ID: 15776222
Title: Morphometric characterization of synapses in the primate prefrontal cortex formed by afferents from the mediodorsal thalamic nucleus.
Abstract: The main thalamic afferentation of the prefrontal cortex (PFC) originates in the mediodorsal nucleus (MD). Although it is suggested that this pathway is affected in schizophrenia, there is a lack of functional and structural data regarding its synaptic organization. The scope of this study was to characterize the ultrastructural features of thalamocortical synapses formed by afferents from the MD by applying anterograde tract tracing, immunohistochemical detection of parvalbumin (PV, a probable marker of thalamocortical endings), and quantitative electron microscopic techniques to the PFC of the macaque monkey. Our findings indicate that anterogradely-labeled and PV-immunoreactive boutons exhibit similar ultrastructural properties, characterized by their larger size, higher incidence of release sites and a higher occurrence of mitochondria when compared to non-labeled, excitatory-like endings in the middle layers of the PFC. Although most of the contacts were made on spines in both cases, PV-immunopositive axon terminals apparently targeted dendritic shafts at about twice the frequency found for anterogradely-labeled afferents from the MD (20.5% and 9.5%, respectively). This result suggests diversity among thalamocortical and/or PV-immunoreactive axon terminals of the PFC. In accordance with studies in other cortical areas, our findings suggest that corollary discharge through the mediodorsal thalamocortical projection is also adapted to synaptic transmission with high efficacy and probably exhibits marked short-term temporal dynamics in the PFC.

ID: 17093408
Title: Influence of the thalamus on spatial visual processing in frontal cortex.
Abstract: Each of our movements activates our own sensory receptors, and therefore keeping track of self-movement is a necessary part of analysing sensory input. One way in which the brain keeps track of self-movement is by monitoring an internal copy, or corollary discharge, of motor commands. This concept could explain why we perceive a stable visual world despite our frequent quick, or saccadic, eye movements: corollary discharge about each saccade would permit the visual system to ignore saccade-induced visual changes. The critical missing link has been the connection between corollary discharge and visual processing. Here we show that such a link is formed by a corollary discharge from the thalamus that targets the frontal cortex. In the thalamus, neurons in the mediodorsal nucleus relay a corollary discharge of saccades from the midbrain superior colliculus to the cortical frontal eye field. In the frontal eye field, neurons use corollary discharge to shift their visual receptive fields spatially before saccades. We tested the hypothesis that these two components-a pathway for corollary discharge and neurons with shifting receptive fields-form a circuit in which the corollary discharge drives the shift. First we showed that the known spatial and temporal properties of the corollary discharge predict the dynamic changes in spatial visual processing of cortical neurons when saccades are made. Then we moved from this correlation to causation by isolating single cortical neurons and showing that their spatial visual processing is impaired when corollary discharge from the thalamus is interrupted. Thus the visual processing of frontal neurons is spatiotemporally matched with, and functionally dependent on, corollary discharge input from the thalamus. These experiments establish the first link between corollary discharge and visual processing, delineate a brain circuit that is well suited for mediating visual stability, and provide a framework for studying corollary discharge in other sensory systems.

ID: 24998031
Title: The functional anatomy of schizophrenia: A dynamic causal modeling study of predictive coding.
Abstract: This paper tests the hypothesis that patients with schizophrenia have a deficit in selectively attending to predictable events. We used dynamic causal modeling (DCM) of electrophysiological responses - to predictable and unpredictable visual targets - to quantify the effective connectivity within and between cortical sources in the visual hierarchy in 25 schizophrenia patients and 25 age-matched controls. We found evidence for marked differences between normal subjects and schizophrenia patients in the strength of extrinsic backward connections from higher hierarchical levels to lower levels within the visual system. In addition, we show that not only do schizophrenia subjects have abnormal connectivity but also that they fail to adjust or optimize this connectivity when events can be predicted. Thus, the differential intrinsic recurrent connectivity observed during processing of predictable versus unpredictable targets was markedly attenuated in schizophrenia patients compared with controls, suggesting a failure to modulate the sensitivity of neurons responsible for passing sensory information of prediction errors up the visual cortical hierarchy. The findings support the proposed role of abnormal connectivity in the neuropathology and pathophysiology of schizophrenia.

ID: 26108951
Title: Failure to use corollary discharge to remap visual target locations is associated with psychotic symptom severity in schizophrenia.
Abstract: Corollary discharge (CD) refers to "copies" of motor signals sent to sensory areas, allowing prediction of future sensory states. They enable the putative mechanisms supporting the distinction between self-generated and externally generated sensations. Accordingly, many authors have suggested that disturbed CD engenders psychotic symptoms of schizophrenia, which are characterized by agency distortions. CD also supports perceived visual stability across saccadic eye movements and is used to predict the postsaccadic retinal coordinates of visual stimuli, a process called remapping. We tested whether schizophrenia patients (SZP) show remapping disturbances as evidenced by systematic transsaccadic mislocalizations of visual targets. SZP and healthy controls (HC) performed a task in which a saccadic target disappeared upon saccade initiation and, after a brief delay, reappeared at a horizontally displaced position. HC judged the direction of this displacement accurately, despite spatial errors in saccade landing site, indicating that their comparison of the actual to predicted postsaccadic target location relied on accurate CD. SZP performed worse and relied more on saccade landing site as a proxy for the presaccadic target, consistent with disturbed CD. This remapping failure was strongest in patients with more severe psychotic symptoms, consistent with the theoretical link between disturbed CD and phenomenological experiences in schizophrenia.

ID: 26305115
Title: Corollary Discharge Failure in an Oculomotor Task Is Related to Delusional Ideation in Healthy Individuals.
Abstract: Predicting the sensory consequences of saccadic eye movements likely plays a crucial role in planning sequences of saccades and in maintaining visual stability despite saccade-caused retinal displacements. Deficits in predictive activity, such as that afforded by a corollary discharge signal, have been reported in patients with schizophrenia, and may lead to the emergence of positive symptoms, in particular delusions of control and auditory hallucinations. We examined whether a measure of delusional thinking in the general, non-clinical population correlated with measures of predictive activity in two oculomotor tasks. The double-step task measured predictive activity in motor control, and the in-flight displacement task measured predictive activity in trans-saccadic visual perception. Forty-one healthy adults performed both tasks and completed a questionnaire to assess delusional thinking. The quantitative measure of predictive activity we obtained correlated with the tendency towards delusional ideation, but only for the motor task, and not the perceptual task: Individuals with higher levels of delusional thinking showed less self-movement information use in the motor task. Variation of the degree of self-generated movement knowledge as a function of the prevalence of delusional ideation in the normal population strongly supports the idea that corollary discharge deficits measured in schizophrenic patients in previous researches are not due to neuroleptic medication. We also propose that this difference in results between the perceptual and the motor tasks may point to a dissociation between corollary discharge for perception and corollary discharge for action.

