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1.
Int J Mol Sci ; 25(10)2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38791517

RESUMEN

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.


Asunto(s)
Proteínas del Sistema Complemento , Espinas Dendríticas , Microglía , Poli I-C , Animales , Microglía/metabolismo , Microglía/efectos de los fármacos , Microglía/inmunología , Ratones , Femenino , Embarazo , Espinas Dendríticas/metabolismo , Poli I-C/farmacología , Proteínas del Sistema Complemento/metabolismo , Proteínas del Sistema Complemento/inmunología , Efectos Tardíos de la Exposición Prenatal , Fagocitosis , Modelos Animales de Enfermedad , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/metabolismo , Sinapsis/metabolismo , Sinapsis/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos
2.
Sci Rep ; 12(1): 114, 2022 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-34997092

RESUMEN

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.


Asunto(s)
Ondas Encefálicas , Ritmo Circadiano , Microglía/patología , Red Nerviosa/patología , Corteza Somatosensorial/patología , Animales , Ondas Encefálicas/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización del Ritmo Circadiano/metabolismo , Regulación de la Expresión Génica , Masculino , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatología , Compuestos Orgánicos/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/metabolismo , Corteza Somatosensorial/fisiopatología , Factores de Tiempo
3.
J Psychopharmacol ; 35(11): 1356-1364, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34694190

RESUMEN

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.


Asunto(s)
Agonistas de Receptores de Cannabinoides/farmacología , Dronabinol/farmacología , Ritmo Gamma/efectos de los fármacos , Uso de la Marihuana/efectos adversos , Inhibición Neural/efectos de los fármacos , Filtrado Sensorial/efectos de los fármacos , Corteza Somatosensorial/efectos de los fármacos , Adulto , Femenino , Humanos , Magnetoencefalografía , Masculino , Adulto Joven
4.
Pharmacol Res Perspect ; 9(6): e00850, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34676996

RESUMEN

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.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Neuralgia/tratamiento farmacológico , Paclitaxel/efectos adversos , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Ratones , Neuralgia/inducido químicamente , Paclitaxel/administración & dosificación , Corteza Somatosensorial/citología , Corteza Somatosensorial/efectos de los fármacos
5.
Nat Commun ; 12(1): 6112, 2021 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-34671051

RESUMEN

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.


Asunto(s)
Interneuronas/fisiología , Accidente Cerebrovascular/terapia , Péptido Intestinal Vasoactivo/metabolismo , Animales , Clozapina/análogos & derivados , Clozapina/uso terapéutico , Humanos , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Ratones , Inhibición Neural/efectos de los fármacos , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Recuperación de la Función , Corteza Somatosensorial/citología , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/fisiología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología
6.
Neurosci Lett ; 765: 136268, 2021 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-34571088

RESUMEN

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.


Asunto(s)
Epilepsia Tipo Ausencia/metabolismo , Convulsiones/metabolismo , Corteza Somatosensorial/metabolismo , Péptido Intestinal Vasoactivo/farmacología , Ácido gamma-Aminobutírico/metabolismo , Animales , Femenino , Ratas , Ratas Wistar , Corteza Somatosensorial/efectos de los fármacos
7.
Sci Rep ; 11(1): 17525, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34471145

RESUMEN

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.


Asunto(s)
Acetilcolina/metabolismo , Neuronas Colinérgicas/metabolismo , Corteza Somatosensorial/metabolismo , Percepción del Tacto/fisiología , Animales , Antagonistas Colinérgicos/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Femenino , Masculino , Ratones , Ratones Transgénicos , Estimulación Física , Escopolamina/farmacología , Corteza Somatosensorial/efectos de los fármacos
8.
Front Immunol ; 12: 691590, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34349758

RESUMEN

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.


Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Furanos/uso terapéutico , Lignanos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Calcio/fisiología , Encefalomielitis Autoinmune Experimental/fisiopatología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Furanos/farmacología , Lignanos/farmacología , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fármacos Neuroprotectores/farmacología , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/fisiología
9.
Sci Rep ; 11(1): 13110, 2021 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-34162952

RESUMEN

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.


Asunto(s)
Anestésicos Combinados/farmacología , Encéfalo/efectos de los fármacos , Dexmedetomidina/farmacología , Isoflurano/farmacología , Ketamina/farmacología , Xilazina/farmacología , Animales , Encéfalo/diagnóstico por imagen , Dexmedetomidina/administración & dosificación , Neuroimagen Funcional , Infusiones Intravenosas , Isoflurano/administración & dosificación , Ketamina/administración & dosificación , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Corteza Somatosensorial/diagnóstico por imagen , Corteza Somatosensorial/efectos de los fármacos , Xilazina/administración & dosificación
10.
Medicine (Baltimore) ; 100(25): e26356, 2021 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-34160405

RESUMEN

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.


