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Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.
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Retroalimentación Fisiológica , Microglía/fisiología , Inhibición Neural , Neuronas/fisiología , 5'-Nucleotidasa/metabolismo , Potenciales de Acción , Adenosina/metabolismo , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antígenos CD/metabolismo , Apirasa/metabolismo , Calcio/metabolismo , Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Inhibición Neural/genética , Receptor de Adenosina A1/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Factores de TiempoRESUMEN
HIV-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV-protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the CNS and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here, we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and a shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice, but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. Significance Statement Around half of people living with HIV also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein TAT causes toxicity that is thought to contribute to HAND. Here, we show that an antiepileptic drug, levetiracetam (LEV), prevented synaptic and cognitive impairments that develop in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-treatment for neuroprotection in HAND.
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Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration.
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Metanfetamina , Masculino , Animales , Ratones , Metanfetamina/farmacología , Porción Compacta de la Sustancia Negra , Locus Coeruleus , Neuronas , Axones , MonoaminooxidasaRESUMEN
Methamphetamine abuse is associated with an increased risk of developing Parkinson's disease (PD). Recently, it was found that methamphetamine increases mitochondrial oxidant stress in substantia nigra pars compacta (SNc) dopaminergic neurons by releasing vesicular dopamine (DA) and stimulating mitochondrially-anchored monoamine oxidase (MAO). As mitochondrial oxidant stress is widely thought to be a driver of SNc degeneration in PD, these observations provide a potential explanation for the epidemiological linkage. To test this hypothesis, mice were administered methamphetamine (5 mg/kg) for 28 consecutive days with or without pretreatment with an irreversible MAO inhibitor. Chronic methamphetamine administration resulted in the degeneration of SNc dopaminergic neurons and this insult was blocked by pretreatment with a MAO inhibitor - confirming the linkage between methamphetamine, MAO and SNc degeneration. To determine if shorter bouts of consumption were as damaging, mice were given methamphetamine for two weeks and then studied. Methamphetamine treatment elevated both axonal and somatic mitochondrial oxidant stress in SNc dopaminergic neurons, was associated with a modest but significant increase in firing frequency, and caused degeneration after drug cessation. While axonal stress was sensitive to MAO inhibition, somatic stress was sensitive to Cav1 Ca2+ channel inhibition. Inhibiting either MAO or Cav1 Ca2+ channels after methamphetamine treatment attenuated subsequent SNc degeneration. Our results not only establish a mechanistic link between methamphetamine abuse and PD, they point to pharmacological strategies that could lessen PD risk for patients with a methamphetamine use disorder.
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Dopaminérgicos/toxicidad , Neuronas Dopaminérgicas/efectos de los fármacos , Metanfetamina/toxicidad , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , Animales , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Mitocondrias/patología , Técnicas de Cultivo de Órganos , Estrés Oxidativo/fisiología , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.
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Cocaína/farmacología , Neuronas/metabolismo , Receptores de Dopamina D1/metabolismo , Conducta Espacial/efectos de los fármacos , Familia de Proteínas del Síndrome de Wiskott-Aldrich/metabolismo , Animales , Inhibidores de Captación de Dopamina/farmacología , Fenómenos Electrofisiológicos/genética , Potenciales Postsinápticos Excitadores/genética , Potenciales Postsinápticos Excitadores/fisiología , Ratones Noqueados , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiología , Fosforilación/efectos de los fármacos , Receptores de Dopamina D1/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Familia de Proteínas del Síndrome de Wiskott-Aldrich/genéticaRESUMEN
The striatum is richly innervated by mesencephalic dopaminergic neurons that modulate a diverse array of cellular and synaptic functions that control goal-directed actions and habits. The loss of this innervation has long been thought to be the principal cause of the cardinal motor symptoms of Parkinson's disease (PD). Moreover, chronic, pharmacological overstimulation of striatal dopamine (DA) receptors is generally viewed as the trigger for levodopa-induced dyskinesia (LID) in late-stage PD patients. Here, we discuss recent advances in our understanding of the relationship between the striatum and DA, particularly as it relates to PD and LID. First, it has become clear that chronic perturbations of DA levels in PD and LID bring about cell type-specific, homeostatic changes in spiny projection neurons (SPNs) that tend to normalize striatal activity. Second, perturbations in DA signaling also bring about non-homeostatic aberrations in synaptic plasticity that contribute to disease symptoms. Third, it has become evident that striatal interneurons are major determinants of network activity and behavior in PD and LID. Finally, recent work examining the activity of SPNs in freely moving animals has revealed that the pathophysiology induced by altered DA signaling is not limited to imbalance in the average spiking in direct and indirect pathways, but involves more nuanced disruptions of neuronal ensemble activity.
