Neuronal ensembles in amygdala, hippocampus, and prefrontal cortex track differential components of contextual fear.

Although the circuit mediating contextual fear conditioning has been extensively described, the precise contribution that specific anatomical nodes make to behavior has not been fully elucidated. To clarify the roles of the dorsal hippocampus (DH), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) in contextual fear conditioning, activity within these regions was mapped using cellular compartment analysis of temporal activity using fluorescence in situ hybridization (catFISH) for Arc mRNA. Rats were delay-fear conditioned or immediately shocked (controls) and thereafter reexposed to the shocked context to test for fear memory recall. Subsequent catFISH analyses revealed that in the DH, cells were preferentially reactivated during the context test, regardless of whether animals had been fear conditioned or immediately shocked, suggesting that the DH encodes spatial information specifically, rather then the emotional valence of an environment. In direct contrast, neuronal ensembles in the BLA were only reactivated at test if animals had been fear conditioned, suggesting that the amygdala specifically tracks the emotional properties of a context. Interestingly, Arc expression in the mPFC was consistent with both amygdala- and hippocampus-like patterns, supporting a role for the mPFC in both fear and contextual processing. Collectively, these data provide crucial insight into the region-specific behavior of neuronal ensembles during contextual fear conditioning and demonstrate a dissociable role for the hippocampus and amygdala in processing the contextual and emotional properties of a fear memory.

Isomorphisms between psychological processes and neural mechanisms: from stimulus elements to genetic markers of activity.

Traditional learning theory has developed models that can accurately predict and describe the course of learned behavior. These "psychological process" models rely on hypothetical constructs that are usually thought to be not directly measurable or manipulable. Recently, and mostly in parallel, the neural mechanisms underlying learning have been fairly well elucidated. The argument in this essay is that we can successfully uncover isomorphisms between process and mechanism and that this effort will help advance our theories about both processes and mechanisms. We start with a brief review of error-correction circuits as a successful example. Then we turn to the concept of stimulus elements, where the conditional stimulus is hypothesized to be constructed of a multitude of elements only some of which are sampled during any given experience. We discuss such elements with respect to how they explain acquisition of associative strength as an incremental process. Then we propose that for fear conditioning, stimulus elements and basolateral amygdala projection neurons are isomorphic and that the activational state of these "elements" can be monitored by the expression of the mRNA for activity-regulated cytoskeletal protein (ARC). Finally we apply these ideas to analyze recent data examining ARC expression during contextual fear conditioning and find that there are indeed many similarities between stimulus elements and amygdala neurons. The data also suggest some revisions in the conceptualization of how the population of stimulus elements is sampled from.

Stimulus salience determines defensive behaviors elicited by aversively conditioned serial compound auditory stimuli.

Assessing the imminence of threatening events using environmental cues enables proactive engagement of appropriate avoidance responses. The neural processes employed to anticipate event occurrence depend upon which cue properties are used to formulate predictions. In serial compound stimulus (SCS) conditioning in mice, repeated presentations of sequential tone (CS1) and white noise (CS2) auditory stimuli immediately prior to an aversive event (US) produces freezing and flight responses to CS1 and CS2, respectively (Fadok et al., 2017). Recent work reported that these responses reflect learned temporal relationships of CS1 and CS2 to the US (Dong et al., 2019). However, we find that frequency and sound pressure levels, not temporal proximity to the US, are the key factors underlying SCS-driven conditioned responses. Moreover, white noise elicits greater physiological and behavioral responses than tones even prior to conditioning. Thus, stimulus salience is the primary determinant of behavior in the SCS paradigm, and represents a potential confound in experiments utilizing multiple sensory stimuli.

