Pierre Veinante

GABA- and peptide-immunoreactivities co-localize in the rat central extended amygdala

THE central amygdaloid nucleus and the lateral bed nucleus of the stria terminalis are two similar telencephalic structures belonging to the central extended amygdala. These regions contain numerous peptidergic and GABAergic neurones which maintain the neurones projecting to the brain stem under tight intrinsic control. Using immunocytochemistry in colchicinetreated rats, we showed that, in the lateral subdivision of the central amygdaloid nucleus and in the dorsal part of the lateral bed nucleus of the stria terminalis, a population of GABAergic neurones is able to co-synthesize either corticotropin-releasing factor or methionineenkephalin, but never both peptides. These results suggest that, in the GABAergic intrinsic circuits of the central extended amygdala, co-liberated peptides can have a modulatory role on GABAergic actions.

Neuronal circuits underlying acute morphine action on dopamine neurons

Morphine is a highly potent analgesic with high addictive potential in specific contexts. Although dopamine neurons of the ventral tegmental area (VTA) are widely believed to play an essential role in the development of drug addiction, neuronal circuits underlying morphine action on dopamine neurons have not been fully elucidated. Here we combined in vivo electrophysiology, tract-tracing experiments, and targeted neuronal inactivation to dissect a neural circuit for acute morphine action on dopamine neurons in rats. We found that in vivo, morphine targets the GABAergic tail of the VTA, also called the rostromedial tegmental nucleus, to increase the firing of dopamine neurons through the activation of VTA μ opioid receptors expressed on tail of the VTA/rostromedial tegmental nucleus efferents. Our data also reveal that in the absence of VTA glutamatergic tone, there is no morphine-induced activation of dopamine neurons. These results define the anatomical organization and functional role of a neural circuit for acute morphine action on dopamine neurons.

The amygdala between sensation and affect: a role in pain

The amygdala is a structure of the temporal lobe thought to be involved in assigning emotional significance to environmental information and triggering adapted physiological, behavioral and affective responses. A large body of literature in animals and human implicates the amygdala in fear. Pain having a strong affective and emotional dimension, the amygdala, especially its central nucleus (CeA), has also emerged in the last twenty years as key element of the pain matrix. The CeA receives multiple nociceptive information from the brainstem, as well as highly processed polymodal information from the thalamus and the cerebral cortex. It also possesses the connections that allow influencing most of the descending pain control systems as well as higher centers involved in emotional, affective and cognitive functions. Preclinical studies indicate that the integration of nociceptive inputs in the CeA only marginally contributes to sensory-discriminative components of pain, but rather contributes to associated behavior and affective responses. The CeA doesn’t have a major influence on responses to acute nociception in basal condition, but it induces hypoalgesia during aversive situation, such as stress or fear. On the contrary, during persistent pain states (inflammatory, visceral, neuropathic), a long-lasting functional plasticity of CeA activity contributes to an enhancement of the pain experience, including hyperalgesia, aversive behavioral reactions and affective anxiety-like states.

γ-Aminobutyric Acid Cells with Cocaine-Induced ΔFosB in the Ventral Tegmental Area Innervate Mesolimbic Neurons

BACKGROUNDnThe transcription factor DeltaFosB is implicated in the plasticity induced by drugs of abuse. We showed that psychostimulants induce DeltaFosB in gamma-aminobutyric acid (GABA) cells of a caudal subregion of the ventral tegmental area (VTA) that was named tail of the VTA (tVTA). Although tVTA mostly shares VTA inputs, its outputs remain to be characterized.nnnMETHODSnThe tVTA efferents were studied by iontophoretic injections of the anterograde tracer biotinylated dextran amine (BDA). To further study VTA inputs arising from tVTA, injections of the retrograde tracer Fluoro-Gold were combined with multiple labeling by immunohistochemistry in rats treated with cocaine. Indirect projections from the tVTA to the nucleus accumbens were assessed with a double-tracing approach, cholera toxin B subunit (CTB) being delivered in the nucleus accumbens and BDA in the tVTA.nnnRESULTSnTract-tracing studies showed that tVTA heavily projects to the midbrain dopaminergic system and revealed terminal appositions with dopamine cells in the VTA. Double-labeling studies demonstrated that this tVTA output is mostly GABAergic, includes cells in which cocaine exposure induces DeltaFosB, and displays appositions to dopamine cells projecting to the nucleus accumbens.nnnCONCLUSIONSnThe GABA neurons expressing DeltaFosB in the tVTA after cocaine exposure project to the dopamine mesolimbic neurons.

The antero-posterior heterogeneity of the ventral tegmental area.

