RESUMEN
Prepulse inhibition (PPI) is a neurophysiological finding that is decreased in schizophrenia patients and has been used in pathophysiology studies of schizophrenia and the development of antipsychotic drugs. PPI is affected by several drugs including amphetamine, ketamine, and nicotinic agents, and it is reported that several brain regions and modulatory neurotransmitters are involved in PPI. Here we showed that mice with IRSp53 deletion in each dopaminergic, cholinergic, oxytocinergic, and serotoninergic modulatory neurons showed a decrease in PPI. Other than PPI, there were no other behavioral changes among IRSp53 deletion mice. Through this study, we could reconfirm that dysfunction of each modulatory neuron such as dopamine, acetylcholine, oxytocin, and serotonin can result in PPI impairment, and it should be considered that PPI could be broadly affected by changes in one of a certain kind of modulatory neurons.
Asunto(s)
Encéfalo/metabolismo , Neuronas Colinérgicas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Proteínas del Tejido Nervioso/genética , Inhibición Prepulso , Neuronas Serotoninérgicas/metabolismo , Acetilcolina/metabolismo , Animales , Encéfalo/patología , Mapeo Encefálico , Neuronas Colinérgicas/patología , Dopamina/metabolismo , Neuronas Dopaminérgicas/patología , Eliminación de Gen , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , Ruido , Oxitocina/metabolismo , Reflejo de Sobresalto , Neuronas Serotoninérgicas/patología , Serotonina/metabolismoRESUMEN
Spinal cord injury (SCI) interrupts long-projecting descending spinal neurons and disrupts the spinal central pattern generator (CPG) that controls locomotion. The intrinsic mechanisms underlying re-wiring of spinal neural circuits and recovery of locomotion after SCI are unclear. Zebrafish shows axonal regeneration and functional recovery after SCI making it a robust model to study mechanisms of regeneration. Here, we use a two-cut SCI model to investigate whether recovery of locomotion can occur independently of supraspinal connections. Using this injury model, we show that injury induces the localization of a specialized group of intraspinal serotonergic neurons (ISNs), with distinctive molecular and cellular properties, at the injury site. This subpopulation of ISNs have hyperactive terminal varicosities constantly releasing serotonin activating 5-HT1B receptors, resulting in axonal regrowth of spinal interneurons. Axon regrowth of excitatory interneurons is more pronounced compared to inhibitory interneurons. Knock-out of htr1b prevents axon regrowth of spinal excitatory interneurons, negatively affecting coordination of rostral-caudal body movements and restoration of locomotor function. On the other hand, treatment with 5-HT1B receptor agonizts promotes functional recovery following SCI. In summary, our data show an intraspinal mechanism where a subpopulation of ISNs stimulates axonal regrowth resulting in improved recovery of locomotor functions following SCI in zebrafish.
Asunto(s)
Axones/fisiología , Recuperación de la Función , Neuronas Serotoninérgicas/fisiología , Traumatismos de la Médula Espinal , Animales , Electrofisiología , Interneuronas , Locomoción , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Neuronas Serotoninérgicas/patología , Serotonina/metabolismo , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Pez CebraRESUMEN
The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the locus coeruleus-noradrenergic system (LC-NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 mild cognitive impairment, 135 Alzheimer's disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD-an objective measure, which compares an individual's structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual's age). Further analyses were carried out on reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the serotoninergic (5-HT), dopaminergic (DA) and cholinergic (Ach) systems were contrasted with the noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems. Results supported by Bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g., cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.
Asunto(s)
Neuronas Adrenérgicas/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Reserva Cognitiva/fisiología , Sustancia Gris/diagnóstico por imagen , Locus Coeruleus/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Anciano , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Atención/fisiología , Teorema de Bayes , Estudios de Casos y Controles , Neuronas Colinérgicas/patología , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Neuronas Dopaminérgicas/patología , Escolaridad , Ejercicio Físico/fisiología , Femenino , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Humanos , Locus Coeruleus/patología , Locus Coeruleus/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Neuroimagen , Tamaño de los Órganos , Neuronas Serotoninérgicas/patología , Factores SexualesRESUMEN
In chronic smokers, nicotine withdrawal symptoms during tobacco cessation can lead to smoking relapse. In rodent models, chronic exposure to nicotine elicited physical dependence, whereas acute antagonism of nicotinic acetylcholine receptors (nAChRs) immediately precipitated withdrawal symptoms. Although the central serotonergic system plays an important role in nicotine withdrawal, the exact serotonergic raphe nuclei regulating these symptoms remain unknown. We used transgenic mice expressing archaerhodopsinTP009 or channelrhodopsin-2[C128S] exclusively in the central serotonergic neurons to selectively manipulate serotonergic neurons in each raphe nucleus. Nicotine withdrawal symptoms were precipitated by an acute injection of mecamylamine, a nonspecific nAChR antagonist, following chronic nicotine consumption. Somatic signs were used as measures of nicotine withdrawal symptoms. Acute mecamylamine administration significantly increased ptosis occurrence in nicotine-drinking mice compared with that in control-drinking mice. Optogenetic inhibition of the serotonergic neurons in the median raphe nucleus (MRN), but not of those in the dorsal raphe nucleus (DRN), mimicked the symptoms observed during mecamylamine-precipitated nicotine withdrawal even in nicotine-naïve mice following the administration of acute mecamylamine injection. Optogenetic activation of the serotonergic neurons in the MRN nearly abolished the occurrence of ptosis in nicotine-drinking mice. The serotonergic neurons in the MRN, but not those in the DRN, are necessary for the occurrence of somatic signs, a nicotine withdrawal symptom, and the activation of these neurons may act as a potential therapeutic strategy for preventing the somatic manifestations of nicotine withdrawal.
Asunto(s)
Nicotina/efectos adversos , Núcleos del Rafe/patología , Neuronas Serotoninérgicas/patología , Síndrome de Abstinencia a Sustancias/patología , Animales , Femenino , Masculino , Mecamilamina , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Optogenética , Receptores Nicotínicos/metabolismo , Serotonina/metabolismoRESUMEN
HIV-1 infection affects approximately 37 million individuals, and approximately 50% of seropositive individuals will develop symptoms of clinical depression and/or apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1-induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.
Asunto(s)
Antidepresivos/farmacología , Apatía/efectos de los fármacos , Depresión/tratamiento farmacológico , Escitalopram/farmacología , Infecciones por VIH/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Conducta de Elección/efectos de los fármacos , Dendritas/efectos de los fármacos , Dendritas/patología , Dendritas/virología , Depresión/complicaciones , Depresión/fisiopatología , Depresión/virología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/virología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , VIH-1/patogenicidad , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/patología , Núcleo Accumbens/virología , Ratas , Ratas Transgénicas , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/patología , Neuronas Serotoninérgicas/virología , Sinapsis/efectos de los fármacos , Sinapsis/patología , Sinapsis/virología , Transmisión Sináptica/efectos de los fármacos , Resultado del TratamientoRESUMEN
Axonal damage is an early step in traumatic and neurodegenerative disorders of the central nervous system (CNS). Damaged axons are not able to regenerate sufficiently in the adult mammalian CNS, leading to permanent neurological deficits. Recently, we showed that inhibition of the autophagic protein ULK1 promotes neuroprotection in different models of neurodegeneration. Moreover, we demonstrated previously that axonal protection improves regeneration of lesioned axons. However, whether axonal protection mediated by ULK1 inhibition could also improve axonal regeneration is unknown. Here, we used an adeno-associated viral (AAV) vector to express a dominant-negative form of ULK1 (AAV.ULK1.DN) and investigated its effects on axonal regeneration in the CNS. We show that AAV.ULK1.DN fosters axonal regeneration and enhances neurite outgrowth in vitro. In addition, AAV.ULK1.DN increases neuronal survival and enhances axonal regeneration after optic nerve lesion, and promotes long-term axonal protection after spinal cord injury (SCI) in vivo. Interestingly, AAV.ULK1.DN also increases serotonergic and dopaminergic axon sprouting after SCI. Mechanistically, AAV.ULK1.DN leads to increased ERK1 activation and reduced expression of RhoA and ROCK2. Our findings outline ULK1 as a key regulator of axonal degeneration and regeneration, and define ULK1 as a promising target to promote neuroprotection and regeneration in the CNS.