ID: 26740647
Title: Saccadic Corollary Discharge Underlies Stable Visual Perception.
Abstract: Saccadic eye movements direct the high-resolution foveae of our retinas toward objects of interest. With each saccade, the image jumps on the retina, causing a discontinuity in visual input. Our visual perception, however, remains stable. Philosophers and scientists over centuries have proposed that visual stability depends upon an internal neuronal signal that is a copy of the neuronal signal driving the eye movement, now referred to as a corollary discharge (CD) or efference copy. In the old world monkey, such a CD circuit for saccades has been identified extending from superior colliculus through MD thalamus to frontal cortex, but there is little evidence that this circuit actually contributes to visual perception. We tested the influence of this CD circuit on visual perception by first training macaque monkeys to report their perceived eye direction, and then reversibly inactivating the CD as it passes through the thalamus. We found that the monkey's perception changed; during CD inactivation, there was a difference between where the monkey perceived its eyes to be directed and where they were actually directed. Perception and saccade were decoupled. We established that the perceived eye direction at the end of the saccade was not derived from proprioceptive input from eye muscles, and was not altered by contextual visual information. We conclude that the CD provides internal information contributing to the brain's creation of perceived visual stability. More specifically, the CD might provide the internal saccade vector used to unite separate retinal images into a stable visual scene. Visual stability is one of the most remarkable aspects of human vision. The eyes move rapidly several times per second, displacing the retinal image each time. The brain compensates for this disruption, keeping our visual perception stable. A major hypothesis explaining this stability invokes a signal within the brain, a corollary discharge, that informs visual regions of the brain when and where the eyes are about to move. Such a corollary discharge circuit for eye movements has been identified in macaque monkey. We now show that selectively inactivating this brain circuit alters the monkey's visual perception. We conclude that this corollary discharge provides a critical signal that can be used to unite jumping retinal images into a consistent visual scene.

ID: 27581454
Title: Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.
Abstract: Shank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines. In support of this hypothesis, we find that zinc is a potent regulator of Shank3 activation and dynamics in rat hippocampal neurons. Moreover, we show that zinc modulation of synaptic transmission is Shank3 dependent. Interestingly, an autism spectrum disorder (ASD)-associated variant of Shank3 (Shank3(R87C)) retains its zinc sensitivity and supports zinc-dependent activation of AMPAR-mediated synaptic transmission. However, elevated zinc was unable to rescue defects in trans-synaptic signaling caused by the R87C mutation, implying that trans-synaptic increases in neurotransmitter release are not necessary for the postsynaptic effects of zinc. Together, these data suggest that Shank3 is a key component of a zinc-sensitive signaling system, regulating synaptic strength that may be impaired in ASD. Shank3 is a postsynaptic protein associated with neurodevelopmental disorders such as autism and schizophrenia. In this study, we show that Shank3 is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic transmission. Intriguingly, an autism-associated mutation in Shank3 partially impairs this signaling system. Therefore, perturbation of zinc homeostasis may impair, not only synaptic functionality and plasticity, but also may lead to cognitive and behavioral abnormalities seen in patients with psychiatric disorders.

ID: 30272139
Title: Reconfiguration of Dynamic Functional Connectivity in Sensory and Perceptual System in Schizophrenia.
Abstract: Schizophrenia is thought as a self-disorder with dysfunctional brain connectivity. This self-disorder is often attributed to high-order cognitive impairment. Yet due to the frequent report of sensorial and perceptual deficits, it has been hypothesized that self-disorder in schizophrenia is dysfunctional communication between sensory and cognitive processes. To further verify this assumption, the present study comprehensively examined dynamic reconfigurations of resting-state functional connectivity (rsFC) in schizophrenia at voxel level, region level, and network levels (102 patients vs. 124 controls). We found patients who show consistently increased rsFC variability in sensory and perceptual system, including visual network, sensorimotor network, attention network, and thalamus at all the three levels. However, decreased variability in high-order networks, such as default mode network and frontal-parietal network were only consistently observed at region and network levels. Taken together, these findings highlighted the rudimentary role of elevated instability of information communication in sensory and perceptual system and attenuated whole-brain integration of high-order network in schizophrenia, which provided novel neural evidence to support the hypothesis of disrupted perceptual and cognitive function in schizophrenia. The foci of effects also highlighted that targeting perceptual deficits can be regarded as the key to enhance our understanding of pathophysiology in schizophrenia and promote new treatment intervention.

ID: 30278791
Title: Impaired Motion Processing in Schizophrenia and the Attenuated Psychosis Syndrome: Etiological and Clinical Implications.
Abstract: The ability to perceive the motion of biological objects, such as faces, is a critical component of daily function and correlates with the ability to successfully navigate social situations (social cognition). Deficits in motion perception in schizophrenia were first demonstrated about 20 years ago but remain understudied, especially in the early, potentially prodromal, stages of the illness. The authors examined the neural bases of visual sensory processing impairments, including motion, in patients with schizophrenia (N=63) and attenuated psychosis (clinical high risk) (N=32) compared with age-matched healthy control subjects (N=67). Electrophysiological recordings during stimulus and motion processing were analyzed using oscillatory (time frequency) approaches that differentiated motion-onset-evoked activity from stimulus-onset sensory-evoked responses. These were compared with functional MRI (fMRI) measures of motion processing. Significant deficits in motion processing were observed across the two patient groups, and these deficits predicted impairments in both face-emotion recognition and cognitive function. In contrast to motion processing, sensory-evoked stimulus-onset responses were intact in patients with attenuated psychosis, and, further, the relative deficit in motion-onset responses compared with stimulus-onset responses predicted transition to schizophrenia. In patients with schizophrenia, motion detection deficits mapped to impaired activation in motion-sensitive visual cortex during fMRI. Additional visual impairments in patients with schizophrenia, not present in patients with attenuated psychosis, implicated other visual regions, including the middle occipital gyrus and pulvinar thalamic nucleus. The study findings emphasize the importance of sensory-level visual dysfunction in the etiology of schizophrenia and in the personal experience of individuals with the disorder and demonstrate that motion-processing deficits may predate illness onset and contribute to impaired function even in patients with attenuated psychosis.

ID: 30500536
Title: Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor.
Abstract: N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to schizophrenia. Zinc and pH are physiological allosteric modulators of NMDARs, with GluN2A-containing receptors inhibited by nanomolar concentrations of divalent zinc and by excursions to low pH. Despite the widespread importance of zinc and proton modulation of NMDARs, the molecular mechanism by which these ions modulate receptor activity has proven elusive. Here, we use cryoelectron microscopy to elucidate the structure of the GluN1/GluN2A NMDAR in a large ensemble of conformations under a range of physiologically relevant zinc and proton concentrations. We show how zinc binding to the amino terminal domain elicits structural changes that are transduced though the ligand-binding domain and result in constriction of the ion channel gate.

ID: 30630882
Title: Structural Thalamofrontal Hypoconnectivity Is Related to Oculomotor Corollary Discharge Dysfunction in Schizophrenia.
Abstract: By predicting sensory consequences of actions, humans can distinguish self-generated sensory inputs from those that are elicited externally. This is one mechanism by which we achieve a subjective sense of agency over our actions. Corollary discharge (CD) signals-"copies" of motor signals sent to sensory areas-permit such predictions, and CD abnormalities are a hypothesized mechanism for the agency disruptions in schizophrenia that characterize a subset of symptoms. Indeed, behavioral evidence of altered CD, including in the oculomotor system, has been observed in schizophrenia patients. A pathway projecting from the superior colliculus to the frontal eye fields (FEFs) via the mediodorsal thalamus (MD) conveys oculomotor CD associated with saccadic eye movements in nonhuman primates. This animal work provides a promising translational framework in which to investigate CD abnormalities in clinical populations. In the current study, we examined whether structural connectivity of this MD-FEF pathway relates to oculomotor CD functioning in schizophrenia. Twenty-two schizophrenia patients and 24 healthy control participants of both sexes underwent diffusion tensor imaging, and a large subset performed a trans-saccadic perceptual task that yields measures of CD. Using probabilistic tractography, we identified anatomical connections between FEF and MD and extracted indices of microstructural integrity. Patients exhibited compromised microstructural integrity in the MD-FEF pathway, which was correlated with greater oculomotor CD abnormalities and more severe psychotic symptoms. These data reinforce the role of the MD-FEF pathway in transmitting oculomotor CD signals and suggest that disturbances in this pathway may relate to psychotic symptom manifestation in patients.SIGNIFICANCE STATEMENT People with schizophrenia sometimes experience abnormalities in a sense of agency, which may stem from abnormal sensory predictions about their own actions. Consistent with this notion, the current study found reduced structural connectivity in patients with schizophrenia in a specific brain pathway found to transmit such sensorimotor prediction signals in nonhuman primates. Reduced structural connectivity was correlated with behavioral evidence for impaired sensorimotor predictions and psychotic symptoms.

