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A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor (Oxtr) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species (n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.

Research over the past decades has demonstrated the explanatory power of emotions, feelings, motivations, moods, and other affective processes when trying to understand and predict how we think and behave. In this consensus article, we ask: has the increasingly recognized impact of affective phenomena ushered in a new era, the era of affectivism?

There is disagreement on how best to define and investigate fear. Nature Neuroscience asked Dean Mobbs to lead experts from the fields of human and animal affective neuroscience to discuss their viewpoints on how to define fear and how to move forward with the study of fear.

While interest in active avoidance has recently been resurgent, many concerns relating to the nature of this form of learning remain unresolved. By separating stimulus and response acquisition, aversive Pavlovian-instrumental transfer can be used to measure the effect of avoidance learning on threat processing with more control than typical avoidance procedures. However, the motivational substrates that contribute to the aversive transfer effect have not been thoroughly examined. In three studies using rodents, the impact of a variety of aversive signals on shock-avoidance responding (i.e., two-way shuttling) was evaluated. Fox urine, as well as a tone paired with the delivery of the predator odor were insufficient modulatory stimuli for the avoidance response. Similarly, a signal for the absence of food did not generate appropriate aversive motivation to enhance shuttling. Only conditioned Pavlovian stimuli that had been paired with unconditioned threats were capable of augmenting shock-avoidance responding. This was true whether the signaled outcome was the same (e.g., shock) or different (e.g., klaxon) from the avoidance outcome (i.e., shock). These findings help to characterize the aversive transfer effect and provide a more thorough analysis of its generalization to warning signals for different kinds of threats. This feature of aversive motivation has not been demonstrated using conventional avoidance procedures and could be potentially useful for applying avoidance in treatment settings.

When patients seek professional help for mental disorders, they often do so because of troubling subjective affective experiences. While these subjective states are at the center of the patient's symptomatology, scientific tools for studying them and their cognitive antecedents are limited. Here, we explore the use of concepts and analytic tools from the science of consciousness, a field of research that has faced similar challenges in having to develop robust empirical methods for addressing a phenomenon that has been considered difficult to pin down experimentally. One important strand is the operationalization of some relevant processes in terms of metacognition and confidence ratings, which can be rigorously studied in both humans and animals. By assessing subjective experience with similar approaches, we hope to develop new scientific approaches for studying affective processes and promoting psychological resilience in the face of debilitating emotional experiences. [ABSTRACT FROM AUTHOR]

Signaled active avoidance (SigAA) is the key experimental procedure for studying the acquisition of instrumental responses toward conditioned threat cues. Traditional analytic approaches (e.g., general linear model) often obfuscate important individual differences, although individual differences in learned responses characterize both animal and human learning data. However, individual differences models (e.g., latent growth curve modeling) typically require large samples and onerous computational methods. Here, we present an analytic methodology that enables the detection of individual differences in SigAA performance at a high accuracy, even when a single animal is included in the data set (i.e., n = 1 level). We further show an online software that enables the easy application of our method to any SigAA data set.

How does the brain identify stimuli that are relevant for predictingimportant events and how does it distinguish spuriousrelationships from truly predictive ones? We examined twocontrasting theoretical frameworks: in the first, learning proceedsby considering a fixed hypothesis of the environment’sstatistical structure (the set of predictive and causal relationships)and adjusting strength parameters for these relationshipsto optimize predictions. In contrast, the second approach directlyassesses ambiguity in predictive relationships by evaluatingmultiple hypothesis of the environment’s statistical structure.We compared these frameworks in an animal model ofaversive conditioning, allowing us to also manipulate the underlyingbrain systems. We show that when facing novel predictivestimuli, rats initially adopt a structure learning strategy,but switch to updating parameters during subsequent learning

In an interview with Neuron , Joseph LeDoux outlines his early work on consciousness in split-brain patients, his transition into studying emotional behavior in rodents, and his continued exploration of consciousness in books and other writings. He describes how his research fused with his interest in music, which he pursued though his band, The Amygdaloids, and their unique genre, "heavy mental." [ABSTRACT FROM AUTHOR]

The creation of auditory threat Pavlovian memory requires an initial learning stage in which a neutral conditioned stimulus (CS), such as a tone, is paired with an aversive one (US), such as a shock. In this phase, the CS acquires the capacity of predicting the occurrence of the US and therefore elicits conditioned defense responses. Norepinephrine (NE), through ß-adrenergic receptors in the amygdala, enhances threat memory by facilitating the acquisition of the CS-US association, but the nature of this effect has not been described. Here we show that NE release, induced by the footshock of the first conditioning trial, promotes the subsequent enhancement of learning. Consequently, blocking NE transmission disrupts multitrial but not one-trial conditioning. We further found that increasing the time between the conditioning trials eliminates the amplificatory effect of NE. Similarly, an unsignaled footshock delivered in a separate context immediately before conditioning can enhance learning. These results help define the conditions under which NE should and should not be expected to alter threat processing and fill an important gap in the understanding of the neural processes relevant to the pathophysiology of stress and anxiety disorders.

The updating of a memory is triggered whenever it is reactivated and a mismatch from what is expected (i.e., prediction error) is detected, a process that can be unraveled through the memory's sensitivity to protein synthesis inhibitors (i.e., reconsolidation). As noted in previous studies, in Pavlovian threat/aversive conditioning in adult rats, prediction error detection and its associated protein synthesis-dependent reconsolidation can be triggered by reactivating the memory with the conditioned stimulus (CS), but without the unconditioned stimulus (US), or by presenting a CS-US pairing with a different CS-US interval than during the initial learning. Whether similar mechanisms underlie memory updating in the young is not known. Using similar paradigms with rapamycin (an mTORC1 inhibitor), we show that preweaning rats (PN18-20) do form a long-term memory of the CS-US interval, and detect a 10-sec versus 30-sec temporal prediction error. However, the resulting updating/reconsolidation processes become adult-like after adolescence (PN30-40). Our results thus show that while temporal prediction error detection exists in preweaning rats, specific infant-type mechanisms are at play for associative learning and memory.

Distinguishing threatening from nonthreatening stimuli is essential for survival and stimulus generalization is a hallmark of anxiety disorders. While auditory threat learning produces long-lasting plasticity in primary auditory cortex (Au1), it is not clear whether such Au1 plasticity regulates memory specificity or generalization. We used muscimol infusions in rats to show that discriminatory threat learning requires Au1 activity specifically during memory acquisition and retrieval, but not during consolidation. Memory specificity was similarly disrupted by infusion of PKM? inhibitor peptide (ZIP) during memory storage. Our findings show that Au1 is required at critical memory phases and suggest that Au1 plasticity enables stimulus discrimination.