RESUMO
Animals traversing different environments encounter both stable background stimuli and novel cues, which are thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Here, we show that each of the â¼1,000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of more than 70 genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional rheostat whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.
Assuntos
Neurônios Receptores Olfatórios/metabolismo , Sensação/genética , Transcrição Gênica , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Odorantes , Bulbo Olfatório/metabolismo , Receptores Odorantes/metabolismo , Transcriptoma/genéticaRESUMO
Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.
Assuntos
Microglia/metabolismo , Inibição Neural/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal , Regulação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Parvalbuminas/metabolismo , Fenótipo , Receptores de GABA-B/metabolismo , Sinapses/fisiologia , Transcrição GênicaRESUMO
Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here, we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time.
Assuntos
Comportamento Animal , Corpo Estriado/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Cálcio/metabolismo , Corpo Estriado/efeitos dos fármacos , Eletrodos Implantados , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fotometria , Receptores de Dopamina D1/deficiência , Receptores de Dopamina D1/genéticaRESUMO
Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein-coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the "necklace" subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here, we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically relevant ligands, including pheromones and fatty acids, in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.
Assuntos
Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Olfato , Animais , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Odorantes , Neurônios Receptores Olfatórios/metabolismo , FilogeniaRESUMO
Anosmia, the loss of the sense of smell, is one of the main neurological manifestations of COVID-19. Although the SARS-CoV-2 virus targets the nasal olfactory epithelium, current evidence suggests that neuronal infection is extremely rare in both the olfactory periphery and the brain, prompting the need for mechanistic models that can explain the widespread anosmia in COVID-19 patients. Starting from work identifying the non-neuronal cell types that are infected by SARS-CoV-2 in the olfactory system, we review the effects of infection of these supportive cells in the olfactory epithelium and in the brain and posit the downstream mechanisms through which sense of smell is impaired in COVID-19 patients. We propose that indirect mechanisms contribute to altered olfactory system function in COVID-19-associated anosmia, as opposed to neuronal infection or neuroinvasion into the brain. Such indirect mechanisms include tissue damage, inflammatory responses through immune cell infiltration or systemic circulation of cytokines, and downregulation of odorant receptor genes in olfactory sensory neurons in response to local and systemic signals. We also highlight key unresolved questions raised by recent findings.
Assuntos
Anosmia , COVID-19 , Anosmia/virologia , Humanos , COVID-19/complicações , Neurônios Receptores Olfatórios/fisiologia , Animais , SARS-CoV-2RESUMO
The olfactory system is an ideal and tractable system for exploring how the brain transforms sensory inputs into behaviour. The basic tasks of any olfactory system include odour detection, discrimination and categorization. The challenge for the olfactory system is to transform the high-dimensional space of olfactory stimuli into the much smaller space of perceived objects and valence that endows odours with meaning. Our current understanding of how neural circuits address this challenge has come primarily from observations of the mechanisms of the brain for processing other sensory modalities, such as vision and hearing, in which optimized deep hierarchical circuits are used to extract sensory features that vary along continuous physical dimensions. The olfactory system, by contrast, contends with an ill-defined, high-dimensional stimulus space and discrete stimuli using a circuit architecture that is shallow and parallelized. Here, we present recent observations in vertebrate and invertebrate systems that relate the statistical structure and state-dependent modulation of olfactory codes to mechanisms of perception and odour-guided behaviour.
Assuntos
Invertebrados , Odorantes , Condutos Olfatórios , Olfato , Vertebrados , Animais , Invertebrados/fisiologia , Vertebrados/fisiologia , Olfato/fisiologia , Humanos , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologiaRESUMO
Spontaneous animal behaviour is built from action modules that are concatenated by the brain into sequences1,2. However, the neural mechanisms that guide the composition of naturalistic, self-motivated behaviour remain unknown. Here we show that dopamine systematically fluctuates in the dorsolateral striatum (DLS) as mice spontaneously express sub-second behavioural modules, despite the absence of task structure, sensory cues or exogenous reward. Photometric recordings and calibrated closed-loop optogenetic manipulations during open field behaviour demonstrate that DLS dopamine fluctuations increase sequence variation over seconds, reinforce the use of associated behavioural modules over minutes, and modulate the vigour with which modules are expressed, without directly influencing movement initiation or moment-to-moment kinematics. Although the reinforcing effects of optogenetic DLS dopamine manipulations vary across behavioural modules and individual mice, these differences are well predicted by observed variation in the relationships between endogenous dopamine and module use. Consistent with the possibility that DLS dopamine fluctuations act as a teaching signal, mice build sequences during exploration as if to maximize dopamine. Together, these findings suggest a model in which the same circuits and computations that govern action choices in structured tasks have a key role in sculpting the content of unconstrained, high-dimensional, spontaneous behaviour.
