Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
1.
Eur J Neurosci ; 59(10): 2522-2534, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38650479

RESUMEN

Dopamine neurons signal the salience of environmental stimuli and influence learning, although it is less clear if these neurons also determine the salience of memories. Ventral tegmental area (VTA) dopamine neurons increase their firing in the presence of new objects and reduce it upon repeated, inconsequential exposures, marking the shift from novelty to familiarity. This study investigates how dopamine neuron activity during repeated familiar object exposure affects an animal's preference for new objects in a subsequent novel object recognition (NOR) test. We hypothesize that a single familiarization session will not sufficiently lower dopamine activity, such that the memory of a familiar object remains salient, leading to equal exploration of familiar and novel objects and weaker NOR discrimination. In contrast, multiple familiarization sessions likely suppress dopamine activity more effectively, reducing the salience of the familiar object and enhancing subsequent novelty discrimination. Our experiments in mice indicated that multiple familiarization sessions reduce VTA dopamine neuron activation, as measured by c-Fos expression, and enhance novelty discrimination compared with a single familiarization session. Dopamine neurons that show responsiveness to novelty were primarily located in the paranigral nucleus of the VTA and expressed vesicular glutamate transporter 2 transcripts, marking them as dopamine-glutamate neurons. Chemogenetic inhibition of dopamine neurons during a single session paralleled the effects of multiple sessions, improving NOR. These findings suggest that a critical role of dopamine neurons during the transition from novelty to familiarity is to modulate the salience of an object's memory.


Asunto(s)
Neuronas Dopaminérgicas , Ratones Endogámicos C57BL , Reconocimiento en Psicología , Área Tegmental Ventral , Animales , Reconocimiento en Psicología/fisiología , Neuronas Dopaminérgicas/fisiología , Neuronas Dopaminérgicas/metabolismo , Área Tegmental Ventral/fisiología , Ratones , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/genética
2.
Eur J Neurosci ; 59(10): 2535-2548, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38720367

RESUMEN

The maturation of forebrain dopamine circuitry occurs over multiple developmental periods, extending from early postnatal life until adulthood, with the precise timing of maturation defined by the target region. We recently demonstrated in the adult mouse brain that axon terminals arising from midbrain dopamine neurons innervate the anterior corpus callosum and that oligodendrocyte lineage cells in this white matter tract express dopamine receptor transcripts. Whether corpus callosal dopamine circuitry undergoes maturational changes between early adolescence and adulthood is unknown but may be relevant to understanding the dramatic micro- and macro-anatomical changes that occur in the corpus callosum of multiple species during early adolescence, including in the degree of myelination. Using quantitative neuroanatomy, we show that dopamine innervation in the forceps minor, but not the rostral genu, of the corpus callosum, is greater during early adolescence (P21) compared to adulthood (>P90) in wild-type mice. We further demonstrate with RNAscope that, as in the adult, Drd1 and Drd2 transcripts are expressed at higher levels in oligodendrocyte precursor cells (OPCs) and decline as these cells differentiate into oligodendrocytes. In addition, the number of OPCs that express Drd1 transcripts during early adolescence is double the number of those expressing the transcript during early adulthood. These data further implicate dopamine in axon myelination and myelin regulation. Moreover, because developmental (activity-independent) myelination peaks during early adolescence, with experience-dependent (activity-dependent) myelination greatest during early adulthood, our data suggest that potential roles of dopamine on callosal myelination shift between early adolescence and adulthood, from a developmental role to an experience-dependent role.


Asunto(s)
Cuerpo Calloso , Ratones Endogámicos C57BL , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Animales , Ratones , Cuerpo Calloso/metabolismo , Cuerpo Calloso/crecimiento & desarrollo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Masculino , Neuronas Dopaminérgicas/metabolismo , Dopamina/metabolismo , Células Precursoras de Oligodendrocitos/metabolismo , Femenino
3.
Cell Mol Neurobiol ; 39(2): 255-263, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30552621

