bioRxiv Subject Collection: Neuroscience's Journal

Dichotomy between extracellular signatures of active dendritic chemical synapses and gap junctions
Background and motivation: Local field potentials (LFPs) are compound signals comprising synaptic currents and several transmembrane currents from active structures, which represent the dynamic flow of information across the brain. Although LFP analyses have remained largely limited to chemical synaptic inputs, neurons and other cell types also receive gap junctional inputs that play essential roles in neuronal and network physiology. Gap junctional inputs have been historically excluded from LFP analyses because, unlike synaptic receptors, these inputs are not mediated by transmembrane currents that involve the extracellular space. However, the voltage response to gap junctional inputs onto active compartments triggers several transmembrane currents across the neuron. Therefore, two fundamental questions required for enhanced accuracy of LFP interpretations are: (i) Do gap junctional inputs onto active compartments contribute to LFPs? (ii) Are there differences in extracellular signatures associated with gap junctional vs. chemical synaptic inputs onto active compartments? Methodology: We built morphologically realistic conductance-based neuronal models and placed a 3D array of extracellular electrodes spanning the somato-dendritic stretch. We employed different types of inputs: (i) synchronous; (ii) random; and (iii) rhythmic (1-128 Hz). We computed LFPs at all electrodes and analyzed the spatiotemporal profiles of intra- and extra-cellular voltages for several model configurations, involving different input types, with active vs. passive dendrites, with gap junctions vs. chemical synapses, and in the presence vs. absence of different ion channels. Results: We demonstrate a striking reversal in the polarity of extracellular potentials associated with synchronous inputs through chemical synapses vs. gap junctions onto active dendrites. Whereas synchronous inputs through chemical synapses yielded a negative deflection in proximal electrodes, those onto gap junctions manifested a positive deflection. Importantly, we observed extracellular dipoles only when inputs arrived through chemical synapses, but not with gap junctions. Remarkably, the slow hyperpolarization-activation cyclic nucleotide-gated (HCN) channels, which typically conduct inward currents, mediated outward currents triggered by the fast voltage transition caused by synchronous inputs. With random inputs, extracellular potentials in proximal electrodes were largely negative with chemical synapses but were biphasic with gap junctional inputs. Finally, with rhythmic inputs arriving through gap junctions, we found strong suppression of LFP power at higher frequencies. There were frequency-dependent differences in the spike phase associated with the LFP, depending on whether inputs arrived through gap junctions or chemical synapses. LFP differences across all input types were mediated by the relative dominance of synaptic currents vs. voltage-driven transmembrane currents with chemical synapses vs. gap junctions, respectively. Implications: Our analyses unveil a prominent role for gap junctional connections in shaping the spatiotemporal and spectral profiles of extracellular potentials, with critical implications for polarities and spatial spread of LFPs. The stark dichotomies in extracellular signatures associated with gap junctional vs. chemical synaptic inputs imply that conclusions could be erroneous if cells were incorrectly assumed to be exclusively receiving chemical synaptic inputs.

Methamphetamine-induced adaptation of learning rate dynamics depend on baseline performance.
The ability to calibrate learning according to new information is a fundamental component of an organisms ability to adapt to changing conditions. Yet, the exact neural mechanisms guiding dynamic learning rate adjustments remain unclear. Catecholamines appear to play a critical role in adjusting the degree to which we use new information over time, but individuals vary widely in the manner in which they adjust to changes. Here, we studied the effects of a low dose of methamphetamine (MA), and individual differences in these effects, on probabilistic reversal learning dynamics in a within-subject, double-blind, randomized design. Participants first completed a reversal learning task during a drug-free baseline session to provide a measure of baseline performance. Then they completed the task during two sessions, one with MA (20 mg oral) and one with placebo (PL). First, we showed that, relative to PL, MA modulates the ability to dynamically adjust learning from prediction errors. Second, this effect was more pronounced in participants who performed poorly at baseline. These results present novel evidence for the involvement of catecholaminergic transmission on learning flexibility and highlights that baseline performance modulates the effect of the drug.

Evidence for low affinity of GABA at the vesicular monoamine transporter VMAT2. Implications for transmitter co-release from dopamine neurons
Background and Purpose: Midbrain dopamine (DA) neurons comprise a heterogeneous population of cells. For instance, some DA neurons express the vesicular glutamate transporter VGLUT2 allowing these cells to co-release DA and glutamate. Additionally, GABA may be co-released from DA neurons. However, most cells do not express the canonical machinery to synthesize GABA or the vesicular GABA transporter VGAT. Instead, GABA seems to be taken up into DA neurons by a plasmalemmal GABA transporter (GAT1) and stored in synaptic vesicles via the vesicular monoamine transporter VMAT2. Yet, it remains unclear whether GABA indeed interacts with VMAT2, or whether another transmitter could be responsible for the observed inhibitory effects attributed to GABA. Experimental Approach: We used radiotracer flux measurements in VMAT2 expressing HEK-293 cells and synaptic vesicles from rodents to determine whether GABA qualifies as substrate at VMAT2. mRNA in situ hybridization was employed to determine expression of VMAT2 and GAT1 transcripts in DA neurons of mouse and in human midbrains. Key Results: We found that GABA reduced uptake of VMAT2 substrates in rodent synaptic vesicle preparations from striatum and cerebellum at millimolar concentrations but had no effect in VMAT2-expressing cells indicating that key components are missing in a non-neuronal system. Roughly 60 % of murine and human DA neurons in the substantia nigra express VMAT2 and GAT1 suggesting that many may be capable of co-releasing DA and GABA. Conclusion and Implication: Our experiments suggest that GABA is a low-affinity substrate at VMAT2 with potential implications for basal ganglia physiology and disease.

