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Tuduri, P.

Publications and source records attributed to Tuduri, P..

4 recordsLinked to original sources

D2-expressing neurons of the anterior paraventricular nucleus of the thalamus modulate learned aversive and safety salience

Associative learning provides a means to assign appropriate value signals to experiences that animals can later use to make appropriate value-based choices. By generalizing from prior aversive experiences and comparing with a current experience, animals can learn the relative aversive ("better or worse than") value or relative positive safety value between experiences. Yet, how such relative value signals are acquired during learning remain poorly known. The paraventricular nucleus of the thalamus (PVT) is critical for the control of salience and valence signals. It is therefore well-placed to be involved in learning relative aversive value and learned safety. Using a newly-developed conditioned place preference task, we uncover specific behavioral signatures associated with learning relative aversive value and learned safety, and related value-based choices. We then show that neurons expressing dopamine D2 receptor (D2+) in the anterior PVT (aPVT) are preferentially recruited by both relative aversive value learning and learned safety. Using a pharmacogenetic strategy, we demonstrate that aPVT D2+, but not D2-, neurons are involved in learning relative- but not absolute- aversive value. Finally, we show that aPVT D2+, but not D2-, neurons are also critical for the encoding of learned safety. Overall, our findings reveal a novel role of aPVT D2+ neurons in computing relative aversive/safety value signals between experiences during learning to promote appropriate value-based choices.

animal behavior and cognition↗

Dopamine D2 Receptors modulate hippocampal theta rhythm through somatostatin interneurons

Spatiomolecular mapping of hippocampal dopamine receptor D2 (D2R) neurons revealed that in addition to hilar mossy cells, hippocampal SST-INs and, to a lesser extent, PV-INs expressed D2R. However, while the role of D2R signaling onto mossy cells has been characterized, the consequence of D2R activation onto hippocampal SST-INs and PV-INs is unknown. By combining pharmacological approaches and patch-clamp recordings in organotypic hippocampal slices from control or mice lacking Drd2 selectively in SST-INs and PV-INs, we found that D2R activation increase excitability in SST-INs while it decreases in PV-INs. These D2R-mediated changes rely on distinct intracellular pathways, involving the non-canonical {beta}- arrestin-dependent pathway in SST-INs and the G protein-dependent pathway in PV-INs. Finally, our study also unveiled that D2R activation modulates theta oscillations through SST- INs D2R signaling.

neuroscience↗

Modulation of hippocampal network oscillation by PICK1-dependent cell surface expression of mGlu3 receptors

mGlu3 receptors control the sleep/wake architecture which plays a role in the glutamatergic pathophysiology of schizophrenia. Interestingly, mGlu3 receptors expression is decreased in the brain of schizophrenic patients. However, little is known about the molecular mechanisms regulating mGlu3 receptors at the cell membrane. Subcellular receptor localization is strongly dependent on proteinprotein interactions. Here we show that mGlu3 interacts with PICK1 and that their binding is important for receptor surface expression and function. Disruption of their interaction via an mGlu3 C-terminal mimicking peptide or an inhibitor of the PDZ domain of PICK1 altered the functional expression of mGlu3 receptors. Consequently, we investigated whether disruption of the mGlu3-PICK1 interaction affects hippocampal theta oscillations in vitro and in vivo. We found a decreased frequency of theta oscillations in organotypic hippocampal slices, similar to what previously observed in mGlu3 -/- mice. In addition, hippocampal theta power was reduced during REM sleep, NREM sleep and wake states after intra-ventricular administration of the mGlu3 C-terminal mimicking peptide. Targeting the mGlu3-PICK1 complex could thus be relevant to the pathophysiology of schizophrenia.

neuroscience↗

The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures. We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazol systemic injection), LSP2-9166 induces an antiepileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found LSP2-9166 reduced seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti epileptic drug on established seizures in both models tested. Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling.

neuroscience↗