bioRxiv Subject Collection: Neuroscience's Journal

The connectional diaschisis and normalization of cortical language network dynamics after basal ganglia and thalamus stroke
Stroke affecting the basal ganglia and thalamus can lead to language deficits. In addition to the lesion's direct impact on language processing, connectional diaschisis involving cortical-subcortical interactions also plays a critical role. This study investigated connectional diaschisis using the "dynamic meta-networking framework of language" in patients with basal ganglia and thalamus stroke, analyzing longitudinal resting-state fMRI data collected at 2 weeks (n = 32), 3 months (n = 19), and one year post-stroke (n = 23). As expected, we observed dynamic cortico-subcortical interactions between cortical language regions and subcortical regions in healthy controls (HC, n = 25). The cortical language network exhibited dynamic domain-segregation patterns in HCs, severely disrupted in the acute phase following stroke. The connectional diaschisis manifested as dual effects characterized by both hypo- and hyper-connectivity, which positively and negatively correlated with language deficits, respectively. State-specific changes in nodal and topological properties were also identified. Throughout language recovery, cortical language network dynamics gradually normalized toward sub-optimal domain-segregation patterns, accompanied by the normalization of nodal and topological properties. These findings underscore the crucial role of cortico-subcortical interactions in language processing.

Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. While the contribution of peripheral organs remains incompletely understood, recent evidence suggests that brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) could play a role in diseased context as ALS. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed significant changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting ALS-related features such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content, which negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS, contributing to skeletal muscle degeneration through the secretion of dysfunctional EVs. This study provides novel insights into the role of BAT in ALS pathogenesis and highlights potential therapeutic targets for mitigating muscle wasting in ALS patients.

Hypersensitivity controlled by mir-9a modulates female receptivity of Drosophila melanogaster.
Female Drosophila melanogaster undergo a complex behavioral transformation following mating, characterized by increased sensory sensitivity and altered reproductive behaviors. In this study, we investigated the role of miR-9a, a conserved microRNA, in regulating these post-mating changes. We found that miR-9a mutant females exhibited a hypersensitivity phenotype, with increased rejection of courting males, delayed onset of sexual receptivity, and abnormal mating termination behavior. This phenotype was associated with aberrant overgrowth of adult body wall sensory neurons, suggesting a link between neuronal hypersensitivity and reproductive behavior. To further elucidate the underlying mechanisms, we performed genetic interaction studies with sens and bru2, genes known to interact with miR-9a. We found that removing one copy of sens or bru2 in miR-9a mutant backgrounds rescued the female rejection phenotype and normalized neuronal morphology. This suggests that miR-9a regulates sensory neuron development and female receptivity by modulating the expression of target genes like sens and bru2. Our findings reveal a novel role for miR-9a in regulating sensory hypersensitivity and reproductive behaviors in Drosophila. This research provides valuable insights into the molecular mechanisms underlying post-mating behavioral adaptations and neural development. Additionally, our findings highlight the potential of Drosophila as a model organism for investigating the role of miR-9 family members in neuronal specification and function, with implications for understanding sensory processing and neural plasticity in other organisms.

Evidence for an efferent-based prediction contributing to implicit motor adaptation
Models of sensorimotor adaptation have proposed that implicit adaptation is driven by error signals created by discrepancies between various sensory information sources. While proprioception has been suggested as a critical source for the error signals driving adaptation, the role of an efferent-based motor prediction has largely been neglected. In this study, we examined the effect of dissociating the afferent and efferent information available during implicit adaptation. Participants moved a visual cursor towards targets by applying horizontal forces to a stationary handle at a central home location. During perturbation trials, the cursor followed an invariant path rotated relative to the target. Participants were instructed to ignore this task-irrelevant cursor feedback and to isometrically "reach" towards the target. Participants implicitly adapted in the isometric task, even when the hand never actually moved to the target. Moreover, the level of adaptation surpassed that of a typical clamped reaching paradigm by nearly twofold. This was confirmed in a secondary experiment where participants performed actual reaching movements and demonstrated significantly less adaptation. Our findings suggest that while afferent proprioceptive feedback of hand position around the target most likely plays a role in adaptation, it is not necessary to induce adaptation.

