bioRxiv Subject Collection: Neuroscience's Journal

Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies
GBA mutations are major risk factors for Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), two common -synucleinopathies associated with cognitive impairment. Here, we investigated the role of GBA mutations in cognitive decline by utilizing Gba L444P mutant mice, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice showed early cognitive deficits but no PD-like motor deficits up to 12 months old. Conversely, SNCA tg mice displayed age-related motor deficits but no cognitive abnormalities. Gba-SNCA mice exhibited exacerbated motor deficits and cognitive decline. Immunohistological analysis revealed cortical phospho--synuclein pathology in SNCA tg mice, which was exacerbated in Gba-SNCA mice, especially in layer 5 cortical neurons. Significantly, Gba mutant mice did not show -synuclein pathology. Single-nucleus RNA sequencing of cortices instead uncovered selective synaptic vesicle cycle defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via robust downregulation in gene networks regulating synapse vesicle cycle and synapse assembly. Meanwhile SNCA tg mice displayed broader synaptic changes. Immunohistochemical and electron microscopic analyses validated these findings. Together, our results indicate that Gba mutations, while exacerbating pre-existing -synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through -synuclein-independent mechanisms, likely involving dysfunction in synaptic vesicle endocytosis. Additionally, Gba-SNCA mice are a valuable model for studying cognitive and motor deficits in PD and DLB.

40 Hz sensory stimulation enhances CA3-CA1 coordination and prospective coding during navigation in a mouse model of Alzheimer's disease
40 Hz sensory stimulation ("flicker") has emerged as a new technique to potentially mitigate pathology and improve cognition in mouse models of Alzheimer's disease (AD) pathology. However, it remains unknown how 40 Hz flicker affects neural codes essential for memory. Accordingly, we investigate the effects of 40 Hz flicker on neural representations of experience in the hippocampus of the 5XFAD mouse model of AD by recording 1000s of neurons during a goal-directed spatial navigation task. We find that an hour of daily exposure to 40 Hz audio-visual stimulation over 8 days leads to higher coordination between hippocampal subregions CA3 and CA1 during navigation. Consistent with CA3's role in generating sequential activity that represents future positions, 40 Hz flicker exposure increased prospective coding of future positions. In turn, prospective coding was more prominent during efficient navigation behavior. Our findings show how 40 Hz flicker enhances key hippocampal activity during behavior that is important for memory.

Expression of sex steroid receptors and sex differences of Otp glutamatergic neurons of the medial extended amygdala
The medial extended amygdala (EAme) is part of the social behavior network and its subdivisions show expression of sex steroid receptors, which participate in the regulation of sexually dimorphic behaviors. However, EAme subdivisions are highly heterogeneous in terms of neuron subtypes, with different subpopulations being involved in regulation of different aspects of social and non-social behaviors. To further understand the role of the different EAme neurons and their contribution to sexual differences, here we studied one of its major subtypes of glutamatergic neurons, those derived from the telencephalon-opto-hypothalamic domain that coexpress Otp and Foxg1 genes during development. Our results showed that the vast majority of the Otp glutamatergic neurons of the medial amygdala and BSTM in both sexes express Ar, Esr1 (ER-alpha) and Esr2 (ER-beta) mRNA. Moreover, the high percentage of receptors expression in the Otp neurons (between 93 and 100%) indicates that probably the majority of the Otp neurons of EAme are coexpressing the three receptors. In addition, Otp neurons of the posterodorsal medial amygdala have a larger soma and occupy more space in males than in females. These and other features of the Otp neurons regarding their expression of sex steroid receptors likely contribute to some of the sexually-dimorphic behaviors regulated by EAme.

Distractor anticipation during working memory is associated with theta and beta oscillations across spatial scales
Anticipating distractors during working memory maintenance is critical to reduce their disruptive effects. In this study, we aimed to identify the oscillatory correlates of this process across different spatial scales of neural activity. We simultaneously recorded local field potentials (LFP) from the LPFC and electroencephalograms (EEG) from the scalp of monkeys performing a modified memory-guided saccade (MGS) task. The monkeys were required to remember the location of a target visual stimulus while anticipating distracting visual stimulus, flashed at 50% probability during the delay period. We found significant theta-band activity across spatial scales during anticipation of a distractor, closely linked with underlying working memory dynamics, through decoding and cross-temporal generalization analyses. EEG particularly reflected reactivation of memory around the anticipated time of a distractor, even in the absence of stimuli. During this anticipated time, beta-band activity exhibited transiently enhanced intrahemispheric communication between the LPFC and occipitoparietal brain areas. These oscillatory phenomena were observed only when the monkeys successfully performed the task, implicating their possible functional role in mitigating anticipated distractors. Our results demonstrate that distractor anticipation recruits multiple oscillatory processes across the brain during working memory maintenance, with a key activity observed predominantly in the theta and beta bands.

Repulsion of CA3 / dentate gyrus representations is driven by distinct internal beliefs in the face of ambiguous sensory input
Recent human neuroimaging studies of episodic memory have revealed a counterintuitive phenomenon in the hippocampus: when events are highly similar, corresponding hippocampal activity patterns are sometimes less correlated than activity patterns associated with unrelated events. This phenomenon (repulsion) is not accounted for by most theories of the hippocampus, and the conditions that trigger repulsion remain poorly understood. Here, we used a spatial route-learning task and high-resolution fMRI in humans to test whether hippocampal repulsion is fundamentally driven by internal beliefs about the environment. By precisely measuring participants' internal beliefs and actively manipulating them, we show that repulsion selectively occurred in hippocampal subfields CA3 and dentate gyrus when visual input was ambiguous, or even identical, but internal beliefs were distinct. These findings firmly establish conditions that elicit repulsion and have broad relevance to theories of hippocampal function and to the fields of human episodic memory and rodent spatial navigation.

A common stay-on-goal mechanism in anterior cingulate cortex for information and effort choices
Humans and non-humans alike often make choices to gain information, even when the information cannot be used to change the outcome. Prior research has shown the anterior cingulate cortex (ACC) is important for evaluating options involving reward-predictive information. Here we studied the role of ACC in information choices using optical inhibition to evaluate the contribution of this region during specific epochs of decision making. Rats could choose between an uninformative option followed by a cue that predicted reward 50% of the time vs. a fully informative option that signaled outcomes with certainty, but was rewarded only 20% of the time. Reward seeking during the informative S+ cue decreased following ACC inhibition, indicating a causal contribution of this region in supporting reward expectation to a cue signaling reward with certainty. Separately in a positive control experiment and in support of a known role for this region in sustaining high-effort behavior for preferred rewards, we observed reduced lever presses and lower breakpoints in effort choices following ACC inhibition. The lack of changes in reward latencies in both types of decisions indicate the motivational value of rewards remained intact, revealing instead a common role for ACC in maintaining persistence toward certain and valuable rewards.

Modulation of leg trajectory by transcranial magnetic stimulation during walking
The primary motor cortex is involved in initiation and adaptive control of locomotion. However, the role of the motor cortex in controlling gait trajectories remains unclear. In animals, cortical neuromodulation allows for precise control of step height. We hypothesized that a similar control framework applies to humans, whereby cortical stimulation would primarily increase foot elevation. Transcranial magnetic stimulation (TMS) was applied over the motor cortex to assess the involvement of the corticospinal tract over the limb trajectory during human walking. Eight healthy adults (aged 20-32 years) participated in treadmill walking at 1.5 km/h. TMS was applied over the left motor cortex at an intensity of 120% of the threshold to elicit a dorsiflexion of the right ankle during the swing phase of gait. Electromyographic (EMG) measurements and three-dimensional (3D) lower limb kinematics were collected. When delivered during the early swing phase, TMS led to a significant increase in the maximum height of the right toe by a mean of 40.7% +/- 14.9% (25.6mm +/- 9.4 mm, p = 0.0352) and knee height by 57.8%+/-16.8%; (32mm +/- 9.3 mm; p = 0.008) across participants. These findings indicate that TMS can influence limb trajectory during walking, highlighting its potential as a tool for studying cortical control of locomotion.

Type 2 diabetes remodels collateral circulation and promotes leukocyte adhesion following ischemic stroke
Type 2 diabetes mellitus (T2DM) is associated with impaired leptomeningeal collateral compensation and poor stroke outcome. Neutrophils tethering and rolling on endothelium after stroke can also independently reduce flow velocity. However, the chronology and topological changes in collateral circulation in T2DM is not yet defined. Here, we describe the spatial and temporal blood flow dynamics and vessel remodeling in pial arteries and veins and leukocyte-endothelial adhesion following middle cerebral artery (MCA) stroke using two-photon microscopy in awake control and T2DM mice. Relative to control mice prior to stroke, T2DM mice already exhibited smaller pial vessels with reduced flow velocity. Following stroke, T2DM mice displayed persistently reduced blood flow in pial arteries and veins, resulting in a poor recovery of downstream penetrating arterial flow and a sustained deficit in microvascular flow. There was also persistent increase of leukocyte adhesion to the endothelium of veins, coincided with elevated neutrophils infiltration into brain parenchyma in T2DM mice compared to control mice after stroke. Our data suggest that T2DM-induced increase in chronic inflammation may contribute to the remodeling of leptomeningeal collateral circulation and the observed hemodynamics deficiency that potentiates poor stroke outcome.

SC10X/U: A High-density Electrode System for Non-Invasive Recording of Neural Activity of the Cervical Spinal Cord
Objective: To design and develop a high-density (HD) electrode system that describes the position of surface electrodes for recording electrophysiological signals from the human cervical spinal cord. The system is intended to standardize experimental recordings and facilitate the subsequent analysis of evoked and spontaneous spinal cord neural activity, using high-density electrospinography (HD-ESG). Method: The proposed system (SC10-X/U) describes the locations of up to 76 channels with a unique nomenclature, where the division of the spinal cord (SC) electrode space was inspired by the EEG 10-10 system. As proof of concept, spinal evoked potentials in response to median nerve stimulation at the wrist were recorded from 10 participants and characterized based on a 64-channel derivation from the SC10-X/U system. Results: Following the design criteria, the SC10-X/U defines 76 electrode positions and its configuration. HD-ESG system was utilized to successfully record evoked spinal responses and significant N13 and P9 potential were observed in response to the stimulation. The spinal N13 potential had a latency of 13.2 +- 1.1ms (mean +- SD) after stimulation. A topographic map of the N13 electro-spinal activity using the 64-channel recording system revealed an epicentre at C5-C7 dorsal-vertebral locations (ML4 - ML6 electrodes). Conclusion: The proposed SC10-X/U system will facilitate standardized recording and analysis of high-density ESG signals from the human cervical spinal cord. The system defines electrode locations to promote standardization across different individuals, studies, and clinical and research centres. The HD-ESG evoked potentials recorded using the proposed system were comparable to those observed in previous non-HD studies. The presented topographic maps conform to known neurophysiological and neuroanatomical findings. This served to validate the design and development of the electrode system and patch for future studies.

Twelve phosphomimetic mutations induce the assembly of recombinant full-length human tau into paired helical filaments
The assembly of tau into amyloid filaments is associated with more than twenty neurodegenerative diseases, collectively termed tauopathies. Cryo-EM structures of brain-derived tau filaments revealed that specific structures define different diseases, triggering a quest for the development of experimental model systems that replicate the structures of disease. Here, we describe twelve phosphomimetic, serine/threonine to aspartate, mutations in tau, which we termed PAD12, that collectively induce the in vitro assembly of full-length tau into filaments with the same structure as that of paired helical filaments extracted from the brains of individuals with Alzheimer's disease. Solution-state nuclear magnetic resonance spectroscopy suggests that phosphomimetic mutations in the carboxy-terminal domain of tau may facilitate filament formation by disrupting an intramolecular interaction between two IVYK motifs. PAD12 tau can be used for both nucleation-dependent and multiple rounds of seeded assembly in vitro, as well as for the seeding of tau biosensor cells. PAD12 tau can be assembled into paired helical filaments under various shaking conditions, with the resulting filaments being stable for extended periods of time. They can be labelled with fluorophores and biotin. Tau filaments extracted from the brains of individuals with Alzheimer's disease brains have been known to be made of hyperphosphorylated and abnormally phosphorylated full-length tau, but it was not known if the presence of this post-translational modification is more than a mere correlation. Our findings suggest that hyperphosphorylation of tau may be sufficient for the formation of the Alzheimer tau fold. PAD12 tau will be a useful tool for the study of molecular mechanisms of neurodegeneration.

