Brn3bactsviaTac2 to regulatedefensive responses to visual threat
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ABSTRACT: Defensive responses to visually threatening stimuli represent an essential fear-related survival instinct, widely detected across species. The neural circuitry mediating visually triggered defensive responses has been delineated in the midbrain. However, the molecular mechanisms regulating the development and function of these circuits remain unresolved. Here we show that midbrain-specific deletion of the transcription factor Brn3b causes a loss of neurons projecting to the lateral posterior nucleus of the thalamus. Brn3b deletion also downregulates the expression of the neuropeptide tachykinin 2 (Tac2). Furthermore, Brn3b mutant mice display impaired defensive freezing responses to visual threat precipitated by social isolation. This behavioral phenotype could be ameliorated by overexpressing Tac2, suggesting that Tac2 acts downstream of Brn3b in regulating defensive responses to threat. Together, our experiments identify specific genetic components critical for the functional organization of midbrain fear-related visual circuits. Similar mechanisms may contribute to the development and function of additional long-range brain circuits underlying fear-associated behavior.
Project description:Respiratory defensive behaviors, like coughing, play a crucial role in protecting the respiratory system, ensuring its integrity and optimal function. How these critical behaviors are regulated by sensory stimuli within the body remains largely unknown. Here, we show that the nucleus of the solitary tract (NTS) in mice, a key hub in the brain for processing internal sensory signals and mediating interoceptive processes, contains heterogenous neuronal populations that differentially control breathing. Within these subtypes, activation of tachykinin 1 (Tac1) neurons triggers a specific respiratory behavior. Our detailed characterization of respiratory defensive behaviors reveals that these responses are cough-like behaviors. Chemogenetic silencing or genetic ablation of Tac1 neurons significantly reduces cough-like behaviors induced by tussive challenges. These Tac1 neurons receive synaptic inputs from the bronchopulmonary chemosensory and mechanosensory neurons in the vagal ganglion, and directly integrate the medullary regions to control sequential phases of cough-like defensive behaviors. We propose that these Tac1 neurons are a key component of the airway-vagal-brain neural circuit that controls cough-like defensive behaviors in mice, and they coordinate the downstream modular circuits to elicit the sequential motor pattern of forceful expiratory responses.
Project description:Mature cortical sensory areas are specialized to process unique sensory stimuli. Recent evidence shows that in the mouse embryo sensory cortices are prepared to respond to an incoming input from the periphery. However, whether these sensory circuits originate as modality specific modules, or they are segregated over time remains unknown. Here, we demonstrate that visual and somatosensory circuits originate as functionally intermingled modules, as whisker-pad stimulations at prenatal life led to a multimodal response activating both primary visual and somatosensory cortices. This multimodal response is switched to unimodal at birth via the superior colliculus, a midbrain structure where both modalities converge. Retinal afferent to the superior colliculus prompts the gating of visual from somatosensory circuits achieving sensory modality specificity at birth. Blocking stage I retinal waves resulted in prolonged convergence of somatosensory and visual circuits at the superior colliculus, which led to long-term consequences in the molecular identity of the superior colliculus and caused defects in eye-specific segregation and retinotopy. Hence, the superior colliculus stands as a key developmental regulator of sensory circuits by channeling modality stimuli to their appropriate sensory pathway.
Project description:Retinal ganglion cells (RGCs) are the projection neurons in the retina that connect the visual sensing tissue to the brain. We found that Ascl1/Brn3b/Isl1 transcription factor combination can quickly and efficiently reprogramming mouse embryonic fibroblasts (MEFs) into retinal ganglion cell-like neurons (iRGCs). Using RNA-seq, we analyzed the transcriptomes of MEFs infected with Ascl1/Brn3b/Isl1-overexpressing viruses on day 2 or day 7 of reprogramming, or the final iRGCs on day 13 of reprogramming.
Project description:Social creatures must attend to threat signals from conspecifics and respond appropriately, both behaviorally and physiologically. In this work, we show a threat-sensitive immune signaling that orchestrates psychological processes and is amenable to social modulation. Repeated encounters with socially-cued threats triggered neutrophil priming preferentially in males. Meningeal niche-specific neutrophil activity was correlated with attenuated defensive responses to cues. The neutrophil-specific membrane protein CD177 responded to threat-predicting social cues, and its genetic ablation abrogated male behavioral phenotypes. Neutrophil CD177 signaling facilitated optimal meningeal IFN-γ production, which blunted neural response to threatening stimuli by enhancing intrinsic GABAergic inhibition within the prelimbic cortex. Initiation of meningeal neutrophil-mediated IFN-γ signaling was sensitized by negative emotional states and governed by socially dependent androgen release. This male-biased hormone/neutrophil regulatory axis is seemingly conserved in humans. Our findings provide insights into how immune responses influence behavioral responses to threats, suggesting a possible neuroimmune basis of emotional regulation.
Project description:Visual information is conveyed from the eye to the brain by distinct types of Retinal Ganglion Cells (RGCs). It is largely unknown how RGCs acquire their defining morphological and physiological features and connect to upstream and downstream synaptic partners. The three Brn3/Pou4f transcription factors (TFs) participate in the combinatorial code for RGC type specification but their exact molecular roles are still unclear. We use deep sequencing to define (i) transcriptomes of Brn3a and/or Brn3b positive RGCs, (ii) Brn3a and/or Brn3b dependent RGC transcripts and (iii) transcriptomes of retinorecipient areas of the brain at developmental stages relevant for axon guidance, dendrite formation and synaptogenesis. We reveal a combinatorial code of transcription factors, adhesion molecules and determinants of neuronal morphology that are differentially expressed in specific RGC populations and selectively regulated by Brn3a and/or Brn3b. This comprehensive molecular code provides a basis for understanding neuronal cell type specification in RGCs.
Project description:Fear extinction is an adaptive behavioral process critical for organism’s survival, but deficiency in extinction may lead to PTSD. While the amygdala and its neural circuits are critical for fear extinction, the molecular identity and organizational logic of cell types that lie at the core of these circuits remain unclear. Here we report that mice deficient for amygdala-enriched gastrin-releasing peptide gene (Grp-/-) exhibit enhanced neuronal activity in the basolateral amygdala (BLA) and stronger fear conditioning, as well as deficient extinction in stress-enhanced fear learning (SEFL). rAAV2-retro-based tracing combined with visualization of the GFP knocked in the Grp gene showed that BLA receives several GRPergic conditioned stimulus projections: from the indirect auditory thalamus-to-auditory cortex pathway, medial prefrontal cortex, ventral hippocampus and ventral tegmental area. Transcription of dopamine-related genes was decreased in BLA of Grp-/- mice following SEFL extinction recall, suggesting that the GRP may mediate fear extinction regulation by dopamine.
Project description:Innate behaviors, like fear, are basic behaviors which animals possess to ensure their survival and reproduction. Now we know that in animals, for example mouse, different behaviors are controlled by different or similar neural circuits. Whether these behaviors are coded by specific genes are not clear. In this project, we used single-cell sequencing to solve this problem in fear and hunting behaviors.