RESUMEN

Many PET tracers enable determination of fluctuations in neurotransmitter release, yet glutamate specifically can not be visualized in a noninvasive manner. Several studies point to the possibility of visualizing fluctuations in glutamate release by changes in affinity of the mGluR5 radioligand [11C]ABP688. These studies use pharmacological challenges to alter glutamate levels, and so probe release, but have not measured chronic alterations in receptor occupancy due to altered neurotransmission relevant to chronic neuropsychiatric disorders or their treatment. In this regard, the GLS1 heterozygous mouse has known reductions in activity of the glutamate-synthetic enzyme glutaminase, brain glutamate levels and release. We imaged this model to elucidate glutamatergic systems. Dynamic [11C]ABP688 microPET scans were performed for mGluR5. Western blot was used as an ex vivo validation. No significant differences were found in BPND between WT and GLS1 Hets. SPM showed voxel-wise increased in BPND in GLS1 Hets compared to WT consistent with lower synaptic glutamate. This was not due to alterations in mGluR5 levels, as western blot results showed lower mGluR5 levels in GLS1 Hets. We conclude that because of the chronic glutaminase deficiency and subsequent decrease in glutamate, the mGluR5 protein levels are lowered. Due to these decreased endogenous glutamate levels, however, there is increased [11C]ABP688 binding to the allosteric site in selected regions. We speculate that lower endogenous glutamate leads to less conformational change to the receptors, and thus higher availability of the binding site. The lower mGluR5 levels, however, lessen [11C]ABP688 binding in GLS1 Hets, in part masking the increase in binding due to diminished endogenous glutamate levels as confirmed with voxel-wise analysis.


Asunto(s)
Radioisótopos de Carbono/química , Glutaminasa/metabolismo , Imagen Molecular , Oximas/química , Piridinas/química , Receptor del Glutamato Metabotropico 5/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Glutamina/metabolismo , Heterocigoto , Ratones
4.
J Neurosci ; 35(49): 16259-71, 2015 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-26658874

RESUMEN

In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. SIGNIFICANCE STATEMENT: Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are capable of glutamate cotransmission. With conditional expression of channelrhodopsin in dopamine neurons, we systematically explored dopamine neuron connections in the forebrain and identified regionally specific dopamine neuron excitatory connections. Establishing that only a subset of forebrain regions receive excitatory connections from dopamine neurons will help to determine the function of dopamine neuron glutamate cotransmission, which likely involves transmission of precise temporal signals and enhancement of the dynamic range of dopamine neuron signals.


Asunto(s)
Neuronas Dopaminérgicas/fisiología , Ácido Glutámico/metabolismo , Red Nerviosa/fisiología , Vías Nerviosas/fisiología , Prosencéfalo/citología , Animales , Channelrhodopsins , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurotransmisores/farmacología , Fosfopiruvato Hidratasa/metabolismo , Prosencéfalo/fisiología , Transducción Genética , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/citología
5.
bioRxiv ; 2023 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-37961265

RESUMEN

Dopamine neurons signal the salience of environmental stimuli, influencing learning and motivation. However, research has not yet identified whether dopamine neurons also modulate the salience of memory content. Dopamine neuron activity in the ventral tegmental area (VTA) increases in response to novel objects and diminishes as objects become familiar through repeated presentations. We proposed that the declined rate of dopamine neuron activity during familiarization affects the salience of a familiar object's memory. This, in turn, influences the degree to which an animal distinguishes between familiar and novel objects in a subsequent novel object recognition (NOR) test. As such, a single familiarization session may not sufficiently reduce dopamine activity, allowing the memory of a familiar object to maintain its salience and potentially attenuating NOR. In contrast, multiple familiarization sessions could lead to more pronounced dopamine activity suppression, strengthening NOR. Our data in mice reveals that, compared to a single session, multiple sessions result in decreased VTA dopamine neuron activation, as indicated by c-Fos measurements, and enhanced novelty discrimination. Critically, when VTA dopamine neurons are chemogenetically inhibited during a single familiarization session, NOR improves, mirroring the effects of multiple familiarization sessions. In summary, our findings highlight the pivotal function of dopamine neurons in familiarity and suggest a role in modulating the salience of memory content.

