Hypothalamic perifornical Urocortin-3 neurons modulate defensive responses to a potential threat stimulus.
Ontology highlight
ABSTRACT:
SUBMITTER: Horii-Hayashi N
PROVIDER: S-EPMC7770982 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
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.
| S-EPMC4738254 | biostudies-other
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.
| S-EPMC7606611 | biostudies-literature
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.
| S-EPMC4452410 | biostudies-literature
Project description:Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4(+) T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3(+)) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response.
| S-EPMC3625304 | biostudies-literature
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.
| S-EPMC4546605 | biostudies-literature
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.
| S-EPMC3633986 | biostudies-literature
Project description:Experimental extinction serves as a model for psychiatric treatments based on associative learning. However, the effects of extinction are often transient, as evidenced by postextinction return of defensive behaviors. From a therapeutic perspective, an inherent problem with extinction may be that mere omission of threat is not sufficient to reduce future threat uncertainty. The current study tested an augmented form of extinction that replaced, rather than merely omitted, expected threat outcomes with novel nonthreat outcomes, with the goal of reducing postextinction return of defensive behaviors.Thirty-two healthy male Sprague-Dawley rats and 47 human adults underwent threat conditioning to a conditioned stimulus paired with an electrical shock. Subjects then underwent a standard extinction protocol with shock omitted or an augmented extinction protocol wherein the shock was replaced by a surprising tone. Tests of postextinction recovery occurred 24 hours later in the absence of the tone.Replacing the shock with a novel nonthreat outcome, as compared with shock omission, reduced postextinction recovery (freezing in rats and anticipatory skin conductance responses in humans) when tested 24 hours later. Self-reported intolerance of uncertainty was positively correlated with recovery following standard extinction in humans, providing new evidence that postextinction recovery is related to sensitivity to future threat uncertainty.These findings provide cross-species evidence of a novel strategy to enhance extinction that may have broad implications for how to override associative learning that has become maladaptive and offer a simple technique that could be straightforwardly adapted and implemented in clinical situations.
| S-EPMC4469636 | biostudies-literature
Project description:The paraventricular hypothalamus (PVH) regulates stress, feeding behaviors and other homeostatic processes, but whether PVH also drives defensive states remains unknown. Here we showed that photostimulation of PVH neurons in mice elicited escape jumping, a typical defensive behavior. We mapped PVH outputs that densely terminate in the ventral midbrain (vMB) area, and found that activation of the PVH?vMB circuit produced profound defensive behavioral changes, including escape jumping, hiding, hyperlocomotion, and learned aversion. Electrophysiological recordings showed excitatory postsynaptic input onto vMB neurons via PVH fiber activation, and in vivo studies demonstrated that glutamate transmission from PVH?vMB was required for the evoked behavioral responses. Photostimulation of PVH?vMB fibers induced cFos expression mainly in non-dopaminergic neurons. Using a dual optogenetic-chemogenetic strategy, we further revealed that escape jumping and hiding were partially contributed by the activation of midbrain glutamatergic neurons. Taken together, our work unveils a hypothalamic-vMB circuit that encodes defensive properties, which may be implicated in stress-induced defensive responses.
| S-EPMC6664144 | biostudies-literature
Project description:Individuals exposed to traumatic stressors follow divergent patterns including resilience and chronic stress. However, researchers utilizing animal models that examine learned or instrumental threat responses thought to have translational relevance for Posttraumatic Stress Disorder (PTSD) and resilience typically use central tendency statistics that assume population homogeneity. This approach potentially overlooks fundamental differences that can explain human diversity in response to traumatic stressors. The current study tests this assumption by identifying and replicating common heterogeneous patterns of response to signaled active avoidance (AA) training. In this paradigm, rats are trained to prevent an aversive outcome (shock) by performing a learned instrumental behavior (shuttling between chambers) during the presentation of a conditioned threat cue (tone). We test the hypothesis that heterogeneous trajectories of threat avoidance provide more accurate model fit compared to a single mean trajectory in two separate studies. Study 1 conducted 3 days of signaled AA training (n = 81 animals) and study 2 conducted 5 days of training (n = 186 animals). We found that four trajectories in both samples provided the strongest model fit. Identified populations included animals that acquired and retained avoidance behavior on the first day (Rapid Avoiders: 22 and 25%); those who never successfully acquired avoidance (Non-Avoiders; 20 and 16%); a modal class who acquired avoidance over 3 days (Modal Avoiders; 37 and 50%); and a population who demonstrated a slow pattern of avoidance, failed to fully acquire avoidance in study 1 and did acquire avoidance on days 4 and 5 in study 2 (Slow Avoiders; 22.0 and 9%). With the exception of the Slow Avoiders in Study 1, populations that acquired demonstrated rapid step-like increases leading to asymptotic levels of avoidance. These findings indicate that avoidance responses are heterogeneous in a way that may be informative for understanding both resilience and PTSD as well as the nature of instrumental behavior acquisition. Characterizing heterogeneous populations based on their response to threat cues would increase the accuracy and translatability of such models and potentially lead to new discoveries that explain diversity in instrumental defensive responses.
| S-EPMC4173321 | biostudies-literature
Project description:Recent studies have reported the presence of single neurons with strong responses to visual inputs in the human medial temporal lobe. Here we show how repeated stimulus presentation--photos of celebrities and familiar individuals, landmark buildings, animals, and objects--modulates the firing rate of these cells: a consistent decrease in the neural activity was registered as images were repeatedly shown during experimental sessions. The effect of repeated stimulus presentation was not the same for all medial temporal lobe areas. These findings are consistent with the view that medial temporal lobe neurons link visual percepts to declarative memory.
| S-EPMC2807242 | biostudies-literature