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Bianca Silva
Institute of Molecular and Cellular Pharmacology, French National Centre for Scientific Research, Université Côte d'Azu, Valbonne, France
How are consolidated memories modified on the basis of experience? In this project we aimed to unravel the neural mechanisms at the basis of memory update. Understanding this biological process allows us to decipher how new information is constantly incorporated into existing memory, how a newly formed memory is integrated into previous knowledge and how the fine balance between memory stability and memory flexibility is maintained. By using fear memory extinction as a model of memory update, we combined neuronal circuit mapping, fiber photometry, chemogenetic and closed-loop optogenetic manipulations in mice, and showed that the extinction of remote (30-day old) fear memories depends on thalamic nucleus reuniens (NRe) inputs to the basolateral amygdala (BLA). We find that remote, but not recent (1-day old), fear extinction activates NRe to BLA inputs, which become potentiated upon fear reduction. Both monosynaptic NRe to BLA, and total NRe activity increase shortly before freezing cessation, suggesting that the NRe registers and transmits safety signals to the BLA. Accordingly, pan-NRe and pathway-specific NRe to BLA inhibition impairs, while their activation facilitates fear extinction. These findings identify the NRe as a crucial BLA regulator for extinction, and provide the first functional description of the circuits underlying the experience-based modification of consolidated fear memories.
Anthony Kischel
Synaptogenesis Group , Life Science & Biotechnology Center, Łukasiewicz Research Network – PORT Polish Center for Technology Development, Wrocław, Poland
The angiomotin family, composed of AMOT, AMOTL1, and AMOTL2, has been discovered to regulate angiogenesis by organizing the tight junctions, thereby establishing the cell polarity. The functions of angiomotins in the brain remain widely unknown. AMOT has been proposed to regulate dendritic spine development and dendritic tree complexity. Our current project is focused on AMOTL1's role in neurons. We have performed a panel of behavioral tests on AMOTL1 KO mice. Mutant mice exhibit locomotor hyperactivity in the open field, increased risk-taking behavior, turning behavior, and hypersensitivity to low doses of amphetamine, a compound that increases synaptic dopamine levels. Interestingly, AMOTL1 KO mice exhibit episodes of backward walking, usually induced in rodents by the administration of hallucinogenic drugs. Altogether, our results show that AMOTL1 KO mice recapitulate many features of Mania models and show a function of AMOTL1 in the brain for the first time.
Funding: NCN grant Opus 2019/33/B/NZ3/02528.
Katarzyna Hryniewiecka1, Magdalena Majkowska2, Ewa Kublik2, Joanna Urban-Ciećko3, Marta Wiśniewska2
1Laboratory of Molecular Neurobiology, Center of New Technologies, University of Warsaw, Warsaw, Poland
2Laboratory of Emotions Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
3Laboratory of Electrophysiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
TCF7L2 is a high-confidence risk gene for neurodevelopmental disorders (NDs), but its role in their pathogenesis is unknown. It is highly expressed in the thalamus – a candidate structure for NDs pathogenesis - regulating its electrophysiological maturation. To understand the role of thalamus-expressed Tcf7l2 in signal processing in thalamo-cortical circuits, we investigated consequences of its deficiency in the somatosensory circuit: first- and higher-order thalamic nuclei (VPM and POM) and the barrel cortex. Tcf7l2 postnatal thalamic knockout mice were used to assess signal gating mechanism in vivo (with prepulse inhibition paradigm and Neuropixels recordings). Moreover, we measured spontaneous miniature postsynaptic currents in vitro. Male knockout mice showed gating deficits across all considered areas - VPM (t(11) = 2.73, p <0.01); cortical layer 4 (t(17) = 2.22, p <0.05); 5 (t(22) = 2.17, p <0.05); 6 (U =23, p <0.0001) and POM (t(57) - 2.63, p <0.01). In females, minor differences were observed in VPM (t(30) = 2.13, p <0.05) and cortical layer 5 (t(25) = 2.31, p <0.05). Patch-clamp showed that the frequency of mIPSC was greatly decreased in VPM (U = 66, p <0.0001), while neurons of cortical layers 4 (U = 22, p <0.01) and 6 (t(13) = 2.51, p <0.05) showed frequency decrease in mEPSC. TCF7L2 deficiency in thalamic neurons leads to signal processing impairments in thalamo-cortical circuits. While the deficit in inhibitory activity in the thalamus is congruent with the impairment of gating, the decrease of excitation in cortical neurons might indicate the presence of compensatory mechanisms.
Funding: NCN OPUS 19 2020/37/B/NZ4/03261.
