ABSTRACT
It has been shown that AMP-activated protein kinase (AMPK) is involved in the nociceptive processing. This observation has prompted us to investigate the effects of the AMPK activator metformin on the paclitaxel-induced mechanical allodynia, a well-established model of neuropathic pain. Mechanical allodynia was induced by four intraperitoneal (i.p) injections of paclitaxel (2 mg/kg.day) in mice. Metformin was administered per os (p.o.). Naltrexoneandglibenclamide were used to investigate mechanisms mediating metformin activity. Concentrations of cytokines in the dorsal root ganglia (DRG) and thalamus were determined. After a single p.o. administration, the two highest doses of metformin (500 and 1000 mg/kg) attenuated the mechanical allodynia. This response was attenuated by all doses of metformin (250, 500 and 1000 mg/kg) when two administrations, 2 h apart, were carried out. Naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, p.o.), attenuated metformin activity. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and CXCL-1 in the DRG were increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentrations of TNF-α, IL-1ß and CXCL-1 in the DRG. Concentration of IL-6, but not TNF-α, in the thalamus was increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentration of IL-6 in the thalamus. In summary, metformin exhibits activity in the model of neuropathic pain induced by paclitaxel. This activity may be mediated by activation of opioidergic pathways and reduced production of TNF-α, IL-1ß and CXCL-1 in the DRG and IL-6 in the thalamus.
Subject(s)
Metformin , Neuralgia , Mice , Animals , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Paclitaxel/adverse effects , Tumor Necrosis Factor-alpha/metabolism , Metformin/pharmacology , Ganglia, Spinal/metabolism , AMP-Activated Protein Kinases/metabolism , Interleukin-6/metabolism , Cytokines/metabolism , Neuralgia/chemically induced , Neuralgia/drug therapy , Neuralgia/metabolism , Thalamus/metabolismABSTRACT
Epidemiological studies showed that Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) frequently co-occur; however, the precise mechanism is not well understood. A unique animal model (Tg-SwDI mice) was developed to investigate the early-onset and robust accumulation of both parenchymal and vascular Aß in the brain. Tg-SwDI mice have been extensively used to study the mechanisms of cerebrovascular dysfunction, neuroinflammation, neurodegeneration, and cognitive decline observed in AD/CAA patients and to design biomarkers and therapeutic strategies. In the present study, we documented interesting new features in the thalamus of Tg-SwDI mice: 1) a sharp increase in the expression of ionized calcium-binding adapter molecule 1 (Iba-1) in microglia in 6-month-old animals; 2) microglia clustering at six months that disappeared in old animals; 3) N-truncated/modified AßN3(pE) peptide in 9-month-old female and 12-month-old male mice; 4) an age-dependent increase in translocator protein (TSPO) expression. These findings reinforce the versatility of this model for studying multiple pathological issues involved in AD and CAA.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Animals , Female , Male , Mice , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides , Brain/metabolism , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/genetics , Cerebral Amyloid Angiopathy/metabolism , Disease Models, Animal , Mice, Transgenic , Microglia/metabolism , Pyrrolidonecarboxylic Acid/metabolism , Pyrrolidonecarboxylic Acid/therapeutic use , Thalamus/metabolismABSTRACT
SUMMARY: S100 proteins belong group of calcium-binding proteins and are present in physiological intracellular and extracellular regulatory activities, such as cell differentiation, and act in inflammatory and neoplastic pathological processes. Recently, its expressions in the nervous system have been extensively studied, seeking to elucidate its action at the level of the thalamus: A structure of the central nervous system that is part of important circuits, such as somatosensory, behavioral, memory and cognitive, as well as being responsible for the transmission and regulation of information to the cerebral cortex. This article is an integrative review of scientific literature, which analyzed 12 studies present in Pubmed. The analysis showed that the relationship of S100 proteins and the thalamus has been described in neoplastic processes, mental disorders, hypoxia, trauma, stress, infection, Parkinson's disease and epilepsy. In summary, it is possible to conclude that this protein family is relevant as a marker in processes of thalamic injury, requiring further studies to better understand its clinical, preclinical meanings and its prognostic value.
Las proteínas S100 pertenecen al grupo de proteínas fijadoras de calcio y están presentes en actividades reguladoras fisiológicas intracelulares y extracelulares, como la diferenciación celular, y actúan en procesos patológicos inflamatorios y neoplásicos. Recientemente, sus expresiones en el sistema nervioso han sido ampliamente estudiadas, buscando dilucidar su acción a nivel del tálamo: una estructura del sistema nervioso central que forma parte de importantes circuitos, como el somatosensorial, conductual, de memoria y cognitivo, así como además de ser responsable de la transmisión y regulación de la información a la corteza cerebral. Este artículo es una revisión integradora de la literatura científica, que analizó 12 estudios presentes en Pubmed. El análisis mostró que la relación de las proteínas S100 y el tálamo ha sido descrita en procesos neoplásicos, trastornos mentales, hipoxia, trauma, estrés, infección, enfermedad de Parkinson y epilepsia. En resumen, es posible concluir que esta familia de proteínas es relevante como marcador en procesos de lesión talámica, requiriendo más estudios para comprender mejor su significado clínico, preclínico y su valor pronóstico.