Multivariate analysis of multimodal brain structure predicts individual differences in risk and intertemporal preference
Large changes to brain structure (e.g., from damage or disease) can explain alterations in behavior. It is therefore plausible that smaller structural differences in healthy samples can be used to better understand and predict individual differences in behavior. Despite the brain's multivariate and distributed structure-to-function mapping, most studies have used univariate analyses of individual structural brain measures. Here we used a multivariate approach in a multimodal data set composed of volumetric, surface-based, diffusion-based, and functional resting-state MRI measures to predict reliable individual differences in risk and intertemporal preferences. We show that combining twelve brain structure measures led to better predictions across tasks than using any individual measure, and by examining model coefficients, we visualize the relative contribution of different brain measures from different brain regions. Using a multivariate approach to brain structure-to-function mapping that combines across many brain structure properties, along with reliably measured behavior phenotypes, may increase out-of-sample prediction accuracies and insight into neural underpinnings. Furthermore, this methodological approach may be useful to improve predictions and neural insight across basic, translational, and clinical research fields.

The perineurium integrates leptin with its sympathetic outflow to protect against obesity
The regulatory mechanism of leptin's afferent action in the brain, constituting a negative feedback loop, is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the relative strengths of the afferent and efferent arms remains ambiguous. Using single-cell RNA sequencing on murine sympathetic ganglia, we identified the unique expression of both the leptin receptor (LepR) and the beta 2 adrenergic receptor (Adrb2) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues. We show that LepR+ Sympathetic Perineurial Cells (SPCs) are molecularly similar to endothelial cells and that conditional knockout of Adrb2 in LepR+ SPCs predisposes mice to obesity without affecting food intake. Notably, we found that hyperleptinemia associated with obesity causes apoptosis in SPCs, leading to a significant erosion of the perineurial barrier and concomitant adipose sympathetic neuropathy. We further show that this deleterious effect can be reversed by sympathomimetic beta 2 adrenergic receptor agonism. These results have relevance to human obesity, as we observed a synergistic effect of highly common polymorphisms of LEPR and ADRB2 on the risk of increased BMI in a large European population. We propose that SPCs are the nexus of leptin action by integrating the afferent and efferent arms of the neuroendocrine loop to influence its setpoint.

Macrovascular contributions to resting-state fMRI signals: A comparison between EPI and bSSFP at 9.4 Tesla
The draining-vein bias of T2*-weighted sequences, like gradient echo echo-planar imaging (GRE-EPI), can limit the spatial specificity of functional MRI (fMRI). The underlying extravascular signal changes increase with field strength (B0) and the perpendicularity of draining veins to the main axis of B0, and are therefore particularly problematic at ultra-high field (UHF). In contrast, simulations showed that T2-weighted sequences are less affected by the draining-vein bias, depending on the amount of rephasing of extravascular signal. As large pial veins on the cortical surface follow the cortical folding tightly, their orientation can be approximated by the cortical orientation to B0. In our work, we compare the influence of the cortical orientation to B0 on the resting-state fMRI signal of three sequences aiming to understand their macrovascular contribution. While 2D GRE-EPI and 3D GRE-EPI (both T2*-weighted) showed a high dependence on the cortical orientation to B0, especially on the cortical surface, this was not the case for 3D balanced steady-state free precession (bSSFP) (T2/T1-weighted). Here, a slight increase of orientation dependence was shown in depths closest to WM. And while orientation dependence decreased with increased distance to the veins for both EPI sequences, no change in orientation dependence was observed in bSSFP. This indicates the low macrovascular contribution to the bSSFP signal, making it a promising sequence for layer fMRI at UHF.

MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity
Lewy pathology, consisting of Lewy bodies and Lewy neurites, is the pathological hallmark of synucleinopathies such as Parkinson's disease and dementia with Lewy bodies, but it is generally thought to represent late-stage pathological changes. In contrast, alpha-synuclein oligomers are regarded as early-stage pathology, likely involved in disease progression and cellular toxicity. Oligomers, however, are not detected by standard immunohistochemistry but require specific detection techniques such as the proximity ligation assay (PLA). Here, we describe the MJF-14 PLA, a new PLA towards aggregated alpha-synuclein with unprecedented specificity, attained by the utilization of aggregate conformation-specific alpha-synuclein antibody MJFR-14-6-4-2 (hereafter MJF-14). Signal in the assay directly correlates with alpha-synuclein aggregation in SH-SY5Y cells, as treatment with aggregation inhibitor ASI1D significantly lowers PLA signal. In human cortical neurons, MJF-14 PLA detects pre-formed fibril-induced aggregation, especially prominent when using stealth PFFs invisible to the MJF-14 antibody. Co-labelling of MJF-14 PLA and pS129-alpha-synuclein immunofluorescence in post-mortem dementia with Lewy bodies cases showed that while the MJF-14 PLA reveals extensive non-inclusion pathology, it is not sensitive towards Lewy bodies. In Parkinson's disease brain, direct comparison of PLA and IHC with the MJF-14 antibody, combined with machine learning-based quantification, showed striking alpha-synuclein pathology preceding the formation of conventional Lewy pathology. The majority of the PLA-revealed non-inclusion pathology was found in the neuropil, including some clearly located in the presynaptic terminals. With this work, we introduce an improved alpha-synuclein aggregate PLA to uncover abundant non-inclusion pathology, which deserves future validation with multiple brain bank resources and in different synucleinopathies.

The dynamic gene regulatory landscape of the mouse brain in response to sleep deprivation
Sleep deprivation (SD) negatively impacts nearly all brain functions including cognition, memory consolidation and metabolism. However, the gene regulatory networks that underlie these biological effects are not well understood. In order to identify these networks, we conducted a multiomic analysis to analyse how gene expression, chromatin accessibility, enhancer activity and DNA methylation change with acute SD in mice. By studying three brain regions involved in different aspects of sleep - the cortex (CTX), dentate gyrus (DG), and suprachiasmatic nucleus (SCN) - we found that the effects of SD on the multiome varied widely, impacting physiological processes specific to each area, from spine formation in the dentate gyrus to neuropeptide release in the SCN. Our integrated analysis showed that distinct brain region-specific networks of regulatory factors dynamically alter the epigenomic landscape in response to SD to orchestrate transcriptional responses. These findings provide new understanding of the regulatory grammar encoded within the genome, which enables a general physiological signal like SD to produce unique effects in a tissue-specific context.

