bioRxiv Subject Collection: Neuroscience's Journal

Contributions of genetic variation in astrocytes to cell and molecular mechanisms of risk and resilience to late onset Alzheimer's disease
Reactive astrocytes are associated with Alzheimers disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill-defined. Here we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from forty-four individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag-mass spectrometry. We demonstrate the utility of this resource in examining gene- and pathway-level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC-astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC-derived astrocytes from AD individuals are concordantly dysregulated in AD brain tissue. This includes increased prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components and reduced proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC-derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins. This study establishes an experimental system that integrates genetic information with a heterogeneous set of iPSCs to identify genetic contributions to molecular pathways affecting AD risk and resilience.

The Computational Auditory Signal Processing and Perception Model (CASP): A Revised Version
This study introduces a revised version of the computational auditory signal processing and perception (CASP) model (Jepsen et al., 2008), which has undergone substantial updates and refinements aimed at enhancing its accuracy and usability across various applications. A primary motivation for the revision was the integration of a more realistic non-linear inner hair cell (IHC) model to address the limitations of its more simplistic predecessor. Demonstrating backwards compatibility, the revised model exhibited similar predictive power to previous CASP implementations across conditions of intensity discrimination, simultaneous and forward masking, and modulation detection, effectively accounting for data from normal-hearing listeners. Additionally, improved decision-making strategies and a streamlined model configuration further enhance the models usability and accessibility. Overall, the revised CASP offers a more accurate and intuitive framework for simulating auditory processing and perception across diverse conditions and tasks. The revised model may be a useful tool in studying the influence of the ears nonlinear response properties on internal representations, particularly concerning the effects of sensorineural hearing loss on auditory perception.

Structural disconnections caused by white matter hyperintensities in post-stroke spatial neglect
White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, affect a wide range of cognitive dysfunctions, including spatial neglect. The latter is a disorder of spatial attention and exploration typically after right hemisphere brain damage. To explore the impact of WMH on neglect-related structural disconnections, the present study investigated the indirectly quantified structural disconnectome induced by either stroke lesion alone, WMH alone, or their combination. Further, we compared different measures of structural disconnections - voxel-wise, pairwise, tract-wise, and parcel-wise - to identify neural correlates and predict acute neglect severity. We observed that WMH-derived disconnections alone were not associated to neglect behavior. However, when combined with disconnections derived from individual stroke lesions, pre-stroke WMH contributed to post-stroke neglect severity by affecting right frontal and subcortical substrates, like the middle frontal gyrus, basal ganglia, thalamus, and the fronto-pontine tract. Predictive modeling demonstrated that voxel-wise disconnection data outperformed other measures of structural disconnection, explaining 42% of the total variance. Compared to using stroke lesion anatomy, prediction performance can be improved by either estimating stroke-based structural disconnections or delineating the combined anatomy of stroke lesion and WMH. We conclude that pre-stroke alterations in the white matter microstructure due to WMH contribute to post-stroke deficits in spatial attention, likely by impairing the integrity of human attention networks.

Dynorphin modulates motivation through a pallido-amygdala cholinergic circuit
The endogenous opioid peptide dynorphin and its receptor {kappa}-opioid receptor (KOR) have been implicated in divergent behaviors, but the underlying mechanisms remain elusive. Here we show that dynorphin released from nucleus accumbens dynorphinergic neurons exerts powerful modulation over a ventral pallidum (VP) disinhibitory circuit, thereby controlling cholinergic transmission to the amygdala and motivational drive in mice. On one hand, dynorphin acts postsynaptically via KORs on local GABAergic neurons in the VP to promote disinhibition of cholinergic neurons, which release acetylcholine into the amygdala to invigorate reward-seeking behaviors. On the other hand, dynorphin also acts presynaptically via KORs on dynorphinergic terminals to limit its own release. Such autoinhibition keeps cholinergic neurons from prolonged activation and release of acetylcholine, and prevents perseverant reward seeking. Our study reveals how dynorphin exquisitely modulate motivation through cholinergic system, and provides an explanation for why these neuromodulators are involved in motivational disorders, including depression and addiction.

