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The substantia nigra pars compacta (SNc), one of the main dopaminergic nuclei of the brain, exerts a regulatory function on the basal ganglia circuitry via the nigro-striatal pathway but its possible dopaminergic innervation of the thalamus has been only investigated in non-human primates. The impossibility of tract-tracing studies in humans has boosted advanced MRI techniques and multi-shell high-angular resolution diffusion MRI (MS-HARDI) has promised to shed more light on the structural connectivity of subcortical structures. Here, we estimated the possible dopaminergic innervation of the human thalamus via an MS-HARDI tractography of the SNc in healthy human young adults. Two MRI data sets were serially acquired using MS-HARDI schemes from ADNI and HCP neuroimaging initiatives in a group of 10 healthy human subjects (5 males, age range: 25-30 years). High resolution 3D-T1 images were independently acquired to individually segment the thalamus and the SNc. Starting from whole-brain probabilistic tractography, all streamlines through the SNc reaching the thalamus were counted, separately for each hemisphere, after excluding streamlines through the substantia nigra pars reticulata and all those reaching the basal ganglia, the cerebellum and the cortex. We found a reproducible structural connectivity between the SNc and the thalamus, with an average of ~12% of the total number of streamlines encompassing the SNc and terminating in the thalamus, with no other major subcortical or cortical structures involved. The first principal component map of dopamine receptor density from a normative PET image data set suggested similar dopamine levels across SNc and thalamus. This is the first quantitative report from in-vivo measurements in humans supporting the presence of a direct nigro-thalamic dopaminergic projection. While histological validation and concurrent PET-MRI remains needed for ultimate proofing of existence, given the potential role of this pathway, the possibility to achieve a good reproducibility of these measurements in humans might enable the monitoring of dopaminergic-related disorders, towards targeted personalized therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Cirillo, Caiazzo, Franza, Cirillo, Papa and Esposito.)

The endocannabinoid system comprises highly versatile signaling functions within the nervous system. It is reported to modulate the release of several neurotransmitters, consequently affecting the activity of neuronal circuits. Investigations have highlighted its roles in numerous processes, including appetite-stimulating characteristics, particularly for palatable food. Moreover, endocannabinoids are shown to fine-tune dopamine-signaled processes governing motivated behavior. Specifically, it has been demonstrated that excitatory and inhibitory inputs controlled by the cannabinoid type 1 receptor (CB1) regulate dopaminergic neurons in the mesocorticolimbic pathway. In the present study, we show that mesencephalic dopaminergic (mesDA) neurons in the ventral tegmental area (VTA) express CB1, and we investigated the consequences of specific deletion of CB1 in cells expressing the transcription factor Engrailed-1 (En1). To this end, we validated a new genetic mouse line EN1-CB1-KO, which displays a CB1 knockout in mesDA neurons beginning from their differentiation, as a tool to elucidate the functional contribution of CB1 in mesDA neurons. We revealed that EN1-CB1-KO mice display a significantly increased immobility time and shortened latency to the first immobility in the forced swim test of adult mice. Moreover, the maximal effort exerted to obtain access to chocolate-flavored pellets was significantly reduced under a progressive ratio schedule. In contrast, these mice do not differ in motor skills, anhedonia- or anxiety-like behavior compared to wild-type littermates. Taken together, these findings suggest a depressive-like or despair behavior in an inevitable situation and a lack of motivation to seek palatable food in EN1-CB1-KO mice, leading us to propose that CB1 plays an important role in the physiological functions of mesDA neurons. In particular, our data suggest that CB1 directly modifies the mesocorticolimbic pathway implicated in depressive-like/despair behavior and motivation. In contrast, the nigrostriatal pathway controlling voluntary movement seems to be unaffected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Baddenhausen, Lutz and Hofmann.)

Introduction: The medical and recreational use of cannabis has increased in the United States. Its chronic use can have detrimental effects on the neurobiology of the brain-effects that are age-dependent. This was an exploratory study looking at the effects of chronically inhaled vaporized cannabis on brain structure in adult female mice., Methods: Adult mice were exposed daily to vaporized cannabis (10.3% THC and 0.05% CBD) or placebo for 21 days. Following cessation of treatment mice were examined for changes in brain structure using voxel-based morphometry and diffusion weighted imaging MRI. Data from each imaging modality were registered to a 3D mouse MRI atlas with 139 brain areas., Results: Mice showed volumetric changes in the forebrain particularly the prefrontal cortex, accumbens, ventral pallidum, and limbic cortex. Many of these same brain areas showed changes in water diffusivity suggesting alterations in gray matter microarchitecture., Discussion: These data are consistent with much of the clinical findings on cannabis use disorder. The sensitivity of the dopaminergic system to the daily exposure of vaporized cannabis raises concerns for abuse liability in drug naïve adult females that initiate chronic cannabis use., Competing Interests: CF has a financial interest in Animal Imaging Research, a company that makes radiofrequency electronics and holders for animal imaging. CF and PK have a partnership interest in Ekam Solutions a company that develops 3D MRI atlases for animal research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Taylor, Nweke, Vincent, Oke, Kulkarni and Ferris.)

