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1.
Nat Commun ; 12(1): 1115, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602917

RESUMO

Animals form and update learned associations between otherwise neutral sensory cues and aversive outcomes (i.e., punishment) to predict and avoid danger in changing environments. When a cue later occurs without punishment, this unexpected omission of aversive outcome is encoded as reward via activation of reward-encoding dopaminergic neurons. How such activation occurs remains unknown. Using real-time in vivo functional imaging, optogenetics, behavioral analysis and synaptic reconstruction from electron microscopy data, we identify the neural circuit mechanism through which Drosophila reward-encoding dopaminergic neurons are activated when an olfactory cue is unexpectedly no longer paired with electric shock punishment. Reduced activation of punishment-encoding dopaminergic neurons relieves depression of olfactory synaptic inputs to cholinergic neurons. Synaptic excitation by these cholinergic neurons of reward-encoding dopaminergic neurons increases their odor response, thus decreasing aversiveness of the odor. These studies reveal how an excitatory cholinergic relay from punishment- to reward-encoding dopaminergic neurons encodes the absence of punishment as reward, revealing a general circuit motif for updating aversive memories that could be present in mammals.


Assuntos
Dopamina/metabolismo , Drosophila melanogaster/fisiologia , Punição , Recompensa , Animais , Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico , Neurônios Dopaminérgicos/fisiologia , Memória/fisiologia , Reversão de Aprendizagem , Olfato/fisiologia , Sinapses/fisiologia
2.
Neurosci Lett ; 740: 135466, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152457

RESUMO

The sense of taste provides information regarding the nutrient content, safety or potential toxicity of an edible. This is accomplished via a combination of innate and learned taste preferences. In conditioned taste aversion (CTA), rats learn to avoid ingesting a taste that has previously been paired with gastric malaise. Recent evidence points to a role of cholinergic muscarinic signaling in the amygdala for the learning and storage of emotional memories. The present study tested the participation of muscarinic receptors in the amygdala during the formation of CTA by infusing the non-specific antagonist scopolamine into the basolateral or central subnuclei before or after conditioning, as well as before retrieval. Our data show that regardless of the site of infusion, pre-conditioning administration of scopolamine impaired CTA acquisition whereas post-conditioning infusion did not affect its storage. Also, infusions into the basolateral but not in the central amygdala before retrieval test partially reduced the expression of CTA. Our results indicate that muscarinic receptors activity is required for acquisition but not consolidation of CTA. In addition, our data add to recent evidence pointing to a role of cholinergic signaling in peri-hippocampal structures in the process of memory retrieval.


Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Receptores Muscarínicos/fisiologia , Transdução de Sinais/fisiologia , Paladar/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Emoções , Masculino , Consolidação da Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Microinjeções , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/fisiologia , Ratos , Ratos Wistar , Receptores Muscarínicos/efeitos dos fármacos , Escopolamina/administração & dosagem , Escopolamina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Paladar/efeitos dos fármacos
3.
J Neurosci ; 41(7): 1529-1552, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33328292

RESUMO

The basal ganglia are important for movement and reinforcement learning. Using mice of either sex, we found that the main basal ganglia GABAergic output in the midbrain, the substantia nigra pars reticulata (SNr), shows movement-related neural activity during the expression of a negatively reinforced signaled locomotor action known as signaled active avoidance; this action involves mice moving away during a warning signal to avoid a threat. In particular, many SNr neurons deactivate during active avoidance responses. However, whether SNr deactivation has an essential role driving or regulating active avoidance responses is unknown. We found that optogenetic excitation of SNr or striatal GABAergic fibers that project to an area in the pedunculopontine tegmentum (PPT) within the midbrain locomotor region abolishes signaled active avoidance responses, while optogenetic inhibition of SNr cells (mimicking the SNr deactivation observed during an active avoidance behavior) serves as an effective conditioned stimulus signal to drive avoidance responses by disinhibiting PPT neurons. However, preclusion of SNr deactivation, or direct inhibition of SNr fibers in the PPT, does not impair the expression of signaled active avoidance, indicating that SNr output does not drive the expression of a signaled locomotor action mediated by the midbrain. Consistent with a permissive regulatory role, SNr output provides information about the state of the ongoing action to downstream structures that mediate the action.SIGNIFICANCE STATEMENT During signaled active avoidance behavior, subjects move away to avoid a threat when directed by an innocuous sensory stimulus. Excitation of GABAergic cells in the substantia nigra pars reticulata (SNr), the main output of the basal ganglia, blocks signaled active avoidance, while inhibition of SNr cells is an effective stimulus to drive active avoidance. Interestingly, many SNr cells inhibit their firing during active avoidance responses, suggesting that SNr inhibition could be driving avoidance responses by disinhibiting downstream areas. However, interfering with the modulation of SNr cells does not impair the behavior. Thus, SNr may regulate the active avoidance movement in downstream areas that mediate the behavior, but does not drive it.


