbidities. Disrupted sleep is a severe comorbidity, causing an increase in the suicide rate, due to CPSP's pain symptom. Melatonin is a well-known jet-lag compound, which helps in entrainment of sleep cycle. Accordingly, whether melatonin as a therapeutic measurement for the regulation of sleep disturbance related to central post stroke pain remains unclear. Exogenous melatonin administration entrained the disrupted 24 h circadian cycle, more effectively after 2 and 3 week of administration. The effect of melatonin was persisted on 4th week too, when melatonin administration was discontinued. Also, melatonin ameliorated the pain due to distorted sleep-activity behavior after melatonin administration for 3 weeks. The low levels of melatonin in blood plasma due to CPSP were restored after 3 weeks of melatonin administration. After 30 mg/kg melatonin administrations for 3 weeks, all the disrupted resting and activity behaviors were reduced during light and dark periods. The results suggested that melatonin significantly ameliorated CPSP's pain symptoms and comorbid sleep disturbance showing in activity behavior.

Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes.

BACKGROUND: The sino atrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN. METHODS: Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes. RESULTS: We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells. CONCLUSIONS: Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.

Detection of pentylenetetrazol-induced seizure activity in the 19-21 Hz beta range using a magnetic coil induction method.

INTRODUCTION: A force transducer or automatic scoring system is not sufficient to detect small or fine seizure activity. To improve previous assessments of epileptic behavior, a novel coil method was developed to detect an early behavioral marker for epileptic seizures. METHODS: The present study used the γ-aminobutyric acid (GABA) receptor antagonist pentylenetetrazol (PTZ) to induce seizure activity and epileptic behavior in mice. A coil method was used to detect motor seizures consisting of small amplitude 19-21 Hz muscle contractions. RESULTS: Seizure activity in the 19-21 Hz range detected by the coil method was positively correlated with generalized clonic seizures with a kangaroo posture after PTZ administration. GABA receptor agonist valproic acid and ethosuximide decreased PTZ-induced 19-21 Hz seizure activity. The pattern of the amplitude ratio (%) of 19-21 Hz seizure activity after administration of the GABAA/C receptor antagonist picrotoxin was similar to the group that was treated with PTZ but different from the group that was treated with the nonselective muscarinic receptor agonist pilocarpine. The coil method detected 19-21 Hz seizure activity after PTZ administration. However, the force transducer method did not detect 19-21 Hz seizure activity. CONCLUSIONS: The coil method was more sensitive than the force transducer method for detecting epileptic behaviors. The findings may indicate a novel behavioral marker that can be detected by the coil method to reveal epileptic seizures, thus improving our understanding of the brain mechanisms of action and specific brain waves that are associated with PTZ-induced 19-21 Hz seizure activity.

Tricyclic antidepressants and selective serotonin reuptake inhibitors but not anticonvulsants ameliorate pain, anxiety, and depression symptoms in an animal model of central post-stroke pain.

BACKGROUND: Central post-stroke pain (CPSP) is a type of neuropathic pain caused by dysfunction in the spinothalamocortical pathway. However, no animal studies have examined comorbid anxiety and depression symptoms. Whether the typical pharmacological treatments for CPSP, which include antidepressants, selective serotonin reuptake inhibitors (SSRIs), and anticonvulsants, can treat comorbid anxiety and depression symptoms in addition to pain remains unclear? The present study ablated the ventrobasal complex of the thalamus (VBC) to cause various CPSP symptoms. The effects of the tricyclic antidepressants amitriptyline and imipramine, the SSRI fluoxetine, and the anticonvulsant carbamazepine on pain, anxiety, and depression were examined. RESULTS: The results showed that VBC lesions induced sensitivity to thermal pain, measured using a hot water bath; mechanical pain, assessed by von Frey test; anxiety behavior, determined by the open-field test, elevated plus-maze test, and zero-maze test; and depression behavior, assessed by the forced swim test. No effect on motor activity in the open-field test was observed. Amitriptyline reduced thermal and mechanical pain sensitivity and anxiety but not depression. Imipramine suppressed thermal and mechanical pain sensitivity, anxiety, and depression. Fluoxetine blocked mechanical but not thermal pain sensitivity, anxiety, and depression. However, carbamazepine did not affect pain, anxiety, or depression. CONCLUSION: In summary, antidepressants and SSRIs but not anticonvulsants can effectively ameliorate pain and comorbid anxiety and depression in CPSP. The present findings, including discrepancies in the effects observed following treatment with anticonvulsants, antidepressants, and SSRIs in this CPSP animal model, can be applied in the clinical setting to guide the pharmacological treatment of CPSP symptoms.

Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer's Disease in an Animal Model.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that causes cognitive impairment and other neuropsychiatric symptoms. Previously, little research has thus far investigated whether methamphetamine (MAMPH) can enhance cognitive function or ameliorate AD symptoms. This study examined whether a low dose of MAMPH can induce conditioned taste aversion (CTA) learning, or can increase plasma corticosterone levels, neural activity, and neural plasticity in the medial prefrontal cortex (mPFC) (responsible for cognitive function), the nucleus accumbens (NAc) and the amygdala (related to rewarding and aversive emotion), and the hippocampus (responsible for spatial learning). Furthermore, the excitations or lesions of the prelimbic cortex (PrL) can affect MAMPH-induced CTA learning, plasma corticosterone levels, and neural activity or plasticity in the mPFC [i.e., PrL, infralimbic cortex (IL), cingulate cortex 1 (Cg1)], the NAc, the amygdala [i.e., basolateral amygdala (BLA) and central amygdala (CeA)], and the hippocampus [i.e., CA1, CA2, CA3, and dentate gyrus (DG)]. In the experimental procedure, the rats were administered either saline or NMDA solutions, which were injected into the PrL to excite or destroy PrL neurons. Additionally, rats received 0.1% saccharin solution for 15 min, followed by intraperitoneal injections of either normal saline or 1 mg/kg MAMPH to induce CTA. A one-way ANOVA was performed to analyze the effects of saccharin intake on CTA, plasma corticosterone levels, and the expression of c-Fos and p-ERK. The results showed that the MAMPH induced CTA learning and increased plasma corticosterone levels. The mPFC, and particularly the PrL and IL and the DG of the hippocampus, appeared to show increased neural activity in c-Fos expression or neural plasticity in p-ERK expression. The excitation of the PrL neurons upregulated neural activity in c-Fos expression and neural plasticity in p-ERK expression in the PrL and IL. In summary, MAMPH may be able to improve cognitive and executive function in the brain and reduce AD symptoms. Moreover, the excitatory modulation of the PrL with MAMPH administration can facilitate MAMPH-induced neural activity and plasticity in the PrL and IL of the mPFC. The present data provide clinical implications for developing a possible treatment for AD in an animal model.

Involvement of the ventral tegmental area but not periaqueductal gray matter in the paradoxical rewarding and aversive effects of morphine.

The paradoxical effects of reward and aversion with abused drugs may interact to produce drug addiction, which is the so-called paradoxical effect hypothesis of abused drugs. However, there is no research examining how the ventral tegmental area (VTA) or periaqueductal gray matter (PAG) regulates morphine's paradoxical effect of reward and aversion. The present study addresses this issue, utilizing a high concentration of N-methyl-D-aspartic acid (NMDA) via injections to destroy the VTA or the PAG. Moreover, the study employed the new "pre- and postassociation" experimental paradigm (2010) to test whether the simultaneous rewarding and aversive effects of morphine can be affected by an NMDA lesion in the VTA or the PAG. The results indicated that the NMDA lesion of the VTA simultaneously reduced morphine-induced conditioned suppression of saccharin solution intake in conditioned taste aversion (CTA) and morphine-induced spent time in the preference compartment in conditioned place preference (CPP), whereas the PAG lesion did not change either measure. Thus, the VTA, but not the PAG, appears to contribute to the paradoxical effect reward in CPP and aversion in CTA induced by morphine. The VTA's involvement in morphine-induced CTA aversion and CPP reward supports the paradoxical effect hypothesis of abused drugs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BDNF Protein and BDNF mRNA Expression of the Medial Prefrontal Cortex, Amygdala, and Hippocampus during Situational Reminder in the PTSD Animal Model.

