Biology subjects

Lukas, M.

Publications and source records attributed to Lukas, M..

6 recordsLinked to original sources

bioRxiv2025

Synergistic olfactory nerve input and cholinergic neuromodulation can activate ERK in rat olfactory bulb vasopressin cells

Social discrimination in rats relies on vasopressin cells (VPCs) intrinsic to the olfactory bulb (OB). We had observed that VPCs responded to electrical stimulation of the olfactory nerve in acute OB slices with inhibitory postsynaptic potentials, and that the neuromodulator acetylcholine could revert these responses to excitation, resulting in action potentials (AP). Moreover, in behaving rats that were exposed to conspecifics, more VPCs were immunopositive to the neural activity marker pERK (pERK+ VPC) than in control rats. However, it is unclear whether these two observations, the increased ERK activation in vivo, and the generation of APs in the presence of ACh in vitro, can be actually mapped onto each other. Here we investigated ERK activation in acute OB slices from transgenic VP-eGFP rats upon either chemical stimulation or tetanic olfactory nerve stimulation. Both KCl and NMDA stimulation resulted in substantial pERK induction across bulbar layers and caused VPC spiking in whole-cell recordings, but only NMDA slightly increased pERK+ VPC percentage. Tetanic olfactory nerve stimulation yielded localized, column-like ERK activation of neurons across bulbar layers. The presence of ACh during tetanic stimulation substantially and specifically increased percentages of pERK+ VPCs within columns, indicating that columnar pERK+ VPCs were preferentially activated by coincident cholinergic neuromodulation and synaptic input. Our results validate pERK induction as a tool to monitor synaptic VPC excitation in the OB, and imply that depolarization of VPCs alone is insufficient to activate ERK. We propose that synaptically evoked APs are a prerequisite for pERK induction in VPCs.

neuroscience↗

bioRxiv2024

Vasopressin differentially modulates the excitability of rat olfactory bulb neuron subtypes

Vasopressin (VP) is essential for social memory already at the level of the olfactory bulb (OB), and OB VP cells are activated by social interaction. However, it remains unclear how VP modulates olfactory processing to enable enhanced discrimination of very similar odors, e.g., rat body odors. So far, it has been shown that VP reduces firing rates in mitral cells (MCs) during odor presentation in-vivo and decreases the amplitudes of olfactory nerve-evoked excitatory postsynaptic potentials (ON-evoked EPSPs) in external tufted cells in-vitro. We performed whole-cell patch-clamp recordings and population Ca2+ imaging on acute rat OB slices. We recorded ON-evoked EPSPs as well as spontaneous inhibitory postsynaptic currents (IPSCs) from two types of projection neurons, middle tufted cells (mTCs) and MCs. VP bath-application reduced the amplitudes of ON-evoked EPSPs and the frequencies of spontaneous IPSCs in mTCs but did not change those in MCs. Therefore, we analyzed ON evoked-EPSPs in inhibitory interneurons, i.e., periglomerular cells (PGCs) and granule cells (GCs), to search for the origin of increased inhibition in mTCs. However, VP did not increase the amplitudes of evoked EPSPs in either type of interneurons. We next performed two-photon population Ca2+ imaging in the glomerular layer and the superficial GC layer of responses to stronger ON stimulation than during patch-clamp experiments that should evoke action potentials in the measured cells. We observed that VP application increased ON-evoked Ca2+ influx in juxtaglomerular cell and GC somata and decreased it in the intraglomerular neuropil. Thus, our findings indicate inhibition by VP on projection neurons via strong ON input-mediated inhibitory interneuron activity.

neuroscience↗

bioRxiv2020

Top-down acetylcholine enables social discrimination via unlocking action potential generation in olfactory bulb vasopressin cells

Social discrimination in rats requires activation of the intrinsic bulbar vasopressin system, but it is unclear how this system comes into operation, as olfactory nerve stimulation primarily inhibits bulbar vasopressin cells (VPCs). Here we show that stimulation with a conspecific can activate bulbar VPCs, indicating that VPC activation depends on more than olfactory cues during social interaction. A series of in-vitro electrophysiology, pharmacology and immunohistochemistry experiments implies that acetylcholine probably originating from centrifugal projections can enable olfactory nerve-evoked action potentials in VPCs. Finally, cholinergic activation of the vasopressin system contributes to vasopressin-dependent social discrimination, since recognition of a known rat was blocked by bulbar infusion of the muscarinic acetylcholine receptor antagonist atropine and rescued by additional bulbar application of vasopressin. Thus, we demonstrated that top-down cholinergic modulation of bulbar VPC activity is involved in social discrimination in rats.

