The non-coding RNA subunit of telomerase provides the template for telomerase activity. In diverse fungi, 3' end processing of telomerase RNA involves a single cleavage by the spliceosome. Here, we examine how human telomerase RNA (hTR) primary transcripts are processed into the mature form of precisely 451 nt. We find that the splicing inhibitor isoginkgetin mimics the effects of RNA exosome inhibition and causes accumulation of long hTR transcripts. Depletion of exosome components and accessory factors reveals functions for the cap binding complex (CBC) and the nuclear exosome targeting (NEXT) complex in hTR turnover. Whereas longer transcripts are predominantly degraded, shorter precursor RNAs are oligo-adenylated by TRF4-2 and either processed by poly(A)-specific ribonuclease (PARN) or degraded by the exosome. Our results reveal that hTR biogenesis involves a kinetic competition between RNA processing and degradation and suggest treatment options for telomerase insufficiency disorders.

These results suggest that progressive fear attenuation mediated by repetitive exposure is accompanied by sustained neuronal activation and not reverted to a pre-conditioning brain state. These findings contribute to the identification of brain areas as targets for therapeutic approaches against traumatic memories.

Fear and trauma generate some of the longest-lived memories. Despite the corresponding need to better understand how enduring fear memories can be attenuated, the underlying brain circuits remain largely unknown. Here, using a combination of neuronal circuit mapping, in vivo fiber photometry, chemogenetic and closed-loop optogenetic manipulation of neuronal activity in mice, we show that the extinction of remote, i.e., 30-day old, fear memories depends on thalamic nucleus reuniens (NRe) inputs to the basolateral amygdala (BLA). We find that remote fear memory extinction activates NRe to BLA inputs, which are potentiated upon fear reduction. Furthermore, both monosynaptic NRe to BLA, and total NRe activity increase shortly before the end of freezing bouts during remote fear extinction, suggesting that the NRe registers and transmits extinction signals to the BLA. Accordingly, pan-NRe as well as pathway-specific NRe to BLA inhibition impairs, while their activation facilitates remote fear extinction. These findings provide the first functional description of the circuits underlying remote fear memory extinction and identify the NRe as a crucial upstream regulator of the BLA for this process.

No abstract

Significance Memory formation relies on a plethora of functions, including epigenetic modifications. Over recent years, multiple studies have indicated the potential of HDAC inhibitors (HDACis) as cognitive enhancers, but their mode of action is not fully understood. Here, we tested whether HDACi treatment improves memory formation via “cognitive epigenetic priming,” stipulating that HDACis—without inherent target specificity—specifically enhance naturally occurring plasticity processes. We found that combining HDACis with fear learning, but not either treatment alone, enhances synaptic plasticity as well as memory-promoting transcriptional signaling in the hippocampus, a brain area recruited by fear learning, but not in unrelated areas. These results lend experimental support to the theory of cognitive epigenetic priming.