6.
Brain Struct Funct ; 228(8): 1993-2006, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37668732

RESUMEN

Oligodendrocyte progenitor cells (OPCs) receive synaptic innervation from glutamatergic and GABAergic axons and can be dynamically regulated by neural activity, resulting in activity-dependent changes in patterns of axon myelination. However, it remains unclear to what extent other types of neurons may innervate OPCs. Here, we provide evidence implicating midbrain dopamine neurons in the innervation of oligodendrocyte lineage cells in the anterior corpus callosum and nearby white matter tracts of male and female adult mice. Dopaminergic axon terminals were identified in the corpus callosum of DAT-Cre mice after injection of an eYFP reporter virus into the midbrain. Furthermore, fast-scan cyclic voltammetry revealed monoaminergic transients in the anterior corpus callosum, consistent with the anatomical findings. Using RNAscope, we further demonstrate that ~ 40% of Olig2 + /Pdfgra + cells and ~ 20% of Olig2 + /Pdgfra- cells in the anterior corpus callosum express Drd1 and Drd2 transcripts. These results suggest that oligodendrocyte lineage cells may respond to dopamine released from midbrain dopamine axons, which could affect myelination. Together, this work broadens our understanding of neuron-glia interactions with important implications for myelin plasticity by identifying midbrain dopamine axons as a potential regulator of corpus callosal oligodendrocyte lineage cells.


Asunto(s)
Cuerpo Calloso , Neuronas Dopaminérgicas , Femenino , Masculino , Animales , Ratones , Linaje de la Célula , Dopamina , Neuroglía , Mesencéfalo
7.
bioRxiv ; 2023 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-37873436

RESUMEN

Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1ß as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.

8.
Front Neural Circuits ; 15: 665386, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34093138

RESUMEN

Discovered just over 20 years ago, dopamine neurons have the ability to cotransmit both dopamine and glutamate. Yet, the functional roles of dopamine neuron glutamate cotransmission and their implications for therapeutic use are just emerging. This review article encompasses the current body of evidence investigating the functions of dopamine neurons of the ventral midbrain that cotransmit glutamate. Since its discovery in dopamine neuron cultures, further work in vivo confirmed dopamine neuron glutamate cotransmission across species. From there, growing interest has led to research related to neural functioning including roles in synaptic signaling, development, and behavior. Functional connectome mapping reveals robust connections in multiple forebrain regions to various cell types, most notably to cholinergic interneurons in both the medial shell of the nucleus accumbens and the lateral dorsal striatum. Glutamate markers in dopamine neurons reach peak levels during embryonic development and increase in response to various toxins, suggesting dopamine neuron glutamate cotransmission may serve neuroprotective roles. Findings from behavioral analyses reveal prominent roles for dopamine neuron glutamate cotransmission in responses to psychostimulants, in positive valence and cognitive systems and for subtle roles in negative valence systems. Insight into dopamine neuron glutamate cotransmission informs the pathophysiology of neuropsychiatric disorders such as addiction, schizophrenia and Parkinson Disease, with therapeutic implications.


Asunto(s)
Neuronas Dopaminérgicas , Ácido Glutámico , Dopamina , Núcleo Accumbens , Sinapsis
9.
Biol Psychiatry ; 90(12): 829-842, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-32950210

RESUMEN

BACKGROUND: Increased physical activity is a common feature of anorexia nervosa (AN). Although high activity levels are associated with greater risk of developing AN, particularly when combined with dieting, most individuals who diet and exercise maintain a healthy body weight. It is unclear why some individuals develop AN while most do not. A rodent model of resilience and vulnerability to AN would be valuable to research. Dopamine, which is believed to play a crucial role in AN, regulates both reward and activity and may modulate vulnerability. METHODS: Adolescent and young adult female C57BL/6N mice were tested in the activity-based anorexia (ABA) model, with an extended period of food restriction in adult mice. ABA was also tested in dopamine transporter knockdown mice and wild-type littermates. Mice that adapted to conditions and maintained a stable body weight were characterized as resilient. RESULTS: In adults, vulnerable and resilient phenotypes emerged in both the ABA and food-restricted mice without wheels. Vulnerable mice exhibited a pronounced increase in running throughout the light cycle, which dramatically peaked prior to requiring removal from the experiment. Resilient mice exhibited an adaptive decrease in total running, appropriate food anticipatory activity, and increased consumption, thereby achieving stable body weight. Hyperdopaminergia accelerated progression of the vulnerable phenotype. CONCLUSIONS: Our demonstration of distinct resilient and vulnerable phenotypes in mouse ABA significantly advances the utility of the model for identifying genes and neural substrates mediating AN risk and resilience. Modulation of dopamine may play a central role in the underlying circuit.