Assuntos
Gânglios da Base/fisiologia , Locomoção/fisiologia , Mesencéfalo/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Feminino , Masculino , Camundongos , Fibras Nervosas/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Optogenética , Parte Reticular da Substância Negra/fisiologia , Núcleo Tegmental Pedunculopontino/fisiologia , Ácido gama-Aminobutírico/fisiologia
4.
PLoS Comput Biol ; 16(9): e1008163, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32898146

RESUMO

Learning to avoid harmful consequences can be a costly trial-and-error process. In such situations, social information can be leveraged to improve individual learning outcomes. Here, we investigated how participants used their own experiences and others' social cues to avoid harm. Participants made repeated choices between harmful and safe options, each with different probabilities of generating shocks, while also seeing the image of a social partner. Some partners made predictive gaze cues towards the harmful choice option while others cued an option at random, and did so using neutral or fearful facial expressions. We tested how learned social information about partner reliability transferred across contexts by letting participants encounter the same partner in multiple trial blocks while facing novel choice options. Participants' decisions were best explained by a reinforcement learning model that independently learned the probabilities of options being safe and of partners being reliable and combined these combined these estimates to generate choices. Advice from partners making a fearful facial expression influenced participants' decisions more than advice from partners with neutral expressions. Our results showed that participants made better decisions when facing predictive partners and that they cached and transferred partner reliability estimates into new blocks. Using simulations we show that participants' transfer of social information into novel contexts is better adapted to variable social environments where social partners may change their cuing strategy or become untrustworthy. Finally, we found no relation between autism questionnaire scores and performance in our task, but do find autism trait related differences in learning rate parameters.


Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/fisiologia , Comportamento Social , Comportamento de Escolha/fisiologia , Comunicação , Biologia Computacional , Sinais (Psicologia) , Fixação Ocular/fisiologia , Humanos
5.
Nat Commun ; 11(1): 4484, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901027

RESUMO

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.


Assuntos
Aprendizagem da Esquiva/fisiologia , Hipocampo/fisiologia , Proteínas Proto-Oncogênicas c-fos/fisiologia , Animais , Ansiedade/metabolismo , Comportamento Animal/fisiologia , Técnicas de Inativação de Genes , Inativação Gênica , Hipocampo/anatomia & histologia , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/deficiência , Proteínas Proto-Oncogênicas c-fos/genética , Comportamento Social , Estresse Psicológico
6.
PLoS One ; 15(8): e0238373, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866215

RESUMO

The term "retroactive avoidance" refers to a special class of effects of future stimulus presentations on past behavioral responses. Specifically, it refers to the anticipatory avoidance of aversive stimuli that were unpredictable through random selection after the response. This phenomenon is supposed to challenge the common view of the arrow of time and the direction of causality. Preliminary evidence of "retroactive avoidance" has been published in mainstream psychological journals and started a heated debate about the robustness and the true existence of this effect. A series of seven experiments published in 2014 in the Journal of Consciousness Studies (Maier et al., 2014) tested the influence of randomly drawn future negative picture presentations on avoidance responses based on key presses preceding them. The final study in that series used a sophisticated quantum-based random stimulus selection procedure and implemented the most severe test of retroactive avoidance within this series. Evidence for the effect, though significant, was meager and anecdotal, Bayes factor (BF10) = 2. The research presented here represents an attempt to exactly replicate the original effect with a high-power (N = 2004) preregistered multi-lab study. The results indicate that the data favored the null effect (i.e., absence of retroactive avoidance) with a BF01 = 4.38. Given the empirical strengths of the study, namely its preregistration, multi-lab approach, high power, and Bayesian analysis used, this failed replication questions the validity and robustness of the original findings. Not reaching a decisive level of Bayesian evidence and not including skeptical researchers may be considered limitations of this study. Exploratory analyses of the change in evidence for the effect across time, performed on a post-hoc basis, revealed several potentially interesting anomalies in the data that might guide future research in this area.


