Rewarding properties of L-Dopa in experimental parkinsonism are mediated by sensitized dopamine D1 receptors in the dorsal striatum.

Treatment of Parkinson's disease (PD) is based on the use of dopaminergic drugs, such as L-Dopa and dopamine receptor agonists. These substances counteract motor symptoms, but their administration is accompanied by motor and non-motor complications. Among these latter conditions a neurobehavioral disorder similar to drug abuse, known as dopamine dysregulation syndrome (DDS), is attracting increasing interest because of its profound negative impact on the patients' quality of life.

Dopamine D2 receptor activation counteracts olfactory dysfunction and related cellular abnormalities in experimental parkinsonism.

Olfactory dysfunction is a common non-motor symptom associated with Parkinson's disease (PD). This condition usually appears before the onset of the cardinal motor symptoms and is still poorly understood. Here, we generated a mouse model of early-stage PD based on partial 6-hydroxydopamine (6-OHDA) lesion of the dorsal striatum to reproduce the olfactory deficit and associated cellular and electrophysiological anomalies observed in patients.

Serotonergic and dopaminergic neurons in the dorsal raphe are differentially altered in a mouse model for parkinsonism.

Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input.

Maternal Aggression Driven by the Transient Mobilisation of a Dormant Hormone-Sensitive Circuit.

Aggression, a sexually dimorphic behaviour, is prevalent in males and typically absent in virgin females. Following parturition, however, the transient expression of aggression in adult female mice protects pups from predators and infanticide by male conspecifics. While maternal hormones are known to elicit nursing, their potential role in maternal aggression remains elusive.

Investigating affective neuropsychiatric symptoms in rodent models of Parkinson's disease.

Affective neuropsychiatric disorders such as depression, anxiety and apathy are among the most frequent non-motor symptoms observed in people with Parkinson's disease (PD). These conditions often emerge during the prodromal phase of the disease and are generally considered to result from neurodegenerative processes in meso-corticolimbic structures, occurring in parallel to the loss of nigrostriatal dopaminergic neurons. Depression, anxiety, and apathy are often treated with conventional medications, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and dopaminergic agonists.

A mouse model of sleep disorders in Parkinson's disease showing distinct effects of dopamine D2-like receptor activation.

Excessive daytime sleepiness (EDS) and sleep fragmentation are often observed in Parkinson's disease (PD) patients and are poorly understood despite their considerable impact on quality of life. We examined the ability of a neurotoxin-based mouse model of PD to reproduce these disorders and tested the potential counteracting effects of dopamine replacement therapy. Experiments were conducted in female mice with a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, leading to the loss of dopamine neurons projecting to the dorsal and ventral striatum.

Haloperidol-Induced Immediate Early Genes in Striatopallidal Neurons Requires the Converging Action of cAMP/PKA/DARPP-32 and mTOR Pathways.

Antipsychotics share the common pharmacological feature of antagonizing the dopamine 2 receptor (D2R), which is abundant in the striatum and involved in both the therapeutic and side effects of this drug's class. The pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-sized spiny neurons (MSNs), leads to a plethora of molecular, cellular and behavioral adaptations, which are central in the action of antipsychotics. Here, we focused on the cell type-specific (D2R-MSNs) regulation of some striatal immediate early genes (IEGs), such as cFos, Arc and Zif268.

A hypothalamic dopamine locus for psychostimulant-induced hyperlocomotion in mice.

The lateral septum (LS) has been implicated in the regulation of locomotion. Nevertheless, the neurons synchronizing LS activity with the brain's clock in the suprachiasmatic nucleus (SCN) remain unknown. By interrogating the molecular, anatomical and physiological heterogeneity of dopamine neurons of the periventricular nucleus (PeVN; A14 catecholaminergic group), we find that Th/Dat1 cells from its anterior subdivision innervate the LS in mice.

Disrupted gene expression perturbs spontaneous Ca activity causing abnormal brain development and increased anxiety.

The L-type voltage-gated Ca channel gene is a risk gene for various psychiatric conditions, including schizophrenia and bipolar disorder. However, the cellular mechanism by which contributes to psychiatric disorders has not been elucidated. Here, we report that the embryonic deletion of in neurons destined for the cerebral cortex using an strategy disturbs spontaneous Ca activity and causes abnormal brain development and anxiety.

A Guide to the Generation of a 6-Hydroxydopamine Mouse Model of Parkinson's Disease for the Study of Non-Motor Symptoms.

In Parkinson's disease (PD), a large number of symptoms affecting the peripheral and central nervous system precede, develop in parallel to, the cardinal motor symptoms of the disease. The study of these conditions, which are often refractory to and may even be exacerbated by standard dopamine replacement therapies, relies on the availability of appropriate animal models. Previous work in rodents showed that injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in discrete brain regions reproduces several non-motor comorbidities commonly associated with PD, including cognitive deficits, depression, anxiety, as well as disruption of olfactory discrimination and circadian rhythm.

Involvement of Autophagy in Levodopa-Induced Dyskinesia.

Background: Autophagy is intensively studied in cancer, metabolic and neurodegenerative diseases, but little is known about its role in pathological conditions linked to altered neurotransmission. We examined the involvement of autophagy in levodopa (l-dopa)-induced dyskinesia, a frequent motor complication developed in response to standard dopamine replacement therapy in parkinsonian patients.

Methods: We used mouse and non-human primate models of Parkinson's disease to examine changes in autophagy associated with chronic l-dopa administration and to establish a causative link between impaired autophagy and dyskinesia.