Asunto(s)
Anorexia Nerviosa , Animales , Anorexia , Anorexia Nerviosa/genética , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Fenotipo
10.
J Neurosci ; 28(36): 9037-46, 2008 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-18768698

RESUMEN

Goal-directed actions are sensitive to work-related response costs, and dopamine in nucleus accumbens is thought to modulate the exertion of effort in motivated behavior. Dopamine-rich striatal areas such as nucleus accumbens also contain high numbers of adenosine A(2A) receptors, and, for that reason, the behavioral and neurochemical effects of the adenosine A(2A) receptor agonist CGS 21680 [2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine] were investigated. Stimulation of accumbens adenosine A(2A) receptors disrupted performance of an instrumental task with high work demands (i.e., an interval lever-pressing schedule with a ratio requirement attached) but had little effect on a task with a lower work requirement. Immunohistochemical studies revealed that accumbens neurons that project to the ventral pallidum showed adenosine A(2A) receptors immunoreactivity. Moreover, activation of accumbens A(2A) receptors by local injections of CGS 21680 increased extracellular GABA levels in the ventral pallidum. Combined contralateral injections of CGS 21680 into the accumbens and the GABA(A) agonist muscimol into ventral pallidum (i.e., "disconnection" methods) also impaired response output, indicating that these structures are part of a common neural circuitry regulating the exertion of effort. Thus, accumbens adenosine A(2A) receptors appear to regulate behavioral activation and effort-related processes by modulating the activity of the ventral striatopallidal pathway. Research on the effort-related functions of these forebrain systems may lead to a greater understanding of pathological features of motivation, such as psychomotor slowing, anergia, and fatigue in depression.


Asunto(s)
Globo Pálido/fisiología , Neostriado/fisiología , Núcleo Accumbens/fisiología , Esfuerzo Físico/fisiología , Receptor de Adenosina A2A/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Toxina del Cólera/metabolismo , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Agonistas del GABA/farmacología , Globo Pálido/efectos de los fármacos , Masculino , Muscimol/farmacología , Neostriado/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Fenetilaminas/farmacología , Esfuerzo Físico/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Péptido Intestinal Vasoactivo/metabolismo , Ácido gamma-Aminobutírico/metabolismo
11.
Neurochem Int ; 129: 104482, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31170424

RESUMEN

Dopamine (DA) neuron projections to the striatum are functionally heterogeneous with diverse behavioral roles. We focus here on DA neuron projections to the nucleus accumbens (NAc) medial Shell, their distinct anatomical and functional connections, and discuss their role in motivated behavior. We first review rodent studies showing that a subpopulation of DA neurons in the medial ventral tegmental area (VTA) project to the NAc medial Shell. Using a combinatorial strategy, we show that the majority of DA neurons projecting to the NAc Shell express vesicular glutamate transporter 2 (VGLUT2) making them capable of glutamate co-transmission (DA-GLU neurons). In the NAc dorsal medial Shell, all of the DA neuron terminals arise from DA-GLU neurons, while in the lateral NAc Shell, DA neuron terminals arise from both DA-GLU neurons and DA-only neurons, without VGLUT2. DA-GLU neurons make excitatory connections to the three major cells types, spiny projection neurons, fast-spiking interneuron and cholinergic interneurons (ChIs). The strongest DA-GLU neuron excitatory connections are to ChIs. Photostimulation of DA-GLU neuron terminals in the slice drives ChIs to burst fire. Finally, we review studies that address specially the behavioral function of this subpopulation of DA neurons in extinction learning and latent inhibition. Taking into account findings from anatomical and functional connectome studies, we propose that DA-GLU neuron connections to ChIs in the medial Shell play a crucial role in switching behavioral responses under circumstances of altered cue-reinforcer contingencies.