Assuntos
Comportamento Animal , Reforço Psicológico , Recompensa , Animais , Camundongos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Sinais (Psicologia) , Optogenética , FotometriaRESUMO
Olfaction is fundamentally distinct from other sensory modalities. Natural odor stimuli are complex mixtures of volatile chemicals that interact in the nose with a receptor array that, in rodents, is built from more than 1,000 unique receptors. These interactions dictate a peripheral olfactory code, which in the brain is transformed and reformatted as it is broadcast across a set of highly interconnected olfactory regions. Here we discuss the problems of characterizing peripheral population codes for olfactory stimuli, of inferring the specific functions of different higher olfactory areas given their extensive recurrence, and of ultimately understanding how odor representations are linked to perception and action. We argue that, despite the differences between olfaction and other sensory modalities, addressing these specific questions will reveal general principles underlying brain function.
Assuntos
Encéfalo/fisiologia , Rede Nervosa/fisiologia , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologia , Olfato/fisiologia , Animais , Humanos , OdorantesRESUMO
Keypoint tracking algorithms can flexibly quantify animal movement from videos obtained in a wide variety of settings. However, it remains unclear how to parse continuous keypoint data into discrete actions. This challenge is particularly acute because keypoint data are susceptible to high-frequency jitter that clustering algorithms can mistake for transitions between actions. Here we present keypoint-MoSeq, a machine learning-based platform for identifying behavioral modules ('syllables') from keypoint data without human supervision. Keypoint-MoSeq uses a generative model to distinguish keypoint noise from behavior, enabling it to identify syllables whose boundaries correspond to natural sub-second discontinuities in pose dynamics. Keypoint-MoSeq outperforms commonly used alternative clustering methods at identifying these transitions, at capturing correlations between neural activity and behavior and at classifying either solitary or social behaviors in accordance with human annotations. Keypoint-MoSeq also works in multiple species and generalizes beyond the syllable timescale, identifying fast sniff-aligned movements in mice and a spectrum of oscillatory behaviors in fruit flies. Keypoint-MoSeq, therefore, renders accessible the modular structure of behavior through standard video recordings.
Assuntos
Algoritmos , Comportamento Animal , Aprendizado de Máquina , Gravação em Vídeo , Animais , Camundongos , Comportamento Animal/fisiologia , Gravação em Vídeo/métodos , Movimento/fisiologia , Drosophila melanogaster/fisiologia , Humanos , MasculinoRESUMO
Innate vocal sounds such as laughing, screaming or crying convey one's feelings to others. In many species, including humans, scaling the amplitude and duration of vocalizations is essential for effective social communication1-3. In mice, female scent triggers male mice to emit innate courtship ultrasonic vocalizations (USVs)4,5. However, whether mice flexibly scale their vocalizations and how neural circuits are structured to generate flexibility remain largely unknown. Here we identify mouse neurons from the lateral preoptic area (LPOA) that express oestrogen receptor 1 (LPOAESR1 neurons) and, when activated, elicit the complete repertoire of USV syllables emitted during natural courtship. Neural anatomy and functional data reveal a two-step, di-synaptic circuit motif in which primary long-range inhibitory LPOAESR1 neurons relieve a clamp of local periaqueductal grey (PAG) inhibition, enabling excitatory PAG USV-gating neurons to trigger vocalizations. We find that social context shapes a wide range of USV amplitudes and bout durations. This variability is absent when PAG neurons are stimulated directly; PAG-evoked vocalizations are time-locked to neural activity and stereotypically loud. By contrast, increasing the activity of LPOAESR1 neurons scales the amplitude of vocalizations, and delaying the recovery of the inhibition clamp prolongs USV bouts. Thus, the LPOA disinhibition motif contributes to flexible loudness and the duration and persistence of bouts, which are key aspects of effective vocal social communication.
Assuntos
Hipotálamo/fisiologia , Vocalização Animal/fisiologia , Animais , Corte , Receptor alfa de Estrogênio/metabolismo , Feminino , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/fisiologia , Área Pré-Óptica/citologia , Área Pré-Óptica/fisiologia , Sinapses/metabolismo , Fatores de Tempo , Ondas UltrassônicasRESUMO
The cortex organizes sensory information to enable discrimination and generalization1-4. As systematic representations of chemical odour space have not yet been described in the olfactory cortex, it remains unclear how odour relationships are encoded to place chemically distinct but similar odours, such as lemon and orange, into perceptual categories, such as citrus5-7. Here, by combining chemoinformatics and multiphoton imaging in the mouse, we show that both the piriform cortex and its sensory inputs from the olfactory bulb represent chemical odour relationships through correlated patterns of activity. However, cortical odour codes differ from those in the bulb: cortex more strongly clusters together representations for related odours, selectively rewrites pairwise odour relationships, and better matches odour perception. The bulb-to-cortex transformation depends on the associative network originating within the piriform cortex, and can be reshaped by passive odour experience. Thus, cortex actively builds a structured representation of chemical odour space that highlights odour relationships; this representation is similar across individuals but remains plastic, suggesting a means through which the olfactory system can assign related odour cues to common and yet personalized percepts.
