Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2 pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2 model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2 and other ER stress-related conditions.

Short open reading frames (sORFs) are frequently overlooked because of their historical classification as non-coding elements or dismissed as "transcriptional noise". However, advanced genomic and proteomic technologies have allowed for screening and validating sORFs-encoded peptides, revealing their fundamental regulatory roles in cellular processes and sparking a growing interest in microprotein biology. In neuroscience, microproteins serve as neurotransmitters in signal transmission and regulate metabolism and emotions, exerting pivotal effects on neurological conditions such as nerve injury, neurogenic tumors, inflammation, and neurodegenerative diseases. This review summarizes the origins, characteristics, classifications, and functions of microproteins, focusing on their molecular mechanisms in neurological disorders. Potential applications, future perspectives, and challenges are discussed.

Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by motor disfunction, seizures, intellectual disability, speech deficits, and autism-like behavior, showing high comorbidity with Autism Spectrum Disorders (ASD). It is known that stimulation of the serotonin receptor 7 (5-HT7R) can rescue some of the behavioral and neuroplasticity dysfunctions in animal models of Fragile X and Rett syndrome, two pathologies associated with ASD. In view of these observations, we hypothesised that alterations of 5-HT7R signalling might also be involved in AS. To test this hypothesis, we stimulated 5-HT7R with the selective agonist LP-211 to investigate its possible beneficial effects on synaptic dysfunctions and altered behavior in the AS mice model. In mutant mice, we observed impairment of the synaptic machinery of protein synthesis, which was reversed by 5-HT7R activation. Moreover, stimulation of 5-HT7R was able to: i) enhance dendritic spine density in hippocampal neurons, which was reduced in AS mice; ii) restore impaired long-term potentiation (LTP) in hippocampal slices of the AS mice; iii) improve cognitive performance of the mutant animals subjected to the fear conditioning paradigm. Altogether, our results, showing beneficial effects of 5-HT7R stimulation in restoring molecular and cognitive deficits associated with AS, suggest that targeting 5-HT7R could be a promising therapeutic approach for the pathology.

Ezrin-Radixin-Moesin (ERM) proteins are actin-binding proteins that contribute to morphological changes in dendritic spines. Despite their significant role in regulating spine structure, the role of ERM proteins in the nucleus accumbnes (NAcc) is not well known, especially in in the context of risk-reward decision-making. Here, we measured the relationship between synaptic excitation and inhibition (E/I ratio) from medium spiny neurons in the NAcc core obtained in the rat after a rat gambling task (rGT). Then, after surgery of a phosphomimetic pseudo-active mutant form of radixin (Rdx-T564D) in the NAcc core, we examined its role in synaptic plasticity and the accompanying risk-choice behavior in rGT. We found that basal E/I ratio in the NAcc core was higher in risk-averse rats than risk-seeking rats. However, it was significantly reduced in risk-averse rats similar to that in risk-seeking rats in the presence of Rdx-T564D in the NAcc core. Furthermore, the head sizes of spines were shifted in risk-averse rats expressing Rdx-T564D in the NAcc core, similar to those observed in risk-seeking rats. The effects of Rdx-T564D in risk-averse rats were again manifested as behavioral changes, with reduced selection of optimal choices and increased selection of disadvantageous ones. In this study, we demonstrated that manipulation of radixin phosphorylation status in the NAcc core can alter glutamatergic synaptic transmission and spine structure at this site, as well as risk choice behaviors in the rGT. These novel findings illustrate that radixin in the NAcc core plays a significant role in determining risk preference during the rGT.

Functional and molecular alterations in the cerebellum are among the most widely recognised associates of autism spectrum disorders (ASD). As a critical computational hub of the brain, the cerebellum controls and coordinates a range of motor, affective and cognitive processes. Despite well-described circuits and integrative mechanisms, specific changes that underlie cerebellar impairments in ASD remain elusive. Studies in experimental animals have been critical in uncovering molecular pathology and neuro-behavioural correlates, providing a model for investigating complex disease conditions. Herein, we review commonalities and differences of the most extensively characterised genetic lines of ASD with reference to the cerebellum. We revisit structural, functional, and molecular alterations which may contribute to neurobehavioral phenotypes. The cross-model analysis of this study provides an integrated outlook on the role of cerebellar alterations in pathobiology of ASD that may benefit future translational research and development of therapies.

The hypothalamic arcuate nucleus (ARC) contains two main populations of neurons essential for energy homeostasis: neuropeptide Y (NPY) neurons, which are orexigenic and stimulate food intake, and proopiomelanocortin (POMC) neurons, which have an anorexigenic effect. Located near the blood-brain barrier, ARC neurons sense blood-borne signals such as leptin, insulin, and glucose. Exogenous substances, such as nicotine, can also alter ARC neuron activity and energy balance. Nicotine, an addictive drug used worldwide, inhibits appetite, and reduces body weight, although its mechanisms in regulating ARC neurons are not well understood. Using electrophysiological techniques in brain slices, we investigated the effects of nicotine on POMC and NPY neurons at physiological glucose concentrations. We found that nicotine increased the firing rate of POMC and inhibited NPY neurons. Additionally, nicotine-enhanced glutamatergic inputs to POMC cells and GABAergic inputs to NPY neurons, mediated by α7 and α4β2 nicotinic acetylcholine receptors (nAChRs), respectively. These findings can contribute to the understanding of the anorexigenic effects of nicotine in smokers.

Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells. By using conditional genetic mouse models, here we found that cannabinoid CB receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway. Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB-deficient mice. Overall, this study identifies CB receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.

Most neurons are influenced by multiple neuromodulatory inputs that converge on common effectors. Mechanisms that route these signals are key to selective neuromodulation but are poorly understood. G protein-gated inwardly rectifying K (GIRK or Kir3) channels mediate postsynaptic inhibition evoked by G protein-coupled receptors (GPCRs) that signal via inhibitory G proteins. GIRK-dependent signaling is modulated by Regulator of G protein Signaling proteins RGS6 and RGS7, but their selectivity for distinct GPCR-GIRK signaling pathways in defined neurons is unclear. We compared how RGS6 and RGS7 impact GIRK channel regulation by the GABA receptor (GABAR), 5HT receptor (5HTR), and A adenosine receptor (AR) in hippocampal neurons. Our data show that RGS6 and RGS7 make non-redundant contributions to GABAR- and 5HTR-GIRK signaling and compartmentalization and suggest that GPCR-G protein preferences and the substrate bias of RGS proteins, as well as receptor-dependent differences in Gα engagement and effector access, shape GPCR-GIRK signaling dynamics in hippocampal neurons.

The chronic activation of immune cells can participate in the development of pathological conditions such as neurodegenerative diseases including Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, compelling evidence indicates that purinergic signaling plays a key role in neuro-immune cell functions. The extracellular release of adenosine 5'-triphosphate (ATP), and its breakdown products (ADP and adenosine) provide the versatile basis for complex purinergic signaling through the activation of several families of receptors. G-protein coupled adenosine A receptors, ionotropic P2X and G-protein coupled P2Y receptors for ATP and other nucleotides are abundant and widely distributed in neurons, microglia, and astrocytes of the central nervous system as well as in peripheral immune cells. These receptors are strongly linked to inflammation, with a functional interplay that may influence the intricate purinergic signaling involved in inflammatory responses. In the present review, we examine the roles of the purinergic receptors in neuro-immune cell functions with particular emphasis on AR, P2X4 and P2X7 and their possible relevance to specific neurodegenerative disorders. Understanding the molecular mechanisms governing purinergic receptor interaction will be crucial for advancing the development of effective immunotherapies targeting neurodegenerative diseases.

Sleep constitutes a brain state of disengagement from the external world that supports memory consolidation and restores cognitive resources. The precise mechanisms how sleep and its varied stages support information processing remain largely unknown. Synaptic scaling models imply that daytime learning accumulates neural information, which is then consolidated and downregulated during sleep. Currently, there is a lack of in-vivo data from humans and rodents that elucidate if, and how, sleep renormalizes information processing capacities. From an information-theoretical perspective, a consolidation process should entail a reduction in neural pattern variability over the course of a night. Here, in a cross-species intracranial study, we identify a tradeoff in the neural population code during sleep where information coding efficiency is higher in the neocortex than in hippocampal archicortex in humans than in rodents as well as during wakefulness compared to sleep. Critically, non-REM sleep selectively reduces information coding efficiency through pattern repetition in the neocortex in both species, indicating a transition to a more robust information coding regime. Conversely, the coding regime in the hippocampus remained consistent from wakefulness to non-REM sleep. These findings suggest that new information could be imprinted to the long-term mnemonic storage in the neocortex through pattern repetition during sleep. Lastly, our results show that task engagement increased coding efficiency, while medically-induced unconsciousness disrupted the population code. In sum, these findings suggest that neural pattern variability could constitute a fundamental principle underlying cognitive engagement and memory formation, while pattern repetition reflects robust coding, possibly underlying the consolidation process.