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Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Discinesia Inducida por Medicamentos/fisiopatología , Enfermedad de Parkinson/fisiopatología , Animales , Cuerpo Estriado/metabolismo , Neuronas Dopaminérgicas/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Humanos , Levodopa/efectos adversos , Enfermedad de Parkinson/metabolismoRESUMEN
INTRODUCTION: Little attention has been paid to the built environment of outpatient opioid treatment programs, despite the need to increase access to medications for opioid use disorder, particularly among people of color. The aims of this study were to rate the attractiveness of publicly-funded opioid treatment programs (OTPs) in Los Angeles County and explore whether less attractive OTPs are found in disadvantaged neighborhoods. METHODS: We conducted observations of the exteriors of all OTPs located in specialty substance use disorder treatment clinics in Los Angeles County in 2021 (N = 44). We created an attractiveness index based on attractiveness of the building exteriors and the surrounding grounds, the presence of disorder such as garbage and graffiti, and the presence of bars on the windows. We tested whether less attractive facilities were more likely to be situated in disadvantaged neighborhoods with high concentrations of racial/ethnic minorities. RESULTS: Most building exteriors were found to have an ordinary level of attractiveness or rated as unattractive. The grounds were largely unattractive. We found a significant negative association between attractiveness and neighborhood disadvantage. CONCLUSION: This project was a preliminary study of the physical conditions of OTPs in Los Angeles. We found was that the physical conditions of OTPs in LA County were generally poor. Research has identified many individual and structural barriers to treatment for people with opioid use disorders. Future research should empirically test the association between the built environment of treatment clinics and access to treatment, particularly in communities of color.
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Analgésicos Opioides , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Los Angeles , Trastornos Relacionados con Opioides/tratamiento farmacológico , Atención AmbulatoriaRESUMEN
Elevating serotonin (5-HT) levels with selective serotonin reuptake inhibitors (SSRIs) is the most widely used treatment for depression. However, current therapies are ineffective, have delayed benefit, or cause side effects in many patients. Here, we define a mechanism downstream of 5-HT1A receptors that mediates antidepressant-like behavior and is profoundly and selectively enhanced by genetic disruption of regulators of G protein signaling (RGS) activity at G(alpha)i2. Animals rendered insensitive to RGS protein regulation through a mutation in G(alpha)i2 (G184S) exhibited spontaneous antidepressant- and anxiolytic-like behaviors. Mice expressing RGS-insensitive G(alpha)i2 also exhibited increased cortical and hippocampal phosphorylation of glycogen synthase kinase-3beta, a constitutively active proapoptotic kinase that is inhibited through phosphorylation in response to serotonin, SSRIs, and 5-HT1 receptor agonists. Both behavioral and biochemical phenotypes were blocked by treatment with WAY 100635, a 5-HT1A-selective antagonist. RGS-insensitive mice were also 5-10 times more responsive to the antidepressant-like effects of the SSRI fluvoxamine and 5-HT1A-selective agonist 8-hydroxy-2-dipropylaminotetralin. In contrast, the antidepressant potency of agents acting through nonserotonergic mechanisms was unchanged as was 5-HT1A action on body temperature. The findings point to a critical role for endogenous RGS proteins to suppress the antidepressant-like effects of 5-HT1A receptor activation. By selectively enhancing the beneficial effects of serotonin, inhibition of RGS proteins represents a therapeutic approach for the treatment of mood disorders.
