Il nucleo rostromediale del tegmento: caratterizzazione elettrofisiologica e ruolo nella neurobiologia delle sostanze d'abuso

Recent findings have underlined that the rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area, is an important site involved in aversion processes (Jhou et al., 2009a;2009b). RMTg contains GABAergic neurons responding to noxious stimuli, that are densely innervated by the lateral habenula (LHb) and provide a major inhibitory projection to reward-encoding dopamine (DA) midbrain neurons (Jhou et al., 2009a, 2009b). Perseverance of drug seeking in spite of negative and unpleasant consequences is one of the key features of drug addiction, possibly mediated by response suppression within neural pathways mediating aversion. Here, utilizing single unit extracellular recordings in anesthetized rats, we first investigated whether addicting drugs (morphine, the cannabinoid agonist WIN55212-2, cocaine and nicotine) affect RMTg neuron activity. We discovered that 73.2% of putative RMTg GABAergic neurons were excited by aversive stimuli (paw pinch). Moreover, LHb electrical stimulation activated 46.3% of RMTg neurons at short latency (5.5±0.3 ms). When addictive compounds were injected, only cells responding both to LHb activation and paw pinch were selected. Morphine, WIN55212-2 (WIN) and cocaine inhibited RMTg neuron firing rate in vivo. In contrast, nicotine strongly excited RMTg firing rate. In the follow-up study we investigated whether the previous drugs of abuse affect RMTg-evoked inhibition of DA neurons. To this aim, we studied acute effects of morphine, WIN, cocaine, and nicotine on the inhibitory effects induced on DA cells by RMTg stimulation. The electrical stimulation of the RMTg induced a complete suppression of spontaneous activity in 53.3% of the DA neurons examined, lasting on average 82.5±6.1 ms. The duration of inhibition was inversely correlated (r= -0.71, p<0.0001) to the discharge rate of DA neurons, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA neurons. Both morphine and WIN depressed this RMTg-induced inhibition of DA neurons in vivo. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results suggest that drugs of abuse profoundly influence both RMTg neuron activity and synaptic responses of DA neurons evoked by RMTg activation. These newly characterized neurons, as important inhibitory afferents to midbrain DA cells, might take place in the complex interplay between the neural circuits mediating aversion and reward. 1.Jhou TC et al. (2009a). The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61: 786-800. 2.Jhou TC et al. (2009b). The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol 513: 566-596

Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction

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

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

Inhibition within the lateral habenula—implications for affective disorders

The lateral habenula (LHb) is a key brain region implicated in the pathology of major depressive disorder (MDD). Specifically, excitatory LHb neurons are known to be hyperactive in MDD, thus resulting in a greater excitatory output mainly to downstream inhibitory neurons in the rostromedial tegmental nucleus. This likely results in suppression of downstream dopaminergic ventral tegmental area neurons, therefore, resulting in an overall reduction in reward signalling. In line with this, increasing evidence implicates aberrant inhibitory signalling onto LHb neurons as a co-causative factor in MDD, likely as a result of disinhibition of excitatory neurons. Consistently, growing evidence now suggests that normalising inhibitory signalling within the LHb may be a potential therapeutic strategy for MDD. Despite these recent advances, however, the exact pharmacological and neural circuit mechanisms which control inhibitory signalling within the LHb are still incompletely understood. Thus, in this review article, we aim to provide an up-to-date summary of the current state of knowledge of the mechanisms by which inhibitory signalling is processed within the LHb, with a view of exploring how this may be targeted as a future therapy for MDD

Maternal immune activation disrupts dopamine system in the offspring

Background: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia. Methods: Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology. Results: Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity. Conclusions: These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human patholog

PPAR-Alpha Agonists as Novel Antiepileptic Drugs: Preclinical Findings

Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in a4 or b2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-a (PPARa), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing b2 subunits. On these bases, we tested whether PPARa agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ,100% of mice. A single dose of the synthetic PPARa agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARa antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARa agonists abolished nicotine-induced sIPSC increases. PPARa within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role

THE TYRRHENIAN SECTION OF SAN GIOVANNI DI SINIS (SARDINIA):STRATIGRAPHIC RECORD OF AN IRREGULAR SINGLE HIGH STAND

A new analysis of the most representative Upper Pleistocene (Tyrrhenian, MIS 5e) section of San Giovanni di Sinis (Oristano, Sardinia) has provided a more detailed genetic stratigraphy of a low wave energy beach and temperate lagoon up to emerged peri-lagoonal facies deposits. These peri-lagoonal facies contain remains of fossil vertebrates, which, though few and fragmentary, bear witness to an at least temporary freshwater palaeoenvironment and the presence of deers and terrapins. Besides, the stratigraphy of this outcrop shows shoreface-backshore sandstones overlaying an erosion surface cut on the vertebrate-bearing layers. Facies analysis and sequence stratigraphy of the succession have provided support to a new eustatic interpretation significance. In fact, there appears to be evidence of one irregular single eustatic highstand, rather than two eustatic peaks as previously believed. The facies evolution and the local stratigraphic disconformities are interpreted as being associated with a lateral shift of the depositional environment within the same system formed during the MIS 5e sea level variations. As sea water level continued to rise so an erosional unconformity, caused by wave ravinement, formed between the low wave energy beach-lagoon sequence and the successive wave dominated beach facies sequence. This interpretation is supported by comparison with other sections of the Tyrrhenian in western Sardinia. The maximum sea level attained during the Tyrrhenian stage is a clear indication of a warm-temperate climate which can be correlated to the well known orbital interglacial configuration when the eustatic signal of Greenland's ice sheet melting occurred. SHORT NOTE

The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview

The lateral habenula (LHb) is an epithalamic region with a crucial role in the regulation of midbrain monoaminergic systems. Over the past few years a renewed interest in the LHb has emerged due to studies highlighting its central role in encoding rewarding and aversive aspects of stimuli. Moreover, an increasing number of functional as well as behavioral indications provide substantial evidence supporting a role of LHb in neuropsychiatric diseases, including mood disorders and drug addiction. Cellular and synaptic adaptations in the LHb may therefore represent a critical phenomenon in the etiology of these diseases. In the current review we describe the anatomical and functional connections allowing the LHb to control the dopamine and serotonin systems, as well as possible roles of these connections in motivated behaviors and neuropsychiatric disorders. Finally, we discuss how drug exposure and stressful conditions alter the cellular physiology of the LHb, highlighting a role for the LHb in the context of drug addiction and depression

Limiting habenular hyperactivity ameliorates maternal separation-driven depressive-like symptoms

Early-life stress primes depression in adulthood. This study shows that early maternal separation leads to lateral habenula (LHb) hyperactivity and causes depressive-like phenotypes, the latter being reversible when LHb hyperactivity is reduced chemogenetically or through deep-brain stimulation

Synaptic and cellular profile of neurons in the lateral habenula.

International audienceThe lateral habenula (LHb) is emerging as a crucial structure capable of conveying rewarding and aversive information. Recent evidence indicates that a rapid increase in the activity of LHb neurons drives negative states and avoidance. Furthermore, the hyperexcitability of neurons in the LHb, especially those projecting to the midbrain, may represent an important cellular correlate for neuropsychiatric disorders like depression and drug addiction. Despite the recent insights regarding the implications of the LHb in the context of reward and aversion, the exact nature of the synaptic and cellular players regulating LHb neuronal functions remains largely unknown. Here we focus on the synaptic and cellular physiology of LHb neurons. First, we discuss the properties of excitatory transmission and the implications of glutamate receptors for long-term synaptic plasticity; second, we review the features of GABAergic transmission onto LHb neurons; and finally, we describe the contribution that neuromodulators such as dopamine (DA) and serotonin may have for LHb neuronal physiology. We relate these findings to the role that the LHb can play in processing aversive and rewarding stimuli, both in health and disease states