Asunto(s)
Toxinas Botulínicas Tipo A/administración & dosificación , Espasticidad Muscular/tratamiento farmacológico , Fármacos Neuromusculares/administración & dosificación , Rehabilitación de Accidente Cerebrovascular/métodos , Accidente Cerebrovascular/complicaciones , Adulto , Anciano , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Terapia por Ejercicio/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Nervio Mediano/efectos de los fármacos , Nervio Mediano/fisiopatología , Persona de Mediana Edad , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/etiología , Espasticidad Muscular/fisiopatología , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/fisiopatología , Accidente Cerebrovascular/fisiopatología , Resultado del Tratamiento , Extremidad Superior/inervación , Adulto Joven
11.
Sci Rep ; 11(1): 9567, 2021 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-33953244

RESUMEN

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.


Asunto(s)
Anestésicos Intravenosos/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Potenciales Evocados/efectos de los fármacos , Isoflurano/farmacología , Corteza Somatosensorial/efectos de los fármacos , Uretano/farmacología , Animales , Animales Recién Nacidos , Femenino , Masculino , Ratas , Ratas Wistar , Corteza Somatosensorial/irrigación sanguínea
12.
Exp Neurol ; 342: 113734, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33945789

RESUMEN

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.


Asunto(s)
Acetilcisteína/administración & dosificación , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/metabolismo , Transportadores de Sulfato/metabolismo , Simportadores/metabolismo , Animales , Animales Modificados Genéticamente , Animales Recién Nacidos , Femenino , Depuradores de Radicales Libres/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/metabolismo , Transportadores de Sulfato/genética , Simportadores/genética
13.
J Neurosci ; 41(15): 3400-3417, 2021 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-33853934

RESUMEN

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.


Asunto(s)
Analgésicos Opioides/toxicidad , Potenciales Evocados Somatosensoriales , Fentanilo/toxicidad , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Potenciales Sinápticos , Adaptación Fisiológica , Animales , Conducta Animal , Femenino , Ritmo Gamma , Masculino , Ratones , Ratones Endogámicos C57BL , Neurogénesis , Percepción , Embarazo , Células Piramidales/efectos de los fármacos , Células Piramidales/patología , Células Piramidales/fisiología , Corteza Somatosensorial/citología , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/crecimiento & desarrollo
14.
Arch Toxicol ; 95(6): 2151-2162, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33847776

RESUMEN

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.


Asunto(s)
Hiperalgesia/inducido químicamente , Inflamación/inducido químicamente , Compuestos de Metilmercurio/toxicidad , Animales , Citocinas/metabolismo , Hiperalgesia/fisiopatología , Inflamación/patología , Masculino , Microglía/efectos de los fármacos , Microglía/patología , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/patología
15.
Mol Pain ; 17: 17448069211008697, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33853400

RESUMEN

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.


Asunto(s)
Giro del Cíngulo/diagnóstico por imagen , Neuralgia/diagnóstico por imagen , Traumatismos de los Nervios Periféricos/diagnóstico por imagen , Corteza Somatosensorial/diagnóstico por imagen , Analgésicos/farmacología , Animales , Aprepitant/farmacología , Macaca fascicularis , Imagen por Resonancia Magnética , Masculino , Antagonistas del Receptor de Neuroquinina-1/farmacología , Estimulación Física , Pregabalina/farmacología , Corteza Somatosensorial/efectos de los fármacos
16.
Exp Neurol ; 341: 113687, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33713656