Assuntos
Aprendizagem da Esquiva/fisiologia , Encéfalo/fisiologia , Estudantes/psicologia , Adulto , Teorema de Bayes , Feminino , Humanos , Masculino , Adulto Jovem
7.
Nat Commun ; 11(1): 4220, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839437

RESUMO

Post-traumatic stress disorder (PTSD) is characterized by emotional hypermnesia on which preclinical studies focus so far. While this hypermnesia relates to salient traumatic cues, partial amnesia for the traumatic context can also be observed. Here, we show in mice that contextual amnesia is causally involved in PTSD-like memory formation, and that treating the amnesia by re-exposure to all trauma-related cues cures PTSD-like hypermnesia. These findings open a therapeutic perspective based on trauma contextualization and the underlying hippocampal mechanisms.


Assuntos
Amnésia/prevenção & controle , Amnésia/terapia , Condicionamento Psicológico/fisiologia , Memória/fisiologia , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Transtornos de Estresse Pós-Traumáticos/terapia , Amnésia/fisiopatologia , Animais , Aprendizagem da Esquiva/fisiologia , Sinais (Psicologia) , Emoções , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transtornos de Estresse Pós-Traumáticos/fisiopatologia
8.
Neuron ; 107(4): 717-730.e5, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32562662

RESUMO

The prelimbic (PL) area and basolateral amygdala (lateral [LA] and basolateral [BL] nuclei) have closely related functions and similar extrinsic connectivity. Reasoning that the computational advantage of such redundancy should be reflected in differences in how these structures represent information, we compared the coding properties of PL and amygdala neurons during a task that requires rats to produce different conditioned defensive or appetitive behaviors. Rather than unambiguous regional differences in the identities of the variables encoded, we found gradients in how the same variables are represented. Whereas PL and BL neurons represented many different parameters through minor variations in firing rates, LA cells coded fewer task features with stronger changes in activity. At the population level, whereas valence could be easily distinguished from amygdala activity, PL neurons could distinguish both valence and trial identity as well as or better than amygdala neurons. Thus, PL has greater representational capacity.


Assuntos
Potenciais de Ação/fisiologia , Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Comportamento Animal/fisiologia , Medo/fisiologia , Modelos Neurológicos , Vias Neurais/fisiologia , Ratos , Recompensa
9.
Sci Rep ; 10(1): 9476, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528048

RESUMO

Intraspecific floral colour polymorphism is a common trait of food deceptive orchids, which lure pollinators with variable, attractive signals, without providing food resources. The variable signals are thought to hinder avoidance learning of deceptive flowers by pollinators. Here, we analysed the cognitive mechanisms underlying the choice of free-flying stingless bees Scaptotrigona aff. depilis trained to visit a patch of artificial flowers that displayed the colours of Ionopsis utricularioides, a food deceptive orchid. Bees were trained in the presence of a non-rewarding colour and later tested with that colour vs. alternative colours. We simulated a discrete-polymorphism scenario with two distinct non-rewarding test colours, and a continuous-polymorphism scenario with three non-rewarding test colours aligned along a chromatic continuum. Bees learned to avoid the non-rewarding colour experienced during training. They thus preferred the novel non-rewarding colour in the discrete-polymorphic situation, and generalized their avoidance to the adjacent colour of the continuum in the continuous-polymorphism situation, favouring thereby the most distant colour. Bees also visited less flowers and abandoned faster a non-rewarding monomorphic patch than a non-rewarding polymorphic patch. Our cognitive analyses thus reveal that variable deceptive orchids disrupt avoidance learning by pollinators and exploit their generalization abilities, which make them favour distinct morphs.