Whether BDNF protein and BDNF mRNA expression of the medial prefrontal cortex (mPFC; cingulated cortex area 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), amygdala, and hippocampus (CA1, CA2, CA3, and dentate gyrus (DG)) was involved in fear of posttraumatic stress disorder (PTSD) during the situational reminder of traumatic memory remains uncertain. Footshock rats experienced an inescapable footshock (3 mA, 10 s), and later we have measured fear behavior for 2 min in the footshock environment on the situational reminder phase. In the final retrieval of situational reminder, BDNF protein and mRNA levels were measured. The results showed that higher BDNF expression occurred in the Cg1, PrL, and amygdala. Lower BDNF expression occurred in the IL, CA1, CA2, CA3, and DG. BDNF mRNA levels were higher in the mPFC and amygdala but lower in the hippocampus. The neural connection analysis showed that BDNF protein and BDNF mRNA exhibited weak connections among the mPFC, amygdala, and hippocampus during situational reminders. The present data did not support the previous viewpoint in neuroimaging research that the mPFC and hippocampus revealed hypoactivity and the amygdala exhibited hyperactivity for PTSD symptoms. These findings should be discussed with the previous evidence and provide clinical implications for PTSD.

Basolateral Amygdala but Not Medial Prefrontal Cortex Contributes to Chronic Fluoxetine Treatments for PTSD Symptoms in Mice.

Do chronic fluoxetine treatments reduced footshock-induced posttraumatic stress disorder (PTSD) symptoms, including fear and comorbid depression, in the situational reminder phase? Moreover, are the subareas of the medial prefrontal cortex (mPFC), including the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), and basolateral amygdala (BLA), involved in the fluoxetine amelioration of PTSD symptoms? These two crucial issues were addressed in the present study. All mice were injected with chronic fluoxetine or normal saline treatments for the adaptation (14 days), footshock fear conditioning (1 day), and situational reminder (3 days) phases. After adaptation, the mice were subjected to footshock (2 mA, 10 seconds) or nonfootshock and stayed 2 min in a footshock box for 2 min for fear conditioning. Later, they were placed in the footshock box for 2 min in the situational reminder phase. In the final session of the situational reminder phase, a forced swimming test (FST) and immunohistochemical staining were conducted. The results indicated that footshock induced fear and comorbid depression. Meanwhile, chronic fluoxetine treatments reduced fear and depression behaviors. The Cg1, PrL, IL, and BLA were seemingly to increase c-Fos expression after footshock-induced PTSD symptoms in the situational reminder phase. The fluoxetine treatments reduced only the BLA's c-Fos expression. The findings suggest that BLA contributes to the fluoxetine amelioration of PTSD symptoms; however, the mPFC, including the Cg1, PrL, and IL, did not mediate PTSD symptoms' amelioration stemming from fluoxetine. The present data might help us to further understand the neural mechanism of fluoxetine treatments in PTSD symptoms.

A Wireless Magnetic Resonance Device for Optogenetic Applications in an Animal Model.

The currents of optical stimulation devices with tethered or untethered systems have various disadvantages, including optical fiber breakage, disrupted animal movements, heavy batteries carried on heads, and high-frequency electromagnetic impacts. Our novel wireless remote control was developed to address these issues. The novel wireless device uses a magnetic resonance technique to modify the deficits of the conventional magnetic induction or radio-frequency power sources. The present device emits a strong and steady electromagnetic power. It is cheaper than previous versions, and the receiver coil on its head is very light (≦ 1 g). For the present wireless remote-controlled device, the electromagnetic field's range (i.e., +5 cm and -5 cm of the outside coil) is larger than the range for the magnetic induction and radio-frequency power sources. The present device controls animals' behavior by the electromagnetic field's effective range via photostimulation. The novel wireless remote-controlled device with a magnetic resonance technique can be applied in many behavioral tasks in mice and rats. To avoid the adverse effects of high radio frequency and to extend the electromagnetic field's range, this novel technique serves as a helpful tool to modulate the neuronal activity of target neurons in specific brain areas for optogenetic experiments.

Spontaneous Cingulate High-Current Spikes Signal Normal and Pathological Pain States.

