Dopamine-Mediated Alterations in Brain-Wide Functional Dynamics Measured by fMRI

Drug addiction is a complex, multifaceted disease characterized by compulsive drug-seeking and drug-taking behavior despite adverse consequences. In accordance with its complex nature, several neural systems are likely to be dysregulated to promote maladaptive behaviors associated with addiction. For instance, dopaminergic signaling within the mesolimbic dopamine (DA) system is thought to be critical for reward prediction, an adaptive process that likely goes awry in addiction. While it is well known that DA release events occur in mesolimbic terminal fields such as the nucleus accumbens (NAc) in response to reward predictive cues, including those associated with drugs of abuse, how DA release events affect network adaptation across the entire brain has largely been unexplored. To address this, we selectively activated ventral tegmental area (VTA) dopaminergic (THVTA) neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging (fMRI). We demonstrated DAergic modulation activates several anatomically distinct regions throughout the brain, many of which receive little to no direct dopaminergic input. We also showed that explicit pairing of midbrain dopamine neuron activity and a sensory stimulus can dramatically enhance the brain-wide representation of that specific sensory stimulus. Next, since drugs of abuse increase extracellular DA in the mesolimbic pathway of the brain, we utilized a rodent model of addiction to explore whether functional connectivity is altered after self-administration of cocaine. We found that cocaine self-administration orchestrates dynamic shifts in functional connectivity across many anatomically defined neuronal network nodes. Overall, these findings suggest that DA not only controls plasticity in direct target regions, but may effectively modulate brain-wide network plasticity as well. This research may provide critical insight into the circuit-level maladaptations that underlie compulsive drug-seeking behavior, and the chronic cycles of abstinence and relapse that characterize addiction in humans.Doctor of Philosoph

Therapeutic methods for psychosomatic disorders in oto-rhino-laryngology

Psychosomatic disorders such as tinnitus, acute hearing loss, attacks of dizziness, globus syndrome, dysphagias, voice disorders and many more are quite common in ear, nose and throat medicine. They are mostly caused by a number of factors, although the bio-psycho-social model does play an important role. Initial contact with a psychosomatically ill patient and compiling a first case history are important steps to psychosomatic oriented therapy. This contribution will sum up the most important otorhinolaryngological diseases with psychosomatic comorbidity and scientifically evaluated methods of treatment. The contribution will also introduce the reader to important psychosomatic treatment methods from psychotherapeutic relaxation techniques to talk therapy. To conclude, the contribution will discuss the criteria for outpatient as well as inpatient treatment and look at the advantages of psychosomatically oriented therapy, both for the patient and for the doctor

Adolescências e usos de drogas: intensidades e desigualdades em variações da experiência