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Antidepresivos/farmacología , Subunidad alfa de la Proteína de Unión al GTP Gi2/metabolismo , Proteínas RGS/antagonistas & inhibidores , Receptor de Serotonina 5-HT1A/metabolismo , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Subunidad alfa de la Proteína de Unión al GTP Gi2/genética , Técnicas de Sustitución del Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Fenotipo , Piperazinas/farmacología , Piridinas/farmacología , Proteínas RGS/genética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Transducción de SeñalRESUMEN
Methamphetamine (meth) is an addictive psychostimulant and there are no FDA-approved treatment options for patients suffering from meth use disorders. In addition to being addictive, meth is also neurotoxic and chronic administration results in degeneration of substantia nigra pars compacta (SNc) dopamine and locus coeruleus (LC) norepinephrine neurons in mice. Optimal treatment strategies for meth use disorders would attenuate maladaptive meth-seeking behavior as well as provide neuroprotection. The L-type calcium channel inhibitor isradipine and the monoamine oxidase (MAO) inhibitor rasagiline both prevent chronic meth-induced SNc and LC degeneration but effects on meth-seeking are unknown. To test whether these clinically available compounds can mitigate meth-seeking, mice were implanted with chronic indwelling jugular vein catheters and allowed to self-administer meth (0.1 mg/kg/infusion) for 10 consecutive days (2-hrs/day) on a fixed ratio (FR) 1 schedule of reinforcement with meth infusions paired to a cue light. One day after the last self-administration session mice were tested for cue-associated meth-seeking behavior wherein the meth-associated cue light was contingently presented but meth reinforcement withheld. Isradipine (3 mg/kg) attenuated cue-associated meth-seeking in both male and female mice. In contrast, rasagiline (1 mg/kg) had no effect on seeking in either sex. These results suggest that isradipine may have the potential to serve as a dual-purpose pharmacotherapy for meth use disorders by attenuating seeking behavior and providing neuroprotection.
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Estimulantes del Sistema Nervioso Central , Metanfetamina , Ratones , Masculino , Femenino , Animales , Metanfetamina/farmacología , Isradipino/farmacología , Canales de Calcio Tipo L , Señales (Psicología) , Autoadministración , Comportamiento de Búsqueda de Drogas/fisiologíaRESUMEN
BACKGROUND: Methamphetamine (meth) dependence presents a substantial socioeconomic burden. Despite the need, there is no FDA-approved pharmacotherapy for psychostimulant dependence. We consider 5-HT2C receptors as viable therapeutic targets. We recently revealed that the atypical antidepressant, mirtazapine, attenuates meth-seeking in a rodent model of human substance abuse. Mirtazapine historically has been considered to be an antagonist at 5-HT2C receptors, but more recently shown to exhibit inverse agonism at constitutively active 5-HT2C receptors. To help distinguish the roles for antagonism vs. inverse agonism, here we explored the ability of a more selective 5-HT2C inverse agonist, SB 206553 to attenuate meth-seeking behavior, and compared its effects to those obtained with 5-HT2C antagonists, SDZ Ser 082 and SB 242084. To do so, rats were trained to self-administer meth and tested for seeking-like behavior in cue reactivity sessions consisting of contingently presenting meth-associated cues without meth reinforcement. We also explored motor function to determine the influence of SB 206553 and SDZ Ser 082 on motor activity in the presence and absence of meth. RESULTS: Like mirtazapine, pretreatment with SB 206553 (1.0, 5.0, and 10.0 mg/kg), attenuated meth-seeking. In contrast, the antagonists, SDZ Ser 082 (0.1, 0.3, and 1.0 mg/kg) and SB 242084 (3.0 mg/kg) had no effect on cue reactivity (CR). SB 242084 (3.0 mg/kg) failed to attenuate the effects of 5.0 and 10 mg/kg SB 206553 on CR. Motor function was largely unaltered by the 5-HT2C ligands; however, SB 206553, at the highest dose tested (10.0 mg/kg), attenuated meth-induced rearing behavior. CONCLUSIONS: The lack of effect by 5-HT2C antagonists suggests that meth-seeking and meth-evoked motor activity are independent of endogenous 5-HT acting at 5-HT2C receptors. While SB 206553 dramatically impacted meth-evoked behaviors it is unclear whether the observed effects were 5-HT2C receptor mediated. Thus, SB 206553 deserves further attention in the study of psychostimulant abuse disorders.
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Estimulantes del Sistema Nervioso Central/efectos adversos , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Indoles/farmacología , Metanfetamina/efectos adversos , Piridinas/farmacología , Antagonistas de la Serotonina/farmacología , Aminopiridinas/farmacología , Análisis de Varianza , Animales , Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Autoadministración , Factores de TiempoRESUMEN
Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in axons of substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) dopamine neurons. Chronic administration of meth results in SNc degeneration and MAO inhibition is neuroprotective, whereas, the VTA is resistant to degeneration. This differential vulnerability is attributed, at least in part, to the presence of L-type Ca2+ channel-dependent mitochondrial stress in SNc but not VTA dopamine neurons. MAO is also expressed in other monoaminergic neurons such as noradrenergic locus coeruleus (LC) and serotonergic dorsal raphe (DR) neurons. The impact of meth on mitochondrial stress in LC and DR neurons is unknown. In the current study we used a genetically encoded redox biosensor to investigate meth-induced MAO-dependent mitochondrial stress in LC and DR neurons. Similar to SNc and VTA neurons, meth increased MAO-dependent mitochondrial stress in axonal but not somatic compartments of LC norepinephrine and DR serotonin neurons. Chronic meth administration (5 mg/kg; 28-day) resulted in degeneration of LC neurons and MAO inhibition was neuroprotective whereas DR neurons were resistant to degeneration. Activating L-type Ca2+ channels increased mitochondrial stress in LC but not DR axons and inhibiting L-type Ca2+ channels in vivo with isradipine prevented meth-induced LC degeneration. These data suggest that similar to recent findings in SNc and VTA dopamine neurons, the differential vulnerability between LC and DR neurons can be attributed to the presence of L-type Ca2+ channel-dependent mitochondrial stress. Taken together, the present study demonstrates that both meth-induced MAO- and L-type Ca2+ channel-dependent mitochondrial stress are necessary for chronic meth-induced neurodegeneration.
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Methamphetamine (meth) is an addictive psychostimulant and illicit use presents significant personal and socioeconomic harm. Behavioral studies support the involvement of the dorsal striatum in drug-seeking but stimulant induced dysfunction in this region is understudied. The dorsal striatum can be subdivided into the dorsomedial (DMS) and dorsolateral (DLS) striatum with the DMS implicated in goal-directed and DLS in habitual behaviors; both regions are primarily composed of GABAergic direct (dSPNs) and indirect pathway (iSPNs) spiny projection neurons. To examine the effect of repeated meth on SPNs, mice were administered meth (2 mg/kg) for ten consecutive days and intrinsic excitability, dendritic excitability, and spine density were examined. DMS iSPN intrinsic excitability was increased at 1 day but decreased at 21 days of abstinence. In contrast, DMS dSPN intrinsic excitability was unchanged at either timepoint. Dendritic excitability and spine densities were unaltered in DMS iSPNs and dSPNs at 1 and 21 days of abstinence. The effect of repeated meth on iSPN excitability was specific to the DMS; DLS iSPN intrinsic excitability, dendritic excitability, and spine density were unchanged at 1 and 21 days of abstinence. These findings point toward DMS iSPN dysfunction in meth use disorders with differential dysfunction dependent on abstinence duration.
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Estimulantes del Sistema Nervioso Central , Metanfetamina , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Cuerpo Estriado/metabolismo , Interneuronas , Metanfetamina/efectos adversos , Metanfetamina/metabolismo , Ratones , NeostriadoRESUMEN
Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in substantia nigra pars compacta (SNc) axons; chronic administration produces SNc degeneration that is prevented by MAO inhibition suggesting that MAO-dependent axonal mitochondrial stress is a causal factor. To test whether meth similarly increases mitochondrial stress in ventral tegmental area (VTA) axons, we used a genetically encoded redox biosensor to assess mitochondrial stress ex vivo. Meth increased MAO-dependent mitochondrial stress in both SNc and VTA axons. However, despite having the same meth-induced stress as SNc neurons, VTA neurons were resistant to chronic meth-induced degeneration indicating that meth-induced MAO-dependent mitochondrial stress in axons was necessary but not sufficient for degeneration. To determine whether L-type Ca2+ channel-dependent stress differentiates SNc and VTA axons, as reported in the soma, the L-type Ca2+ channel activator Bay K8644 was used. Opening L-type Ca2+ channels increased axonal mitochondrial stress in SNc but not VTA axons. To first determine whether mitochondrial stress was necessary for SNc degeneration, mice were treated with the mitochondrial antioxidant mitoTEMPO. Chronic meth-induced SNc degeneration was prevented by mitoTEMPO thereby confirming the necessity of mitochondrial stress. Similar to results with the antioxidant, both MAO inhibition and L-type Ca2+ channel inhibition also prevented SNc degeneration. Taken together the presented data demonstrate that both MAO- and L-type Ca2+ channel-dependent mitochondrial stress is necessary for chronic meth-induced degeneration.
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Neuronas Dopaminérgicas/efectos de los fármacos , Metanfetamina/farmacología , Enfermedades Neurodegenerativas/patología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Animales , Antioxidantes/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Inhibidores de la Monoaminooxidasa/farmacologíaRESUMEN
Romanian rural villages are struggling to survive present times when youngsters leave for a better life in the city while elders work the land like a hundred years ago. Our paper integrates human environments research with public health preparedness, presenting the Èigani (Gypsy/Roma) ethnic group from rural Romania as an example to the world. The future security of mankind will require a new understanding of the human place in its environment. That will lead to a new society, not the most powerful or intelligent, but the one that is more adaptable to changes, with sensitive and interconnected community members. Therefore, the Èigani ethnic group that fought for its rights and flourished despite unfavorable odds, including the recent COVID-19 pandemic, represents the best example for a new world that prioritizes humans, promotes health and wellbeing, facilitating innovation and transformative networks environmental integration. This research attempts to quantify the Èigani's unique attributes that helped their communities survive and made them more adaptive to change. Always marginalized, they identified the other ethnic groups' weaknesses to penetrate the villages and learned to use the smartphone apps to communicate, for their trades, coppersmith, metal roof tiles and drainage systems. Our research was based on Geographical Information System, Microsoft Power Bi analytics data visualization tools and statistical analysis with SPSS V20 to demonstrate what enables their flourishing and what resistance they face locally. We argue that the Èigani's intense social cooperation, strong sense of family, community and mutual assistance helped them to fight COVID-19, generating their significant adaptability to the societal changes and their power to keep intact their cultural identity. The results show how the constant growing Èigani population changed and may change Romania's rural environments in the future.