Assuntos
Abelhas/fisiologia , Cognição/fisiologia , Comportamento Alimentar/fisiologia , Polinização/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Cor , Flores/fisiologia , Orchidaceae/fisiologia , Pólen/fisiologia
10.
PLoS One ; 15(6): e0233441, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502175

RESUMO

This paper employs a solution to the agent-guidance problem in an environment with obstacles, whose avoidance techniques have been extensively used in the last years. There is still a gap between the solution times required to obtain a trajectory and those demanded by real world applications. These usually face a tradeoff between the limited on-board processing performance and the high volume of computing operations demanded by those real-time applications. In this paper we propose a deferred decision-based technique that produces clusters used for obstacle avoidance as the agent moves in the environment, like a driver that, at night, enlightens the road ahead as her/his car moves along a highway. By considering the spatial and temporal relevance of each obstacle throughout the planning process and pruning areas that belong to the constrained domain, one may relieve the inherent computational burden of avoidance. This strategy reduces the number of operations required and increases it on demand, since a computationally heavier problem is tackled only if the simpler ones are not feasible. It consists in an improvement based solely on problem modeling, which, by example, may offer processing times in the same order of magnitude than the lower-bound given by the relaxed form of the problem.


Assuntos
Automação/métodos , Previsões/métodos , Aprendizagem da Esquiva/fisiologia , Simulação por Computador , Locomoção , Movimento (Física) , Programação Linear , Software
11.
J Neurosci ; 40(23): 4551-4564, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32350040

RESUMO

Forming effective responses to threatening stimuli requires the adequate and coordinated emergence of stress-related internal states. Such ability depends on early-life experiences and, in connection, the adequate formation of neuromodulatory systems, particularly serotonergic signaling. Here, we assess the serotonergic background of experience-dependent behavioral responsiveness using male and female zebrafish (Danio rerio). For the first time, we have characterized a period during behavioral metamorphosis in which zebrafish are highly reactive to their environment. Absence of social stimuli during this phase established by isolated rearing fundamentally altered the behavioral phenotype of postmetamorphic zebrafish in a challenge-specific manner, partially due to reduced responsiveness and an inability to develop stress-associated arousal state. In line with this, isolation differentially affected whole-brain serotonergic signaling in resting and stress-induced conditions, an effect that was localized in the dorsal pallium and was negatively associated with responsiveness. Administration of the serotonin receptor 1A partial agonist buspirone prevented the isolation-induced serotonin response to novelty in the level of the whole brain and the forebrain as well, without affecting catecholamine levels, and rescued stress-induced arousal along with challenge-induced behaviors, which together indicates functional connection between these changes. In summary, there is a consistent negative association between behavioral responsiveness and serotonergic signaling in zebrafish, which is well recognizable through the modifying effects of developmental perturbation and pharmacological manipulations as well. Our results imply a conserved serotonergic mechanism that context-dependently modulates environmental reactivity and is highly sensitive to experiences acquired during a specific early-life time window, a phenomenon that was previously only suggested in mammals.SIGNIFICANCE STATEMENT The ability to respond to challenges is a fundamental factor in survival. We show that zebrafish that lack appropriate social stimuli in a sensitive developmental period show exacerbated alertness in nonstressful conditions while failing to react adequately to stressors. This shift is reflected inversely by central serotonergic signaling, a system that is implicated in numerous mental disorders in humans. Serotonergic changes in brain regions modulating responsivity and behavioral impairment were both prevented by the pharmacological blockade of serotonergic function. These results imply a serotonergic mechanism in zebrafish that transmits early-life experiences to the later phenotype by shaping stress-dependent behavioral reactivity, a phenomenon that was previously only suggested in mammals. Zebrafish provide new insights into early-life-dependent neuromodulation of behavioral stress-responses.


Assuntos
Nível de Alerta/fisiologia , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Receptor 5-HT1A de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/fisiologia , Animais , Nível de Alerta/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Feminino , Masculino , Isolamento Social/psicologia , Peixe-Zebra
12.
Nat Commun ; 11(1): 2076, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350283

RESUMO

Learning and memory are regulated by neuromodulatory pathways, but the contribution and temporal requirement of most neuromodulators in a learning circuit are unknown. Here we identify the evolutionarily conserved neuromedin U (NMU) neuropeptide family as a regulator of C. elegans gustatory aversive learning. The NMU homolog CAPA-1 and its receptor NMUR-1 are required for the retrieval of learned salt avoidance. Gustatory aversive learning requires the release of CAPA-1 neuropeptides from sensory ASG neurons that respond to salt stimuli in an experience-dependent manner. Optogenetic silencing of CAPA-1 neurons blocks the expression, but not the acquisition, of learned salt avoidance. CAPA-1 signals through NMUR-1 in AFD sensory neurons to modulate two navigational strategies for salt chemotaxis. Aversive conditioning thus recruits NMU signaling to modulate locomotor programs for expressing learned avoidance behavior. Because NMU signaling is conserved across bilaterian animals, our findings incite further research into its function in other learning circuits.