Exposure to heavy metals has been associated with psychiatric disorders and recent studies suggest an association between childhood lead (Pb 2+ ) intoxication and schizophrenia (SZ). In animal models, Pb 2+ exposure recapitulates key neuropathological and dopaminergic system alterations present in SZ. Given the high comorbidity of mental disorders such as SZ and substance abuse, coupled with evidence showing that Pb 2+ exposure affects addiction circuits, we hypothesized that early life Pb 2+ exposure could sensitize neuronal systems relevant to SZ and substance abuse. To this goal, we examined the effects of chronic developmental Pb 2+ exposure on the acute locomotor response to cocaine (0, 5, and 15 mg kg -1 ) and behavioral sensitization. We also examined the role of the dopaminergic system in the psychostimulant effects of cocaine, and measured D1-dopamine receptor (D1R) levels in the rat brain using [ 3 H]-SCH23390 quantitative receptor autoradiography, as well as the ability of the D1R antagonist SCH23390 to block the cocaine effects on locomotor activation. These studies were performed in male and female rats at different developmental ages consisting of juveniles (postnatal, PN14), early-adolescent (PN28), late adolescent (PN50), and adults (PN120). Our results show that chronic developmental Pb 2+ exposure increases the acute locomotor response to the higher dose of cocaine in Pb 2+ -exposed male adolescent (PN28 and PN50) rats, and to the lower dose of cocaine in adolescent female rats. No changes in the locomotor activity were detected in adult rats. Behavioral sensitization experiments showed a sustained sensitization in early adolescent Pb 2+ -exposed male but not female rats. The cocaine-induced effects on locomotor activity were abrogated by injection of a D1R antagonist suggesting the involvement of this dopamine receptor subtype. Furthermore, Pb 2+ -induced increases D1R levels in several brain regions were prominent in juveniles and early adolescence but not in late adolescence or in adults. In summary, early chronic developmental Pb 2+ exposure results in age and sex-dependent effect on the locomotor response to cocaine, suggesting differential susceptibilities to the neurotoxic effects of Pb 2+ exposure. Our data provides further support to the notion that Pb 2+ exposure is an environmental risk factor for psychiatric disorders and substance abuse., Competing Interests: KS was employed by InVitro Cell Research, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Albores-Garcia, Stansfield, McGlothan, Bursac and Guilarte.)

After sensory information is encoded into neural signals at the periphery, it is processed through multiple brain regions before perception occurs (i.e., sensory processing). Recent work has begun to tease apart how neuromodulatory systems influence sensory processing. Vagus nerve stimulation (VNS) is well-known as an effective and safe method of activating neuromodulatory systems. There is a growing body of studies confirming VNS has immediate effects on sensory processing across multiple sensory modalities. These immediate effects of VNS on sensory processing are distinct from the more well-documented method of inducing lasting neuroplastic changes to the sensory pathways through repeatedly delivering a brief VNS burst paired with a sensory stimulus. Immediate effects occur upon VNS onset, often disappear upon VNS offset, and the modulation is present for all sensory stimuli. Conversely, the neuroplastic effect of pairing sub-second bursts of VNS with a sensory stimulus alters sensory processing only after multiple pairing sessions, this alteration remains after cessation of pairing sessions, and the alteration selectively affects the response properties of neurons encoding the specific paired sensory stimulus. Here, we call attention to the immediate effects VNS has on sensory processing. This review discusses existing studies on this topic, provides an overview of the underlying neuromodulatory systems that likely play a role, and briefly explores the potential translational applications of using VNS to rapidly regulate sensory processing., Competing Interests: All authors have financial interest in Sharper Sense, a company developing methods of enhancing sensory processing with VNS., (Copyright © 2022 Rodenkirch, Carmel and Wang.)