Galanin receptor 1 expressing neurons in hippocampal-prefrontal circuitry modulate goal directed attention and impulse control
While amino acid neurotransmitters are the main chemical messengers in the brain, they are co-expressed with neuropeptides which are increasingly recognized as modulators of cognitive pathways. For example, the neuropeptide galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. In a recent study in rats, we discovered that direct pharmacological stimulation of galanin receptor type 1 (GalR1) in the ventral prefrontal cortex (vPFC) and ventral hippocampus (vHC) led to opposing effects on attention and impulse control behavior. In the present study, we investigate how subtypes of neurons expressing GalR1 in these two areas differentially contribute to these behaviors. We first establish that GalR1 is predominantly expressed in glutamatergic neurons in both the vPFC and HC. We develop a novel viral approach to gain genetic access to GalR1-expressing neurons and demonstrate that optogenetic excitation of GalR1 expressing neurons in the vPFC, but not vHC, selectively disrupts attention in a complex behavioral task. Finally, using fiber photometry, we measure the bulk calcium dynamics in GalR1-expressing neurons during the same task to demonstrate opposing activity in vPFC and vHC. These results are consistent with our previous work demonstrating differential behavioral effects induced by GalR1 activating in vPFC and vHC. These results indicate the distinct neuromodulatory and behavioral contributions of galanin mediated by subclasses of neurons in the hippocampal and prefrontal circuitry.

Unravelling the neurocognitive mechanisms underlying counterconditioning in humans
Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS+ images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS+ and CS- category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+-specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS+ exemplars presented during CC, and retroactively also for CS+ exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.

White matter connections of human ventral temporal cortex are organized by cytoarchitecture, eccentricity, and category-selectivity from birth
Category-selective regions in ventral temporal cortex (VTC) have a consistent anatomical organization, which is hypothesized to be scaffolded by white matter connections. However, it is unknown how white matter connections are organized from birth. Here, we scanned newborn to 6-month-old infants and adults and used a data-driven approach to determine the organization of the white matter connections of VTC. We find that white matter connections are organized by cytoarchitecture, eccentricity, and category from birth. Connectivity profiles of functional regions in the same cytoarchitectonic area are similar from birth and develop in parallel, with decreases in endpoint connectivity to lateral occipital, and parietal, and somatosensory cortex, and increases to lateral prefrontal cortex. Additionally, connections between VTC and early visual cortex are organized topographically by eccentricity bands and predict eccentricity biases in VTC. These data have important implications for theories of cortical functional development and open new possibilities for understanding typical and atypical white matter development.

Molecular architecture of the altered cortical complexity in autism
Autism Spectrum Disorder (ASD) is characterized by difficulties in social interaction, communication challenges, and repetitive behaviors. Despite extensive research, the molecular mechanisms underlying these neurodevelopmental abnormalities remain elusive. We integrated microscale brain gene expression data with macroscale MRI data from 1829 participants, including individuals with ASD and healthy controls, from the Autism Brain Imaging Data Exchange (ABIDE) I and II. Using fractal dimension (FD) as an index for quantifying cortical complexity, we identified significant regional alterations in ASD, within the left temporoparietal, left peripheral visual, right central visual, left somatomotor (including the insula), and left ventral attention networks. Partial least squares (PLS) regression analysis revealed gene sets associated with these cortical complexity changes, enriched for biological functions related to synaptic transmission, synaptic plasticity, mitochondrial dysfunction, and chromatin organization. Cell-specific analyses, protein-protein interaction (PPI) network analysis and gene temporal expression profiling further elucidated the dynamic molecular landscape associated with these alterations. These findings indicate that ASD-related alterations in cortical complexity are closely linked to specific genetic pathways. The combined analysis of neuroimaging and transcriptomic data enhances our understanding of how genetic factors contribute to brain structural changes in ASD.

Learning and modality independent time cells tile stimulus and post-stimulus period.
Hippocampal cells represent multiple dimensions of stimulus and behavioural context. Time-cells encode the dimension of time between events, but it is unclear if their properties depend on the behavioural paradigm. We find that in the sub-second time-scales of trace eyeblink conditioning (TEC), time cells occur both in stimulus and post-stimulus periods, and are insensitive both to modality and to state of learning. This contrasts with time-cell stimulus-dependence in delay non-match to sample (DNMS) tasks (~10 seconds). We observe 87% turnover of time-cells on successive days, but those time-cells which persist retain selectivity to stimulus and post-stimulus periods respectively. Finally, we show that 60% of time-encoding cells are active after the stimulus period, potentially providing an event trace for the network to link to later stimuli. Overall, TEC time-cells have distinct properties during turnover and are independent from behavioural state and contingency compared to DNMS.