Assuntos
Odorantes/análise , Córtex Olfatório/anatomia & histologia , Córtex Olfatório/fisiologia , Condutos Olfatórios , Compostos Orgânicos/análise , Compostos Orgânicos/química , Animais , Masculino , Camundongos , Bulbo Olfatório/citologia , Bulbo Olfatório/fisiologia , Córtex Olfatório/citologia , Percepção Olfatória/fisiologia , OlfatoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Animals evolved in complex environments, producing a wide range of behaviors, including navigation, foraging, prey capture, and conspecific interactions, which vary over timescales ranging from milliseconds to days. Historically, these behaviors have been the focus of study for ecology and ethology, while systems neuroscience has largely focused on short timescale behaviors that can be repeated thousands of times and occur in highly artificial environments. Thanks to recent advances in machine learning, miniaturization, and computation, it is newly possible to study freely moving animals in more natural conditions while applying systems techniques: performing temporally specific perturbations, modeling behavioral strategies, and recording from large numbers of neurons while animals are freely moving. The authors of this review are a group of scientists with deep appreciation for the common aims of systems neuroscience, ecology, and ethology. We believe it is an extremely exciting time to be a neuroscientist, as we have an opportunity to grow as a field, to embrace interdisciplinary, open, collaborative research to provide new insights and allow researchers to link knowledge across disciplines, species, and scales. Here we discuss the origins of ethology, ecology, and systems neuroscience in the context of our own work and highlight how combining approaches across these fields has provided fresh insights into our research. We hope this review facilitates some of these interactions and alliances and helps us all do even better science, together.
Assuntos
Comportamento Animal/fisiologia , Ecologia/tendências , Etologia/tendências , Navegação Espacial/fisiologia , Biologia de Sistemas/tendências , Animais , Ecologia/métodos , Etologia/métodos , Aprendizado de Máquina/tendências , Roedores , Biologia de Sistemas/métodosRESUMO
Both canonical olfactory sensory neurons (OSNs) and sensory neurons belonging to the guanylate cyclase D (GCD) "necklace" subsystem are housed in the main olfactory epithelium, which is continuously bombarded by toxins, pathogens, and debris from the outside world. Canonical OSNs address this challenge, in part, by undergoing renewal through neurogenesis; however, it is not clear whether GCD OSNs also continuously regenerate and, if so, whether newborn GCD precursors follow a similar developmental trajectory to that taken by canonical OSNs. Here, we demonstrate that GCD OSNs are born throughout adulthood and can persist in the epithelium for several months. Phosphodiesterase 2A is upregulated early in the differentiation process, followed by the sequential downregulation of ß-tubulin and the upregulation of CART protein. The GCD and MS4A receptors that confer sensory responses upon GCD neurons are initially expressed midway through this process but become most highly expressed once CART levels are maximal late in GCD OSN development. GCD OSN maturation is accompanied by a horizontal migration of neurons toward the central, curved portions of the cul-de-sac regions where necklace cells are concentrated. These findings demonstrate that-like their canonical counterparts-GCD OSNs undergo continuous renewal and define a GCD-specific developmental trajectory linking neurogenesis, maturation, and migration.
Assuntos
Diferenciação Celular , Guanilato Ciclase/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Animais , Movimento Celular , Proliferação de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Regulação para Baixo , Feminino , Guanilato Ciclase/deficiência , Guanilato Ciclase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Proteínas do Tecido Nervoso/metabolismo , Neurogênese , Mucosa Olfatória/citologia , Mucosa Olfatória/metabolismo , Neurônios Receptores Olfatórios/citologia , Tubulina (Proteína)/metabolismo , Regulação para CimaRESUMO
Understanding the brain requires understanding behavior. New machine vision and learning techniques are poised to revolutionize our ability to analyze behaviors exhibited by animals in the laboratory. Here we describe one such method, Motion Sequencing (MoSeq), which combines three-dimensional (3D) imaging with unsupervised machine learning techniques to identify the syllables and grammar that comprise mouse body language. This Q&A situates MoSeq within the array of novel methods currently being developed for behavioral analysis, enumerates its relative strengths and weaknesses, and describes its future trajectory.
