Biology subjects

Tomaszewski, K. F.

Publications and source records attributed to Tomaszewski, K. F..

5 recordsLinked to original sources

bioRxiv2024

Projections from thalamic nucleus reuniens to medial septum enable extinction of remote fear memory

Aversive experiences lead to the formation of long-lasting memories. Despite the need to better understand how enduring fear memories can be attenuated, the underlying brain circuits remain largely unknown. In this study, employing a combination of genetic manipulations, neuronal circuit mapping, and chemogenetics in mice, we identify a new projection from the thalamic nucleus reuniens (RE) to the medial septum (MS), and show that this circuit is involved in the extinction of remote (30-day old), but not recent (1-day old), fear memories. These findings provide the first functional description of the RE[->]MS circuit and highlight the significance of the thalamo-septal regions in memory organization as a function of memory age, a phenomenon known as systems consolidation.

neuroscience↗

bioRxiv2023

Identification of neuronal ensembles involved in remote fear memory extinction impairments

Remote memory consolidation, extinction, and its impairments have been of interest to researchers for years, especially due to its clinical relevance in patients with emotional disorders, like PTSD (Post Traumatic Stress Disorder), anxiety, and phobias. Its neuronal substrates are key elements to understand the persistent nature of remote memory and open a new perspective to novel therapeutic approaches for human fear-related disorders. While the majority of reports investigate the mechanisms and ensembles of recent fear memory extinction (hours to days following conditioning), only a few refer to the remote time point (i.e. weeks after conditioning), usually describing successful memory extinction. The neuronal correlates of impaired remote fear memory extinction were yet beyond the scope. Here we present selective impairment of contextual remote fear memory extinction in alpha calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation-limited mice (T286A+/-). To map brain regions involved in this phenomenon, we applied screening of c-Fos expression, a neuroplasticity marker, across 23 brain areas following contextual fear conditioning and extinction of recent (1-day old) and remote (30-days old) fear memory in WT and T286A+/- mice. Following impaired remote fear memory extinction in T286A+/- mice, we found upregulated c-Fos expression in the entorhinal cortex (ENT), nucleus reuniens (RE), centromedial (CM), mediodorsal (MD), anterodorsal (AD) thalamic nuclei, and medial septum (MS), compared to WT animals performing normal remote fear memory extinction. Thus our data suggest that CaMKII-autophosphorylation-dependent c-Fos expression in these areas controls distant contextual fear extinction and may shed light on these brain regions as potential targets for therapeutic strategies against emotional disorders such as PTSD.

animal behavior and cognition↗

bioRxiv2023

Phosphorylation of PSD-95 at Serine 73 in dCA1 is required for extinction of contextual fear

The updating of contextual memories is essential for survival in a changing environment. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular mechanisms of contextual fear memory updating remain poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic manipulations in vivo, combined with ex vivo 3D electron microscopy and electrophysiology, we identify a novel, synaptic mechanism that is induced during attenuation of contextual fear memories and involves phosphorylation of PSD-95 at Serine 73 in dCA1. Our data provide the proof that PSD-95-dependent synaptic plasticity in dCA1 is required for updating of contextual fear memory.

neuroscience↗

bioRxiv2022

Keratin 8 is a scaffolding and regulatory protein of ERAD complexes

Early recognition and enhanced degradation of misfolded proteins by the endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) cause defective protein secretion and membrane targeting, as exemplified for Z-alpha 1 antitrypsin (Z-A1AT), responsible for alpha-1-antitrypsin deficiency (A1ATD) and F508del-CFTR (cystic fibrosis transmembrane conductance regulator) responsible for cystic fibrosis (CF). Prompted by our previous observation that decreasing Keratin 8 (K8) expression increased trafficking of F508del-CFTR to the plasma membrane, we investigated whether K8 impacts trafficking of soluble misfolded Z-A1AT protein. The subsequent goal of this study was to elucidate the mechanism underlying the K8-dependent regulation of protein trafficking, focusing on the ERAD pathway. The results show that diminishing K8 concentration in HeLa cells enhances secretion of both Z-A1AT and wild type (WT) A1AT with a 13-fold and 4-fold increase, respectively. K8 down-regulation triggers ER failure and cellular apoptosis when ER stress is jointly elicited by conditional expression of the s heavy chains, as previously shown for Hrd1 knock-out. Simultaneous K8 silencing and Hrd1 knock-out did not show any synergistic effect, consistent with K8 acting in the Hrd1-governed ERAD step. Fractionation experiments reveal that K8 is recruited to ERAD complexes containing Derlin2, Sel1 and Hrd1 proteins upon expression of Z/WT-A1AT and F508del-CFTR. Treatment of the cells with c407, a small molecule inhibiting K8 interaction, decreases K8 and Derlin2 recruitment to high-order ERAD complexes. This was associated with increased Z-A1AT secretion in both HeLa and Z-homozygous A1ATD patients respiratory cells. Overall, we provide evidence that K8 acts as an ERAD modulator. It may play a scaffolding protein role for early-stage ERAD complexes, regulating Hrd1-governed retrotranslocation initiation/ubiquitination processes. Targeting K8-containing ERAD complexes is an attractive strategy for the pharmacotherapy of A1ATD.

cell biology↗

bioRxiv2020

PSD-95 in dorsal CA1 contributes to the persistence of fear memory

The ability to extinguish fearful memories is essential for survival. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular basis of fear memory extinction remains poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic and chemogenetic manipulations in vivo combined with PSD-95 immunostaining and 3D electron microscopy ex vivo, we demonstrate that phosphorylation of PSD-95 at serine 73 PSD-95(S73) is necessary for contextual fear extinction-induced expression of PSD-95 and synaptic plasticity. Moreover, PSD-95(S73) phosphorylation is not necessary for fear memory formation and recall but is required for extinction of contextual fear. Overall, our data shows how PSD-95-dependent synaptic plasticity in the hippocampus contributes to the persistence of fear memories.

neuroscience↗