Three Dimensional Multiscalar Neurovascular Nephron Connectivity Map of the Human Kidney Across the Lifespan
The human kidney is a vital organ with a remarkable ability to coordinate the activity of up to a million nephrons, its main functional tissue unit (FTU), and maintain homeostasis. We developed tissue processing and analytical methods to construct a 3D map of neurovascular nephron connectivity of the human kidney and glean insights into how this structural organization enables coordination of various functions of the nephron, such as glomerular filtration, solute and water absorption, secretion by the tubules, and regulation of blood flow and pressure by the juxtaglomerular apparatus, in addition to how these functions change across disease and lifespans. Using light sheet fluorescence microscopy (LSFM) and morphometric analysis we discovered changes in anatomical orientation of the vascular pole, glomerular density, volume, and innervation through postnatal development and ageing. The extensive nerve network exists from cortex FTUs to medullary loop of Henle, providing connectivity within segments of the same nephron, and between separate nephrons. The nerves organize glomeruli into discreet communities (in the same network of nerves). Adjacent glomerular communities are connected to intercommunal, mother glomeruli, by nerves, a pattern repeating throughout the cortex. These neuro-nephron networks are not developed in postnatal kidneys and are disrupted in diseased kidneys (diabetic or hydronephrosis). This structural organization likely poises the entire glomerular and juxtaglomerular FTUs to synchronize responses to perturbations in fluid homeostasis, utilizing mother glomeruli as network control centers.

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses
Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

Understanding human amygdala function with artificial neural networks
The amygdala is a cluster of subcortical nuclei that receives diverse sensory inputs and projects to the cortex, midbrain and other subcortical structures. Numerous accounts of amygdalar contributions to social and emotional behavior have been offered, yet an overarching description of amygdala function remains elusive. Here we adopt a computationally explicit framework that aims to develop a model of amygdala function based on the types of sensory inputs it receives, rather than individual constructs such as threat, arousal, or valence. Characterizing human fMRI signal acquired as participants viewed a full-length film, we developed encoding models that predict both patterns of amygdala activity and self-reported valence evoked by naturalistic images. We use deep image synthesis to generate artificial stimuli that distinctly engage encoding models of amygdala subregions that systematically differ from one another in terms of their low-level visual properties. These findings characterize how the amygdala compresses high-dimensional sensory inputs into low-dimensional representations relevant for behavior.

Contrast gain control is a reparameterization of a population response curve
Neurons in primary visual cortex (area V1) adapt in different degrees to the average contrast of the environment, suggesting that the representation of visual stimuli may interact with the state of cortical gain control in complex ways. To investigate this possibility, we measured and analyzed the responses of neural populations to visual stimuli as a function of contrast in different environments, each characterized by a unique distribution of contrast. Our findings reveal that, for a given stimulus, the population response can be described by a vector function r(g_e c), where the gain g_e is a decreasing function of the mean contrast of the environment. Thus, gain control can be viewed as a reparameterization of a population response curve, which is invariant across environments. Different stimuli are mapped to distinct curves, all originating from a common origin, corresponding to a zero-contrast response. Altogether, our findings provide a straightforward, geometric interpretation of contrast gain control at the population level and show that changes in gain are well coordinated among members of a neural population.

Pharyngeal neuronal mechanisms governing sour taste perception in Drosophila melanogaster
Sour taste, which is elicited by low pH, may serve to help animals distinguish appetitive from potentially harmful food sources. In all species studied to date, the attractiveness of oral acids is contingent on concentration. Many carboxylic acids are attractive at ecologically relevant concentrations but become aversive beyond some maximal concentration. Recent work found that Drosophila ionotropic receptors IR25a and IR76b expressed by sweet-responsive gustatory receptor neurons (GRNs) in the labellum, a peripheral gustatory organ, mediate appetitive feeding behaviors toward dilute carboxylic acids. Here, we disclose the existence of pharyngeal sensors in D. melanogaster that detect ingested carboxylic acids and are also involved in the appetitive responses to carboxylic acids. These pharyngeal sensors rely on IR51b, IR94a, and IR94h, together with IR25a and IR76b, to drive responses to carboxylic acids. We then demonstrate that optogenetic activation of either Ir94a+ or Ir94h+ GRNs promotes an appetitive feeding response, confirming their contributions to appetitive feeding behavior. Our discovery of internal pharyngeal sour taste receptors opens up new avenues for investigating the internal sensation of tastants in insects.