Sex-biased effect of sodium leak channel NALCN deletion in striatal Drd2 spiny projection neurons
The sodium leak channel NALCN is an important modulator of neuronal excitability, yet its specific role in striatal medium-sized spiny neurons remains largely unexplored. In this study, considering that Nalcn transcripts are enriched in the dorsal and ventral striatum of Drd2-SPNs, we investigated the functional impact of NALCN deletion in Drd2-expressing SPNs in both male and female mice. Electrophysiological recordings revealed significant sex differences, with male SPNs exhibiting altered membrane properties and increased excitability, while females showed more subtle changes. Interestingly, eticlopride-induced intracellular signaling was selectively enhanced in female SPNs lacking NALCN. Behaviorally, male mice exhibited reduced motivation in food-seeking tasks and impaired discrimination of threat cues. Our findings uncover an important, sex-specific role for NALCN in regulating striatal function and behavior and underscore its significance in maintaining normal striatal function.

Cortex-wide characterization of decision-making neural dynamics during spatial navigation
Decision-making during freely moving behaviors involves complex interactions among many cortical and subcortical regions. However, the spatiotemporal coordination across regions to generate a decision is less understood. Using a head-mounted widefield microscope, cortex-wide calcium dynamics were recorded in mice expressing GCaMP7f as they navigated an 8-maze using two paradigms. The first was an alternating pattern that required short term memory of the previous trial to make the correct decision and the second after a rule change to a fixed path in which rewards were delivered only on the left side. Identification of cortex-wide activation states revealed differences between the two paradigms. There was a higher probability for a visual/retrosplenial cortical state during the alternating paradigm and higher probability of a secondary motor and posterior parietal state during left-only. Three state sequences (motifs) illustrated both anterior and posterior activity propagations across the cortex. The anterior propagating motifs had the highest probability around the decision and propagating motifs peaked following the decision. The latter, likely reflecting internal feedback to influence future actions, were more common in the left-only paradigm. Therefore, the probabilities and sequences of cortical states differ when working memory is required versus a fixed trajectory reward paradigm.

Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn+PFFs-induced rat model for Parkinson's disease
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, -Synuclein (-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PD risk. Additionally, elevated TNF levels and -Syn-reactive T cells in circulation suggest a strong link between innate and adaptive immune responses in PD. We have previously reported that reduced levels of the class II transactivator, the master regulator of MHCII expression, increases susceptibility to -Syn-induced PD-like pathology in rats and are associated with higher serum levels of soluble TNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant, XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models, fails to protect against robust -Syn-induced PD-like pathology in rats. We used a model combining rAAV-mediated -Syn overexpression in SNpc with striatal injection of -Syn preformed fibrils two weeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV--Syn. We observed up to 70% loss of striatal dopaminergic fibers without treatment, and no protective effects on dopaminergic neurodegeneration after XPro1595 administration. Pathological -Syn levels as well as microglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595 treatment. An increase in IL-6 and IL-1{beta} levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients.

RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa
Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration worldwide. It is characterized by the sequential death of rod and cone photoreceptors, the cells responsible for night and daylight vision, respectively. Although mutations in RP are mostly rod-specific, there is a secondary degeneration of cones. One possible mechanism behind cone death is metabolic dysregulation. Photoreceptors are highly metabolically active, consuming large quantities of glucose and producing substantial amounts of lactate. The retinal pigment epithelium (RPE) mediates the transport of glucose from the blood to photoreceptors and, in turn, removes lactate, which it can use as its own source of fuel. The model for metabolic dysregulation in RP suggests that, following the death of rods, lactate levels are substantially diminished causing the RPE to withhold glucose, resulting in nutrient deprivation for cones. Here, we present adeno-associated viral vector-mediated delivery of monocarboxylate transporter 2 (MCT2) into RPE cells with the aim of promoting lactate uptake from the blood and encouraging the passage of glucose to cones. We demonstrate prolonged survival and function of cones in rat and mouse RP models, revealing a possible gene agnostic therapy for preserving vision in RP. We also present the use of fluorescence lifetime imaging-based biosensors for lactate and glucose within the eye. Using this technology, we show changes to lactate and glucose levels within MCT2-expressing RPE, suggesting cone survival is impacted by RPE metabolism.

The YTHDF Proteins Shape the Brain Gene Signatures of Alzheimer's Disease
The gene signatures of Alzheimer's Disease (AD) brains reflect an output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To identify the most significant factor that shapes the AD brain signature, we developed a machine learning model (DEcode-tree) to integrate cellular and molecular factors explaining differential gene expression in AD. Our model indicates that YTHDF proteins, the canonical readers of N6-methyladenosine RNA modification (m6A), are the most influential predictors of the AD brain signature. We then show that protein modules containing YTHDFs are downregulated in human AD brains, and knocking out YTHDFs in iPSC-derived neural cells recapitulates the AD brain gene signature in vitro. Furthermore, eCLIP-seq analysis revealed that YTHDF proteins influence AD signatures through both m6A-dependent and independent pathways. These results indicate the central role of YTHDF proteins in shaping the gene signature of AD brains.

Omega-3 fatty acid normalizes postsynaptic density proteins via miRNAs regulation in hippocampus and prevents DEHP-induced impairment of learning and memory in mice
DEHP is the most widely used plasticizer in many products. However, growing evidence has indicated that DEHP may induce neurotoxicity. DEHP exposure affects mircoRNAs (miRNAs) expression in brain. A growing body of evidence suggests that nutrients and other bioactive food components prevent neurotoxicity through regulation of miRNA expression. Due to the increasing concern about the risks of DEHP to human health, we explored the neuroprotective effect of Omega-3 fatty acid (Omega-3FA) on subchronic DEHP-induced neurotoxicity in mice, and the potential involved miRNAs and their targets in the protective action of Omega-3FA against DEHP-induced neurotoxicity. Omega-3FA protected against the DEHP-induced impairment of learning and memory and alleviated the thinning of postsynaptic density (PSD) thickness in hippocampal synapses. We observed that there are fourteen up or down regulated miRNAs associated PSD in DEHP exposure which were normalized by Omega-3FA treatment. Protein targets in PSD of these differentially expressed miRNAs were predicted. Furthermore, the expression levels of protein mGluR5, Homer1, and NMDAR2B were carried out via Western blot, for further verifying PSD associated miRNAs' targets are involved in neuroprotection of Omega-3FA against DEHP. These findings suggested that Omega-3FA protected DEHP-induced impairment of learning and memory as well as synaptic structure alteration in the hippocampus by regulating the expression of PSD associated miRNAs and their targets. Thus, Omega-3FA should be included in diet to prevent or suppress neurotoxicity caused by continuous exposure to DEHP.

Convergent olfactory circuits for courtship in Drosophila revealed by ds-Tango
Animals exhibit sex-specific behaviors that are governed by sexually dimorphic circuits. One such behavior in male Drosophila melanogaster, courtship, is regulated by various sensory modalities, including olfaction. Here, we reveal how sexually dimorphic olfactory pathways in male flies converge at the third-order, onto lateral horn output neurons, to regulate courtship. To achieve this, we developed ds-Tango, a modified version of the monosynaptic tracing and manipulation tool trans-Tango. In ds-Tango, two distinct configurations of trans-Tango are positioned in series, thus providing selective genetic access not only to the monosynaptic partners of starter neurons but also to their disynaptic connections. Using ds-Tango, we identified a node of convergence for three sexually dimorphic olfactory pathways. Silencing this node results in deficits in sex recognition of potential partners. Our results identify lateral horn output neurons required for proper courtship behavior in male flies and establish ds-Tango as a tool for disynaptic circuit tracing.

Topography of putative bidirectional interaction between hippocampal sharp wave ripples and neocortical slow oscillations
Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across neocortex and the mechanisms enabling it remain unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with widefield imaging of dorsal neocortex, we found spatially and temporally precise bidirectional hippocampo-neocortical interaction. HPC multi-unit activity and SWR probability were correlated with UP/DOWN states in mouse default mode network (DMN), with highest modulation by RSC in deep sleep. Further, some SWRs were preceded by the high rebound excitation accompanying DMN DOWN[->]UP transitions, while large-amplitude SWRs were often followed by DOWN states originating in RSC. We explain these electrophysiological results with a model in which HPC and RSC are weakly coupled excitable systems capable of bi-directional perturbation and suggest RSC may act as a gateway through which SWRs can perturb downstream cortical regions via cortico-cortical propagation of DOWN states.

A GABA-A receptor response to CBD following status epilepticus in the medial entorhinal cortex of the rat
Cannabidiol is a non-psychoactive phytocannabinoid that has been implicated as a potential therapeutic in numerous neurological diseases. Perhaps the most widespread therapeutic use of CBD has been in the form of Epidiolex, which is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis. Whilst the effectiveness of CBD in seizure reduction is clear, its mechanism of action is complex, and reflects the wide range of pharmacodynamic targets that includes receptors, ion channels and enzymes. This study investigated the effects of action of cannabidiol (CBD) on GABAergic transmission in layer II of the medial entorhinal cortex in animals that had previously undergone a period of status epilepticus (SE). Spontaneous post-synaptic currents were recorded from medial entorhinal cortex layer II pyramidal cells in animals 1-7 after SE and in age matched controls as well as in tissue resected from children with temporal lobe epilepsy (TLE). CBD enhanced GABAAR-mediated inhibition by increasing decay times and inhibitory charge transfer across the postsynaptic membrane in status epilepticus (SE) but did not alter GABAergic transmission in age-matched control rats. The SE-induced effects of CBD were blocked by ligands acting as inverse agonists at the benzodiazepine site of the GABAAR receptor and the effects of CBD were additive to low-doses of benzodiazepine and barbiturate agonists, consistent with allosteric actions on the GABAAR. Similar effects were observed in both SE rat and human layer II neurons. Overall, these data suggest CBD may act as a positive allosteric modulator (PAM) at postsynaptic GABAARs and this action appears to develop following SE.

Effector selection precedes movement specification: evidence from repetition effects in motor planning
Motor performance is influenced by movements that were performed shortly prior. For example, reaction times (RTs) for successive movements are reduced when executed with the same effector, even if the specifics of the consecutive movements differ. These findings have been taken to support the notion that repetition effects in motor planning reflect the involvement of effector-specific motor plans. However, previous studies have confounded motor and visual aspects of repetition: movements have typically been instructed via visual cues, and movement repetition, therefore, implied repeating also the visual cue, so that the latter may be (at least partly) responsible for the observed RT effects. In the present study, participants performed two movements in succession, a prime and a probe action, either with their left or right hand and in one of two directions, inward or outward relative to the body midline. We used different cues for prime and probe actions, so that movement repetitions did not involve repetition of the visual cue. Participants initiated successive same-limb movements faster than different-limb movements, but this RT advantage was smaller than observed in previous work. Moreover, repeating movement direction also led to a decrease in RT, though only in combination with hand repetition. Whereas these findings imply that visual cue repetition can contribute to accelerated RTs in movement repetition, they confirm that the recent motor history affects motor planning. Furthermore, they support the idea of a hierarchical framework of motor planning in which effector selection precedes specification of motor parameters.

Over supplementation of folic acid reduces survival 24 hours after hypoxia in male and female Drosophila melanogaster
Hypoxia is a major component of ischemic stroke. Nutrition has been established as a modifiable risk factor for ischemic stroke. Over-supplementation of folic acid (FA) has become an increasing problem in the U.S and other countries as more people are consuming at or above the recommended daily amount of FA. The impact of over-supplementation of FA on hypoxia is not well understood. This study aimed to investigate how FA over-supplementation impacts hypoxia outcomes using Drosophila melanogaster as a model. Adult w1118 Drosophila melanogaster were placed on control and 100 micromolar folic acid supplemented diets (FASD). Progeny 5 to 6 days old were exposed to hypoxia for two hours prior to returning to normoxic conditions to model reperfusion. Using liquid chromatography-tandem mass spectrometry, elevated FA levels were observed in FASD flies. Escape behavior was also demonstrated in hypoxia larvae, and increased hypoxia-induced mortality was exacerbated in FASD flies; however, diet did not influence hypoxia-medicated reductions in climbing motivation and ability. Data obtained suggests that hypoxia has a negative effect on survival and climbing behavior in the flies, and that FA over-supplementation has selected negative health outcomes after hypoxia.

The role of dopaminergic, cholinergic and noradrenergic networks in hyposmia in Parkinson's disease
Background: Olfactory impairment is frequently observed in Parkinson's disease (PD) before motor symptom onset. Patients with isolated rapid eye movement sleep behaviour disorder (iRBD) are at risk to develop PD and present olfactory dysfunction. Subcortical neuromodulatory nuclei including the substantia nigra, the nucleus basalis of Meynert, and the locus coeruleus, may all contribute to olfactory dysfunction. Objective: The objective of this study was to understand the network alterations underlying olfactory dysfunction in PD and in the early prodromal iRBD patients using multimodal MRI. Methods: PD (n = 107), iRBD patients (n = 35) and healthy controls (HC, n = 39) were recruited from the ICEBERG cohort for a cross-sectional study. We separated subjects in Healthy Controls, iRBD patients, and PD patients with or without RBD and with or without anosmia. Olfactory, motor, and cognitive scores were assessed and combined with multimodal imaging. Results: We found that olfaction positively correlated with (i) striatal DaT signal in PD patients; (ii) neuromelanin contrast in the locus coeruleus and (iii) Nucleus Basalis of Meynert grey matter (GM) volume in all patients. These signals were uncorrelated with motor and cognitive scores. Functional connectivity was reduced in regions of the cholinergic olfactory network in anosmic patients. Functional connectivity was also reduced in the noradrenergic network of patients with RBD. Discussion: Our results indicate the implication of the cholinergic network in PD patients with anosmia and a contribution of the noradrenergic network to olfactory dysfunction, only in patients with RBD.

ALS-associated RNA binding proteins converge on UNC13A transcription through regulation of REST
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Although multiple pathophysiological mechanisms have been identified, a unified molecular basis for ALS has remained elusive. The ALS-associated RNA binding protein (RBP) TDP-43 has previously been shown to stabilize UNC13A mRNA by preventing cryptic exon inclusion. We here show that three ALS-associated RBPs, MATR3, FUS, and hnRNPA1 regulate UNC13A expression by targeting the silencing transcription factor REST. These three RBPs bind to and downregulate REST mRNA and thereby promote UNC13A transcription. REST overexpression was detected not only in response to the loss of each of these three RBPs in cultured cells but also in motor neurons of individuals with familial or sporadic ALS. The functional convergence of four RBPs on the regulation of UNC13A, a gene essential for synaptic transmission, highlights a pivotal contribution of these proteins to maitainance of synaptic integrity. Our findings thus provide key insight into ALS pathogenesis and a basis for the development of new therapeutic agents.

Distinct optimization of motor control and learning: Self-paced motor learning achieves different motor patterns from overtrained
Self-paced movement, resulting from extensive training and optimization, serves as an ideal model for investigating internal objectives without external constraints within the sensorimotor system. Previous studies have shown that the self-paced movement is consistent within individuals but inconsistent across individuals, highlighting a robust, unique optimization in motor control. Although motor learning is similarly an optimization process, it is unknown whether the internal objectives are shared with motor control and learning, i.e., whether it replicates the motor patterns identified by self-paced motor control. As the optimality principles typically address redundancy, a human behavioral experiment was designed to equate movement distance for motor control and learning, comparing redundant motion parameters, movement velocity, and duration, through detailed analysis that accommodates their nonlinear interaction and significant inter-individual baseline differences. Participants, instructed to use their preferred velocities and duration, exhibited minimal intra-individual variability in motion parameters. Notably, visuomotor shift perturbations exclusively affected velocity, while changes in target distances affected both velocity and duration. These findings suggest that the sensorimotor system employs distinct optimization mechanisms for motor control and learning to resolve redundancy.

Decoding the transcriptomic signatures of psychological trauma in human cortex and amygdala
Psychological trauma has profound effects on brain function and precipitates psychiatric disorders in vulnerable individuals, however, the molecular mechanisms linking trauma with psychiatric risk remain incompletely understood. Using RNA-seq data postmortem brain tissue of a cohort of 304 donors (N=136 with trauma exposure), we investigated transcriptional signatures of trauma exposures in two cortical regions (dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex) and two amygdala regions (medial amygdala and basolateral amygdala) associated with stress processing and regulation. We focused on dissecting heterogeneity of traumatic experiences in these transcriptional signatures by investigating exposure to several trauma types (childhood, adulthood, complex, single acute, combat, and interpersonal traumas) and interactions with sex. Overall, amygdala regions were more vulnerable to childhood traumas, whereas cortical regions were more vulnerable to adulthood trauma (regardless of childhood experience). Using cell-type-specific expression imputation, we identified a strong transcriptional response of medial amygdala excitatory neurons to childhood trauma, which coincided with dysregulation observed in a human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons exposed to hydrocortisone. We resolved multiscale coexpression networks for each brain region and identified modules enriched in trauma signatures and whose connectivity was altered with trauma. Trauma-associated coexpression modules provide insight into coordinated functional dysregulation with different traumas and point to potential gene targets for further dissection. Together, these data provide a characterization of the long-lasting human encoding of traumatic experiences in corticolimbic regions of human brain.

Preemptive minocycline decreases allodynia and depressive-like behaviors in a peripheral neuropathy rat model: a preliminary study
Background and Objective: The neuroimmune system plays a critical role at all phases of chronic pain including at its onset. We therefore hypothesized that preemptive immunomodulation could decrease susceptibility and/or offer protection to pain. Materials and Methods: Six days before the spared nerve injury (SNI), Wistar Han rats were treated with either the immunomodulator minocycline (MIN) or vehicle (VEH). After that, half of the animals from each group switch treatments for additional 7 days, resulting in 4 groups: continuous treatment (MIN/MIN), pretreatment (MIN/VEH), early treatment (VEH/MIN) and the control (VEH/VEH). Mechanical allodynia was recorded using Von Frey test until 4 weeks after SNI where depressive-like behaviors of the animals were also assessed using sucrose preference test. Results: The continuous treatment provided sustained protection against mechanical allodynia, with rats in this group showing a significantly higher threshold to pain sensitivity compared to those in VEH/VEH. In contrast, pain relief effects were not observed with MIN/VEH and VEH/MIN. Additionally, animals in MIN/MIN, and VEH/MIN exhibited decreased anhedonic-like behavior at 30 days after SNI, relative to the control. Conclusions: The exposure to an anti-inflammatory drug circa the installation of a neuropathic lesion had a positive impact on allodynia and on anhedonic behavior for a relatively long period after treatment cessation. The results support the assertions that pain trajectories can be altered at pain early stages by targeting the neuroimmune system. This proof-of-concept has the potential to be broadened to other drugs and/or therapeutical schemes

Frequency-specific hemispheric bias in phase entrainment of neural oscillations in unilateral spatial neglect
Left unilateral spatial neglect (USN), typically caused by a right hemisphere lesion, impairs left-side stimulus perception. Attention influences perception via cortical oscillations, shown as phase shifts and power changes in electroencephalography (EEG). Given this relationship, USN may stem from hemispheric imbalance in synchronizing cortical oscillations internally and externally. We studied this using steady-state visual evoked potentials (SSVEPs) from flickering stimuli of various frequencies. Our study included USN and non-USN patients with a right hemisphere lesion, but no hemianopsia, as well as healthy controls. Importantly, we confirmed that the affected hemisphere's visual cortex in both patient groups responded to all flickering frequencies, ensuring a valid comparison. Comparing SSVEP power between the intact and affected hemispheres revealed no differences in non-USN patients. In USN patients, both hemispheres responded equally to most frequencies; however, SSVEP power was enhanced in the intact visual cortex with 9-Hz stimulation, resulting in a significant hemispheric bias. This bias was not caused by deficiencies in generating oscillations (we observed no significant differences in spontaneous pre-stimulus alpha oscillations) but rather by abnormal alpha-band synchronization with external inputs. Further analyses revealed increased phase-amplitude coupling between alpha phase and gamma amplitude in the intact hemisphere and elevated transfer entropy from the right visual cortex to the left frontal cortex in USN patients. These results reveal that USN involves complex alterations in neural synchronization stemming from imbalanced entrainment of oscillators to alpha-frequency stimuli, beyond merely local damage. This alpha-specific effect provides insights into frequency-specific synchronization in spatial attention, potentially guiding targeted therapies.

Enhanced Fear Extinction Through Infralimbic Perineuronal Net Digestion: The Modulatory Role of Adolescent Alcohol Exposure
Perineuronal nets (PNNs) are specialized components of the extracellular matrix that play a critical role in learning and memory. In a Pavlovian fear conditioning paradigm, degradation of PNNs affects the formation and storage of fear memories. This study examined the impact of adolescent intermittent ethanol (AIE) exposure by vapor inhalation on the expression of PNNs in the adult rat prelimbic (PrL) and infralimbic (IfL) subregions of the medial prefrontal cortex. Results indicated that following AIE, the total number of PNN positive cells in the PrL cortex increased in layer II/III but did not change in layer V. Conversely, in the IfL cortex, the number of PNN positive cells decreased in layer V, with no change in layer II/III. In addition, the intensity of PNN staining was significantly altered by AIE exposure, which narrowed the distribution of signal intensity, reducing the number of high and low intensity PNNs. Given these changes in PNNs, the next experiment assessed the effects of AIE and PNN digestion on extinction of a conditioned fear memory. In Air control rats, digestion of PNNs by bilateral infusion of Chondroitinase ABC (ChABC) into the IfL cortex enhanced fear extinction and reduced contextual fear renewal. In contrast, both fear extinction learning and contextual fear renewal remained unchanged following PNN digestion in AIE exposed rats. These results highlight the sensitivity of prefrontal PNNs to adolescent alcohol exposure and suggest that ChABC-induced plasticity is reduced in the IfL cortex following AIE exposure.

Endogenous neuronal DNA double-strand breaks are not sufficient to drive brain aging and neurodegeneration
Loss of genomic information due to the accumulation of somatic DNA damage has been implicated in aging and neurodegeneration. Somatic mutations in human neurons increase with age, but it is unclear whether this is a cause or a consequence of brain aging. Here, we clarify the role of endogenous, neuronal DNA double-strand breaks (DSBs) in brain aging and neurodegeneration by generating mice with post-developmental inactivation of the classical non-homologous end-joining (C-NHEJ) core factor Xrcc4 in forebrain neurons. Xrcc4 is critical for the ligation step of C-NHEJ and has no known function outside of DSB repair. We find that, unlike their wild-type counterparts, C-NHEJ-deficient neurons accumulate high levels of DSB foci with age, indicating that neurons undergo frequent DSBs that are typically efficiently repaired by C-NHEJ across their lifespan. Genome-wide mapping reveals that endogenous neuronal DSBs preferentially occur in promoter regions and other genic features. Analysis of 3-D genome organization shows intra-chromosomal clustering and loop extrusion of neuronal DSB regions. Strikingly, however, DSB accumulation caused by loss of C-NHEJ induces only minor epigenetic alterations and does not significantly affect gene expression, 3-D genome organization, or mutational outcomes at neuronal DSBs. Despite extensive aging-associated accumulation of neuronal DSBs, mice with neuronal Xrcc4 inactivation do not show neurodegeneration, neuroinflammation, reduced lifespan, or impaired memory and learning behavior. We conclude that the formation of spontaneous neuronal DSBs caused by normal cellular processes is insufficient to cause brain aging and neurodegeneration, even in the absence of C-NHEJ, the principal neuronal DSB repair pathway.

The Neural Oscillatory Basis of Perspective-Taking in Autistic and Non-Autistic Adolescents using MEG
Taking another's perspective is a high-level mental skill underlying many aspects of social cognition. Perspective-taking is usually an embodied egocentric process whereby people mentally rotate themselves away from their physical location into the other's orientation. This is accompanied by increased theta-band (3-7Hz) brain oscillations within a widespread fronto-parietal cortical network including the temporoparietal junction. Individuals with autism spectrum disorder (ASD) have been reported to experience challenges with high-level perspective-taking, particularly when adopting embodied strategies. To investigate the potential neurophysiological basis of these autism-related individual differences, we used magnetoencephalography in combination with a well-replicated perspective-taking paradigm in a group of 18 autistic and 17 age-matched non-autistic adolescents. Findings revealed that increasing the angle between self and other perspective resulted in prolonged reaction times for the autistic group during perspective-taking. This was accompanied by reduced theta power across a wide network of regions typically active during social cognitive tasks. On the other hand, the autistic group showed greater alpha power decreases in visual cortex compared with the non-autistic group across all perspective-taking conditions. These divergent theta and alpha power effects, coupled with steeper response time slopes, suggest that autistic individuals may rely more on alternative cognitive strategies, such as mental object rotation, rather than an egocentric embodied approach. Finally, no group differences were found when participants were asked to track, rather than take, another's viewpoint, suggesting that autism-related individual differences are specific to high-level perspective-taking.

Neural Correlates of Psychedelic, Sleep, and Sedated States Support Global Theories of Consciousness
Understanding neural mechanisms of consciousness remains a challenging question in neuroscience. A central debate in the field concerns whether consciousness arises from global interactions that involve multiple brain regions or focal neural activity, such as in sensory cortex. Additionally, global theories diverge between the Global Neuronal Workspace (GNW) hypothesis, which emphasizes frontal and parietal areas, and the Integrated Information Theory (IIT), which focuses on information integration within posterior cortical regions. To disentangle the global vs. local and frontoparietal vs. posterior dilemmas, we measured global functional connectivity and local neural synchrony with functional magnetic resonance imaging (fMRI) data across a spectrum of conscious states in humans induced by psychedelics, sleep, and deep sedation. We found that psychedelic states are associated with increased global functional connectivity and decreased local neural synchrony. In contrast, non-REM sleep and deep sedation displayed the opposite pattern, suggesting that consciousness arises from global brain network interactions rather than localized activity. This mirror-image pattern between enhanced and diminished states was observed in both anterior-posterior (A-P) and posterior-posterior (P-P) brain regions but not within the anterior part of the brain alone. Moreover, anterior transmodal regions played a key role in A-P connectivity, while both posterior transmodal and posterior unimodal regions were critical for P-P connectivity. Overall, these findings provide empirical evidence supporting global theories of consciousness in relation to varying states of consciousness. They also bridge the gap between two prominent theories, GNW and IIT, by demonstrating how different theories can converge on shared neuronal mechanisms.

Spontaneous alpha-band lateralization extends persistence of visual information in iconic memory by modulating cortical excitability.
Pre-stimulus alpha oscillations in the visual cortex modulate neuronal excitability, influencing sensory processing and decision-making. While this relationship has been demonstrated mostly in detection tasks with low-visibility stimuli, interpretations of such effects can be ambiguous due to biases, making it difficult to clearly distinguish between perception-related and decision-related effects. In this study, we investigated how spontaneous fluctuations in pre-stimulus alpha power affect iconic memory, a high-capacity, ultra-short visual memory store. Data from 49 healthy adults (34 female and 15 male) was analyzed. We employed a partial report task, where a brief display of six stimuli was followed by a report cue indicating the target stimulus. In this paradigm, accuracy at short stimulus-cue onset asynchronies (SOAs) is typically high, reflecting the initial availability of sensory information, but it rapidly declines at intermediate SOAs due to the decay of the iconic memory trace, stabilizing at a low asymptote at long SOAs, representing the limited capacity of short-term memory. Crucially, performance in this task is constrained by the temporal persistence of sensory information, not by low visibility or response bias. We found that strong pre-stimulus alpha power enhanced performance by amplifying initial stimulus availability without affecting the speed of iconic decay. This effect was driven predominantly by stronger pre-stimulus alpha power in the hemisphere ipsilateral to the to-be-reported target, likely suppressing neuronal excitability of neurons coding irrelevant stimuli. Our findings underscore the role of alpha oscillations in modulating neuronal excitability and visual perception, independent of decision-making strategies implicated in prior studies.

The computational bottleneck of basal ganglia output (and what to do about it)
What the basal ganglia do is an oft-asked question; answers range from the selection of actions to the specification of movement to the estimation of time. Here I argue that how the basal ganglia do what they do is a less-asked but equally important question. I show that the output regions of the basal ganglia create a stringent computational bottleneck, both structurally, because they have far fewer neurons than do their target regions, and dynamically, because of their tonic, inhibitory output. My proposed solution to this bottleneck is that the activity of an output neuron is setting the weight of a basis function, a function defined by that neuron's synaptic contacts. I illustrate how this may work in practice, allowing basal ganglia output to shift cortical dynamics and control eye movements via the superior colliculus. This solution can account for troubling issues in our understanding of the basal ganglia: why we see output neurons increasing their activity during behaviour, rather than only decreasing as predicted by theories based on disinhibition, and why the output of the basal ganglia seems to have so many codes squashed into such a tiny region of the brain.

α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease
-Synuclein (-syn) strains can serve as discriminators between Parkinsons disease (PD) from other -synucleinopathies. The relationship between -syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of -syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct -syn strains in PD patients correlating to their level of cognitive impairment. This study presents evidence that individuals with PD have different -syn strains that change in accordance with their cognitive status and highlights the potential of -syn strain dynamics to guide future diagnosis, management, and stratification of PD patients.

One Sentence SummaryDistinct features of -syn strains change with cognitive decline in Parkinsons disease.

Psilocybin Reduces Grooming in the SAPAP3 Knockout Mouse Model of Compulsive Behaviour
Psilocybin is a serotonergic psychedelic compound which shows promise for treating compulsive behaviours. This is particularly pertinent as compulsive disorders require research into new pharmacological treatment options as the current frontline treatments such as selective serotonin reuptake inhibitors, require chronic administration, have significant side effects, and leave almost half of the clinical population refractory to treatment.

In this study, we investigated psilocybin administration in male and female SAPAP3 knockout (KO) mice, a well-validated mouse model of obsessive compulsive and related disorders. We assessed the effects of acute psilocybin (1 mg/kg, intraperitoneal) administration on head twitch and locomotor behaviour as well as anxiety- and compulsive-like behaviours at multiple time-points (1-, 3- and 8-days post-injection).

While psilocybin did not have any effect on anxiety-like behaviours, we revealed for the first time that acute psilocybin administration led to enduring reductions in compulsive behaviour in male SAPAP3 KO mice and reduced grooming behaviour in female WT and SAPAP3 KO mice. We also found that psilocybin increased locomotion in wild-type littermates but not in SAPAP3 KO mice, suggesting in vivo serotonergic dysfunctions in KO animals. On the other hand, the typical head-twitch response following acute psilocybin (confirming its hallucinogenic-like effect at this dose) was observed in both genotypes.

Our novel findings suggest that acute psilocybin may have potential to reduce compulsive-like behaviours (up to 1 week after a single injection). Our study can inform future research directions as well as supporting the utility of psilocybin as a novel treatment option for compulsive disorders.

The language network ages well: Preserved selectivity, lateralization, and within-network functional synchronization in older brains
Healthy aging is associated with structural and functional brain changes. However, cognitive abilities differ from one another in how they change with age: whereas executive functions, like working memory, show age-related decline, aspects of linguistic processing remain relatively preserved (Hartshorne et al., 2015). This heterogeneity of the cognitive-behavioral landscape in aging predicts differences among brain networks in whether and how they should change with age. To evaluate this prediction, we used individual-subject fMRI analyses (precision fMRI) to examine the language-selective network (Fedorenko et al., 2024) and the Multiple Demand (MD) network, which supports executive functions (Duncan et al., 2020), in older adults (n=77) relative to young controls (n=470). In line with past claims, relative to young adults, the MD network of older adults shows weaker and less spatially extensive activations during an executive function task and reduced within-network functional synchronization. However, in stark contrast to the MD network, we find remarkable preservation of the language network in older adults. Their language network responds to language as strongly and selectively as in younger adults, and is similarly lateralized and internally synchronized. In other words, the language network of older adults looks indistinguishable from that of younger adults. Our findings align with behavioral preservation of language skills in aging and suggest that some networks remain young-like, at least on standard measures of function and connectivity.

Significance StatementAll organs, including brains, change as we age. However, the brain is not a uniform structure: it comprises multiple distinct networks, each supporting a different aspect of perception, motor control, and cognition. We examine two cognitive brain networks using fMRI and--across two independent cohorts--find a clear dissociation: the so-called Multiple Demand network, which supports executive functions (e.g., working memory), shows clear age-related decline; however, the language-selective network, which supports comprehension and production, remains young-like on all measures of network function and connectivity, in line with the preservation of linguistic skills in older adults. These findings challenge the notion of generalized brain aging and highlight the importance of dissociable components in the brain and mind.

Variable Presence of an Evolutionarily New Brain Structure is Related to Trait Impulsivity
BackgroundImpulsivity is a multidimensional construct reflecting poor constraint over ones behaviors. Clinical psychology research identifies separable impulsivity dimensions that are each unique transdiagnostic indicators for psychopathology. Yet, despite this apparent clinical importance, the shared and unique neuroanatomical correlates of these factors remain largely unknown. Concomitantly, neuroimaging research identifies variably present human brain structures implicated in cognition and disorder: the folds (sulci) of the cerebral cortex located in the latest developing and most evolutionarily expanded hominoid-specific association cortices.

MethodsWe tethered these two fields to test whether variability in one such structure in anterior cingulate cortex (ACC)--the paracingulate sulcus (PCGS)--was related to individual differences in trait impulsivity. 120 adult participants with internalizing or externalizing psychopathology completed a magnetic resonance imaging scan and the Three-Factor Impulsivity Index. Using precision imaging techniques, we manually identified the PCGS, when present, and acquired quantitative folding metrics (PCGS length and ACC local gyrification index).

ResultsNeuroanatomical-behavioral analyses revealed that participants with leftward or symmetrical PCGS patterns had greater severity of Lack of Follow Through (LFT)--which captures inattention and lack of perseverance--than those with rightward asymmetry. Neuroanatomical-functional analyses identified that the PCGS co-localized with a focal locus found in a neuroimaging meta-analysis on a feature underlying LFT. Both quantitative folding metrics did not relate to any impulsivity dimension.

ConclusionsThis study advances understanding of the neuroanatomical correlates of impulsivity and establishes the notion that the topographical organization of distinct, hominoid-specific cortical expanses underlie separable impulsivity dimensions with robust, transdiagnostic implications for psychopathology.

Equivalence between representational similarity analysis, centered kernel alignment, and canonical correlations analysis
Centered kernel alignment (CKA) and representational similarity analysis (RSA) of dissimilarity matrices are two popular methods for comparing neural systems in terms of representational geometry. Although they follow a conceptually similar approach, typical implementations of CKA and RSA tend to result in numerically different outcomes. Here, I show that these two approaches are largely equivalent once one incorporates a mean-centering step into RSA. This equivalence holds for both linear and nonlinear variants of these methods. These connections are simple to derive, but appear to have been thus far overlooked in the context of comparing neural representations. By unifying these measures, this paper hopes to simplify a complex and fragmented literature on this subject.

Enriched environment requires remodeling of hippocampal perineuronal nets to trigger memory improvement in Alzheimer's mouse model
Alzheimers disease (AD) is a major neurodegenerative disorder influenced by both genetic and environmental factors. Engaging in mentally stimulating activities is believed to reduce cognitive decline by establishing a cognitive reserve, though the underlying neurobiological mechanisms remain elusive. In this study, we explore the role of parvalbumin-expressing inhibitory neurons (PV) and their associated perineuronal nets (PNN) in cognitive deficits observed in AD. Using the Tg2576 mouse model, we demonstrate that 10 days of exposure to an enriched environment (EE) significantly restores spatial and social memory, accompanied by an increase in PV and PV/PNN cell populations in the hippocampus. Notably, preventing PV/PNN remodeling in the CA1 region during EE abolishes the spatial memory improvements, whereas localized neuregulin-1 (NRG1) injections induce PV/PNN remodeling and restore memory function. These findings suggest that hippocampal PV/PNN remodeling is essential for the cognitive benefits of EE in AD, highlighting this neuronal population as a critical substrate for cognitive reserve. This study provides new insights into the mechanisms by which environmental factors may mitigate cognitive decline in AD, offering potential avenues for therapeutic interventions.

Highlights10-day environmental enrichment increases PV+ and PV+/PNN+ in the hippocampus of Tg2576 mouse model of AD

Blocking PV/PNN remodeling during EE prevents memory recovery in Tg2576 mice

Enhancing PV/PNN remodeling with NRG1 leads to restored memory in Tg2576 mice

PV/PNN remodeling in area CA1 affects spatial memory, while in CA2, it impacts social memory

Impulsive adolescents exhibit inefficient processing and a low decision threshold when decoding facial expressions of emotions
Background: Borderline personality disorder (BPD) is a debilitating psychiatric illness whose symptoms frequently emerge during adolescence. Initial studies in adults suggest that the interpersonal difficulties common in BPD may emerge from disrupted processing of social and emotional stimuli. Less is known about these processes in adolescents with BPD symptoms, despite substantial changes in socioemotional processing during this developmental period. Methods: 86 adolescents and young adults with and without BPD symptoms completed an emotional interference task involving the identification of a facial emotion expression in the presence of a conflict or congruent emotion word. We used hierarchical drift diffusion modeling to index speed of processing and decision boundary. Using Bayesian multilevel regression, we characterized age-related differences in facial emotion processing. We then examined whether BPD symptom dimensions were associated with facial emotion processing on this task. To determine the specificity of our effects, we analyzed behavioral data from a corresponding nonemotional interference task. Results: Impulsivity, but not negative affectivity or interpersonal dysfunction, predicted inefficient processing when presented with conflicting negative emotional stimuli. Across both tasks, impulsivity in adolescents was further associated with a lower decision boundary. Impulsive adolescents were especially likely to make fast, but inaccurate decisions about another person's emotional state. Conclusion: Impulsive adolescents with BPD symptoms are prone to making errors when appraising facial expressions of emotions, which may potentiate or worsen interpersonal conflicts. Our findings highlight the role of lower-level social cognitive processes in interpersonal difficulties among vulnerable youth during a sensitive developmental window.