Esta pesquisa teve como objetivo problematizar os enlaçamentos entre “drogas” e “adolescência”, situados como dispositivos de saber-poder-subjetivação, buscando pistas para pensar o(s) cuidado(s) à luz do saber das experiências de jovens adultos quando adolescentes. Tendo como referência aportes da pesquisa-intervenção em análise institucional e da cartografia, nos valemos das noções de dispositivo e de experiência em Michel Foucault, para traçar o seguinte percurso: a) revisão da produção científica (artigos indexados) sobre o enunciado “drogas na adolescência”; b) discussão da instituição da adolescência – regulada pelo dispositivo do desenvolvimento – e do dispositivo das drogas – que produz a droga como “problema”; e c) análise de narrativas sobre experiências com drogas na(s) adolescência(s), realizadas a partir de conversas-entrevistas com seis jovens adultos, que consumiram drogas nas adolescências, e com os quais temos relação para além da situação de pesquisa. De modo hegemônico, a noção de comportamento de risco (ao desenvolvimento) é a tônica da literatura revisada, enfatizando uma visão da adolescência como preparação ao “acabamento” adulto e, por consequência, ações de cuidado pautadas pela norma universal da abstinência-sobriedade. As pesquisas do campo antiproibicionista dão lugar a diferentes contornos simbólicos, saberes e práticas em que o uso de drogas se faz presente, enfatizando a indissociabilidade entre sujeitos, contextos e substâncias na produção de modos de uso e de pensar o cuidado COM pessoas que usam drogas. As conversas-entrevistas abordaram diferentes relações com as substâncias, possibilitando traçar dimensões históricas e intensivas do vivido. As narrativas buscaram apontar, nas experiências, os vetores coletivos de subjetivação, que configuram modos de viver e de usar drogas. Diferentemente da perspectiva da “proteção-tutela”, que captura a adolescência como fase de desenvolvimento a ser controlada rumo ao adulto produtivo, as narrativas dos jovens sinalizam diferentes agenciamentos coletivos, produzindo modos de viver, sentir e usar drogas, apontando a urgência de escutar os fluxos das vidas que pulsam e de propor ações de cuidado que privilegiem a normatividade como variação e criação de normas para siThis research aimed to problematize the linkages between “drugs” and “adolescence”, located as devices of knowledge-power-subjectivation, looking for clues to think about the care (s) in the light of the knowledge of the experiences of young adults when adolescents . Taking as a reference the contribution of research-intervention in institutional analysis and cartography, we use the notions of device and experience in Michel Foucault to trace the following path: a) review of scientific production (indexed articles) on the statement “drugs in adolescence ”; b) discussion of the institution of adolescence - regulated by the developmental device - and the drug device - which produces the drug as a "problem"; and c) analysis of narratives about experiences with drugs in adolescence, carried out through conversation-interviews with six young adults who used drugs in adolescence and with whom we have a relationship beyond the research situation. In a hegemonic way, the notion of risk behavior (to development) is the keynote of the reviewed literature, emphasizing a view of adolescence as preparation for the adult “finish”, and, consequently, care actions guided by the universal norm of abstinencesobriety . Research in the anti-prohibition field gives rise to different symbolic contours, knowledge and practices in which drug use is present, emphasizing the inseparability between subjects, contexts and substances in the production of ways of using and thinking about the care of people who use drugs . The interview-conversations addressed different relationships with the substances, making it possible to trace historical and intensive dimensions of the experience. The narratives sought to point out, in the experiences, the collective vectors of subjectivation that configure ways of living and using drugs. Unlike the “protection-guardianship” perspective, which captures adolescence as a development phase to be controlled towards the productive adult, the narratives of young people signal different collective agencies producing ways of living, feeling and using drugs, pointing out the urgency of listening to pulses of life that pulsate and to propose care actions that privilege normativity as variation and creation of norms for oneselfConselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNP

Amygdala and bed nucleus of the stria terminalis circuitry: Implications for addiction-related behaviors

Complex motivated behavioral processes, such as those that can go awry following substance abuse and other neuropsychiatric disorders, are mediated by a distributive network of neurons that reside throughout the brain. Neural circuits within the amygdala regions, such as the basolateral amygdala (BLA), and downstream targets such as the bed nucleus of the stria terminalis (BNST), are critical neuroanatomical structures for orchestrating emotional behavioral responses that may influence motivated actions such as the reinstatement of drug seeking behavior. Here, we review the functional neurocircuitry of the BLA and the BNST, and discuss how these circuits may guide maladaptive behavioral processes such as those seen in addiction. Thus, further study of the functional connectivity within these brain regions and others may provide insight for the development of new treatment strategies for substance use disorders

Coordination of Brain-Wide Activity Dynamics by Dopaminergic Neurons

Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (THVTA) neurons, as well as from more global maladaptation in neurocircuit function. However, whether THVTA activity affects large-scale brain-wide function remains unknown. Here we selectively activated THVTA neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging. Applying a standard generalized linear model analysis approach, our results indicate that selective optogenetic stimulation of THVTA neurons enhanced cerebral blood volume signals in striatal target regions in a dopamine receptor-dependent manner. However, brain-wide voxel-based principal component analysis of the same data set revealed that dopaminergic modulation activates several additional anatomically distinct regions throughout the brain, not typically associated with dopamine release events. Furthermore, explicit pairing of THVTA neuronal activation with a forepaw stimulus of a particular frequency expanded the sensory representation of that stimulus, not exclusively within the somatosensory cortices, but brain-wide. These data suggest that modulation of THVTA neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct THVTA input

Activation of Prefrontal Cortical Parvalbumin Interneurons Facilitates Extinction of Reward-Seeking Behavior