ID: 31351985
Title: Corollary Discharge for Action and Cognition.
Abstract: In motor systems, a copy of the movement command known as corollary discharge is broadcast to other regions of the brain to warn them of the impending movement. The premise of this review is that the concept of corollary discharge may generalize in revealing ways to the brain's cognitive systems. An oculomotor pathway from the brain stem to frontal cortex provides a well-established example of how corollary discharge is instantiated for sensorimotor processing. Building on causal evidence from inactivation of the pathway, we motivate forward models as a tool for understanding the contributions of corollary discharge to perception and movement. Finally, we extend the definition of corollary discharge to account for signals that may be used for cognitive forward models of decision making. This framework may provide new insights into signals and circuits that contribute to sequential decision processes, the breakdown of which may account for some symptoms of psychiatric disorders.

ID: 32201032
Title: Context-dependent dynamic functional connectivity alteration of lateral occipital cortex in schizophrenia.
Abstract: Schizophrenia has long been associated with dysfunction in visual perception. One important region underlying this is lateral occipital cortex (LOC), a mid-level visual region critical for object recognition. Although LOC of patients has exhibited structural and functional abnormalities in MR brain imaging studies, how it interacts with other networks over time under rest and with task demands remains to be clarified. The present study investigated the spatial-temporal interaction of LOC with other brain networks by examining functional connectivity communities of the brain over time. We found increased temporal instability of LOC connectivity over time under both resting and task-switching conditions in patients. In the resting state, LOC of patients had increased interaction with the frontoparietal task-control network (FPTC) and thalamus compared with controls, while during task switching, LOC showed increased interaction with the default mode network (DMN). Temporal instability of LOC connectivity was positively correlated with patients' switching cost during task performance and with hallucination severity. These results indicate that reduced stability of LOC connectivity may be an important factor underlying neurocognitive dysfunctions and symptom severity in schizophrenia.

ID: 32561673
Title: Ketamine Affects Prediction Errors about Statistical Regularities: A Computational Single-Trial Analysis of the Mismatch Negativity.
Abstract: The auditory mismatch negativity (MMN) is significantly reduced in schizophrenia. Notably, a similar MMN reduction can be achieved with NMDA receptor (NMDAR) antagonists. Both phenomena have been interpreted as reflecting an impairment of predictive coding or, more generally, the "Bayesian brain" notion that the brain continuously updates a hierarchical model to infer the causes of its sensory inputs. Specifically, neurobiological interpretations of predictive coding view perceptual inference as an NMDAR-dependent process of minimizing hierarchical precision-weighted prediction errors (PEs), and disturbances of this putative process play a key role in hierarchical Bayesian theories of schizophrenia. Here, we provide empirical evidence for this theory, demonstrating the existence of multiple, hierarchically related PEs in a "roving MMN" paradigm. We applied a hierarchical Bayesian model to single-trial EEG data from healthy human volunteers of either sex who received the NMDAR antagonist S-ketamine in a placebo-controlled, double-blind, within-subject fashion. Using an unrestricted analysis of the entire time-sensor space, our trial-by-trial analysis indicated that low-level PEs (about stimulus transitions) are expressed early (102-207 ms poststimulus), while high-level PEs (about transition probability) are reflected by later components (152-199 and 215-277 ms) of single-trial responses. Furthermore, we find that ketamine significantly diminished the expression of high-level PE responses, implying that NMDAR antagonism disrupts the inference on abstract statistical regularities. Our findings suggest that NMDAR dysfunction impairs hierarchical Bayesian inference about the world's statistical structure. Beyond the relevance of this finding for schizophrenia, our results illustrate the potential of computational single-trial analyses for assessing potential pathophysiological mechanisms.

ID: 32680937
Title: Organization of Corollary Discharge Neurons in Monkey Medial Dorsal Thalamus.
Abstract: A corollary discharge (CD) is a copy of a neuronal command for movement sent to other brain regions to inform them of the impending movement. In monkeys, a circuit from superior colliculus (SC) through medial-dorsal nucleus of the thalamus (MD) to frontal eye field (FEF) carries such a CD for saccadic eye movements. This circuit provides the clearest example of such internal monitoring reaching cerebral cortex. In this report we first investigated the functional organization of the critical MD relay by systematically recording neurons within a grid of penetrations. In two male rhesus macaque monkeys (Macaca mulatta), we found that lateral MD neurons carrying CD signals discharged before saccades to ipsilateral as well as contralateral visual fields instead of just contralateral fields, often had activity over large movement fields, and had activity from both central and peripheral visual fields. Each of these characteristics has been found in FEF, but these findings indicate that these characteristics are already present in the thalamus. These characteristics show that the MD thalamic relay is not passive but instead assembles inputs from the SC before transmission to cortex. We next determined the exact location of the saccade-related CD neurons using the grid of penetrations. The neurons occupy an anterior-posterior band at the lateral edge of MD, and we established this band in stereotaxic coordinates to facilitate future study of CD neurons. These observations reveal both the organizational features of the internal CD signals within the thalamus, and the location of the thalamic relay for those signals.SIGNIFICANCE STATEMENT A corollary discharge (CD) circuit within the brain keeps an internal record of physical movements. In monkeys and humans, one such CD keeps track of rapid eye movements, and in monkeys, a circuit carrying this CD extends from midbrain to cerebral cortex through a relay in the thalamus. This circuit provides guidance for eye movements, contributes to stable visual perception, and when defective, might be related to difficulties that schizophrenic patients have in recognizing their own movements. This report facilitates the comparison of the circuit in monkeys and humans, particularly for comparison of the location of the thalamic relay in monkeys and in humans.

ID: 33046551
Title: Activity Dependent Inhibition of AMPA Receptors by Zn2.
Abstract: Zn2+ has been shown to have a wide range of modulatory effects on neuronal AMPARs. However, the mechanism of modulation is largely unknown. Here we show that Zn2+ inhibits GluA2(Q) homomeric receptors in an activity- and voltage-dependent manner, indicating a pore block mechanism. The rate of inhibition is slow, in the hundreds of milliseconds at millimolar Zn2+ concentrations; hence, the inhibition is only observed in the residual nondesensitizing currents. Consequently, the inhibition is higher for GluA2 receptors in complex with auxiliary subunits γ2 and γ8 where the residual activation is larger. The extent of inhibition is also dependent on charge at site 607, the site that undergoes RNA editing in GluA2 subunits replacing glutamine to arginine, with the percent inhibition being lower and IC50 being higher for the edited GluA2(R) relative to unedited GluA2(Q) and to GluA2(Q607E), a mutation observed in the genetic screen of a patient exhibiting developmental delays. We also show that Zn2+ inhibition is significant during rapid repetitive activity with pulses of millimolar concentrations of glutamate in both receptors expressed in HEK cells as well as in native receptors in cortical neurons of C57BL/6J mice of either sex, indicating a physiological relevance of this inhibition.SIGNIFICANCE STATEMENT Zn2+ is present along with glutamate in synaptic vesicles and coreleased during synaptic transmission, modulating the postsynaptic ionotropic glutamate receptors. While Zn2+ inhibition of the NMDA subtype of the ionotropic glutamate receptors is well characterized, the mechanism of modulation of the AMPA subtype is much less known. Here we have systematically studied Zn2+ inhibition of AMPARs by varying calcium permeability, auxiliary subunits, and activation levels and show that Zn2+ inhibits AMPARs in an activity-dependent manner, opening up this pathway as a means to pharmacologically modulate the receptors.

