Search Results (846)

Background. MiR-218 is a micro-RNA expressed in two isoforms (miR-218-1 and miR-218-2) in the brain and, within the mesencephalic area, it represents a specific regulator of differentiation and functional maturation of the dopamine-releasing neurons (DAn). Deletion of miR-218 isoforms within the midbrain alters the expression of synaptic mRNAs, the neuronal excitability of DAn of the substantia nigra pars compacta (SNpc), and their ability to release dopamine (DA) within the dorsal striatum. Objectives. Here we have investigated if miR-218 impacts the function of the DAn population adjacent to SNpc, the mesencephalic ventral tegmental area (VTA) innervating the nucleus accumbens (NAcc), and the medial prefrontal cortex. Methods. With the use of miR-218-1, miR-218-2, and double conditional knock-out mice (KO1, c-KO2, c-dKO), we performed electrophysiological recordings in VTA DAn to investigate firing activity, measurements of DA release in NAcc slices by constant potential amperometry (CPA), and in vivo behavioral analysis. Results. We find that KO1 VTA neurons display hyperexcitability in comparison with c-KO2, c-dKO, and wild type (WT) neurons. DA efflux in the NAcc core and shell is reduced in all single- and double-conditional KO striatal slices in comparison with controls. The KO1 mice display a tendency toward an anxiety-like trait, as revealed by the elevated plus maze test. Conclusions. Our data indicate that miR-218-1 is the isoform that mainly regulates VTA DA neuron excitability whereas both miR-218-1 and miR-218-2 impair DA release in the mesoaccumbens pathway. Full article

Background: Parkinson’s disease (PD) is a neurodegenerative disorder for which no curative therapies currently exist. Experimental models employing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduce PD features such as striatal dopaminergic dysfunction and motor deficits. Various MPTP dosing regimens are used to screen drug candidates for PD, but their validity is limited because of the predominant use of young male animals. Sex bias is another issue that is underrepresented in PD research, since females are more susceptible to this pathology. Here, we studied the model of bolus administration of MPTP (30 mg/kg) in aged female mice and assessed its sensitivity to the antioxidants fullerene C₆₀ and fullerenol C₆₀(OH)₂₄, given that oxidative stress is a key contributor to PD. Methods: 12-month-old female C57BL/6 mice received fullerene (0.1 mg/kg/day, via diet) or fullerenol (0.15 mg/kg/day, via drinking water). On day 10, mice were injected with MPTP. We studied tremor, piloerection, and behavior in the pole test, rotarod, pole test, and open field. High-performance liquid chromatography (HPLC) was employed to study dopaminergic neurotransmission, and the expression levels of its molecular regulators and nitric oxide synthase (NOS)-related targets were investigated using RT-PCR in the striatum and cortex. Results: MPTP-challenged mice displayed profound impairment in markers of dopaminergic neurotransmission and cellular distress, and showed disrupted motor behavior and vegetative functions. Antioxidant-treated animals that received a bolus injection of MPTP demonstrated partial preservation of tremor response, dopaminergic parameters, and iNOS and nNOS gene expression, although motor performance in the pole test was only modestly improved. Fullerenol appeared more effective in decreasing MPTP-induced neurochemical changes. Conclusions: The applied MPTP model showed its validity in mimicking PD features and was sensitive to low doses of antioxidants, suggesting its usefulness for screening drugs that target oxidative and nitrosative stress. The neuroprotective effects of fullerene-based compounds suggest their potential utility in the treatment of PD. Full article

Understanding the mechanisms behind academic buoyancy, the ability to effectively cope with everyday academic challenges, is essential for identifying the factors and mechanisms that help students maintain their motivation and cope with routine academic pressures. One potential underlying mechanism is reward sensitivity, or the capacity to experience pleasure both in anticipating and receiving reward-related stimuli. We hypothesized that individuals with higher sensitivity to anticipated reward would exhibit greater academic buoyancy. To test this in an academic context, we modified the Monetary Incentive Delay (MID) task into a School Grade Incentive Delay (SGID) task, where participants work towards a fictitious school grade by winning or losing points on each of the trials. In this study, we investigated whether the SGID activates the neural reward circuitry similar to the traditional MID and whether this is associated with academic buoyancy. The SGID task activated key brain regions associated with reward anticipation, validating its use for studying reward processing in academic contexts. Importantly, we found a negative association between academic buoyancy and right amygdala activation during reward anticipation, suggesting that buoyant students may benefit from reduced emotional reactivity when anticipating rewards. Further research in larger samples is needed to capture the full complexity of reward processing in relation to academic buoyancy. Full article

Background/Objectives: Potassium (K⁺) channels are essential transmembrane proteins that regulate ion flow, playing a critical role in regulating action potentials and neuronal transmission. Although K⁺ channel openers (agonists, K⁺ Ag) are widely used in treating neurological and psychiatric disorders, their precise mechanisms of action remain unclear. Our study explored how K⁺ channel openers might influence the expression of voltage-gated K⁺ channels (Kv) in rat brain. Methods: Briefly, eight rats per group received intraperitoneal injections of diazoxide (Dia), chlorzoxazone (Chl), or flupirtine (Flu). Two hours post-injection, the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), dorsal hippocampus (dHIP), and ventral hippocampus (vHIP) were collected for mRNA expression analysis of various Kv. Results: Dia administration altered expression of Kcna6 in the NAc, dSTR, and vHIP, and Kcnq2 in the PFC, dSTR, and dHIP. The mRNA levels of Kcna2 and Kcna3 changed in the NAc, dHIP, and vHIP, while Kcna6 expression increased in the PFC, dHIP, and vHIP of rats treated with Chl. Injection of Flu resulted in altered expression for Kcna1 in the NAc, dSTR, and dHIP; Kcna3 in the PFC, NAc, dHIP, and vHIP; Kcna6 in the dSTR, dHIP, and vHIP; and Kcnq2 and Kcnq3 in the PFC, dHIP, and vHIP. We also found dose-dependent changes. Conclusions: To our knowledge, this is the first study to identify the effects of potassium channel openers on gene expression within the mesocorticolimbic and nigrostriatal dopaminergic systems. These findings reveal a novel molecular mechanism underlying the action of these drugs in the brain. Importantly, our results have broader implications for translational neuroscience, particularly in the context of repurposing FDA-approved drugs, such as diazoxide and chlorzoxazone, for the treatment of neurological disorders. Full article

Traumatic brain injury (TBI), even when mild, has been associated with the presence of depression. Depression is a mood disorder characterized by persistent negative thoughts and sadness and is challenging to treat due to the multiple mechanisms involved in its pathophysiology, including increased nitric oxide (NO) levels. There are no completely safe and effective pharmacological strategies to treat this disorder. Mucuna pruriens (MP) has been shown to possess neuroprotective properties by regulating inflammatory responses and nitric oxide synthase activity. In this study, we evaluated the antidepressant-like effect of MP in male Wistar rats with induced mild traumatic brain injury (mTBI). MP extract (50 mg/kg i.p.) was administered immediately after mTBI and every 24 h for five days. We used the rats’ preference for sucrose consumption to assess the presence of depression-like behavior and analyzed the nitrite and nitrate levels in their cerebral cortex, striatum, midbrain, and nucleus accumbens. Untreated animals with mTBI showed a reduced preference for sucrose than those treated with MP, whose preference for sucrose was similar to that of sham animals. Increased nitrite and nitrate levels were observed in different brain regions in the TBI subjects; however, this increase was not observed in MP-treated animals. MP reduces behavior associated with depression and the brain NO levels in rats with mTBI. Full article

Methamphetamine (METH) is an extremely addictive drug which continues to cause significant harm to individuals and communities. In the present study we trained male rats to self-administer METH for 20 days, followed by 9 days of foot shock exposure. All rats escalated their METH intake during the first 20 days. The rats that continued to self-administer METH in the presence of aversive stimuli were termed shock-resistant (SR), while those that reduced their intake were shock-sensitive (SS). RNA sequencing showed numerous differentially expressed genes (DEGs) in the prefrontal cortex, nucleus accumbens, dorsal striatum, and midbrain. Ingenuity pathway analysis linked DEGs to addiction-related mechanisms. We identified shared genes with similar expression patterns across four brain regions (SR: Fos and Ahsp; SS: Tet1, Cym, and Tmem30c). The identified genes play key roles in addiction-related brain functions, such as neuronal activity, stress response, and epigenetic regulation, and their importance in METH addiction is highlighted. These genes represent promising targets for developing new treatments aimed at reversing neuroadaptations caused by METH use. Full article

Background/Objectives: Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Experimental models that replicate core features of PD are critical to investigate underlying mechanisms and therapeutic strategies. Here we evaluated the effects of an acute unilateral intrastriatal lesion induced by 6-hydroxydopamine (6-OHDA) on neuronal loss and the associated inflammatory response. Methods: Adult male Wistar rats received an injection of 6-OHDA into the right striatum, while the contralateral side received vehicle. Motor behavior was assessed by cylinder and open field tests on post-lesion days (PLDs) 7 and 14. Brains were analyzed by immunohistochemistry for tyrosine hydroxylase (TH), glial response (GFAP and Iba1), and caspase-3 at PLD +14. Results: A marked reduction in TH-immunoreactivity in the lesioned striatum was observed, with ~40% loss of TH-positive neurons in the ipsilateral SNpc. Surviving neurons displayed a 28% increase in soma size compared to the contralateral side. The lesion was accompanied by robust astrocytic and microglial activation at the injection site, as well as enhanced GFAP immunoreactivity in the ipsilateral SN pars reticulata. Apoptotic profiles emerged in the SNpc at PLD +14. Functionally, these alterations were reflected in significant motor asymmetry and decreased locomotor activity. Conclusions: Our findings demonstrate that neuroinflammation accompanies early dopaminergic degeneration following intrastriatal 6-OHDA administration, contributing to motor deficits. Future studies with older animals and broader behavioral and anatomical assessments—including regions such as the ventral tegmental area and motivational or anxiety-related paradigms—may enhance translational relevance. Full article

Background: Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel (Kir) being a key determinant of striatal medium spiny neuron (MSN) activity that strongly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. Methods and Results: Here, we used DA depletion mouse models that have hyperfunctional DA receptors such that potential DA regulation of Kir may be enhanced and relatively large and thus detected reliably. We show that in striatal brain slices from normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and an increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In brain slices from parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently more strongly increasing D1-MSN spike firing that is behavior-promoting. This DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl₂). In behaving parkinsonian mice, BaCl₂ microinjection into the dorsal striatum stimulates movement and also occludes the motor stimulation of D1R agonism. Conclusions: Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates the profound motoric and behavioral stimulation of striatal D1R activation in normal and parkinsonian animals. Full article

Parkinson’s disease is the second most common neurodegenerative movement disorder caused by the death of dopaminergic neurons in the Substantia nigra. The motor symptoms of Parkinson’s disease only become apparent in the late stages, whereas non-motor impairments often manifest earlier. Therefore, devising adequate experimental models to study the pathogenesis of Parkinson’s disease is of fundamental scientific importance. In this study, we aimed to evaluate the behavioral and neurochemical characteristics in a model of the premotor stage of parkinsonism in mice induced by chronic administration of a low dose of methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP. Administering 3 mg/kg of the toxin for 35 days does not cause motor deficits, except in fine motor skills, and results in impaired spatial learning. In addition, this stage is characterized by the depletion of striatum and prefrontal cortex dopamine, decreased tyrosine hydroxylase in striatum and Substantia nigra, increased cytochrome oxidase and superoxide dismutase expression, and microglia activation. Concluding, the presented model made it possible to identify a complex of physiological and neurochemical disorders characteristic of the early stage of Parkinsonism. Full article

Astrocyte-derived extracellular vesicles (ADEVs) have emerged as promising neuroprotective agents for ischemic stroke. In this study, we evaluated the therapeutic potential of hypoxia-conditioned ADEVs (HxEVs) administered intracerebroventricularly in a rat model of transient middle cerebral artery occlusion (tMCAO). Serial magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) was performed at 1, 7, 14, and 21 days post-stroke. HxEV treatment produced a significant reduction in infarct volume from day 1, sustained through day 21, and was accompanied by improvements in motor and sensory recovery. DTI analyses showed progressive normalization of fractional anisotropy (FA) and radial diffusivity (RD), particularly in the corpus callosum and striatum, reflecting microstructural repair. In contrast, mean diffusivity (MD) was less sensitive to these treatment effects. Regional differences in therapeutic response were evident, with earlier and more sustained recovery in the corpus callosum than in other brain regions. Histological findings confirmed greater preservation of dendrites and axons in HxEV-treated animals, supporting the role of these vesicles in accelerating post-stroke neurorepair. Together, these results demonstrate that hypoxia-conditioned ADEVs promote both structural and functional recovery after ischemic stroke. They also highlight the value of DTI-derived biomarkers as non-invasive tools to monitor neurorepair. The identification of region-specific therapeutic effects and the validation of reliable imaging markers provide a strong foundation for future research and development. Full article

Hypoxia at altitudes above 3000 m poses a significant threat to organ health and physiological homeostasis, particularly in metabolically active tissues such as the brain. Many of the cellular alterations induced by hypoxia are associated with the excessive generation of reactive oxygen species (ROS) and the resulting oxidative stress. In this study, we investigated the effects of exposure duration and altitude levels on oxidative homeostasis in the rat hypothalamus, cortex, hippocampus, and striatum. We assessed ROS production, malondialdehyde (MDA) levels, the antioxidant activities of superoxide dismutase (SOD), and catalase, as well as molecular biomarkers of oxidative stress, cell death, and inflammation. Our findings demonstrated that ROS, MDA and SOD levels increased across all brain regions, particularly in response to higher altitude exposure. Conversely, catalase activity decreased under the same conditions. At the molecular level, we observed overexpression of key biomarkers related to oxidative stress, cell death, and inflammation, especially at extreme altitudes. Furthermore, these effects were most pronounced in the hippocampus, cortex, and striatum. In conclusion, our data indicate that hypoxic exposure at higher altitudes significantly contributes to the oxidative disruption of brain homeostasis in rats. Full article

Striatum can be described as a brain region containing a general neuronal mechanism to associate actions or events with reward. In particular, neural activity in the human striatum is modulated by social actions and, critically, by the conjunction of social actions and own reward. To perform this function, dopamine and oxytocin signaling reaching the striatum represent a key factor. These neurotransmitters, in both humans and animals, are released in response to afferent vagal and sensory stimulation, as well as sexual and social interactions, conveying information related to reward and pleasure associated with an event. Dopamine and oxytocin have several effects in common, but of particular interest is evidence indicating that they can mutually modulate their action. The present review focuses on available data delineating interactions between dopaminergic and oxytocinergic signaling in the striatum. In this context, recent data on the possible role played by striatal astrocytes and microglia as key modulators of this crosstalk will be briefly discussed. Full article

The rare and rapidly progressive neurodegenerative disease multiple system atrophy (MSA) mainly affects the striatum and other subcortical brain regions. In this atypical Parkinsonian syndrome, the protein alpha-synuclein aggregates and misfolds in neurons as well as glial cells and is released in elevated amounts by hypoexcitable neurons. Mitochondrial dysregulation affects the biosynthesis of coenzyme Q10 and the activity of the respiratory chain, as shown in an induced pluripotent stem cell (iPSC) model. Proteome studies of cerebrospinal fluid and brain tissue from MSA patients yielded inconsistent results regarding possible protein changes due to small and combined groups of atypical Parkinsonian syndromes. In this study, we analysed the cellular proteome of MSA patient-derived striatal GABAergic medium spiny neurons. We observed 25 significantly upregulated and 16 significantly downregulated proteins in MSA cell lines compared to matched healthy controls. Various protein types involved in diverse molecular functions and cellular processes emphasise the multifaceted pathomechanisms of MSA. These data could contribute to the development of novel disease-modifying treatment strategies for MSA patients. Full article

Allopregnanolone (allo) and isoallopregnanolone (isoallo) are neuroactive steroid epimers that differ in hydroxyl orientation at carbon three. Allo is a potent GABA-A receptor agonist, while isoallo acts as an antagonist, influencing brain function through their interconversion. Their metabolism varies across brain regions due to enzyme distribution, with AKR1C1–AKR1C3 active in the brain and AKR1C4 restricted to the liver. In rats, AKR1C9 (liver) and AKR1C14 (intestine) perform similar roles. Beyond AKR1Cs, HSD17Bs regulate steroid balance, with HSD17B6 active in the liver, thyroid, and lung, while HSD17B10, a mitochondrial enzyme, influences metabolism in high-energy tissues. Our current data obtained using the GC-MS/MS platform show that allo and isoallo in rats undergo significant metabolic conversion, suggesting a regulatory role in neurosteroid action. High allo levels following isoallo injection indicate brain interconversion, while isoallo clears more slowly from blood and undergoes extensive conjugation. Metabolite patterns differ between brain and plasma—allo injection leads to 5α-DHP and isoallo production, whereas isoallo treatment primarily yields allo. Human plasma contains mostly sulfate/glucuronided steroids (2.4–6% non-sulfate/glucuronided), whereas male rats exhibit much higher free steroid levels (29–56%), likely due to the absence of zona reticularis. These findings highlight tissue-specific enzymatic differences, which may impact neurosteroid regulation and CNS disorders. Full article

The aggregation of α-synuclein (αSyn) is a central feature of Parkinson’s disease (PD) and other synucleinopathies. The efficient clearance of αSyn depends largely on the autophagy–lysosomal pathway. Emerging genetic evidence highlights the role of pleckstrin homology and RUN domain-containing M1 protein (PLEKHM1), a critical regulator of autophagosome–lysosome fusion, in the pathogenesis of multiple neurodegenerative diseases. This study investigates the possible effects of increased PLEKHM1 expression on αSyn pathology and neurodegeneration in mice. We utilized a mouse model of PD that is based on A53T-αSyn overexpression, achieved by the stereotactic injection of recombinant adeno-associated viral vectors (rAAV) into the substantia nigra. Additionally, this study explores the effect of PLEKHM1 overexpression on the autophagy–lysosomal pathway under physiological conditions, using transgenic autophagy reporter mice. PLEKHM1 overexpression facilitated the αSyn-induced degeneration of dopaminergic somata in the substantia nigra and degeneration of dopaminergic axon terminals in the striatum. In concert with αSyn expression, PLEKHM1 also potentiated microglial activation. The extent of αSyn pathology, as reported by staining for phosphorylated αSyn, was not affected by PLEKHM1. Using RFP-EGFP-LC3 autophagy reporter mice, rAAV-mediated PLEKHM1 overexpression reduced lysosomal and autolysosomal area, increased LAMP1-LC3 colocalization, and decreased the autolysosome-to-autophagosome ratio. Concurrently, PLEKHM1 overexpression in both genotypes caused p62 accumulation, accompanied by reduced overlap with lysosomal and autophagosomal markers but increased colocalization with autolysosomal markers, indicating impaired cargo degradation during late-stage autophagy. Taken together, elevated PLEKHM1 levels exacerbate neurodegeneration in αSyn-overexpressing mice, possibly by impairing autophagic flux. Now, with in vivo evidence complementing genetic data, alterations in PLEKHM1 expression appear to compromise autophagy, potentially enhancing neuronal vulnerability to secondary insults like αSyn pathology. Full article