Gata2, Nkx2-2 and Skor2 form a transcription factor network regulating development of a midbrain GABAergic neuron subtype with characteristics of REM-sleep regulatory neurons.

The midbrain reticular formation (MRF) is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including sleep regulation. However, the molecular characteristics and development of MRF neurons are poorly understood. As the transcription factor, Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region.

ADHD-like behaviors caused by inactivation of a transcription factor controlling the balance of inhibitory and excitatory neuron development in the mouse anterior brainstem.

The neural circuits regulating motivation and movement include midbrain dopaminergic neurons and associated inhibitory GABAergic and excitatory glutamatergic neurons in the anterior brainstem. Differentiation of specific subtypes of GABAergic and glutamatergic neurons in the mouse embryonic brainstem is controlled by a transcription factor Tal1. This study characterizes the behavioral and neurochemical changes caused by the absence of Tal1 function.

Behavioral responses of mGluR3-KO mice to the lipopolysaccharide-induced innate inflammatory reaction.

Acute lipopolysaccharide (LPS) administration induces innate inflammatory signalling and produces sickness reaction characterized by reduced drinking, eating and reduced locomotor exploration, as well as emotional changes indicating increased helplessness/despair. LPS administration has been used to model behavioral and emotional responses to inflammatory reactions. Our aim was to find out whether the lack of metabotropic glutamate receptor 3 (mGluR3) in the knockout (KO) mice affects behavioral effects of LPS in vivo, as mGluR3 may have a role in inflammatory signalling.

Conditioned Aversion and Neuroplasticity Induced by a Superagonist of Extrasynaptic GABA Receptors: Correlation With Activation of the Oval BNST Neurons and CRF Mechanisms.

THIP (gaboxadol), a superagonist of the δ subunit-containing extrasynaptic GABA receptors, produces persistent neuroplasticity in dopamine (DA) neurons of the ventral tegmental area (VTA), similarly to rewarding drugs of abuse. However, unlike them THIP lacks abuse potential and induces conditioned place aversion in mice. The mechanism underlying the aversive effects of THIP remains elusive.

The lack of conditioned place preference, but unaltered stimulatory and ataxic effects of alcohol in mGluR3-KO mice.

Background: Alcohol use associates with environmental cues that can later reinstate drinking patterns without any alcohol exposure. Alcohol-induced reward, when combined with contextual signals of various sensory modalities in the central synapses of mesolimbic reward circuitries, can lead to the formation of conditioned responses.

Aims: As the activation of glutamatergic synapses is pivotal in such processes, we aimed to investigate whether the metabotropic glutamate receptor subtype 3 plays a role in alcohol-induced behaviours including place preference.

Attenuation of Novelty-Induced Hyperactivity of Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.

Gene-targeted mice with deficient AMPA receptor GluA1 subunits ( mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the mice, while not affecting the wild-type littermate controls.

Rapid analysis of intraperitoneally administered morphine in mouse plasma and brain by microchip electrophoresis-electrochemical detection.

Animal studies remain an essential part of drug discovery since in vitro models are not capable of describing the complete living organism. We developed and qualified a microchip electrophoresis-electrochemical detection (MCE-EC) method for rapid analysis of morphine in mouse plasma using a commercial MCE-EC device. Following liquid-liquid extraction (LLE), we achieved within-run precision of 3.

Dopaminergic-GABAergic interplay and alcohol binge drinking.

The dopamine D receptor (DR), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of DR increases GABA α6 subunit in the ventral striatum.

Normal extinction and reinstatement of morphine-induced conditioned place preference in the GluA1-KO mouse line.

Extinction and reinstatement of morphine-induced conditioned place preference were studied in glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor GluA1 subunit-deficient mice (global GluA1-KO mice). In line with previous findings, both acquisition and expression of conditioned place preference to morphine (20 mg/kg, subcutaneously) were fully functional in GluA1 KO mice compared with wild-type littermate controls (GluA1-WT), thus enabling the study of extinction. With a 10-session extinction paradigm, the GluA1 KO mice showed complete extinction similar to that of the GluA1-WT mice.

Basal Forebrain and Brainstem Cholinergic Neurons Differentially Impact Amygdala Circuits and Learning-Related Behavior.

The central cholinergic system and the amygdala are important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala, but it is unclear how these projections impact amygdala processes. Using optogenetic circuit-mapping strategies in choline acetyltransferase (ChAT)-cre mice, we demonstrate that amygdala-projecting basal forebrain and brainstem ChAT-containing neurons can differentially affect amygdala circuits and behavior.

Conditioned Reward of Opioids, but not Psychostimulants, is Impaired in GABA-A Receptor δ Subunit Knockout Mice.

Extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ-GABA Rs) are emerging as targets for a number of neuropsychopharmacological drugs, including the direct GABA site agonist gaboxadol and neuroactive steroids. Among other regions, these δ-GABA Rs are functionally expressed in the ventral tegmental area (VTA), the cell body region of mesocorticolimbic dopamine (DA) system important for motivated behaviours, and in the target region, the nucleus accumbens. Gaboxadol and neurosteroids induce VTA DA neuron plasticity ex vivo, by inhibiting the VTA GABA neurons, and aversive place conditioning, which are absent in the δ-GABA R knockout mice (δ-KO).

Accumbal Cholinergic Interneurons Differentially Influence Motivation Related to Satiety Signaling.