Assuntos
Aprendizagem da Esquiva/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Rede Nervosa/fisiologia , Neuropeptídeos/metabolismo , Transdução de Sinais , Cloreto de Sódio/efeitos adversos , Paladar/fisiologia , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Comportamento Animal , Proteínas de Caenorhabditis elegans/química , Cálcio/metabolismo , Alimentos , Modelos Biológicos , Mutação/genética , Filogenia , Células Receptoras Sensoriais/fisiologia
13.
PLoS Biol ; 18(5): e3000674, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32396574

RESUMO

Animals use auditory cues generated by defensive responses of others to detect impending danger. Here we identify a neural circuit in rats involved in the detection of one such auditory cue, the cessation of movement-evoked sound resulting from freezing. This circuit comprises the dorsal subnucleus of the medial geniculate body (MGD) and downstream areas, the ventral area of the auditory cortex (VA), and the lateral amygdala (LA). This study suggests a role for the auditory offset pathway in processing a natural sound cue of threat.


Assuntos
Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Corpos Geniculados/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Sinais (Psicologia) , Masculino , Ratos Sprague-Dawley
14.
J Neurosci ; 40(24): 4773-4787, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393535

RESUMO

Flexible initiation or suppression of actions to avoid aversive events is crucial for survival. The prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex (mPFC) have been implicated in different aspects of avoidance and reward-seeking, but their respective contribution in instigating versus suppressing actions in aversive contexts remains to be clarified. We examined mPFC involvement in different forms of avoidance in rats well trained on different cued lever-press avoidance tasks. Active/inhibitory avoidance required flexible discrimination between auditory cues signaling foot-shock could be avoided by making or withholding instrumental responses. On a simpler active avoidance task, a single cue signaled when a lever press would avoid shock. PL inactivation disrupted active but not inhibitory avoidance on the discriminative task while having no effect on single-cued avoidance. In comparison, IL inactivation broadly impaired active and inhibitory avoidance. Conversely, on a cued appetitive go/no-go task, both IL and PL inactivation impaired inhibitory but not active reward-seeking, the latter effect being diametrically opposite to that observed on the avoidance task. These findings highlight the complex manner in which different mPFC regions aid in initiating or inhibiting actions in the service of avoiding aversive outcomes or obtaining rewarding ones. IL facilitates active avoidance but suppress inappropriate actions in appetitive and aversive contexts. In contrast, contextual valence plays a critical role in how the PL is recruited in initiating or suppressing actions, which may relate to the degree of cognitive control required to flexibly negotiate response or motivational conflicts and override prepotent behaviors.SIGNIFICANCE STATEMENT Choosing to make or withhold actions in a context-appropriate manner to avoid aversive events or obtain other goals is a critical survival skill. Different medial prefrontal cortex (mPFC) regions have been implicated in certain aspects of avoidance, but their contributions to instigating or suppressing actions remains to be clarified. Here, we show that the dorsal, prelimbic (PL) region of the medial PFC aids active avoidance in situations requiring flexible mitigation of response conflicts, but also aids in withholding responses to obtain rewards. In comparison the ventral infralimbic (IL) cortex plays a broader role in active and inhibitory avoidance as well as suppressing actions to obtain rewards. These findings provide insight into mechanisms underlying normal and maladaptive avoidance behaviors and response inhibition.


Assuntos
Aprendizagem da Esquiva/fisiologia , Cognição/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Animais , Condicionamento Operante/fisiologia , Sinais (Psicologia) , Extinção Psicológica/fisiologia , Masculino , Ratos , Ratos Long-Evans
15.
Neuron ; 106(6): 1026-1043.e9, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32294466

RESUMO

The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice. CeA→SNL neural responses to appetitive and aversive stimuli were modulated by expectation and magnitude consistent with a population-level salience signal, which was required for Pavlovian conditioned reward-seeking and defensive behaviors. CeA→SNL terminal activation elicited reinforcement when linked to voluntary actions but failed to support Pavlovian associations that rely on incentive value signals. Consistent with a disinhibitory mechanism, CeA inputs preferentially target SNL GABA neurons, and CeA→SNL and SNL dopamine neurons respond similarly to salient stimuli. Collectively, our results suggest that amygdala-nigra interactions represent a previously unappreciated mechanism for influencing emotional behaviors.


Assuntos
Comportamento Apetitivo/fisiologia , Aprendizagem da Esquiva/fisiologia , Núcleo Central da Amígdala/fisiologia , Neurônios Dopaminérgicos/fisiologia , Neurônios GABAérgicos/fisiologia , Substância Negra/fisiologia , Animais , Condicionamento Clássico/fisiologia , Emoções , Camundongos , Vias Neurais , Reforço Psicológico , Recompensa , Substância Negra/citologia
16.
Neural Netw ; 127: 96-109, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32335415

RESUMO

The reconsolidation and extinction of aversive memories and their boundary conditions have been extensively studied. Knowing their network mechanisms may lead to the development of better strategies for the treatment of fear and anxiety-related disorders. In 2011, Osan et al. developed a computational model for exploring such phenomena based on attractor dynamics, Hebbian plasticity and synaptic degradation induced by prediction error. This model was able to explain, in a single formalism, experimental findings regarding the freezing behavior of rodents submitted to contextual fear conditioning. In 2017, through the study of inhibitory avoidance in rats, Radiske et al. showed that the previous knowledge of a context as non-aversive is a boundary condition for the reconsolidation of the shock memory subsequently experienced in that context. In the present work, by adapting the model of Osan et al. (2011) to simulate the experimental protocols of Radiske et al. (2017), we show that such boundary condition is compatible with the dynamics of an attractor network that supports synaptic labilization common to reconsolidation and extinction. Additionally, by varying parameters such as the levels of protein synthesis and degradation, we predict behavioral outcomes, and thus boundary conditions that can be tested experimentally.


Assuntos
Aprendizagem da Esquiva , Consolidação da Memória , Redes Neurais de Computação , Animais , Aprendizagem da Esquiva/fisiologia , Medo/fisiologia , Medo/psicologia , Humanos , Masculino , Consolidação da Memória/fisiologia , Ratos
17.
J Neurosci ; 40(21): 4219-4229, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32303647

RESUMO

In Drosophila, the mushroom bodies (MB) constitute the central brain structure for olfactory associative memory. As in mammals, the cAMP/PKA pathway plays a key role in memory formation. In the MB, Rutabaga (Rut) adenylate cyclase acts as a coincidence detector during associative conditioning to integrate calcium influx resulting from acetylcholine stimulation and G-protein activation resulting from dopaminergic stimulation. Amnesiac encodes a secreted neuropeptide required in the MB for two phases of aversive olfactory memory. Previous sequence analysis has revealed strong homology with the mammalian pituitary adenylate cyclase-activating peptide (PACAP). Here, we examined whether amnesiac is involved in cAMP/PKA dynamics in response to dopamine and acetylcholine co-stimulation in living flies. Experiments were conducted with both sexes, or with either sex. Our data show that amnesiac is necessary for the PKA activation process that results from coincidence detection in the MB. Since PACAP peptide is cleaved by the human membrane neprilysin hNEP, we searched for an interaction between Amnesiac and Neprilysin 1 (Nep1), a fly neprilysin involved in memory. We show that when Nep1 expression is acutely knocked down in adult MB, memory deficits displayed by amn hypomorphic mutants are rescued. Consistently, Nep1 inhibition also restores normal PKA activation in amn mutant flies. Taken together, the results suggest that Nep1 targets Amnesiac degradation to terminate its signaling function. Our work thus highlights a key role for Amnesiac in establishing within the MB the PKA dynamics that sustain middle-term memory (MTM) formation, a function modulated by Nep1.SIGNIFICANCE STATEMENT The Drosophila amnesiac gene encodes a secreted neuropeptide whose expression is required for specific memory phases in the mushroom bodies (MB), the olfactory memory center. Here, we show that Amnesiac is required for PKA activation resulting from coincidence detection, a mechanism by which the MB integrate two spatially distinct stimuli to encode associative memory. Furthermore, our results uncover a functional relationship between Amnesiac and Neprilysin 1 (Nep1), a membrane peptidase involved in memory and expressed in the MB. These results suggest that Nep1 modulates Amnesiac levels. We propose that on conditioning, Amnesiac release from the MB allows, via an autocrine process, the sustaining of PKA activation-mediating memory, which subsequently is inactivated by Nep1 degradation.


