Involvement of cAMP-Dependent Protein Kinase in the Nucleus Accumbens in Cocaine Versus Social Interaction Reward

Evidence suggests that PKA activity in the nucleus accumbens (NAc) plays an essential role in reward-related learning. In this study, we investigated whether PKA is differentially involved in the expression of learning produced by either natural reinforcers or psychostimulants. For that purpose, we inhibited PKA through a bilateral infusion of Rp-cAMPS, a specific PKA inhibitor, directly into the NAc. The effects of PKA inhibition in the NAc on the expression of concurrent conditioned place preference (CPP) for cocaine (drug) and social interaction (natural reward) in rats were evaluated. We found that PKA inhibition increased the expression of cocaine preference. This effect was not due to altered stress levels or decreased social reward. PKA inhibition did not affect the expression of natural reward as intra-NAc Rp-cAMPS infusion did not affect expression of social preference. When rats were trained to express cocaine or social interaction CPP and tested for eventual persisting preference 7 and 14 days after CPP expression, cocaine preference was persistent, but social preference was abolished after the first test. These results suggest that PKA in the NAc is involved in drug reward learning that might lead to addiction and that only drug, but not natural, reward is persistent.     

Type 1 Corticotropin-Releasing Factor Receptor Differentially Modulates Neurotransmitter Levels in the Nucleus Accumbens of Juvenile versus Adult Rats

Adversity is particularly pernicious in early life, increasing the likelihood of developing psychiatric disorders in adulthood. Juvenile and adult rats exposed to social isolation show differences in anxiety-like behaviors and significant changes in dopamine (DA) neurotransmission in the nucleus accumbens (NAc). Brain response to stress is partly mediated by the corticotropin-releasing factor (CRF) system, composed of CRF and its two main receptors, CRF-R1 and CRF-R2. In the NAc shell of adult rats, CRF induces anxiety-like behavior and changes local DA balance. However, the role of CRF receptors in the control of neurotransmission in the NAc is not fully understood, nor is it known whether there are differences between life stages. Our previous data showed that infusion of a CRF-R1 antagonist into the NAc of juvenile rats increased DA levels in response to a depolarizing stimulus and decreased basal glutamate levels. To extend this analysis, we now evaluated the effect of a CRF-R1 antagonist infusion in the NAc of adult rats. Here, we describe that the opposite occurred in the NAc of adult compared to juvenile rats. Infusion of a CRF-R1 antagonist decreased DA and increased glutamate levels in response to a depolarizing stimulus. Furthermore, basal levels of DA, glutamate, and γ-Aminobutyric acid (GABA) were similar in juvenile animals compared to adults. CRF-R1 protein levels and localization were not different in juvenile compared to adult rats. Interestingly, we observed differences in the signaling pathways of CRF-R1 in the NAc of juveniles compared to adult rats. We propose that the function of CRF-R1 receptors is differentially modulated in the NAc according to life stage.     

Stimulating GABAergic Neurons in the Nucleus Accumbens Core Alters the Trigeminal Neuropathic Pain Responses in a Rat Model of Infraorbital Nerve Injury

The nucleus accumbens core (NAcc) is an important component of brain reward circuitry, but studies have revealed its involvement in pain circuitry also. However, its effect on trigeminal neuralgia (TN) and the mechanism underlying it are yet to be fully understood. Therefore, this study aimed to examine the outcomes of optogenetic stimulation of NAcc GABAergic neurons in an animal model of TN. Animals were allocated into TN, sham, and control groups. TN was generated by infraorbital nerve constriction and the optogenetic virus was injected into the NAcc. In vivo extracellular recordings were acquired from the ventral posteromedial nucleus of the thalamus. Alterations of behavioral responses during stimulation “ON” and “OFF” conditions were evaluated. In vivo microdialysis was performed in the NAcc of TN and sham animals. During optogenetic stimulation, electrophysiological recordings revealed a reduction of both tonic and burst firing activity in TN animals, and significantly improved behavioral responses were observed as well. Microdialysis coupled with liquid chromatography/tandem mass spectrometry analysis revealed significant alterations in extracellular concentration levels of GABA, glutamate, acetylcholine, dopamine, and citrulline in NAcc upon optic stimulation. In fine, our results suggested that NAcc stimulation could modulate the transmission of trigeminal pain signals in the TN animal model.     

The Role of Copper Homeostasis in Brain Disease

In the human body, copper is an important trace element and is a cofactor for several important enzymes involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis. Copper is also necessary for cellular processes, such as the regulation of intracellular signal transduction, catecholamine balance, myelination of neurons, and efficient synaptic transmission in the central nervous system. Copper is naturally present in some foods and is available as a dietary supplement. Only small amounts of copper are typically stored in the body and a large amount of copper is excreted through bile and urine. Given the critical role of copper in a breadth of cellular processes, local concentrations of copper and the cellular distribution of copper transporter proteins in the brain are important to maintain the steady state of the internal environment. The dysfunction of copper metabolism or regulatory pathways results in an imbalance in copper homeostasis in the brain, which can lead to a myriad of acute and chronic pathological effects on neurological function. It suggests a unique mechanism linking copper homeostasis and neuronal activation within the central nervous system. This article explores the relationship between impaired copper homeostasis and neuropathophysiological progress in brain diseases.     

The Role of Gut Microbiota and Gut–Brain Interplay in Selected Diseases of the Central Nervous System

The gut microbiome has attracted increasing attention from researchers in recent years. The microbiota can have a specific and complex cross-talk with the host, particularly with the central nervous system (CNS), creating the so-called “gut–brain axis”. Communication between the gut, intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an imbalance in the gut microbiota composition modulates the immune system and function of tissue barriers such as the blood–brain barrier (BBB). Therefore, the aim of this literature review is to describe how the gut–brain interplay may contribute to the development of various neurological disorders, combining the fields of gastroenterology and neuroscience. We present recent findings concerning the effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer’s and Parkinson’s diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD) and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut microbiota composition on the gut–brain axis would help to identify new potential opportunities for therapeutic interventions in the presented diseases.     

Alterations in Rat Accumbens Dopamine,Endocannabinoids and GABA Content During WIN55,212-2 Treatment: The Role of Ghrelin

The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2–induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.     

Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity

A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.     

Modeling of the Progressive Degradation of the Nigrostriatal Dopaminergic System in Mice to Study the Mechanisms of Neurodegeneration and Neuroplasticity in Parkinson’s Disease

The fight against neurodegenerative diseases, including Parkinson’s disease (PD), is among the global challenges of the 21st century. The low efficiency of therapy is due to the late diagnosis and treatment of PD, which take place when there is already significant degradation of the nigrostriatal dopaminergic system, a key link in the regulation of motor function. We have developed a subchronic mouse model of PD by repeatedly administering 1–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP) at gradually increasing doses with a 24 h interval between injections, a period comparable to the time of MPTP metabolism and elimination from the body. This model reproduces the main hallmarks of PD: progressive degeneration of dopaminergic neurons; the appearance of motor disorders with a 70–80% decrease in the level of dopamine in the striatum; an increase in dopamine turnover in the striatum to compensate for dopamine deficiency. When comparing the degradation of the nigrostriatal dopaminergic system and motor disorders in mice in the acute and subchronic models of PD, it has turned out that the resistance of dopaminergic neurons to MPTP increases with its repeated administration. Our subchronic model of PD opens up broad prospects for studying the molecular mechanisms of PD pathogenesis and developing technologies for early diagnosis and preventive treatment.     

SARS-CoV-2 Morbidity in the CNS and the Aged Brain Specific Vulnerability

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be the cause of a fatal disease known as coronavirus disease 2019 (COVID-19) affecting the lungs and other organs. Particular attention has been given to the effects of the infection on the brain due to recurring neurological symptoms associated with COVID-19, such as ischemic or hemorrhagic stroke, encephalitis and myelitis, which are far more severe in the elderly compared to younger patients. The specific vulnerability of the aged brain could derive from the impaired immune defenses, from any of the altered homeostatic mechanisms that contribute to the aging phenotype, and from particular changes in the aged brain involving neurons and glia. While neuronal modifications could contribute indirectly to the damage induced by SARS-CoV-2, glia alterations could play a more direct role, as they are involved in the immune response to viral infections. In aged patients, changes regarding glia include the accumulation of dystrophic forms, reduction of waste removal, activation of microglia and astrocytes, and immunosenescence. It is plausible to hypothesize that SARS-CoV-2 infection in the elderly may determine severe brain damage because of the frail phenotype concerning glial cells.     