The ventral tegmental area (VTA) is a brain region processing salient sensory and emotional information, controlling motivated behaviors, natural or drug-related reward, reward-related learning, mood, and participating in their associated psychopathologies. Mostly studied for its dopamine neurons, the VTA also includes functionally important GABA and glutamate cell populations. Behavioral evidence supports the presence of functional differences between the anterior VTA (aVTA) and the posterior VTA (pVTA), which is the topic of this review. This antero-posterior heterogeneity concerns locomotor activity, conditioned place preference and intracranial self-administration, and can be seen in response to ethanol, acetaldehyde, salsolinol, opioids including morphine, cholinergic agonists including nicotine, cocaine, cannabinoids and after local manipulation of GABA and serotonin receptors. It has also been observed after viral-mediated manipulation of GluR1, phospholipase Cγ (PLCγ) and cAMP response element binding protein (CREB) expression, with impact on reward and aversion-related responses, on anxiety and depression-related behaviors and on pain sensitivity. In this review, the substrates potentially underlying these aVTA/pVTA differences are discussed, including the VTA sub-nuclei and the heterogeneity in connectivity, cell types and molecular characteristics. We also review the role of the tail of the VTA (tVTA), or rostromedial tegmental nucleus (RMTg), which may also participate to the observed antero-posterior heterogeneity of the VTA. This region, partly located within the pVTA, is an inhibitory control center for dopamine activity. It controls VTA and substantia nigra dopamine cells, thus exerting a major influence on basal ganglia functions. This review highlights the need for a more comprehensive analysis of VTA heterogeneity.

Pharmacological recruitment of the GABAergic tail of the ventral tegmental area by acute drug exposure

BACKGROUND AND PURPOSE The tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, is a newly defined brain structure and a potential control centre for dopaminergic activity. It was identified by the induction of DeltaFosB following chronic cocaine exposure. In this work, we screened 20 drugs for their ability to induce FosB/DeltaFosB in the tVTA.

Control of the Nigrostriatal Dopamine Neuron Activity and Motor Function by the Tail of the Ventral Tegmental Area

Midbrain dopamine neurons are implicated in various psychiatric and neurological disorders. The GABAergic tail of the ventral tegmental area (tVTA), also named the rostromedial tegmental nucleus (RMTg), displays dense projections to the midbrain and exerts electrophysiological control over dopamine cells of the VTA. However, the influence of the tVTA on the nigrostriatal pathway, from the substantia nigra pars compacta (SNc) to the dorsal striatum, and on related functions remains to be addressed. The present study highlights the role played by the tVTA as a GABA brake for the nigrostriatal system, demonstrating a critical influence over motor functions. Using neuroanatomical approaches with tract tracing and electron microscopy, we reveal the presence of a tVTA–SNc–dorsal striatum pathway. Using in vivo electrophysiology, we prove that the tVTA is a major inhibitory control center for SNc dopamine cells. Using behavioral approaches, we demonstrate that the tVTA controls rotation behavior, motor coordination, and motor skill learning. The motor enhancements observed after ablation of the tVTA are in this regard comparable with the performance-enhancing properties of amphetamine, a drug used in doping. These findings demonstrate that the tVTA is a major GABA brake for nigral dopamine systems and nigrostriatal functions, and they raise important questions about how the tVTA is integrated within the basal ganglia circuitry. They also warrant further research on the tVTA’s role in motor and dopamine-related pathological contexts such as Parkinson’s disease.

BDNF parabrachio-amygdaloid pathway in morphine-induced analgesia

In addition to its neurotrophic role, brain-derived neurotrophic factor (BDNF) is involved in a wide array of functions, including anxiety and pain. The central amygdaloid nucleus (CeA) contains a high concentration of BDNF in terminals, originating from the pontine parabrachial nucleus. Since the spino-parabrachio-amygdaloid neural pathway is known to convey nociceptive information, we hypothesized a possible involvement of BDNF in supraspinal pain-related processes. To test this hypothesis, we generated localized deletion of BDNF in the parabrachial nucleus using local bilateral injections of adeno-associated viruses in adult floxed-BDNF mice. Basal thresholds of thermal and mechanical nociceptive responses were not altered by BDNF loss and no behavioural deficit was noticed in anxiety and motor tests. However, BDNF-deleted animals displayed a major decrease in the analgesic effect of morphine. In addition, intra-CeA injections of the BDNF scavenger TrkB-Fc in control mice also decreased morphine-induced analgesia. Finally, the number of c-Fos immunoreactive nuclei after acute morphine injection was decreased by 45% in the extended amygdala of BDNF-deleted animals. The absence of BDNF in the parabrachial nucleus thus altered the parabrachio-amygdaloid pathway. Overall, our study provides evidence that BDNF produced in the parabrachial nucleus modulates the functions of the parabrachio-amygdaloid pathway in opiate analgesia.

Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. In vivo electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity. SIGNIFICANCE STATEMENT Chronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain.

The Tail of the Ventral Tegmental Area/Rostromedial Tegmental Nucleus: A Modulator of Midbrain Dopamine Systems

The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) is a recently described brainstem group of gamma-amino butyric acid cells that densely innervate the VTA and the substantia nigra pars compacta, exerting tonic and phasic inhibitory control over the activity of dopamine cells. The molecular impact of psychostimulants on the tVTA/RMTg, the expression of µ-opioid receptors in these neurons, and the dense input from the lateral habenula, together with the brake activity exerted on dopamine systems, are fostering research on tVTA/RMTg functions. This nucleus has already been shown to encode prediction error, control freezing behavior and locomotor activity, influence motor coordination performance and motor skill learning, promote avoidance behaviors, participate in responses to aversive stimuli and drugs of abuse, and to be a key structure for opioid-induced disinhibition of dopamine neurons. This chapter details the current physiological and behavioral knowledge on the tVTA/RMTg.