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1.
Nature ; 622(7981): 120-129, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37674083

RESUMEN

Multimodal astrocyte-neuron communications govern brain circuitry assembly and function1. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions4-7. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons8-10. However, the existence of this mechanism has been questioned11-13 owing to inconsistent data14-17 and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes18-21 and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging22 in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target.


Asunto(s)
Astrocitos , Sistema Nervioso Central , Ácido Glutámico , Transducción de Señal , Adulto , Humanos , Astrocitos/clasificación , Astrocitos/citología , Astrocitos/metabolismo , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Neuronas/metabolismo , Transmisión Sináptica , Calcio/metabolismo , Exocitosis , Análisis de Expresión Génica de una Sola Célula , Proteína 1 de Transporte Vesicular de Glutamato/deficiencia , Proteína 1 de Transporte Vesicular de Glutamato/genética , Eliminación de Gen , Corteza Cerebral/citología , Corteza Cerebral/metabolismo
2.
Mol Psychiatry ; 2023 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-37414924

RESUMEN

The brain's ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes instead to the emergence of pathological traits which are common in addiction and depression. However, the mechanisms and neural dynamics at the single-cell resolution underlying the encoding of associative learning remain elusive. Here, employing a Pavlovian discrimination task in mice we investigate how neuronal populations in the lateral habenula (LHb), a subcortical nucleus whose excitation underlies negative affect, encode the association between conditioned stimuli and a punishment (unconditioned stimulus). Large population single-unit recordings in the LHb reveal both excitatory and inhibitory responses to aversive stimuli. Additionally, local optical inhibition prevents the formation of cue discrimination during associative learning, demonstrating a critical role of LHb activity in this process. Accordingly, longitudinal in vivo two-photon imaging tracking LHb calcium neuronal dynamics during conditioning reveals an upward or downward shift of individual neurons' CS-evoked responses. While recordings in acute slices indicate strengthening of synaptic excitation after conditioning, support vector machine algorithms suggest that postsynaptic dynamics to punishment-predictive cues represent behavioral cue discrimination. To examine the presynaptic signaling in LHb participating in learning we monitored neurotransmitter dynamics with genetically-encoded indicators in behaving mice. While glutamate, GABA, and serotonin release in LHb remain stable across associative learning, we observe enhanced acetylcholine signaling developing throughout conditioning. In summary, converging presynaptic and postsynaptic mechanisms in the LHb underlie the transformation of neutral cues in valued signals supporting cue discrimination during learning.

3.
J Hepatol ; 78(1): 180-190, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35995127

RESUMEN

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has been associated with mild cerebral dysfunction and cognitive decline, although the exact pathophysiological mechanism remains ambiguous. Using a diet-induced model of NAFLD and monocarboxylate transporter-1 (Mct1+/-) haploinsufficient mice, which resist high-fat diet-induced hepatic steatosis, we investigated the hypothesis that NAFLD leads to an encephalopathy by altering cognition, behaviour, and cerebral physiology. We also proposed that global MCT1 downregulation offers cerebral protection. METHODS: Behavioural tests were performed in mice following 16 weeks of control diet (normal chow) or high-fat diet with high fructose/glucose in water. Tissue oxygenation, cerebrovascular reactivity, and cerebral blood volume were monitored under anaesthesia by multispectral optoacoustic tomography and optical fluorescence. Cortical mitochondrial oxygen consumption and respiratory capacities were measured using ex vivo high-resolution respirometry. Microglial and astrocytic changes were evaluated by immunofluorescence and 3D reconstructions. Body composition was assessed using EchoMRI, and liver steatosis was confirmed by histology. RESULTS: NAFLD concomitant with obesity is associated with anxiety- and depression-related behaviour. Low-grade brain tissue hypoxia was observed, likely attributed to the low-grade brain inflammation and decreased cerebral blood volume. It is also accompanied by microglial and astrocytic morphological and metabolic alterations (higher oxygen consumption), suggesting the early stages of an obesogenic diet-induced encephalopathy. Mct1 haploinsufficient mice, despite fat accumulation in adipose tissue, were protected from NAFLD and associated cerebral alterations. CONCLUSIONS: This study provides evidence of compromised brain health in obesity and NAFLD, emphasising the importance of the liver-brain axis. The protective effect of Mct1 haploinsufficiency points to this protein as a novel therapeutic target for preventing and/or treating NAFLD and the associated brain dysfunction. IMPACT AND IMPLICATIONS: This study is focused on unravelling the pathophysiological mechanism by which cerebral dysfunction and cognitive decline occurs during NAFLD and exploring the potential of monocarboxylate transporter-1 (MCT1) as a novel preventive or therapeutic target. Our findings point to NAFLD as a serious health risk and its adverse impact on the brain as a potential global health system and economic burden. These results highlight the utility of Mct1 transgenic mice as a model for NAFLD and associated brain dysfunction and call for systematic screening by physicians for early signs of psychological symptoms, and an awareness by individuals at risk of these potential neurological effects. This study is expected to bring attention to the need for early diagnosis and treatment of NAFLD, while having a direct impact on policies worldwide regarding the health risk associated with NAFLD, and its prevention and treatment.