A modular system to label endogenous presynaptic proteins using split fluorophores in C. elegans
Visualizing the subcellular localization of presynaptic proteins with fluorescent proteins is a powerful tool to dissect the genetic and molecular mechanisms underlying synapse formation and patterning in live animals. Here, we utilize split green and red fluorescent proteins to visualize the localization of endogenously expressed presynaptic proteins at a single neuron resolution in Caenorhabditis elegans. By using CRISPR/Cas9 genome editing, we generated a collection of C. elegans strains in which endogenously expressed presynaptic proteins (RAB-3/Rab3, CLA-1/Piccolo, SYD-2/Liprin-, UNC-10/RIM and ELKS-1/ELKS) are tagged with tandem repeats of GFP11 and/or wrmScarlet11. We show that the expression of wrmScarlet1-10 and GFP1-10 under neuron-specific promoters can robustly label presynaptic proteins in different neuron types. We believe that combinations of knock-in strains and wrmScarlet1-10 and GFP1-10 plasmids are a versatile modular system to examine the localization of endogenous presynaptic proteins in any neuron type.

Ototoxicity-related Changes in GABA Immunolabeling Within the Rat Inferior Colliculus
Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat. The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation. There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al, 1995; Mossop et al, 2000; Salvi et al, 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78% in axodendritic and 82% in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness-diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.

Age-related myelin deficits in the auditory brain stem contribute to cocktail party-deficits
Age-related hearing loss is a global health problem of increasing importance. While the role of peripheral hearing loss is well understood and treatments are available, central hearing loss, the ability of the brain to make sense of sound, is much less well understood and no treatments are available. We report on age-related alterations in the auditory brain stem which compromise a listener's ability to isolate a sound from competing background noises, for example in a crowded restaurant. Sound localization depends on extreme temporal precision on the order of microseconds, and the sound localization pathway shows several specializations towards temporal precision. The pathway from the cochlear nucleus to the medial nucleus of the trapezoid body (MNTB) is heavily myelinated and terminates in the calyx of Held. Using auditory brain stem response measurements (ABRs), we found that the physiological properties of MNTB changes with age. The mechanism is that in older animals, MNTB afferents demyelinate to various degrees, resulting in larger variability in the timing of responses. Myelin is produced by oligodendrocytes, and we found that fewer mature, but more precursor and immature oligodendrocytes are present in MNTB of aged animals, suggesting that the demyelination is an age-related deficit in oligodendrocyte maturation.

Shifts in neural tuning systematically alter sensorimotor learning ability
Sensorimotor learning can change the tuning of neurons in motor-related brain areas and rotate their preferred directions (PDs). These PD rotations are commonly interpreted as reflecting motor command changes; however, cortical neurons that display PD rotations also contribute to sensorimotor learning. Sensorimotor learning should, therefore, alter not only motor commands but also the tuning of neurons responsible for this learning, and thus impact subsequent learning ability. Here, we investigate this possibility with computational modeling and by directly measuring adaptive responses during sensorimotor learning in humans. Modeling shows that the PD rotations induced by sensorimotor learning, predict specific anisotropic changes in PD distributions that in turn predict a specific spatial pattern of changes in learning ability. Remarkably, experiments in humans then reveal large, systematic changes in learning ability in a spatial pattern that precisely reflects these model-predicted changes. We find that this pattern defies conventional wisdom and implements Newton's method, a learning rule where the step size is inversely proportional rather than proportional to the learning gradient's amplitude, limiting overshooting in the adaptive response. Our findings indicate that PD rotation provides a mechanism whereby the motor system can simultaneously learn how to move and learn how to learn.

Pervasive neurovascular dysfunction in the ventromedial prefrontal cortex of female depressed suicides with a history of childhood abuse
Exposure to early life adversity (ELA) poses a significant global public health concern, with profound pathophysiological implications for affected individuals. Studies suggest that ELA contributes to endothelial dysfunction, bringing into question the functional integrity of the neurovascular unit in brain regions vulnerable to chronic stress. Despite the importance of the neurovasculature in maintaining normal brain physiology, human neurovascular cells remain poorly characterized, particularly with regard to their contributory role in ELA-associated pathophysiologies. In this study, we present the first comprehensive transcriptomic analysis of intact microvessels isolated from postmortem ventromedial prefrontal cortex samples from adult healthy controls (CTRL) and matched depressed suicides with histories of ELA. Our findings point to substantive differences between men and women, with the latter exhibiting widespread gene expression changes at the neurovascular unit, including the key vascular nodal regulators KLF2 and KLF4, alongside a broad downregulation of immune-related pathways. These results suggest that the neurovascular unit plays a larger role in the neurobiological consequences of ELA in human females.

