Search Results (349)

Until now, neurodegenerative diseases like Alzheimer’s and Parkinson’s have been studied separately in biochemistry and therapeutic drug development, and no causal link has ever been established between them. This study has developed a Unified Theory, which establishes that the regulation of axon and dendrite-specific 4E-BP2 deamidation rates controls the occurrence and progression of neurodegenerative diseases. This is based on identifying axon-specific 4E-BP2 deamidation as a universal denominator for the biochemical processes of deamidation, translational control, oxidative stress, and neurodegeneration. This was achieved by conducting a thorough and critical review of 224 scientific publications regarding (a) deamidation, (b) translational control in protein synthesis initiation, (c) neurodegeneration and (d) oxidative stress, and by applying my discovery of the fundamental neurobiological mechanism behind neuron-specific 4E-BP2 deamidation to practical applications in medicine. Based on this newly developed Unified Theory and my critical review of the scientific literature, I also designed three biochemical flowsheets of (1) in-vivo deamidation, (2) protein synthesis initiation and translational control, and (3) 4E-BP2 deamidation as a control system of the four biochemical processes. The Unified Theory of Neurodegeneration Pathogenesis based on axon deamidation, developed in this work, paves the way to controlling the occurrence and progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s through a unique, neuron-specific regulatory system that is 4E-BP2 deamidation, caused by the proteasome-poor environment in neuronal projections, consisting mainly of axons. Full article

The integration of multisensory inputs plays a crucial role in shaping perception and behavior, particularly in the visual system. The collicular pathway, encompassing the optic tectum in non-mammalian vertebrates and the superior colliculus (SC) in mammals, is a key hub for integrating sensory information and mediating adaptive motor responses. Comparative studies across species reveal evolutionary adaptations that enhance sensory processing and contribute to compensatory mechanisms following neuronal injury. The present review outlines the structure and function of the multisensory visual pathways, emphasizing the retinocollicular projections, and their multisensory integration, which depends on synaptic convergence of afferents conveying information from different sensory modalities. The cellular mechanisms underlying multimodal integration remain to be fully clarified, and further investigations are needed to clarify the link between neuronal activity in response to multisensory stimulation and behavioral response involving motor activity. By exploring the interplay between fundamental neuroscience and translational applications, we aim to address multisensory integration as a pivotal target for its potential role in visual rehabilitation strategies. Full article

We examined the neuroanatomical substrates and signaling mechanisms underlying the suppressive effect of GLP1 on homeostatic and hedonic feeding. Electrophysiological and behavioral studies were conducted in agouti-related peptide (AgRP)-cre and tyrosine hydroxylase (TH)-cre mice, and AgRP-cre/pituitary adenylyl cyclase-activating polypeptide (PACAP) type I receptor (PAC1R)^fl/fl animals. GLP1 (30 pmol) delivered directly into the arcuate nucleus (ARC) decreased homeostatic feeding and diminished the rate of consumption. This anorexigenic effect was associated with an inhibitory outward current in orexigenic neuropeptide Y (NPY)/AgRP neurons. GLP1 injected into the ventral tegmental area reduced binge feeding, coupled with decrements in the rate of consumption and the percent daily caloric consumption during the binge interval. These reductions were associated with a GLP1-induced outward current in mesolimbic (A₁₀) dopamine neurons. GLP1 administered into the ventromedial nucleus (VMN) reduced homeostatic feeding that again was associated with a diminished rate of consumption and abrogated by the GLP1 receptor antagonist exendin 9–39 and in AgRP-cre/PAC1R^fl/fl mice. This suppressive effect was linked with a GLP-induced inward current in VMN PACAP neurons, and further supported by the fact that GLP1 neurons in the nucleus tractus solitarius project to the VMN. Conversely, intra-VMN GLP1 had modest effects on binge feeding behavior. Finally, apoptotic ablation of VMN PACAP neurons obliterated the anorexigenic effect of intra-VMN GLP1 on homeostatic feeding in PACAP-cre mice but not their wildtype counterparts. Collectively, these data demonstrate that GLP1 acts within the homeostatic and hedonic circuits to curb appetitive behavior by exciting PACAP neurons, and inhibiting NPY/AgRP and A₁₀ dopamine neurons. Full article

The dorsomedial caudate–putamen (dmCPu), a key input structure of the basal ganglia, plays a crucial role in goal-directed behaviors and the transition to habits. The functional specialization of the dmCPu along its anteroposterior axis suggests that distinct prefrontal cortex (PFC) subregions may differentially contribute to these processes. However, the precise topographical organization of PFC and adjacent areas projections to the anterior and posterior dmCPu remains poorly understood. We employed retrograde tracing using Fluoro-Gold to map the projections from PFC subregions and adjacent areas to the anterior and posterior dmCPu in male Sprague Dawley rats. Histological verification and immunohistochemical labeling were conducted to confirm injection sites and neuronal labeling. Quantitative analyses were performed to assess the effects of injection site placement (anterior vs. posterior dmCPu), laterality (ipsilateral vs. contralateral), and cortical subregion on projection density. The posterior dmCPu received significantly higher projection densities than the anterior dmCPu, with a pronounced ipsilateral dominance across all cortical subregions. Among the subregions examined, the cingulate cortex exhibited the highest number of labeled neurons projecting to the dmCPu, with distinct patterns of connectivity between anterior and posterior injection sites. Notably, motor and somatosensory cortical projections were more prominent in the posterior dmCPu, whereas cingulate projections demonstrated robust anteroposterior and lateralized differences. These findings provide a comprehensive map of the topographical organization of cortical inputs to the dmCPu, highlighting differential connectivity patterns that may underlie distinct functional roles in goal-directed and habitual behaviors. This work advances our understanding of corticostriatal circuits and their relevance to adaptive behaviors and neuropsychiatric disorders. Full article

Background: All the processes leading to neurodegeneration cannot be addressed with just one medication. Combinations of drugs affecting various disease mechanisms concurrently could demonstrate improved effect in slowing the course of Parkinson’s disease (PD). Objective: This was a drug-repurposing experiment designed to assess several combinations of nine drugs for possible added or synergistic efficacy using in vitro models of PD. Methods: We evaluated 44 combinations of the nine medications (sodium phenylbutyrate, terazosin, exenatide, ambroxol, deferiprone, coenzyme-Q10, creatine, dasatinib and tauroursodeoxycholic acid) selected for their previously demonstrated evidence of their impact on different targets, showing neuroprotective properties in preclinical models of PD. We utilized wild-type induced pluripotent stem-cell-derived human dopaminergic neurons treated with 1-methyl-4-phenylpyridinium for initial screening. We retested some combinations using an idiopathic PD patient-derived induced pluripotent stem cell line and alpha-synuclein triplication line. We assessed anti-neuroinflammatory effects using human microglia cells. As metrics, we evaluated neurite length, number of branch points per mm², the number of live neurons, neurofilament heavy chain and pro-inflammatory cytokines. Results: We have identified four combinations of two to three drugs that showed an additive protective effect in some endpoints. Only the combination of sodium phenylbutyrate, exenatide and tauroursodeoxycholic acid showed improvement in four endpoints studied. Conclusions: We demonstrated that some of the medications, used in combination, can exert an additive neuroprotective effect in preclinical models of PD that is superior to that of each of the compounds individually. This project can lead to the development of the first treatment for PD that can slow or prevent its progression. Full article

Self-Organizing Map (SOM) neural networks can project complex, high-dimensional data onto a two-dimensional plane for data visualization, enabling an intuitive understanding of the distribution and symmetric structures of such data, thereby facilitating the clustering and anomaly detection of complex high-dimensional data. However, this algorithm is sensitive to the initial weight matrix and suffers from insufficient feature extraction. To address these issues, this paper proposes an improved SOM based on virtual winning neurons (virtual-winner SOMs, vwSOMs). In this method, the principal component analysis (PCA) is utilized to generate the initial weight matrix, allowing the weights to better capture the main features of the data and thereby enhance clustering performance. Subsequently, when new input sample data are mapped to the output layer, multiple neurons with a high similarity in the weight matrix are selected to calculate a virtual winning neuron, which is then used to update the weight matrix to comprehensively represent the input data features within a minimal error range, thus improving the algorithm’s robustness. Multiple datasets were used to analyze the clustering performance of vwSOM. On the Iris dataset, the S is 0.5262, the F1 value is 0.93, the ACC value is 0.9412, and the VA is 0.0012, and the experimental result with the Wine dataset shows that the S is 0.5255, the F1 value is 0.93, the ACC value is 0.9401, and the VA is 0.0014. Finally, to further demonstrate the performance of the algorithm, we use the more complex Waveform dataset; the S is 0.5101, the F1 value is 0.88, the ACC value is 0.8931, and the VA is 0.0033. All the experimental results show that the proposed algorithm can significantly improve clustering accuracy and have better stability, and its algorithm complexity can meet the requirements for real-time data processing. Full article

The transplantation of human neurons into the central nervous system (CNS) offers transformative opportunities for modeling neurodegenerative diseases in vivo. This study evaluated the survival, integration, and functional properties of cryopreserved forebrain GABAergic neurons (iGABAs) derived from human induced pluripotent stem cells (iPSCs) across three species used in translational research. iGABAs were stereotactically injected into the striatum of Sprague–Dawley rats, immunodeficient RNU rats, R6/2 Huntington’s disease (HD) mice, wild-type controls, and Cynomolgus monkeys. Post-transplantation, long-term assessments revealed robust neuronal survival, extensive neurite outgrowth, and integration with host CNS environments. In immunodeficient rats, iGABAs innervated the neuraxis, extending from the prefrontal cortex to the midbrain, while maintaining mature neuronal phenotypes without uncontrolled proliferation. Similarly, grafts in nonhuman primates showed localized survival and stable phenotype at one month. In the neurodegenerative milieu of HD mice, iGABAs survived up to six months, projecting into the host striatum and white matter, with evidence of mutant huntingtin aggregates localized within the graft, indicating pathological protein transfer. These findings underscore the utility of cryopreserved iGABAs as a reproducible, scalable model for disease-specific CNS investigations and mechanistic studies of proteinopathic propagation. This work establishes a critical platform for studying neurodegenerative diseases and developing therapeutic interventions. Full article

Organisms maintain circadian rhythms corresponding to approximately 24 h in the absence of external environmental cues, and they synchronize the phases of their autonomous circadian clocks to light–dark cycles, feeding timing, and other factors. The suprachiasmatic nucleus (SCN) occupies the top position of the hierarchy in the mammalian circadian system and functions as a photic-dependent oscillator, while the food-entrainable circadian oscillator (FEO) entrains the clocks of the digestive peripheral tissues and behaviors according to feeding timing. In mammals, neuropeptide Y (NPY) from the intergeniculate leaflet (IGL) neurons projected onto the SCN plays an important role in entraining circadian rhythms to feeding conditions. However, the relationship between the FEO and SCN has been unclear under various feeding conditions. In this study, novel NPY::Venus transgenic (Tg) mice, which expressed the NPY fused to Venus fluorescent protein, were generated to investigate the secretion of NPY on the SCN from the IGL. NPY-containing secretory granules with Venus signals in the SCN slices of the Tg mice could be observed using confocal and super-resolution microscopy. We observed that the number of NPY secretory granules released on the SCNs increased during fasting, and these mice were valuable tools for further investigating the role of NPY secretion from the IGL to the SCN in mediating interactions between the FEO and the SCN. Full article

This manuscript aims to illustrate a quantum-classical dissipative theory (suited to be converted to effective algorithms for numerical simulations) within the long-term project of studying molecular processes in the brain. Other approaches, briefly sketched in the text, have advocated the need to deal with both quantum and classical dynamic variables when studying the brain. At variance with these other frameworks, the manuscript’s formalism allows us to explicitly treat the classical dynamical variables. The theory must be dissipative not because of formal requirements but because brain processes appear to be dissipative at the molecular, physiological, and high functional levels. We discuss theoretically that using Brownian dynamics or the Nosè-Hoover-Chain thermostat to perform computer simulations provides an effective way to introduce an arrow of time for open quantum systems in a classical environment. In the future, We plan to study classical models of neurons and astrocytes, as well as their networks, coupled to quantum dynamical variables describing, e.g., nuclear and electron spins, HOMO and LUMO orbitals of phenyl and indole rings, ion channels, and tunneling protons. Full article

Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global cause of death within two decades. Huntington’s disease (HD) is a rare, progressive ND caused by an autosomal-dominant mutation in the huntingtin (HTT) gene, leading to severe neuronal loss in the brain and resulting in debilitating motor, cognitive, and psychiatric symptoms. Given the complex pathology of HD, biomarkers are essential for performing early diagnosis, monitoring disease progression, and evaluating treatment efficacy. However, the identification of consistent HD biomarkers is challenging due to the prolonged premanifest HD stage, HD’s heterogeneous presentation, and its multiple underlying biological pathways. This study involves a 10-year bibliometric analysis of HD biomarker research, revealing key research trends and gaps. The study also features a comprehensive literature review of emerging HD biomarkers, concluding the need for better stratification of HD patients and well-designed longitudinal studies to validate HD biomarkers. Promising candidate wet HD biomarkers— including neurofilament light chain protein (NfL), microRNAs, the mutant HTT protein, and specific metabolic and inflammatory markers— are discussed, with emphasis on their potential utility in the premanifest HD stage. Additionally, biomarkers reflecting brain structural deficits and motor or behavioral impairments, such as neurophysiological (e.g., motor tapping, speech, EEG, and event-related potentials) and imaging (e.g., MRI, PET, and diffusion tensor imaging) biomarkers, are evaluated. The findings underscore that the discovery and validation of reliable HD biomarkers urgently require improved patient stratification and well-designed longitudinal studies. Reliable biomarkers, particularly in the premanifest HD stage, are crucial for optimizing HD clinical management strategies, enabling personalized treatment approaches, and advancing clinical trials of HD-modifying therapies. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain associated with ageing and is the most prevalent form of dementia, affecting an estimated 55 million people worldwide, with projections suggesting this number will exceed 150 million by 2050. With its increasing prevalence, AD represents a significant global health challenge with potentially serious social and economic consequences. Diagnosing AD is particularly challenging as it requires timely recognition. Currently, there is no effective therapy for AD; however, certain medications may help slow its progression. Existing diagnostic methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and biomarker analysis in cerebrospinal fluid tend to be expensive and invasive, making them impractical for widespread use. Consequently, research into non-invasive biomarkers that enable early detection and screening for AD is a crucial area of contemporary clinical investigation. One promising approach for the early diagnosis of AD may be retinal imaging. As an extension of the central nervous system, the retina offers a distinctive opportunity for non-invasive brain structure and function assessment. Considering their shared embryological origins and the vascular and immunological similarities between the eye and brain, alterations in the retina may indicate pathological changes in the brain, including those specifically related to AD. Studies suggest that structural and vascular changes in the retina, particularly within the neuronal network and blood vessels, may act as markers of cerebral changes caused by AD. These retinal alterations have the potential to act as biomarkers for early diagnosis. Since AD is typically diagnosed only after a significant neuronal loss has occurred, identifying early diagnostic markers could enable timely intervention and help prevent disease progression. Non-invasive retinal imaging techniques, such as optical coherence tomography (OCT) and OCT angiography, provide accessible methods for the early detection of changes linked to AD. This review article focuses on the potential of retinal imaging as a non-invasive biomarker for early diagnosis of AD. Investigating the ageing of the retina and its connections to neurodegenerative processes could significantly enhance the diagnosis, monitoring, and treatment of AD, paving the way for new diagnostic and therapeutic approaches. Full article

The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function. Full article

Background/Objectives: Learning is classically modeled to consist of an acquisition period followed by a mastery period when the skill no longer requires conscious control and becomes automatic. Dopamine neurons projecting to the ventral striatum (VS) produce a teaching signal that shifts from responding to rewarding or aversive events to anticipating cues, thus facilitating learning. However, the role of the dopamine-receptive neurons in the ventral striatum, particularly in encoding decision-making processes, remains less understood. Methods: Here, we introduce an operant conditioning paradigm using open-source microcontrollers to train mice in three sequential learning phases. Phase I employs classical conditioning, associating a 5 s sound cue (CS) with a sucrose–water reward. In Phase II, the CS is replaced by a lever press as the requirement for reward delivery, marking an operant conditioning stage. Phase III combines these elements, requiring mice to press the lever during the CS to obtain the reward. We recorded calcium signals from direct pathway spiny projection neurons (dSPNs) in the VS throughout the three phases of training. Results: We find that dSPNs are specifically engaged when the mouse makes a decision to perform a reward-seeking action in response to a CS but are largely inactive during actions taken outside the CS. Conclusions: These findings suggest that direct pathway neurons in the VS contribute to decision-making in learned action–outcome associations, indicating a specialized role in initiating operant behaviors. Full article

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. However, the core biology of the disorder that leads to the hypofunctioning of the cerebral dopaminergic network requires further elucidation. We investigated midbrain synaptic changes in male rats exposed to repeated hypoxia during the equivalent of extreme prematurity, which is a new animal model of the hyperactive/impulsive presentation of ADHD. We used a novel combination of a lentiviral vector, peroxidase-immunonanogold double-labelling, three-dimensional serial section transmission electron microscopy and stereological techniques to investigate the synapses formed between GABAergic axons of the rostromedial tegmental nucleus (RMTg) and dopaminergic neurons of the posterior ventral tegmental area (pVTA). This is a key site that sends extensive dopaminergic projections to the forebrain. We also compared the results to our previous study on a schizophrenia risk factor that produces cerebral hyperdopaminergia. In total, 117 reconstructed synapses were compared. Repeated hypoxic rats had a significantly thicker (22%) and longer (18%) postsynaptic density at RMTg GABAergic-pVTA dopaminergic synapses compared to their controls. These results were opposite to those previously observed in rats exposed to a schizophrenia risk factor. These findings for repeated hypoxic rats suggest that the enhanced inhibition of pVTA dopaminergic neurons may contribute to hypodopaminergia in ADHD motor hyperactivity. Synaptic triads, a key component of pVTA circuitry, were not detected in repeated hypoxic rats, indicating a marked deficit. The current knowledge may guide development in males of novel, site-specific ADHD drugs, which is necessary due to the rising prevalence of ADHD, the chronic nature of ADHD symptoms and the limitations of the currently available medications. Full article

The claustrum is a small but densely interconnected brain structure that is innervated by axons containing serotonin (5-HT), a neuromodulator that has been implicated in control of sleep and in the actions of psychedelic drugs. However, little is known about how 5-HT influences the claustrum. We have combined whole-cell patch-clamp measurements of ionic currents, flash photolysis, and receptor pharmacology to characterize the 5-HT responses of individual claustral projection neurons (PNs) in mouse brain slices. Serotonin application elicited a long-lasting outward current in claustral PNs. This current was due to an increase in membrane permeability to K⁺ ions and was mediated mainly by the type 1A 5-HT receptor (5-HTR-1A). The 5-HT-induced K⁺ current hyperpolarized, and thereby inhibited, the PNs by reducing action potential firing. Focal uncaging of 5-HT revealed that inhibitory 5-HTR-1As were located at both the soma and dendrites of PNs. We conclude that 5-HT creates a net inhibition in the claustrum, an action that should decrease claustrum sensitivity to excitatory input from other brain areas and thereby contribute to 5-HT action in the brain. Full article