Subject(s)
Humans , Thalamus/metabolism , S100 Proteins/metabolism , Calcium-Binding Proteins/metabolism , Biomarkers , Diencephalon/metabolismABSTRACT
Encephalopathy associated with hemolytic uremic syndrome is produced by enterohemorrhagic E. coli (EHEC) infection, which releases the virulence factors Shiga toxin (Stx) and lipopolysaccharide (LPS). Neurological compromise is a poor prognosis and mortality factor of the disease, and the thalamus is one of the brain areas most frequently affected. We have previously demonstrated the effectiveness of anti-inflammatory drugs to ameliorate the deleterious effects of these toxins. However, the thalamic production of cytokines involved in pro-inflammatory processes has not yet been acknowledged. The aim of this work attempts to determine whether systemic sublethal Stx2a or co-administration of Stx2a with LPS are able to rise a proinflammatory profile accompanying alterations of the neurovascular unit in anterior and lateral ventral nuclei of the thalamus (VA-VL) and motor behavior in mice. After 4 days of treatment, Stx2a affected the lectin-bound microvasculature distribution while increasing the expression of GFAP in reactive astrocytes and producing aberrant NeuN distribution in degenerative neurons. In addition, increased swimming latency was observed in a motor behavioral test. All these alterations were heightened when Stx2a was co-administered with LPS. The expression of pro-inflammatory cytokines TNFα, INF-γ and IL-2 was detected in VA-VL. All these effects were concomitant with increased expression of the Stx receptor globotriaosylceramide (Gb3), which hints at receptor involvement in the neuroinflammatory process as a key finding of this study. In conclusion, Stx2a to Gb3 may be determinant in triggering a neuroinflammatory event, which may resemble clinical outcomes and should thus be considered in the development of preventive strategies.
Subject(s)
Escherichia coli Infections , Shiga Toxin 2 , Animals , Cytokines/metabolism , Escherichia coli/metabolism , Lipopolysaccharides/toxicity , Mice , Shiga Toxin/metabolism , Shiga Toxin 2/toxicity , Thalamus/metabolism , TrihexosylceramidesABSTRACT
Membrane potential oscillations of thalamocortical (TC) neurons are believed to be involved in the generation and maintenance of brain rhythms that underlie global physiological and pathological brain states. These membrane potential oscillations depend on the synaptic interactions of TC neurons and their intrinsic electrical properties. These oscillations may be also shaped by increased output responses at a preferred frequency, known as intrinsic neuronal resonance. Here, we combine electrophysiological recordings in mouse brain slices, modern pharmacological tools, dynamic clamp, and computational modeling to study the ionic mechanisms that generate and modulate TC neuron resonance. We confirm findings of pioneering studies showing that most TC neurons display resonance that results from the interaction of the slow inactivation of the low-threshold calcium current IT with the passive properties of the membrane. We also show that the hyperpolarization-activated cationic current Ih is not involved in the generation of resonance; instead it plays a minor role in the stabilization of TC neuron impedance magnitude due to its large contribution to the steady conductance. More importantly, we also demonstrate that TC neuron resonance is amplified by the inward rectifier potassium current IKir by a mechanism that hinges on its strong voltage-dependent inward rectification (i.e., a negative slope conductance region). Accumulating evidence indicate that the ion channels that control the oscillatory behavior of TC neurons participate in pathophysiological processes. Results presented here points to IKir as a new potential target for therapeutic intervention.NEW & NOTEWORTHY Our study expands the repertoire of ionic mechanisms known to be involved in the generation and control of resonance and provides the first experimental proof of previous theoretical predictions on resonance amplification mediated by regenerative hyperpolarizing currents. In thalamocortical neurons, we confirmed that the calcium current IT generates resonance, determined that the large steady conductance of the cationic current Ih curtails resonance, and demonstrated that the inward rectifier potassium current IKir amplifies resonance.