Aleksandra Nogaj1,Aleksandra Trenk1, Kinga Przybylska1, Anna Gugula1, Andrew L. Gundlach2, Anna Blasiak1
1Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland
2The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
Oxytocin (OXT) and relaxin-3 (RLN3) play crucial roles in regulating social behavior, stress responses, and anxiety. Research suggests KCNQ potassium channels involvement in both excitatory OXT and inhibitory RLN3 signaling. Receptors for OXT (OXTR) and RLN3 (RXFP3) are expressed by ventral hippocampal CA3 area (vCA3) neurons, known for the involvement in social behavior and anxiety control. However, the potential interplay between OXT and RLN3 in modulating vCA3 activity remains unexplored.
Fluorescence in situ hybridization (ISH) identified the neurochemical profile of OXTR and RXFP3 mRNA-expressing neurons in the vCA3. Our findings revealed that the majority of OXTR-positive neurons also expressed vGAT1 mRNA, and a subset of these co-expressed RXFP3 mRNA. Interestingly, RXFP3 mRNA was found in both inhibitory (vGAT1+) and excitatory (vGlut2+) vCA3 neurons.
Ex vivo multielectrode array (MEA) and patch-clamp recordings demonstrated that OXTR activation had an excitatory, while RXFP3 activation had an inhibitory effect on vCA3 neurons. Importantly, both effects were attenuated by XE-911, a selective KCNQ blocker.
Our findings suggest that OXT/OXTR and RLN3/RXFP3 signaling exert opposing effects on subpopulations of vCA3 neurons through differential modulation of KCNQ channels. Further studies are warranted to elucidate how these interactions contribute to behavioral outcomes.
Funding: National_Science_Centre_Poland (UMO-2018/30/E/NZ4/00687; UMO-2023/49/B/NZ4/01885).
Ana Rita Costa, Jakub Mlost, Iskra Pollak Dorocic
SciLifeLab, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
The intricate interplay between serotonin (5-HT) neurotransmission and specific neural circuits plays a crucial role in regulating various behavioral responses. Here, we investigate the role of distinct serotonergic projection pathways originating from the dorsal raphe nucleus (DRN) in modulating behavior, focusing on projections to the basolateral amygdala (BLA), ventral tegmental area (VTA), and lateral hypothalamic area (LHA). Using a combination of behavioral tests, including the elevated plus maze (EPM) and open field test (OFT), coupled with chemogenetics and in vivo calcium imaging in SERT-cre mice, as well as advanced machine-learning techniques, we explore the behavioral outcomes resulting from selective manipulation of these pathways. We have established increased activity of serotonergic neurons projecting to BLA, VTA and LHA by fiber photometry, when the animals spend time in the open arms of EPM. We have also discovered that chemogenetic inhibition of neurons projecting to BLA elicits changes in exploratory behavior and anxiety-like behavior. Unsupervised learning classifier technique allows us to cluster a number of stereotypic behavioral motifs in OFT that can be modulated by a specific chemogenetic modulation of distinct serotonergic projections. Our findings delineate the role of projection-specific serotonin pathways in shaping different behavioral responses and highlight the nuanced functional neuroanatomy of DR.
Funding: Polish National Agency of Academic Exchange BPN/BEK/2021/1/00152 and SciLifeLab RED Postdoctoral Fellowships fund.
Oskar Markkula1, Viviana M.F. Ritacco1, Melis Bayer1, Ian D. Forsythe2, Conny Kopp-Scheinpflug1
1Division of Neurobiology, Faculty of Biology, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany
2School of Psychology & Vision Sciences, College of Life Sciences, University of Leicester, Leicester, UK
Aims: SCA13 patients exhibit an extracerebellar auditory phenotype characterized by sound localization deficits, despite normal audiograms. This phenotype is caused by the R420H point mutation in the KCNC3 gene which encodes for Kv3.3 subunits of high-voltage gated potassium channels. Here, we investigate how this mutation leads to disruption of temporal processing along the auditory pathway. Methods: The R420H mouse model was created using CRISPR-Cas9. Whole-cell patch-clamp electrophysiology and afferent synaptic stimulation in acute mouse brain slices were used to characterize neural firing properties of affected auditory neurons. Degrees of neurodegeneration were assessed via cell number, cell size, p62/cleaved caspase expression and subcellular distribution of Kv3.3. Results: In contrast to cerebellar Purkinje neurons, auditory brainstem neurons survive in age-matched SCA13 mice. Action potential (AP) half-widths of lateral superior olive (LSO) neurons increased in duration by around 2–3 fold. Recovery from refractory periods between APs were insufficient and this prevented the characteristic high-frequency AP following in response to synaptic train inputs. Coimmunolabelling of Kv3.3 protein with the vesicular glutamate transporter protein (VGluT1) and neuronal glycine transporter protein (GlyT2) indicated expression of Kv3.3 in excitatory and inhibitory synapses, respectively.
Conclusions: The largely prolonged AP duration in LSO neurons disrupts high-frequency firing which likely contributes the sound localization deficits observed in the human kindred of SCA13. The survival of LSO neurons in 6-month old homozygote mice are in stark contrast to the loss of Purkinje neurons in the same mice and may provide a target to investigate neuroprotective mechanisms in degenerative disease models.
