Negative experiences are quickly learned and long remembered. Key unresolved issues in the field of emotional memory include identifying the loci and dynamics of memory storage and retrieval. The present study examined neural activity in the higher-order auditory cortex Te2 and basolateral amygdala (BLA) and their crosstalk during the recall of recent and remote fear memories. To this end, we obtained local field potentials and multiunit activity recordings in Te2 and BLA of rats that underwent recall at 24 h and 30 d after the association of an acoustic conditioned (CS, tone) and an aversive unconditioned stimulus (US, electric shock). Here we show that, during the recall of remote auditory threat memories in rats, the activity of the Te2 and BLA is highly synchronized in the theta frequency range. This functional connectivity stems from memory consolidation processes because it is present during remote, but not recent, memory retrieval. Moreover, the observed increase in synchrony is cue and region specific. A preponderant Te2-to-BLA directionality characterizes this dialogue, and the percentage of time Te2 theta leads the BLA during remote memory recall correlates with a faster latency to freeze to the auditory conditioned stimulus. The blockade of this information transfer via Te2 inhibition with muscimol prevents any retrieval-evoked neuronal activity in the BLA and animals are unable to retrieve remote memories. We conclude that memories stored in higher-order sensory cortices drive BLA activity when distinguishing between learned threatening and neutral stimuli.

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How and where sensory stimuli, such as tones or lights, are linked to valence is an important unresolved question in the field of neuroscience. The auditory cortex is essential to analyse the identity and the behavioural importance of tones paired with emotional events. On the contrary, whether the auditory cortex may also encode information on the emotional-motivational valence of sounds is much more controversial. Here, we reviewed recent studies showing that the activity of cortical neurons reflects information about the content of emotional stimuli paired with tones. Critically, the blockade of these neuronal processes prevents animals from recognising sounds as aversive or pleasant. Based on these findings, we proposed a conceptual model in which the auditory cortex may incorporate ascending information from subcortical nuclei about the valence of sounds in sound representations and may consequently drive the activity of subcortical structures towards emotionally laden tones. This hypothesis may also have important implications in the characterisation of neural circuits engaged by maladaptive affective disorders, such as phobias.

Sox2 is a transcription factor active in the nervous system, within different cell types, ranging from radial glia neural stem cells to a few specific types of differentiated glia and neurons. Mutations in the human SOX2 transcription factor gene cause various central nervous system (CNS) abnormalities, involving hippocampus and eye defects, as well as ataxia. Conditional Sox2 mutation in mouse, with different Cre transgenes, previously recapitulated different essential features of the disease, such as hippocampus and eye defects. In the cerebellum, Sox2 is active from early embryogenesis in the neural progenitors of the cerebellar primordium; Sox2 expression is maintained, postnatally, within Bergmann glia (BG), a differentiated cell type essential for Purkinje neurons functionality and correct motor control. By performing Sox2 Cre-mediated ablation in the developing and postnatal mouse cerebellum, we reproduced ataxia features. Embryonic Sox2 deletion (with Wnt1Cre) leads to reduction of the cerebellar vermis, known to be commonly related to ataxia, preceded by deregulation of Otx2 and Gbx2, critical regulators of vermis development. Postnatally, BG is progressively disorganized, mislocalized, and reduced in mutants. Sox2 postnatal deletion, specifically induced in glia (with GLAST-CreERT2), reproduces the BG defect, and causes (milder) ataxic features. Our results define a role for Sox2 in cerebellar function and development, and identify a functional requirement for Sox2 within postnatal BG, of potential relevance for ataxia in mouse mutants, and in human patients.

The medial prefrontal cortex and the basolateral amygdala (BLA) are essential for discriminating between harmful and safe stimuli. The primary auditory cortex (Te1) sends projections to both sites, but whether and how it interacts with these areas during fear discrimination are poorly understood. Here we show that in male rats that can differentiate between a new tone and a threatening one, the selective optogenetic inhibition of Te1 axon terminals into the prelimbic (PL) cortex shifted discrimination to fear generalization. Meanwhile, no effects were detected when Te1 terminals were inhibited in the BLA. Using a combination of local field potential and multiunit recordings, we show that in animals that discriminate successfully between a new tone and a harmful one, the activity of the Te1 and the PL cortex becomes immediately and tightly synchronized in the slow-gamma range (40-70 Hz) at the onset of the new tone. This enhanced synchronization was not present in other frequency ranges, such as the theta range. Critically, the level of gamma synchrony predicted the behavioral choice (i.e., no freezing or freezing) of the animals. Moreover, in the same rats, gamma synchrony was absent before the fear-learning trial and when animals should discriminate between an olfactory stimulus and the auditory harmful one. Thus, our findings reveal that the Te1 and the PL cortex dynamically establish a functional connection during auditory fear-discrimination processes, and that this corticocortical oscillatory mechanism drives the behavioral choice of the animals. Identifying neural networks that infer safety versus danger is of great interest in the scientific field. Fear generalization reduces the chances of an animal's survival and leads to psychiatric diseases, such as post-traumatic stress disorders and phobias in humans. Here we demonstrate that animals able to differentiate a new tone from a previous threating tone showed synchronization between the prefrontal and primary auditory cortices. Critically, this connectivity precedes and predicts the behavioral outcome of the animal. Optogenetic inhibition of this functional connectivity leads to fear generalization. To the best of our knowledge, this study is the first to demonstrate that a corticocortical dialogue occurring between sensory and prefrontal areas is a key node for fear-discrimination processes.