Subject(s)
Action Potentials , Cerebral Cortex/physiology , Neurons/physiology , Potassium Channels, Inwardly Rectifying/metabolism , Thalamus/physiology , Animals , Calcium Channels/metabolism , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Mice , Models, Neurological , Neurons/metabolism , Sodium Channels/metabolism , Thalamus/cytology , Thalamus/metabolismABSTRACT
RATIONALE: The abuse of psychostimulants has adverse consequences on the physiology of the central nervous system. In Argentina, and other South American countries, coca paste or "PACO" (cocaine and caffeine are its major components) is massively consumed with deleterious clinical consequences for the health and well-being of the general population. A scant number of studies have addressed the consequences of stimulant combination of cocaine and caffeine on the physiology of the somatosensory thalamocortical (ThCo) system. OBJECTIVES: Our aim was to study ion conductances that have important implications regulating sleep-wake states 24-h after an acute or chronic binge-like administration of a cocaine and caffeine mixture following previously analyzed pasta base samples ("PACO"-like binge") using mice. METHODS: We randomly injected (i.p.) male C57BL/6JFcen mice with a binge-like psychostimulants regimen during either 1 day (acute) or 1 day on/1 day off during 13 days for a total of 7 binges (chronic). Single-cell patch-clamp recordings of VB neurons were performed in thalamocortical slices 24 h after the last psychostimulant injection. We also recorded EEG/EMG from mice 24 h after being systemically treated with chronic administration of cocaine + caffeine versus saline, vehicle. RESULTS: Our results showed notorious changes in the intrinsic properties of the VB nucleus neurons that persist after 24-h of either acute or chronic binge administrations of combined cocaine and caffeine ("PACO"-like binge). Functional dysregulation of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type VGC (voltage-gated calcium) channels was described 24-h after acute/chronic "PACO"-like administrations. Furthermore, intracellular basal [Ca2+] disturbances resulted a key factor that modulated the availability and the activation of T-type channels, altering T-type "window currents." As a result, all these changes ultimately shaped the low-threshold spikes (LTS)-associated Ca2+ transients, regulated the membrane excitability, and altered sleep-wake transitions. CONCLUSION: Our results suggest that deleterious consequences of stimulants cocaine and caffeine combination on the thalamocortical physiology as a whole might be related to potential neurotoxic effects of soaring intracellular [Ca2+].
Subject(s)
Caffeine/adverse effects , Calcium Channels, T-Type/metabolism , Central Nervous System Stimulants/adverse effects , Cocaine/adverse effects , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Neurons/drug effects , Action Potentials/drug effects , Animals , Caffeine/administration & dosage , Central Nervous System Stimulants/administration & dosage , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cocaine/administration & dosage , Drug Synergism , Male , Mice , Mice, Inbred C57BL , Patch-Clamp Techniques , Random Allocation , Sleep-Wake Transition Disorders/chemically induced , South America , Thalamus/drug effects , Thalamus/metabolismABSTRACT
BACKGROUND: To investigate the thalamic neurotransmitters and functional connections in the development of chronic constriction injury (CCI)-induced neuropathic pain. METHODS: The paw withdrawal threshold was measured by mechanical stimulation the right hind paw with the von frey hair in the rats of CCI-induced neuropathic pain. The N-acetylaspartate (NAA) and Glutamate (Glu) in thalamus were detected by magnetic resonance spectrum (MRS) process. The thalamic functional connectivity with other brain regions was scanned by functional magnetic resonance image (fMRI). RESULTS: The paw withdrawal threshold of the ipsilateral side showed a noticeable decline during the pathological process. Increased concentrations of Glu and decreased levels of NAA in the thalamus were significantly correlated with mechanical allodynia in the neuropathic pain states. The thalamic regional homogeneity (ReHo) decreased during the process of neuropathic pain. The functional connectivity among the thalamus with the insula and somatosensory cortex were significantly increased at different time points (7, 14, 21 days) after CCI surgery. CONCLUSION: Our study suggests that dynamic changes in thalamic NAA and Glu levels contribute to the thalamic functional connection hyper-excitation during CCI-induced neuropathic pain. Enhanced thalamus-insula functional connection might have a significant effect on the occurrence of neuropathic pain.