Satiety, rather than all or none, can instead be viewed as a cumulative decrease in the drive to eat that develops over the course of a meal. The nucleus accumbens (NAc) is known to play a critical role in this type of value reappraisal, but the underlying circuits that influence such processes are unclear. Although NAc cholinergic interneurons (CINs) comprise only a small proportion of NAc neurons, their local impact on reward-based processes provides a candidate cell population for investigating the neural underpinnings of satiety.

Cellular activation of hypothalamic hypocretin/orexin neurons facilitates short-term spatial memory in mice.

The hypothalamic hypocretin/orexin (HO) system holds a central role in the regulation of several physiological functions critical for food-seeking behavior including mnemonic processes for effective foraging behavior. It is unclear however whether physiological increases in HO neuronal activity can support such processes. Using a designer rM3Ds receptor activation approach increasing HO neuronal activity resulted in improved short-term memory for novel locations.

Nicotinic α4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits.

Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4β2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHβE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals.

Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits.

The lateral hypothalamus (LH) is a key regulator of multiple vital behaviors. The firing of brain-wide-projecting LH neurons releases neuropeptides promoting wakefulness (orexin/hypocretin; OH), or sleep (melanin-concentrating hormone; MCH). OH neurons, which coexpress glutamate and dynorphin, have been proposed to excite their neighbors, including MCH neurons, suggesting that LH may sometimes coengage its antagonistic outputs.

GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area.

GABAA receptors are the main fast inhibitory neurotransmitter receptors in the mammalian brain, and targets for many clinically important drugs widely used in the treatment of anxiety disorders, insomnia and in anesthesia. Nonetheless, there are significant risks associated with the long-term use of these drugs particularly related to development of tolerance and addiction. Addictive mechanisms of GABAA receptor drugs are poorly known, but recent findings suggest that those drugs may induce aberrant neuroadaptations in the brain reward circuitry.

Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit-deficient mice by chronic treatment targeting glutamatergic transmission.

Malfunction of glutamate transmission is implicated in several neuropsychiatric disorders. Gria1-/- mouse line with knocked-out GluA1 subunits of ionotropic AMPA glutamate receptor displays several behavioural features of schizoaffective disorder. Typically, these mice show hyperactivity provoked by environmental novelty, which is attenuated after 4-week treatment with the standard mood-stabilisers lithium and valproate and the mood-stabilising anticonvulsants topiramate and lamotrigine (Maksimovic, M.

Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice.

Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1-/- mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the Gria1-/- mice.

Neurosteroid Agonist at GABAA receptor induces persistent neuroplasticity in VTA dopamine neurons.

The main fast-acting inhibitory receptors in the mammalian brain are γ-aminobutyric acid type-A (GABAA) receptors for which neurosteroids, a subclass of steroids synthesized de novo in the brain, constitute a group of endogenous ligands with the most potent positive modulatory actions known. Neurosteroids can act on all subtypes of GABAA receptors, with a preference for δ-subunit-containing receptors that mediate extrasynaptic tonic inhibition. Pathological conditions characterized by emotional and motivational disturbances are often associated with perturbation in the levels of endogenous neurosteroids.

Importance of GluA1 subunit-containing AMPA glutamate receptors for morphine state-dependency.

In state-dependency, information retrieval is most efficient when the animal is in the same state as it was during the information acquisition. State-dependency has been implicated in a variety of learning and memory processes, but its mechanisms remain to be resolved. Here, mice deficient in AMPA-type glutamate receptor GluA1 subunits were first conditioned to morphine (10 or 20 mg/kg s.

GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons.

Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor plasticity at the excitatory synapses of these neurons. Benzodiazepines that suppress the inhibitory GABAergic interneurons in the VTA via facilitation of synaptic GABA(A) receptors have induced neuroplasticity in dopamine neurons due to this disinhibitory mechanism.

Excessive novelty-induced c-Fos expression and altered neurogenesis in the hippocampus of GluA1 knockout mice.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit-deficient (GluA1-/-) mice display novelty-induced hyperactivity, cognitive and social defects and may model psychiatric disorders, such as schizophrenia and depression/mania. We used c-Fos expression in GluA1-/- mice to identify brain regions responsible for novelty-induced hyperlocomotion. Exposure to a novel cage for 2 h significantly increased c-Fos expression in many brain regions in both wild-type and knockout mice.

Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice.

Rationale: Neuronal histamine has a prominent role in sleep-wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward.

Objective: The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice.

Materials And Methods: Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP).

Reduced benzodiazepine tolerance, but increased flumazenil-precipitated withdrawal in AMPA-receptor GluR-A subunit-deficient mice.

Pharmacotherapy with benzodiazepines is compromised by rapid sedative tolerance and diverse withdrawal symptoms. To assess the role of AMPA-type glutamate receptor GluR-A subunits in neuroadaptation to subchronic benzodiazepine treatment, GluR-A subunit-deficient mice were rendered tolerant by a high-dose seven-day flurazepam treatment (40 mg/kg, s.c.

The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists.

Inhalation anesthetics activate and cannabinoid agonists inhibit TWIK-related acid-sensitive K(+) channels (TASK)-1 two-pore domain leak K(+) channels in vitro. Many neuromodulators, such as noradrenaline, might also manifest some of their actions by modifying TASK channel activity. Here, we have characterized the basal behavioral phenotype of TASK-1 knockout mice and tested their sensitivity to the inhalation anesthetics halothane and isoflurane, the alpha(2) adrenoreceptor agonist dexmedetomidine, and the cannabinoid agonist WIN55212-2 mesylate [R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3,-de]-1,4-benzoxazinyl]-(1-naphtalenyl)methanone mesylate)].