Asunto(s)
Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Axones/metabolismo , Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos , Regeneración Nerviosa , Traumatismos del Nervio Óptico/terapia , Nervio Óptico/metabolismo , Traumatismos de la Médula Espinal/terapia , Médula Espinal/metabolismo , Animales , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Axones/patología , Células Cultivadas , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Regulación hacia Abajo , Femenino , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proyección Neuronal , Nervio Óptico/patología , Traumatismos del Nervio Óptico/genética , Traumatismos del Nervio Óptico/metabolismo , Traumatismos del Nervio Óptico/patología , Ratas Wistar , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/patología , Médula Espinal/patología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Factores de Tiempo , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
Environmental and occupational metal exposure poses serious global concerns. Metal exposure have severally been associated with neurotoxicity and brain damage. Furthermore, receptor for advanced glycation end products (RAGE) is also implicated in neurological disorders, particularly those with altered glucose metabolism. Here, we examine potential compounding effect of metal exposure and RAGE expression on dopamine (DA) and serotonin (SER) neurons in C. elegans. In addition, we evaluate the effect of RAGE expression on DA and SER neurons in hyperglycemic conditions. Newly generated RAGE-expressing C. elegans tagged with green fluorescent proteins (GFP) in DAergic and SERergic neurons were treated with cadmium (Cd) or manganese (Mn). Additionally, the RAGE-expressing worms were also exposed to high glucose conditions. Results showed metals induced neurodegeneration both in the presence and absence of RAGE expression, but the manner of degeneration differed between Cd and Mn treated nematodes. Furthermore, RAGE-expressing worms showed significant neurodegeneration in both DAergic and SERergic neurons. Our results indicate co-occurrence of metal exposure and RAGE expression can induce neurodegeneration. Additionally, we show that RAGE expression can exacerbate hyperglycemic induced neurodegeneration.
Asunto(s)
Intoxicación por Cadmio/metabolismo , Caenorhabditis elegans/metabolismo , Neuronas Dopaminérgicas/metabolismo , Intoxicación por Manganeso/metabolismo , Degeneración Nerviosa , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Neuronas Serotoninérgicas/metabolismo , Animales , Animales Modificados Genéticamente , Cloruro de Cadmio , Intoxicación por Cadmio/etiología , Intoxicación por Cadmio/genética , Intoxicación por Cadmio/patología , Caenorhabditis elegans/genética , Cloruros , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Glucosa/toxicidad , Compuestos de Manganeso , Intoxicación por Manganeso/etiología , Intoxicación por Manganeso/genética , Intoxicación por Manganeso/patología , Receptor para Productos Finales de Glicación Avanzada/genética , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/patologíaRESUMEN
Major depressive disorder (MDD) is a leading cause of disability worldwide, with a poorly known pathophysiology and sub-optimal treatment, based on serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. We review existing theories on MDD, paying special attention to the role played by the ventral anterior cingulate cortex (vACC) or its rodent equivalent, infralimbic cortex (IL), which tightly control the activity of brainstem monoamine neurons (including raphe 5-HT neurons) via descending afferents. Further, astrocytes regulate excitatory synapse activity via glutamate reuptake through astrocytic transporters EAAT1 and EAAT2 (GLAST and GLT-1 in rodents), and alterations of astrocyte number/function have been reported in MDD patients and suicide victims. We recently assessed the impact of reducing GLAST/GLT-1 function in IL on emotional behavior and serotonergic function in rodents. The acute pharmacological blockade of GLT-1 with dihydrokainate (DHK) in rat IL evoked an antidepressant-like effect mediated by local AMPA-R activation and a subsequent enhancement of serotonergic function. No effects were produced by DHK microinfusion in prelimbic cortex (PrL). In the second model, a moderate small interfering RNAs (siRNA)-induced reduction of GLAST and GLT-1 expression in mouse IL markedly increased local glutamatergic neurotransmission and evoked a depressive-like phenotype (reversed by citalopram and ketamine), and reduced serotonergic function and BDNF expression in cortical/hippocampal areas. As for DHK, siRNA microinfusion in PrL did not evoke behavioral/neurochemical effects. Overall, both studies support a critical role of the astrocyte-neuron communication in the control of excitatory neurotransmission in IL, and subsequently, on emotional behavior, via the downstream associated changes on serotonergic function.