Effects of two different compounds on seizure suppression using the zebrafish PTZ-seizure model
Epilepsies are a common and severe neurological condition characterized by spontaneous and recurrent seizures. Although anti-seizure medications are effective for most patients, about 30% remain pharmacoresistant. Moreover, uncontrolled seizures are associated with risk factors and shortened life expectancy for individuals with refractory epilepsy. Preclinical studies are an essential step for drug discovery and the zebrafish (Danio rerio) has been successfully employed for this purpose. In this study, we applied the zebrafish PTZ-seizure model to investigate the effect of two compounds on seizure suppression, Tripeptide (p-BTX-I) and the Cx43 peptide CX2. Zebrafish larvae at 6 days post-fertilization (dpf) were exposed to both compounds, according to their group, 24h prior to PTZ-seizure induction. We quantified the compounds effect on seizure latency, number of seizures and transcript levels of genes related to inflammation, oxidative stress, and apoptosis (il1b, tnfa, cox1, cox2a, il6, casp3a, casp9, baxa, bcl2a, nox1, sod1 and cat). Our results showed that CX2 at a concentration of 0.1 {micro}M/mL yielded the best outcome for seizure suppression as it reduced the number of seizures and increased the seizure latency. Additionally, CX2 treatment before PTZ-induced seizures decreased the transcript of il1b, il6, tnfa and cox1 genes, all related to inflammation. A bio-distribution study showed that the CX2 reached the zebrafish brain at both times investigated, 1h and 6h. Similarly, the tripeptide exhibited anti-inflammatory and anti-apoptotic action, reducing mRNA expression of the il1b and casp9 genes. Our findings suggest that both Tripeptide and CX2 hold translational potential for seizure suppression.

Templating of Monomeric Alpha-Synuclein Induces Inflammation and SNpc Dopamine Neuron Death in a Genetic Mouse Model of Synucleinopathy.
While the etiology of most cases of Parkinson's disease (PD) are idiopathic, is has been estimated that 5-10 percent of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (alpha-syn). alpha-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, alpha-syn misfolds into multimeric beta-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HPLC, and cytokine analysis, we examined the sequelae of intraparenchymal brain seeding of oligomeric pre-formed fibrils (PFFs) and monomeric a-syn in C57BL/6J (WT) and A53T SNCA mutant mice. We found that injection of PFFs, but not monomeric alpha-syn, into the striatum of C57BL/6J mice induced spread of aggregate alpha-syn, loss of SNpc DA neurons and increased neuroinflammation. However, in A53T SNCA mice, we found that both PFFs and monomeric alpha-syn induced this pathology. This suggests that the conformation changes in alpha-syn seen in the A53T strain can recruit wild-type alpha-syn to a pathological misfolded conformation which may provide a mechanism for the induction of PD in humans with SNCA duplication/triplication.

Low-side and multitone suppression in the base of the gerbil cochlea
The cochlea's mechanical response to sound stimulation is nonlinear, likely due to saturation of the mechano-electric transduction current that is part of an electromechanical feedback loop. The ability of a second tone or tones to reduce the response to a probe tone is one manifestation of nonlinearity, termed suppression. Using optical coherence tomography to measure motion within the organ of Corti, regional motion variations have been observed. Here, we report on the suppression that occurs within the organ of Corti when a high sound level, low frequency suppressor tone was delivered along with a sweep of discreet single-tones. Responses were measured in the base of the gerbil cochlea at two characteristic frequency locations, with two different directions of observation relative to the sensory tissue's anatomical axes. Suppression extended over a wide frequency range in the outer hair cell region, whereas it was typically limited to the characteristic frequency peak in the reticular lamina region and at the basilar membrane. Aspects of the observed suppression were consistent with the effect of a saturating nonlinearity. Recent measurements have noted the three-dimensional nature of organ of Corti motion. The effects of suppression observed here could be due to a combination of reduced motion amplitude and altered vibration axis.

Model of a striatal circuit exploring biological mechanisms underlying decision-making during normal and disordered states
Decision-making requires continuous adaptation to internal and external contexts. Changes in decision-making are reliable transdiagnostic symptoms of neuropsychiatric disorders. We created a computational model demonstrating how the striosome compartment of the striatum constructs a mathematical space for decision-making computations depending on context, and how the matrix compartment defines action value depending on the space. The model explains multiple experimental results and unifies other theories like reward prediction error, roles of the direct versus indirect pathways, and roles of the striosome versus matrix, under one framework. We also found, through new analyses, that striosome and matrix neurons increase their synchrony during difficult tasks, caused by a necessary increase in dimensionality of the space. The model makes testable predictions about individual differences in disorder susceptibility, decision-making symptoms shared among neuropsychiatric disorders, and differences in neuropsychiatric disorder symptom presentation. The model reframes the role of the striosomal circuit in neuroeconomic and disorder-affected decision-making.