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COVID-19 , Pandemias , Anciano , Humanos , Rumanía , Población Rural , SARS-CoV-2RESUMEN
INTRODUCTION: Methamphetamine is a potent psychomotor stimulant, and methamphetamine abusers are up to three times more likely to develop Parkinson's disease (PD) later in life. Prodromal PD may involve gut inflammation and the accumulation of toxic proteins that are transported from the enteric nervous system to the central nervous system to mediate, in part, the degeneration of dopaminergic projections. We hypothesized that self-administration of methamphetamine in rats produces a gut and brain profile that mirrors pre-motor and early-stage PD. METHODS: Rats self-administered methamphetamine in daily 3 h sessions for two weeks. Motor function was assessed before self-administration, during self-administration and throughout the 56 days of forced abstinence. Assays for pathogenic markers (tyrosine hydroxylase, glial fibrillary acidic protein (GFAP), α-synuclein) were conducted on brain and gut tissue collected at one or 56 days after cessation of methamphetamine self-administration. RESULTS: Motor deficits emerged by day 14 of forced abstinence and progressively worsened up to 56 days of forced abstinence. In the pre-motor stage, we observed increased immunoreactivity for GFAP and α-synuclein within the ganglia of the myenteric plexus in the distal colon. Increased α-synuclein was also observed in the substantia nigra pars compacta. At 56 days, GFAP and α-synuclein normalized in the gut, but the accumulation of nigral α-synuclein persisted, and the dorsolateral striatum exhibited a significant loss of tyrosine hydroxylase. CONCLUSION: The pre-motor profile is consistent with gut inflammation and gut/brain α-synuclein accumulation associated with prodromal PD and the eventual development of the neurological disease.
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Metanfetamina , Enfermedad de Parkinson , Animales , Encéfalo/metabolismo , Ratas , Sustancia Negra/metabolismo , alfa-SinucleínaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (H2O2). We show that MAO metabolism of DA does not increase cytosolic H2O2 but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release.
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Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Transporte de Electrón/fisiología , Metabolismo Energético/fisiología , Monoaminooxidasa/metabolismo , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Oxidación-ReducciónRESUMEN
Parkinson's disease (PD) is the most common neurodegenerative movement disorder that results from the progressive degeneration of substantia nigra pars compacta (SNc) dopamine (DA) neurons. As a consequence of SNc degeneration, the striatum undergoes DA depletion causing the emergence of motor symptoms such as resting tremor, bradykinesia, postural instability and rigidity. The primary cell type in the striatum is the spiny projection neuron (SPN), which can be divided into two subpopulations, the direct and indirect pathway; the direct pathway innervates the substantia nigra pars reticulata and internal segment of the globus pallidus whereas the indirect pathway innervates the external segment of the globus pallidus. Proper control of movement requires a delicate balance between the two pathways; in PD dysfunction occurs in both cell types and impairments in synaptic plasticity are found in transgenic and toxin rodent models of PD. However, it is difficult to ascertain how the striatum adapts during different stages of PD, particularly during premotor stages. In the natural evolution of PD, patients experience years of degeneration before motor symptoms arise. To model premotor PD, partial lesion rodents and transgenic mice demonstrating progressive nigral degeneration have been and will continue to be assets to the field. Although, rodent models emulating premotor PD are not fully asymptomatic; modest reductions in striatal DA result in cognitive impairments. This mini review article gives a brief summary of SPN dynamics in animal models of PD.
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Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Trastornos Parkinsonianos , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , RatasRESUMEN
In animal models of Parkinson's disease (PD), principal striatal spiny projection neurons (SPNs) lose axospinous synapses. However, there has been a disagreement about whether this loss is restricted to a specific type of SPN or not, as some studies have reported pruning in both direct pathway SPNs and indirect pathway SPNs, while others have found this pruning to be restricted to indirect pathway SPNs. One possible explanation for the discrepancy is the period between the induction of the parkinsonian state and the assessment of spine loss. To test this hypothesis, transgenic mice were subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopaminergic neurons and then direct pathway SPNs examined in ex vivo brain slices using two photon laser scanning microscopy either one or 2 months afterwards. These studies revealed that 1 month after the lesion, there was no loss of spines in direct pathway SPNs. However, 2 months after the lesion, spine loss was significant in direct pathway SPNs. In addition to reconciling the existing literature on the impact of the parkinsonian state on axospinous synapse elimination in SPNs, our results suggest that the delayed spine loss in direct pathway SPNs is not driven by homeostatic mechanisms [as posited for indirect pathway (iSPNs)], but rather by network pathophysiology.