Forming and breaking associations between emotionally salient environmental stimuli and rewarding or aversive outcomes is an essential component of learned adaptive behavior. Importantly, when cue-reward contingencies degrade, animals must exhibit behavioral flexibility to extinguish prior learned associations. Understanding the specific neural circuit mechanisms that operate during the formation and extinction of conditioned behaviors is critical because dysregulation of these neural processes is hypothesized to underlie many of the maladaptive and pathological behaviors observed in various neuropsychiatric disorders in humans. The medial prefrontal cortex (mPFC) participates in the behavioral adaptations seen in both appetitive and aversive-cue-mediated responding, but the precise cell types and circuit mechanisms sufficient for driving these complex behavioral states remain largely unspecified. Here, we recorded and manipulated the activity of parvalbumin-positive fast spiking interneurons (PV+ FSIs) in the prelimbic area (PrL) of the mPFC in mice. In vivo photostimulation of PV+ FSIs resulted in a net inhibition of PrL neurons, providing a circuit blueprint for behavioral manipulations. Photostimulation of mPFC PV+ cells did not alter anticipatory or consummatory licking behavior during reinforced training sessions. However, optical activation of these inhibitory interneurons to cues associated with reward significantly accelerated the extinction of behavior during non-reinforced test sessions. These data suggest that suppression of excitatory mPFC networks via increased activity of PV+ FSIs may enhance reward-related behavioral flexibility

Deciphering Natural Killer Cell Cytotoxicity Against Medulloblastoma in vitro and in vivo: Implications for Immunotherapy

Melanie Gauthier,1,2 Julien Pierson,3 David Moulin,1 Manon Mouginot,1 Valerie Bourguignon,1 Wassim Rhalloussi,1 Jean-Baptiste Vincourt,1 Dominique Dumas,1 Danièle Bensoussan,1,2 Pascal Chastagner,1,4 Cédric Boura,3 Veronique Decot1,2 1CNRS UMR 7365 IMoPA, Université de Lorraine, Nancy, France; 2Cell Therapy and Tissue Bank Unit, Nancy University Hospital, Vandoeuvre-Les-Nancy, France; 3CNRS UMR7039 CRAN, Université de Lorraine, Nancy, France; 4Pediatric Oncology Department, Nancy University Hospital, Vandoeuvre-Les-Nancy, FranceCorrespondence: Veronique Decot, CNRS UMR 7365, IMoPA, Campus Brabois Santé, 9 av de la foret de Haye, Vandoeuvre-Les-Nancy, 54000, France, Tel +0033 – 649574720, Email [email protected]: Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of these patients remains poor owing to the sequelae and relapse risk. An alternative, or, in addition to the current standard treatment, could be considered immunotherapy, such as Natural Killer cells (NK). NK cells are cytotoxic innate lymphoid cells that play a major role in cancer immunosurveillance. To date, the mechanism of cytotoxicity of NK cells, especially regarding the steps of adhesion, conjugation, cytotoxic granule polarisation in the cell contact area, perforin and granzyme release in two and three dimensions, and therapeutic efficacy in vivo have not been precisely described.Materials and Methods: Each step of NK cytotoxicity against the three MB cell lines was explored using confocal microscopy for conjugation, Elispot for degranulation, flow cytometry, and luminescence assays for target cell necrosis and lysis and mediators released by cytokine array, and then confirmed in a 3D spheroid model. Medulloblastoma-xenografted mice were treated with NK cells. Their persistence was evaluated by flow cytometry, and their efficacy in tumour growth and survival was determined. In addition, their effects on the tumour transcriptome were evaluated.Results: NK cells showed variable affinities for conjugation with MB target cells depending on their subgroup and cytokine activation. Chemokines secreted during NK and MB cell co-culture are mainly associated with angiogenesis and immune cell recruitment. NK cell cytotoxicity induces MB cell death in both 2D and 3D co-culture models. NK cells initiated an inflammatory response in a human MB murine model by modulating the MB cell transcriptome.Conclusion: Our study confirmed that NK cells possess both in vitro and in vivo cytotoxic activity against MB cells and are of interest for the development of immunotherapy.Keywords: cancer, medulloblastoma, immune cells, adoptive transfe

Inhibitory signaling blocks activating receptor clustering and induces cytoskeletal retraction in natural killer cells

Signaling from immunotyrosine-based inhibitory motifs (ITIMs) neutralizes activating signals by inducing a retraction of NK cells from the surface of stimulatory cells

Membrane-Bound IL-21 Promotes Sustained Ex Vivo Proliferation of Human Natural Killer Cells

NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy