Synaptic inhibition in the lateral habenula shapes reward anticipation

The lateral habenula (LHb) supports learning processes enabling the prediction of upcoming rewards. While reward-related stimuli decrease the activity of LHb neurons, whether this anchors on synaptic inhibition to guide reward-driven behaviors remains poorly understood. Here, we combine in vivo two-photon calcium imaging with Pavlovian conditioning in mice and report that anticipatory licking emerges along with decreases in cue-evoked calcium signals in individual LHb neurons. In vivo multiunit recordings and pharmacology reveal that the cue-evoked reduction in LHb neuronal firing relies on GABAA-receptor activation. In parallel, we observe a postsynaptic potentiation of GABAA-receptor-mediated inhibition, but not excitation, onto LHb neurons together with the establishment of anticipatory licking. Finally, strengthening or weakening postsynaptic inhibition with optogenetics and GABAA-receptor manipulations enhances or reduces anticipatory licking, respectively. Hence, synaptic inhibition in the LHb shapes reward anticipation. Keywords: GABA(A) receptors; cue-reward associative behavior; lateral habenula; synaptic inhibition; synaptic plasticit

Morphine withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability.

The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal

Intronic L1 Retrotransposons and Nested Genes Cause Transcriptional Interference by Inducing Intron Retention, Exonization and Cryptic Polyadenylation

Transcriptional interference has been recently recognized as an unexpectedly complex and mostly negative regulation of genes. Despite a relatively few studies that emerged in recent years, it has been demonstrated that a readthrough transcription derived from one gene can influence the transcription of another overlapping or nested gene. However, the molecular effects resulting from this interaction are largely unknown.Using in silico chromosome walking, we searched for prematurely terminated transcripts bearing signatures of intron retention or exonization of intronic sequence at their 3' ends upstream to human L1 retrotransposons, protein-coding and noncoding nested genes. We demonstrate that transcriptional interference induced by intronic L1s (or other repeated DNAs) and nested genes could be characterized by intron retention, forced exonization and cryptic polyadenylation. These molecular effects were revealed from the analysis of endogenous transcripts derived from different cell lines and tissues and confirmed by the expression of three minigenes in cell culture. While intron retention and exonization were comparably observed in introns upstream to L1s, forced exonization was preferentially detected in nested genes. Transcriptional interference induced by L1 or nested genes was dependent on the presence or absence of cryptic splice sites, affected the inclusion or exclusion of the upstream exon and the use of cryptic polyadenylation signals.Our results suggest that transcriptional interference induced by intronic L1s and nested genes could influence the transcription of the large number of genes in normal as well as in tumor tissues. Therefore, this type of interference could have a major impact on the regulation of the host gene expression

Co-chaperones are limiting in a depleted chaperone network

To probe the limiting nodes in the chaperoning network which maintains cellular proteostasis, we expressed a dominant negative mutant of heat shock factor 1 (dnHSF1), the regulator of the cytoplasmic proteotoxic stress response. Microarray analysis of non-stressed dnHSF1 cells showed a two- or more fold decrease in the transcript level of 10 genes, amongst which are the (co-)chaperone genes HSP90AA1, HSPA6, DNAJB1 and HSPB1. Glucocorticoid signaling, which requires the Hsp70 and the Hsp90 folding machines, was severely impaired by dnHSF1, but fully rescued by expression of DNAJA1 or DNAJB1, and partially by ST13. Expression of DNAJB6, DNAJB8, HSPA1A, HSPB1, HSPB8, or STIP1 had no effect while HSP90AA1 even inhibited. PTGES3 (p23) inhibited only in control cells. Our results suggest that the DNAJ co-chaperones in particular become limiting in a depleted chaperoning network. Our results also suggest a difference between the transcriptomes of cells lacking HSF1 and cells expressing dnHSF1

Mild stress accumulation limits GABAergic synaptic plasticity in the lateral habenula.

