Alvaro Nuno‐Perez

University of Lausanne

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Manuel Mameli

University of Lausanne

Anna Tchenio

Université Paris Sciences et Lettres

Salvatore Lecca

University of Lausanne

Arnaud L. Lalive

University of Lausanne

Mauro Congiu

University of Lausanne

Julijana Gjorgjieva

Max Planck Institute for Brain Research

Elizabeth A. D. Hammock

Florida State University

Christian Löhmann

Netherlands Institute for Neuroscience

Jan H. Kirchner

Technical University of Munich

Massimo Trusel

The University of Texas Southwestern Medical Center

Cooperative Institutions

University of Lausanne

Inserm

Sorbonne Université

Institut du Fer à Moulin

Centro Universitário Filadélfia

Centre National de la Recherche Scientifique

Neurosciences Paris-Seine

Heidelberg University

University of Cagliari

Neuroscience Institute

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Biophysical and synaptic properties of NMDA receptors in the lateral habenula

Neuropharmacology (2021)

Alvaro Nuno‐Perez Sarah Mondoloni Anna Tchenio Salvatore Lecca Manuel Mameli

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.

Habenula

10.1016/j.neuropharm.2021.108718

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Citations (7)

Lateral Habenula Gone Awry in Depression: Bridging Cellular Adaptations With Therapeutics

Frontiers in Neuroscience (2018)

Alvaro Nuno‐Perez Anna Tchenio Manuel Mameli Salvatore Lecca

Depression is a highly heterogeneous disease characterized by symptoms spanning from anhedonia and behavioral despair to social withdrawal and learning deficit. Such diversity of behavioral phenotypes suggests that discrete neural circuits may underlie precise aspects of the disease, rendering its treatment an unmet challenge for modern neuroscience. Evidence from humans and animal models indicate that the lateral habenula (LHb), an epithalamic center devoted to processing aversive stimuli, is aberrantly affected during depression. This raises the hypothesis that rescuing maladaptations within this nucleus may be a potential way to, at least partially, treat aspects of mood disorders. In this review article, we will discuss pre-clinical and clinical evidence highlighting the role of LHb and its cellular adaptations in depression. We will then describe interventional approaches aiming to rescue LHb dysfunction and ultimately ameliorate depressive symptoms. Altogether, we aim to merge the mechanistic-, circuit- and behavioral-level knowledge obtained about LHb maladaptations in depression to build a general framework that might prove valuable for potential therapeutic interventions.

Anhedonia

Habenula

10.3389/fnins.2018.00485

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Citations (30)

Oxytocin shapes spontaneous activity patterns in the developing visual cortex by activating somatostatin interneurons

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Paloma P. Maldonado Alvaro Nuno‐Perez Jan H. Kirchner Elizabeth A. D. Hammock Julijana Gjorgjieva

Summary Spontaneous network activity shapes emerging neuronal circuits during early brain development, however how neuromodulation influences this activity is not fully understood. Here, we report that the neuromodulator oxytocin powerfully shapes spontaneous activity patterns. In vivo , oxytocin strongly decreased the frequency and pairwise correlations of spontaneous activity events in visual cortex (V1), but not in somatosensory cortex (S1). This differential effect was a consequence of oxytocin only increasing inhibition in V1 and increasing both inhibition and excitation in S1. The increase in inhibition was mediated by the depolarization and increase in excitability of somatostatin + (SST) interneurons specifically. Accordingly, silencing SST + neurons pharmacogenetically fully blocked oxytocin’s effect on inhibition in vitro as well its effect on spontaneous activity patterns in vivo . Thus, oxytocin decreases the excitatory/inhibitory ratio and modulates specific features of V1 spontaneous activity patterns that are crucial for refining developing synaptic connections and sensory processing later in life.

Neuromodulation

Barrel cortex

Premovement neuronal activity

10.1101/866251

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Citations (1)

Punishment-Predictive Cues Guide Avoidance through Potentiation of Hypothalamus-to-Habenula Synapses

Neuron (2019)

Massimo Trusel Alvaro Nuno‐Perez Salvatore Lecca Harumi Harada Arnaud L. Lalive

Punishment (psychology)

Habenula

Associative learning

10.1016/j.neuron.2019.01.025

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Citations (78)

Mild stress accumulation limits GABAergic synaptic plasticity in the lateral habenula

European Journal of Neuroscience (2021)

Arnaud L. Lalive Alvaro Nuno‐Perez Anna Tchenio Manuel Mameli

Abstract 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 B 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.

Habenula

10.1111/ejn.15581

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Citations (8)

Stress undermines reward-guided cognitive performance through synaptic depression in the lateral habenula

Neuron (2021)

Alvaro Nuno‐Perez Massimo Trusel Arnaud L. Lalive Mauro Congiu Denise Gastaldo

Weighing alternatives during reward pursuit is a vital cognitive computation that, when disrupted by stress, yields aspects of neuropsychiatric disorders. To examine the neural mechanisms underlying these phenomena, we employed a behavioral task in which mice were confronted by a reward and its omission (i.e., error). The experience of error outcomes engaged neuronal dynamics within the lateral habenula (LHb), a subcortical structure that supports appetitive behaviors and is susceptible to stress. A high incidence of errors predicted low strength of habenular excitatory synapses. Accordingly, stressful experiences increased error choices while decreasing glutamatergic neurotransmission onto LHb neurons. This synaptic adaptation required a reduction in postsynaptic AMPA receptors (AMPARs), irrespective of the anatomical source of glutamate. Bidirectional control of habenular AMPAR transmission recapitulated and averted stress-driven cognitive deficits. Thus, a subcortical synaptic mechanism vulnerable to stress underlies behavioral efficiency during cognitive performance.

Habenula

10.1016/j.neuron.2021.01.008

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Citations (46)

In DA Club of Reinforcement: Glutamate, It’s Your Birthday

Neuron (2020)

Alvaro Nuno‐Perez Manuel Mameli

10.1016/j.neuron.2020.07.036

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Citations (22)

Oxytocin Shapes Spontaneous Activity Patterns in the Developing Visual Cortex by Activating Somatostatin Interneurons

Current Biology (2020)

Paloma P. Maldonado Alvaro Nuno‐Perez Jan H. Kirchner Elizabeth A. D. Hammock Julijana Gjorgjieva

Spontaneous network activity shapes emerging neuronal circuits during early brain development prior to sensory perception. However, how neuromodulation influences this activity is not fully understood. Here, we report that the neuromodulator oxytocin differentially shapes spontaneous activity patterns across sensory cortices. In vivo, oxytocin strongly decreased the frequency and pairwise correlations of spontaneous activity events in the primary visual cortex (V1), but it did not affect the frequency of spontaneous network events in the somatosensory cortex (S1). Patch-clamp recordings in slices and RNAscope showed that oxytocin affects S1 excitatory and inhibitory neurons similarly, whereas in V1, oxytocin targets only inhibitory neurons. Somatostatin-positive (SST+) interneurons expressed the oxytocin receptor and were activated by oxytocin in V1. Accordingly, pharmacogenetic silencing of V1 SST+ interneurons fully blocked oxytocin's effect on inhibition in vitro as well its effect on spontaneous activity patterns in vivo. Thus, oxytocin decreases the excitatory/inhibitory (E/I) ratio by recruiting SST+ interneurons and modulates specific features of V1 spontaneous activity patterns that are crucial for the wiring and refining of developing sensory circuits.

10.1016/j.cub.2020.10.028

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Citations (30)

Cocaine withdrawal reduces GABA_BR transmission at entopeduncular nucleus – lateral habenula synapses

European Journal of Neuroscience (2018)

Dorine Tan Alvaro Nuno‐Perez Manuel Mameli Frank J. Meye

Lateral habenula (LHb) hyperactivity plays a pivotal role in the emergence of negative emotional states, including those occurring during withdrawal from addictive drugs. We have previously implicated cocaine-driven adaptations at synapses from the entopeduncular nucleus (EPN) to the LHb in this process. Specifically, ionotropic GABAA receptor (R)-mediated neurotransmission at EPN-to-LHb synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABAB R signaling also controls LHb activity, although its role at EPN-to-LHb synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABAB R-mediated neurotransmission at EPN-to-LHb synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage-clamp recordings from LHb neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABAA R-mediated input to LHb neurons, and a reduced occurrence of GABAB R-signaling at EPN-to-LHb synapses. We then assessed the underlying mechanism of this decrease. Application of GABAB R agonist baclofen evoked similar postsynaptic responses in EPN-innervated LHb neurons in saline- and cocaine-treated mice. Release probability at EPN-to-LHb GABAergic synapses was also comparable between groups. However, incubating brain slices in glutamine to facilitate GABA vesicle filling, normalized GABAB R-currents at EPN-to-LHb synapses in cocaine-treated mice. Overall, we show that during cocaine withdrawal, together with reduced GABAA R transmission, also GABAB R-mediated inhibitory signaling is diminished at EPN-to-LHb synapses, likely via the same presynaptic deficit. In concert, these alterations are predicted to contribute to the emergence of drug withdrawal symptoms, facilitating drug relapse.

Baclofen

GABAB receptor

Muscimol

10.1111/ejn.14120

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Citations (14)

Author response for "Mild stress accumulation limits GABAergic synaptic plasticity in the lateral habenula"

Arnaud L. Lalive Alvaro Nuno‐Perez Anna Tchenio Manuel Mameli

Habenula

10.1111/ejn.15581/v2/response1

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Citations (0)