Asunto(s)
Neuronas Dopaminérgicas/fisiología , Ácido Glutámico/fisiología , Núcleo Accumbens/citología , Potenciales de Acción , Animales , Mapeo Encefálico , Neuronas Colinérgicas/fisiología , Conectoma , Señales (Psicología) , Neuronas Dopaminérgicas/efectos de la radiación , Neuronas Dopaminérgicas/ultraestructura , Extinción Psicológica/fisiología , Miedo/fisiología , Humanos , Interneuronas/fisiología , Ratones , Terminaciones Nerviosas/fisiología , Terminaciones Nerviosas/efectos de la radiación , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/anatomía & histología , Núcleo Accumbens/fisiología , Refuerzo en Psicología , Área Tegmental Ventral/anatomía & histología , Área Tegmental Ventral/fisiología , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo
12.
Neurochem Int ; 129: 104508, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31326460

RESUMEN

Glutaminase mediates the recycling of neurotransmitter glutamate, supporting most excitatory neurotransmission in the mammalian central nervous system. A constitutive heterozygous reduction in GLS1 engenders in mice a model of schizophrenia resilience and associated increases in Gln, reductions in Glu and activity-dependent attenuation of excitatory synaptic transmission. Hippocampal brain slices from GLS1 heterozygous mice metabolize less Gln to Glu. Whether glutaminase activity is diminished in the intact brain in GLS1 heterozygous mice has not been assessed, nor the regional impact. Moreover, it is not known whether pharmacological inhibition would mimic the genetic reduction. We addressed this using magnetic resonance spectroscopy to assess amino acid content and 13C-acetate loading to assess glutaminase activity, in multiple brain regions. Glutaminase activity was reduced significantly in the hippocampus of GLS1 heterozygous mice, while acute treatment with the putative glutaminase inhibitor ebselen did not impact glutaminase activity, but did significantly increase GABA. This approach identifies a molecular imaging strategy for testing target engagement by comparing genetic and pharmacological inhibition, across brain regions.


Asunto(s)
Azoles/farmacología , Encéfalo/enzimología , Glutaminasa/antagonistas & inhibidores , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Compuestos de Organoselenio/farmacología , Aminoácidos/análisis , Animales , Química Encefálica/efectos de los fármacos , Femenino , Glutaminasa/análisis , Glutaminasa/genética , Heterocigoto , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Isoindoles , Masculino , Ratones , Proteínas del Tejido Nervioso/análisis , Proteínas del Tejido Nervioso/genética , Resonancia Magnética Nuclear Biomolecular , Eliminación de Secuencia , Ácido gamma-Aminobutírico/análisis
13.
Schizophr Bull ; 45(1): 127-137, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29471549

RESUMEN

Brain imaging has revealed that the CA1 subregion of the hippocampus is hyperactive in prodromal and diagnosed patients with schizophrenia (SCZ), and that glutamate is a driver of this hyperactivity. Strikingly, mice deficient in the glutamate synthetic enzyme glutaminase have CA1 hypoactivity and a SCZ-resilience profile, implicating glutamate-metabolizing enzymes. To address this further, we examined mice with a brain-wide deficit in the glutamate-metabolizing enzyme glutamate dehydrogenase (GDH), encoded by Glud1, which should lead to glutamate excess due to reduced glutamate metabolism in astrocytes. We found that Glud1-deficient mice have behavioral abnormalities in the 3 SCZ symptom domains, with increased baseline and amphetamine-induced hyperlocomotion as a positive symptom proxy, nest building and social preference as a negative symptom proxy, and reversal/extradimensional set shifting in the water T-maze and contextual fear conditioning as a cognitive symptom proxy. Neuroimaging of cerebral blood volume revealed hippocampal hyperactivity in CA1, which was associated with volume reduction. Parameters of hippocampal synaptic function revealed excess glutamate release and an elevated excitatory/inhibitory balance in CA1. Finally, in a direct clinical correlation using imaging-guided microarray, we found a significant SCZ-associated postmortem reduction in GLUD1 expression in CA1. These findings advance GLUD1 deficiency as a driver of excess hippocampal excitatory transmission and SCZ symptoms, and identify GDH as a target for glutamate modulation pharmacotherapy for SCZ. More broadly, these findings point to the likely involvement of alterations in glutamate metabolism in the pathophysiology of SCZ.