Asunto(s)
Astrocitos/metabolismo , Trastorno Depresivo Mayor/metabolismo , Emociones/fisiología , Ácido Glutámico/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Neuronas Serotoninérgicas/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/psicología , Emociones/efectos de los fármacos , Transportador 1 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 2 de Aminoácidos Excitadores/metabolismo , Humanos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/patología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Suicidio/psicologíaRESUMEN
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra and dopamine depletion in the striatum. Non-dopaminergic systems are also affected, including the serotonergic system. Enhanced striatal serotonergic innervation is a proposed compensatory mechanism for the dopaminergic deficit. Meanwhile a serotonergic deficit has been suggested as preceding the nigrostriatal dopaminergic pathology in PD. Our aim was to assess the serotonergic innervation of the striatum in a model of progressive experimental parkinsonism in macaques, from pre-symptomatic to symptomatic stages. The neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) was administered to adult macaque monkeys using a slow intoxication protocol. The intoxicated animals were classified into asymptomatic, recovered, moderate and severe parkinsonian, based on their motor behavior. The serotonergic innervation was studied by immunohistochemistry against serotonin (5-HT). In the striatum, the density of 5-HT-immunoreactive (5-HT+) axons was estimated with stereology. Images of the striatum in the immunostained sections were taken to compare the distribution patterns of the serotonergic innervation between groups. These patterns were apparently similar among the groups. Axonal density estimations showed no differences in striatal 5-HT+ innervation between the intoxicated groups and the control group. Accordingly, this study fails to find significant changes in the striatal serotonergic axonal innervation in MPTP-treated monkeys, coinciding with previous biochemical findings in our model. However, it is possible that alterations in the serotonergic system in PD could be independent of axonal density changes. Consequently, the proposed role for striatal serotonin serving as a compensatory mechanism for dopaminergic denervation merits further study. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
Asunto(s)
Cuerpo Estriado/metabolismo , Trastornos Parkinsonianos/metabolismo , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Administración Intravenosa , Animales , Cuerpo Estriado/química , Cuerpo Estriado/patología , Macaca fascicularis , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/patología , Primates , Neuronas Serotoninérgicas/química , Neuronas Serotoninérgicas/patologíaRESUMEN
Axonal pathology precedes dopaminergic cell loss in Parkinson's disease (PD), indicating a dying back axonopathy of nigrostriatal projections. Although most attention focused on the dopaminergic system, increasing evidence implies a compromised serotonergic system in PD as well. By combining immunohistological and biochemical approaches, a profound layer-specific reduction of the serotonergic input to the prefrontal cortex (PFC) layers II and V/VI in aged mutant A53T α-synuclein-expressing mice (A53T mice) was detected. In addition, the altered fiber network was characterized by swollen axons and enlarged axonal varicosities within all PFC layers, but most pronounced in PFC layer I. Although prefrontal serotonin levels and synaptic protein expression were preserved, aged A53T mice showed increased levels of kinesin family member 1a and vesicular monoamine transporter 2. Together with increased tryptophan hydroxylase 2 mRNA levels in the raphe nuclei and an elevated serotonin receptor 1b expression in the PFC, these findings point to compensatory mechanisms within the serotonergic system to overcome the reduced neuritic input to the PFC in this transgenic animal model for PD.
Asunto(s)
Envejecimiento/metabolismo , Axones/patología , Degeneración Nerviosa , Enfermedad de Parkinson/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Neuronas Serotoninérgicas/patología , alfa-Sinucleína/metabolismo , Animales , Modelos Animales de Enfermedad , RatonesRESUMEN
Dysfunctions in dopamine (DA) and serotonin (5HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micropositron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5HT2A receptors (5HT2ARs) and 5HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Neuronas Serotoninérgicas/metabolismo , Síndrome de Tourette/tratamiento farmacológico , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiología , Modelos Animales de Enfermedad , Dopamina/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Humanos , Medicina Tradicional China , Nitrilos/toxicidad , Ratas , Receptor de Serotonina 5-HT2A/genética , Receptores de Dopamina D2/genética , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/patología , Serotonina/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genética , Síndrome de Tourette/inducido químicamente , Síndrome de Tourette/genética , Síndrome de Tourette/patologíaRESUMEN
Parkinson's disease (PD) is mostly known as a dopamine deficiency syndrome due the structural and functional changes in striatal projection neurons. However, studies have considered this pathology as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the morphological and immunohistochemical changes associated with behavioral and cognitive alterations in a model of parkinsonism induced by low dose of reserpine. Animals showed anxiety-like behavior and deficits in short-term recognition memory. Besides, Tyrosine Hydroxylase (TH) immunoreactive cells decreased in reserpine (RES) group in CA1 and serotonin (5-HT) immunoreactive cells decreased in RES group in CA1, CA3 and medial prefrontal cortex (mPFC). Moreover, an increase in the area (µm2) of 5 H T labeled ultrastructure (axon terminal) was observed in RES group only in CA1 and mPFC. The evidence of alterations in 5-HT immunoreactive in the premotor phase of model of parkinsonism highlights the importance of looking beyond the nigrostriatal system to elucidate the underling mechanisms and deficits in other neurotransmitters systems. This provides vital information regarding novel interventions for the management of non-motor symptoms. Additionally, the low-dose reserpine treatment has an early effect on axonal ultrastructure. As the axonopathy in PD has been increasingly recognized, the focus on axonal neurobiology is noteworthy for both neuroprotective and restorative therapeutics, and the progressive reserpine rat model can be a useful tool in this search.