Subject(s)
Neuralgia , Neurotransmitter Agents/metabolism , Thalamus/metabolism , Wounds and Injuries/physiopathology , Animals , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Constriction , Glutamic Acid/metabolism , Hyperalgesia , Rats , Thalamus/physiopathologyABSTRACT
Some B vitamins exhibit activities in models of nociceptive pain, inflammatory pain, and neuropathic pain induced by nerve lesions and also in certain painful conditions in humans. In the present study, we investigated the effects of thiamine, riboflavin, and nicotinamide in a neuropathic pain model induced by the chemotherapeutic paclitaxel in mice. Four intraperitoneal (i.p.) administrations of paclitaxel (2 mg/kg day, cumulative dose 8 mg/kg) induced a long-lasting mechanical allodynia. Per os (p.o.) administration of two doses of thiamine (150, 300 and 600 mg/kg), nicotinamide (250, 500 and 1000 mg/kg) or riboflavin (125, 250 and 500 mg/kg), on the seventh day after the first administration of paclitaxel, the mechanical allodynia was attenuated. The antinociceptive activity of all B vitamins was attenuated by glibenclamide (20 and 10 mg/kg, p.o.). Naltrexone (5 and 10 mg/kg, i.p.) attenuated the antinociceptive activity of thiamine. Thiamine, riboflavin, and nicotinamide also reduced the concentrations of tumor necrosis factor-α (TNF-α) and CXCL-1 in dorsal root ganglia (DRG) and thalamus. In conclusion, thiamine, riboflavin, and nicotinamide exhibit antinociceptive activity in the neuropathic pain model induced by paclitaxel. Inhibition of TNF-α and CXCL-1 production in DRG and thalamus, as well as activation of ATP-sensitive potassium channels, underly their antinociceptive activity.
Subject(s)
Chemokine CXCL1/metabolism , Ganglia, Spinal/drug effects , Hyperalgesia/drug therapy , KATP Channels/metabolism , Thalamus/drug effects , Tumor Necrosis Factor-alpha/metabolism , Vitamin B Complex/pharmacology , Animals , Ganglia, Spinal/metabolism , Hyperalgesia/chemically induced , Hyperalgesia/metabolism , Male , Mice , Neuralgia/drug therapy , Neuralgia/metabolism , Niacinamide/pharmacology , Paclitaxel/pharmacology , Riboflavin/pharmacology , Thalamus/metabolism , Thiamine/pharmacologyABSTRACT
BACKGROUND: To investigate the thalamic neurotransmitters and functional connections in the development of chronic constriction injury (CCI)-induced neuropathic pain. METHODS: The paw withdrawal threshold was measured by mechanical stimulation the right hind paw with the von frey hair in the rats of CCI-induced neuropathic pain. The N-acetylaspartate (NAA) and Glutamate (Glu) in thalamus were detected by magnetic resonance spectrum (MRS) process. The thalamic functional connectivity with other brain regions was scanned by functional magnetic resonance image (fMRI). RESULTS: The paw withdrawal threshold of the ipsilateral side showed a noticeable decline during the pathological process. Increased concentrations of Glu and decreased levels of NAA in the thalamus were significantly correlated with mechanical allodynia in the neuropathic pain states. The thalamic regional homogeneity (ReHo) decreased during the process of neuropathic pain. The functional connectivity among the thalamus with the insula and somatosensory cortex were significantly increased at different time points (7, 14, 21 days) after CCI surgery. CONCLUSION: Our study suggests that dynamic changes in thalamic NAA and Glu levels contribute to the thalamic functional connection hyper-excitation during CCI-induced neuropathic pain. Enhanced thalamus-insula functional connection might have a significant effect on the occurrence of neuropathic pain.
Subject(s)
Animals , Rats , Thalamus/metabolism , Wounds and Injuries/physiopathology , Neurotransmitter Agents/metabolism , Neuralgia , Thalamus/physiopathology , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Glutamic Acid/metabolism , Constriction , HyperalgesiaABSTRACT
BACKGROUND: Deep brain stimulation (DBS) refers to the delivery of electric current to specific deep brain structures through implanted electrodes. Recently approved for use in United States, DBS to the anterior nucleus of thalamus (ANT) is a safe and effective alternative treatment for medically refractory seizures. Despite the anti-seizure effects of ANT DBS, preclinical and clinical studies have failed to demonstrate it actions at a whole brain level. OBJECTIVE: Here, we used a magnetic resonance imaging (MRI)-based approach in healthy adult rats to investigate the effects of ANT DBS through the circuit of Papez, which has central role in the generation and propagation of limbic seizures, in temporal lobe epilepsy (TLE). METHODS: After ANT electrode implantation and recovery, ANT DBS and SHAM (sham animals had electrodes implanted but were not stimulated) rats received one single injection of the contrast enhancer, manganese chloride (60 mg/kg, ip). Twelve hours after, rats underwent the baseline scan using the MEMRI (Manganese-Enhanced Magnetic Resonance Imaging) technique. We used the same MEMRI and parvalbumin sequence to follow the DBS delivered during 1 h (130 Hz and 200 µA). Perfusion was followed by subsequent c-Fos and parvalbumin immunostaining of brain sections. RESULTS: Acute unilateral ANT DBS significantly reduced the overall manganese uptake and consequently, the MEMRI contrast in the circuit of Papez. Additionally, c-Fos expression was bilaterally increased in the cingulate cortex and posterior hypothalamus, areas directly connected to ANT, as well as in amygdala and subiculum, within the limbic circuitry. CONCLUSION: Our data indicate that MEMRI can be used to detect whole-brain responses to DBS, as the high frequency stimulation parameters used here caused a significant reduction of cell activity in the circuit of Papez that might help to explain the antiepileptic effects of ANT DBS.