Characterizing BOLD activation patterns in the human hippocampus with laminar fMRI
The human hippocampus has been extensively studied at the macroscale using functional magnetic resonance imaging (fMRI) but the underlying microcircuits at the mesoscale (i.e., at the level of layers) are largely uninvestigated in humans. We target two questions fundamental to hippocampal laminar fMRI: How does the venous bias affect the interpretation of hippocampal laminar responses? And can we establish a benchmark laminar fMRI experiment which robustly elicits single-subject hippocampal activation utilizing the most widely applied GRE-BOLD contrast? We comprehensively characterized GRE-BOLD responses as well as T2*, tSNR and physiological noise as a function of cortical depth in individual subfields of the human hippocampus. Our results show that the vascular architecture differs between subfields leading to subfield-specific laminar biases of GRE-BOLD responses. Using an autobiographical memory paradigm, we robustly acquired depth-specific BOLD responses in hippocampal subfields. In the CA1 subregion, our results indicate a more pronounced trisynaptic path input rather than dominant direct inputs from entorhinal cortex during autobiographical memory retrival. Our study provides unique insights into the hippocampus at the mesoscale level, and will help interpreting hippocampal laminar fMRI responses and allow researchers to test mechanistic hypotheses of hippocampal function.

Delayed accumulation of inhibitory input explains gamma frequency variation with changing contrast in an Inhibition Stabilized Network
Gamma rhythm (30-70 Hz), thought to represent the push-pull activity of excitatory and inhibitory population, can be induced by presenting achromatic gratings in the primary visual cortex (V1) and is sensitive to stimulus properties such as size and contrast. In addition, gamma occurs in short bursts, and shows a "frequency-falloff" effect where its peak frequency is high after stimulus onset and slowly decreases to a steady state. Recently, these size-contrast properties and temporal characteristics were replicated in a self-oscillating Wilson-Cowan (WC) model operating as an Inhibition stabilized network (ISN), stimulated by Ornstein-Uhlenbeck (OU)-type inputs. In particular, frequency-falloff was explained by delayed and slowly accumulated inputs arriving at local inhibitory populations. We hypothesized that if the stimulus is preceded by another higher contrast stimulus, frequency-falloff could be abolished or reversed, since the excessive inhibition will now take more time to dissipate. We presented gratings at different contrasts consecutively to two female monkeys while recording gamma using microelectrode arrays in V1 and confirmed this prediction. Further, this model also replicated a characteristic pattern of gamma frequency modulation to counter-phasing stimuli as reported previously. Thus, the ISN model with delayed surround input replicates gamma frequency responses to time-varying contrasts.

Time-resolved functional connectivity during visuomotor graph learning
Humans naturally attend to patterns that emerge in our perceptual environments, building mental models that allow for future experiences to be processed more effectively and efficiently. Perceptual events and statistical relations can be represented as nodes and edges in a graph, respectively. Recent work in the field of graph learning has shown that human behavior is sensitive to graph topology, but less is known about how that topology might elicit distinct neural responses during learning. Here, we address this gap in knowledge by applying time-resolved network analyses to fMRI data collected during a visuomotor graph learning task to assess neural signatures of learning modular graphs and non-modular lattice graphs. We found that performance on this task was supported by a highly flexible visual system and otherwise relatively stable brain-wide community structure, cohesiveness within the dorsal attention, limbic, default mode, and subcortical systems, and an increasing degree of integration between the visual and ventral attention systems. Additionally, we found that the time-resolved connectivity of the limbic, default mode, temporoparietal, and subcortical systems was associated with enhanced performance for the modular group but not the lattice group. These findings provide evidence for the differential neural processing of statistical structures with distinct topologies and highlight similarities between the neural correlates of graph learning and statistical learning more broadly.

Microglial low-affinity FcγR mediates the phagocytic elimination of dopaminergic neurons in Parkinsons disease degeneration
Microglia-mediated neuroinflammation contributes to dopaminergic (DA) neurodegeneration in Parkinsons disease (PD). It is thought that microglial cells interact with DA neurons of the substantia nigra pars compacta (SNpc), the most vulnerable region in parkinsonian neuropathology, playing a critical role through the process of neuronal loss. However, the specific mechanisms by which microglial reactivity is triggered and exerts such a deleterious effect remains unclear. Experimental models of PD in mice have shown that phagocytosis plays an essential role in the elimination of degenerating neurons, suggesting that blocking this microglial function could be beneficial to preserve remaining DA neurons. In the present work, we pinpoint the role of the Fc{gamma}receptor (F{gamma}R) as a potential trigger of microglial phagocytosis in PD. We found that the Fc{gamma}R is overexpressed in the degenerating SNpc in postmortem samples of PD patients, alongside histological indications of phagocytic microglia. Likewise, experimental models of PD also show increased Fc{gamma}R expression, together with evidence of similar phagocytosis events. Most importantly, blocking Fc{gamma}R in vitro, by using neutralizing antibodies, reduced the microglial-mediated elimination of DA cells. High resolution imaging revealed that the Fc{gamma}R is involved in phagocytic synapse formation, and appeared polarized, and segregated to actin-rich protruding cups, when interacting one-on-one towards single target DA cells. Additionally, by inhibiting Fc{gamma}R downstream actin-polymerizing signaling Cdc42, microglia were unable to eliminate DA cells. Finally, experiments in vivo, using an experimental model of PD in mouse, revealed that passive immunotherapy with Fc{gamma}R neutralizing monoclonal antibodies, as well as inhibiting its downstream signaling Cdc42, protect DA neurons from elimination. These results indicate that the Fc{gamma}R may be a critical factor inducing DA neuron phagocytosis in PD and suggest a novel immunotherapeutic strategy targeting microglia to preserve neuronal loss.

Enhancing Perceptual, Attentional, and Working Memory Demands through Variable Practice Schedules: Insights from High-Density EEG Multi-Scale Analyses
Contextual interference (CI) enhances learning by practicing motor tasks in a random order rather than a blocked order. One hypothesis suggests that the benefits arise from enhanced early perceptual/attentional processes, while another posits that better learning is due to highly activated mnemonic processes. We propose to harness high-density electroencephalography in a multi-scale analysis approach, including topographic analyses, source estimations, and functional connectivity, to examine the intertwined dynamics of attentional and mnemonic processes within short time windows. We recorded scalp activity from 35 participants as they performed an aiming task at three different distances, under both random and blocked conditions using a crossover design. Our results showed that topographies associated with processes related to perception/attention (N1, P3a) and working memory (P3b) were more pronounced in the random condition. Source estimation analyses supported these findings, revealing greater involvement of the perceptual ventral pathway and the anterior cingulate and parietal cortices, along with increased functional connectivity in ventral alpha and frontoparietal theta band networks during random practice. Our results suggest that CI is driven, in the random compared to the blocked condition, by enhanced specific processes such as perceptual, attentional, and mnemonic, as well as large-scale general processes.

eLemur: A cellular-resolution 3D atlas of the mouse lemur brain
The gray mouse lemur (Microcebus murinus), one of the smallest living primates, emerges as a promising model organism for neuroscience research. This is due to its genetic similarity to humans, its evolutionary position between rodents and humans, and its primate-like features encapsulated within a rodent-sized brain. Despite its potential, the absence of a comprehensive reference brain atlas impedes the progress of research endeavors in this species, particularly at the microscopic level. Existing references have largely been confined to the macroscopic scale, lacking detailed anatomical information. Here, we present eLemur, a new resource, comprising a repository of high-resolution brain-wide images immunostained with multiple cell type and structural markers, elucidating the cyto- and chemoarchitecture of the mouse lemur brain. Additionally, it encompasses a segmented two-dimensional (2D) reference and 3D anatomical brain atlas delineated into cortical, subcortical, and other vital regions. Furthermore, eLemur includes a comprehensive 3D cell atlas, providing densities and spatial distributions of non-neuronal and neuronal cells across the mouse lemur brain. Accessible via a web-based viewer (https://eeum-brain.com/#/lemurdatasets), the eLemur resource streamlines data sharing and integration, fostering the exploration of new hypotheses and experimental designs using the mouse lemur as a model organism. Moreover, in conjunction with the growing 3D datasets for rodents, non-human primates, and humans, our eLemur 3D digital framework enhances the potential for comparative analysis and translation research, facilitating the integration of extensive rodent study data into human studies.

Astroglial atrophy associates with loss of nuclear S100A10 in the hippocampus of aged male tree shrews
Astrocytes are glial cells that participate in multiple physiological functions, such as protecting neurons against all types of damage. However, astrocytes develop morphological alterations during aging, such as decreased length, volume, and branch points of their processes, also known as astrocytic atrophy. Until now, the exact mechanism associated with the onset of atrophy is unknown. Tree shrew (Tupaia belangeri) is a long-lived animal from the Scadentia order that develops several age-dependent brain alterations. In this study, we analyzed the morphology of GFAP+ astrocytes in the hippocampal region of adult, old, and aged male tree shrews. Aged animals presented more GFAP+ astrocytes in the proximal subiculum, CA3, and CA2-CA1 subregions than younger animals, being significantly higher only in CA3. However, in aged subjects, the number of atrophic astrocytes was significantly higher in the dentate gyrus and CA2 subregion compared to old animals. Interestingly, in the proximal subiculum, astrocytes had a reduced arborization at all ages evaluated. S100A10, a protein overexpressed by neuroprotective-type astrocytes, was mainly found in the nucleus of astrocytes of adult and old subjects. However, in old and aged animals, S100A10 was located in the cytoplasmic compartment of atrophic astrocytes. Furthermore, in astrocytes of aged tree shrews, cytoplasmic inclusions of S100A10 colocalized with the nuclear export protein, Crm-1. These results suggest that the transport of S100A10 from the nucleus to the cytoplasmic compartment of astrocytes could be a process related to astroglial atrophy during the aging process in the hippocampus of three shrews.

EM-Compressor: Electron Microscopy Image Compression in Connectomics with Variational Autoencoders
The ongoing pursuit to map detailed brain structures at high resolution using electron microscopy (EM) has led to advancements in imaging that enable the generation of connectomic volumes that have reached the petabyte scale and are soon expected to reach the exascale for whole mouse brain collections. To tackle the high costs of managing these large-scale datasets, we have developed a data compression approach employing Variational Autoencoders (VAEs) to significantly reduce data storage requirements. Due to their ability to capture the complex patterns of EM images, our VAE models notably decrease data size while carefully preserving important image features pertinent to connectomics-based image analysis. Through a comprehensive study using human EM volumes (H01 dataset), we demonstrate how our approach can reduce data to as little as 1/128th of the original size without significantly compromising the ability to subsequently segment the data, outperforming standard data size reduction methods. This performance suggests that this method can greatly alleviate requirements for data management for connectomics applications, and enable more efficient data access and sharing. Additionally, we developed a cloud-based application named EM-Compressor on top of this work to enable on-the-fly interactive visualization: https://em-compressor-demonstration.s3.amazonaws.com/EM-Compressor+App.mp4.