Coding of egocentric distance in the macaque ventral intraparietal area
The encoding of three-dimensional visual spatial information is of ultimate importance in everyday life, in particular for successful navigation toward targets or threat avoidance. Eye-movements challenge this spatial encoding: 2-3 times per second, they shift the image of the outside world across the retina. The macaque ventral intraparietal area (VIP) stands out from other areas of the dorsal where pathway of the primate visual cortical system: many neurons encode visual information irrespective of horizontal and vertical eye position. But does this gaze invariance of spatial encoding at the single neuron level also apply to egocentric distance? Here, concurrent with recordings from area VIP, monkeys fixated a central target at one of three distances (vergence), while a visual stimulus was shown at one of seven distances (disparity). Most neurons activity was modulated independently by both disparity and eye vergence, demonstrating a different type of invariance than for visual directions. By using population activity, we were able to decode egocentric distance of a stimulus which demonstrates that egocentric distances are nonetheless represented within the neuronal population. Our results provide further strong evidence for a role of area VIP in 3D space encoding.

Motor sequence learning-induced corticospinal plasticity is biased towards sensorimotor mu rhythm peak phases
Motor cortical (M1) transcranial magnetic stimulation (TMS) increases corticospinal output and improves motor learning when delivered during sensorimotor mu rhythm trough but not peak phases, suggesting that mechanisms supporting motor learning may be most active during mu trough phases. If so, learning-related corticospinal plasticity should be most evident during mu trough phases. Healthy adults were assigned to either a sequence or control group. Participants in the sequence group practiced the implicit serial reaction time task (SRTT), which contained an embedded, repeating 12-item sequence. Participants in the control group practiced a version of the SRTT that contained no sequence. We measured mu phase-independent and phase-dependent MEP amplitudes using EEG-informed single-pulse TMS before, immediately, and 30 minutes after the SRTT in both groups. All participants performed a retention test one hour after SRTT acquisition. In both groups, mu phase-independent MEP amplitudes increased following SRTT acquisition, but the pattern of mu phase-dependent MEP amplitude increases after SRTT acquisition differed between groups. MEP amplitude changes from baseline to 30 minutes after SRTT acquisition more strongly differed across phases in the control relative to the sequence group, with the control group showing smaller increases in peak- than trough-specific MEPs. Contrary to our original hypothesis, results revealed that sequence learning recruits peak- rather than trough-specific neurophysiological mechanisms. Overall, these findings suggest that mu peak phases may provide protected time windows for motor memory consolidation and demonstrate the presence of a mu phase-dependent motor learning mechanism in the human brain.

Significance statementRecent work suggests that the neurophysiological mechanisms supporting motor learning may be most active during sensorimotor mu rhythm trough phases. Here, we evaluated this possibility by measuring mu phase-dependent corticospinal plasticity induced by motor sequence learning. Results provide first evidence that motor sequence learning produced corticospinal plasticity that was more pronounced during mu peak than trough phases, demonstrating the presence of a phase-dependent learning mechanism within the human motor system.

A distinct circuit for biasing visual perceptual decisions and modulating superior colliculus activity through the mouse posterior striatum
The basal ganglia play a key role in visual perceptual decisions. Despite being the primary target in the basal ganglia for inputs from the visual cortex, the posterior striatums (PS) involvement in visual perceptual behavior remains unknown in rodents. We reveal that the PS direct pathway is largely segregated from the dorsomedial striatum (DMS) direct pathway, the other major striatal target for visual cortex. We investigated the role of the PS in visual perceptual decisions by optogenetically stimulating striatal medium spiny neurons in the direct pathway (D1-MSNs) of mice performing a visual change-detection task. PS D1-MSN activation robustly biased visual decisions in a manner dependent on visual context, timing, and reward expectation. We examined the effects of PS and DMS direct pathway activation on neuronal activity in the superior colliculus (SC), a major output target of the basal ganglia. Activation of either direct pathway rapidly modulated SC neurons, but mostly targeted different SC neurons and had opposite effects. These results demonstrate that the PS in rodents provides an important route for controlling visual decisions, in parallel with the better known DMS, but with distinct anatomical and functional properties.