Subject(s)
Anterior Thalamic Nuclei/metabolism , Seizures/therapy , Amygdala/metabolism , Animals , Cell Nucleus/metabolism , Deep Brain Stimulation/methods , Electrodes, Implanted , Epilepsy/metabolism , Epilepsy/therapy , Epilepsy, Temporal Lobe/therapy , Hippocampus/metabolism , Limbic System , Magnetic Resonance Imaging/methods , Male , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Wistar , Seizures/metabolism , Thalamus/metabolismABSTRACT
Thiamine deficiency (TD) has been used as an experimental model in rodents to study the molecular mechanisms of neurodegeneration and its association with behavioral changes. The aims of the present study were to investigate the spatial cognitive performance of pyrithiamine-induced thiamine deficiency (PTD) in adult male rats and disclose the thalamic proteome alterations caused by a severe TD episode. After the onset of the neurological signs, such as seizure and/or loss of righting reflex, the TD treatment was interrupted. Following 15â¯days of recovery, all rats were submitted to the spatial cognitive tasks in the Morris Water Maze (MWM). The results show that the PTD rats exhibited deficits during the learning process, which was reverted by repeated training. However, despite the spatial cognitive recovery, some protein changes were not reversible. The proteomic analysis, using label-free quantification, revealed deregulation of 183 thalamic proteins. Using bioinformatic tools, these proteins were categorized according to Gene Ontology functional annotation and metabolic pathways. We show that a severe TD affects proteins involved in different biological processes, such as, oxidative stress, neurotransmitter synthesis and synaptic vesicle cycle. These could explain the outcome in neurotransmitter release changes caused by TD, previously observed by our group and by other authors. These findings disclose the role of key proteins and metabolic pathways probably involved in the neurodegeneration process induced by TD. These proteins represent relevant molecular targets for future studies focusing also on the molecular basis of selective vulnerability of some brain areas to TD insult.
Subject(s)
Behavior, Animal/physiology , Spatial Learning/physiology , Thalamus/metabolism , Thiamine Deficiency/metabolism , Thiamine/metabolism , Animals , Body Weight/physiology , Cognition/physiology , Eating/physiology , Male , Proteome , Proteomics , Rats , Rats, WistarABSTRACT
The purposes of the present study were to investigate the effects of perinatal thiamine deficiency, from the 11th day of gestation until the 5th day of lactation, on motor behavior and neurochemical parameters in adult rat offspring, using 3-month-old, adult, male Wistar rats. All rats were submitted to motor tests, using the rotarod and paw print tasks. After behavioral tests, their thalamus, cerebellum and spinal cord were dissected for glutamate and GABA quantifications by high performance liquid chromatography. The thiamine-restricted mothers (RM) group showed a significant reduction of time spent on the rotarod at 25 rpm and an increase in hind-base width. A significant decrease of glutamate concentration in the cerebellum and an increase of GABA concentrations in the thalamus were also observed. For the offspring from control mothers (CM) group there were significant correlations between thalamic GABA concentrations and both rotarod performance and average hind-base width. In addition, for rats from the RM group a significant correlation between stride length and cerebellar GABA concentration was found. These results show that the deficiency of thiamine during an early developmental period affects certain motor behavior parameters and GABA and glutamate levels in specific brain areas. Hence, a thiamine deficiency episode during an early developmental period can induce motor impairments and excitatory and inhibitory neurotransmitter changes that are persistent and detectable in later periods of life.
Subject(s)
Brain/metabolism , Glutamic Acid/metabolism , Motor Activity , Thiamine Deficiency/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Cerebellar Cortex/metabolism , Female , Maternal-Fetal Exchange , Medulla Oblongata/metabolism , Postural Balance , Pregnancy , Rats, Wistar , Rotarod Performance Test , Thalamus/metabolismABSTRACT
The subdivisions of the medial geniculate complex can be distinguished based on the immunostaining of calcium-binding proteins and by the properties of the neurons within each subdivision. The possibility of changes in neurochemistry in this and other central auditory areas are important aspects to understand the basis that contributing to functional variations determined by environmental cycles or the animal's cycles of activity and rest. This study investigated, for the first time, day/night differences in the amounts of parvalbumin-, calretinin- and calbindin-containing neurons in the thalamic auditory center of a non-human primate, Sapajus apella. The immunoreactivity of the PV-IR, CB-IR and CR-IR neurons demonstrated different distribution patterns among the subdivisions of the medial geniculate. Moreover, a high number of CB- and CR-IR neurons were found during day, whereas PV-IR was predominant at night. We conclude that in addition to the chemical heterogeneity of the medial geniculate nucleus with respect to the expression of calcium-binding proteins, expression also varied relative to periods of light and darkness, which may be important for a possible functional adaptation of central auditory areas to environmental changes and thus ensure the survival and development of several related functions.
Subject(s)
Calcium-Binding Proteins/metabolism , Geniculate Bodies/metabolism , Animals , Auditory Pathways/cytology , Auditory Pathways/metabolism , Calbindin 2/metabolism , Calbindins/metabolism , Cebus , Circadian Rhythm , Geniculate Bodies/cytology , Immunohistochemistry , In Vitro Techniques , Male , Neurons/metabolism , Parvalbumins/metabolism , Thalamus/metabolismABSTRACT
The sensory thalamus is classically viewed as a relay station of sensory information to cortex, but recent studies suggest that it is sensitive to cognitive demands. There are, however, few experiments designed to test whether this is so. We addressed this problem by analyzing the responses of single neurons recorded in the somatosensory thalamus while trained monkeys reported a decision based on the comparison of two mechanical vibration frequencies applied sequentially to one fingertip. In this task, monkeys must hold the first stimulus frequency (f1) in working memory and compare it to the current sensory stimulus (f2) and must postpone the decision report until a cue triggers the decision motor report, i.e., whether f2 > f1 or f2 < f1. We found that thalamic somatosensory neurons encoded the stimulus frequency either in their periodicity and firing-rate responses, but only during the stimulus periods and not during the working memory and decision components of this task. Furthermore, correlation analysis between behavior and stimulus coding showed that only the firing rate modulations accounted for the overall psychophysical performance. However, these responses did not predict the animal's decision reports on individual trials. Moreover, the sensitivity to changes in stimulus frequency was similar when the monkeys performed the vibrotactile discrimination task and when they were not required to report discrimination. These results suggest that the somatosensory thalamus behaves as a relay station of sensory information to the cortex and that it is insensitive to the cognitive demands of the task used here.
Subject(s)
Somatosensory Cortex/metabolism , Thalamus/metabolism , Animals , Brain Mapping/methods , Choice Behavior , Cognition , Discrimination Learning/physiology , Discrimination, Psychological/physiology , Haplorhini , Memory/physiology , Models, Neurological , Motor Skills , Neurons/metabolism , Neurons/pathology , Probability , Psychomotor Performance/physiology , Psychophysics/methodsABSTRACT
RATIONALE: Repetitive cocaine exposure has been shown to induce GABAergic thalamic alterations. Given the key role of T-type (Ca(V)3) calcium channels in thalamocortical physiology, the direct involvement of these calcium channels in cocaine-mediated effects needs to be further explored. OBJECTIVE: The objective of this study was to investigate the effect of T-type calcium channel blockers on acute and repetitive cocaine administration that mediates thalamocortical alterations in mice using three different T-type blockers: 2-octanol, nickel, and mibefradil. METHODS: During in vitro experiments, whole-cell patch-clamp recordings were conducted in ventrobasal (VB) thalamic neurons from mice treated with acute repetitive cocaine administration (3 x 15 mg/kg, i.p., 1 h apart), under bath application of mibefradil (10 µM), 2-octanol (50 µM), or nickel (200 µM). After systemic administration of T-type calcium channel blockers, we evaluated locomotor activity and also recorded GABAergic neurotransmission onto VB neurons in vitro. RESULTS: Bath-applied mibefradil, 2-octanol, or nickel significantly reduced both GABAergic neurotransmission and T-type currents of VB neurons in cocaine-treated mice. In vivo i.p. pre-administration of either mibefradil (20 mg/kg and 5 mg/kg) or 2-octanol (0.5 mg/kg and 0.07 mg/kg) significantly reduced GABAergic mini frequencies onto VB neurons. Moreover, both mibefradil and 2-octanol were able to decrease cocaine-induced hyperlocomotion. CONCLUSION: The results shown in this study strongly suggest that T-type calcium channels play a key role in cocaine-mediated GABAergic thalamocortical alterations, and further propose T-type channel blockers as potential targets for future pharmacological strategies aimed at treating cocaine's deleterious effects on physiology and behavior.
Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Channels, T-Type/drug effects , Cocaine/toxicity , gamma-Aminobutyric Acid/drug effects , Animals , Calcium Channel Blockers/administration & dosage , Calcium Channels, T-Type/metabolism , Cocaine/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Locomotion/drug effects , Male , Mibefradil/administration & dosage , Mibefradil/pharmacology , Mice , Mice, Inbred C57BL , Nickel/administration & dosage , Nickel/pharmacology , Octanols/administration & dosage , Octanols/pharmacology , Patch-Clamp Techniques , Thalamus/drug effects , Thalamus/metabolism , gamma-Aminobutyric Acid/metabolismABSTRACT
Maternal thiamine deficiency causes changes in cellular energy metabolism that can interfere with offspring brain development. The purpose of the present study was to investigate the effects of thiamine restriction, during lactation, on offspring neurochemistry and cognitive parameters. Male young (31 days old) and adult (75 days old) rats, from control and restricted mothers, were submitted to spatial learning and memory assessment. GABAergic and glutamatergic parameters were measured in thalamus, prefrontal cortex and hippocampus by high performance liquid chromatography (HPLC). The young animals were assessed immediately after thiamine restricted period; the adults, however, underwent a recovery period of 45 days. In young rats, thiamine restriction significantly hindered body weight gain and learning speed; however, it did not affect the brain weight, GABA and glutamate parameters in any of the brain assessed areas. In adult rats the body weight gain was significantly hampered by thiamine restriction, while brain weight and spatial task were not affected. Also, in adult offspring, maternal thiamine restriction significantly decreased the glutamate and GABA contents in the three assessed brain areas and thalamus, respectively. One possible explanation for these findings is that an adjustment of the inhibitory (GABAergic) and stimulatory (glutamatergic) neuromodulation systems occurs, in order to reverse the behavioral deficits detected in young rats but not in adult ones. The present data show, for the first time, that maternal thiamine restriction during lactation induces cognitive impairments and neurochemical changes in offspring, corroborating the important role of thiamine in brain development.
Subject(s)
Animals, Suckling/growth & development , Brain/growth & development , Cognition Disorders/etiology , Lactation/metabolism , Thiamine Deficiency/complications , Thiamine/metabolism , Analysis of Variance , Animals , Animals, Suckling/metabolism , Brain/metabolism , Cognition Disorders/metabolism , Energy Metabolism , Female , Glutamic Acid/metabolism , Hippocampus/growth & development , Hippocampus/metabolism , Male , Maze Learning/physiology , Milk/chemistry , Milk/metabolism , Nutritive Value , Prefrontal Cortex/growth & development , Prefrontal Cortex/metabolism , Rats , Reaction Time/physiology , Thalamus/growth & development , Thalamus/metabolism , Thiamine/analysis , Thiamine Deficiency/etiology , Time Factors , gamma-Aminobutyric Acid/metabolismABSTRACT
The purposes of the present study were to verify the effects of a severe thiamine deficiency episode on spatial cognitive aspects and thalamic serotonergic parameters. The animals were submitted to a severe thiamine deficiency treatment that was interrupted after the onset of the last neurological signs. The results obtained confirm previous findings about TD deficiency effects on cognitive function and, further show that this vitamin increases the thalamic serotonine metabolite, 5-hidroxyindolacetic acid (5-HIAA), level. In addition, the present data shed light on the importance of this metabolite in spatial cognitive function.
Subject(s)
Hydroxyindoleacetic Acid/metabolism , Memory Disorders/metabolism , Serotonin/metabolism , Space Perception/physiology , Thalamus/metabolism , Thiamine Deficiency/metabolism , Analysis of Variance , Animals , Male , Maze Learning/physiology , Memory Disorders/etiology , Neuropsychological Tests , Pyrithiamine , Rats , Rats, Wistar , Thiamine Deficiency/chemically induced , Thiamine Deficiency/complications , Time FactorsABSTRACT
Despite the implication of fronto-striatal circuits in attention-deficit/hyperactivity disorder (ADHD), there is a lack of information on the role of these regions, especially the thalamus, in the heterogeneity of ADHD. We assessed the (1)H-magnetic resonance spectroscopy profile in ventromedial prefrontal cortex (VMPFC)-thalamic-striatal regions bilaterally in three groups of subjects (age range 18-24 years old): ADHD inattentive type (ADHD-I; n = 9), ADHD combined type (ADHD-C; n = 10) and non-ADHD controls (n = 12). The peaks of N-acetylaspartate, Choline (Cho), myo-inositol (mI), creatine (Cr) and glutamate-glutamine-GABA (Glx) to Cr were calculated. Subjects with ADHD-C showed lower mI/Cr ratio in the right VMPFC than controls, higher Cho/Cr ratio in the left thalamus-pulvinar than the ADHD-I group and higher Glx/Cr ratio in left putamen than individuals with ADHD-I and controls. This metabolic profile suggests a disruption of fronto-striato-thalamic structures in the ADHD-C as a result of lower neuronal energetic metabolism.