Prominent 7-12 Hz oscillations in frontal cortical networks in rats have been reported. However, the mechanism of generation and the physiological function of this brain rhythm have not yet been clarified. Multichannel extracellular field potentials of the ACC were recorded and analyzed using the current source density method in halothane-anesthetized rats. Spontaneous high-current spikes (HCSs) were localized in the deep part of layer II/III and upper part of layer V of the ACC. The frequency of HCSs in the ACC was 7-12 Hz, with an amplitude of 6.5 ± 0.76 mV/mm2 and duration of 55.24 ± 2.43 ms. The power density significantly decreased (84.56 ± 6.93%, p < 0.05, t test) after pinching the hindpaw and significantly increased (149.28 ± 15.96%) after treatment with morphine. The suppressive effect of pinching was reversed by naloxone (0.7 mg/kg, i.p.). HCSs coincided with initiation of the depolarization of cingulate neurons and remained in a depolarized upstate. The occurrence of cingulate HCSs was persistently preceded by a hyperpolarization phase and a burst of multiunit spike activity in the medial dorsal thalamic nucleus. Spontaneous field-potential oscillations changed from 10 Hz to a lower band (i.e., ∼7.5 Hz) when a central poststroke pain condition was induced. The central poststroke pain group had a higher average coherence coefficient compared with the control group. Our results indicate that spontaneous cingulate cortical HCSs could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms in physiological and pathological pain states.SIGNIFICANCE STATEMENT This study elucidated the mechanism of generation and physiological function of prominent 7-12 Hz frequency oscillations in frontal cortical networks in rats. Spontaneous cingulate cortical high-current spikes in anesthetized rats could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms. Suppression of the anterior cingulate cortex-filtered EEG during noxious stimulation may have resulted from the desynchronization of high-current spikes in the ACC. The enhancement of fast Fourier transform power after a systemic morphine injection suggested that the opioid system may play an important role in synchronizing cingulate cortical neuronal networks. Spontaneous cingulate high-current spikes may also play an important role in thalamocortical dysrhythmia in central poststroke pain.

Anterior nucleus of paraventricular thalamus mediates chronic mechanical hyperalgesia.

Pain-related diseases are the top leading causes of life disability. Identifying brain regions involved in persistent neuronal changes will provide new insights for developing efficient chronic pain treatment. Here, we showed that anterior nucleus of paraventricular thalamus (PVA) plays an essential role in the development of mechanical hyperalgesia in neuropathic and inflammatory pain models in mice. Increase in c-Fos, phosphorylated extracellular signal-regulated kinase, and hyperexcitability of PVA neurons were detected in hyperalgesic mice. Direct activation of PVA neurons using optogenetics and pharmacological approaches were sufficient to induce persistent mechanical hyperalgesia in naive animals. Conversely, inhibition of PVA neuronal activity using DREADDs (designer receptors exclusively activated by designer drugs) or inactivation of PVA extracellular signal-regulated kinase at the critical time window blunted mechanical hyperalgesia in chronic pain models. At the circuitry level, PVA received innervation from central nucleus of amygdala, a known pain-associated locus. As a result, activation of right central nucleus of amygdala with blue light was enough to induce persistent mechanical hyperalgesia. These findings support the idea that targeting PVA can be a potential therapeutic strategy for pain relief.

Involvement of P2X7 Receptors and BDNF in the Pathogenesis of Central Poststroke Pain.

Central pain is commonly found in patients with neurological complications that are associated with central nervous system insult, such as stroke. It can result directly from central nervous system injury. Impairments in sensory discrimination can make it challenging to differentiate central neuropathic pain from other types of pain or spasticity. Central neuropathic pain may also begin months to years after the injury, further obscuring the recognition of its association with past neurologic injury. This chapter focuses on the involvement of P2X7 receptor and brain-derived neurotrophic factor (BDNF) in central poststroke pain (CPSP). An experimental animal model is introduced that assesses the pathogenesis of central neuropathic pain, and pharmacological approaches and neuromodulatory treatments of this difficult-to-treat pain syndrome are discussed.

Central Poststroke Pain, Comorbidity, and Associated Symptoms in Animal and Human Models.

The objective of the present review paper was to comprehensively introduce the pain symptom and comorbidities of depression, anxiety, and learning and memory dysfunctions in the central poststroke pain (CPSP) of human and animal models. CPSP is a disease in which the lesion or dysfunction of the spinothalamocortical circuits is due to thalamic stroke hemorrhage. According to previous literature, CPSP patients experience impaired explicit and implicit learning and memory in addition to the pain symptom. Moreover, there are associated depression and anxiety comorbidities for CPSP. However, the data from some clinical studies were not supportive of the notion that CPSP patients also experienced induced comorbid depression and anxiety. On the other hand, the motor function test was likely to be inconsistent in terms of the results of human and animal models. The review paper provides some implications for further development of animal models for examinations of CPSP comorbidities of depression, anxiety, learning and memory dysfunction, and motor functions, aside from the central pain symptom. In human models, some conflicting data related to comorbid depression, anxiety, explicit and implicit learning memory, and motor dysfunctions should be re-elucidated in further studies.