Gustatory Thalamic Neurons Mediate Aversive Behaviors
The parvicellular part of the ventral posteromedial nucleus (VPMpc) of the thalamus, also known as the gustatory thalamus, receives input from the parabrachial nucleus and relays taste sensation to the gustatory (or insular) cortex. Prior research has focussed on the role of the VPMpc in relaying taste signals. Here we provide evidence showing that VPMpc also mediates aversive behaviors. By recording calcium transients in vivo from single neurons in mice, we show that neurons expressing cholecystokinin and the mu-opioid receptor in the VPMpc respond to various noxious stimuli and fear memory. Chemogenetic and optogenetic activation of these neurons enhances the response to aversive stimuli, whereas silencing them attenuates aversive behaviors. The VPMpc neurons directly innervate neurons in the insular cortex and rostral lateral amygdala. This study expands the role of the VPMpc to include mediating aversive and threating signals to the insular cortex and lateral amygdala.

Glucocorticoids desensitize CRH neurons to norepinephrine via rapid nitrosylation-dependent regulation of α1 adrenoreceptor trafficking
Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive for somatic stress activation of the hypothalamic-pituitary-adrenal (HPA) axis. We showed that glucocorticoids rapidly desensitize CRH neurons to norepinephrine and suppress inflammation-induced HPA activation via a glucocorticoid receptor- and endocytosis-dependent mechanism. Here, we show that 1 adrenoreceptor (AR1) trafficking is regulated by convergent glucocorticoid and nitric oxide synthase signaling mechanisms. Live-cell imaging of AR1b-eGFP-expressing hypothalamic cells revealed rapid corticosterone-stimulated redistribution of internalized AR1 from rapid recycling endosomes to late endosomes and lysosomes via a nitrosylation-regulated mechanism. Proximity assay demonstrated interaction of glucocorticoid receptors with AR1b and {beta}-arrestin, and showed corticosterone blockade of norepinephrine-stimulated AR1b/{beta}-arrestin interaction, which may prevent AR1b from entering the rapid recycling endosomal pathway. These findings demonstrate a rapid glucocorticoid regulation of G protein-coupled receptor trafficking and provide a molecular mechanism for rapid glucocorticoid desensitization of noradrenergic signaling in CRH neurons.

Extracellular matrix integrity regulates GABAergic plasticity in the hippocampus
The brain's extracellular matrix (ECM) is crucial for neural circuit functionality, synaptic plasticity, and learning. While the role of the ECM in excitatory synapses has been extensively studied, its influence on inhibitory synapses, particularly on GABAergic long-term plasticity, remains poorly understood. This study aims to elucidate the effects of ECM components on inhibitory synaptic transmission and plasticity in the hippocampal CA1 region. We focus on the roles of chondroitin sulfate proteoglycans (CSPGs) and hyaluronic acid in modulating inhibitory postsynaptic currents (IPSCs) at two distinct inhibitory synapses formed by somatostatin (SST)-positive and parvalbumin (PV)-positive interneurons onto pyramidal cells (PCs). Using optogenetic stimulation in brain slices, we observed that acute degradation of ECM constituents by hyaluronidase or chondroitinase-ABC did not affect basal inhibitory synaptic transmission. However, short-term plasticity, particularly burst-induced depression, was enhanced at PV[->]PC synapses following enzymatic treatments. Long-term plasticity experiments demonstrated that CSPGs are essential for NMDA-induced iLTP at SST[->]PC synapses, whereas the digestion of hyaluronic acid by hyaluronidase impaired iLTP at PV[->]PC synapses. This indicates a synapse-specific role of CSPGs and hyaluronic acid in regulating GABAergic plasticity. Additionally, we report the presence of cryptic GABAergic plasticity at PV[->]PC synapses induced by prolonged NMDA application, which became evident after CSPG digestion and was absent under control conditions. Our results underscore the differential impact of ECM degradation on inhibitory synaptic plasticity, highlighting the synapse-specific interplay between ECM components and specific GABAergic synapses. This offers new perspectives in studies on learning and critical period timing.