Subject(s)
Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Attention Deficit Disorder with Hyperactivity/metabolism , Magnetic Resonance Spectroscopy/methods , Prosencephalon/diagnostic imaging , Prosencephalon/metabolism , Adolescent , Aspartic Acid/analogs & derivatives , Aspartic Acid/analysis , Aspartic Acid/metabolism , Attention Deficit Disorder with Hyperactivity/physiopathology , Choline/analysis , Choline/metabolism , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Creatine/analysis , Creatine/metabolism , Diagnosis, Differential , Energy Metabolism/physiology , Female , Frontal Lobe/diagnostic imaging , Frontal Lobe/metabolism , Frontal Lobe/physiopathology , Functional Laterality/physiology , Glutamic Acid/analysis , Glutamic Acid/metabolism , Glutamine/analysis , Glutamine/metabolism , Humans , Inositol/analysis , Inositol/metabolism , Male , Prosencephalon/physiopathology , Pulvinar/diagnostic imaging , Pulvinar/metabolism , Pulvinar/physiopathology , Putamen/diagnostic imaging , Putamen/metabolism , Putamen/physiopathology , Radionuclide Imaging , Thalamus/diagnostic imaging , Thalamus/metabolism , Thalamus/physiopathology , Young Adult , gamma-Aminobutyric Acid/analysis , gamma-Aminobutyric Acid/metabolismABSTRACT
The hypothalamic suprachiasmatic nucleus (SCN) and the thalamic intergeniculate leaflet (IGL) are considered to be the main centers of the mammalian circadian timing system. In primates, the IGL is included as part of the pregeniculate nucleus (PGN), a cell group located mediodorsally to the dorsal lateral geniculate nucleus. This work was carried out to comparatively evaluate the immunohistochemical expression of the calcium-binding proteins calbindin D-28k (CB), parvalbumin (PV), and calretinin (CR) into the circadian brain districts of the common marmoset and the rock cavy. In both species, although no fibers, terminals or perikarya showed PV-immunoreaction (IR) into the SCN, CB-IR perikarya labeling was detected throughout the SCN rostrocaudal extent, seeming to delimit its cytoarchitectonic borders. CR-IR perikarya and neuropil were noticed into the ventral and dorsal portions of the SCN, lacking immunoreactivity in the central core of the marmoset and filling the entire nucleus in the rock cavy. The PGN of the marmoset presented a significant number of CB-, PV-, and CR-IR perikarya throughout the nucleus. The IGL of the rocky cavy exhibited a prominent CB- and CR-IR neuropil, showing similarity to the pattern found in other rodents. By comparing with literature data from other mammals, the results of the present study suggest that CB, PV, and CR are differentially distributed into the SCN and IGL among species. They may act either in concert or in a complementary manner in the SCN and IGL, so as to participate in specific aspects of the circadian regulation.
Subject(s)
Brain/metabolism , Calcium-Binding Proteins/metabolism , Callithrix/metabolism , Circadian Rhythm/physiology , Rodentia/metabolism , Animals , Brain/anatomy & histology , Brain Mapping , Calbindin 2 , Calbindins , Callithrix/anatomy & histology , Immunohistochemistry , Male , Parvalbumins/metabolism , Rodentia/anatomy & histology , S100 Calcium Binding Protein G/metabolism , Species Specificity , Suprachiasmatic Nucleus/anatomy & histology , Suprachiasmatic Nucleus/metabolism , Thalamus/anatomy & histology , Thalamus/metabolismABSTRACT
Barrel formation is delayed in nutritionally restricted rats. The underlying cause of such delay is yet unclear. Because barrels appear upon the arrival of somatosensory thalamo-cortical afferents and the reorientation of the dendritic arborizations of cortical spiny stellate neurons, it is likely that at least one of these processes is altered by nutritional restriction. Also, the serotoninergic afferent system has been implicated in regulating barrel segregation and growth during early postnatal life. We then evaluated the pattern of immunostaining of the serotonin transporter (SERT) and of the serotonin receptor 1B (5-HT(1B)), as well as the growth and arrival time of somatosensory thalamo-cortical afferents, to infer the contribution of these elements in the delayed formation of barrels observed in nutritionally restricted rats. It was found that the rates of development and the segregation of thalamo-cortical fibers were normal in nutritionally restricted rats. SERT, but not 5-HT(1B) immunoreactivity, was decreased in the primary somatosensory cortex during barrel specification. The availability of both proteins in nutritionally restricted rats was lower than that observed in their well fed counterparts at later developmental times. It is concluded that the delayed formation of barrels observed in nutritionally restricted rats is due to a retarded reorientation of dendritic arbors of cortical neurons. This might happen as a secondary effect of decreasing the availability of SERT and/or increasing the availability of 5-HT(1B) receptor early in postnatal life.