Asunto(s)
Conducta Animal/fisiología , Región CA1 Hipocampal , Glutamato Deshidrogenasa/deficiencia , Receptores de Glutamato/metabolismo , Esquizofrenia , Animales , Región CA1 Hipocampal/diagnóstico por imagen , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiopatología , Volumen Sanguíneo Cerebral/fisiología , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Noqueados , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología
14.
Psychopharmacology (Berl) ; 199(4): 515-26, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18491078

RESUMEN

RATIONALE: Nucleus accumbens dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired accumbens DA transmission reallocate their behavior away from food-reinforced activities that have high response requirements and instead select less-effortful types of food-seeking behavior. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related processes, emerging evidence also implicates adenosine A(2A) receptors. OBJECTIVE: The present work was undertaken to test the hypothesis that accumbens A(2A) receptor stimulation would produce effects similar to those produced by DA depletion or antagonism. MATERIALS AND METHODS: Three experiments assessed the effects of the adenosine A(2A) agonist CGS 21680 on performance of a concurrent choice task (lever pressing for preferred food vs. intake of less preferred chow) that is known to be sensitive to DA antagonists and accumbens DA depletions. RESULTS: Systemic injections of CGS 21680 reduced lever pressing but did not increase feeding. In contrast, bilateral infusions of the adenosine A(2A) receptor agonist CGS 21680 (6.0-24.0 ng) into the nucleus accumbens decreased lever pressing for the preferred food but substantially increased consumption of the less preferred chow. Injections of CGS 21680 into a control site dorsal to the accumbens were ineffective. CONCLUSIONS: Taken together, these results are consistent with the hypothesis that local stimulation of adenosine A(2A) receptors in nucleus accumbens produces behavioral effects similar to those induced by accumbens DA depletions. Accumbens adenosine A(2A) receptors appear to be a component of the brain circuitry regulating effort-related choice behavior.


Asunto(s)
Agonistas del Receptor de Adenosina A2 , Adenosina/análogos & derivados , Conducta de Elección/efectos de los fármacos , Núcleo Accumbens/fisiología , Fenetilaminas/farmacología , Adenosina/administración & dosificación , Adenosina/farmacología , Animales , Condicionamiento Operante/efectos de los fármacos , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Masculino , Microinyecciones , Fenetilaminas/administración & dosificación , Esfuerzo Físico/fisiología , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo
15.
Parkinsonism Relat Disord ; 14 Suppl 2: S130-4, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18585081

RESUMEN

Adenosine A(2A) antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A(2A) antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidol-induced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine. Infusions of MSX-3 into the nucleus accumbens core increased locomotion in haloperidol-treated rats, but there were no effects of infusions into the accumbens shell or ventrolateral neostriatum. In contrast, MSX-3 injected into the ventrolateral neostriatum reduced pimozide-induced tremulous jaw movements. Dopamine/adenosine interactions in different striatal subregions are involved in distinct aspects of motor function.


Asunto(s)
Adenosina/metabolismo , Dopamina/metabolismo , Locomoción/fisiología , Enfermedad de Parkinson/etiología , Temblor , Animales , Modelos Animales de Enfermedad , Humanos , Temblor/complicaciones , Temblor/metabolismo , Temblor/fisiopatología
16.
Pharmacol Biochem Behav ; 89(3): 345-51, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18281083

RESUMEN

Adenosine A(2A) receptors are involved in the regulation of several behavioral functions. Adenosine A(2A) antagonists exert antiparkinsonian effects in animal models, and adenosine A(2A) agonists suppress locomotion and impair various aspects of motor control. The present experiments were conducted to study the effects of low doses of the adenosine A(2A) agonist CGS 21680 on lever pressing, specific parameters of food intake, and sedation. In the first experiment, the effects of CGS 21680 on fixed ratio 5 lever pressing were assessed. In the second experiment, rats were tested in 30 min feeding sessions, and also were observed for drug-induced sedation using a sedation rating scale. CGS 21680 (0.025, 0.05, 0.1 mg/kg IP) produced a dose related suppression of lever pressing, and also reduced the amount of food consumed. The feeding effect was largely dependent upon a slowing of the rate of feeding, and there was only a modest suppression of time spent feeding. Doses of CGS 21680 that suppressed lever pressing and feeding also were associated with sedation/drowsiness. In conjunction with other studies, the present results suggest that sedative effects may play an important role in some of the behavioral effects produced by systemic administration of adenosine A(2A) agonists.