Assuntos
Comportamento Animal , Etologia/métodos , Imageamento Tridimensional/métodos , Cinésica , Aprendizado de Máquina , Camundongos/fisiologia , Animais , RatosRESUMO
Sensory information is transmitted to the brain where it must be processed to translate stimulus features into appropriate behavioural output. In the olfactory system, distributed neural activity in the nose is converted into a segregated map in the olfactory bulb. Here we investigate how this ordered representation is transformed in higher olfactory centres in mice. We have developed a tracing strategy to define the neural circuits that convey information from individual glomeruli in the olfactory bulb to the piriform cortex and the cortical amygdala. The spatial order in the bulb is discarded in the piriform cortex; axons from individual glomeruli project diffusely to the piriform without apparent spatial preference. In the cortical amygdala, we observe broad patches of projections that are spatially stereotyped for individual glomeruli. These projections to the amygdala are overlapping and afford the opportunity for spatially localized integration of information from multiple glomeruli. The identification of a distributive pattern of projections to the piriform and stereotyped projections to the amygdala provides an anatomical context for the generation of learned and innate behaviours.
Assuntos
Condutos Olfatórios/anatomia & histologia , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologia , Tonsila do Cerebelo/anatomia & histologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Axônios/fisiologia , Mapeamento Encefálico , Camundongos , Técnicas de Rastreamento Neuroanatômico , Bulbo Olfatório/anatomia & histologia , Bulbo Olfatório/citologia , Bulbo Olfatório/fisiologia , Condutos Olfatórios/citologiaRESUMO
Drosophila show innate olfactory-driven behaviours that are observed in naive animals without previous learning or experience, suggesting that the neural circuits that mediate these behaviours are genetically programmed. Despite the numerical simplicity of the fly nervous system, features of the anatomical organization of the fly brain often confound the delineation of these circuits. Here we identify a neural circuit responsive to cVA, a pheromone that elicits sexually dimorphic behaviours. We have combined neural tracing using an improved photoactivatable green fluorescent protein (PA-GFP) with electrophysiology, optical imaging and laser-mediated microlesioning to map this circuit from the activation of sensory neurons in the antennae to the excitation of descending neurons in the ventral nerve cord. This circuit is concise and minimally comprises four neurons, connected by three synapses. Three of these neurons are overtly dimorphic and identify a male-specific neuropil that integrates inputs from multiple sensory systems and sends outputs to the ventral nerve cord. This neural pathway suggests a means by which a single pheromone can elicit different behaviours in the two sexes.
Assuntos
Drosophila melanogaster/citologia , Drosophila melanogaster/efeitos dos fármacos , Condutos Olfatórios/efeitos dos fármacos , Feromônios/farmacologia , Caracteres Sexuais , Acetatos/farmacologia , Animais , Antenas de Artrópodes/citologia , Antenas de Artrópodes/efeitos dos fármacos , Antenas de Artrópodes/inervação , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/anatomia & histologia , Feminino , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Rastreamento Neuroanatômico , Odorantes , Ácidos Oleicos/farmacologia , Condutos Olfatórios/citologia , Percepção Olfatória/efeitos dos fármacos , Percepção Olfatória/fisiologia , Estimulação Física , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiologia , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Sexual Animal/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Courtship is an innate sexually dimorphic behaviour that can be observed in naive animals without previous learning or experience, suggesting that the neural circuits that mediate this behaviour are developmentally programmed. In Drosophila, courtship involves a complex yet stereotyped array of dimorphic behaviours that are regulated by Fru(M), a male-specific isoform of the fruitless gene. Fru(M) is expressed in about 2,000 neurons in the fly brain, including three subpopulations of olfactory sensory neurons and projection neurons (PNs). One set of Fru(+) olfactory neurons expresses the odorant receptor Or67d and responds to the male-specific pheromone cis-vaccenyl acetate (cVA). These neurons converge on the DA1 glomerulus in the antennal lobe. In males, activation of Or67d(+) neurons by cVA inhibits courtship of other males, whereas in females their activation promotes receptivity to other males. These observations pose the question of how a single pheromone acting through the same set of sensory neurons can elicit different behaviours in male and female flies. Anatomical or functional dimorphisms in this neural circuit might be responsible for the dimorphic behaviour. We therefore developed a neural tracing procedure that employs two-photon laser scanning microscopy to activate the photoactivatable green fluorescent protein. Here we show, using this technique, that the projections from the DA1 glomerulus to the protocerebrum are sexually dimorphic. We observe a male-specific axonal arbor in the lateral horn whose elaboration requires the expression of the transcription factor Fru(M) in DA1 projection neurons and other Fru(+) cells. The observation that cVA activates a sexually dimorphic circuit in the protocerebrum suggests a mechanism by which a single pheromone can elicit different behaviours in males and in females.