A subset of brain regions within adult functional connectivity networks demonstrate high reliability across early development
The human cerebral cortex contains groups of areas that support sensory, motor, cognitive, and affective functions, often categorized as functional networks. These areas show stronger internal and weaker external functional connectivity (FC) and exhibit similar FC profiles within rather than between networks. Previous studies have demonstrated the development of these networks from nascent forms present before birth to their mature, adult-like topography in childhood. However, analyses often still use definitions based on adult functional networks. We aim to assess how this might lead to the misidentification of functional networks and explore potential consequences and solutions.

Our findings suggest that even though adult networks provide only a marginally better than-chance description of the infant FC organization, misidentification was largely driven by specific areas. By restricting functional networks to areas showing adult-like network clustering, we observed consistent within-network FC both within and across scans and throughout development. Additionally, these areas were spatially closer to locations with low variability in network identity among adults. Our analysis aids in understanding the potential consequences of using adult networks "as is" and provides guidance for future research on selecting and utilizing functional network models based on the research question and scenario.

HighlightsO_LISpecialized functional networks in the human cerebral cortex, evident in resting-state fMRI, support sensory, motor, cognitive, and affective functions and evolve throughout the lifespan.
C_LIO_LIExisting studies have focused on age-specific networks for infants, but less on to what extent adult networks can describe infant functional connectivity (FC).
C_LIO_LIAnalysis revealed a subset of areas in infants showing adult-like network organization, with within-network FC exhibiting less variation across age and higher reliability across scans.
C_LIO_LIThese areas are posited near locations with low variability in functional network identity in adults, suggestive of the relationship between developmental sequence and interindividual variability in functional network organization.
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Feature specific neuronal oscillations in cortical layers
The particular role of cortical oscillations has been a long-debated topic that resulted in a variety of theoretical frameworks. Oscillatory activity in the band has been associated with sensory processing, attention as well as other cognitive functions, while{gamma} band oscillations is thought to be related to stimulus feature processing. Current theoretical frameworks rely on the separation of the cortical architecture into layers. Recently, methodological advancements have allowed to test layer specific frameworks on the role of oscillations in cortical computations in healthy human participants. Using EEG-fMRI, we have investigated for the first time both, stimulus feature specificity (line orientation) and the relationship between the laminar BOLD activity and and{gamma} band oscillations. We find{gamma} oscillations to be positively correlated with feature-specific signals in superficial layers as predicted by the literature, but we found a deep layer contribution as well. Furthermore we found a layer (and frequency) dissociation within the band for general, feature unspecific, processes and a feature related process. The power of the -band correlated negatively with feature unspecific neural activity in all cortical layers. We further found that high frequency oscillations were specifically related to stimulus feature specific BOLD signal in deep and superficial layers. More interestingly, we also observed a general modulation effect for negative BOLD signal deflections in line with the inhibitory role of during visual attention in superficial layers. Those findings support the association of{gamma} band oscillations with visual feature processing and further point towards the involvement of multiple oscillations in more general and feature related processes.

Overwriting an instinct: visual cortex instructs learning to suppress fear responses
Fast instinctive responses to environmental stimuli can be crucial for survival, but are not always optimal. Based on prior experience, animals can thus adapt their behavior and suppress instinctive reactions. However, the neural pathways mediating such ethologically relevant forms of learning remain unclear. We show that posterolateral higher visual areas (plHVAs) are crucial for learning to suppress escapes from innate visual threats through a top-down pathway involving the ventrolateral geniculate nucleus (vLGN). plHVAs are no longer necessary after learning: instead, the learnt behavior relies on plasticity within vLGN populations that exert inhibitory control over fear responses. vLGN neurons receiving input from plHVAs enhance their responses to visual threat stimuli during learning through endocannabinoid-mediated long-term suppression of their inhibitory inputs. We thus reveal the detailed circuit, cellular and synaptic mechanisms underlying experience-dependent suppression of fear responses through a novel corticofugal pathway.

Self-association enhances early attentional selection through automatic prioritization of socially salient signals
Efficiently processing self-related information is critical for cognition, yet the earliest mechanisms enabling this self-prioritization remain unclear. By combining a temporal order judgement task with computational modelling based on the Theory of Visual Attention (TVA), we show how mere, arbitrary associations with the self can fundamentally alter attentional selection of sensory information into short-term memory/awareness, by enhancing the attentional weights and processing capacity devoted to encoding socially loaded information. This self-prioritization in attentional selection occurs automatically at early perceptual stages but reduces when active social decoding is required. Importantly, the processing benefits obtained from attentional selection via self-relatedness and via physical salience were additive, suggesting that social and perceptual salience captured attention via separate mechanisms. Furthermore, intra-individual correlations revealed an obligatory self-prioritization effect, whereby self-relatedness overpowered the contribution of perceptual salience in guiding attentional selection. Together, our findings provide evidence for the influence of self-relatedness during earlier, automatic stages of attentional section at the gateway to perception, distinct from later post-attentive processing stages.

JM-20 administration to animals with lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine, partially reverses motor damage and oxidative stress
Previous studies have shown that JM-20, a new chemical hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. Also, we demonstrated that JM-20 blocks the formation of toxic alpha-synuclein aggregated species and aminochrome cytotoxicity. The present study sought to determine the neuroprotective property of JM-20 in animals with a partial lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine (6-OHDA). For in vivo studies, adult male Wistar rats were lesioned in the right substantia nigra pars compacta (SNpc) with 6-OHDA administration. Fifteen days after surgery, the animals asymmetry levels were assessed. Those with asymmetry values higher than 50% were divided into two groups: animals that did not receive any treatment and those that were administered with JM-20 (40 mg/kg, intragastric via gavage) for 27 days. Every seven days, the asymmetry values of the animals were analyzed until day 42 after the surgery. At the end of the experiment, the animals were euthanized and the SNpc and striatum were taken out for the analysis of oxidative stress. Our results reveal a behavioral function progressively recovered in the JM-20-treated animals, diminishing the percentage of motor asymmetry. Also, it improves some oxidative stress markers in the SNpc and the striatum of these animals. Our study provides the preclinical evidence to support the long-term neuroprotective potential of JM-20 in 6-OHDA hemiparkinson rat model, pointing out to its possible use as a disease-modifying agent in PD.

Aging amplifies sex differences in low alpha and low beta EEG oscillations
Biological sex profoundly shapes brain function, yet its precise influence on neural oscillations was poorly understood. Despite decades of research, studies investigating sex-based variations in electroencephalographic (EEG) signals have yielded inconsistent findings that obstructs what may be a potentially crucial source of inter-individual variability in brain function. To address this, we analyzed five publicly available resting-state datasets, comprising EEG data (n=445) and iEEG data (n=103). Our results revealed striking age-dependent sex differences: older adults (30-80 years) exhibited robust sex differences, with males showing heightened low alpha (8-9 Hz) activity in temporal regions and attenuated low beta (16-20 Hz) oscillations in parietal-occipital areas compared to females. Intriguingly, these sex-specific patterns were absent in younger adults (20-30 years), suggesting a complex interplay between sex and aging in shaping brain dynamics. Furthermore, we identified consistent sex-related activity in the precentral gyrus with the results of scalp EEG, potentially driving the observed scalp EEG differences. This multi-level analysis allowed us to bridge the gap between cortical and scalp- level observations, providing a more comprehensive picture of sex-related neural dynamics. To further investigate the functional implications of these oscillatory differences, we conducted correlation analyses to uncover significant associations between sex-specific oscillatory patterns and several lifestyle factors (behavioral and anthropometric measures) in older adults. This comprehensive investigation demonstrates the complex interplay between sex, age, and neural oscillations, revealing the variability in brain dynamics. And our findings highlight the importance of careful demographic consideration in EEG research design to ensure fairness in capturing the full spectrum of neurophysiological diversity.

Significance statementThe influence of biological sex and age on neural oscillations had been a long- standing, unresolved question in EEG research, largely unaddressed due to limited sample sizes and simplistic demographic matching. Our study leverages large-scale, open datasets to tackle this issue, analyzing hundreds of participants across five datasets. Our findings demonstrate substantial sex- based differences in even resting-state EEG baselines, particularly in low alpha and low beta bands, uncovering a significant source of variability in neural activity. By connecting these sex and age-related variations to potential neural circuit mechanisms and lifestyle factors, our findings highlight the importance of careful demographic consideration in EEG research design in EEG experimental design to accurately capture the rich spectrum of neurophysiological variability across the lifespan.