If you notice the skies above you becoming darker, your first thought might be to seek shelter. Experience will have taught you that darkening skies are often a sign of an approaching storm. Learning to recognise changes that occur prior to an unpleasant event can help us avoid danger. But this is not the only strategy people can use to predict when something bad is about to happen. Another option is to use the intensity, or salience, of sensory information. Soldiers fighting on the front line, for example, might rely on the loudness of enemy voices or vehicles to judge how close an advancing enemy is. This information will help them decide when to retreat. Different brain processes are active when individuals use each of these two strategies to predict when an upcoming event will occur. One approach to study these processes is to use a technique called "SCS conditioning". This involves exposing mice to two sounds, followed by a mild electric shock administered to the feet. The first sound is a pure tone; the second is a burst of white noise. After repeated trials, mice begin to show distinct responses to the two sounds. They freeze in response to the tone but run away upon hearing the white noise. These responses parallel behaviors seen in the wild. When mice detect a distant predator, they freeze to avoid detection. But if the predator comes too close for the mice to avoid being spotted, they instead try to flee. Some have argued that in the SCS task, mice learn that the white noise predicts an imminent shock. The mice therefore flee as soon as they hear it. By contrast, they learn that the tone predicts a delayed shock and therefore choose to freeze instead. However, by tweaking the SCS procedure, Hersman et al. now show that even if the white noise occurs before the tone, it is still more likely than the tone to trigger an escape response. In fact, mice are more reactive to white noise than tones even if the sounds are never paired with shocks. This suggests that mice find white noise naturally more noticeable than tones. Moreover, Hersman et al. show that tones can also trigger escape responses if they are sufficiently intense. Together these results suggest that mice use the intensity of the stimuli ­ rather than the length of time between each stimulus and the shock ­ to decide whether to freeze or flee. People with anxiety disorders often show exaggerated responses to things that do not pose a genuine threat. At present the pathways in the brain that are responsible for these excessive reactions are unclear. The results of Hersman et al. will aid research into the brain circuits that detect, assess and respond to threats. Understanding these circuits could in the future lead to better treatments for anxiety disorders.

Cholinergic Signaling Alters Stress-Induced Sensitization of Hippocampal Contextual Learning.

Post-traumatic stress disorder (PTSD) has a profound contextual component, and has been demonstrated to alter future contextual learning. However, the mechanism by which a single traumatic event affects subsequent contextual experiences has not been isolated. Acetylcholine (ACh) is an important modulator of hippocampus-dependent learning such as contextual memory strength. Using Stress-Enhanced Fear Learning (SEFL), which models aspects of PTSD in rats, we tested whether muscarinic acetylcholine receptors (mAChR) in dorsal hippocampus (DH) are required during trauma for the effect of trauma on subsequent contextual fear learning. We infused scopolamine or vehicle into DH immediately before stress, and tested fear in both the trauma context and a novel context after a mild stressor. The results show that during learning, ACh acting on mAChR within the DH is required for sensitization of future contextual fear learning. However, this effect is selective for contextual learning, as this blockade leaves discrete cue sensitization intact. Rather than simply sensitizing the BLA, as previous studies have suggested, SEFL requires cholinergic signaling in DH for contextual sensitization.

Optogenetic excitation of cholinergic inputs to hippocampus primes future contextual fear associations.

Learning about context is essential for appropriate behavioral strategies, but important contingencies may not arise during initial learning. A variant of contextual fear conditioning, context pre-exposure facilitation, allows us to directly test the relationship between novelty-induced acetylcholine release and later contextual associability. We demonstrate that optogenetically-enhanced acetylcholine during initial contextual exploration leads to stronger fear after subsequent pairing with shock, suggesting that novelty-induced acetylcholine release primes future contextual associations.

Assigning Function to Adult-Born Neurons: A Theoretical Framework for Characterizing Neural Manipulation of Learning.

Neuroscientists are concerned with neural processes or computations, but these may not be directly observable. In the field of learning, a behavioral procedure is observed to lead to performance outcomes, but differing inferences on underlying internal processes can lead to difficulties in interpreting conflicting results. An example of this challenge is how many functions have been attributed to adult-born granule cells in the dentate gyrus. Some of these functions were suggested by computational models of the properties of these neurons, while others were hypothesized after manipulations of adult-born neurons resulted in changes to behavioral metrics. This review seeks to provide a framework, based in learning theory classification of behavioral procedures, of the processes that may be underlying behavioral results after manipulating procedure and observing performance. We propose that this framework can serve to clarify experimental findings on adult-born neurons as well as other classes of neural manipulations and their effects on behavior.