RESUMO
Behavioral flexibility for appropriate action selection is an advantage when animals are faced with decisions that will determine their survival or death. In order to arrive at the right decision, animals evaluate information from their external environment, internal state, and past experiences. How these different signals are integrated and modulated in the brain, and how context- and state-dependent behavioral decisions are controlled are poorly understood questions. Studying the molecules that help convey and integrate such information in neural circuits is an important way to approach these questions. Many years of work in different model organisms have shown that dopamine is a critical neuromodulator for (reward based) associative learning. However, recent findings in vertebrates and invertebrates have demonstrated the complexity and heterogeneity of dopaminergic neuron populations and their functional implications in many adaptive behaviors important for survival. For example, dopaminergic neurons can integrate external sensory information, internal and behavioral states, and learned experience in the decision making circuitry. Several recent advances in methodologies and the availability of a synaptic level connectome of the whole-brain circuitry of Drosophila melanogaster make the fly an attractive system to study the roles of dopamine in decision making and state-dependent behavior. In particular, a learning and memory center-the mushroom body-is richly innervated by dopaminergic neurons that enable it to integrate multi-modal information according to state and context, and to modulate decision-making and behavior.
Assuntos
Dopamina/metabolismo , Percepção/fisiologia , Animais , Comportamento Animal , DípterosRESUMO
The regulation of the striatum by the GPCR signaling through neuromodulators is essential for its physiology and physiopathology, so it is necessary to know all the compounds of these pathways. In this study, we identified a new important partner of the dopaminergic pathway: GPRIN3 (a member of the GPRIN family). GPRIN3 is highly expressed in the striatum but with undefined function. Cell sorting of medium spiny neurons (MSNs) in indirect MSNs and direct MSNs indicated the presence of the GPRIN3 gene in both populations with a preferential expression in indirect MSNs. This led us to generate GPRIN3 KO mice by CRISPR/Cas9 and test male animals to access possible alterations in morphological, electrophysiological, and behavioral parameters following its absence. 3D reconstruction analysis of MSNs revealed increased neuronal arborization in GPRIN3 KO and modified passive and active electrophysiological properties. These cellular alterations were coupled with increased motivation and cocaine-induced hyperlocomotion. Additionally, using a specific indirect MSN knockdown, we showed a preferential role for GPRIN3 in indirect MSNs related to the D2R signaling. Together, these results show that GPRIN3 is a mediator of D2R function in the striatum playing a major role in striatal physiology.SIGNIFICANCE STATEMENT The striatum is the main input of the basal ganglia processing information from different brain regions through the combined actions of direct pathway neurons and indirect pathway neurons. Both neuronal populations are defined by the expression of dopamine D1R or D2R GPCRs, respectively. How these neurons signal to the respective G-protein is still debatable. Here we identified GPRIN3 as a putative selective controller of D2R function in the striatum playing a critical role in striatal-associated behaviors and cellular functions. This study represents the identification of a new target to tackle striatal dysfunction associated with the D2R, such as schizophrenia, Parkinson's disease, and drug addiction.
Assuntos
Corpo Estriado/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologiaRESUMO
Melanoma antigen genes (Mage) were first described as tumour markers. However, some of Mage are also expressed in healthy cells where their functions remain poorly understood. Here, we describe an unexpected role for one of these genes, Maged1, in the control of behaviours related to drug addiction. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP) and drug self-administration. Electrophysiological experiments in brain slices and conditional knockout mice demonstrate that Maged1 is critical for cortico-accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex (PFC) and the amygdala, but not in dopaminergic or striatal and other GABAergic neurons, is necessary for cocaine-mediated behavioural sensitization, and its expression in the PFC is also required for cocaine-induced extracellular dopamine (DA) release in the nucleus accumbens (NAc). This work identifies Maged1 as a critical molecule involved in cellular processes and behaviours related to addiction.
Assuntos
Comportamento Aditivo/genética , Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína/farmacologia , Proteínas de Neoplasias/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Cocaína/administração & dosagem , Dependovirus , Dopamina/metabolismo , Deleção de Genes , Ácido Glutâmico/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Reforço Psicológico , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologiaRESUMO
The striatopallidal (STP) and striatonigral (STN) neurons constitute the main neuronal populations of the striatum. Despite the increasing knowledge concerning their involvement in multiple tasks associated with the striatum, it is still challenging to understand the precise differential functions of these two neuronal populations and to identify and study new genes involved in these functions. Here, we describe a reliable approach, applied on adult mouse brain, to generate specific STP and STN neuron gene profiles. STP and STN neurons were identified in the same animal using the transgenic Adora2A-Cre × Z/EG mouse model combined with retrograde labeling, respectively. Gene profiling was generated from FACS-purified neurons leading to the identification of new STP and STN neuron-specific genes. Knock-down models based on Cre-dependent lentiviral vector were developed to investigate their function either in striatal or in STP neurons. Thereby, we demonstrate that ecto-5'-nucleotidase (NT5e) is specifically expressed in STP neurons and is at the origin of most of the extracellular adenosine produced in the striatum. Behavioral analysis of striatal and STP neuron knock-down mouse models as well as NT5e knock-out mice demonstrates the implication of this STP neuron enzyme in motor learning.
