Memory is supported by a specific ensemble of neurons distributed in the brain that form a unique memory trace. We previously showed that neurons in the lateral amygdala expressing elevated levels of cAMP response-element binding protein are preferentially recruited into fear memory traces and are necessary for the expression of those memories. However, it is unknown whether artificially activating just these selected neurons in the absence of behavioral cues is sufficient to recall that fear memory. Using an ectopic rat vanilloid receptor TRPV1 and capsaicin system, we found that activating this specific ensemble of neurons was sufficient to recall established fear memory. Furthermore, this neuronal activation induced a reconsolidation-like reorganization process, or strengthening of the fear memory. Thus, our findings establish a direct link between the activation of specific ensemble of neurons in the lateral amygdala and the recall of fear memory and its subsequent modifications.

Despite considerable progress over the past several decades, our understanding of the mechanisms underlying memory encoding, storage, and expression in a complex neural network are far from complete. In particular, how some neurons rather than others are selectively engaged to encode memory remains largely unknown. Using virus-mediated gene delivery into a small subset of neurons in a given network, molecular imaging of neuronal activity, pharmacological perturbation of specific neurons' activity and animal behavior assays, recent studies have begun to provide insight into molecular and cellular mechanisms responsible for the selection of neurons for inclusion into a memory trace. Here, we focus on a review of recent findings supporting the hypothesis that the level of the transcription factor CREB (cAMP/Ca2+-response element binding protein) is a key factor governing which neurons are recruited to a given memory trace. These recent findings open a new perspective on memory trace at the neural circuit level and also raise many important questions. Future studies employing more advanced neurobiological techniques for targeting defined populations of neurons and manipulating their activity in time and space in a complex neural network will give answers to these newly emerging questions and extend our understanding of the neurobiological basis of the memory trace.

Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or retrieval. To investigate this possibility, we systematically imaged the brain activity patterns in the lateral amygdala, MGm/PIN, and AuV/TeA using activity-dependent induction of immediate early gene zif268 after recent and remote memory retrieval of auditory conditioned fear. Consistent with the critical role of the amygdala in fear memory, the zif268 activity in the lateral amygdala was significantly increased after both recent and remote memory retrieval. Interesting, however, the density of zif268 (+) neurons in both MGm/PIN and AuV/TeA, particularly in layers IV and VI, was increased only after remote but not recent fear memory retrieval compared to control groups. Further analysis of zif268 signals in AuV/TeA revealed that conditioned tone induced stronger zif268 induction compared to familiar tone in each individual zif268 (+) neuron after recent memory retrieval. Taken together, our results support that the lateral amygdala is a key brain site for permanent fear memory storage and suggest that MGm/PIN and AuV/TeA might play a role for remote memory storage or retrieval of auditory conditioned fear, or, alternatively, that these auditory brain regions might have a different way of processing for familiar or conditioned tone information at recent and remote time phases.

In Pavlovian fear conditioning, the lateral amygdala (LA) has been highlighted as a key brain site for association between sensory cues and aversive stimuli. However, learning-related changes are also found in upstream sensory regions such as thalamus and cortex. To isolate the essential neural circuit components for fear memory association, we tested whether direct activation of presynaptic sensory inputs in LA, without the participation of upstream activity, is sufficient to form fear memory in mice. Photostimulation of axonal projections from the two main auditory brain regions, the medial geniculate nucleus of the thalamus and the secondary auditory cortex, was paired with aversive footshock. Twenty-four hours later the same photostimulation induced robust conditioned freezing and this fear memory formation was disrupted when glutamatergic synaptic transmission was locally blocked in the LA. Therefore, our results prove for the first time that synapses between sensory input areas and the LA, previously implicated as a crucial brain site for fear memory formation, actually are sufficient to serve as a conditioned stimulus. Our results strongly support the idea that the LA may be sufficient to encode and store associations between neutral cue and aversive stimuli during natural fear conditioning as a critical part of a broad fear memory engram.

Innate social behaviors, such as mating and fighting, are fundamental to animal reproduction and survival. However, social engagements can also put an individual at risk. Little is known about the neural mechanisms that allow for appropriate risk assessment and the suppression of hazardous social interactions. We have identified the posteromedial nucleus of the cortical amygdala (COApm) as a locus required for the suppression of male mating when a female is sick. Using anatomical tracing, functional imaging, and circuit-level epistatic analyses, we show that suppression of mating with an unhealthy female is mediated by the COApm projections onto the glutamatergic population of the medial amygdalar nucleus (MEA). We further show that the role of the COApm to MEA connection in regulating male mating behavior relies on the neuromodulator thyrotropin-releasing hormone (TRH). TRH is expressed in the COApm while