Level of motivation, responsiveness to rewards and punishment, invigoration of exploratory behaviours, and motor performance are subject to daily fluctuations that emerge from circadian rhythms in neuronal activity of the midbrain's dopaminergic system. While endogenous circadian rhythms are weak in the ventral tegmental area and substantia nigra pars compacta, daily changes in expression of core clock genes, ion channels, neurotransmitter receptors, dopamine-synthesising enzymes, and dopamine transporters, accompanied by changes in electrical activity, are readily observed in these nuclei. These processes cause dopamine levels released in structures innervated by midbrain dopaminergic neurons (e.g., the striatum) to oscillate in a circadian fashion. Additionally, growing evidence show that the master circadian clock located in the suprachiasmatic nucleus of the hypothalamus (SCN) rhythmically influences the activity of the dopaminergic system through various intermediate targets. Thus, circadian changes in the activity of the dopaminergic system and concomitant dopamine release observed on a daily scale are likely to be generated both intrinsically and entrained by the master clock. Previous studies have shown that the information about the value and salience of stimuli perceived by the animal is encoded in the neuronal activity of brain structures innervating midbrain dopaminergic centres. Some of these structures themselves are relatively autonomous oscillators, while others exhibit a weak endogenous circadian rhythm synchronised by the SCN. Here, we place the dopaminergic system as a hub in the extensive network of extra-SCN circadian oscillators and discuss the possible consequences of its daily entrainment for animal physiology and behaviour., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pradel, Drwięga, Chrobok and Błasiak.)

Ankyrin repeat and kinase domain containing 1 (ANKK1) is a member of the receptor-interacting protein serine/threonine kinase family, known to be involved in cell proliferation, differentiation and activation of transcription factors. Genetic variation within the ANKK1 locus is suggested to play a role in vulnerability to addictions. However, ANKK1 mechanism of action is still poorly understood. It has been suggested that ANKK1 may affect the development and/or functioning of dopaminergic pathways. To test this hypothesis, we generated a CRISPR-Cas9 loss of function ankk1 zebrafish line causing a 27 bp insertion that disrupts the ankk1 sequence introducing an early stop codon. We found that ankk1 transcript levels were significantly lower in ankk1 mutant ( ankk1 27 ins ) fish compared to their wild type ( ankk1 +/+ ) siblings. In ankk1 +/+ adult zebrafish brain, ankk1 protein was detected in isocortex, hippocampus, basolateral amygdala, mesencephalon, and cerebellum, resembling the mammalian distribution pattern. In contrast, ankk1 protein was reduced in the brain of ankk1 27 ins/ 27 ins fish. Quantitative polymerase chain reaction analysis revealed an increase in expression of drd2b mRNA in ankk1 27 ins at both larval and adult stages. In ankk1 +/+ adult zebrafish brain, drd2 protein was detected in cerebral cortex, cerebellum, hippocampus, and caudate homolog regions, resembling the pattern in humans. In contrast, drd2 expression was reduced in cortical regions of ankk1 27 ins/ 27 ins being predominantly found in the hindbrain. No differences in the number of cell bodies or axonal projections detected by anti-tyrosine hydroxylase immunostaining on 3 days post fertilization (dpf) larvae were found. Behavioral analysis revealed altered sensitivity to effects of both amisulpride and apomorphine on locomotion and startle habituation, consistent with a broad loss of both pre and post synaptic receptors. Ankk1 27 ins mutants showed reduced sensitivity to the effect of the selective dopamine receptor antagonist amisulpride on locomotor responses to acoustic startle and were differentially sensitive to the effects of the non-selective dopamine agonist apomorphine on both locomotion and habituation. Taken together, our findings strengthen the hypothesis of a functional relationship between ANKK1 and DRD2 , supporting a role for ANKK1 in the maintenance and/or functioning of dopaminergic pathways. Further work is needed to disentangle ANKK1 's role at different developmental stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Leggieri, García-González, Torres-Perez, Havelange, Hosseinian, Mech, Keatinge, Busch-Nentwich and Brennan.)