RESUMEN

BACKGROUND: In the adult brain, increases in neural activity lead to increases in local blood flow. However, in the preterm neonate, studies of cerebral functional haemodynamics have yielded inconsistent results, including negative responses suggesting decreased perfusion and localised tissue hypoxia, probably due to immature neurovascular coupling. Furthermore, the impact of vasoactive medications, such as dopamine and dobutamine used as inotropic therapies in preterm neonates, on cerebrovascular responses to somatosensory input is unknown. We aimed to characterise the cerebral haemodynamic functional response after somatosensory stimulation in the preterm newborn brain, with and without dopamine or dobutamine treatment. METHODS: We studied the cerebral haemodynamic functional response in 13 anaesthetised preterm lambs, using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb) following left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8 s. The 4.8 and 7.8 s stimulations were repeated during dopamine or dobutamine infusion. RESULTS: Stimulation always produced a somatosensory evoked response. Majority of preterm lambs demonstrated positive functional responses (i.e. increased ΔoxyHb) in the contralateral cortex following stimulus trains of all durations. Dopamine increased baseline oxyHb and total Hb, whereas dobutamine increased baseline deoxyHb. Both dopamine and dobutamine reduced the evoked ΔoxyHb responses to 4.8 and 7.8 s stimulations. CONCLUSIONS: Somatosensory stimulation increases cerebral oxygenation in the preterm brain, consistent with increased cerebral blood flow due to neurovascular coupling. Notably, our results show that dopamine/dobutamine reduces oxygen delivery relative to consumption in the preterm brain during somatosensory stimulations, suggesting there may be a risk of intermittent localised tissue hypoxia which has clear implications for clinical practice and warrants further investigation.


Asunto(s)
Circulación Cerebrovascular/efectos de los fármacos , Dobutamina/administración & dosificación , Dopamina/administración & dosificación , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Corteza Somatosensorial/efectos de los fármacos , Animales , Animales Recién Nacidos , Cardiotónicos/administración & dosificación , Circulación Cerebrovascular/fisiología , Potenciales Evocados Somatosensoriales/fisiología , Femenino , Hemodinámica/fisiología , Infusiones Intravenosas , Masculino , Embarazo , Ovinos , Corteza Somatosensorial/fisiología , Espectroscopía Infrarroja Corta/métodos
17.
Brain Res ; 1757: 147304, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33524378

RESUMEN

The present study aimed to investigate the alterations of the GABAergic system in the laterodorsal nucleus (LDN) of the thalamus and the somatosensory cortex (SC) in an experimental model of absence seizure. The effects of pharmacological manipulation of both GABAA and GABAB receptor subunits in the LDN on the generation of spike-wave discharges (SWD) were evaluated. The experiments were carried out in four groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. The expressions of various GABA receptor subunits were studied in the LDN and SC. Furthermore, recordings of unit activity from the LDN and electrocorticography were simultaneously monitored before, during, and after the application of GABAA and GABAB antagonists in the LDN. The generation of SWD in the older WAG/Rij rats was associated with significant alterations in the expression of GABAARα1, GABAARß3, and GABABR2 subunits in the LDN as well as GABAARα1, GABAARß3, GABAARγ2, and GABABR2 subunits in the SC. Furthermore, the occurrence of SWD was associated with a significant reduction of gene expression of GABAARα1 and increase of GABAARß3 in the LDN as well as reduction of GABAARα1, GABAARß3, GABAARγ2, and GABABR2 in the SC. The microionthophoretic application of the GABAA antagonist bicuculline resulted in a significant increase in the population firing rate of LDN neurons as well as the mean number and duration of SWD. The application of the GABAB antagonist CGP35348 significantly increased the population firing rate of LDN neurons but decreased the mean number of SWD. Our data indicate the regulatory effect of the GABAergic system of the LDN and SC in absence seizures.


Asunto(s)
Epilepsia Tipo Ausencia/tratamiento farmacológico , Antagonistas del GABA/farmacología , Receptores de GABA-B/efectos de los fármacos , Corteza Somatosensorial/efectos de los fármacos , Tálamo/efectos de los fármacos , Animales , Bicuculina/farmacología , Modelos Animales de Enfermedad , Electroencefalografía/métodos , Epilepsia Tipo Ausencia/fisiopatología , Masculino , Modelos Genéticos , Vías Nerviosas/efectos de los fármacos , Ratas , Corteza Somatosensorial/fisiopatología , Tálamo/fisiopatología
18.
Brain Res Bull ; 169: 167-183, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33515653