ID: 33608496
Title: Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling.
Abstract: Schizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8A391T) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8A391T mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8WT) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1β protein expression, and increased NFκB following TNFα stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.

ID: 33981006
Title: Schizophrenia-associated LRRTM1 regulates cognitive behavior through controlling synaptic function in the mediodorsal thalamus.
Abstract: Reduced activity of the mediodorsal thalamus (MD) and abnormal functional connectivity of the MD with the prefrontal cortex (PFC) cause cognitive deficits in schizophrenia. However, the molecular basis of MD hypofunction in schizophrenia is not known. Here, we identified leucine-rich-repeat transmembrane neuronal protein 1 (LRRTM1), a postsynaptic cell-adhesion molecule, as a key regulator of excitatory synaptic function and excitation-inhibition balance in the MD. LRRTM1 is strongly associated with schizophrenia and is highly expressed in the thalamus. Conditional deletion of Lrrtm1 in the MD in adult mice reduced excitatory synaptic function and caused a parallel reduction in the afferent synaptic activity of the PFC, which was reversed by the reintroduction of LRRTM1 in the MD. Our results indicate that chronic reduction of synaptic strength in the MD by targeted deletion of Lrrtm1 functionally disengages the MD from the PFC and may account for cognitive, social, and sensorimotor gating deficits, reminiscent of schizophrenia.

ID: 34370167
Title: Effects of Zinc, Mercury, or Lead on [3H]MK-801 and [3H]Fluorowillardiine Binding to Rat Synaptic Membranes.
Abstract: Glutamate (Glu) is considered the most important excitatory amino acid neurotransmitter in the mammalian Central Nervous System. Zinc (Zn) is co-released with Glu during synaptic transmission and interacts with Glutamate receptors and transporters. We performed binding experiments using [3H]MK-801 (NMDA), and [3H]Fluorowillardine (AMPA) as ligands to study Zn-Glutamate interactions in rat cortical synaptic membranes. We also examined the effects of mercury and lead on NMDA or AMPA receptors. Zinc at 1 nM, significantly potentiates [3H]MK-801 binding. Lead inhibits [3H]MK-801 binding at micromolar concentrations. At millimolar concentrations, Hg also has a significant inhibitory effect. These effects are not reversed by Zn (1 nM). Zinc displaces the [3H]FW binding curve to the right. Lead (nM) and Hg (μM) inhibit [3H]FW binding. At certain concentrations, Zn reverses the effects of these metals on [3H]FW binding. These specific interactions serve to clarify the role of Zn, Hg, and Pb in physiological and pathological conditions.

ID: 35320864
Title: Analysis of the Thickness of the Outer Retinal Layer Using Optical Coherence Tomography - A Predictor of Visual Acuity in Schizophrenia.
Abstract: The aim of this study was to evaluate the thickness of the outer retinal layer (ORL) together with macular thickness and changes in the retinal nerve fiber layer (RNFL) in patients with schizophrenia in comparison with healthy controls. This study included 114 eyes of 57 patients diagnosed with schizophrenia and 114 eyes of 57 healthy controls. Central foveal thickness (CFT), central macular thickness (CMT), and ORL thickness were measured in both groups via the images obtained by spectral-domain optical coherence tomography (SD-OCT). RNFL was also assessed in four quadrants (inferior, superior, temporal, nasal). CMT measurements were presented as the average thickness of the macula in the central 1 mm area on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. The ORL thickness was defined as the distance between the external limiting membrane and retinal pigment epithelium at the center of the foveal pit. The mean age of 57 patients was 37 ± 10 years, of whom 34 (60%) were male and 23 (40%) female. No statistically significant difference was found between groups in terms of age and gender (p = 0.8 for age, p = 0.9 for gender). There was no statistically significant difference in the mean CMT between the two groups (p = 0.1). The mean ORL thickness in the two groups was 99.8 ± 8.3 and 103.7 ± 6.2, respectively, and was significantly decreased in the schizophrenia group (p = 0.005). RNFL analysis demonstrated significant thinning in the inferior and superior quadrants compared to healthy controls (p < 0.001 and p = 0.017, respectively). SD-OCT findings - especially ORL and RNFL thickness - may be related to the neurodegenerational changes in schizophrenia. Das Ziel dieser Studie war es, die Dicke der äußeren Netzhautschicht (ORL) zusammen mit der Makuladicke und Veränderungen in der retinalen Nervenfaserschicht (RNFL) bei Patienten mit Schizophrenie im Vergleich zur gesunden Kontrollgruppe zu bewerten. Diese Studie umfasste 114 Augen von 57 Patienten mit diagnostizierter Schizophrenie und 114 Augen von 57 gesunden Kontrollpersonen. Die Dicke der zentralen Fovea (CFT), die Dicke der zentralen Makula (CMT) und die ORL-Dicke wurden in beiden Gruppen über die Bilder gemessen, die durch optische Kohärenztomografie im Spektralbereich (SD-OCT) erhalten wurden. RNFL wurde auch in 4 Quadranten (untere, obere, temporale, nasale) beurteilt. CMT-Messungen wurden als durchschnittliche Dicke der Makula im zentralen 1-mm-Bereich im Raster der Early Treatment Diabetic Retinopathy Study (ETDRS) dargestellt. Die ORL-Dicke wurde als der Abstand zwischen der äußeren Grenzmembran und dem retinalen Pigmentepithel im Zentrum der Foveagrube definiert. Das Durchschnittsalter von 57 Patienten betrug 37 ± 10 Jahre, davon waren 34 (60%) männlich und 23 (40%) weiblich. Es wurde kein statistisch signifikanter Unterschied zwischen den Gruppen in Bezug auf Alter und Geschlecht gefunden (p = 0,8 für Alter, p = 0,9 für Geschlecht). Es gab keinen statistisch signifikanten Unterschied in der mittleren CMT zwischen den beiden Gruppen (p = 0,1). Die mittlere ORL-Dicke in den beiden Gruppen betrug 99,8 ± 8,3 und 103,7 ± 6,2 und war in der Schizophreniegruppe signifikant verringert (p = 0,005). Die RNFL-Analyse zeigte eine signifikante Ausdünnung im unteren und oberen Quadranten im Vergleich zu gesunden Kontrollen (p < 0,001 bzw. p = 0,017). Die SD-OCT-Befunde – insbesondere die ORL und RNFL-Dicke – können mit den neurodegenerativen Veränderungen bei Schizophrenie zusammenhängen.

ID: 36123224
Title: Consider the pons: bridging the gap on sensory prediction abnormalities in schizophrenia.
Abstract: A shared mechanism across species heralds the arrival of self-generated sensations, helping the brain to anticipate, and therefore distinguish, self-generated from externally generated sensations. In mammals, this sensory prediction mechanism is supported by communication within a cortico-ponto-cerebellar-thalamo-cortical loop. Schizophrenia is associated with impaired sensory prediction as well as abnormal structural and functional connections between nodes in this circuit. Despite the pons' principal role in relaying and processing sensory information passed from the cortex to cerebellum, few studies have examined pons connectivity in schizophrenia. Here, we first briefly describe how the pons contributes to sensory prediction. We then summarize schizophrenia-related abnormalities in the cortico-ponto-cerebellar-thalamo-cortical loop, emphasizing the dearth of research on the pons relative to thalamic and cerebellar connections. We conclude with recommendations for advancing our understanding of how the pons relates to sensory prediction failures in schizophrenia.

ID: 36259267
Title: Systematic analysis to identify novel disease indications and plausible potential chemical leads of glutamate ionotropic receptor NMDA type subunit 1, GRIN1.
Abstract: Schizophrenia is a mental illness affecting the normal lifestyle of adults and early adolescents incurring major symptoms as jumbled speech, involvement in everyday activities eventually got reduced, patients always struggle with attention and memory, reason being both the genetic and environmental factors responsible for altered brain chemistry and structure, resulting in schizophrenia and associated orphan diseases. The network biology describes the interactions among genes/proteins encoding molecular mechanisms of biological processes, development, and diseases. Besides, all the molecular networks, protein-protein Interaction Networks have been significant in distinguishing the pathogenesis of diseases and thereby drug discovery. The present meta-analysis prioritizes novel disease indications viz. rare and orphan diseases associated with target Glutamate Ionotropic Receptor NMDA Type Subunit 1, GRIN1 using text mining knowledge-based tools. Furthermore, ZINC database was virtually screened, and binding conformation of selected compounds was performed and resulted in the identification of Narciclasine (ZINC04097652) and Alvespimycin (ZINC73138787) as potential inhibitors. Furthermore, docked complexes were subjected to MD simulation studies which suggests that the identified leads could be a better potential drug to recuperate schizophrenia.

ID: 36535137
Title: Disrupted auditory N1, theta power and coherence suppression to willed speech in people with schizophrenia.
Abstract: The phenomenon of sensory self-suppression - also known as sensory attenuation - occurs when a person generates a perceptible stimulus (such as a sound) by performing an action (such as speaking). The sensorimotor control system is thought to actively predict and then suppress the vocal sound in the course of speaking, resulting in lowered cortical responsiveness when speaking than when passively listening to an identical sound. It has been hypothesized that auditory hallucinations in schizophrenia result from a reduction in self-suppression due to a disruption of predictive mechanisms required to anticipate and suppress a specific, self-generated sound. It has further been hypothesized that this suppression is evident primarily in theta band activity. Fifty-one people, half of whom had a diagnosis of schizophrenia, were asked to repeatedly utter a single syllable, which was played back to them concurrently over headphones while EEG was continuously recorded. In other conditions, recordings of the same spoken syllables were played back to participants while they passively listened, or were played back with their onsets preceded by a visual cue. All participants experienced these conditions with their voice artificially shifted in pitch and also with their unaltered voice. Suppression was measured using event-related potentials (N1 component), theta phase coherence and power. We found that suppression was generally reduced on all metrics in the patient sample, and when voice alteration was applied. We additionally observed reduced theta coherence and power in the patient sample across all conditions. Visual cueing affected theta coherence only. In aggregate, the results suggest that sensory self-suppression of theta power and coherence is disrupted in schizophrenia.

ID: 36584680
Title: Brainstem serotonin neurons selectively gate retinal information flow to thalamus.
Abstract: Retinal ganglion cell (RGC) types relay parallel streams of visual feature information. We hypothesized that neuromodulators might efficiently control which visual information streams reach the cortex by selectively gating transmission from specific RGC axons in the thalamus. Using fiber photometry recordings, we found that optogenetic stimulation of serotonergic axons in primary visual thalamus of awake mice suppressed ongoing and visually evoked calcium activity and glutamate release from RGC boutons. Two-photon calcium imaging revealed that serotonin axon stimulation suppressed RGC boutons that responded strongly to global changes in luminance more than those responding only to local visual stimuli, while the converse was true for suppression induced by increases in arousal. Converging evidence suggests that differential expression of the 5-HT1B receptor on RGC presynaptic terminals, but not differential density of nearby serotonin axons, may contribute to the selective serotonergic gating of specific visual information streams before they can activate thalamocortical neurons.

ID: 36757182
Title: Cortical and thalamic modulation of auditory gating in the posterior parietal cortex of awake mice.
Abstract: Auditory gating (AG) is an adaptive mechanism for filtering out redundant acoustic stimuli to protect the brain against information overload. AG deficits have been found in many mental illnesses, including schizophrenia (SZ). However, the neural correlates of AG remain poorly understood. Here, we found that the posterior parietal cortex (PPC) shows an intermediate level of AG in auditory thalamocortical circuits, with a laminar profile in which the strongest AG is in the granular layer. Furthermore, AG of the PPC was decreased and increased by optogenetic inactivation of the medial dorsal thalamic nucleus (MD) and auditory cortex (AC), respectively. Optogenetically activating the axons from the MD and AC drove neural activities in the PPC without an obvious AG. These results indicated that AG in the PPC is determined by the integrated signal streams from the MD and AC in a bottom-up manner. We also found that a mouse model of SZ (postnatal administration of noncompetitive N-methyl-d-aspartate receptor antagonist) presented an AG deficit in the PPC, which may be inherited from the dysfunction of MD. Together, our findings reveal a neural circuit underlying the generation of AG in the PPC and its involvement in the AG deficit of SZ.

ID: 37585291
Title: Synaptic zinc potentiates AMPA receptor function in mouse auditory cortex.
Abstract: Synaptic zinc signaling modulates synaptic activity and is present in specific populations of cortical neurons, suggesting that synaptic zinc contributes to the diversity of intracortical synaptic microcircuits and their functional specificity. To understand the role of zinc signaling in the cortex, we performed whole-cell patch-clamp recordings from intratelencephalic (IT)-type neurons and pyramidal tract (PT)-type neurons in layer 5 of the mouse auditory cortex during optogenetic stimulation of specific classes of presynaptic neurons. Our results show that synaptic zinc potentiates AMPA receptor (AMPAR) function in a synapse-specific manner. We performed in vivo 2-photon calcium imaging of the same classes of neurons in awake mice and found that changes in synaptic zinc can widen or sharpen the sound-frequency tuning bandwidth of IT-type neurons but only widen the tuning bandwidth of PT-type neurons. These results provide evidence for synapse- and cell-type-specific actions of synaptic zinc in the cortex.

ID: 37678144
Title: Reduced neural connectivity in the caudate anterior head predicts hallucination severity in schizophrenia.
Abstract: Caudate functional abnormalities have been identified as one critical neural substrate underlying sensory gating impairments that lead to auditory phantom hallucinations in both patients with schizophrenia (SZ) and tinnitus, characterized by the perception of internally generated sounds in the absence of external environmental auditory stimuli. In this study, we tested the hypothesis as to whether functional connectivity abnormalities in distinct caudate subdivisions implicated in sensory gating and auditory phantom percepts in tinnitus, which are currently being localized for neuromodulation targeting using deep brain stimulation techniques, would be associated with auditory phantom hallucination severity in SZ. Twenty five SZ and twenty eight demographically-matched healthy control (HC) participants, completed this fMRI resting-state study and clinical assessments. Between-group seed-to-voxel analyses revealed only one region, the caudate anterior head, which showed reduced functional connectivity with the thalamus that survived whole-brain multiple comparison corrections. Importantly, connectivity between the caudate anterior head with thalamus negatively correlated with hallucination severity. In the present study, we deliver the first evidence of caudate subdivision specificity for the neural pathophysiology underlying hallucinations in schizophrenia within a sensory gating framework that has been developed for auditory phantoms in patients with tinnitus. Our findings provide transdiagnostic convergent evidence for the role of the caudate in the gating of auditory phantom hallucinations, observed across patients with SZ and tinnitus by specifying the anterior caudate division is key to mediation of hallucinations, and creating a path towards personalized treatment approaches to arrest auditory phantom hallucinations from reaching perceptual awareness.