Asunto(s)
Encefalopatías , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Dieta Alta en Grasa/efectos adversos , Hígado/patología , Obesidad/metabolismo , Ratones Transgénicos , Encefalopatías/metabolismo , Encefalopatías/patología , Encéfalo/metabolismo , Ratones Endogámicos C57BL
4.
Eur J Neurosci ; 55(2): 377-387, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34963191

RESUMEN

Animals can cope with isolated stressful situations without enduring long-term consequences. However, when exposure to stressors becomes recurrent, behavioural symptoms of anxiety and depression can emerge. Yet, the neuronal mechanisms governing responsivity to isolated stressor remain elusive. Here, we investigate synaptic adaptations following mild stress in the lateral habenula (LHb), a structure engaged in aversion encoding and dysfunctional in depression. We describe that neuronal depolarization in the LHb drives long-term depression of inhibitory, but not excitatory, synaptic transmission (GABA LTD). This plasticity requires nitric oxide and presynaptic GABAB receptors, leading to a decrease in probability of GABA release. Mild stressors such as brief social isolation, or exposure to novel environment in the company of littermates, do not alter GABA LTD. In contrast, GABA LTD is absent after mice experience a novel environment in social isolation. Altogether, our results suggest that LHb GABAergic plasticity is sensitive to stress accumulation, which could represent a threshold mechanism for long-term alterations of LHb function.


Asunto(s)
Habénula , Animales , Habénula/fisiología , Ratones , Plasticidad Neuronal/fisiología , Receptores de GABA-B/metabolismo , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico
5.
Eur J Neurosci ; 50(3): 2124-2133, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30118546

RESUMEN

Lateral habenula (LHb) hyperactivity plays a pivotal role in the emergence of negative emotional states, including those occurring during withdrawal from addictive drugs. We have previously implicated cocaine-driven adaptations at synapses from the entopeduncular nucleus (EPN) to the LHb in this process. Specifically, ionotropic GABAA receptor (R)-mediated neurotransmission at EPN-to-LHb synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABAB R signaling also controls LHb activity, although its role at EPN-to-LHb synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABAB R-mediated neurotransmission at EPN-to-LHb synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage-clamp recordings from LHb neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABAA R-mediated input to LHb neurons, and a reduced occurrence of GABAB R-signaling at EPN-to-LHb synapses. We then assessed the underlying mechanism of this decrease. Application of GABAB R agonist baclofen evoked similar postsynaptic responses in EPN-innervated LHb neurons in saline- and cocaine-treated mice. Release probability at EPN-to-LHb GABAergic synapses was also comparable between groups. However, incubating brain slices in glutamine to facilitate GABA vesicle filling, normalized GABAB R-currents at EPN-to-LHb synapses in cocaine-treated mice. Overall, we show that during cocaine withdrawal, together with reduced GABAA R transmission, also GABAB R-mediated inhibitory signaling is diminished at EPN-to-LHb synapses, likely via the same presynaptic deficit. In concert, these alterations are predicted to contribute to the emergence of drug withdrawal symptoms, facilitating drug relapse.


