Hypothalamic perifornical Urocortin-3 neurons modulate defensive responses to a potential threat stimulus.
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ABSTRACT:
SUBMITTER: Horii-Hayashi N
PROVIDER: S-EPMC7770982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The defensive peripersonal space (DPPS) is a vital "safety margin" surrounding the body. When a threatening stimulus is delivered inside the DPPS, subcortical defensive responses like the hand-blink reflex (HBR) are adjusted depending on the perceived threat content. In three experiments, we explored whether and how defensive responses are affected by the interpersonal interaction within the DPPS of the face. In Experiment 1, we found that the HBR is enhanced when the threat is brought close to the face not only by one's own stimulated hand, but also by another person's hand, although to a significantly lesser extent. In Experiments 2 and 3, we found that the HBR is also enhanced when the hand of the participant enters the DPPS of another individual, either in egocentric or in allocentric perspective. This enhancement is larger in participants with strong empathic tendency when the other individual is in a third person perspective. These results indicate that interpersonal interactions shape perception of threat and defensive responses. These effects are particularly evident in individuals with greater tendency to having empathic concern to other people.
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Project description:Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli1,2. Internal emotional states, such as fear, also persist following exposure to an inciting stimulus3, but it is unclear whether slow neural dynamics are involved in this process. Neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) that express the nuclear receptor protein NR5A1 (also known as SF1) are necessary for defensive responses to predators in mice4-7. Optogenetic activation of these neurons, referred to here as VMHdmSF1 neurons, elicits defensive behaviours that outlast stimulation5,8, which suggests the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdmSF1 neurons in mice exhibit activity that lasts for many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behaviour in an open-field assay, and depended on neurotransmitter release from VMHdmSF1 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdmSF1 neurons. Microendoscopic calcium imaging of VMHdmSF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdmSF1 subpopulations were persistently activated by different modalities of threatening stimulus. Computational modelling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results show that stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that of working memory in the cortex9,10, contribute to a persistent emotional state.
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Project description:The neural circuit mechanisms underlying emotion states remain poorly understood. Drosophila offers powerful genetic approaches for dissecting neural circuit function, but whether flies exhibit emotion-like behaviors has not been clear. We recently proposed that model organisms may express internal states displaying "emotion primitives," which are general characteristics common to different emotions, rather than specific anthropomorphic emotions such as "fear" or "anxiety." These emotion primitives include scalability, persistence, valence, and generalization to multiple contexts. Here, we have applied this approach to determine whether flies' defensive responses to moving overhead translational stimuli ("shadows") are purely reflexive or may express underlying emotion states. We describe a new behavioral assay in which flies confined in an enclosed arena are repeatedly exposed to an overhead translational stimulus. Repetitive stimuli promoted graded (scalable) and persistent increases in locomotor velocity and hopping, and occasional freezing. The stimulus also dispersed feeding flies from a food resource, suggesting both negative valence and context generalization. Strikingly, there was a significant delay before the flies returned to the food following stimulus-induced dispersal, suggestive of a slowly decaying internal defensive state. The length of this delay was increased when more stimuli were delivered for initial dispersal. These responses can be mathematically modeled by assuming an internal state that behaves as a leaky integrator of stimulus exposure. Our results suggest that flies' responses to repetitive visual threat stimuli express an internal state exhibiting canonical emotion primitives, possibly analogous to fear in mammals. The mechanistic basis of this state can now be investigated in a genetically tractable insect species.
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Project description:Preys use their memory - where they sensed a predatory threat and whether a safe shelter is nearby - to dynamically control their survival instinct to avoid harm and reach safety. However, it remains unknown which brain regions are involved, and how such top-down control of innate behavior is implemented at the circuit level. Here, using adult male mice, we show that the anterior hypothalamic nucleus (AHN) is best positioned to control this task as an exclusive target of the hippocampus (HPC) within the medial hypothalamic defense system. Selective optogenetic stimulation and inhibition of hippocampal inputs to the AHN revealed that the HPC→AHN pathway not only mediates the contextual memory of predator threats but also controls the goal-directed escape by transmitting information about the surrounding environment. These results reveal a new mechanism for experience-dependent, top-down control of innate defensive behaviors.