Impact of aging on the GABAB receptor-mediated connectome
GABA B receptors (GABABRs) are heterodimeric seven-transmembrane receptors that interact with a range of proteins and form large protein complexes on cholesterol-rich membrane microdomains. As the brain ages, membrane cholesterol levels exhibit alterations, although it remains unclear how these changes impact protein-protein interactions and downstream signaling. Herein, we studied the structural bases for the interaction between GABABR and the KCC2 transporter, including their protein expression and distribution, and we compared data between young and aged rat cerebella. Also, we analyzed lipid profiles for both groups, and we used molecular dynamics simulations on three plasma membrane systems with different cholesterol concentrations, to further explore the GABABR-transporter interaction. Based on our results, we report that a significant decrease in GABAB2 subunit expression occurs in the aged rat cerebella. After performing a comparative co-immunoprecipitation analysis, we confirm that GABABR and KCC2 form a protein complex in adult and aged rat cerebella, although their interaction levels are reduced substantially as the cerebellum ages. On the other hand, our lipid analyses reveal a significant increase in cholesterol and sphingomyelin levels of the aged cerebella. Finally, we used the Martini coarse-grained model to conduct molecular dynamics simulations, from which we observed that membrane cholesterol concentrations can dictate whether the GABABR tail domains physically establish G protein-independent contacts with a transporter, and the timing when those associations eventually occur. Taken together, our findings illustrate how age-related alterations in membrane cholesterol levels affect protein-protein interactions, and how they could play a crucial role in regulating GABABRs interactome-mediated signaling.

Significance StatementThis study elucidates age-related changes in cerebellar GABAB receptors (GABABRs), KCC2, and plasma membrane lipids, shedding light on mechanisms underlying neurological decline. Molecular dynamics simulations reveal how membrane lipids influence protein-protein interactions, offering insights into age-related neurodegeneration. The findings underscore the broader impact of cerebellar aging on motor functions, cognition, and emotional processing in the elderly. By elucidating plasma membrane regulation and GABAergic dynamics, this research lays the groundwork for understanding aging-related neurological disorders and inspires further investigation into therapeutic interventions.

Characterization of Social and Repetitive Behaviors of Mllt11/Af1q/TcF7c Conditional Knockout Mice
Mllt11 (myeloid/lymphoid or mixed-lineage leukemia translocated to chromosome 11; also known as Af1q/TcF7c) has been identified as a novel regulator of neural development, playing a role in the migration and outgrowth of cortical projection neurons. We previously reported that the conditional inactivation of the Mllt11 gene in the mouse superficial cortex resulted in reduced connectivity of the corpus callosum and white fiber tracts, resulting in reduced cortical thickness. However, the behavioral consequences of Mllt11 loss are unknown. Callosal abnormalities are thought to be present in 3-5% of all neurodevelopmental disorders and reduced corpus callosum volume correlates with core symptoms of autism spectrum disorder (ASD) in humans. Cortical thickness dysregulation is likewise shared among various neurodevelopmental disorders including ASD. We therefore investigated the behavioral consequences of conditional knockout of Mllt11 in upper cortical layer 2/3 projection neurons using transgenic Cux2iresCre mice. Utilizing tasks designed to reflect core ASD symptoms, we examined the behaviors of both male and female conditional knockout animals. These tests included olfaction habituation/dishabituation, three-chambered social approach, marble burying, and nestlet shredding. We found sex-dependent disruptions in social preference, and nestlet shredding in animals lacking Mllt11, with the female mice presenting with more disruptions than the males. Understanding the behavioral phenotype associated with genes of interest specifically in the context of sex differences is crucial to individualized treatment for neurodevelopmental disorders.

Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates the expression of genes associated with anxiolytic-like behavior
We previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents stress-mediated reductions in sociability. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability and/or serve as novel, preclinical treatments for social anxiety. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and promotes social anxiety-like behavior in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used as novel anxiolytics. S1PR3 might be an important hub gene for anxiolytic effects as it reduces inflammatory processes caused by stress and increases transcripts linked to anxiolytic neurotransmission.

HighlightsO_LIThe Sphingosine-1-phosphate receptor 3 (S1PR3) agonist CYM5541 promotes sociability
C_LIO_LIThe S1PR3 antagonist CAY10444 reduces sociability and promotes anxiety-like behavior in females
C_LIO_LICAY10444 increases neuronal activity markers in the amygdala
C_LIO_LIPharmacological activation of S1PR3 regulates the expression of genes in the prefrontal cortex that control a wide range of biological processes, including increasing GABAergic neurotransmission and reducing inflammatory processes
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Social Isolation During Adolescence Differentially Affects Spatial Learning in Adult Male and Female Mice
Social isolation is a risk factor for cognitive impairment. Adolescents may be particularly vulnerable to these effects, because they are in a critical period of development marked by significant physical, hormonal, and social changes. However, it is unclear if the effects of social isolation on learning and memory are similar in both sexes or if they persist into adulthood after a period of recovery. We socially isolated male and female 129Sv/Ev mice throughout adolescence (post-natal days 29-56), provided a 2-week re-socialization recovery period, and then tested spatial learning and cognitive flexibility in the active place avoidance task. After behavioral testing, mice were injected with 5-bromo-2-deoxyuridine (BrdU) so that lasting effects of social isolation on cell proliferation in the dentate gyrus could be examined. We found that in males, isolation led to a modest impairment in the rate of initial spatial learning, whereas in females, initial learning was unaffected. However, when the location of the shock zone was switched during the conflict variant of the task, cognitive flexibility was impaired in females only. Similarly, social isolation reduced cell proliferation in the ventral dentate gyrus only in females. Together, these findings indicate that social isolation during adolescence differentially impairs spatial processing in males and females, with effects that persist into adulthood.

Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease
One of the unifying pathological hallmarks of Parkinsons disease (PD) and dementia with Lewy bodies (DLB) is the presence of misfolded, aggregated, and often phosphorylated forms of the protein -synuclein in neurons. -Synuclein pathology appears in select populations of neurons throughout various cortical and subcortical regions, and little is currently known about why some neurons develop pathology while others are spared. Here, we utilized subcellular-resolution imaging-based spatial transcriptomics (IST) in a transgenic mouse model that overexpresses wild-type human -synuclein (-syn-tg) to evaluate patterns of selective neuronal vulnerability to -synuclein pathology. By performing post-IST immunofluorescence for -synuclein phosphorylated at Ser129 (pSyn), we identified cell types in the cortex and hippocampus that were vulnerable or resistant to developing pSyn pathology. Next, we investigated the transcriptional underpinnings of the observed selective vulnerability using a set of custom probes to detect genes involved in -synuclein processing and toxicity. We identified expression of the kinase:substrate pair Plk2, which phosphorylates -synuclein at Ser129, and human SNCA (hSNCA), as underlying the selective vulnerability to pSyn pathology. Finally, we performed differential gene expression analysis, comparing non-transgenic cells to pSyn- and pSyn+ -syn-tg cells to reveal gene expression changes downstream of hSNCA overexpression and pSyn pathology, which included pSyn-dependent alterations in mitochondrial and endolysosomal genes. This study provides a comprehensive use case of IST, yielding new biological insights into the formation of -synuclein pathology and its downstream effects in a PD/DLB mouse model.

Experience instructs the refinement of feature-selectivity in the mouse primary visual thalamus
Neurons exhibit selectivity for specific features: a property essential for extracting and encoding relevant information in the environment. This feature-selectivity is thought to be modifiable by experience at the level of the cortex. Here, we demonstrate that selective exposure to a feature during development can instruct the population representation for that feature in the primary visual thalamus. This thalamic plasticity is not simply inherited from the cortex because it is still observed when recordings were performed in the absence of cortical feedback. Moreover, plasticity is blocked in mutant mice that exhibit deficits in retinogeniculate refinement, indicating that alterations in feature-selectivity are a direct result of changes in feedforward connectivity. These experience-dependent changes persist into older ages--highlighting the importance of this developmental period in shaping population coding in the thalamus. Our results show that salient environmental features are hard-wired into thalamic circuits during a discrete developmental window.