Asunto(s)
Agonistas del Receptor de Adenosina A2 , Adenosina/análogos & derivados , Condicionamiento Operante/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Fenetilaminas/farmacología , Adenosina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley
17.
Elife ; 72018 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-30295607

RESUMEN

Dopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA neurons do not signal to spiny projection neurons in the medial dStr, while they elicit ionotropic glutamate responses in the lateral dStr. The DA neurons mediating these excitatory signals are in the substantia nigra (SN). Thus, SN dopamine neurons engage different receptors in different postsynaptic neurons in different dStr subregions to convey strikingly different signals. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Asunto(s)
Neuronas Colinérgicas/fisiología , Cuerpo Estriado/fisiología , Neuronas Dopaminérgicas/fisiología , Interneuronas/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Transmisión Sináptica/fisiología , Animales , Cuerpo Estriado/citología , Potenciales Postsinápticos Excitadores/fisiología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Sustancia Negra/citología , Sustancia Negra/fisiología
18.
Behav Brain Res ; 178(2): 190-9, 2007 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-17223207

RESUMEN

There is considerable evidence of interactions between adenosine A2A receptors and dopamine D2 receptors in striatal areas, and antagonists of the A2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 microg or 5.0 microg in 0.5 microl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.


Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Xantinas/farmacología , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inyecciones Intraperitoneales , Masculino , Microinyecciones , Profármacos/administración & dosificación , Profármacos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cross-Talk/efectos de los fármacos , Receptor de Adenosina A2A/fisiología , Xantinas/administración & dosificación
19.
Bio Protoc ; 7(1): e2090, 2017 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-34458420

RESUMEN

Functional connectivity in a neural circuit is determined by the strength, incidence, and neurotransmitter nature of its connections (Chuhma, 2015). Using optogenetics the functional synaptic connections between an identified population of neurons and defined postsynaptic target neurons may be measured systematically in order to determine the functional connectome of that identified population. Here we describe the experimental protocol used to investigate the excitatory functional connectome of ventral midbrain dopamine neurons, mediated by glutamate cotransmission ( Mingote et al., 2015 ). Dopamine neurons are made light sensitive by injecting an adeno-associated virus (AAV) encoding channelrhodopsin (ChR2) into the ventral midbrain of DATIREScre mice. The efficacy and specificity of ChR2 expression in dopamine neurons is verified by immunofluorescence for the dopamine-synthetic enzyme tyrosine hydroxylase. Then, slice patch-clamp recordings are made from neurons in regions recipient to dopamine neuron projections and the incidence and strength of excitatory connections determined. The summary of the incidence and strength of connections in all regions recipient to dopamine neuron projections constitute the functional connectome.

20.
Biol Psychiatry ; 81(1): 43-51, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27692238

RESUMEN

Brain imaging has revealed alterations in dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal subregions. However, the underlying synaptic mechanisms are on a finer scale. Dopamine neuron synaptic actions vary across the striatum, involving variations not only in dopamine release but also in dopamine neuron connectivity, cotransmission, modulation, and activity. Optogenetic studies have revealed that dopamine neurons release dopamine in a synaptic signal mode, and that the neurons also release glutamate and gamma-aminobutyric acid as cotransmitters, with striking regional variation. Fast glutamate and gamma-aminobutyric acid cotransmission convey discrete patterns of dopamine neuron activity to striatal neurons. Glutamate may function not only in a signaling role at a subset of dopamine neuron synapses, but also in mediating vesicular synergy, contributing to regional differences in loading of dopamine into synaptic vesicles. Regional differences in dopamine neuron signaling are likely to be differentially involved in the schizophrenia disease process and likely determine the subregional specificity of the action of psychostimulants that exacerbate the disorder, and antipsychotics that ameliorate the disorder. Elucidating dopamine neuron synaptic signaling offers the potential for achieving greater pharmacological specificity through intersectional pharmacological actions targeting subsets of dopamine neuron synapses.


Asunto(s)
Cuerpo Estriado/fisiopatología , Dopamina/fisiología , Neuronas Dopaminérgicas/fisiología , Esquizofrenia/fisiopatología , Sinapsis/fisiología , Animales , Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Ácido Glutámico/fisiología , Humanos , Ratones , Psicotrópicos/farmacología , Receptores Dopaminérgicos/fisiología , Transmisión Sináptica/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA