Journal of Neuroscience最新文献

Obsessive-Compulsive Disorder (OCD) is a debilitating illness consisting of obsessions and compulsions. OCD severity and treatment response are correlated with avoidant behaviors thought be performed to alleviate obsession-related anxiety. However, little is known about either the role of avoidance in the development of OCD or the interplay between anxiety states and avoidance behaviors. We have developed an instrumental negative reinforcement (i.e. active avoidance) paradigm in which mice must lever-press to avoid upcoming foot shocks. We show that mice (both sexes) can learn this task with high acquisition rates (75%) and that this behavior is largely stable when introducing uncertainty and modifying task structure. Furthermore, mice continue to perform avoidance responses on trials where lever pressing is not reinforced and increase response rates as they are maintained on this paradigm. With this paradigm, we did not find a relationship between negative reinforcement history and anxiety-related behaviors in well-established anxiety assays. Finally, we performed exploratory analyses to identify candidate regions involved in well-trained negative reinforcement using expression of the immediate early gene c-Fos. We detected correlated c-Fos expression in 1) cortico-striatal regions which regulate active avoidance in other paradigms and 2) amygdala circuits known to regulate conditioned defensive behaviors.Significance Statement Studies in patients with OCD suggest that compulsions are performed to avoid perceived threats and modulate anxiety tied to obsessions and/or compulsions. The negative reinforcement of avoidance and alleviated anxiety could therefore be a key driver of compulsive behaviors. However, there are still outstanding questions concerning the relationship between these two behaviors and the neural circuits involved in mediating negative reinforcement. We have developed an operant negative reinforcement paradigm in mice with discrete avoid and escape behaviors that can be learned without prior reward training with high throughput (75% acquisition) with responding that persists during nonreinforced trials. However, no differences were observed between negative reinforcement vs. unshocked and inescapably shocked controls, suggesting that continued negative reinforcement did not impact anxiety.

Humans can easily abstract incoming visual information into discrete semantic categories. Previous research employing functional MRI (fMRI) in humans has identified cortical organizing principles that allow not only for coarse-scale distinctions such as animate versus inanimate objects but also more fine-grained distinctions at the level of individual objects. This suggests that fMRI carries rather fine-grained information about individual objects. However, most previous work investigating fine-grained category representations either additionally included coarse-scale category comparisons of objects, which confounds fine-grained and coarse-scale distinctions, or only used a single exemplar of each object, which confounds visual and semantic information. To address these challenges, here we used multisession human fMRI (female and male) paired with a broad yet homogenous stimulus class of 48 terrestrial mammals, with 2 exemplars per mammal. Multivariate decoding and representational similarity analysis (RSA) revealed high image-specific reliability in low- and high-level visual regions, indicating stable representational patterns at the image level. In contrast, analyses across exemplars of the same animal yielded only small effects in the lateral occipital complex (LOC), indicating rather subtle category effects in this region. Variance partitioning with a deep neural network and shape model showed that across exemplar effects in EVC were largely explained by low-level visual appearance, while representations in LOC appeared to also contain higher category-specific information. These results suggest that representations typically measured with fMRI are dominated by image-specific visual or coarse-grained category information but indicate that commonly employed fMRI protocols may reveal subtle yet reliable distinctions between individual objects.Significance Statement While it has been suggested that functional MRI (fMRI) responses in ventral visual cortex carry fine-grained information about individual objects, much previous research has confounded fine-grained with coarse-scale category information or only used individual visual exemplars, which potentially confounds semantic and visual object information. Here we address these challenges in a multisession fMRI study where participants viewed a highly homogenous stimulus set of 48 land mammals with 2 exemplars per animal. Our results reveal a strong dominance of image-specific effects and additionally indicate subtle yet reliable category-specific effects in lateral occipital complex, underscoring the capacity of commonly employed fMRI protocols to uncover fine-grained visual information.

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here, we report that bilirubin (BIL)-dependent cell death in the auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (I _h), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca²⁺-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, I _h, and death, compromising audition at the young adult stage in HCN1^+/+, but not in HCN1^-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca²⁺ overload, neuronal death, and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.

The transmission of tau pathology has been proposed as one of the major mechanisms for the spatiotemporal spreading of tau pathology in neurodegenerative diseases. Over the last decade, studies have demonstrated that targeting total or pathological tau using tau antibodies can mitigate the development of tau pathology in tauopathy or Alzheimer's disease (AD) mouse models, and multiple tau immunotherapy agents have progressed to clinical trials. Tau antibodies are believed to inhibit the internalization of pathologic seeds and/or block seed elongation after seed internalization. To further address the mechanism of tau antibody inhibition of pathological spread, we conducted immunotherapy studies in mouse primary neurons and wild-type mice (females) seeded with AD patient-derived tau to induce the formation and spreading of tau pathology. Notably, we evaluated the effect of a mouse tau-specific antibody (mTau8) which does not interact with AD-tau seeds in these models. Our results show that mTau8 crosses the blood-brain barrier at levels similar to other antibodies and effectively decreases AD-tau-seeded tau pathology in vitro and in vivo. Importantly, our data suggest that mTau8 binds to endogenous intraneuronal mouse tau, thereby inhibiting the elongation of internalized tau seeds. These findings provide valuable insights into the possible mechanism underlying antibody-based therapies for treating tauopathies.Significance Statement The transmission of tau pathology plays key role in the pathoclinical progression of tauopathy. Studies have shown that tau antibody treatment can mitigate tau pathology in transgenic and spreading models of tauopathy. To explore the mechanisms involved in this procedure, we conducted immunotherapy studies on human tau seeds induced tau spreading models using a mouse tau-specific antibody (mTau8), which does not interact with human-tau seeds. Our findings in the study enhance our understanding of antibody-based therapies for tauopathies.

The hippocampus is the most studied brain region but little is known about signal throughput -- the simplest, yet most essential of circuit operations -- across its multiple stages from perforant path input to CA1 output. Using hippocampal slices derived from male mice, we have found that single-pulse lateral perforant path (LPP) stimulation produces a two-part CA1 response generated by LPP projections to CA3 ('direct path') and the dentate gyrus ('indirect path'). The latter, indirect path was far more potent in driving CA1 but did so only after a lengthy delay. Rather than operating as expected from the much discussed trisynaptic circuit argument, the indirect path used the massive CA3 recurrent collateral system to trigger a high frequency sequence of fEPSPs and spikes. The latter events promoted reliable signal transfer to CA1 but the mobilization time for the stereotyped, CA3 response resulted in surprisingly slow throughput. The circuit transmitted theta (5Hz) but not gamma (50Hz) frequency input, thus acting as a low-pass filter. It reliably transmitted short bursts of gamma input separated by the period of theta wave - CA1 spiking output under these conditions closely resembled the input signal. In all, the primary hippocampal circuit does not behave as a linear, three-part system but instead uses novel filtering and amplification steps to shape throughput and restrict effective input to select patterns. We suggest that the operations described here constitute a default mode for processing cortical inputs with other types of functions being enabled by projections from outside the extended hippocampus.Significance statement Despite intense interest in hippocampal contributions to behavior, surprisingly little is known about how signals are processed across the network linking cortical input to CA1 output. Here, we describe the first input/output relationship for the system with results challenging the traditional tri-synaptic circuit concept. Signal throughput requires mobilization of recurrent activity within CA3 to amplify sparse input from the dentate gyrus into an unexpectedly stereotyped composite response. Potent low-pass filters determine effective input patterns. These results open the way to new analyses of how variables such as aging affect hippocampus and its contributions to behavior while providing material needed for biologically realistic models of the structure.

The interplay between attention, alertness and motor planning is crucial for our manual interactions. To investigate the neural bases of this interaction, and challenging the views that attention cannot be disentangled from motor planning, we instructed human volunteers of both sexes to plan and execute reaching movements while attending to the target, while attending elsewhere, or without constraining attention. We recorded reaction times to reach initiation and pupil diameter and interfered with the functions of the medial posterior parietal cortex (mPPC) with online repetitive transcranial magnetic stimulation to test the causal role of this cortical region in the interplay between spatial attention and reaching. We found that mPPC plays a key role in the spatial association of reach planning and covert attention. Moreover, we have found that alertness, measured by pupil size, is a good predictor of the promptness of reach initiation only if we plan a reach to attended targets, and mPPC is causally involved in this coupling. Different from previous understanding, we suggest that mPPC is neither involved in reach planning per se, nor in sustained covert attention in absence of a reach plan, but it is specifically involved in attention functional to reaching.Significance Statement Attention is required to perform dexterous arm movements. In this work we show the neural bases of the interplay between attention and reaching preparation, with the aim to provide information useful to address effective rehabilitation strategies to treat functional deficits observed in attention-related diseases. We discuss how brain areas are involved in orchestrating attention and reaching by signaling the alignment of their spatial coordinates. Moreover, we found that pupil size changes during reach preparation are related to reach initiation, suggesting a coordination between vigilance and reach promptness when preparing a reach to attended targets.

Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor-expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor-expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling. While the early degeneration of D2 MSNs and impaired GABAergic transmission are well-documented, potassium chloride cotransporter 2 (KCC2), a key regulator of intracellular chloride (Cl^-), and therefore GABAergic signaling, has not been characterized in D1 and D2 MSNs in HD. We aimed to investigate whether Cl^- regulation was differentially altered in D1 and D2 MSNs and may contribute to the early degeneration of D2 MSNs in male and female symptomatic R6/2 mice. We used electrophysiology to record the reversal potential for GABA_A receptors (E_GABA), a read-out for the efficacy of Cl^- regulation, in striatal D1 and D2 MSNs and their corresponding output structures. During the early symptomatic phase (P55-P65)_, Cl^- impairments were observed in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl^- regulation was also dysfunctional in the globus pallidus externa, resulting in GABA-mediated excitation. When we overexpressed KCC2 in D2 MSNs using AAV-mediated delivery, we delayed the onset of motor impairments in R6/2 mice. We demonstrate that Cl^- homeostasis is differentially altered in D1 and D2 MSNs and may contribute to the enhanced susceptibility of D2 MSNs during HD progression.Significance Statement Huntington's Disease is an inherited neurodegenerative disease caused by a repeat expansion in the Huntingtin gene and characterized by the sequential loss of dopamine 2 and dopamine 1 receptor-expressing medium spiny neurons (D2 and D1 MSNs) of the striatum. MSNs release GABA, which depends on proper Cl^- regulation for inhibition. We asked whether Cl^- homeostasis is differentially altered in D1 and D2 MSNs and their output structures, and whether this altered expression contributes to the pattern of degeneration between these two principal striatal cell types. Using electrophysiology, biochemistry, and fluorescence imaging, we determined that Cl^- regulation was impaired in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl^- was also dysregulated in the globus pallidus externa resulting in excitatory GABA.

Primate vision relies on retinotopically organized cortical parcels defined by representations of hemifield (upper versus lower visual field), eccentricity (fovea versus periphery), and area (V1, V2, V3, V4). Here we test for functional signatures of these organizing principles. We used fMRI to measure responses to gratings varying in spatial frequency, color, and saturation across retinotopically defined parcels in two macaque monkeys, and we developed a Sparse Supervised Embedding (SSE) analysis to identify stimulus features that best distinguish cortical parcels from each other. Constraining the SSE model to distinguish just eccentricity representations of the voxels revealed the expected variation of spatial frequency and S-cone modulation with eccentricity. Constraining the model according to the dorsal-ventral location and retinotopic area of each voxel provided unexpected functional signatures, which we investigated further with standard univariate analyses. Posterior parcels (V1) were distinguished from anterior parcels (V4) by differential responses to chromatic and luminance contrast, especially of low spatial frequency gratings. Meanwhile, ventral parcels were distinguished from dorsal parcels by differential responses to chromatic and luminance contrast, especially of colors that modulate all three cone types. The dorsal-ventral asymmetry not only resembled differences between candidate dorsal and ventral subdivisions of human V4, but also extended to include all retinotopic visual areas, starting in V1 and increasing from V1 to V4. The results provide insight into the functional roles of different retinotopic areas and demonstrate the utility of Sparse Supervised Embedding as a data-driven tool for generating hypotheses about cortical function and behavior.Significance Statement This study demonstrates a new analysis, Sparse Supervised Embedding (SSE), which promises to be useful for visualizing and understanding complex neuroimaging datasets. The paper uses SSE to explore the functional roles of retinotopic visual areas (V1, V2, V3, V4, V3a, MT). The results show that retinotopic areas parcellated by representations for eccentricity and upper/lower visual hemifield have functional signatures, which are defined by unique combinations of responses to color, spatial frequency, and contrast. The functional signatures provide hypotheses for the different roles that the parcels play in vision and help resolve apparent differences between human and macaque visual cortex organization.

Humans can recognize their whole-body movements even when displayed as dynamic dot patterns. The sparse depiction of whole-body movements, coupled with a lack of visual experience watching ourselves in the world, has long implicated non-visual mechanisms to self-action recognition. We aimed to identify the neural systems for this ability. Using general linear modeling and multivariate analyses on human brain imaging data from male and female participants, we first found that cortical areas linked to motor processes, including frontoparietal and primary somatomotor cortices, exhibit greater engagement and functional connectivity when recognizing self-generated versus other-generated actions. Next, we show that these regions encode self-identity based on motor familiarity, even after regressing out idiosyncratic visual cues using multiple regression representational similarity analysis. Last, we found the reverse pattern for unfamiliar individuals: encoding localized to occipito-temporal visual regions. These findings suggest that self-awareness from actions emerges from the interplay of motor and visual processes.Significance Statement: We report for the first time that self-recognition from visual observation of our whole-body actions implicates brain regions associated with motor processes. On functional neuroimaging data, we found greater activity and unique representational patterns in brain areas and networks linked to motor processes when viewing our own actions relative to viewing the actions of others. These findings introduce an important role of motor mechanisms in distinguishing the self from others.

The mammalian cochlea amplifies sounds selectively to improve frequency resolution. However, vibrations around the outer hair cells (OHCs) are amplified non-selectively. The mechanism of the selective or non-selective amplification is unknown. This study demonstrates that active force transmission through the extracellular fluid in the organ of Corti (Corti fluid) can explain how the cochlea achieves selective sound amplification despite the non-frequency-selective action of OHCs. Computational model simulations and experiments with excised cochleae from young gerbils of both sexes were exploited. OHC motility resulted in characteristic off-axis motion of the joint between the OHC and Deiters cell (ODJ). Incorporating the Corti fluid dynamics was critical to account for the ODJ motion due to OHC motility. The incorporation of pressure transmission through the Corti fluid resulted in three distinct frequency tuning patterns depending on sites in the organ of Corti. In the basilar membrane, the responses were amplified near the best-responding frequency (BF). In the ODJ region, the responses were amplified non-selectively. In the reticular lamina, the responses were amplified near the BF but suppressed in lower frequencies. The suppressive effect of OHCs was further examined by observing the changes in tuning curves due to local inhibition of OHC motility. The frequency response of the reticular lamina resembled neural tuning, such as the hypersensitivity of tuning-curve tails after hair cell damage. Our results demonstrate how active OHCs exploit the elastic frame and viscous fluid in the organ of Corti to amplify and suppress cochlear vibrations for better frequency selectivity.Significance Statement Active outer hair cells have been considered to selectively amplify the basilar membrane vibrations near the sound's tonotopic location. However, recent observations from different labs showed that outer hair cells' action is non-selective-it spreads over the broad span of traveling waves. These observations challenge the existing theory pegged to basilar-membrane mechanics. The motion at the joint between the outer hair cell and the Deiters (ODJ) cell holds the key to account for the non-selective action of outer hair cells. We show that the characteristic motions at the ODJ are explained coherently when Corti fluid acts as the medium for outer hair cell force transmission. Our results demonstrate how non-selective outer hair cell action produces selective neural responses.