Asunto(s)
Trastornos Parkinsonianos/fisiopatología , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/patología , Animales , Ansiedad/fisiopatología , Encéfalo/metabolismo , Región CA1 Hipocampal/efectos de los fármacos , Cognición/fisiología , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Dopamina/farmacología , Inmunohistoquímica/métodos , Masculino , Memoria a Corto Plazo/fisiología , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/patología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Reserpina/farmacología , Serotonina/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
NB-3 (contactin-6) is a member of the contactin family and has a wide range of roles during central nervous system development and disease. Here, we found that NB-3 was simultaneously induced in the serotonergic raphespinal tract (sRST) axons and in the scar-forming cells after spinal cord injury (SCI). Regrowth of sRST axons was promoted in vivo by blocking NB-3 expression in either sRST axons or scar-forming cells when post-traumatic axons of the sRST tried to penetrate the glial scar. NB-3 deficiency promoted synapse reformation between sRST regenerative axons and motor neurons and enhanced the potential for electrical activity of muscle contraction and motor coordination. In vivo evidence also suggested that NB-3 induction in both sRST axons and scar-forming cells was required to mediate NB-3 signaling inhibition of sRST axon regeneration after SCI. Our findings suggest that NB-3 protein is a potential molecular target for future SCI treatments.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Regeneración Nerviosa/fisiología , Neuronas Serotoninérgicas/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Animales , Axones/metabolismo , Axones/patología , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Moléculas de Adhesión Celular Neuronal/genética , Modelos Animales de Enfermedad , Electromiografía , Técnicas de Silenciamiento del Gen , Ratones , Actividad Motora/fisiología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Recuperación de la Función/fisiología , Neuronas Serotoninérgicas/patología , Médula Espinal/metabolismo , Médula Espinal/patología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patologíaRESUMEN
Virtually all brain circuits are physically embedded in a three-dimensional matrix of fibers that release 5-hydroxytryptamine (5-HT, serotonin). The density of this matrix varies across brain regions and cortical laminae, and it is altered in some mental disorders, including Major Depressive Disorder and Autism Spectrum Disorder. We investigate how the regional structure of the serotonergic matrix depends on the stochastic behavior of individual serotonergic fibers and introduce a new framework for the quantitative analysis of this behavior. In particular, we show that a step-wise random walk, based on the von Mises-Fisher probability distribution, can provide a realistic and mathematically concise description of these fibers. We also consider other stochastic models, including the fractional Brownian motion. The proposed approach seeks to advance the current understanding of the ascending reticular activating system (ARAS) and may also support future theory-guided therapeutic approaches.
Asunto(s)
Trastorno del Espectro Autista/patología , Encéfalo/patología , Trastorno Depresivo Mayor/patología , Fibras Nerviosas/patología , Neuronas Serotoninérgicas/patología , Serotonina/metabolismo , Trastorno del Espectro Autista/metabolismo , Encéfalo/metabolismo , Trastorno Depresivo Mayor/metabolismo , Humanos , Fibras Nerviosas/metabolismo , Neuronas Serotoninérgicas/metabolismo , Procesos EstocásticosRESUMEN
L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson's disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood-brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in line with the initial hypothesis, leaving a poor place to the plethora of mechanisms involving other neurotransmitters or mechanisms of action beyond newly synthesized DA itself. Yet, its mechanism of action is far from clear. It involves numerous distinct cell populations and does not mimic the mechanism of action of dopaminergic agonists. L-DOPA-derived DA is mainly released by serotonergic neurons as a false neurotransmitter, and serotonergic neurons are involved in L-DOPA-induced dyskinesia. The brain pattern and magnitude of DA extracellular levels together with this status of false neurotransmitters suggest that the striatal effects of DA via this mechanism would be minimal. Other metabolic products coming from newly formed DA or through the metabolism of L-DOPA itself could be involved. These compounds can be trace amines and derivatives. They could accumulate within the terminals of the remaining monoaminergic neurons. These "false neurotransmitters," also known for some of them as inducing an "amphetamine-like" mechanism, could reduce the content of biogenic amines in terminals of monoaminergic neurons, thereby impairing the exocytotic process of monoamines including L-DOPA-induced DA extracellular outflow. The aim of this review is to present the mechanism of action of L-DOPA with a specific attention to "false neurotransmission."