Asunto(s)
Cocaína/farmacología , Receptores de GABA-B/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Animales , Conducta Animal/fisiología , Núcleo Entopeduncular/efectos de los fármacos , Habénula/fisiopatología , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/fisiología , Receptores de GABA-B/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
6.
Eur J Neurosci ; 50(6): 2921-2930, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30860301

RESUMEN

Appropriate behavioural strategies to cope with unexpected salient stimuli require synergistic neuronal responses in diverse brain regions. Among them, the epithalamic lateral habenula (LHb) plays a pivotal role in processing salient stimuli of aversive valence. Integrated in the complex motivational circuit, LHb neurons are indeed excited by aversive stimuli, including footshock (Fs). However, whether such excitation is a common feature represented throughout the LHb remains unclear. Here, we combined single-unit extracellular recordings in anaesthetized mice with juxtacellular labelling to describe the nature, location and pharmacological properties of Fs-driven responses within the LHb. We find that, along with Fs-excited cells, about 10% of LHb neurons display Fs-mediated inhibitory responses. Such inhibited neuronal population, in contrast to Fs-excited neurons, display regular and high frequency activity at baseline and is clustered in the medial portion of the LHb. Juxtacellular labelling of Fs-excited and inhibited neurons unravels that both populations are of glutamatergic type, as they co-localized with the EAAC1 glutamatergic transporter but not with the GAD67 GABAergic marker. Moreover, while the excitatory responses to Fs require both AMPA and NMDA receptors, the inhibitory responses rely instead on GABAA channels. Taken together, our results indicate that two functionally and partly segregated LHb neuronal ensembles encode Fs in an opposite fashion. This highlights the neuronal complexity in the LHb for processing aversive external stimuli.


Asunto(s)
Potenciales de Acción/fisiología , Habénula/fisiología , Inhibición Neural/fisiología , Neuronas/fisiología , Animales , Electrochoque , Masculino , Ratones , Vías Nerviosas/fisiología
7.
J Neurosci ; 37(43): 10372-10388, 2017 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-28935766

RESUMEN

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT2B-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT2B receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting in vivo properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to ex vivo dopamine neurons were found in mice lacking 5-HT2B receptors. These data support the idea that the chronic 5-HT2B-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.


Asunto(s)
Cocaína/administración & dosificación , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Núcleo Accumbens/metabolismo , Receptor de Serotonina 5-HT2B/biosíntesis , Transducción de Señal/fisiología , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Femenino , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Núcleo Accumbens/efectos de los fármacos , Proyectos Piloto , Distribución Aleatoria , Receptor de Serotonina 5-HT2B/deficiencia , Autoadministración , Transducción de Señal/efectos de los fármacos
8.
Synapse ; 71(6)2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27862283

RESUMEN

The activity of lateral habenula (LHb) represents a substrate for the encoding of negative-valenced events. The exposure to aversive stimuli in naïve mice is sufficient to trigger a reduction in GABAB -mediated signaling in the LHb. This is ultimately instrumental for the hyperactivity of LHb neurons and for the establishment of depressive-like phenotypes. However, the mechanisms responsible for the induction of this aversion-driven plasticity are missing. Using ex-vivo patch-clamp recordings in slices, here we show that exposing mice to a series of inescapable footshocks (FsE) rapidly reduces baclofen-mediated GABAB currents in the LHb. This plasticity of GABAB signaling requires the activation of the dopamine and stress pathways. Indeed, the systemic administration of dopamine and glucocorticoids receptor antagonists prevents the FsE-induced reduction of GABAB currents in the LHb. To test whether the recruitment of these receptors occurs within the LHb, we exposed slices from control mice to either dopamine or corticosterone. Both manipulations failed to alter the amplitudes of baclofen-mediated GABAB currents. Altogether, these data suggest that dopamine and stress signaling are necessary for the induction of FsE-evoked GABAB plasticity in the LHb. However, the activation of these specific receptors may occur in structures different than the LHb, suggesting a circuit-based mechanism for this form of plasticity. These findings provide mechanistic insights on aversion-driven plasticity within the LHb.


Asunto(s)
Habénula/metabolismo , Plasticidad Neuronal , Receptores Dopaminérgicos/metabolismo , Receptores de GABA-B/metabolismo , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/metabolismo , Animales , Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Habénula/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL
9.
J Psychiatry Neurosci ; 41(3): 192-202, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-26679926

RESUMEN

BACKGROUND: The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(-/-) mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. METHODS: Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(-/-) mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). RESULTS: The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct "modules," or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). LIMITATIONS: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(-/-) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. CONCLUSION: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(-/-) mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.


Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Adolescente , Animales , Mapeo Encefálico , Niño , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Estudios de Seguimiento , Estudios de Asociación Genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleótido Simple , Biología de Sistemas , Transcriptoma , Población Blanca/genética , Factores de Intercambio de Guanina Nucleótido ras/deficiencia , Factores de Intercambio de Guanina Nucleótido ras/genética
10.
Eur J Neurosci ; 42(7): 2372-9, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26286226

RESUMEN

The transition to scientific independence as a principal investigator (PI) can seem like a daunting and mysterious process to postdocs and students - something that many aspire to while at the same time wondering how to achieve this goal and what being a PI really entails. The FENS Kavli Network of Excellence (FKNE) is a group of young faculty who have recently completed this step in various fields of neuroscience across Europe. In a series of opinion pieces from FKNE scholars, we aim to demystify this process and to offer the next generation of up-and-coming PIs some advice and personal perspectives on the transition to independence, starting here with guidance on how to get hired to your first PI position. Rather than providing an exhaustive overview of all facets of the hiring process, we focus on a few key aspects that we have learned to appreciate in the quest for our own labs: What makes a research programme exciting and successful? How can you identify great places to apply to and make sure your application stands out? What are the key objectives for the job talk and the interview? How do you negotiate your position? And finally, how do you decide on a host institute that lets you develop both scientifically and personally in your new role as head of a lab?


Asunto(s)
Investigación Biomédica , Selección de Profesión , Neurociencias , Selección de Personal , Investigadores , Europa (Continente) , Guías como Asunto , Humanos
11.
Proc Natl Acad Sci U S A ; 109(51): 21128-33, 2012 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-23223532

RESUMEN

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.


Asunto(s)
Dopamina/metabolismo , Neuronas/metabolismo , Factores de Intercambio de Guanina Nucleótido ras/genética , Factores de Intercambio de Guanina Nucleótido ras/fisiología , Adolescente , Animales , Encéfalo/metabolismo , Calcio/metabolismo , Niño , Neuronas Dopaminérgicas/metabolismo , Electrofisiología/métodos , Etanol/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Genotipo , Haplotipos , Humanos , Masculino , Ratones , Ratones Transgénicos , ARN Mensajero/metabolismo , Refuerzo en Psicología , Factores de Tiempo , Área Tegmental Ventral/metabolismo
12.
Eur J Neurosci ; 39(7): 1170-8, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24712996

RESUMEN

The lateral habenula (LHb) is an epithalamic region with a crucial role in the regulation of midbrain monoaminergic systems. Over the past few years a renewed interest in the LHb has emerged due to studies highlighting its central role in encoding rewarding and aversive aspects of stimuli. Moreover, an increasing number of functional as well as behavioral indications provide substantial evidence supporting a role of LHb in neuropsychiatric diseases, including mood disorders and drug addiction. Cellular and synaptic adaptations in the LHb may therefore represent a critical phenomenon in the etiology of these diseases. In the current review we describe the anatomical and functional connections allowing the LHb to control the dopamine and serotonin systems, as well as possible roles of these connections in motivated behaviors and neuropsychiatric disorders. Finally, we discuss how drug exposure and stressful conditions alter the cellular physiology of the LHb, highlighting a role for the LHb in the context of drug addiction and depression.


Asunto(s)
Trastorno Depresivo/fisiopatología , Habénula/fisiopatología , Trastornos Relacionados con Sustancias/fisiopatología , Sinapsis/metabolismo , Transmisión Sináptica , Animales , Trastorno Depresivo/metabolismo , Dopamina/metabolismo , Habénula/metabolismo , Habénula/patología , Humanos , Serotonina/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Sinapsis/fisiología
13.
Neuron ; 112(16): 2669-2685, 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-38772374

RESUMEN

Behavioral strategies for survival rely on the updates the brain continuously makes based on the surrounding environment. External stimuli-neutral, positive, and negative-relay core information to the brain, where a complex anatomical network rapidly organizes actions, including approach or escape, and regulates emotions. Human neuroimaging and physiology in nonhuman primates, rodents, and teleosts suggest a pivotal role of the lateral habenula in translating external information into survival behaviors. Here, we review the literature describing how discrete habenular modules-reflecting the molecular signatures, anatomical connectivity, and functional components-are recruited by environmental stimuli and cooperate to prompt specific behavioral outcomes. We argue that integration of these findings in the context of valence processing for reinforcing or discouraging behaviors is necessary, offering a compelling model to guide future work.