Synaptic networks determine brain function. Highly complex interconnected brain synaptic networks provide output even under fluctuating or pathological conditions. Relevant to the treatment of brain disorders, understanding the limitations of such functional networks becomes paramount. Here we use the example of Parkinson's Disease (PD) as a system disorder, with PD symptomatology emerging only when the functional reserves of neurons, and their interconnected networks, are unable to facilitate effective compensatory mechanisms. We have denoted this the "threshold theory" to account for how PD symptoms develop in sequence. In this perspective, threshold functions are delineated in a quantitative, synaptic, and cellular network context. This provides a framework to discuss the development of specific symptoms. PD includes dysfunction and degeneration in many organ systems and both peripheral and central nervous system involvement. The threshold theory accounts for and explains the reasons why parallel gradually emerging pathologies in brain and peripheral systems generate specific symptoms only when functional thresholds are crossed, like tipping points. New and mounting evidence demonstrate that PD and related neurodegenerative diseases are multisystem disorders, which transcends the traditional brain-centric paradigm. We believe that representation of threshold functions will be helpful to develop new medicines and interventions that are specific for both pre- and post-symptomatic periods of neurodegenerative disorders.

The development and refinement of neuronal circuitry allow for stabilized and efficient neural recruitment, supporting adult-like behavioral performance. During adolescence, the maturation of PFC is proposed to be a critical period (CP) for executive function, driven by a break in balance between glutamatergic excitation and GABAergic inhibition (E/I) neurotransmission. During CPs, cortical circuitry fine-tunes to improve information processing and reliable responses to stimuli, shifting from spontaneous to evoked activity, enhancing the SNR, and promoting neural synchronization. Harnessing 7T MR spectroscopy and EEG in a longitudinal cohort (N = 164, ages 10-32 years, 283 neuroimaging sessions), we outline associations between age-related changes in glutamate and GABA neurotransmitters and EEG measures of cortical SNR. We find developmental decreases in spontaneous activity and increases in cortical SNR during our auditory steady state task using 40Hz stimuli. Decreases in spontaneous activity were associated with glutamate levels in DLPFC, while increases in cortical SNR were associated with more balanced Glu and GABA levels. These changes were associated with improvements in working memory performance. This study provides evidence of CP plasticity in the human PFC during adolescence, leading to stabilized circuitry that allows for the optimal recruitment and integration of multisensory input, resulting in improved executive function.

Listening in complex sound environments requires rapid segregation of different sound sources, e.g., having a conversation with multiple speakers or other environmental sounds. Efficient processing requires fast encoding of inputs to adapt to target sounds and identify relevant information from past experiences. This adaptation process represents an early phase of implicit learning of the sound statistics to form auditory memory. The auditory cortex (ACtx) plays a crucial role in this implicit learning process, but the underlying circuits are unknown. In awake mice, we recorded neuronal responses in different ACtx subfields using in vivo 2-photon imaging of excitatory and inhibitory (parvalbumin; PV) neurons. We used a paradigm adapted from human studies that induced rapid implicit learning from passively presented complex sounds and imaged A1 Layer 4 (L4), A1 L2/3, and A2 L2/3. In this paradigm, a frozen spectro-temporally complex 'Target' sound randomly re-occurred within a stream of other random complex sounds. All ACtx subregions contained distinct groups of cells specifically responsive to complex acoustic sequences, indicating that even thalamocortical input layers (A1 L4) respond to complex sounds. Subgroups of excitatory and inhibitory cells in all subfields showed decreased responses for re-occurring Target sounds, indicating that ACtx is highly involved in the early implicit learning phase. At the population level, activity was more decorrelated to Target sounds independent of the duration of frozen token, subregions, and cell type. These findings suggest that ACtx and its input layers contribute to the early phase of auditory memory for complex sounds, suggesting a parallel strategy across ACtx areas and between excitatory and inhibitory neurons.

How we combine minimal linguistic units into larger structures remains an unresolved topic in neuroscience. Language processing involves the abstract construction of 'vertical' and 'horizontal' information simultaneously (e.g., phrase structure, morphological agreement), but previous paradigms have been constrained in isolating only one type of composition and have utilized poor spatiotemporal resolution. Using intracranial recordings, we report multiple experiments designed to separate phrase structure from morphosyntactic agreement. Epilepsy patients (n = 10) were presented with auditory two-word phrases grouped into pseudoword-verb ('trab run') and pronoun-verb either with or without Person agreement ('they run' vs. 'they runs'). Phrase composition and Person violations both resulted in significant increases in broadband high gamma activity approximately 300 ms after verb onset in posterior middle temporal gyrus (pMTG) and posterior superior temporal sulcus (pSTS), followed by inferior frontal cortex (IFC) at 500 ms. While sites sensitive to only morphosyntactic violations were distributed, those sensitive to both composition types were generally confined to pSTS/pMTG and IFC. These results indicate that posterior temporal cortex shows the earliest sensitivity for hierarchical linguistic structure across multiple dimensions, providing neural resources for distinct windows of composition. This region is comprised of sparsely interwoven heterogeneous constituents that afford cortical search spaces for dissociable syntactic relations.

To encode allocentric space information of a viewing object, it is important to relate perceptual information in the first-person perspective to the representation of an entire scene which would be constructed before. A substantial number of studies investigated the constructed scene information (e.g., cognitive map). However, only few studies have focused on its influence on perceptual processing. Therefore, we designed a visually guided saccade task requiring monkeys to gaze at objects in different locations on different backgrounds clipped from large self-designed mosaic pictures (parental pictures). In each trial, we presented moving backgrounds prior to object presentations, indicating a frame position of the background image on a parental picture. We recorded single-unit activities from 377 neurons in the posterior inferotemporal (PIT) cortex of two macaques. Equivalent numbers of neurons showed space-related (119 of 377) and object-related (125 of 377) information. The space-related neurons coded the gaze locations and background images jointly rather than separately. These results suggest that PIT neurons represent a particular location within a particular background image. Interestingly, frame positions of background images on parental pictures modulated the space-related responses dependently on parental pictures. As the frame positions could be acquired by only preceding visual experiences, the present results may provide neuronal evidence of a mnemonic effect on current perception, which might represent allocentric object location in a scene beyond the current view.

Executive control of behaviour entails keeping a fine balance between response execution and action inhibition. The most anterior part of the prefrontal cortex (frontopolar cortex) is highly developed in anthropoids; however, no previous study has examined its essential (indispensable) role in regulating the interplay between action execution and inhibition. In this cross-species study, we examine the performance of humans and macaque monkeys in the context of a stop-signal task and then assess the consequence of selective and bilateral damage to frontopolar cortex on monkeys' behaviour. Humans and monkeys showed significant within-session practice-related adjustments in both response execution (increase in response time (RT) and decrease in response variabilities) and action inhibition (enhanced inhibition). Furthermore, both species expressed context-dependent (post-error and post-stop) behavioral adjustments. In post-lesion testing, frontopolar-damaged monkeys had a longer RT and lower percentage of timeout trials, compared to their pre-lesion performance. The practice-related changes in mean RT and in RT variability were significantly heightened in frontopolar-damaged monkeys. They also showed attenuated post-error, but exaggerated post-stop, behavioural adjustments. Importantly, frontopolar damage had no significant effects on monkeys' inhibition ability. Our findings indicate that frontopolar cortex plays a critical role in allocation of control to response execution, but not action inhibition.

Our understanding of how otoferlin, the major calcium sensor in inner hair cells (IHCs) synaptic transmission, contributes to the overall dynamics of synaptic vesicle (SV) trafficking remains limited. To address this question, we generated a knock-in mouse model expressing an otoferlin-GFP protein, where GFP was fused to its C-terminal transmembrane domain. Similar to the wild type protein, the GFP-tagged otoferlin showed normal expression and was associated with IHC SV. Surprisingly, while the heterozygote Otof mice exhibited a normal hearing function, homozygote Otof mice were profoundly deaf attributed to severe reduction in SV exocytosis. Fluorescence recovery after photobleaching revealed a markedly increased mobile fraction of the otof-GFP-associated SV in Otof IHCs. Correspondingly, 3D-electron tomographic of the ribbon synapses indicated a reduced density of SV attached to the ribbon active zone. Collectively, these results indicate that otoferlin requires a free intravesicular C-terminal end for normal SV docking and fusion.

Accurate definition of the borders of cortical visual areas is essential for the study of neuronal processes leading to perception. However, data used for definition of areal boundaries have suffered from issues related to resolution, uniform coverage, or suitability for objective analysis, leading to ambiguity. Here, we present a novel approach that combines widefield optical imaging, presentation of naturalistic movies, and encoding model analysis, to objectively define borders in the primate extrastriate cortex. We applied this method to test conflicting hypotheses about the third-tier visual cortex, where areal boundaries have remained controversial. We demonstrate pronounced tuning preferences in the third-tier areas, and an organizational structure in which the dorsomedial area (DM) contains representations of both the upper and lower contralateral quadrants, and is located immediate anterior to V2. High-density electrophysiological recordings with a Neuropixels probe confirm these findings. Our encoding-model approach offers a powerful, objective way to disambiguate areal boundaries.

Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.