Asunto(s)
Cuerpo Estriado , Dopamina/metabolismo , Levodopa/uso terapéutico , Neurotransmisores/metabolismo , Enfermedad de Parkinson , Neuronas Serotoninérgicas , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/patologíaRESUMEN
Activation of pain (nociceptive) fibers can sensitize neural circuits within the spinal cord, inducing an increase in excitability (central sensitization) that can foster chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. In adult animals, the co-transporter KCC2 maintains a low intracellular concentration of the anion Cl-. As a result, when the GABA-A receptor is engaged, Cl- flows in the neuron which has a hyperpolarizing (inhibitory) effect. Spinal cord injury (SCI) can down-regulate KCC2 and reverse the flow of Cl-. Under these conditions, engaging the GABA-A receptor can have a depolarizing (excitatory) effect that fosters the development of nociceptive sensitization. The present paper explores how SCI alters GABA function and provides evidence that the loss of descending fibers alters pain transmission to the brain. Prior work has shown that, after SCI, administration of a GABA-A antagonist blocks the development of capsaicin-induced nociceptive sensitization, implying that GABA release plays an essential role. This excitatory effect is linked to serotonergic (5HT) fibers that descend through the dorsolateral funiculus (DLF) and impact spinal function via the 5HT-1A receptor. Supporting this, blocking the 5HT-1A receptor, or lesioning the DLF, emulated the effect of SCI. Conversely, spinal application of a 5HT-1A agonist up-regulated KCC2 and reversed the effect of bicuculline treatment. Finally, lesioning the DLF reversed how a GABA-A antagonist affects a capsaicin-induced aversion in a place conditioning task; in sham operated animals, bicuculline enhanced aversion whereas in DLF-lesioned rats biciculline had an antinociceptive effect.
Asunto(s)
Plasticidad Neuronal , Dolor/fisiopatología , Neuronas Serotoninérgicas/patología , Traumatismos de la Médula Espinal/patología , Ácido gamma-Aminobutírico/fisiología , Animales , Bicuculina/farmacología , Capsaicina/farmacología , Condicionamiento Operante/efectos de los fármacos , Antagonistas del GABA/farmacología , Masculino , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Neuronas Serotoninérgicas/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Simportadores/metabolismo , Ácido gamma-Aminobutírico/farmacología , Cotransportadores de K ClRESUMEN
Plasticity of neural circuits takes many forms and plays a fundamental role in regulating behavior to changing demands while maintaining stability. For example, during spinal cord development neurotransmitter identity in neurons is dynamically adjusted in response to changes in the activity of spinal networks. It is reasonable to speculate that this type of plasticity might occur also in mature spinal circuits in response to injury. Because serotonergic signaling has a central role in spinal cord functions, we hypothesized that spinal cord injury (SCI) in the fresh water turtle Trachemys scripta elegans may trigger homeostatic changes in serotonergic innervation. To test this possibility we performed immunohistochemistry for serotonin (5-HT) and key molecules involved in the determination of the serotonergic phenotype before and after SCI. We found that as expected, in the acute phase after injury the dense serotonergic innervation was strongly reduced. However, 30 days after SCI the population of serotonergic cells (5-HT+) increased in segments caudal to the lesion site. These cells expressed the neuronal marker HuC/D and the transcription factor Nkx6.1. The new serotonergic neurons did not incorporate the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) and did not express the proliferating cell nuclear antigen (PCNA) indicating that novel serotonergic neurons were not newborn but post-mitotic cells that have changed their neurochemical identity. Switching towards a serotonergic neurotransmitter phenotype may be a spinal cord homeostatic mechanism to compensate for the loss of descending serotonergic neuromodulation, thereby helping the outstanding functional recovery displayed by turtles. The 5-HT1A receptor agonist (±)-8-Hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) blocked the increase in 5-HT+ cells suggesting 5-HT1A receptors may trigger the respecification process.
