RESUMO
Our immune system and brain interact on multiple scales, but how the brain represents and remembers immune challenges remains unclear. In this issue of Cell, Koren et al. (2021) reveal that the brain's insular cortex stores information about inflammation in the body. Strikingly, these immunological "memory engrams" can restore the initial disease state when reactivated.
Assuntos
Encéfalo , Córtex Insular , Humanos , Sistema Imunitário , InflamaçãoRESUMO
Emotions are fundamental to our experience and behavior, affecting and motivating all aspects of our lives. Scientists of various disciplines have been fascinated by emotions for centuries, yet even today vigorous debates abound about how to define emotions and how to best study their neural underpinnings. Defining emotions from an evolutionary perspective and acknowledging their important functional roles in supporting survival allows the study of emotion states in diverse species. This approach enables taking advantage of modern tools in behavioral, systems, and circuit neurosciences, allowing the precise dissection of neural mechanisms and behavior underlying emotion processes in model organisms. Here we review findings about the neural circuit mechanisms underlying emotion processing across species and try to identify points of convergence as well as important next steps in the pursuit of understanding how emotions emerge from neural activity.
Assuntos
Emoções , Neurociências , Evolução Biológica , EncéfaloRESUMO
Neuroscientists studying the neural correlates of mouse behavior often lack access to the brain-wide activity patterns elicited during a specific task of interest. Fortunately, large-scale imaging is becoming increasingly accessible thanks to modalities such as Ca2+ imaging and functional ultrasound (fUS). However, these and other techniques often involve challenging cranial window procedures and are difficult to combine with other neuroscience tools. We address this need with an open-source 3D-printable cranial implant-the COMBO (ChrOnic Multimodal imaging and Behavioral Observation) window. The COMBO window enables chronic imaging of large portions of the brain in head-fixed mice while preserving orofacial movements. We validate the COMBO window stability using both brain-wide fUS and multisite two-photon imaging. Moreover, we demonstrate how the COMBO window facilitates the combination of optogenetics, fUS, and electrophysiology in the same animals to study the effects of circuit perturbations at both the brain-wide and single-neuron level. Overall, the COMBO window provides a versatile solution for performing multimodal brain recordings in head-fixed mice.
Assuntos
Encéfalo , Optogenética , Animais , Camundongos , Encéfalo/fisiologia , Encéfalo/diagnóstico por imagem , Optogenética/métodos , Neurônios/fisiologia , Camundongos Endogâmicos C57BL , Crânio/fisiologia , Masculino , Comportamento Animal/fisiologia , Imagem Multimodal/métodos , Ultrassonografia/métodos , Impressão TridimensionalRESUMO
Orexins (also called hypocretins) are hypothalamic neuropeptides that carry out essential functions in the central nervous system; however, little is known about their release and range of action in vivo owing to the limited resolution of current detection technologies. Here we developed a genetically encoded orexin sensor (OxLight1) based on the engineering of circularly permutated green fluorescent protein into the human type-2 orexin receptor. In mice OxLight1 detects optogenetically evoked release of endogenous orexins in vivo with high sensitivity. Photometry recordings of OxLight1 in mice show rapid orexin release associated with spontaneous running behavior, acute stress and sleep-to-wake transitions in different brain areas. Moreover, two-photon imaging of OxLight1 reveals orexin release in layer 2/3 of the mouse somatosensory cortex during emergence from anesthesia. Thus, OxLight1 enables sensitive and direct optical detection of orexin neuropeptides with high spatiotemporal resolution in living animals.
Assuntos
Encéfalo/metabolismo , Imagem Molecular/métodos , Receptores de Orexina/genética , Orexinas/análise , Proteínas Recombinantes/metabolismo , Animais , Comportamento Animal , Feminino , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Receptores de Orexina/metabolismo , Orexinas/genética , Orexinas/farmacologia , Fótons , Proteínas Recombinantes/genética , Reprodutibilidade dos Testes , Sono/fisiologiaRESUMO
Socioemotional behaviors rely on the integration of information across multiple systems in the brain. In this issue of Neuron, Mague et al. (2022) characterize a multi-regional functional network that coordinates positively valenced social interactions in mice.
Assuntos
Encéfalo , Comportamento Social , Animais , Comportamento Apetitivo/fisiologia , Encéfalo/fisiologia , Camundongos , NeurôniosRESUMO
Animal behavior is shaped by a variety of "internal states"-partially hidden variables that profoundly shape perception, cognition, and action. The neural basis of internal states, such as fear, arousal, hunger, motivation, aggression, and many others, is a prominent focus of research efforts across animal phyla. Internal states can be inferred from changes in behavior, physiology, and neural dynamics and are characterized by properties such as pleiotropy, persistence, scalability, generalizability, and valence. To date, it remains unclear how internal states and their properties are generated by nervous systems. Here, we review recent progress, which has been driven by advances in behavioral quantification, cellular manipulations, and neural population recordings. We synthesize research implicating defined subsets of state-inducing cell types, widespread changes in neural activity, and neuromodulation in the formation and updating of internal states. In addition to highlighting the significance of these findings, our review advocates for new approaches to clarify the underpinnings of internal brain states across the animal kingdom.
Assuntos
Comportamento Animal , Encéfalo , Animais , Nível de Alerta , Encéfalo/fisiologia , Cognição , MotivaçãoRESUMO
What are emotions and how should we study them? These questions give rise to ongoing controversy amongst scientists in the fields of neuroscience, psychology and philosophy, and have resulted in different views on emotions [1-6]. In this review, we define emotions as functional states that bear essential roles in promoting survival and thus have emerged through evolution. Emotions trigger behavioral, somatic, hormonal, and neurochemical reactions, referred to as expressions of emotion. We discuss recent studies on emotion expression across species and highlight emerging common principles. We argue that detailed and multidimensional analyses of emotion expressions are key to develop biology-based definitions of emotions and to reveal their neuronal underpinnings.
Assuntos
Expressão Facial , Neurociências , Emoções , NeurôniosRESUMO
How does the brain maintain fear within an adaptive range? We found that the insular cortex acts as a state-dependent regulator of fear that is necessary to establish an equilibrium between the extinction and maintenance of fear memories in mice. Whereas insular cortex responsiveness to fear-evoking cues increased with their certainty to predict harm, this activity was attenuated through negative bodily feedback that arose from heart rate decelerations during freezing. Perturbation of body-brain communication by vagus nerve stimulation disrupted the balance between fear extinction and maintenance similar to insular cortex inhibition. Our data reveal that the insular cortex integrates predictive sensory and interoceptive signals to provide graded and bidirectional teaching signals that gate fear extinction and illustrate how bodily feedback signals are used to maintain fear within a functional equilibrium.
Assuntos
Medo , Retroalimentação Fisiológica , Córtex Insular/fisiologia , Animais , Condicionamento Clássico , Sinais (Psicologia) , Extinção Psicológica , Frequência Cardíaca , Interocepção , Masculino , Rememoração Mental , Camundongos , Camundongos Endogâmicos C57BL , Nervo Vago/fisiologiaRESUMO
We investigated rearrangements of connectivity between hippocampal mossy fibers and CA3 pyramidal neurons. We found that mossy fibers establish 10-15 local terminal arborization complexes (LMT-Cs) in CA3, which exhibit major differences in size and divergence in adult mice. LMT-Cs exhibited two types of long-term rearrangements in connectivity in the adult: progressive expansion of LMT-C subsets along individual dendrites throughout life, and pronounced increases in LMT-C complexities in response to an enriched environment. In organotypic slice cultures, subsets of LMT-Cs also rearranged extensively and grew over weeks and months, altering the strength of preexisting connectivity, and establishing or dismantling connections with pyramidal neurons. Differences in LMT-C plasticity reflected properties of individual LMT-Cs, not mossy fibers. LMT-C maintenance and growth were regulated by spiking activity, mGluR2-sensitive transmitter release from LMTs, and PKC. Thus, subsets of terminal arborization complexes by mossy fibers rearrange their local connectivities in response to experience and age throughout life.
Assuntos
Fibras Nervosas/fisiologia , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Células Piramidais/citologia , Fatores Etários , Animais , Dendritos/fisiologia , Abrigo para Animais , Potenciação de Longa Duração/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de ÓrgãosRESUMO
Understanding the neurobiological underpinnings of emotion relies on objective readouts of the emotional state of an individual, which remains a major challenge especially in animal models. We found that mice exhibit stereotyped facial expressions in response to emotionally salient events, as well as upon targeted manipulations in emotion-relevant neuronal circuits. Facial expressions were classified into distinct categories using machine learning and reflected the changing intrinsic value of the same sensory stimulus encountered under different homeostatic or affective conditions. Facial expressions revealed emotion features such as intensity, valence, and persistence. Two-photon imaging uncovered insular cortical neuron activity that correlated with specific facial expressions and may encode distinct emotions. Facial expressions thus provide a means to infer emotion states and their neuronal correlates in mice.
Assuntos
Córtex Cerebral/fisiologia , Emoções/fisiologia , Expressão Facial , Vias Neurais/fisiologia , Neurônios/fisiologia , Animais , Córtex Cerebral/citologia , Masculino , CamundongosRESUMO
The insular cortex (IC) plays key roles in emotional and regulatory brain functions and is affected across psychiatric diseases. However, the brain-wide connections of the mouse IC have not been comprehensively mapped. Here, we traced the whole-brain inputs and outputs of the mouse IC across its rostro-caudal extent. We employed cell-type-specific monosynaptic rabies virus tracings to characterize afferent connections onto either excitatory or inhibitory IC neurons, and adeno-associated viral tracings to label excitatory efferent axons. While the connectivity between the IC and other cortical regions was highly bidirectional, the IC connectivity with subcortical structures was often unidirectional, revealing prominent cortical-to-subcortical or subcortical-to-cortical pathways. The posterior and medial IC exhibited resembling connectivity patterns, while the anterior IC connectivity was distinct, suggesting two major functional compartments. Our results provide insights into the anatomical architecture of the mouse IC and thus a structural basis to guide investigations into its complex functions.
Assuntos
Mapeamento Encefálico , Córtex Cerebral/anatomia & histologia , Camundongos/anatomia & histologia , Neurônios/citologia , Animais , Feminino , MasculinoRESUMO
There is now conclusive evidence for widespread ongoing structural plasticity of presynaptic boutons and axon side-branches in the adult brain. The plasticity complements that of postsynaptic spines, but axonal plasticity samples larger volumes of neuropil, and has a larger impact on circuit remodeling. Axons from distinct neurons exhibit unique ratios of stable (t1/2>9 months) and dynamic (t1/2 5-20 days) boutons, which persist as spatially intermingled subgroups along terminal arbors. In addition, phases of side-branch dynamics mediate larger scale remodeling guided by synaptogenesis. The plasticity is most pronounced during critical periods; its patterns and outcome are controlled by Hebbian mechanisms and intrinsic neuronal factors. Novel experience, skill learning, life-style, and age can persistently modify local circuit structure through axonal structural plasticity.
Assuntos
Encéfalo/citologia , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Terminações Pré-Sinápticas/fisiologia , AnimaisRESUMO
Triggering behavioral adaptation upon the detection of adversity is crucial for survival. The insular cortex has been suggested to process emotions and homeostatic signals, but how the insular cortex detects internal states and mediates behavioral adaptation is poorly understood. By combining data from fiber photometry, optogenetics, awake two-photon calcium imaging and comprehensive whole-brain viral tracings, we here uncover a role for the posterior insula in processing aversive sensory stimuli and emotional and bodily states, as well as in exerting prominent top-down modulation of ongoing behaviors in mice. By employing projection-specific optogenetics, we describe an insula-to-central amygdala pathway to mediate anxiety-related behaviors, while an independent nucleus accumbens-projecting pathway regulates feeding upon changes in bodily state. Together, our data support a model in which the posterior insular cortex can shift behavioral strategies upon the detection of aversive internal states, providing a new entry point to understand how alterations in insula circuitry may contribute to neuropsychiatric conditions.
Assuntos
Adaptação Fisiológica/fisiologia , Comportamento Animal/fisiologia , Córtex Cerebral/fisiologia , Vias Neurais/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Whether you see the person you are in love with, try to listen to your own heartbeat, suffer from a headache, or crave for a chocolate cookie, one part of your brain is sure to increase its activity strongly: the insular cortex. The insular cortex, or 'insula' for short, is part of the cerebral cortex. J.C. Reil, a German neurologist, first named this brain structure in the early 19th century. Subsequent research findings have implicated the insula in an overwhelming variety of functions ranging from sensory processing to representing feelings and emotions, autonomical and motor control, risk prediction and decision-making, bodily- and self-awareness, and complex social functions like empathy. How is one single brain area involved in so many different tasks? Is the insula comprised of several functional regions? How are these related? And, are there any common themes underlying the apparently so heterogeneous roles of the insula?
Assuntos
Córtex Cerebral/anatomia & histologia , Córtex Cerebral/fisiologia , Vias Neurais/fisiologia , Córtex Cerebral/fisiopatologia , Humanos , Transtornos Mentais/fisiopatologia , Vias Neurais/fisiopatologiaRESUMO
Insular cortex (IC) contributes to a variety of complex brain functions, such as communication, social behavior, and self-awareness through the integration of sensory, emotional, and cognitive content. How the IC acquires its integrative properties remains unexplored. We compared the emergence of multisensory integration (MSI) in the IC of behaviorally distinct mouse strains. While adult C57BL/6 mice exhibited robust MSI, this capacity was impaired in the inbred BTBR T+tf/J mouse model of idiopathic autism. The deficit reflected weakened γ-aminobutyric acid (GABA) circuits and compromised postnatal pruning of cross-modal input. Transient pharmacological enhancement by diazepam in BTBR mice during an early sensitive period rescued inhibition and integration in the adult IC. Moreover, impaired MSI was common across three other monogenic models (GAD65, Shank3, and Mecp2 knockout mice) displaying behavioral phenotypes and parvalbumin-circuit abnormalities. Our findings offer developmental insight into a key neural circuit relevant to neuropsychiatric conditions like schizophrenia and autism.
Assuntos
Córtex Cerebral/fisiologia , Neurônios GABAérgicos/fisiologia , Vias Neurais/crescimento & desenvolvimento , Sensação/fisiologia , Animais , Transtorno Autístico/genética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/crescimento & desenvolvimento , Diazepam/farmacologia , Modelos Animais de Doenças , Neurônios GABAérgicos/efeitos dos fármacos , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/fisiologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/fisiologia , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Sensação/efeitos dos fármacos , Sensação/genética , Especificidade da EspécieRESUMO
In adult animals, fear conditioning induces a permanent memory that is resilient to erasure by extinction. In contrast, during early postnatal development, extinction of conditioned fear leads to memory erasure, suggesting that fear memories are actively protected in adults. We show here that this protection is conferred by extracellular matrix chondroitin sulfate proteoglycans (CSPGs) in the amygdala. The organization of CSPGs into perineuronal nets (PNNs) coincided with the developmental switch in fear memory resilience. In adults, degradation of PNNs by chondroitinase ABC specifically rendered subsequently acquired fear memories susceptible to erasure. This result indicates that intact PNNs mediate the formation of erasure-resistant fear memories and identifies a molecular mechanism closing a postnatal critical period during which traumatic memories can be erased by extinction.
Assuntos
Tonsila do Cerebelo/fisiologia , Proteoglicanas de Sulfatos de Condroitina/fisiologia , Extinção Psicológica , Medo , Memória/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/crescimento & desenvolvimento , Animais , Condroitina ABC Liase/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Condicionamento Clássico , Sinais (Psicologia) , Matriz Extracelular/fisiologia , Aprendizagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade NeuronalRESUMO
We investigated how experience regulates the structure of a defined neuronal circuit in adult mice. Enriched environment (EE) produced a robust and reversible increase in hippocampal stratum lucidum synapse numbers, mossy fiber terminal (LMT) numbers, and spine plus synapse densities at LMTs, whereas a distinct mechanism depending on Rab3a promoted LMT volume growth. In parallel, EE increased postsynaptic CA3 pyramidal neuron Wnt7a/b levels. Inhibiting Wnt signaling through locally applied sFRP-1 suppressed the effects of EE on synapse numbers and further reduced synapse numbers in control mice. Wnt7 applied to CA3 mimicked the effects of EE on synapse and LMT numbers. CA3 Wnt7a/b levels were enhanced by excitatory activity and reduced by sFRP-1. Synapse numbers and Wnt7a/b levels peaked in mice aged 6-12 months; a decline in aged mice was reversed by EE. Therefore, behavioral experience specifically regulates adult global stratum lucidum synapse numbers and hippocampal network structure through Wnt signaling.