Assuntos
5'-Nucleotidase/metabolismo , Corpo Estriado/fisiologia , Aprendizagem/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , 5'-Nucleotidase/genética , Animais , Corpo Estriado/citologia , Citometria de Fluxo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Técnicas de Transferência de Genes , Globo Pálido/citologia , Proteínas de Fluorescência Verde/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Destreza Motora/fisiologia , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptor A2A de Adenosina/genética , Receptores de Dopamina D2/genéticaRESUMO
Excitability and synaptic transmission make neurons high-energy consumers. However, neurons do not store carbohydrates or lipids. Instead, they need support cells to fuel their metabolic demands. This role is assumed by glia, both in vertebrates and invertebrates. Many questions remain regarding the coupling between neuronal activity and energy demand on the one hand, and nutrient supply by glia on the other hand. Here, we review recent advances showing that fly glia, similar to their role in vertebrates, fuel neurons in times of high energetic demand, such as during memory formation and long-term storage. Vertebrate glia also play a role in the modulation of neurons, their communication, and behavior, including food search and feeding. We discuss recent literature pointing to similar roles of fly glia in behavior and metabolism.
Assuntos
Neuroglia , Neurônios , Animais , Carboidratos , Lipídeos , Neurônios/fisiologiaRESUMO
Motherhood induces a drastic, sometimes long-lasting, change in internal state and behavior in many female animals. How a change in reproductive state or the discrete event of mating modulates specific female behaviors is still incompletely understood. Using calcium imaging of the whole brain of Drosophila females, we find that mating does not induce a global change in brain activity. Instead, mating modulates the pheromone response of dopaminergic neurons innervating the fly's learning and memory center, the mushroom body (MB). Using the mating-induced increased attraction to the odor of important nutrients, polyamines, we show that disruption of the female fly's ability to smell, for instance the pheromone cVA, during mating leads to a reduction in polyamine preference for days later indicating that the odor environment at mating lastingly influences female perception and choice behavior. Moreover, dopaminergic neurons including innervation of the ß'1 compartment are sufficient to induce the lasting behavioral increase in polyamine preference. We further show that MB output neurons (MBON) of the ß'1 compartment are activated by pheromone odor and their activity during mating bidirectionally modulates preference behavior in mated and virgin females. Their activity is not required, however, for the expression of polyamine attraction. Instead, inhibition of another type of MBON innervating the ß'2 compartment enables expression of high odor attraction. In addition, the response of a lateral horn (LH) neuron, AD1b2, which output is required for the expression of polyamine attraction, shows a modulated polyamine response after mating. Taken together, our data in the fly suggests that mating-related sensory experience regulates female odor perception and expression of choice behavior through a dopamine-gated learning circuit.
Assuntos
Proteínas de Drosophila , Drosophila , Animais , Cálcio , Dopamina , Neurônios Dopaminérgicos/fisiologia , Drosophila/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Feminino , Corpos Pedunculados/fisiologia , Odorantes , Feromônios , Poliaminas , Olfato/fisiologiaRESUMO
In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.
Assuntos
Comportamento Apetitivo/fisiologia , Dopamina/metabolismo , Motivação , Corpos Pedunculados/metabolismo , Neurônios/metabolismo , Octopamina/metabolismo , Animais , Comportamento Animal , Neurônios Dopaminérgicos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Alimentos , Fome , Corpos Pedunculados/citologia , Corpos Pedunculados/fisiologia , Vias Neurais/fisiologia , Odorantes , Receptores de Dopamina D1/metabolismo , Recompensa , OlfatoRESUMO
Animals rely heavily on their sense of olfaction to perform various vital interactions with an ever-in-flux environment. The turbulent and combinatorial nature of air-borne odorant cues demands the employment of various coding strategies, which allow the animal to attune to its internal needs and past or present experiences. Furthermore, these internal needs can be dependent on internal states such as hunger, reproductive state and sickness. Neuromodulation is a key component providing flexibility under such conditions. Understanding the contributions of neuromodulation, such as sensory neuron sensitization and choice bias requires manipulation of neuronal activity on a local and global scale. With Drosophila's genetic toolset, these manipulations are feasible and even allow a detailed look on the functional role of classical neuromodulators such as dopamine, octopamine and neuropeptides. The past years unraveled various mechanisms adapting chemosensory processing and perception to internal states such as hunger and reproductive state. However, future research should also investigate the mechanisms underlying other internal states including the modulatory influence of endogenous microbiota on Drosophila behavior. Furthermore, sickness induced by pathogenic infection could lead to novel insights as to the neuromodulators of circuits that integrate such a negative postingestive signal within the circuits governing olfactory behavior and learning. The enriched emporium of tools Drosophila provides will help to build a concrete picture of the influence of neuromodulation on olfaction and metabolism, adaptive behavior and our overall understanding of how a brain works.
RESUMO
The striatum is a key brain structure involved in the processing of cognitive flexibility, which results from the balance between the flexibility demanded for novel learning of motor actions and the inflexibility required to preserve previously learned actions. In particular, the dorsolateral portion of the striatum (DLS) is engaged in the learning of action sequence. This process is temporally driven by fine adjustments in the function of the two main neuronal populations of the striatum, known as the direct pathway medium spiny neurons (dMSNs) and indirect pathway medium spiny neurons (iMSNs). Here, using optogenetics, behavioral, and electrophysiological tools, we addressed the relative role of both neuronal populations in the acquisition of a reversal dual action sequence in the DLS. While the channelrhodopsin-induced activation of dMSNs and iMSNs of the DLS did not induce changes in the learning rate of the sequence, the specific activation of the dMSNs of the DLS facilitated the acquisition of a reversal dual action sequence; the activation of iMSNs induced a significant deficit in the acquisition of the same task. Taken together our results indicate an antagonistic relationship between dMSNs and iMSNs on the acquisition of a reversal dual action sequence.
RESUMO
The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution.