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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 GABA

The nervous system can associate neutral cues with rewards to promote appetitive adaptive behaviors. The lateral habenula (LHb) contributes to such behaviors as rewards and reward-predictive cues inhibit this structure and engage LHb-to-dopamine circuits. However, the mechanistic understanding of reward encoding within the LHb remains unknown. We report that, in mice, acquisition of anticipatory licking in a reward-conditioning task potentiates postsynaptic GABAergic transmission, leaving excitatory synapses unaffected. Conversely, LHb-targeted manipulations of postsynaptic GABAergic function via pharmacological blockade or impairment of GABAA receptor trafficking decrease anticipatory licking. Hence, inhibitory signaling within LHb enables the expression of appetitive behaviors.

Acetylcholine (ACh), released in the hippocampus from fibers originating in the medial septum/diagonal band of Broca (MSDB) complex, is crucial for learning and memory. The CA2 region of the hippocampus has received increasing attention in the context of social memory. However, the contribution of ACh to this process remains unclear. Here, we show that in mice, ACh controls social memory. Specifically, MSDB cholinergic neurons inhibition impairs social novelty discrimination, meaning the propensity of a mouse to interact with a novel rather than a familiar conspecific. This effect is mimicked by a selective antagonist of nicotinic AChRs delivered in CA2. Ex vivo recordings from hippocampal slices provide insight into the underlying mechanism, as activation of nAChRs by nicotine increases the excitatory drive to CA2 principal cells via disinhibition. In line with this observation, optogenetic activation of cholinergic neurons in MSDB increases the firing of CA2 principal cells in vivo. These results point to nAChRs as essential players in social novelty discrimination by controlling inhibition in the CA2 region.

Summary 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., Graphical abstract, Highlights • A specific phase during an appetitive cognitive task engages LHb neuronal dynamics • The strength of excitatory synapses in LHb neurons predicts cognitive performance • Stress triggers cognitive impairments and disrupts LHb neuronal activity • Deficits in reward-guided behaviors require a decrease in LHb AMPAR transmission, Effective evaluation of costs and benefits is fundamental for survival and vulnerable to stress. Nuno-Perez et al. show that the strength of AMPAR transmission within the mouse lateral habenula governs the incidence of non-rewarded choices in a reward-guided task. Stress weakens habenular excitatory synapses and consequently augments non-rewarded decisions.

The control of locomotion is fundamental to vertebrate animal survival. Defensive situations require an animal to rapidly decide whether to run away or suppress locomotor activity to avoid detection. While much of the neural circuitry involved in defensive action selection has been elucidated, top-down modulation of brainstem locomotor circuitry remains unclear. Here we provide evidence for the existence and functionality of a monosynaptic connection from the central amygdala (CeA) to the mesencephalic locomotor region (MLR) that inhibits locomotion in unconditioned and conditioned defensive behavior in mice. We show that locomotion stimulated by airpuff coincides with increased activity of MLR glutamatergic neurons. Using retrograde tracing and ex vivo electrophysiology, we find that the CeA makes a monosynaptic connection with the MLR. In the open field, in vivo stimulation of this projection suppressed spontaneous locomotion, whereas inhibition of this projection had no effect. However, inhibiting CeA terminals within the MLR increased both neural activity and locomotor responses to airpuff. Finally, using a conditioned avoidance paradigm known to activate CeA neurons, we find that inhibition of the CeA projection increased successful escape, whereas activating the projection reduced escape. Together these results provide evidence for a new circuit substrate influencing locomotion and defensive behaviors.

Summary Throughout life, individuals learn to predict a punishment via its association with sensory stimuli. This process ultimately prompts goal-directed actions to prevent the danger, a behavior defined as avoidance. Neurons in the lateral habenula (LHb) respond to aversive events as well as to environmental cues predicting them, supporting LHb contribution to cue-punishment association. However, whether synaptic adaptations at discrete habenular circuits underlie such associative learning to instruct avoidance remains elusive. Here, we find that, in mice, contingent association of an auditory cue (tone) with a punishment (foot shock) progressively causes cue-driven LHb neuronal excitation during avoidance learning. This process is concomitant with the strengthening of LHb AMPA receptor-mediated neurotransmission. Such a phenomenon occludes long-term potentiation and occurs specifically at hypothalamus-to-habenula synapses. Silencing hypothalamic-to-habenulainputs or optically inactivating postsynaptic AMPA receptors within the LHb disrupts avoidance learning. Altogether, synaptic strengthening at a discrete habenular circuit transforms neutral stimuli into salient punishment-predictive cues to guide avoidance.

The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct- and indirect-pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of the BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically-distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how the BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.

International audience; 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.

Reinforcement has long been thought to require striatal synaptic plasticity. Indeed, direct striatal manipulations such as self-stimulation of direct-pathway projection neurons (dMSNs) are sufficient to induce reinforcement within minutes. However, it’s unclear what role, if any, is played by downstream circuitry. Here, we used dMSN self-stimulation in mice as a model for striatum-driven reinforcement and mapped the underlying circuitry across multiple basal ganglia nuclei and output targets. We found that mimicking the effects of dMSN activation on downstream circuitry, through optogenetic suppression of basal ganglia output nucleus substantia nigra reticulata (SNr) or activation of SNr targets in the brainstem or thalamus, was also sufficient to drive rapid reinforcement. Remarkably, silencing motor thalamus—but not other selected targets of SNr—was the only manipulation that reduced dMSN-driven reinforcement. Together, these results point to an unexpected role for basal ganglia output to motor thalamus in striatum-driven reinforcement.

Movement suppression in Parkinson's disease (PD) is thought to arise from increased efficacy of the indirect pathway basal ganglia circuit, relative to the direct pathway. However, the underlying pathophysiological mechanisms remain elusive. To examine whether changes in the strength of synaptic inputs to these circuits contribute to this imbalance, we obtained paired whole-cell recordings from striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs) and optically stimulated inputs from sensorimotor cortex or intralaminar thalamus in brain slices from control and dopamine-depleted mice. We found that dopamine depletion selectively decreased synaptic strength at thalamic inputs to dMSNs, suggesting that thalamus drives asymmetric activation of basal ganglia circuitry underlying parkinsonian motor impairments. Consistent with this hypothesis, in vivo chemogenetic and optogenetic inhibition of thalamostriatal terminals reversed motor deficits in dopamine-depleted mice. These results implicate thalamostriatal projections in the pathophysiology of PD and support interventions targeting thalamus as a potential therapeutic strategy.

GABAB receptors are expressed in neurons of the dopamine system where they bidirectionally modulate activity and release of glutamate, GABA, and dopamine itself. Dopamine has many functions including signaling of salient external stimuli and prediction errors that optimize decision-making, as well as motivation and initiation of movement. GABAB receptors thus exert a second-order modulation, with effects on locomotion, motivation, and reward learning. Moreover, recent findings indicate that neuronal activity may induce a plasticity of GABAB receptor signaling. In this chapter, we review the structural and functional features of GABAB receptor signaling in the dopaminergic system, from subcellular specialization to plasticity and fine-tuning of mesolimbic circuits. Beyond a physiological role GABAB receptors may also affect disease, such as addiction. GABAB receptors may therefore constitute an interesting target for pharmacological interventions to treat this condition.

G-protein-gated inwardly rectifying potassium (GIRK) channels, which help control neuronal excitability, are important for the response to drugs of abuse. Here, we describe a novel pathway for morphine-dependent enhancement of GIRK channel signaling in hippocampal neurons. Morphine treatment for ∼20 h increased the colocalization of GIRK2 with PSD95, a dendritic spine marker. Western blot analysis and quantitative immunoelectron microscopy revealed an increase in GIRK2 protein and targeting to dendritic spines.In vivoadministration of morphine also produced an upregulation of GIRK2 protein in the hippocampus. The mechanism engaged by morphine required elevated intracellular Ca2+and was insensitive to pertussis toxin, implicating opioid receptors that may couple to Gq G-proteins. Met-enkephalin, but not the μ-selective (DAMGO) and δ-selective (DPDPE) opioid receptor agonists, mimicked the effect of morphine, suggesting involvement of a heterodimeric opioid receptor complex. Peptide (KN-93) inhibition of CaMKII prevented the morphine-dependent change in GIRK localization, whereas expression of a constitutively activated form of CaMKII mimicked the effects of morphine. Coincident with an increase in GIRK2 surface expression, functional analyses revealed that morphine treatment increased the size of serotonin-activated GIRK currents and Ba2+-sensitive basal K+currents in neurons. These results demonstrate plasticity in neuronal GIRK signaling that may contribute to the abusive effects of morphine.

Benzodiazepines are widely prescribed drugs used to treat anxiety and insomnia, induce muscle relaxation, control epileptic seizures, promote anaesthesia or produce amnesia. Benzodiazepines are also abused for recreational purposes and the number of benzodiazepine abusers is unfortunately increasing. Within weeks of chronic use, tolerance to the pharmacological effects can develop and withdrawal becomes apparent once the drug is no longer available, which are both conditions indicative of benzodiazepine dependence. Diagnosis of addiction (i.e. compulsive use despite negative consequences) may follow in vulnerable individuals. Here, we review the historical and current use of benzodiazepines from their original synthesis, discovery and commercialisation to the recent identification of the molecular mechanism by which benzodiazepines induce addiction. These results have identified the mechanisms underlying the activation of midbrain dopamine neurons by benzodiazepines, and how these drugs can hijack the mesocorticolimbic reward system. Such knowledge calls for future developments of new receptor subtype specific benzodiazepines with a reduced addiction liability.

Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir(3)) channels, however, are poorly understood. Here, we show that 1 day after methamphetamine (METH) or cocaine exposure both synaptically evoked and baclofen-activated GABA(B)R-GIRK currents were significantly depressed in VTA GABA neurons and remained depressed for 7 days. Presynaptic inhibition mediated by GABA(B)Rs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABA(B1) and GIRK2, which occurred coincident with dephosphorylation of serine 783 (S783) in GABA(B2), a site implicated in regulating GABA(B)R surface expression. Inhibition of protein phosphatases recovered GABA(B)R-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABA(B)R signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system.