Unraveling the Spatiotemporal Distribution of VPS13A in the Mouse Brain

Loss-of-function mutations in the human vacuolar protein sorting the 13 homolog A (VPS13A) gene cause Chorea-acanthocytosis (ChAc), with selective degeneration of the striatum as the main neuropathologic feature. Very little is known about the VPS13A expression in the brain. The main objective of this work was to assess, for the first time, the spatiotemporal distribution of VPS13A in the mouse brain. We found VPS13A expression present in neurons already in the embryonic stage, with stable levels until adulthood. VPS13A mRNA and protein distributions were similar in the adult mouse brain. We found a widespread VPS13A distribution, with the strongest expression profiles in the pons, hippocampus, and cerebellum. Interestingly, expression was weak in the basal ganglia. VPS13A staining was positive in glutamatergic, GABAergic, and cholinergic neurons, but rarely in glial cells. At the cellular level, VPS13A was mainly located in the soma and neurites, co-localizing with both the endoplasmic reticulum and mitochondria. However, it was not enriched in dendritic spines or the synaptosomal fraction of cortical neurons. In vivo pharmacological modulation of the glutamatergic, dopaminergic or cholinergic systems did not modulate VPS13A concentration in the hippocampus, cerebral cortex, or striatum. These results indicate that VPS13A has remarkable stability in neuronal cells. Understanding the distinct expression pattern of VPS13A can provide relevant information to unravel pathophysiological hallmarks of ChAc.     

Development of the Periventricular Nucleus as a Brain Center,Containing Dopaminergic Neurons and Neurons Expressing Individual Enzymes of Dopamine Synthesis

We have recently shown that the periventricular nucleus (PeVN) of adult rats is a “mixed dopaminergic (DAergic) center” containing three thousand neurons: DAergic neurons and those expressing one of the dopamine (DA)-synthesizing enzymes. This study aims to evaluate the development of the PeVN as a mixed DAergic center in rats in the perinatal period, critical for brain morphogenesis. During this period, the PeVN contains DAergic neurons and monoenzymatic neurons expressing individual enzymes of DA synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). In the perinatal period, the total number of such neurons triples, mainly due to monoenzymatic neurons; the content of L-DOPA, the end product of monoenzymatic TH neurons, doubles; and the content of DA, the end product of monoenzymatic AADC neurons and DAergic neurons, increases sixfold. Confocal microscopy has shown that, in the PeVN, all types of neurons and their processes are in close relationships, which suggests their mutual regulation by L-DOPA and DA. In addition, monoenzymatic and DAergic fibers are close to the third cerebral ventricle, located in the subependymal zone, between ependymal cells and in the supraependymal zone. These observations suggest that these fibers deliver L-DOPA and DA to the cerebrospinal fluid, participating in the neuroendocrine regulation of the brain.     

The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer’s disease, or the most common neurodegenerative motor disorder, Parkinson’s disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle–brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle–brain axis in neurodegenerative diseases are outlined.     

The Role of BDNF in Experimental and Clinical Traumatic Brain Injury

Traumatic brain injury is one of the leading causes of mortality and morbidity in the world with no current pharmacological treatment. The role of BDNF in neural repair and regeneration is well established and has also been the focus of TBI research. Here, we review experimental animal models assessing BDNF expression following injury as well as clinical studies in humans including the role of BDNF polymorphism in TBI. There is a large heterogeneity in experimental setups and hence the results with different regional and temporal changes in BDNF expression. Several studies have also assessed different interventions to affect the BDNF expression following injury. Clinical studies highlight the importance of BDNF polymorphism in the outcome and indicate a protective role of BDNF polymorphism following injury. Considering the possibility of affecting the BDNF pathway with available substances, we discuss future studies using transgenic mice as well as iPSC in order to understand the underlying mechanism of BDNF polymorphism in TBI and develop a possible pharmacological treatment.     

Transcriptional Profiling of Whisker Follicles and of the Striatum in Methamphetamine Self-Administered Rats

Methamphetamine (MA) use disorder is a chronic neuropsychiatric disease characterized by recurrent binge episodes, intervals of abstinence, and relapses to MA use. Therefore, identification of the key genes and pathways involved is important for improving the diagnosis and treatment of this disorder. In this study, high-throughput RNA sequencing was performed to find the key genes and examine the comparability of gene expression between whisker follicles and the striatum of rats following MA self-administration. A total of 253 and 87 differentially expressed genes (DEGs) were identified in whisker follicles and the striatum, respectively. Multivariate and network analyses were performed on these DEGs to find hub genes and key pathways within the constructed network. A total of 129 and 49 genes were finally selected from the DEG sets of whisker follicles and of the striatum. Statistically significant DEGs were found to belong to the classes of genes involved in nicotine addiction, cocaine addiction, and amphetamine addiction in the striatum as well as in Parkinson’s, Huntington’s, and Alzheimer’s diseases in whisker follicles. Of note, several genes and pathways including retrograde endocannabinoid signaling and the synaptic vesicle cycle pathway were common between the two tissues. Therefore, this study provides the first data on gene expression levels in whisker follicles and in the striatum in relation to MA reward and thereby may accelerate the research on the whisker follicle as an alternative source of biomarkers for the diagnosis of MA use disorder.     

Key Role of Astrocytes in Postnatal Brain and Retinal Angiogenesis

Angiogenesis is a key process in various physiological and pathological conditions in the nervous system and in the retina during postnatal life. Although an increasing number of studies have addressed the role of endothelial cells in this event, the astrocytes contribution in angiogenesis has received less attention. This review is focused on the role of astrocytes as a scaffold and in the stabilization of the new blood vessels, through different molecules release, which can modulate the angiogenesis process in the brain and in the retina. Further, differences in the astrocytes phenotype are addressed in glioblastoma, one of the most devastating types of brain cancer, in order to provide potential targets involved in the cross signaling between endothelial cells, astrocytes and glioma cells, that mediate tumor progression and pathological angiogenesis. Given the relevance of astrocytes in angiogenesis in physiological and pathological conditions, future studies are required to better understand the interrelation between endothelial and astrocyte signaling pathways during this process.     

Diurnal Expression of the Per2 Gene and Protein in the Lateral Habenular Nucleus

The suprachiasmatic nucleus plays an important role in generating circadian rhythms in mammals. The lateral habenular nucleus (LHb) is closely linked to this structure. Interestingly, the LHb shows a rhythmic firing rate in vivo and in vitro, and sustained oscillation of rhythmic genes in vitro. However, under the in vivo condition, whether rhythmic gene expression in the LHb has circadian rhythms remains unknown. In this study, we examined LHb tissue in rats to determine Period2 (Per2) gene and protein expression at six zeitgeber time points (ZT2, ZT6, ZT10, ZT14, ZT18, and ZT22) in a 12-h light and 12-h dark (LD) environment. We found that in the LD environment, Per2 gene expression and PER2 protein levels in the LHb were higher in the day and lower in the night, showing periodic oscillation, with a peak at ZT10 and a trough at ZT22 (Per2 mRNA) and ZT18 (PER2 protein). We conclude that Per2 expression and PER2 protein levels in the LHb have rhythmic oscillation in vivo. This study provides a basis for further study on the role of the LHb in the circadian rhythm system.     

The Therapeutic Role of Exercise and Probiotics in Stressful Brain Conditions

Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurological disorders such as Parkinson’s disease, Alzheimer’s dementia, ischemic stroke, and head and spinal cord injury. The increased production of reactive oxygen species (ROS) has been associated with mitochondrial dysfunction, altered metal homeostasis, and compromised brain antioxidant defence. All these changes have been reported to directly affect synaptic activity and neurotransmission in neurons, leading to cognitive dysfunction. In this context two non-invasive strategies could be employed in an attempt to improve the aforementioned stressful brain status. In this regard, it has been shown that exercise could increase the resistance against oxidative stress, thus providing enhanced neuroprotection. Indeed, there is evidence suggesting that regular physical exercise diminishes BBB permeability as it reinforces antioxidative capacity, reduces oxidative stress, and has anti-inflammatory effects. However, the differential effects of different types of exercise (aerobic exhausted exercise, anaerobic exercise, or the combination of both types) and the duration of physical activity will be also addressed in this review as likely determinants of therapeutic efficacy. The second proposed strategy is related to the use of probiotics, which can also reduce some biomarkers of oxidative stress and inflammatory cytokines, although their underlying mechanisms of action remain unclear. Moreover, various probiotics produce neuroactive molecules that directly or indirectly impact signalling in the brain. In this review, we will discuss how physical activity can be incorporated as a component of therapeutic strategies in oxidative stress-based neurological disorders along with the augmentation of probiotics intake.