Assuntos
Aprendizagem da Esquiva/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Drosophila/genética , Memória/fisiologia , Corpos Pedunculados/metabolismo , Neprilisina/metabolismo , Neuropeptídeos/genética , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Neuropeptídeos/metabolismo , Olfato/fisiologia
18.
Neuron ; 106(6): 977-991.e4, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32289250

RESUMO

Forming long-term memory (LTM) often requires repetitive experience spread over time. Studies in Drosophila suggest aversive olfactory LTM is optimal after spaced training, multiple trials of differential odor conditioning with rest intervals. Memory after spaced training is frequently compared to that after the same number of trials without intervals. Here we show that, after spaced training, flies acquire additional information and form an aversive memory for the shock-paired odor and a slowly emerging and more persistent "safety-memory" for the explicitly unpaired odor. Safety-memory acquisition requires repetition, order, and spacing of the training trials and relies on triggering specific rewarding dopaminergic neurons. Co-existence of aversive and safety memories is evident as depression of odor-specific responses at different combinations of junctions in the mushroom body output network; combining two outputs appears to signal relative safety. Having complementary aversive and safety memories augments LTM performance after spaced training by making the odor preference more certain.


Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico/fisiologia , Memória de Longo Prazo/fisiologia , Neurônios/fisiologia , Odorantes , Segurança , Animais , Neurônios Dopaminérgicos/fisiologia , Drosophila melanogaster , Corpos Pedunculados/fisiologia , Olfato , Fatores de Tempo
19.
Neuron ; 106(6): 927-939.e5, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32289251

RESUMO

The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.


Assuntos
Aprendizagem da Esquiva/fisiologia , Reação de Fuga/fisiologia , Nociceptividade/fisiologia , Núcleos Parabraquiais/fisiologia , Animais , Núcleo Central da Amígdala/fisiologia , Camundongos , Vias Neurais/fisiologia , Neurônios Eferentes/fisiologia , Optogenética , Dor , Substância Cinzenta Periaquedutal/fisiologia , Núcleos Septais/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia
20.
J Psychosom Res ; 133: 110100, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32224346

RESUMO

OBJECTIVE: Emotional difficulties are common in functional movement disorders (FMD), yet their contribution to the disease remains unclear. We explored the potential role of emotional difficulties as risk and maintaining factors of FMD by looking at the effect of emotions on attention. METHOD: The dot-probe task was used to investigate attentional biases induced by emotional faces in 25 patients with FMD and 25 healthy controls (HC). A pair of faces, one emotional (happy, angry, sad) and the other neutral, was displayed on a monitor to either the left or the right side of a central fixation cross. The face disappeared and a dot was flashed in place of one of the faces. Participants had to indicate the location of the dot. All participants completed the Toronto Alexithymia Scale. Psychological assessment of 23 patients also involved the Short Form Health Survey, the Hamilton Anxiety and the Hamilton Depression Rating Scales. RESULTS: A general attentional bias away from emotional faces was noted for the FMD group compared to the HC. A more fine-tuned analysis revealed an attentional bias specifically away from sad faces for the FMD. CONCLUSION: Our findings suggest a specific effect of emotions on attention in FMD that likely involves avoidance of sadness. Since this was not related to alexithymia or mood, we excluded these factors in explaining the results. Attentional bias away from sad faces correlated with general health, suggesting that avoidance of sadness might contribute to the perception of a better general health status in FMD.


Assuntos
Aprendizagem da Esquiva/fisiologia , Emoções , Transtornos dos Movimentos/psicologia , Adulto , Afeto , Sintomas Afetivos/complicações , Atenção , Expressão Facial , Feminino , Humanos , Masculino , Transtornos dos Movimentos/complicações , Adulto Jovem
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