There is a change concerning the next Nencki Institute Seminar on Thursday, June 17th.
We will have two presenters first Kamil Tomaszewski, a PhD student in the Laboratory of Molecular Basis of Behavior led by Prof. Katarzyna Radwańska, will give a lecture entitled: A thalamo-septal circuit mediates extinction of remote fear memories.
Memory formation and updating require an orchestrated action of multiple brain regions. A detailed description of the circuits is crucial to understand the complexity of memory processing. Current knowledge describes how the recent memory (24-hour old) is encoded, stored, and recalled. It is, however, less understood how time affects memory processing and the circuits involved in it.
Alpha Ca2+/calmodulin-dependent kinase II (αCaMKII) plays a pivotal role in synaptic plasticity as well as memory formation and extinction. Here I show that αCaMKII autophosphorylation-deficient heterozygous mice (T286A+/-) present an impaired remote (30-days old) but not recent fear memory extinction. This observation suggests that αCaMKII autophosphorylation is involved in long-term memory processing in the brain.
Using c-Fos immunostaining, I examined the activation of 24 brain regions upon recent and remote fear extinction in WT and T286A+/- mice. Identification of neuronal substrates of remote fear extinction and its impairment allowed me to test their role in vivo, through chemogenetic manipulation of specific brain regions and projections. Next, using graph-theoretical concepts I compared global properties of functional networks of successful vs. impaired extinction.
I found that extinction of remote fear is associated with higher activation of the septal area, entorhinal cortex, and basolateral amygdalar complex, while its impairment hyper-activates septal area, entorhinal cortex, and thalamic regions.
The chemogenetic inactivation of medial septum (MS) during contextual fear extinction training results in impaired extinction of remote, but not recent fear memory. Whereas inhibition of nucleus reuniens (RE) impairs extinction of the remote, and facilitates the recent fear memory, revealing the time-dependent dual role of RE in contextual fear memory processing. Consequently, inhibition of the RE to MS projections (RE-MS) results in impaired remote fear extinction, which suggests that MS-projecting RE neurons control MS activity during extinction learning of remote contextual fear.
Taken together my results suggest that RE is actively involved in the processing of freshly acquired contextual fear memories and together with MS suppresses ones that happened in the past. Moreover, the RE-MS pathway is a part of the neuronal circuits that mediate remote fear memory extinction.
Then in the second part of the seminar, we will hear a talk by a PhD student Adria-Jaume Roura Canalda, from the Laboratory of Molecular Neurobiology led by Prof. Bożena Kamińska.
Title: A multi-omics study of high-grade glioma reveals relevant cancer features, immune gene expression signatures and abnormally activated transcription factors.
High-grade gliomas (HGGs), the most common and aggressive primary brain tumors in adults, inevitably recur due to incomplete surgery or therapy resistance. Therapeutic resistance, recurrence, and poor clinical outcomes are all linked to intratumoral genomic and cellular heterogeneity in HGGs. Their transcriptomic profiles after recurrence have not been thoroughly investigated. In the first part of my talk, I’ll discuss the results of targeted sequencing of cancer-related genes and transcriptomics in 16 pairs of primary and recurrent HGGs. We observed that the majority of somatic mutations found in primary HGGs were not found in relapsed tumors, and the presence of focal CNAs in the EGFR and PTEN genes was significantly negatively correlated. When compared to primary HGGs, transcriptomic analysis revealed that genes involved in mRNA splicing, cell cycle, and DNA repair are down-regulated, while genes involved in interferon signaling and phosphatidylinositol (PI) metabolism are up-regulated. M2 macrophages and immature dendritic cells were found to be enriched in recurrent HGGs in an in silico analysis of the tumor microenvironment, indicating a prominent immunosuppressive signature. Immunohistochemistry confirmed the accumulation of those cells in recurrent HGGs. Our findings point to a significant transcriptomic deregulation in recurrent HGG, as well as a significant infiltration of immature dendritic cells, both of which are novel factors to consider when introducing frontline immunotherapies in HGGs.
In the second half of my presentation, I’ll talk about gene expression deregulation and transcription factors (TFs) in established human glioblastoma cell lines (LN18 and LN229) and glioblastoma tumors. TF expression or activity changes are linked to a number of human diseases, including cancer. Several studies have shown that the expression of TFs involved in cell proliferation, survival, and apoptosis is altered in GBM, but the specific regulation of TFs in overexpressed GBM genes that are critical for cancer progression remains largely unknown. I’ll discuss the results of in silico TF binding sites identification in chromatin accessibility data (ATAC-seq) as well as their integration with transcriptomics and DNA methylation data. Our most intriguing finding suggests that the transcription factor c-Jun is involved in the regulation of overexpressed genes such as VIM, FOSL2 or TRIB1, some of which have been linked to the epithelial to mesenchymal cancer transition and tumor invasion. Overall, our analysis strategy allowed us to determine which crucial TFs that may play key roles in GBMs in comparison with benign tumors.
Meeting ID: 966 1729 0469