Observational fear learning in rodents is a type of context-dependent fear conditioning in which an unconditioned stimulus (US) is provided vicariously by observing conspecific others receiving foot ...shocks. This suggests the involvement of affective empathy, with several recent studies showing many similarities between this behavior and human empathy. Neurobiologically, it is important to understand the neural mechanisms by which the vicarious US activates the fear circuit via the affective pain system, obviating the sensory pain pathway and eventually leading to fear memory formation. This paper reviews current studies on the neural mechanisms underlying observational fear learning and provides a perspective on future research on this subject.
Observational fear, a rodent model of affective empathy, is context-dependent fear conditioning in which an unconditioned stimulus is vicariously provided. Keum and Shin discuss neural mechanisms underlying observational fear, highlighting that neural substrates for empathy overlap with observational fear.
While the interaction of the cardinal rhythms of non-rapid-eye-movement (NREM) sleep—the thalamo-cortical spindles, hippocampal ripples, and the cortical slow oscillations—is thought to be critical ...for memory consolidation during sleep, the role spindles play in this interaction is elusive. Combining optogenetics with a closed-loop stimulation approach in mice, we show here that only thalamic spindles induced in-phase with cortical slow oscillation up-states, but not out-of-phase-induced spindles, improve consolidation of hippocampus-dependent memory during sleep. Whereas optogenetically stimulated spindles were as efficient as spontaneous spindles in nesting hippocampal ripples within their excitable troughs, stimulation in-phase with the slow oscillation up-state increased spindle co-occurrence and frontal spindle-ripple co-occurrence, eventually resulting in increased triple coupling of slow oscillation-spindle-ripple events. In-phase optogenetic suppression of thalamic spindles impaired hippocampus-dependent memory. Our results suggest a causal role for thalamic sleep spindles in hippocampus-dependent memory consolidation, conveyed through triple coupling of slow oscillations, spindles, and ripples.
•Spindles in-phase with slow oscillation up-states boost hippocampus-dependent memory•Phase coupling of slow oscillations, spindles, and ripples underlies memory formation•Thalamic spindle stimulation drives cross-regional co-occurrence of spindles•Thalamic inhibition phase-locked to slow oscillation up-states impairs memory
Latchoumane et al. demonstrate a causal role of sleep spindles in memory formation. They show that optogenetic induction of thalamic spindles, when phase-locked to the slow oscillation up-state, enhances the triple coupling of slow oscillations-spindles-ripples together with hippocampus-dependent memory consolidation.
Empathy enables social mammals to recognize and share emotion with others and is well‐documented in non‐human primates. During the past few years, systematic observations have showed that a primal ...form of empathy also exists in rodents, indicating that empathy has an evolutionary continuity. Now, using rodents exhibiting emotional empathy, the molecular and cellular study of empathy in animals has begun in earnest. In this article, we will review recent reports that indicate that rodents can share states of fear with others, and will try to highlight new understandings of the neural circuitry, biochemistry and genetics of empathic fear. We hope that the use of rodent models will enhance understanding of the mechanisms of human empathy and provide insights into how to treat social deficits in neuropsychiatric disorders characterized by empathy impairment.
In this review, we discuss recent studies that investigated the behavioral or molecular mechanisms of rodent observational fear.
Prior experience of social hierarchy is known to modulate emotional contagion, a basic form of affective empathy. However, it is not known whether this behavioral effect occurs through changes in an ...individual's traits due to their experience of social hierarchy or specific social interrelationships between the individuals. Groups of four mice with an established in‐group hierarchy were used to address this in conjunction with a tube test. The rank‐1 and rank‐4 mice were designated as the dominant or subordinate groups, respectively. The two individuals in between were designated as the intermediate groups, which were then used as the observers in observational fear learning (OFL) experiments, an assay for emotional contagion. The intermediate observers showed greater OFL responses to the dominant demonstrator than the subordinate demonstrators recruited from the same home‐cage. When the demonstrators were strangers from different cages, the intermediate observers did not distinguish between dominant and subordinate, displaying the same level of OFL. In a reverse setting in which the intermediate group was used as the demonstrator, the subordinate observers showed higher OFL responses than the dominant observers, and this occurred only when the demonstrators were cagemates of the observers. Furthermore, the bigger the rank difference between a pair, the higher the OFL level that the observer displayed. Altogether, these results demonstrate that the hierarchical interrelationship established between a given pair of animals is critical for expressing emotional contagion between them rather than any potential changes in intrinsic traits due to the experience of dominant/subordinate hierarchy.
Practitioner points
Subordinate observer or dominant demonstrator resulted in higher affective empathic response in familiar pairs but not unfamiliar pairs.
The relative social rank of the observer with respect to the demonstrator had a negative linear correlation with the affective empathic response of the observer in familiar pairs but not unfamiliar pairs.
The effect of social rank on affective empathy is attributed to the prior social hierarchical interrelationship between them and is not due to intrinsic attributes of an individual based on one's dominance rank.
Subordinate observer or dominant demonstrator resulted in higher empathic response in familiar pair.
The hierarchical effect on empathy was not observed toward an unfamiliar partner.
The relative hierarchy is sufficient to distinguish the difference in empathy.
A large forebrain circuit, including the thalamus, amygdala and frontal cortical regions, is responsible for the establishment and extinction of fear‐related memories. Understanding interactions ...among these three regions is critical to deciphering the basic mechanisms of fear. With the advancement of molecular and optogenetics techniques, the mouse has become the main species used to study fear‐related behaviours. However, the basic connectivity pattern of the forebrain circuits involved in processing fear has not been described in this species. In this study we mapped the connectivity between three key nodes of the circuit, i.e. the basolateral nucleus of the amygdala (BLA), the mediodorsal nucleus of the thalamus (MD) and the medial prefrontal cortex, which were shown to have closed triangular connectivity in rats. In contrast to rat, we found no evidence for this closed loop in mouse. There was no major input from the BLA to the MD and little overlap between medial prefrontal regions connected with both the BLA and MD. The common nodes in the frontal cortex, which displayed reciprocal connection with both the BLA and MD were the agranular insular cortex and the border zone of the cingulate and secondary motor cortex. In addition, the BLA can indirectly affect the MD via the orbital cortex. We attribute the difference between our results and earlier rat studies to methodological problems rather than to genuine species difference. Our data demonstrate that the BLA and MD communicate via cortical sectors, the roles in fear‐related behaviour of which have not been extensively studied. In general, our study provides the morphological framework for studies of murine fear‐related behaviours.
We report that the three key nodes of the fear circuit in the mouse forebrain (prelimibic/infralimbic cortex, basolateral amygdala and mediordorsal thalamic nucleus) display no closed triangular connectivity. Rather, amygdalar and thalamic information are integrated via well‐defined cortical sectors (cingulate/M2 cortex and orbital cortices) whose roles in fear‐related behaviour have not been extensively studied. The study provides the morphological framework for the studies of murine fear related behaviours.
Biological organisms demonstrate remarkable agility in complex environments, especially in comparison to engineered robotic systems. In part, this is due to an organism's ability to detect ...disturbances and react to them quickly. To address the challenge of quickly sensing these same disturbances in robotic systems, this study proposes and demonstrates large‐area soft sensing skins designed to sense disturbances on unmanned aerial vehicles (UAVs) in flight. These skins are enabled by high‐resolution soft strain sensors embedded into a large‐area skin through a modular molding process that spans feature sizes from tens of microns to 0.675 m. The electronics of the sensing system enable the soft skins to be sampled fast enough to capture dynamic loads on a wing. Overall, the large‐area soft sensing skin demonstrates high sensitivity, mechanical robustness, and consistent sensor readings across static and dynamic tests. The use of the soft sensing skin during UAV flight demonstrates that the sensing skin can capture relevant flight dynamics on small UAVs. These results pave the way to large‐area soft sensing skins for fast and robust control of a wide variety of robotic systems.
A large‐area soft sensing skin, inspired by hawkmoth wings, combines 14 soft capacitive strain sensors with microscale features across a skin length of 0.675 m. The skin is integrated with a flexible electronics interface and used to measure wing deformation on a UAV during flight, thereby illustrating the benefits of a robust sensing skin with a large number of sensors.
Empathy is crucial for our emotional experience and social interactions, and its abnormalities manifest in various psychiatric disorders. Observational fear is a useful behavioral paradigm for ...assessing affective empathy in rodents. However, specific genes that regulate observational fear remain unknown. Here we showed that 129S1/SvImJ mice carrying a unique missense variant in neurexin 3 (Nrxn3) exhibited a profound and selective enhancement in observational fear. Using the CRISPR/Cas9 system, the arginine-to-tryptophan (R498W) change in Nrxn3 was confirmed to be the causative variant. Selective deletion of Nrxn3 in somatostatin-expressing (SST+) interneurons in the anterior cingulate cortex (ACC) markedly increased observational fear and impaired inhibitory synaptic transmission from SST+ neurons. Concordantly, optogenetic manipulation revealed that SST+ neurons in the ACC bidirectionally controlled the degree of socially transmitted fear. Together, these results provide insights into the genetic basis of behavioral variability and the neurophysiological mechanism controlling empathy in mammalian brains.
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•The 129S1 mouse strain exhibits a selective enhancement in observational fear•A missense variant (R498W) in Nrxn3 causes elevation of observational fear•Selective deletion of Nrxn3 in SST+ neurons reduces GABA release in the ACC•SST+ inhibitory neurons in the ACC control the degree of socially transmitted fear
Keum et al. demonstrate that a protein variant in the Nrxn3 gene causes an enhancement in observational fear and that Nrxn3-dependent inhibitory synaptic functions in somatostatin-positive interneurons in the anterior cingulate cortex control the degree of empathy fear.
A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting ...effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.
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