neuroscience↗

bioRxiv2020

Concerted but segregated actions of oxytocin and vasopressin within the ventral and dorsal lateral septum determine female aggression

In contrast to males, aggression in females has been rarely studied. Here, we established a rat model of enhanced female aggression using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialyses approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), are required for female aggression. Accordingly, increased excitability of OXT-responsive neurons in the vLS and decreased excitability of AVP-responsive neurons in the dLS were essential to evoke female aggression. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data demonstrate that septal release of OXT and AVP affects female aggression by differential regulation of the excitatory-inhibitory balance within subnetworks of the LS.

neuroscience↗

bioRxiv2020

Repetitive Transcranial Magnetic Stimulation Activates Glial Cells and Inhibits Neurogenesis after Pneumococcal Meningitis

Pneumococcal meningitis (PM) causes damage to the hippocampus, a brain structure critically involved in learning and memory. Hippocampal injury - which compromises neurofunctional outcome - occurs as apoptosis of progenitor cells and immature neurons of the hippocampal dentate granule cell layer thereby impairing the regenerative capacity of the hippocampal stem cell niche. Repetitive transcranial magnetic stimulation (rTMS) harbours the potential to modulate the proliferative activity of this neuronal stem cell niche. In this study, specific rTMS protocols - namely continuous and intermittent theta burst stimulation (cTBS and iTBS) - were applied on infant rats microbiologically cured from PM by five days of antibiotic treatment. Following two days of exposure to TBS, differential gene expression was analysed by whole transcriptome analysis using RNAseq. cTBS provoked a prominent effect in inducing differential gene expression in the cortex and the hippocampus, whereas iTBS only affect gene expression in the cortex. TBS induced polarisation of microglia and astrocytes towards an inflammatory phenotype, while reducing neurogenesis, neuroplasticity and regeneration. cTBS was further found to induce the release of pro-inflammatory cytokines in vitro. We conclude that cTBS intensified neuroinflammation after PM, which translated into increased release of pro-inflammatory mediators thereby inhibiting neuroregeneration.

neuroscience↗

bioRxiv2018

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

Oncogenic MYC activation promotes cellular proliferation in Burkitt lymphoma (BL), but also induces cell cycle arrest and apoptosis mediated by TP53, a tumor suppressor gene that is mutated in 40% of BL cases. To identify therapeutic targets in BL, we investigated molecular dependencies in BL cell lines using RNAi-based, loss-of-function screening. By integrating genotypic and RNAi data, we identified a number of genotype-specific dependencies including the dependence of TCF3/ID3 mutant cell lines on TCF3 and of MYD88 mutant cell lines on TLR signaling. TP53 wild-type (TP53wt) BL were dependent on MDM4, a negative regulator of TP53. In BL cell lines, MDM4 knockdown induced cell cycle arrest and decreased tumor growth in a xenograft model in a p53-dependent manner, while small molecule inhibition of the MDM4-p53 interaction restored p53 activity resulting in cell cycle arrest. Consistent with the pathogenic effect of MDM4 upregulation in BL, we found that TP53wt BL samples were enriched for gain of chromosome 1q which includes the MDM4 locus. 1q gain was also enriched across non-BL cancer cell lines (n=789) without TP53 mutation (23% in TP53wt and 12% in TP53mut, p<0.001). In a set of 216 cell lines representing 19 cancer entities from the Achilles project, MDM4 was the strongest genetic dependency in TP53wt cell lines (p<0.001).\n\nOur findings show that in TP53wt BL, MDM4-mediated inhibition of p53 is a mechanism to evade cell cycle arrest. The data highlight the critical role of p53 as a tumor suppressor in BL, and identifies MDM4 as a key functional target of 1q gain in a wide range of cancers, which is therapeutically targetable.

cancer biology↗