Background: The pathogenesis of dystonia is remarkably diverse. Some types of dystonia, such as DYT5 (DYT- GCH1 ) and tardive dystonia, are related to dysfunction of the dopaminergic system. Furthermore, on pathological examination, cell loss in the substantia nigra (SN) of patients with dystonia has been reported, suggesting that impaired dopamine production may be involved in DYT5 and in other types of dystonia. Objectives: To investigate functional dopaminergic impairments, we compared patients with dystonia and those with Parkinson's disease (PD) with normal controls using neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and dopamine transporter single photon emission computed tomography (DAT SPECT). Methods: A total of 18, 18, and 27 patients with generalized or segmental dystonia, patients with PD, and healthy controls, respectively, were examined using NM-MRI. The mean area corresponding to NM in the SN (NM-SN) was blindly quantified. DAT SPECT was performed on 17 and eight patients with dystonia and PD, respectively. The imaging data of DAT SPECT were harmonized with the Japanese database using striatum phantom calibration. These imaging data were compared between patients with dystonia or PD and controls from the Japanese database in 256 healthy volunteers using the calibrated specific binding ratio (cSBR). The symptoms of dystonia were evaluated using the Fahn-Marsden Dystonia Rating Scale (FMDRS), and the correlation between the results of imaging data and FMDRS was examined. Results: The mean areas corresponding to NM in the SN (NM-SN) were 31 ± 4.2, 28 ± 3.8, and 43 ± 3.8 pixels in patients with dystonia, PD, and in healthy controls, respectively. The mean cSBRs were 5 ± 0.2, 2.8 ± 0.2, 9.2 (predictive) in patients with dystonia, PD, and in healthy controls, respectively. The NM-SN area ( r = -0.49, p < 0.05) and the cSBR ( r = -0.54, p < 0.05) were inversely correlated with the FMDRS. There was no significant difference between the dystonia and PD groups regarding NM-SN ( p = 0.28). In contrast, the cSBR was lower in patients with PD than in those with dystonia ( p < 0.5 × 10 -6 ). Conclusions: Impairments of the dopaminergic system may be involved in developing generalized and segmental dystonia. SN abnormalities in patients with dystonia were supposed to be different from degeneration in PD., Competing Interests: Unrelated to this study, FY receives grants from InSightec, Ltd. for a trial on focused ultrasound for Parkinson's disease. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ikezawa, Yokochi, Okiyama, Kumada, Tojima, Kamiyama, Hanakawa, Matsuda, Tanaka, Nakata and Isozaki.)

The dopaminergic system (DS) is one of the most important neuromodulator systems involved in complex functions that are compromised in both autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), conditions that frequently occur in overlap. This evidence suggests that both disorders might have common neurobiological pathways involving the DS. Therefore, the aim of this study was to examine the DRD1 and DRD2 dopamine receptor single nucleotide polymorphisms (SNPs) as potential risk factors for ASD, ADHD, and ASD/ADHD overlap. Genetic data were obtained from four groups: 75 ASD patients, 75 ADHD patients, 30 patients with ASD/ADHD overlap, and 75 healthy controls. All participants were between 2 and 17 years old. We compared the genotypic and allelic frequency of 18 SNPs among all of the study groups. Moreover, in the case of statistically significant differences, odds ratios (OR) were obtained to evaluate if the presence of SNPs might be a risk factor of developing a specific clinical phenotype. This study found that DRD1 and DRD2 receptors SNPs might be considered as potential risk factors for ASD and ADHD. However, only DRD2-12 ( rs7131465 ) was significantly associated with a higher risk for the ASD/ADHD overlap. These data support the hypothesis of the genetic neuromodulation of the DS in the neurobiology of these conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mariggiò, Palumbi, Vinella, Laterza, Petruzzelli, Peschechera, Gabellone, Gentile, Vincenti and Margari.)

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical and experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, and enhanced inflammation. These changes are associated with cognitive decline and neurobehavioral deficits. Although aging is not a disease, it is a significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, and general disease susceptibility. Conversely, life events related to mental stress and trauma can also lead to accelerated age-associated disorders and dementia. Here, we review human studies and studies on mice and rats, such as those modeling human neurodegenerative diseases, that have helped elucidate (1) the dynamics and mechanisms underlying the biological and pathological aging of the main projecting systems in the brain (glutamatergic, cholinergic, and dopaminergic) and (2) the effect of defective glutamatergic, cholinergic, and dopaminergic projection on disabilities associated with aging and neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Detailed knowledge of the mechanisms of age-related diseases can be an important element in the development of effective ways of treatment. In this context, we briefly analyze which adverse changes associated with neurodegenerative diseases in the cholinergic, glutaminergic and dopaminergic systems could be targeted by therapeutic strategies developed as a result of our better understanding of these damaging mechanisms., Competing Interests: The authors declare that this study was partially sponsored by TauRx Therapeutics Ltd. The funder was not involved in the paper design, collection, analysis, interpretation of reviewed literature resources, the writing of this article or the decision to submit it for publication., (Copyright © 2021 Gasiorowska, Wydrych, Drapich, Zadrozny, Steczkowska, Niewiadomski and Niewiadomska.)

Trans-regulation of G protein-coupled receptors (GPCRs) by leucine-rich repeat (LRR) transmembrane proteins has emerged as a novel type of synaptic molecular interaction in the last decade. Several studies on LRR-GPCR interactions have revealed their critical role in synapse formation and in establishing synaptic properties. Among them, LRR-GPCR interactions between extracellular LRR fibronectin domain-containing family proteins (Elfn1 and Elfn2) and metabotropic glutamate receptors (mGluRs) are particularly interesting as they can affect a broad range of synapses through the modulation of signaling by glutamate, the principal excitatory transmitter in the mammalian central nervous system (CNS). Elfn-mGluR interactions have been investigated in hippocampal, cortical, and retinal synapses. Postsynaptic Elfn1 in the hippocampus and cerebral cortex mediates the tonic regulation of excitatory input onto somatostatin-positive interneurons (INs) through recruitment of presynaptic mGluR7. In the retina, presynaptic Elfn1 binds to mGluR6 and is necessary for synapse formation between rod photoreceptor cells and rod-bipolar cells. The repertoire of binding partners for Elfn1 and Elfn2 includes all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both Elfn1 and Elfn2 can alter mGluR-mediated signaling through trans-interaction. Importantly, both preclinical and clinical studies have provided support for the involvement of the Elfn1-mGluR7 interaction in attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and epilepsy. In fact, Elfn1-mGluR7-associated disorders may reflect the altered function of somatostatin-positive interneuron inhibitory neural circuits, the mesolimbic and nigrostriatal dopaminergic pathway, and habenular circuits, highlighting the need for further investigation into this interaction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Matsunaga and Aruga.)

Cocaine use disorder and methamphetamine use disorder are chronic, relapsing disorders with no US Food and Drug Administration-approved interventions. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool that has been increasingly investigated as a possible therapeutic intervention for substance use disorders. rTMS may have the ability to induce beneficial neuroplasticity in abnormal circuits and networks in individuals with addiction. The aim of this review is to highlight the rationale and potential for rTMS to treat cocaine and methamphetamine dependence: we synthesize the outcomes of studies in healthy humans and animal models to identify and understand the neurobiological mechanisms of rTMS that seem most involved in addiction, focusing on the dopaminergic and glutamatergic systems. rTMS-induced changes to neurotransmitter systems include alterations to striatal dopamine release and metabolite levels, as well as to glutamate transporter and receptor expression, which may be relevant for ameliorating the aberrant plasticity observed in individuals with substance use disorders. We also discuss the clinical studies that have used rTMS in humans with cocaine and methamphetamine use disorders. Many such studies suggest changes in network connectivity following acute rTMS, which may underpin reduced craving following chronic rTMS. We suggest several possible future directions for research relating to the therapeutic potential of rTMS in addiction that would help fill current gaps in the literature. Such research would apply rTMS to animal models of addiction, developing a translational pipeline that would guide evidence-based rTMS treatment of cocaine and methamphetamine use disorder., (Copyright © 2020 Moretti, Poh and Rodger.)

Salt (sodium chloride) is an essential dietary requirement, but excessive consumption has long-term adverse consequences. A high-salt diet (HSD) increases the risk of chronic diseases such as cardiovascular conditions and diabetes and is also associated with poor sleep quality. Little is known, however, about the neural circuit mechanisms that mediate HSD-induced sleep changes. In this study, we sought to identify the effects of HSD on the sleep and related neural circuit mechanisms of Drosophila . Strikingly, we found that HSD causes young Drosophila to exhibit a fragmented sleep phenotype similar to that of normal aging individuals. Importantly, we further showed that HSD slightly impairs circadian rhythms and that the HSD-induced sleep changes are dependent on the circadian rhythm system. In addition, we demonstrated that HSD-induced sleep changes are dopaminergic-system dependent. Together, these results provide insight into how elevated salt in the diet can affect sleep quality., (Copyright © 2019 Xie, Wang, Ling, Yang, Yang and Chen.)

Parkinson's disease (PD) is manifested by progressive motor, autonomic, and cognitive disturbances. Dopamine (DA) synthesizing neurons in the substantia nigra (SN) degenerate, causing a decline in DA level in the striatum that leads to the characteristic movement disorders. A disease-modifying therapy to arrest PD progression remains unattainable with current pharmacotherapies, most of which cause severe side effects and lose their efficacy with time. For this reason, there is a need to seek new therapies supporting the pharmacological treatment of PD. Motor therapy is recommended for pharmacologically treated PD patients as it alleviates the symptoms. Molecular mechanisms behind the beneficial effects of motor therapy are unknown, nor is it known whether such therapy may be neuroprotective in PD patients. Due to obvious limitations, human studies are unlikely to answer these questions; therefore, the use of animal models of PD seems indispensable. Motor therapy in animal models of PD characterized by the loss of dopaminergic neurons has neuroprotective and neuroregenerative effects, and the completeness of neuronal protection may depend on (i) degree of neuronal loss, (ii) duration and intensity of exercise, and (iii) time elapsed between insult and commencing of training. As the physical activity is neuroprotective for dopaminergic neurons, the question arises what is the mechanism of this protective action. A current hypothesis assumes a central role of neurotrophic factors in the neuroprotection of dopaminergic neurons, even though it is still not clear whether increased DA level in the nigrostriatal axis results from neurogenesis of dopaminergic neurons in the SN, recovery of the phenotype of dopaminergic neurons, increased sprouting of the residual dopaminergic axons in the striatum, or generation of local striatal neurons from inhibitory interneurons. In the present review, we discuss studies describing the influence of physical exercise on the PD-like changes manifested in animal models of the disease and focus our interest on the current state of knowledge on the mechanism of neuroprotection induced by physical activity as a supportive therapy in PD., (Copyright © 2019 Palasz, Niewiadomski, Gasiorowska, Wysocka, Stepniewska and Niewiadomska.)

Disrupted-in-schizophrenia 1 (DISC1) is a key protein involved in behavioral processes and various mental disorders, including schizophrenia and major depression. A transgenic rat overexpressing non-mutant human DISC1, modeling aberrant proteostasis of the DISC1 protein, displays behavioral, biochemical and anatomical deficits consistent with aspects of mental disorders, including changes in the dorsal striatum, an anatomical region critical in the development of behavioral disorders. Herein, dorsal striatum of 10 transgenic DISC1 (tgDISC1) and 10 wild type (WT) littermate control rats was used for synaptosomal preparations and for performing liquid chromatography-tandem mass spectrometry (LC-MS)-based quantitative proteomics, using isobaric labeling (TMT10plex). Functional enrichment analysis was generated from proteins with level changes. The increase in DISC1 expression leads to changes in proteins and synaptic-associated processes including membrane trafficking, ion transport, synaptic organization and neurodevelopment. Canonical pathway analysis assigned proteins with level changes to actin cytoskeleton, Gαq, Rho family GTPase and Rho GDI, axonal guidance, ephrin receptor and dopamine-DARPP32 feedback in cAMP signaling. DISC1-regulated proteins proposed in the current study are also highly associated with neurodevelopmental and mental disorders. Bioinformatics analyses from the current study predicted that the following biological processes may be activated by overexpression of DISC1, i.e., regulation of cell quantities, neuronal and axonal extension and long term potentiation. Our findings demonstrate that the effects of overexpression of non-mutant DISC1 or its misassembly has profound consequences on protein networks essential for behavioral control. These results are also relevant for the interpretation of previous as well as for the design of future studies on DISC1.

Sleep helps to protect and renew hippocampus-dependent declarative learning. Less is known about forms of learning that mainly engage the dopaminergic reward system. Animal studies showed that exogenous melatonin modulates the responses of the dopaminergic reward system and acts as a neuroprotectant promoting memory. In humans, melatonin is mainly secreted in darkness during evening hours supporting sleep. In this study, we investigate the effects of a short period of daytime sleep (nap) and endogenous melatonin on reward learning. Twenty-seven healthy, adult students took part in an experiment, either taking a 90-min afternoon nap or watching videos (within-subject design). Before and after the sleep vs. wake interval, saliva melatonin levels and reward learning were measured, and in the nap condition, a polysomnogram was obtained. Reward learning was assessed using a two-alternative probabilistic reinforcement-learning task. Sleep itself and subjective arousal or valence had no significant effects on reward learning. However, this study showed for the first time that an afternoon nap can elicit a small but significant melatonin response in about 41% of the participants and that the magnitude of the melatonin response predicts subsequent reward learning. Only in melatonin responders did a short nap improve reward learning. The difference between melatonin-responders and non-responders occurred very early during learning indicating that melatonin might have improved working memory rather than reward learning. Future studies should use paradigms differentiating working memory and reward learning to clarify which aspect of human feedback learning might profit from melatonin.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disease displaying negative impacts on both the health and social ability of patients and considerable economical costs. The classical anti-parkinsonian drugs based in dopaminergic replacement are the standard treatment, but several motor side effects emerge during long-term use. This mini-review presents the rationale to several efforts from pre-clinical and clinical studies using adenosine receptor antagonists as a non-dopaminergic therapy. As several studies have indicated that the monotherapy with adenosine receptor antagonists reaches limited efficacy, the usage as a co-adjuvant appeared to be a promising strategy. The formulation of multi-targeted drugs, using adenosine receptor antagonists and other neurotransmitter systems than the dopaminergic one as targets, have been receiving attention since Parkinson's disease presents a complex biological impact. While pharmacological approaches to cure or ameliorate the conditions of PD are the leading strategy in this area, emerging positive aspects have arisen from non-pharmacological approaches and adenosine function inhibition appears to improve both strategies.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson's disease-like symptoms following administration to mice, monkeys, and humans. A common view is that MPTP is metabolized to 1-methyl-4-phenylpyridinium ion (MPP(+)) to induce its neurodegenerative effects on dopaminergic neurons in the substantia nigra (SN). Moreover, the hippocampus contains dopaminergic fibers, which are projecting from the ventral tegmental area, SN and pars compacta and contain the whole machinery required for dopamine synthesis making them sensitive to MPTP and MPP(+). Here, we present data showing that acute bath-application of MPP(+) elicited a dose-dependent facilitation followed by a depression of synaptic transmission of hippocampal Schaffer collaterals-CA1 synapses in mice. The effects of MPP(+) were not mediated by D1/D5- and D2-like receptor activation. Inhibition of the dopamine transporters did not prevent but increased the depression of excitatory post-synaptic field potentials. In the search for a possible mechanism, we observed that MPP(+) reduced the appearance of polyspikes in population spikes recorded in str. pyramidale and increased the frequency of miniature inhibitory post-synaptic currents. The acute effect of MPP(+) on synaptic transmission was attenuated by co-application of a GABAA receptor antagonist. Taking these data together, we suggest that MPP(+) affects hippocampal synaptic transmission by enhancing some aspects of the hippocampal GABAergic system.