Asunto(s)
Habénula , Habénula/fisiología , Animales , Humanos , Vías Nerviosas/fisiología , Red Nerviosa/fisiología , Red Nerviosa/diagnóstico por imagen , Emociones/fisiología
14.
Science ; 385(6713): 1081-1086, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39236168

RESUMEN

Negative emotional contagion-witnessing others in distress-affects an individual's emotional responsivity. However, whether it shapes coping strategies when facing future threats remains unknown. We found that mice that briefly observe a conspecific being harmed become resilient, withstanding behavioral despair after an adverse experience. Photometric recordings during negative emotional contagion revealed increased serotonin (5-HT) release in the lateral habenula. Whereas 5-HT and emotional contagion reduced habenular burst firing, limiting 5-HT synthesis prevented burst plasticity. Enhancing raphe-to-habenula 5-HT was sufficient to recapitulate resilience. In contrast, reducing 5-HT release in the habenula made witnessing a conspecific in distress ineffective to promote the resilient phenotype after adversity. These findings reveal that 5-HT supports vicarious emotions and leads to resilience by tuning definite patterns of habenular neuronal activity.


Asunto(s)
Emociones , Habénula , Resiliencia Psicológica , Serotonina , Animales , Masculino , Ratones , Adaptación Psicológica , Habénula/metabolismo , Habénula/fisiología , Plasticidad Neuronal , Neuronas/metabolismo , Neuronas/fisiología , Núcleos del Rafe/metabolismo , Serotonina/metabolismo , Femenino
15.
J Neurosci ; 32(36): 12641-6, 2012 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-22956853

RESUMEN

Addictive drugs share the ability to increase dopamine (DA) levels and trigger synaptic adaptations in the mesocorticolimbic system, two cellular processes engaged in the early stages of drug seeking. Neurons located in the lateral habenula (LHb) modulate the activity of DA neurons and DA release, and adaptively tune goal-directed behaviors. Whether synaptic modifications in LHb neurons occur upon drug exposure remains, however, unknown. Here, we assessed the influence of cocaine experience on excitatory transmission onto subsets of LHb neurons using a combination of retrograde tracing and ex vivo patch-clamp recordings in mice. Recent evidence demonstrates that AMPA receptors lacking the GluA2 subunit mediate glutamatergic transmission in LHb neurons. We find that cocaine selectively potentiates AMPA receptor-mediated EPSCs in LHb neurons that send axons to the rostromedial tegmental nucleus, a GABAergic structure that modulates the activity of midbrain DA neurons. Cocaine induces a postsynaptic accumulation of AMPA receptors without modifying their subunit composition or single-channel conductance. As a consequence, a protocol pairing presynaptic glutamate release with somatic hyperpolarization, to increase the efficiency of GluA2-lacking AMPA receptors, elicited a long-term potentiation in neurons only from cocaine-treated mice. This suggests that cocaine resets the rules for the induction of synaptic long-term plasticity in the LHb. Our study unravels an early, projection-specific, cocaine-evoked synaptic potentiation in the LHb that may represent a permissive step for the functional reorganization of the mesolimbic system after drug exposure.


Asunto(s)
Cocaína/farmacología , Habénula/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Sinapsis/efectos de los fármacos , Animales , Femenino , Habénula/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Potenciales Sinápticos/efectos de los fármacos , Potenciales Sinápticos/fisiología
16.
Neuron ; 111(7): 1094-1103.e8, 2023 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-36731469

RESUMEN

Parental behaviors secure the well-being of newborns and concomitantly limit negative affective states in adults, which emerge when coping with neonatal distress becomes challenging. Whether negative-affect-related neuronal circuits orchestrate parental actions is unknown. Here, we identify parental signatures in lateral habenula neurons receiving bed nucleus of stria terminalis innervation (BNSTLHb). We find that LHb neurons of virgin female mice increase their activity following pup distress vocalization and are necessary for pup-call-driven aversive behaviors. LHb activity rises during pup retrieval, a behavior worsened by LHb inactivation. Intersectional cell identification and transcriptional profiling associate BNSTLHb cells to parenting and outline a gene expression in female virgins similar to that in mothers but different from that in non-parental virgin male mice. Finally, tracking and manipulating BNSTLHb cell activity demonstrates their specificity for encoding negative affect and pup retrieval. Thus, a negative affect neural circuit processes newborn distress signals and may limit them by guiding female parenting.