RESUMEN

Extinction learning and memory have been broadly investigated at both behavioral and neural levels, but sensory system contributions to extinction processes have been less explored. Using a sound-reward extinction paradigm in male rats, we reveal both cortical and subcortical forms of plasticity associated with the cue-specificity of behavioral extinction memory. In the auditory cortex, frequency tuning narrowed by up to two-thirds of an octave around the remembered extinguished sound cue. Subcortical signals revealed in the auditory brainstem response (ABR) in the same animals developed smaller amplitudes of some (but not all) ABR peaks evoked by the extinguished sound frequency. Interestingly, treatment with an inhibitor of histone deacetylase 3 (HDAC3-i) facilitated both auditory cortical tuning bandwidth changes and changes in subcortical peak amplitude evoked only by the extinguished sound frequency. These neurophysiological changes were correlated to each other, and to the highly precise extinction behavior enabled by HDAC3-i (compared to vehicle controls). Thus, we show for the first time that HDAC3 regulates the specificity of sensory features consolidated in extinction memory. Further, the sensory cortical changes in tuning bandwidth recapitulate known effects of blocking HDAC3 to enhance cue specificity in other behavioral tasks. Therefore, the findings demonstrate how some forms of sensory neuroplasticity may encode specific sensory features of learning experiences in order to enable cue-specific behaviors.


Asunto(s)
Vías Auditivas/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Memoria/fisiología , Corteza Somatosensorial/fisiología , Animales , Vías Auditivas/efectos de los fármacos , Señales (Psicología) , Epigénesis Genética/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas , Masculino , Memoria/efectos de los fármacos , Ratas Sprague-Dawley , Recompensa , Corteza Somatosensorial/efectos de los fármacos
19.
J Integr Neurosci ; 20(4): 813-823, 2021 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-34997706

RESUMEN

The purpose of our research was to evaluate whether ginsenoside Rb1 has neuroprotective effects against lipopolysaccharide (LPS)-induced brain injury. ICR mice were intraperitoneally (i.p.) injected with 20 or 40 mg/kg Rb1 or saline for 7 consecutive days. On the 7th day, 30 minutes after Rb1 or saline administration, a single dose of LPS (LPS group, Rb1+LPS group) or saline (control group) was injected i.p. into the mice. Results demonstrated that Rb1 treatment could significantly improve the behavior performance of LPS mice in both the open field test and the beam walking test. Rb1 can also markedly attenuate the neuronal lesion in both hippocampus and somatosensory cortex in the brain of LPS mice. In addition, Rb1 treatment also significantly inhibits the LPS-induced neuroinflammation in the brain, indicated by reduced reactive microglia and decreased IL-1ß production. Both immunostaining and western blot results suggest that Rb1 can further enhance the LPS-induced GLT-1 expression and alleviate LPS-induced GS reduction in the brain. Our findings show that Rb1 has a protective effect on LPS-induced neuronal damage in the CA1 of the hippocampus and in the somatosensory area of the cerebral cortex in mice, which is likely to be the basis for its improvement of locomotor and motor coordination. Rb1 regulating the function of astrocytes and microglia through GLT-1 and GS in astrocytes may be involved in its neuroprotective effects.


Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Ginsenósidos/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Corteza Somatosensorial/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Lipopolisacáridos/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Microglía/efectos de los fármacos , Enfermedades Neuroinflamatorias/inducido químicamente
20.
Cereb Cortex ; 31(2): 1182-1200, 2021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33063109

RESUMEN

As axons from the raphe nuclei densely innervate the somatosensory cortex, we investigated how serotonin (5-HT) modulates transmitter release in layer II pyramidal cells of rat barrel cortex. In the presence of tetrodotoxin and gabazine, 10 µM 5-HT caused a waxing and waning in the frequency of miniature excitatory postsynaptic currents (mEPSC) with no effect on amplitude. Specifically, within 15 min of recording the mEPSC frequency initially increased by 28 ± 7%, then dropped to below control (-15 ± 3%), before resurging back to 27 ± 7% larger than control. These changes were seen in 47% of pyramidal cells (responders) and were mediated by 5-HT2C receptors (5-HT2CR). Waxing resulted from phospholipase C activation, IP3 production, and Ca2+ release from presynaptic stores. Waning was prevented if PKC was blocked. In contrast, in paired recordings, the unitary EPSC amplitude was reduced by 50 ± 3% after 5-HT exposure in almost all cases with no significant effect on paired-pulse ratio and synaptic dynamics. This sustained EPSC reduction was also caused by 5-HT2R, but was mediated by presynaptic Gßγ subunits likely limiting influx through CaV2 channels. EPSC reduction, together with enhanced spontaneous noise in a restricted subset of inputs, could temporarily diminish the signal-to-noise ratio and affect the computation in the neocortical microcircuit.


Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Células Piramidales/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Serotonina/farmacología , Corteza Somatosensorial/metabolismo , Animales , Técnicas de Cultivo de Órganos , Células Piramidales/efectos de los fármacos , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT2C/metabolismo , Corteza Somatosensorial/citología , Corteza Somatosensorial/efectos de los fármacos
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