NMDA Receptor and L-Type Calcium Channel Modulate Prion Formation.

Transmissible neurodegenerative prion diseases are characterized by the conversion of the cellular prion protein (PrP) to misfolded isoforms denoted as prions or PrP. Although the conversion can occur in the test tube containing recombinant prion protein or cell lysates, efficient prion formation depends on the integrity of intact cell functions. Since neurons are main targets for prion replication, we asked whether their most specialized function, i.

Sleep Disorders in Rodent Models of Parkinson's Disease.

Sleep disorders are frequently diagnosed in Parkinson's disease and manifested in the prodromal and advanced stages of the disease. These conditions, which in some cases affect more than 50% of Parkinson's disease (PD) patients, include hypersomnia, often manifested as excessive daytime sleepiness, insomnia, characterized by delayed initiation and fragmentation of sleep at night, and disruption of rapid eye movement (REM) sleep, resulting in loss of atonia and dream enactment. Standard dopamine replacement therapies for the treatment of motor symptoms are generally inadequate to combat sleep abnormalities, which seriously affect the quality of life of PD patients.

On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson's Disease.

Adenosine A2A receptors (A2ARs) have attracted considerable attention as an important molecular target for the design of Parkinson's disease (PD) therapeutic compounds. Here, we studied the transcriptional regulation of the A2AR gene in human peripheral blood mononuclear cells (PBMCs) obtained from PD patients and in the striatum of the well-validated, 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We report an increase in A2AR mRNA expression and protein levels in both human cells and mice striata, and in the latter we could also observe a consistent reduction in DNA methylation at gene promoter and an increase in histone H3 acetylation at lysine 9.

Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice.

Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR) transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA) task in mice and the ability of typical and atypical antipsychotic drugs (APDs) to rectify the PCP-mediated impairment.

A neural network for intermale aggression to establish social hierarchy.

Intermale aggression is used to establish social rank. Several neuronal populations have been implicated in aggression, but the circuit mechanisms that shape this innate behavior and coordinate its different components (including attack execution and reward) remain elusive. We show that dopamine transporter-expressing neurons in the hypothalamic ventral premammillary nucleus (PMv neurons) organize goal-oriented aggression in male mice.

Inhibition of mTORC1 Signaling Reverts Cognitive and Affective Deficits in a Mouse Model of Parkinson's Disease.

Non-motor symptoms, including cognitive deficits and affective disorders, are frequently diagnosed in Parkinson's disease (PD) patients and are only partially alleviated by dopamine replacement therapy. Here, we used a 6-hydroxydopamine (6-OHDA) mouse model of PD to examine the effects exerted on non-motor symptoms by inhibition of the mammalian target of rapamycin complex 1 (mTORC1), which is involved in the control of protein synthesis, cell growth, and metabolism. We show that rapamycin, which acts as an allosteric inhibitor of mTORC1, counteracts the impairment of novel object recognition.

Signal transduction in L-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression.

A large number of signaling abnormalities have been implicated in the emergence and expression of L-DOPA-induced dyskinesia (LID). The primary cause for many of these changes is the development of sensitization at dopamine receptors located on striatal projection neurons (SPN). This initial priming, which is particularly evident at the level of dopamine D1 receptors (D1R), can be viewed as a homeostatic response to dopamine depletion and is further exacerbated by chronic administration of L-DOPA, through a variety of mechanisms affecting various components of the G-protein-coupled receptor machinery.

Publisher Correction: An interactive framework for whole-brain maps at cellular resolution.

In the version of this article initially published online, Daniel Fürth was not listed as a corresponding author. The error has been corrected in the print, PDF and HTML versions of this article.

An interactive framework for whole-brain maps at cellular resolution.

To deconstruct the architecture and function of brain circuits, it is necessary to generate maps of neuronal connectivity and activity on a whole-brain scale. New methods now enable large-scale mapping of the mouse brain at cellular and subcellular resolution. We developed a framework to automatically annotate, analyze, visualize and easily share whole-brain data at cellular resolution, based on a scale-invariant, interactive mouse brain atlas.

cJun N-terminal kinase (JNK) mediates cortico-striatal signaling in a model of Parkinson's disease.

The cJun N-terminal kinase (JNK) signaling pathway has been extensively studied with regard to its involvement in neurodegenerative processes, but little is known about its functions in neurotransmission. In a mouse model of Parkinson's disease (PD), we show that the pharmacological activation of dopamine D1 receptors (D1R) produces a large increase in JNK phosphorylation. This effect is secondary to dopamine depletion, and is restricted to the striatal projection neurons that innervate directly the output structures of the basal ganglia (dSPN).

The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning.

The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo.

Dopamine Depletion Impairs Bilateral Sensory Processing in the Striatum in a Pathway-Dependent Manner.

Parkinson's disease (PD) is a movement disorder caused by the loss of dopaminergic innervation, particularly to the striatum. PD patients often exhibit sensory impairments, yet the underlying network mechanisms are unknown. Here we examined how dopamine (DA) depletion affects sensory processing in the mouse striatum.

Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model.

Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs).

l-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role?

In Parkinson's disease (PD), l-DOPA therapy leads to the emergence of motor complications including l-DOPA-induced dyskinesia (LID). LID relies on a sequence of pre- and postsynaptic neuronal events, leading to abnormal corticostriatal neurotransmission and maladaptive changes in striatal projection neurons. In recent years, additional non-neuronal mechanisms have been proposed to contribute to LID.