The glial cell line-derived neurotrophic factor (GDNF) is a well-established trophic agent for dopaminergic (DA) neurons in vitro and in vivo. GDNF is necessary for maintenance of neuronal morphological and neurochemical phenotype and protects DA neurons from toxic damage. Numerous studies on animal models of Parkinson's disease (PD) have reported beneficial effects of GDNF on nigrostriatal DA neuron survival. However, translation of these observations to the clinical setting has been hampered so far by side effects associated with the chronic continuous intra-striatal infusion of recombinant GDNF. In addition, double blind and placebo-controlled clinical trials have not reported any clinically relevant effect of GDNF on PD patients. In the past few years, experiments with conditional Gdnf knockout mice have suggested that GDNF is necessary for maintenance of DA neurons in adulthood. In parallel, new methodologies for exogenous GDNF delivery have been developed. Recently, it has been shown that a small population of scattered, electrically interconnected, parvalbumin positive (PV+) GABAergic interneurons is responsible for most of the GDNF produced in the rodent striatum. In addition, cholinergic striatal interneurons appear to be also involved in the modulation of striatal GDNF. In this review, we summarize current knowledge on brain GDNF delivery, homeostasis, and its effects on nigrostriatal DA neurons. Special attention is paid to the therapeutic potential of endogenous GDNF stimulation in PD.

Approach and avoidance behaviors-the primary responses to the environmental stimuli of danger, novelty and reward-are associated with the brain structures that mediate cognitive functionality, reward sensitivity and emotional expression. Individual differences in approach and avoidance behaviors are modulated by the functioning of amygdaloid-hypothalamic-striatal and striatal-cerebellar networks implicated in action and reaction to salient stimuli. The nodes of these networks are strongly interconnected and by acting on them the endocannabinoid and dopaminergic systems increase the intensity of appetitive or defensive motivation. This review analyzes the approach and avoidance behaviors in humans and rodents, addresses neurobiological and neurochemical aspects of these behaviors, and proposes a possible synaptic plasticity mechanism, related to endocannabinoid-dependent long-term potentiation (LTP) and depression that allows responding to salient positive and negative stimuli.

Bipolar disorders (BDs) and addictions constitute reciprocal risk factors and are best considered under a unitary perspective. The concepts of allostasis and allostatic load (AL) may contribute to the understanding of the complex relationships between BD and addictive behaviors. Allostasis entails the safeguarding of reward function stability by recruitment of changes in the reward and stress system neurocircuitry and it may help to elucidate neurobiological underpinnings of vulnerability to addiction in BD patients. Conceptualizing BD as an illness involving the cumulative build-up of allostatic states, we hypothesize a progressive dysregulation of reward circuits clinically expressed as negative affective states (i.e., anhedonia). Such negative affective states may render BD patients more vulnerable to drug addiction, fostering a very rapid transition from occasional drug use to addiction, through mechanisms of negative reinforcement. The resulting addictive behavior-related ALs, in turn, may contribute to illness progression. This framework could have a heuristic value to enhance research on pathophysiology and treatment of BD and addiction comorbidity.