Asunto(s)
Habénula , Neuronas , Ratones , Animales , Masculino , Femenino , Neuronas/fisiología , Reacción de Prevención , Afecto , Habénula/fisiología
17.
Nat Commun ; 14(1): 5749, 2023 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-37717033

RESUMEN

Microglia, the innate immune cells of the central nervous system, actively participate in brain development by supporting neuronal maturation and refining synaptic connections. These cells are emerging as highly metabolically flexible, able to oxidize different energetic substrates to meet their energy demand. Lactate is particularly abundant in the brain, but whether microglia use it as a metabolic fuel has been poorly explored. Here we show that microglia can import lactate, and this is coupled with increased lysosomal acidification. In vitro, loss of the monocarboxylate transporter MCT4 in microglia prevents lactate-induced lysosomal modulation and leads to defective cargo degradation. Microglial depletion of MCT4 in vivo leads to impaired synaptic pruning, associated with increased excitation in hippocampal neurons, enhanced AMPA/GABA ratio, vulnerability to seizures and anxiety-like phenotype. Overall, these findings show that selective disruption of the MCT4 transporter in microglia is sufficient to alter synapse refinement and to induce defects in mouse brain development and adult behavior.


Asunto(s)
Ansiedad , Microglía , Animales , Ratones , Sistema Nervioso Central , Ácido Láctico , Proteínas de Transporte de Membrana , Plasticidad Neuronal
18.
Biol Psychiatry ; 93(11): 966-975, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36958999

RESUMEN

BACKGROUND: Astrocytes control synaptic activity by modulating perisynaptic concentrations of ions and neurotransmitters including dopamine (DA) and, as such, could be involved in the modulating aspects of mammalian behavior. METHODS: We produced a conditional deletion of the vesicular monoamine transporter 2 (VMAT2) specifically in astrocytes (aVMTA2cKO mice) and studied the effects of the lack of VMAT2 in prefrontal cortex (PFC) astrocytes on the regulation of DA levels, PFC circuit functions, and behavioral processes. RESULTS: We found a significant reduction of medial PFC (mPFC) DA levels and excessive grooming and compulsive repetitive behaviors in aVMAT2cKO mice. The mice also developed a synaptic pathology, expressed through increased relative AMPA versus NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioral and synaptic phenotypes were rescued by re-expression of mPFC VMAT2 and L-DOPA treatment, showing that the deficits were driven by mPFC astrocytes that are critically involved in developmental DA homeostasis. By analyzing human tissue samples, we found that VMAT2 is expressed in human PFC astrocytes, corroborating the potential translational relevance of our observations in mice. CONCLUSIONS: Our study shows that impairment of the astrocytic control of DA in the mPFC leads to symptoms resembling obsessive-compulsive spectrum disorders such as trichotillomania and has a profound impact on circuit function and behaviors.


Asunto(s)
Astrocitos , Dopamina , Ratones , Animales , Humanos , Astrocitos/fisiología , Aseo Animal , Sinapsis/fisiología , Corteza Prefrontal/fisiología , Mamíferos
19.
Neuron ; 110(8): 1280-1283, 2022 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-35447097

RESUMEN

Neurons can release multiple neurotransmitters. Are they packaged in segregated pools of vesicles or within the same ones? In this issue of Neuron, Kim et al., 2022, examined features of GABA-glutamate co-release at basal ganglia to habenula synapses.


Asunto(s)
Ácido Glutámico , Vesículas Sinápticas , Neuronas , Sinapsis , Ácido gamma-Aminobutírico
20.
Transl Psychiatry ; 12(1): 3, 2022 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-35013094

RESUMEN

Throughout life, individuals experience a vast array of positive and aversive events that trigger adaptive behavioural responses. These events are often unpredicted and engage actions that are likely anchored on innate behavioural programs expressed by each individual member of virtually all animal species. In a second step, environmental cues, that are initially neutral, acquire value through the association with external sensory stimuli, and become instrumental to predict upcoming positive or negative events. This process ultimately prompts learned goal-directed actions allowing the pursuit of rewarding experience or the avoidance of a danger. Both innate and learned behavioural programs are evolutionarily conserved and fundamental for survival. Among the brain structures participating in the encoding of positive/negative stimuli and contributing to innate and learned behaviours is the epithalamic lateral habenula (LHb). The LHb provides top-down control of monoaminergic systems, responds to unexpected appetitive/aversive stimuli as well as external cues that predict the upcoming rewards or punishments. Accordingly, the LHb controls a number of behaviours that are innate (originating from unpredicted stimuli), and learned (stemming from predictive cues). In this review, we will discuss the progresses that rodent's experimental work made in identifying how LHb activity governs these vital processes, and we will provide a view on how these findings integrate within a complex circuit connectivity.


Asunto(s)
Habénula , Afecto , Animales , Aprendizaje , Vías Nerviosas , Recompensa
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