Primary somatosensory cortex CB1 and 5­HT1A receptors interaction in the penicillin model of epilepsy.

Cannabinoid and serotonin systems regulate many biological processes. The aim of the present study was to investigate the functional interaction between the cannabinoid and serotonergic systems of the primary somatosensory region (S1) of the brain in epileptiform activity caused by penicillin. The ACEA (an agonist of CB1 receptor), AM­251 (an antagonist of CB1 receptor), 8­OH­DPAT (an agonist of 5­HT1A receptor) and WAY­100635 (an antagonist of 5­HT1A receptor) were administered into the S1 after the same site administration of penicillin in urethane­anesthetized rats. Electrocorticographic recording was done for a 90­min period. The spike waves number and amplitude were recorded in 15­min intervals. Areas under the curve (AUC) of the above­mentioned spike alterations was calculated in 90 min. Spike waves with frequency of 30/min and amplitude of 1.3 mV were appeared after penicillin microinjection. The ACEA (50 ng), 8­OH­DPAT (500 ng) and ACEA (10 ng) plus 8­OH­DPAT (100 ng) reduced epileptiform activity. The AM­251 (50 ng) and WAY­100365 (500 ng) prevented the reducing effects of ACEA (50 ng) and 8­OH­DPAT (500 ng). The AM­251 alone increased spike waves frequency. The AUC results supported the effects of the above­mentioned treatments. The results showed that activating CB1 and 5­HT1A receptors in the S1 may reduce the epileptiform activity caused by penicillin. Therefore, alone and together activation of central CB1 and 5­HT1A receptors might be considered in the management of epilepsy treatment.

A mouse model of schizophrenia induced by autoantibodies against SFT2D2.

Schizophrenia (SCZ) is a highly heterogeneous, severe neuropsychiatric disorder of unknown etiopathology. Increasing data indicate an overlap between schizophrenia and pathological processes related to immunological dysregulation as well as inflammation, such as high levels of pro-inflammatory substances in patients' blood and cerebrospinal fluid and autoantibodies against synaptic and nerve cell membrane proteins. Autoantibodies against SFT2D2 have been reported in patients with SCZ. However, their roles in inflammation have not yet been established. We performed a continuous intracerebroventricular infusion of polyclonal rabbit anti-SFT2D2-IgG in male C57BL/6 mice. Behavioral tests were conducted after 2 weeks of treatment. Our results showed an increased density of microglia and activated astrocytes in the primary somatosensory cortex of the anti-SFT2D2-IgG-infused mice. Quantitative reverse transcription-polymerase chain reactions showed that the expression of pro-inflammatory genes was upregulated in the primary somatosensory cortex and hippocampus of the anti-SFT2D2-IgG-infused mice. Additionally, the mice exhibited defective sensorimotor gating, memory deficits, motor impairment, and anxiety-related behaviors without signs of depression. These findings indicate that anti-SFT2D2 autoantibodies can induce encephalitis, cause a series of behavioral changes associated with schizophrenia, and offer a model for testing novel therapies to improve treatment strategies for a subgroup of patients with SCZ.

Glial activation in pain and emotional processing regions in the nitroglycerin mouse model of chronic migraine.

OBJECTIVE: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine. BACKGROUND: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain. METHODS: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed. RESULTS: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification. CONCLUSIONS: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed.

PolyI:C Maternal Immune Activation on E9.5 Causes the Deregulation of Microglia and the Complement System in Mice, Leading to Decreased Synaptic Spine Density.

Maternal immune activation (MIA) is a risk factor for multiple neurodevelopmental disorders; however, animal models developed to explore MIA mechanisms are sensitive to experimental factors, which has led to complexity in previous reports of the MIA phenotype. We sought to characterize an MIA protocol throughout development to understand how prenatal immune insult alters the trajectory of important neurodevelopmental processes, including the microglial regulation of synaptic spines and complement signaling. We used polyinosinic:polycytidylic acid (polyI:C) to induce MIA on gestational day 9.5 in CD-1 mice, and measured their synaptic spine density, microglial synaptic pruning, and complement protein expression. We found reduced dendritic spine density in the somatosensory cortex starting at 3-weeks-of-age with requisite increases in microglial synaptic pruning and phagocytosis, suggesting spine density loss was caused by increased microglial synaptic pruning. Additionally, we showed dysregulation in complement protein expression persisting into adulthood. Our findings highlight disruptions in the prenatal environment leading to alterations in multiple dynamic processes through to postnatal development. This could potentially suggest developmental time points during which synaptic processes could be measured as risk factors or targeted with therapeutics for neurodevelopmental disorders.

Effects of focal cortical cooling on somatosensory evoked potentials in rats.

Although the focal brain cooling technique is widely used to examine brain function, the effects of cortical temperature at various levels on sensory information processing and neural mechanisms remain underexplored. To elucidate the mechanisms of temperature modulation in somatosensory processing, this study aimed to examine how P1 and N1 deflections of somatosensory evoked potentials (SEPs) depend on cortical temperature and how excitatory and inhibitory inputs contribute to this temperature dependency. SEPs were generated through electrical stimulation of the contralateral forepaw in anesthetized rats. The SEPs were recorded while cortical temperatures were altered between 17-38 °C either without any antagonists, with a gamma-aminobutyric acid type A (GABAA) receptor antagonist (gabazine), with an aminomethylphosphonic acid (AMPA) receptor antagonist (NBQX), or with an N-Methyl-D-aspartic acid (NMDA) receptor antagonist ([R]-CPP). The effects of different gabazine concentrations (0, 1, and 10 µM) were examined in the 35-38 °C range. The P1/N1 amplitudes and their peak-to-peak differences plotted against cortical temperature showed an inverted U relationship with a maximum at approximately 27.5 °C when no antagonists were administered. The negative correlation between these amplitudes and temperatures of ≥ 27.5 °C plateaued after gabazine administration, which occurred progressively as the gabazine concentration increased. In contrast, the correlation remained negative after the administration of NBQX and (R)-CPP. These results suggest that GABAergic inhibitory inputs contribute to the negative correlation between SEP amplitude and cortical temperature around the physiological cortical temperature.

Cortical diurnal rhythms remain intact with microglial depletion.

Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms.

Longitudinal functional imaging of VIP interneurons reveals sup-population specific effects of stroke that are rescued with chemogenetic therapy.

Stroke profoundly disrupts cortical excitability which impedes recovery, but how it affects the function of specific inhibitory interneurons, or subpopulations therein, is poorly understood. Interneurons expressing vasoactive intestinal peptide (VIP) represent an intriguing stroke target because they can regulate cortical excitability through disinhibition. Here we chemogenetically augmented VIP interneuron excitability in a murine model of photothrombotic stroke and show that it enhances somatosensory responses and improves recovery of paw function. Using longitudinal calcium imaging, we discovered that stroke primarily disrupts the fidelity (fraction of responsive trials) and predictability of sensory responses within a subset of highly active VIP neurons. Partial recovery of responses occurred largely within these active neurons and was not accompanied by the recruitment of minimally active neurons. Importantly, chemogenetic stimulation preserved sensory response fidelity and predictability in highly active neurons. These findings provide a new depth of understanding into how stroke and prospective therapies (chemogenetics), can influence subpopulations of inhibitory interneurons.

Goshajinkigan attenuates paclitaxel-induced neuropathic pain via cortical astrocytes.

The anticancer agents platinum derivatives and taxanes such as paclitaxel (PCX) often cause neuropathy known as chemotherapy-induced peripheral neuropathy with high frequency. However, the cellular and molecular mechanisms underlying such neuropathy largely remain unknown. Here, we show new findings that the effect of Goshajinkigan (GJG), a Japanese KAMPO medicine, inhibits PCX-induced neuropathy by acting on astrocytes. The administration of PCX in mice caused the sustained neuropathy lasting at least 4 weeks, which included mechanical allodynia and thermal hyperalgesia but not cold allodynia. PCX-evoked pain behaviors were associated with the sensitization of all primary afferent fibers. PCX did not activate microglia or astrocytes in the spinal cord. However, it significantly activated astrocytes in the primary sensory (S1) cortex without affecting S1 microglial activation there. GJG significantly inhibited the PCX-induced mechanical allodynia by 50% and thermal hyperalgesia by 90%, which was in accordance with the abolishment of astrocytic activation in the S1 cortex. Finally, the inhibition of S1 astrocytes by an astrocyte-toxin L-alpha-aminoadipic acid abolished the PCX-induced neuropathy. Our findings suggest that astrocytes in the S1 cortex would play an important role in the pathogenesis of PCX-induced neuropathy and are a potential target for its treatment.

Aberrant inhibitory processing in the somatosensory cortices of cannabis-users.

BACKGROUND: Delta-9 tetrahydrocannabinol (THC) is a major exogenous psychoactive agent, which acts as a partial agonist on cannabinoid (CB1) receptors. THC is known to inhibit presynaptic neurotransmission and has been repeatedly linked to acute decrements in cognitive function across multiple domains. Previous electrophysiological studies of sensory gating have shown specific deficits in inhibitory processing in cannabis-users, but to date these findings have been limited to the auditory cortices, and the degree to which these aberrations extend to other brain regions remains largely unknown. METHODS: We used magnetoencephalography (MEG) and a paired-pulse somatosensory stimulation paradigm to probe inhibitory processing in 29 cannabis-users (i.e. at least four times per month) and 41 demographically matched non-user controls. MEG responses to each stimulation were imaged in both the oscillatory and time domain, and voxel time-series data were extracted to quantify the dynamics of sensory gating, oscillatory gamma activity, evoked responses, and spontaneous neural activity. RESULTS: We observed robust somatosensory responses following both stimulations, which were used to compute sensory gating ratios. Cannabis-users exhibited significantly impaired gating relative to non-users in somatosensory cortices, as well as decreased spontaneous neural activity. In contrast, oscillatory gamma activity did not appear to be affected by cannabis use. CONCLUSIONS: We observed impaired gating of redundant somatosensory information and altered spontaneous activity in the same cortical tissue in cannabis-users compared to non-users. These data suggest that cannabis use is associated with a decline in the brain's ability to properly filter repetitive information and impairments in cortical inhibitory processing.

Vasoactive intestinal peptide (VIP) conducts the neuronal activity during absence seizures: GABA seems to be the main mediator of VIP.

Absence epilepsy is classified as a childhood generalized epilepsy syndrome with distinctive electroencephalographic patterns. The Wistar Albino Glaxo originating from Rijswijk (WAG/Rij) strain is a very well validated animal model of absence epilepsy that also shows behavioral deficits. In addition to the gastrointestinal system, VIP is highly expressed throughout numerous brain regions, and it plays crucial roles as a neurotransmitter and as a neuromodulatory, neurotrophic and neuroprotective factor in both the central and peripheral nervous systems. In this study, adult WAG/Rij rats were divided into two groups (n = 10): a group that was administered VIP (25 ng/kg i.p.) every 2 days for 15 days and an age-matched control group that was administered physiological saline. Electrical brain activity and behavior (depressive- like behavior, learning and memory and anxiety) were investigated in both groups. In addition, the extracellular concentrations of GABA and glutamate and the GABA/glutamate ratio were measured by high-performance liquid chromatography in microdialysate samples collected from the somatosensorial cortex of WAG/Rij rats. Our results demonstrated that VIP treatment significantly suppressed the total duration and number of spike wave discharges in WAG/Rij rats. However, VIP had no significant effect on behavior. VIP increased the extracellular concentration of GABA and the GABA/glutamate ratio in the somatosensory cortex. In conclusion, VIP has suppressive effects on absence seizures, possibly by increasing the GABA concentration and inducing the transformation of glutamate to GABA in the somatosensory cortex of WAG/Rij rats.

Cholinergic modulation of sensory processing in awake mouse cortex.

Cholinergic modulation of brain activity is fundamental for awareness and conscious sensorimotor behaviours, but deciphering the timing and significance of acetylcholine actions for these behaviours is challenging. The widespread nature of cholinergic projections to the cortex means that new insights require access to specific neuronal populations, and on a time-scale that matches behaviourally relevant cholinergic actions. Here, we use fast, voltage imaging of L2/3 cortical pyramidal neurons exclusively expressing the genetically-encoded voltage indicator Butterfly 1.2, in awake, head-fixed mice, receiving sensory stimulation, whilst manipulating the cholinergic system. Altering muscarinic acetylcholine function re-shaped sensory-evoked fast depolarisation and subsequent slow hyperpolarisation of L2/3 pyramidal neurons. A consequence of this re-shaping was disrupted adaptation of the sensory-evoked responses, suggesting a critical role for acetylcholine during sensory discrimination behaviour. Our findings provide new insights into how the cortex processes sensory information and how loss of acetylcholine, for example in Alzheimer's Disease, disrupts sensory behaviours.

Arctigenin Exerts Neuroprotective Effect by Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis In Vivo.

Multiple sclerosis (MS) is a chronic disease in the central nervous system (CNS), characterized by inflammatory cells that invade into the brain and the spinal cord. Among a bulk of different MS models, the most widely used and best understood rodent model is experimental autoimmune encephalomyelitis (EAE). Arctigenin, a botanical extract from Arctium lappa, is reported to exhibit pharmacological properties, including anti-inflammation and neuroprotection. However, the effects of arctigenin on neural activity attacked by inflammation in MS are still unclear. Here, we use two-photon calcium imaging to observe the activity of somatosensory cortex neurons in awake EAE mice in vivo and found added hyperactive cells, calcium influx, network connectivity, and synchronization, mainly at preclinical stage of EAE model. Besides, more silent cells and decreased calcium influx and reduced network synchronization accompanied by a compensatory rise in functional connectivity are found at the remission stage. Arctigenin treatment not only restricts inordinate individually neural spiking, calcium influx, and network activity at preclinical stage but also restores neuronal activity and communication at remission stage. In addition, we confirm that the frequency of AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) is also increased at preclinical stage and can be blunted by arctigenin. These findings suggest that excitotoxicity characterized by calcium influx is involved in EAE at preclinical stage. What is more, arctigenin exerts neuroprotective effect by limiting hyperactivity at preclinical stage and ameliorates EAE symptoms, indicating that arctigenin could be a potential therapeutic drug for neuroprotection in MS-related neuropsychological disorders.

Characterization of brain-wide somatosensory BOLD fMRI in mice under dexmedetomidine/isoflurane and ketamine/xylazine.

Mouse fMRI under anesthesia has become increasingly popular due to improvement in obtaining brain-wide BOLD response. Medetomidine with isoflurane has become well-accepted for resting-state fMRI, but whether this combination allows for stable, expected, and robust brain-wide evoked response in mice has yet to be validated. We thus utilized intravenous infusion of dexmedetomidine with inhaled isoflurane and intravenous infusion of ketamine/xylazine to elucidate whether stable mouse physiology and BOLD response are obtainable in response to simultaneous forepaw and whisker-pad stimulation throughout 8 h. We found both anesthetics result in hypercapnia with depressed heart rate and respiration due to self-breathing, but these values were stable throughout 8 h. Regardless of the mouse condition, brain-wide, robust, and stable BOLD response throughout the somatosensory axis was observed with differences in sensitivity and dynamics. Dexmedetomidine/isoflurane resulted in fast, boxcar-like, BOLD response with consistent hemodynamic shapes throughout the brain. Ketamine/xylazine response showed higher sensitivity, prolonged BOLD response, and evidence for cortical disinhibition as significant bilateral cortical response was observed. In addition, differing hemodynamic shapes were observed between cortical and subcortical areas. Overall, we found both anesthetics are applicable for evoked mouse fMRI studies.

Cortical somatosensory processing after botulinum toxin therapy in post-stroke spasticity.

ABSTRACT: In dystonic and spastic movement disorders, abnormalities of motor control and somatosensory processing as well as cortical modulations associated with clinical improvement after botulinum toxin A (BoNT-A) treatment have been reported, but electrophysiological evidence remains controversial. In the present observational study, we aimed to uncover central correlates of post-stroke spasticity (PSS) and BoNT-A-related changes in the sensorimotor cortex by investigating the cortical components of somatosensory evoked potentials (SEPs). Thirty-one chronic stroke patients with PSS of the upper limb were treated with BoNT-A application into the affected muscles and physiotherapy. Clinical and electrophysiological evaluations were performed just before BoNT-A application (W0), then 4 weeks (W4) and 11 weeks (W11) later. PSS was evaluated with the modified Ashworth scale (MAS). Median nerve SEPs were examined in both upper limbs with subsequent statistical analysis of the peak-to-peak amplitudes of precentral P22/N30 and postcentral N20/P23 components. At baseline (W0), postcentral SEPs were significantly lower over the affected cortex. At follow up, cortical SEPs did not show any significant changes attributable to BoNT-A and/or physiotherapy, despite clear clinical improvement. Our results imply that conventional SEPs are of limited value in evaluating cortical changes after BoNT-A treatment and further studies are needed to elucidate its central actions.

Effects of urethane and isoflurane on the sensory evoked response and local blood flow in the early postnatal rat somatosensory cortex.

Functional studies in the central nervous system are often conducted using anesthesia. While the dose-dependent effects of anesthesia on neuronal activity have been extensively characterized in adults, little is known about the effects of anesthesia on cortical activity and cerebral blood flow in the immature central nervous system. Substitution of electrophysiological recordings with the less-invasive technique of optical intrinsic signal imaging (OIS) in vivo allowed simultaneous recordings of sensory-evoked functional response and local blood flow changes in the neonatal rat barrel cortex. Using OIS we characterize the effects of two widely used anesthetics-urethane and isoflurane. We found that both anesthetics suppressed the sensory-evoked optical intrinsic signal in a dose-dependent manner. Dependence of the cortical response suppression matched the exponential decay model. At experimental levels of anesthesia, urethane affected the evoked cortical response less than isoflurane, which is in agreement with the results of electrophysiological recordings demonstrated by other authors. Changes in oxygenation and local blood flow also showed negative correlation with both anesthetics. The high similarity in immature patterns of activity recorded in different regions of the developing cortex suggested similar principles of development regardless of the cortical region. Therefore the indicated results should be taken into account during functional explorations in the entire developing cortex. Our results also point to urethane as the anesthetic of choice in non-survival experimental recordings in the developing brain as it produces less prominent impairment of cortical neuronal activity in neonatal animals.

Perineuronal net abnormalities in Slc13a4+/- mice are rescued by postnatal administration of N-acetylcysteine.

Disruptions to either sulfate supply or sulfation enzymes can affect brain development and have long-lasting effects on brain function, yet our understanding of the molecular mechanisms governing this are incomplete. Perineuronal nets (PNNs) are highly sulfated, specialized extracellular matrix structures that regulate the maturation of synaptic connections and neuronal plasticity. We have previously shown that mice heterozygous for the brain sulfate transporter Slc13a4 have abnormal social interactions, memory, exploratory behaviors, stress and anxiety of postnatal origin, pointing to potential deficits in PNN biology, and implicate SLC13A4 as a critical factor required for regulating normal synaptic connectivity and function. Here, we sought to investigate aberrant PNN formation as a potential mechanism contributing to the functional deficits displayed by Slc13a4+/- mice. Following social interactions, we reveal reduced neuronal activation in the somatosensory cortex of Slc13a4+/- mice, and altered inhibitory and excitatory postsynaptic currents. In line with this, we found a reduction in parvalbumin-expressing neurons decorated with PNNs, as well as reduced expression of markers for PNN maturation. Finally, we reveal that postnatal administration of N-acetylcysteine prevented PNN abnormalities from manifesting in Slc13a4+/- adult animals. Collectively, these data highlight a central role for postnatal SLC13A4 in normal PNN formation, circuit function and subsequent animal behavior.

Pharmacological modulation of brain activation to non-noxious stimulation in a cynomolgus macaque model of peripheral nerve injury.

In vivo neuroimaging could be utilized as a noninvasive tool for elaborating the CNS mechanism of chronic pain and for elaborating mechanisms of potential analgesic therapeutics. A model of unilateral peripheral neuropathy was developed in the cynomolgus macaque, a species that is phylogenetically close to humans. Nerve entrapment was induced by placing a 4 mm length of polyvinyl cuff around the left common sciatic nerve. Prior to nerve injury, stimulation of the foot with a range of non-noxious von Frey filaments (1, 4, 8, 15, and 26 g) did not evoke brain activation as observed with functional magnetic resonance imaging (fMRI). Two weeks after injury, stimulation of the ipsilateral foot with non-noxious filaments activated the contralateral insula/secondary somatosensory cortex (Ins/SII) and anterior cingulate cortex (ACC). By contrast, no activation was observed with stimulation of the contralateral foot. Robust bilateral activation of thalamus was observed three to five weeks after nerve injury. Treatment with the clinical analgesic pregabalin reduced evoked activation of Ins/SII, thalamus and ACC whereas treatment with the NK1 receptor antagonist aprepitant reduced activation of the ipsilateral (left) thalamus. Twelve to 13 weeks after nerve injury, treatment with pregabalin reduced evoked activation of all regions of interest (ROI). By contrast, brain activation persisted in most ROI, except the ACC, following aprepitant treatment. Activation of the contralateral Ins/SII and bilateral thalamus was observed six months after nerve injury and pregabalin treatment suppressed activation of these nuclei. The current findings demonstrated persistent changes in CNS neurons following nerve injury as suggested by activation with non-painful mechanical stimulation. Furthermore, it was possible to functionally distinguish between a clinically efficacious analgesic drug, pregabalin, from a drug that has not demonstrated significant clinical analgesic efficacy, aprepitant. In vivo neuroimaging in the current nonhuman model could enhance translatability.

Perinatal Fentanyl Exposure Leads to Long-Lasting Impairments in Somatosensory Circuit Function and Behavior.

One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams' health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups' developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduction in S1 synaptic excitation, evidenced by decreases in release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents (mEPSCs), as well as increased frequency of miniature inhibitory postsynaptic currents (mIPSCs). In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation. Consistent with these changes, electrocorticograms (ECoGs) reveal suppressed ketamine-evoked γ oscillations. Morphologic analysis of S1 pyramidal neurons indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphologic changes. These findings demonstrate the lasting sequelae of perinatal fentanyl exposure on sensory processing and function.SIGNIFICANCE STATEMENT This is the first study to show that exposure to fentanyl in the womb results in behavioral, circuitry, and synaptic effects that last at least to adolescence. We also show, for the first time, that this exposure has different, lasting effects on synapses in different cortical areas.

Methylmercury induces hyperalgesia/allodynia through spinal cord dorsal horn neuronal activation and subsequent somatosensory cortical circuit formation in rats.

Methylmercury (MeHg) is known to cause serious neurological deficits in humans. In this study, we investigated the occurrence of MeHg-mediated neuropathic pain and identified the underlying pathophysiological mechanism in a rat model of MeHg exposure. Rats were exposed to MeHg (20 ppm in drinking water) for 3 weeks. Neurological damage was observed in the primary afferent neuronal system, including the dorsal root nerve and the dorsal column of the spinal cord. The MeHg-exposed rats showed hyperalgesia/allodynia, compared to controls, as evidenced by a significant decrease in the threshold of mechanical pain evaluated using an algometer with calibrated forceps. Immunohistochemistry revealed the accumulation of activated microglia in the dorsal root nerve, dorsal column, and dorsal horn of the spinal cord. Western blot analyses of the dorsal part of the spinal cord demonstrated an increase in inflammotoxic and inflammatory cytokines and a neuronal activation related protein, phospho-CRE bunding protein (CREB). The results suggest that dorsal horn neuronal activation was mediated by inflammatory factors excreted by accumulated microglia. Furthermore, analyses of the cerebral cortex demonstrated increased expression of phospho-CREB and thrombospondin-1, which is known to be an important factor for excitatory synapse formation, specifically in the somatosensory cortical area. In addition, the expression of pre- and post-synaptic markers was increased in this cortex area. These results suggested that the new cortical circuit was wired specifically in the somatosensory cortex. In conclusion, MeHg-mediated dorsal horn neuronal activation with inflammatory microglia might induce somatosensory cortical rewiring, leading to hyperalgesia/allodynia.