Recent researches reported behavioral and emotional impairment in Parkinson's disease (PD), even in the earliest stages. This impairment affects also decision-making and learning processes. The Iowa gambling task (IGT) is commonly used to examine the decision-making capacity. The purpose of the present study was to investigate the neural correlates of feedback evaluation in the decision-making process into a learning context, using IGT and event-related potentials (ERPs) in a group of non-demented medicated PD patients. Fifteen PD patients and 15 healthy controls were recruited for the study. PD patients were administrated a basic neuropsychological assessment oriented to exclude cognitive impairments. Both groups underwent the computerized IGT during electroencephalography (EEG) registration. To analyse ERPs, continuous EEG data were epoched within a time-window starting 1000 ms before and ending 1000 ms after feedback presentation and averaged separately for positive (i.e., win condition) and negative (i.e., loss condition) feedbacks. Behavioral data revealed a significant lower performance of PD patients (p < 0.05) compared with the controls. While controls demonstrated a correct feedback evaluation, PD patients did not show any learning, selecting more disadvantageous decks even in the last part of task. Furthermore, ERPs results revealed that controls showed a significant difference (p < 0.05) in ERPs morphology recorded after the win and the loss conditions, suggesting that positive and negative feedbacks were differently evaluated and processed. PD patients showed a different pattern: their ERPs morphology was the same for positive and negative feedback. Interestingly, our ERPs results suggest that in PD patients an incorrect evaluation of context-relevant outcomes could be the reason of a poor performance in decision-making tasks, and could explain cognitive and behavioral problems related to impulse control disorder.

The brain's ability to integrate different behavioral and cognitive processes relies on its capacity to generate neural oscillations in a cooperative and coordinated manner. Cross-frequency coupling (CFC) has recently been proposed as one of the mechanisms involved in organizing brain activity. Here we investigated the phase-to-amplitude CFC (PA-CFC) patterns of the oscillatory activity in the cortico-basal ganglia network of healthy, freely moving rats. Within-structure analysis detected consistent PA-CFC patterns in the four regions analyzed, with the phase of delta waves modulating the amplitude of activity in the gamma (low-gamma ~50 Hz; high-gamma ~80 Hz) and high frequency ranges (high frequency oscillations HFO, ~150 Hz). Between-structure analysis revealed that the phase of delta waves parses the occurrence of transient episodes of coherence in the gamma and high frequency bands across the entire network, providing temporal windows of coherence between different structures. Significantly, this specific spatio-temporal organization was affected by the action of dopaminergic drugs. Taken together, our findings suggest that delta-mediated PA-CFC plays a key role in the organization of local and distant activities in the rat cortico-basal ganglia network by fine-tuning the timing of synchronization events across different structures.

When we talk about drug addiction, we are really dealing with an extremely complex system in which there still remain many unknowns and where many empty spaces or missing links are still present. Recent studies have identified changes in the expression profiles of several specific miRNAs which affect the interactions between these molecules and their targets in various illnesses, including addiction, and which may serve as valuable targets for more efficient therapies. In this review, we summarize results which clearly demonstrate that several morphine-related miRNAs have roles in the mechanisms that define addiction. In this regard, morphine has been shown to have an important role in the regulation of different miRNAs, such as miR-let-7 [which works as a mediator of the movement of the mu opioid receptor (MOR) mRNA into P-bodies, leading to translational repression], miR-23b (involved in linking MOR expression and morphine treatment at the post-transcriptional level), and miR-190 (a key post-transcriptional repressor of neurogenic differentiation, NeuroD). Fentanyl increases NeuroD levels by reducing the amount of miR-190, but morphine does not affect the levels of NeuroD. We also discuss the relationship between morphine, miRNAs, and the immune system, based on the discovery that morphine treatment of monocytes led to a decrease in several anti-HIV miRNAs (mir-28, 125b, 150, and 382). This review is centered on miR-133b and its possible involvement in addiction through the effects of morphine. We establish the importance of miR-133b as a regulatory factor by summarizing its activity in different pathological processes, especially cancer. Using the zebrafish as a research model, we discuss the relationship between mir-133b, the dopaminergic system, and morphine, considering: (1) that morphine modulates the expression of miR-133b and of its target transcript Pitx3, (2) the role of the zebrafish mu opioid receptor (zfMOR) in morphine-induced regulation of miR-133b, which depends on ERK1/2, (3) that morphine regulates miR-133b in hippocampal neurons, and (4) the role of delta opioid receptors in morphine-induced regulation of miR-133b. We conclude that the control of miR-133b levels may be a mechanism for the development of addiction to morphine, or other drugs of abuse that increase dopaminergic levels in the extracellular space. These results show that miR-133b is a possible new target for the design of new treatments against addictive disorders.