Asunto(s)
Neuronas Serotoninérgicas/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Regeneración de la Medula Espinal/fisiología , Médula Espinal/fisiopatología , Proteínas Anfibias/metabolismo , Animales , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Receptor de Serotonina 5-HT1A/metabolismo , Neuronas Serotoninérgicas/patología , Médula Espinal/patología , Traumatismos de la Médula Espinal/patología , Factores de Transcripción/metabolismo , TortugasRESUMEN
During the last decade, the serotonergic system has emerged as a key player in the appearance of L-DOPA-induced dyskinesia in animal models of Parkinson's disease. Clinical investigations, based on imaging and postmortem analyses, suggest that the serotonin neurons are also involved in the etiology of this complication of long-term L-DOPA treatment in parkinsonian patients. These findings have stimulated efforts to develop new therapies using drugs targeting the malfunctioning serotonin neurons. In this review, we summarize the experimental and clinical data obtained so far and discuss the prospects for further development of this therapeutic strategy.
Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/efectos adversos , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/patología , Animales , Discinesia Inducida por Medicamentos/metabolismo , HumanosRESUMEN
The objective of the present study was to evaluate the possibilities for the use of the changes in the AgNOR staining patterns in the neurons of the dorsal raphe nucleus (DRN) for the purposes of the medical differential diagnostics of the cases of death from chronic alcohol intoxication. We elucidated the characteristics of the activity of protein biosynthesis including the number and the area of the nucleoli in the nuclei of the neurons of the individuals who had died from chronic alcohol intoxication (n=20) in comparison with the subjects of the control group (n=13). To reveal the morphological structures associated with protein biosynthesis in the nucleoli of the serotoninergic neurons of the dorsal raphe nucleus in the brain, the histological preparations were stained with the use of the silver-staining technique for nucleolar organizer regions (AgNOR). The comparative statistical analysis of the results thus obtained with the calculated confidence coefficients was carried out. The aggregated analysis of all the dorsal raphe subnuclei revealed the impairment of the AgNOR staining characteristics in the neurons of the subjects who had died from chronic alcohol intoxication in comparison with those of the subjects comprising the control group. It is concluded that the results of the study can be used for differential diagnostics of deaths from chronic alcohol intoxication and other causes.
Asunto(s)
Alcoholismo/metabolismo , Encéfalo/metabolismo , Patologia Forense/métodos , Biosíntesis de Proteínas , Neuronas Serotoninérgicas/metabolismo , Adulto , Alcoholismo/patología , Autopsia , Encéfalo/patología , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/patología , Humanos , Masculino , Persona de Mediana Edad , Neuronas Serotoninérgicas/patologíaRESUMEN
It is widely held that injured neurons in the central nervous system do not undergo axonal regrowth. However, there is mounting evidence that serotonin axons are a notable exception. Serotonin axons undergo long-distance regrowth in the neocortex after amphetamine lesion, and, following a penetrating stab injury, they can regrow from cut ends to traverse the stab rift. Traumatic brain injury (TBI) is clinically prevalent and can lead to pathologies, such as depression, that are related to serotonergic dysfunction. Thus, whether serotonin axons can regrow after TBI is an important question. We used two models for TBI-a persistent open skull condition and controlled cortical impact-to evoke injury in adult female mouse neocortex, and assessed serotonin axon density 1 week, 1 month, and 3 months after injury by serotonin transporter immunohistochemistry. We found that after both forms of TBI, serotonin axon density is decreased posterior but not anterior to the injury site when measured in layer 1 at 1 week post surgery, and that serotonin axons are capable of regrowing into the distal zone to increase density by 1 month post surgery. This pattern is consistent with the anterior-to-posterior course of serotonin axons in the neocortex. TBI in these models is associated with significant reactive astrogliosis both anterior and posterior to the impact, but the degree of reactive astrogliosis is not correlated with serotonin axon density when measured 1 week after TBI. Microglial density remains constant following both types of injuries, but microglial condensation was detected 1 week after controlled cortical impact.