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Project description:How humans react to threats is a topic of broad theoretical importance, and also relevant for understanding anxiety disorders. Many animal threat reactions exhibit a common structure, a finding supported by human evaluations of written threat scenarios that parallel patterns of rodent defensive behavior to actual threats. Yet the factors that underlie these shared behavioral patterns remain unclear. Dimensional accounts rooted in Darwin's conception of antithesis explain many defensive behaviors. Across species, it is also clear that defensive reactions depend on specific situational factors, a feature long emphasized by psychological appraisal theories. Our study sought to extend prior investigations of human judgments of threat to a broader set of threats, including natural disasters, threats from animals, and psychological (as opposed to physical) threats. Our goal was to test whether dimensional and specific patterns of threat evaluation replicate across different threat classes. 85 healthy adult subjects selected descriptions of defensive behaviors that indicated how they would react to 29 threatening scenarios. Scenarios differed with respect to ten factors, e.g., perceived dangerousness or escapability. Across scenarios, we correlated these factor ratings with the pattern of defensive behaviors subjects endorsed. A decision tree hierarchically organized these correlation patterns to successfully predict each scenario's most common reaction, both for the original sample of subjects and a separate replication group (n = 22). At the top of the decision tree, degree of dangerousness interacted with threat type (physical or psychological) to predict dimensional approach/avoidance behavior. Subordinate nodes represented specific defensive responses evoked by particular contexts. Our ecological approach emphasizes the interplay of situational factors in evoking a broad range of threat reactions. Future studies could test predictions made by our results to help understand pathological threat processing, such as seen in anxiety disorders, and could begin to test underlying neural mechanisms.
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Project description:Ciliary neurotrophic factor (CNTF) induces neurogenesis, reduces feeding, and induces weight loss. However, the central mechanisms by which CNTF acts are vague. We employed the mHypoE-20/2 line that endogenously expresses the CNTF receptor to examine the direct effects of CNTF on mRNA levels of urocortin-1, urocortin-2, agouti-related peptide, brain-derived neurotrophic factor, and neurotensin. We found that treatment of 10 ng/ml CNTF significantly increased only urocortin-1 mRNA by 1.84-fold at 48 h. We then performed intracerebroventricular injections of 0.5 mg/mL CNTF into mice, and examined its effects on urocortin-1 neurons post-exposure. Through double-label immunohistochemistry using specific antibodies against c-Fos and urocortin-1, we showed that central CNTF administration significantly activated urocortin-1 neurons in specific areas of the hypothalamus. Taken together, our studies point to a potential role for CNTF in regulating hypothalamic urocortin-1-expressing neurons to mediate its recognized effects on energy homeostasis, neuronal proliferaton/survival, and/or neurogenesis.
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Project description:Psychological stressors, like the nearby presence of a predator, can be strong enough to induce physiological/hormonal alterations, leading to appetite changes. However, little is known about how threats can alter feeding-related hypothalamic circuit functions. Here, we found that proenkephalin (Penk)-expressing lateral hypothalamic (LHPenk) neurons of mice exposed to predator scent stimulus (PSS) show sensitized responses to high-fat diet (HFD) eating, whereas silencing of the same neurons normalizes PSS-induced HFD overconsumption associated with a negative emotional state. Downregulation of endogenous enkephalin peptides in the LH is crucial for inhibiting the neuronal and behavioral changes developed after PSS exposure. Furthermore, elevated corticosterone after PSS contributes to enhance the reactivity of glucocorticoid receptor (GR)-containing LHPenk neurons to HFD, whereas pharmacological inhibition of GR in the LH suppresses PSS-induced maladaptive behavioral responses. We have thus identified the LHPenk neurons as a critical component in the threat-induced neuronal adaptation that leads to emotional overconsumption.
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