Calcium-triggered (de)ubiquitination events in synapses
Neuronal communication relies on neurotransmitter release from synaptic vesicles (SVs), whose dynamics are controlled by calcium-dependent pathways, as many thoroughly studied phosphorylation cascades. However, little is known about other post-translational modifications, as ubiquitination. To address this, we analysed resting and stimulated synaptosomes (isolated synapses) by quantitative mass spectrometry. We identified more than 5,000 ubiquitination sites on [~]2,000 proteins, the majority of which participate in SV recycling processes. Several proteins showed significant changes in ubiquitination in response to calcium influx, with the most pronounced changes in CaMKII and the clathrin adaptor protein AP180. To validate this finding, we generated a CaMKII mutant lacking the ubiquitination target site (K291) and analysed it both in neurons and non-neuronal cells. K291 ubiquitination influences CaMKII activity and synaptic function by modulating its autophosphorylation at a functionally important site (T286). We suggest that ubiquitination in response to synaptic activity is an important regulator of synaptic function.

Photopharmacological activation of adenosine A1receptor signaling suppresses seizures in a mousemodel for temporal lobe epilepsy
Up to 30% of epilepsy patients suffer from drug-resistant epilepsy (DRE). The search for innovative therapies is therefore important to close the existing treatment gap in these patients. The adenosinergic system possesses potent anticonvulsive effects, mainly through the adenosine A1 receptor (A1R). However, clinical application of A1R agonists is hindered by severe systemic side effects. To achieve local modulation of A1Rs, we employed a photopharmacological approach using a caged version of the A1R agonist N6-cyclopentyladenosine, termed cCPA. We performed the first in vivo study with intracerebroventricularly (ICV) administered cCPA to investigate the potential to uncage sufficient amounts of cCPA in the hippocampus by local illumination in order to suppress hippocampal excitability and seizures in mice. Using hippocampal evoked potential recordings, we showed a reduction in hippocampal neurotransmission after photo-uncaging of cCPA, similar to that obtained with ICV injection of CPA. Furthermore, in the intrahippocampal kainic acid mouse model for DRE, photo-uncaging of CPA in the epileptic hippocampus resulted in a strong suppression of seizures. Finally, we demonstrated that intrahippocampal photo-uncaging of CPA resulted in less impairment of motor performance in the rotarod test compared to ICV administration of CPA. These results provide a proof of concept for photopharmacological A1R modulation as an effective precision treatment for DRE.

Beta-frequency sensory stimulation enhances gait rhythmicity through strengthened coupling between striatal networks and stepping movement
Stepping movement is delta (1-4 Hz) rhythmic and depends on sensory inputs. In addition to delta rhythms, beta (10-30 Hz) frequency dynamics are also prominent in the motor circuits and are coupled to neuronal delta rhythms both at the network and the cellular levels. Since beta rhythms are broadly supported by cortical and subcortical sensorimotor circuits, we explore how beta-frequency sensory stimulation influences delta-rhythmic stepping movement, and dorsal striatal circuit regulation of stepping. We delivered audiovisual stimulation at 10 Hz or 145 Hz to mice voluntarily locomoting, while simultaneously recording stepping movement, striatal cellular calcium dynamics and local field potentials (LFPs). We found that 10 Hz, but not 145 Hz stimulation prominently entrained striatal LFPs. Even though sensory stimulation at both frequencies promoted locomotion and desynchronized striatal network, only 10 Hz stimulation enhanced the delta rhythmicity of stepping movement and strengthened the coupling between stepping and striatal LFP delta and beta oscillations. These results demonstrate that higher frequency sensory stimulation can modulate lower frequency dorsal striatal neural dynamics and improve stepping rhythmicity, highlighting the translational potential of non-invasive beta-frequency sensory stimulation for improving gait.

Cerebellar output neurons impair non-motor behaviors by altering development of extracerebellar connectivity
The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the minimum requirement for these neurons is for motor coordination and not learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.

Default Mode Network activation at task switches reflects mental task-set structure
Recent findings challenge traditional views of the Default Mode Network (DMN) as purely task-negative or self-oriented, showing increased DMN activity during demanding switches between externally-focused tasks (Crittenden et al., 2015; Smith et al., 2018; Zhou et al., 2024). However, it is unclear what modulates the DMN at switches, with transitions within a stimulus domain activating DMN regions in some studies but not others. Differences in the number of tasks suggest that complexity or structure of the set of tasks may be important. In this fMRI study, we examined whether the DMN's response to task switches depends on the complexity of the active set of tasks, manipulated by the number of tasks in a run, or abstract task groupings based on instructional order. Core DMN activation at task switches was unaffected by the number of currently relevant tasks. Instead, it depended on the order in which groups of tasks had been learnt. Multivariate decoding revealed that Core DMN hierarchically represents individual tasks, task domains, and higher-order task groupings based on instruction order. We suggest that, as the complexity of instructions increases, rules are increasingly organized into higher-level chunks, and Core DMN activity is highest at switches between chunks.

Humans forage for reward in reinforcement learning tasks
How do we make good decisions in uncertain environments? In psychology and neuroscience, the classic answer is that we calculate the value of each option and then compare the values to choose the most rewarding, modulo some exploratory noise. An ethologist, conversely, would argue that we commit to one option until its value drops below a threshold, at which point we start exploring other options. In order to determine which view better describes human decision-making, we developed a novel, foraging-inspired sequential decision-making model and used it to ask whether humans compare to threshold ("Forage") or compare alternatives ("Reinforcement-Learn" [RL]). We found that the foraging model was a better fit for participant behavior, better predicted the participants' tendency to repeat choices, and predicted the existence of held-out participants with a pattern of choice that was almost impossible under RL. Together, these results suggest that humans use foraging computations, rather than RL, even in classic reinforcement learning tasks.

Population connective field modeling reveals retinotopic visual cortex organization in the prenatal human brain
The visual space is sampled by cortical field maps in which nearby neuronal populations encode nearby locations of images received from the retina. Whether this retinotopic cortical organization already emerges in the prenatal human brain before visual experience is currently unknown. To answer this question in vivo, we applied population connective field modeling to 526 functional magnetic resonance imaging datasets ranging from prenatal to young adult age. We found retinotopically organized eccentricity and polar angle connectivity maps in V2 of the visual cortex as early as in the 21st week of gestation while connective field model fits increased significantly throughout development. These results highlight that retinotopic cortical maps develop in the second trimester of pregnancy, predating visual experience.

Structurally targeted mutagenesis identifies key residues supporting α-synuclein misfolding in multiple system atrophy
Multiple system atrophy (MSA) and Parkinsons disease (PD) are caused by misfolded -synuclein spreading throughout the central nervous system. While familial PD is linked to several point mutations in -synuclein, there are no known mutations associated with MSA. Our previous work investigating differences in -synuclein misfolding between the two disorders showed that the familial PD mutation E46K inhibits replication of MSA prions both in vitro and in vivo, providing key evidence to support the hypothesis that -synuclein adopts unique strains in patients. Here, to further interrogate -synuclein misfolding, we engineered a panel of cell lines harboring both PD-linked and novel mutations designed to identify key residues that facilitate -synuclein misfolding in MSA. These data were paired with in silico analyses using Maestro software to predict the effect of each mutation on the ability of -synuclein to misfold into one of the reported MSA cryo-electron microscopy conformations. In many cases, our modeling accurately identified mutations that facilitated or inhibited MSA replication. However, Maestro was occasionally unable to predict the effect of a mutation on MSA propagation in vitro, demonstrating the challenge of using computational tools to investigate intrinsically disordered proteins. Finally, we used our cellular models to determine the mechanism underlying the E46K-driven inhibition of MSA replication, finding that the E46/K80 salt bridge is necessary to support -synuclein misfolding. Overall, our studies use a structure-based approach to investigate -synuclein misfolding, resulting in the creation of a powerful panel of cell lines that can be used to interrogate MSA strain biology.

Age-related differences in working memory subprocesses decomposed by the reference-back paradigm
We used a data-driven approach to study the electrophysiological correlates of the working memory subprocesses revealed by the reference-back paradigm. In the absence of prior research, we focused on how aging affects the four subprocesses: updating, substitution, gate opening, and gate closing. We conducted our experiment with 25 younger adults (M=20.17{+/-}1.47) and 23 older adults (M=67.35{+/-}4.01) using the reference-back paradigm. Significant reaction time costs were observed for all four subprocesses, but age-related differences were found only in substitution, which was larger in older than younger adults, indicating it as being the most vulnerable subprocess in aging. Using difference waves, we identified event-related potential components that characterize the subprocesses we studied. Regarding updating: three occipital negativities between 80-180 ms, 300-400 ms, and 400-1,000 ms were observed, with only the latter range showing age group differences. Source analysis showed larger activity differences in the right frontal and temporal areas for younger adults. Regarding substitution: a frontal positivity between 250-600 ms emerged in younger adults, while a posterior positivity between 550-750 ms was found in older adults indicating different underlying processes supported by sLORETA results. Regarding gate opening: three parieto-occipital components were identified: a negativity between 150-250 ms, a positivity between 300-500 ms, and a positivity between 500-700 ms, all showing age-related differences. Regarding gate closing: we found an occipital negativity between 150-300 ms and a frontal positivity between 300-600 ms, neither of which changed between the age groups. From our findings, we conclude that the process of protecting information (gate closing) remains stable with age, despite older adults' sensitivity to interference. Conversely, gate opening is sensitive to age-related changes, likely to be resulting in different brain activity patterns during substitution being the updating of working memory with new information.

Novel quantal analysis method reveals conservation of injected charge by excitatory synapses across cortical cells of different sizes
In chemical synapses of the central nervous system (CNS), information is transmitted via the presynaptic release of a vesicle (or 'quantum') of neurotransmitter, which elicits a postsynaptic electrical response with an amplitude termed the 'quantal size'. This key determinant of neural computation is hard to measure reliably due to its small size and the multiple sources of noise within neurons and electrophysiological recordings. Measuring amplitudes of miniature postsynaptic currents (mPSCs) or potentials (mPSPs) at the cell soma potentially offers a technically straightforward way to estimate quantal sizes, as each of these miniature responses (or 'minis') is elicited by the spontaneous release of a single neurotransmitter vesicle. However, a somatically recorded mini is typically massively attenuated compared with at its input site, and a significant fraction are indistinguishable from (or cancelled out by) background noise fluctuations. Here we describe a novel quantal analysis method that estimates electrical size of the synapse by combining separate somatic recordings of background physiological noise and minis with simulations. With the help of a genetic algorithm, simulations are successfully used to infer the combined amplitude and rise time distribution of minis that would otherwise be inaccessible due to low signal to noise ratio. The estimated distributions reveal a striking inverse dependence of mean minis' amplitudes on cell's total capacitance (a proxy for the size of cells) that firmly supports the conservation of the electrical size of excitatory cortical synapses in rats. We incorporate the novel quantal analysis method into our patch clamp data analysis software called 'minis'.

Frontal Theta Oscillations and Cognitive Flexibility: Age-Related Modulations in EEG Activity
Cognitive flexibility, the ability to adapt one's behaviour in changing environments, declines during aging. Electroencephalography (EEG) studies demonstrate that the P300 and midfrontal theta oscillations are sensitive to attentional set-shifting - a measure of cognitive flexibility. Few is known about the electrocortical modulations underlying set-shifting in healthy older adults. Here, we investigated aging effects on set-shifting performance by analysing the P300 and theta power in 20 young (mean age: 22.5 {+/-} 2.9 years) and 19 older (mean age: 69.4 {+/-} 6.1 years) adults. While increasing shift difficulty (e.g. intra- vs. extradimensional shifts) led to increased reaction times (RTs) and higher error rates in both age groups, older adults showed an additional increase in RT variability. Older adults showed higher P300 latencies and P300 amplitude decreased during set-shifting in both groups. Young adults exhibited amplified midfrontal theta power with increasing shift difficulty whereas older adults showed an overall decrease. This study suggests that set-shifting in healthy older adults occurs without midfrontal theta modulation indicating that different neural substrates are recruited compared to young adults.

Pharmacological rescue of motor circuit dysfunction in a Drosophila model of paroxysmal dyskinesia
Background: Paroxysmal dyskinesias (PxDs) are characterised by bouts of involuntary dystonic and choreiform movements. The patho-mechanisms underlying these debilitating disorders remain poorly understood, and drug treatments are often limited. We recently generated a Drosophila model of a PxD-linked mutation causing BK potassium channel gain-of-function (BK GOF), and showed that BK GOF perturbs movement in Drosophila by disrupting neurodevelopment. However, whether locomotor capacity in BK GOF flies can be pharmacologically restored following neurodevelopmental insults has remained unclear. Objective: To identify pharmacological suppressors of motor defects caused by BK GOF. Methods: Using adult BK GOF flies, we performed an unbiased, in vivo, locomotion-based screen of 370 FDA-approved drugs. To test the impact of positive hits from this screen on motor circuit activity, we used optical imaging to record the intrinsic rhythmic activity of Drosophila larval motor circuits driving peristalsis and turning behaviors. Results: We found that inhibitors of acetylcholinesterase - a protein that degrades acetylcholine in cholinergic synapses - partially rescued movement defects caused by BK GOF. Inhibition of acetylcholinesterase also partially restored intrinsic activity of motor circuits controlling forward movement and turning in BK GOF larvae. Conclusions: Our findings indicate that elevating cholinergic tone can reverse motor circuit dysfunction in an animal model of PxD caused by BK GOF. Furthermore, our study provides proof-of-principle that Drosophila can be utilised for screens to uncover putative drug treatments for involuntary movement disorders.

Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation
Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimer's-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in C. elegans. Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimer's disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.

Structured neural fluctuations can generate noise invariance and inter-areal gating at distinct timescales
The brain processes, computes, and categorizes sensory input. But even in sensory brain areas, the relationship between input signals and neuronal spiking activity is complex and non-linear. Fast subsecond fluctuations in neuronal population responses dominate the temporal dynamics of neural circuits. Traditional approaches have treated this activity as "noise" that can be averaged away by taking the mean spiking rate over wide time bins or over multiple trial repetitions, but this ignores much of the temporal dynamics that naturally occur in neural systems. We find that subsecond flares of increased population activity are layer- and cell-type specific, and large-scale computational modelling suggests they may serve as an inter-areal gating mechanism. Moreover, we find that most of the neural variability is restricted to a population-gain axis. This observation explains why neural systems can function in the presence of excessive variability: population-level spiking dynamics generate invariance to the majority of neural noise.

The biomechanical state of the effector affects motor control and provides measures of single trial inhibition in a stop signal task
The Stop Signal Task (SST) has been the benchmark for studying the behavioral and physiological basis of movement generation and inhibition. In our study, we extended the scope beyond physiological findings related to muscle activity, focusing our analysis on the initial biomechanical state of the effector. By incorporating a force sensitive resistor (FSR), we continuously monitored the force applied by the effector (here the index finger) during a button release version of the SST. This modified task design allowed us to examine both the baseline force before the relevant Go signal was presented and during the covert state of movement preparation. Notably, variations in force over time in response to the Go signal revealed differences across trials where movement was either generated or successfully inhibited, depending on the amount of force during the baseline period. Specifically, higher baseline force was associated with a delayed movement generation, which simultaneously slowed down the force release, facilitating successful inhibition when requested. Our results highlight the influence of biomechanical variables in movement control, which should be accounted for by the models developed for investigating the physiology of this ability.

Decision-making shapes dynamic inter-areal communication within macaque ventral frontal cortex
Macaque ventral frontal cortex is comprised of a set of anatomically heterogeneous and highly interconnected areas. Collectively these areas have been implicated in many higher-level affective and cognitive processes, most notably the adaptive control of decision-making. Despite this appreciation, little is known about how subdivisions of ventral frontal cortex dynamically interact with each other during decision-making. Here we assessed functional interactions between areas by analyzing the activity of thousands of single neurons recorded from eight anatomically defined subdivisions of ventral frontal cortex in macaques performing a visually guided two-choice probabilistic task for different fruit juices. We found that the onset of stimuli and reward delivery globally increased communication between all parts of ventral frontal cortex. Inter-areal communication was, however, temporally specific, occurred through unique activity subspaces between areas, and depended on the encoding of decision variables. In particular, areas 12l and 12o showed the highest connectivity with other areas while being more likely to receive information from other parts of ventral frontal cortex than to send it. This pattern of functional connectivity suggests a role for these two areas in integrating diverse sources of information during decision processes. Taken together, our work reveals the specific patterns of inter-areal communication between anatomically connected subdivisions of ventral frontal cortex that are dynamically engaged during decision-making.

Sleep and circadian rhythm activity alterations during adolescence in a mouse model of neonatal fentanyl withdrawal syndrome
Purpose: Fentanyl, a highly potent synthetic opioid, is a major contributor to the ongoing opioid epidemic. During adulthood, fentanyl is known to induce pronounced sleep and circadian disturbances during use and withdrawal. Children exposed to opioids in utero are likely to develop neonatal opioid withdrawal syndrome, and display sleep disturbances after birth. However, it is currently unknown how neonatal opioid withdrawal from fentanyl impacts sleep and circadian rhythms in mice later in life. Methods: To model neonatal opioid withdrawal syndrome, mice were treated with fentanyl from postnatal days 1 through 14, analogous to the third trimester of human gestation. After weaning, fentanyl and saline treated mice underwent non-invasive sleep and circadian rhythm monitoring during adolescence postnatal days 23 through 30. Results: Neonatal fentanyl exposure led to reduced duration of wake and a decrease in the number of bouts of non-rapid eye movement sleep. Further, neonatally exposed mice displayed an increase in the average duration of rapid eye movement sleep bouts, reflecting an overall increase in the percent time spent in rapid eye movement sleep across days. Conclusions: Neonatal fentanyl exposure leads to altered sleep-wake states during adolescence in mice.

GPT-3 reveals selective insensitivity to global vs. local linguistic context in speech produced by treatment-naive patients with positive thought disorder
Background: Early psychopathologists proposed that certain features of positive thought disorder, the disorganized language output produced by some people with schizophrenia, suggest an insensitivity to global, relative to local, discourse context. This idea has received support from carefully controlled psycholinguistic studies in language comprehension. In language production, researchers have so far remained reliant on subjective qualitative rating scales to assess and understand speech disorganization. Now, however, recent advances in large language models mean that it is possible to quantify sensitivity to global and local context objectively by probing lexical probability (the predictability of a word given its preceding context) during natural language production. Methods: For each word in speech produced by 60 first-episode psychosis patients and 35 healthy, demographically-matched controls, we extracted lexical probabilities from GPT-3 based on contexts that ranged from very local--a single preceding word: P(Wn | Wn-1)--to global--up to 50 preceding words: P(Wn|Wn-50, Wn-49, ..., Wn-1). Results: We show, for the first time, that disorganized speech is characterized by disproportionate insensitivity to global, versus local, linguistic context. Critically, this global-versus-local insensitivity selectively predicted clinical ratings of positive thought disorder, above and beyond overall symptom severity. There was no evidence of a relationship with negative thought disorder (impoverishment). Conclusions: We provide an automated, interpretable measure that can potentially be used to quantify speech disorganization in schizophrenia. Our findings directly link the clinical phenomenology of thought disorder to neurocognitive constructs that are grounded in psycholinguistic theory and neurobiology.

Representation of visual uniformity in the lateral prefrontal cortex
Visual illusions tend to have early visual cortical correlates. However, this general trend may not apply to our subjective impression of a detailed and uniform visual world, which may be considered illusory given the paucity of peripheral processing. Using a psychophysically calibrated visual illusion, we assessed the patterns of hemodynamic activity in the human brain that distinguished between the illusory percept of uniformity in the periphery (i.e., Gabor patches having identical orientations) from the accurate perception of incoherence. We identified voxel patterns in the lateral prefrontal cortex that predicted perceived uniformity, which could also generalize to scene uniformity in naturalistic movies. Because similar representations of visual uniformity can also be found in the intermediate and late layers of a feedforward convolutional neural network, the perception of uniformity may involve high-level coding of abstract properties of the entire scene as a whole, that is distinct from the filling-in of specific details in early visual areas.

Additive effects of cerebrovascular disease functional connectome phenotype and plasma p-tau181 on longitudinal neurodegeneration and cognitive outcomes
INTRODUCTIONWe investigated the effects of multiple cerebrovascular disease (CeVD) neuroimaging markers on brain functional connectivity (FC), and how such CeVD-related FC changes interact with plasma p-tau181 (Alzheimers disease (AD) marker) to influence downstream neurodegeneration and cognitive changes.

METHODSMultivariate associations between four CeVD markers and whole-brain FC in 529 participants across the dementia spectrum were examined using partial least squares correlation. Interactive effects of CeVD-related FC patterns and p-tau181 on longitudinal grey matter volume and cognitive changes were investigated using linear mixed-effects models.

RESULTSWe identified a brain FC phenotype associated with high CeVD burden across all markers. Further, expression of this general CeVD-related FC phenotype and p-tau181 contributed additively, but not synergistically, to baseline and longitudinal grey matter volumes and cognitive changes.

DISCUSSIONOur findings suggest that CeVD exerts global effects on the brain connectome and highlight the additive nature of AD and CeVD on neurodegeneration and cognition.

Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy
Tauopathies, which include Alzheimers disease (AD) share a common defining factor, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequalae. We uncovered a novel PTM of tau, named citrullination, caused by peptidyl arginine deiminase (PAD) enzymes. PAD induced citrullination irreversibly converts arginine residues to citrulline, producing net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimers disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule binding repeat domain (MBR), and C-terminal domain (C-term) on full length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimers disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher phospho-tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.

Advancing Thalamic Nuclei Segmentation: The Impact of Compressed Sensing and FastSurfer on MRI Processing
The thalamus is a collection of gray matter nuclei that play a crucial role in sensorimotor processing and modulation of cortical activity. Characterizing thalamic nuclei is particularly relevant for patient populations with Parkinsons disease, epilepsy, dementia, and schizophrenia. However, severe head motion in these populations poses a significant challenge for in vivo mapping of thalamic nuclei. Recent advancements have leveraged the compressed sensing (CS) framework to accelerate acquisition times in MPRAGE sequence variants, while fast segmentation tools like FastSurfer have reduced processing times in MRI research.

In this study, we evaluated thalamic nuclei segmentations derived from six different MPRAGE variants with varying degrees of CS acceleration (from about 9 to about 1 minute acquisitions), using both FreeSurfer and FastSurfer for segmentation. Our findings show minimal sequence effects with no systematic bias, and low volume variability across sequences for the whole thalamus and major thalamic nuclei. Notably, CS-accelerated sequences produced less variable volumes compared to non-CS sequences. Additionally, segmentations of thalamic nuclei by FreeSurfer and FastSurfer were highly comparable.

We provide first evidence supporting that a good segmentation quality of thalamic nuclei with compressed sensing T1-weighted image acceleration in a clinical 3T MRI system is possible. Our findings encourage future applications of fast T1-weighted MRI to study deep gray matter. CS-accelerated sequences and rapid segmentation methods are promising tools for future studies aiming to characterize thalamic nuclei in vivo at 3T in both healthy individuals and clinical populations.

Key points1) MPRAGE variants can be accelerated with Compressed Sensing without increasing volume variability in thalamus and major thalamic nuclei; 2) Thalamic nuclei segmentations on FastSurfer whole-brain data provide comparable results to FreeSurfer.

A Systematic Review of the Neuroprotective Role and Biomarker Potential of GDF15 in Neurodegeneration
Neurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15.