Animals can cope with isolated stressful situations without enduring long-term consequences. However, when exposure to stressors becomes recurrent, behavioural symptoms of anxiety and depression can emerge. Yet, the neuronal mechanisms governing responsivity to isolated stressor remain elusive. Here, we investigate synaptic adaptations following mild stress in the lateral habenula (LHb), a structure engaged in aversion encoding and dysfunctional in depression. We describe that neuronal depolarization in the LHb drives long-term depression of inhibitory, but not excitatory, synaptic transmission (GABA LTD). This plasticity requires nitric oxide and presynaptic GABA <sub>B</sub> receptors, leading to a decrease in probability of GABA release. Mild stressors such as brief social isolation, or exposure to novel environment in the company of littermates, do not alter GABA LTD. In contrast, GABA LTD is absent after mice experience a novel environment in social isolation. Altogether, our results suggest that LHb GABAergic plasticity is sensitive to stress accumulation, which could represent a threshold mechanism for long-term alterations of LHb function

Biophysical and synaptic properties of NMDA receptors in the lateral habenula.

Excitatory synaptic transmission in the lateral habenula (LHb), an evolutionarily ancient subcortical structure, encodes aversive stimuli and affective states. Habenular glutamatergic synapses contribute to these processes partly through the activation of AMPA receptors. Yet, N-methyl-d-aspartate receptors (NMDARs) are also expressed in the LHb and support the emergence of depressive symptoms. Indeed, local NMDAR blockade in the LHb rescues anhedonia and behavioral despair in rodent models of depression. However, the subunit composition and biophysical properties of habenular NMDARs remain unknown, thereby hindering their study in the context of mental health. Here, we performed electrophysiological recordings and optogenetic-assisted circuit mapping in mice, to study pharmacologically-isolated NMDAR currents in LHb neurons that receive innervation from different brain regions (entopeduncular nucleus, lateral hypothalamic area, bed nucleus of the stria terminalis, or ventral tegmental area). This systematic approach revealed that habenular NMDAR currents are sensitive to TCN and ifenprodil - drugs that specifically inhibit GluN2A- and GluN2B-containing NMDARs, respectively. Whilst these pharmacological effects were consistently observed across inputs, we detected region-specific differences in the current-voltage relationship and decay time of NMDAR currents. Finally, inspired by the firing of LHb neurons in vivo, we designed a burst protocol capable of eliciting calcium-dependent long-term potentiation of habenular NMDAR transmission ex vivo. Altogether, we define basic biophysical and synaptic properties of NMDARs in LHb neurons, opening new avenues for studying their plasticity processes in physiological as well as pathological contexts

INHOMOGENEOUS DEPHASING INHIBITION BY A STRONG STOCHASTIC FIELD

On s'intéresse à la formation de signaux optiques transitoires cohérents produits, lors de la remise en phase de dipôles créés sous l'action d'une impulsion lumineuse large bande. Un effet d'inhibition du déphasage inhomogène est attendu qui repose sur l'hypothèse d'absence de corrélation à long terme dans le champ excitateur. Le modèle théorique ainsi développé est appliqué au cas particulier des échos de photons stimulés en configuration non colinéaire. L'effet d'inhibition prédit est observé dans une vapeur de calcium.We examine the formation of coherent transient optical signals produced by the rephasing of dipoles which are built up by a strong broadband light pulse. The inhibition of inhomogeneous dephasing by a strong stochastic field is predicted with provision that the light field satisfies the short-time correlation condition. The model is applied to the specific situation of stimulated photon echo in an angled beam configuration. The expected inhibition effect is demonstrated in a calcium vapor

Stochastic field-induced nonlocal resonances in four-wave mixing

We explore theoretically the signal generated by a fluctuating radiation field via a four-wave mixing process in an atomic vapor undergoing Markovian dephasing collisions. We consider specifically a broadband laser field well detuned from the atomic resonance and calculate the signal generated using counterpropagating pump fields as a function of the time delay of the incident probe field. We assume that the pulse duration is long compared to the correlation time of the incident fields. By considering the various time-ordered pathways and treating the incident-field amplitudes as random Gaussian variables, we find that the signal generated is dominated by two specific pathways that depend only on the incident-field bandwidth and the decay rate of the ground to excited state coherence. An interesting aspect of the far-impact-detuning case is that the signal is dominated by resonances involving spatially separated atoms. Our formalism provides a basis for describing the effects of mode correlations on four-wave-mixing signals generated by stochastic fields