ID: 38025441
Title: The effect of multisensory semantic congruency on unisensory object recognition in schizophrenia.
Abstract: Multisensory, as opposed to unisensory processing of stimuli, has been found to enhance the performance (e.g., reaction time, accuracy, and discrimination) of healthy individuals across various tasks. However, this enhancement is not as pronounced in patients with schizophrenia (SZ), indicating impaired multisensory integration (MSI) in these individuals. To the best of our knowledge, no study has yet investigated the impact of MSI deficits in the context of working memory, a domain highly reliant on multisensory processing and substantially impaired in schizophrenia. To address this research gap, we employed two adopted versions of the continuous object recognition task to investigate the effect of single-trail multisensory encoding on subsequent object recognition in 21 schizophrenia patients and 21 healthy controls (HC). Participants were tasked with discriminating between initial and repeated presentations. For the initial presentations, half of the stimuli were audiovisual pairings, while the other half were presented unimodal. The task-relevant stimuli were then presented a second time in a unisensory manner (either auditory stimuli in the auditory task or visual stimuli in the visual task). To explore the impact of semantic context on multisensory encoding, half of the audiovisual pairings were selected to be semantically congruent, while the remaining pairs were not semantically related to each other. Consistent with prior studies, our findings demonstrated that the impact of single-trial multisensory presentation during encoding remains discernible during subsequent object recognition. This influence could be distinguished based on the semantic congruity between the auditory and visual stimuli presented during the encoding. This effect was more robust in the auditory task. In the auditory task, when congruent multisensory pairings were encoded, both participant groups demonstrated a multisensory facilitation effect. This effect resulted in improved accuracy and RT performance. Regarding incongruent audiovisual encoding, as expected, HC did not demonstrate an evident multisensory facilitation effect on memory performance. In contrast, SZs exhibited an atypically accelerated reaction time during the subsequent auditory object recognition. Based on the predictive coding model we propose that this observed deviations indicate a reduced semantic modulatory effect and anomalous predictive errors signaling, particularly in the context of conflicting cross-modal sensory inputs in SZ.

ID: 38061467
Title: Activation of Metabotropic Glutamate Receptor 3 Modulates Thalamo-accumbal Transmission and Rescues Schizophrenia-Like Physiological and Behavioral Deficits.
Abstract: Polymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear. We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits. We first established that PCP treatment augmented excitatory transmission onto dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell. These data demonstrate that activation of mGlu3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia.

ID: 38143202
Title: The pulvinar as a hub of visual processing and cortical integration.
Abstract: The pulvinar nucleus of the thalamus is a crucial component of the visual system and plays significant roles in sensory processing and cognitive integration. The pulvinar's extensive connectivity with cortical regions allows for bidirectional communication, contributing to the integration of sensory information across the visual hierarchy. Recent findings underscore the pulvinar's involvement in attentional modulation, feature binding, and predictive coding. In this review, we highlight recent advances in clarifying the pulvinar's circuitry and function. We discuss the contributions of the pulvinar to signal modulation across the global cortical network and place these findings within theoretical frameworks of cortical processing, particularly the global neuronal workspace (GNW) theory and predictive coding.

ID: 38245499
Title: Abnormal Oculomotor Corollary Discharge Signaling as a Trans-diagnostic Mechanism of Psychosis.
Abstract: Corollary discharge (CD) signals are "copies" of motor signals sent to sensory areas to predict the corresponding input. They are a posited mechanism enabling one to distinguish actions generated by oneself vs external forces. Consequently, altered CD is a hypothesized mechanism for agency disturbances in psychosis. Previous studies have shown a decreased influence of CD signals on visual perception in individuals with schizophrenia-particularly in those with more severe positive symptoms. We therefore hypothesized that altered CD may be a trans-diagnostic mechanism of psychosis. We examined oculomotor CD (using the blanking task) in 49 participants with schizophrenia or schizoaffective disorder (SZ), 36 bipolar participants with psychosis (BPP), and 40 healthy controls (HC). Participants made a saccade to a visual target. Upon saccade initiation, the target disappeared and reappeared at a horizontally displaced position. Participants indicated the direction of displacement. With intact CD, participants can make accurate perceptual judgements. Otherwise, participants may use saccade landing site as a proxy of pre-saccadic target to inform perception. Thus, multi-level modeling was used to examine the influence of target displacement and saccade landing site on displacement judgements. SZ and BPP were equally less sensitive to target displacement than HC. Moreover, regardless of diagnosis, SZ and BPP with more severe positive symptoms were more likely to rely on saccade landing site. These results suggest that altered CD may be a trans-diagnostic mechanism of psychosis.

ID: 38422784
Title: Sleep spindle activity and psychotic experiences: Examining the mediating roles of attentional performance and perceptual distortions in a daytime nap study.
Abstract: Decreased sleep spindle activity in individuals with psychotic disorders is well studied, but its contribution to psychotic symptom formation is not well understood. This study explored potential underlying mechanisms explaining the association between decreased sleep spindle activity and psychotic symptoms. To this end, we analysed the links between sleep spindle activity and psychotic experiences and probed for the mediating roles of attentional performance and perceptual distortions in a community sample of young adults (N = 70; 26.33 ± 4.84 years). Polysomnography was recorded during a 90-min daytime nap and duration, amplitude, and density from slow (10-13 Hz) and fast (13-16 Hz) spindles were extracted. Attentional performance was assessed via a test battery and with an antisaccadic eye movement task. Psychotic experiences (i.e., paranoid thoughts; hallucinatory experiences) and perceptual distortions (i.e., anomalous perceptions; sensory gating deficits) were assessed via self-report questionnaires. We conducted sequential mediation analyses with spindle activity as predictor, psychotic experiences as dependent variable, and attentional performance and perceptual distortions as mediators. We found reduced right central spindle amplitude to be associated with paranoid thoughts. Increased antisaccadic error rate was associated with anomalous perceptions and perceptual distortions were associated with psychotic experiences. We did not find significant mediation effects. The findings support the notion that reduced sleep spindle activity is involved in the formation of paranoid thoughts and that decreased antisaccadic performance is indicative of perceptual distortions as potential precursors for psychotic experiences. However, further research is needed to corroborate the proposed mediation hypothesis.

ID: 38830758
Title: Trans-synaptic Association of Vesicular Zinc Transporter 3 and Shank3 Supports Synapse-Specific Dendritic Spine Structure and Function in the Mouse Auditory Cortex.
Abstract: Shank3 is a synaptic scaffolding protein that assists in tethering and organizing structural proteins and glutamatergic receptors in the postsynaptic density of excitatory synapses. The localization of Shank3 at excitatory synapses and the formation of stable Shank3 complexes is regulated by the binding of zinc to the C-terminal sterile-alpha-motif (SAM) domain of Shank3. Mutations in the SAM domain of Shank3 result in altered synaptic function and morphology, and disruption of zinc in synapses that express Shank3 leads to a reduction of postsynaptic proteins important for synaptic structure and function. This suggests that zinc supports the localization of postsynaptic proteins via Shank3. Many regions of the brain are highly enriched with free zinc inside glutamatergic vesicles at presynaptic terminals. At these synapses, zinc transporter 3 (ZnT3) moves zinc into vesicles where it is co-released with glutamate. Alterations in ZnT3 are implicated in multiple neurodevelopmental disorders, and ZnT3 knock-out (KO) mice-which lack synaptic zinc-show behavioral deficits associated with autism spectrum disorder and schizophrenia. Here we show that male and female ZnT3 KO mice have smaller dendritic spines and miniature excitatory postsynaptic current amplitudes than wildtype (WT) mice in the auditory cortex. Additionally, spine size deficits in ZnT3 KO mice are restricted to synapses that express Shank3. In WT mice, synapses that express both Shank3 and ZnT3 have larger spines compared to synapses that express Shank3 but not ZnT3. Together these findings suggest a mechanism whereby presynaptic ZnT3-dependent zinc supports postsynaptic structure and function via Shank3 in a synapse-specific manner.

ID: 38988003
Title: Schizophrenia-Like Deficits and Impaired Glutamate/Gamma-aminobutyric acid Homeostasis in Zfp804a Conditional Knockout Mice.
Abstract: Zinc finger protein 804A (ZNF804A) was the first genome-wide associated susceptibility gene for schizophrenia (SCZ) and played an essential role in the pathophysiology of SCZ by influencing neurodevelopment regulation, neurite outgrowth, synaptic plasticity, and RNA translational control; however, the exact molecular mechanism remains unclear. A nervous-system-specific Zfp804a (ZNF804A murine gene) conditional knockout (cKO) mouse model was generated using clustered regularly interspaced short palindromic repeat/Cas9 technology and the Cre/loxP method. Multiple and complex SCZ-like behaviors, such as anxiety, depression, and impaired cognition, were observed in Zfp804a cKO mice. Molecular biological methods and targeted metabolomics assay validated that Zfp804a cKO mice displayed altered SATB2 (a cortical superficial neuron marker) expression in the cortex; aberrant NeuN, cleaved caspase 3, and DLG4 (markers of mature neurons, apoptosis, and postsynapse, respectively) expressions in the hippocampus and a loss of glutamate (Glu)/γ-aminobutyric acid (GABA) homeostasis with abnormal GAD67 (Gad1) expression in the hippocampus. Clozapine partly ameliorated some SCZ-like behaviors, reversed the disequilibrium of the Glu/GABA ratio, and recovered the expression of GAD67 in cKO mice. Zfp804a cKO mice reproducing SCZ-like pathological and behavioral phenotypes were successfully developed. A novel mechanism was determined in which Zfp804a caused Glu/GABA imbalance and reduced GAD67 expression, which was partly recovered by clozapine treatment. These findings underscore the role of altered gene expression in understanding the pathogenesis of SCZ and provide a reliable SCZ model for future therapeutic interventions and biomarker discovery.

ID: 39181388
Title: The Mechanisms of Persisting Disability in Schizophrenia: Imprecise Predictive Coding via Corticostriatothalamic-Cortical Loop Dysfunction.
Abstract: Persisting symptoms and disability remain a problem for an appreciable proportion of people with schizophrenia despite treatment with antipsychotic medication. Improving outcomes requires an understanding of the nature and mechanisms of the pathological processes underlying persistence. Classical features of schizophrenia, which include disorganization and impoverishment of mental activity, are well-recognized early clinical features that predict poor long-term outcome. Substantial evidence indicates that these features reflect imprecise predictive coding. Predictive coding provides an overarching framework for understanding efficient functioning of the nervous system. Imprecise predictive coding also has the potential to precipitate acute psychosis characterized by reality distortion (delusions and hallucinations) at times of stress. On the other hand, substantial evidence indicates that persistent reality distortion itself gives rise to poor occupational and social function in the long term. Furthermore, abuse of psychotomimetic drugs, which exacerbate reality distortion, contributes to poor long-term outcome in schizophrenia. Neural circuits involved in modulating volitional acts are well understood to be implicated in addiction. Plastic changes in these circuits may account for the association between psychotomimetic drug abuse and poor outcomes in schizophrenia. We propose a mechanistic model according to which unbalanced inputs to the corpus striatum disturb the precision of subcortical modulation of cortical activity supporting volitional action. This model accounts for the evidence that early classical symptoms predict poor outcome, while in some circumstances, persistent reality distortion also predicts poor outcome. This model has implications for the development of novel treatments that address the risk of persisting symptoms and disabilities in schizophrenia.

ID: 39922063
Title: Auditory MMN is associated with the volume of thalamic higher order nuclei in individuals with psychotic disorders and healthy controls.
Abstract: Predictive coding is a theoretical framework that integrates models of brain dysconnectivity and psychopathology in psychosis. Thalamocortical dysconnectivity as well as reduced thalamic volumes have been reported in psychotic disorders. However, the role of the thalamus in predictive coding is not clear. We examined the relationship between magnetic resonance imaging (MRI)- based thalamic nuclei volumes and mismatch negativity (MMN), a purported index of prediction error signaling known to be impaired in psychosis. We obtained MRI and MMN using a roving paradigm from individuals with SCZ spectrum disorder (SSD, n = 60) or bipolar disorder (BD, n = 69) and HC (n = 252). We segmented volumes of 25 thalamic nuclei bilaterally and tested their associations with MMN amplitude using linear models while covarying for age, sex, diagnosis, and intracranial volumes (ICV). We did not find group differences in thalamic volumes that could account for differences in MMN, neither did we find significant volume × diagnosis interactions on MMN for any of the 25 nuclei examined. Across the whole sample, significant positive associations were found between MMN amplitude and the volumes of several higher-order thalamic nuclei, including the mediodorsal medial and lateral nuclei, anterior and medial pulvinar, nucleus reuniens, as well as the lateral geniculate nucleus. The results demonstrate a positive association between MMN amplitude and volumes of thalamic association nuclei in patients with psychotic disorders and HC. These findings may suggest a modulatory role of the thalamus in prediction error signaling.

ID: 39930095
Title: A thalamic hub-and-spoke network enables visual perception during action by coordinating visuomotor dynamics.
Abstract: For accurate perception and motor control, an animal must distinguish between sensory experiences elicited by external stimuli and those elicited by its own actions. The diversity of behaviors and their complex influences on the senses make this distinction challenging. Here, we uncover an action-cue hub that coordinates motor commands with visual processing in the brain's first visual relay. We show that the ventral lateral geniculate nucleus (vLGN) acts as a corollary discharge center, integrating visual translational optic flow signals with motor copies from saccades, locomotion and pupil dynamics. The vLGN relays these signals to correct action-specific visual distortions and to refine perception, as shown for the superior colliculus and in a depth-estimation task. Simultaneously, brain-wide vLGN projections drive corrective actions necessary for accurate visuomotor control. Our results reveal an extended corollary discharge architecture that refines early visual transformations and coordinates actions via a distributed hub-and-spoke network to enable visual perception during action.

ID: 40954276
Title: Cerebral glutamate levels over two years in initially antipsychotic-naïve first-episode patients with psychosis are related to clinical symptoms and cognition.
Abstract: Although emerging evidence supports glutamatergic dysfunction in schizophrenia, clinical trials with glutamatergic compounds have overall been negative. This may be due to changes in glutamate levels during the course of illness. To address this, we measured glutamate levels in dorsal anterior cingulate cortex (dACC) and left thalamus in 57 initially antipsychotic-naïve patients with first-episode psychosis (FEP) aged 22.6 ± 5.0 years (58% females) and 55 healthy controls (HC) on a 3T MR scanner at baseline, after six weeks (48 FEP and 53 HC), six months (37 FEP and 49 HC), and two years (35 FEP and 45 HC). Positive and negative symptoms and cognitive function in tests of attention and spatial working memory were assessed at all visits. Linear mixed models were used in statistical analyses. We found lower glutamate levels in dACC in FEP (p = 0.03) that was associated with deficits in attention at all visits (p < 0.05). Thalamic glutamate levels did not differ between groups, but higher levels were related to more pronounced positive symptoms at all visits (p = 0.02). The relation between thalamic glutamate levels and negative symptoms was altered over time (negative symptoms*time: p = 0.003) due to a significant positive association after two years (p = 0.04) but not at other visits. For other metabolites, thalamic NAA were lower in FEP (p = 0.04) and total creatine was increased after 6 weeks treatment (p = 0.01), whereas dACC glx levels were lower after two years (p = 0.02). The results suggest that greater positive symptom severity is related to higher thalamic glutamate levels and cognitive deficits to lower dACC glutamate levels during the first two years of illness. Furthermore, higher thalamic glutamate levels after two years are associated with more severe negative symptomatology. Findings imply that glutamatergic compounds decreasing thalamic and increasing dACC glutamate levels may be beneficial in FEP over the first two years of illness.

ID: 41090773
Title: Nucleus Reuniens-Elicited Delta Oscillations Disable the Prefrontal Cortex in Schizophrenia.
Abstract: Schizophrenia (SZ) is a severe mental disorder associated with an array of symptoms characterized as positive, negative and cognitive dysfunctions. While SZ is a multifaceted disorder affecting several regions of the brain, altered thalamocortical systems have emerged as a leading contributor to SZ. Specifically, it has been shown that: (1) the thalamus is functionally disconnected from the prefrontal cortex (PFC) in SZ; (2) neural activity and blood flow to the PFC are greatly diminished in SZ (hypofrontality); and (3) delta oscillations are abnormally present in the PFC during the waking state in SZ. We suggest that the abnormal delta oscillations drive the other PFC signs of SZ. Specifically, decreases in energy required to maintain delta, would initiate the reduced PFC perfusion of SZ (hypofrontality), and contribute to the 'mismatched' thalamic and PFC activity of SZ. As SZ involves glutamate (NMDAR) hypofunction and dopamine hyperfunction, both NMDAR antagonists and dopamine agonists produce marked increases in delta oscillations in nucleus reuniens (RE) of the thalamus and its target structures, including the PFC. This would suggest that RE is a primary source for the elicitation of PFC delta activity, and the presence of delta during waking (together with associated signs) would indicate that the prefrontal cortex is disabled (or non-functional) in schizophrenia.

ID: 41646396
Title: Ascending and descending motor pathways converge in the centrolateral nucleus of the thalamus.
Abstract: Corollary discharge (CD) signals are copies of motor commands that inform the brain of impending movements. Dysfunction in CD has been implicated in a variety of disorders, from schizophrenia to Parkinson's disease. In the current study, we used intersectional viral tracing techniques, electron microscopy, and dual opsin optogenetics to investigate potential CD circuits in mice. We focused on the centrolateral (CL) nucleus of the thalamus to relate our findings to previous studies of CD carried out in primates. We found that single neurons in the CL integrate ascending inputs from premotor neurons in the superior colliculus with descending inputs from neurons in layer 5 of the motor cortex; these integrated signals are subsequently sent to the striatum and motor cortex. These results suggest that CL circuits may detect the relative timing of cortical and subcortical movement commands, providing an important feedback loop for ongoing adjustments of movement planning and initiation.

ID: 41654197
Title: An emerging role for synaptic Zn2+ in substance use disorders.
Abstract: Synaptic zinc (Zn2+) modulates dopamine and glutamate neurotransmission by binding to the dopamine transporter and glutamate receptors. Among other neurotransmitters, dopamine and glutamate critically regulate physiological processes and behaviors relevant to substance use disorders (SUDs) and addiction. In addition, Zn2+ interacts with inhibitory neurotransmitter systems, including GABA and glycine receptors, further influencing the excitatory-inhibitory balance within circuits relevant to addiction. Nevertheless, the specific involvement of synaptic Zn2+ in such processes is unknown. We propose that synaptic Zn2+ serves as an environmentally derived factor that can influence the vulnerability to and development of SUDs and addiction via its interaction with proteins that regulate dopamine and glutamate neurotransmission in addiction-relevant brain circuits.

ID: 41656814
Title: [Retinal protective effects of zinc-loaded magnesium oxide nanoparticles in a glutamate-excitotoxicity glaucoma model].
Abstract: Glaucoma is pathologically characterized by the progressive loss of retinal ganglion cells (RGCs). Currently, effective strategies for protection of RGCs in glaucoma remain lacking, and nanomaterials represent promising drug-delivery carriers. This study aims to investigate the effects of zinc-loaded magnesium oxide nanoparticles (MgO-Zn²⁺ nanoparticles, MgO-Zn NPs) on glutamate-induced RGC injury, and to evaluate their in vivo and in vitro biocompatibility and neuroprotective potential. MgO-Zn NPs were prepared and characterized by transmission electron microscope and energy-dispersive spectroscopy. In vitro cytotoxicity was systematically evaluated in the R28 rat retinal precursor cell line using the cell counting kit-8 (CCK-8) assay. In vivo, an excitotoxic retinal injury model was established in C57/BL mice by intravitreal injection of N-methyl-D-aspartate (NMDA), followed by MgO-Zn NP intervention. RGC numbers and apoptosis were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Retinal-layer structure was examined by hematoxylin and eosin (HE) staining. Flash visual evoked potential (F-VEP) was used to evaluate RGC visual-conduction function, and RNA sequencing was performed to analyze pathways and functions of differentially expressed genes, with further validation of associated protein-expression differences. Transmission electron microscope and energy-dispersive spectroscopy confirmed the morphological and compositional characteristics of MgO-Zn NPs, indicating successful composite synthesis. CCK-8 results showed that MgO-Zn NPs at 75 µg/mL exhibited no cytotoxicity in R28 cells. After intravitreal injection of MgO-Zn NPs in mice, no significant ocular surface or corneal adverse reactions were observed, indicating favorable ocular tolerance. TUNEL staining showed that RGC numbers in the excitotoxic model were significantly lower than those in normal mice (P<0.05), confirming successful model establishment, whereas MgO-Zn NPs significantly reduced NMDA-induced RGC apoptosis (P<0.05). HE staining showed partial structural restoration of retinal layers after MgO-Zn NP intervention (P<0.05). F-VEP measurements showed prolonged P2 latency and decreased amplitude in model mice (both P<0.001), while MgO-Zn NP intervention resulted in partial recovery of P2 latency and amplitude (both P<0.05). RNA sequencing indicated that MgO-Zn NPs alleviated NMDA-induced retinal transcriptome abnormalities, with differentially expressed genes mainly associated with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway and the mammalian target of rapamycin (mTOR) signaling pathway. Immunofluorescence staining further showed that MgO-Zn NPs significantly decreased retinal p-Akt and p-mTOR expression levels (both P<0.01). MgO-Zn NPs may serve as a dual-functional glaucoma treatment candidate, providing retinal-neuron protection while acting as an intraocular drug-delivery carrier. 目的: 青光眼的病理特征主要表现为视网膜神经节细胞(retinal ganglion cells，RGCs)的进行性丧失。目前针对青光眼尚缺乏有效的RGCs保护策略，纳米材料是有潜力的药物递送载体。本研究旨在探索载锌氧化镁纳米颗粒(MgO-Zn²⁺ nanoparticles，MgO-Zn NPs)对谷氨酸诱导RGCs损伤的作用，并评价其体内外生物相容性及神经保护潜能。方法: 制备MgO-Zn NPs。通过透射电子显微镜及能谱分析等对MgO-Zn NPs进行表征。体外实验以大鼠视网膜前体细胞系R28为研究对象，采用细胞计数试剂盒8(cell counting kit-8，CCK-8)法系统评估MgO-Zn NPs的细胞毒性。体内实验以C57/BL小鼠为研究对象，通过玻璃体内注射N-甲基-D-天冬氨酸(N-methyl-D-aspartate，NMDA)建立小鼠视网膜兴奋毒性模型，并用MgO-Zn NPs干预。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法(terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling，TUNEL)染色评估小鼠视网膜RGCs的数量及凋亡情况。采用苏木精-伊红(hematoxylin and eosin，HE)染色检查小鼠的视网膜层结构。采用闪光视觉诱发电位(flash visual evoked potential，F-VEP)评价RGCs视觉传导功能。对小鼠视网膜组织进行RNA测序，分析差异表达基因的通路及功能，并进一步验证小鼠视网膜组织相关蛋白质表达水平的差异。结果: 透射电子显微镜及能谱分析成功证实了MgO-Zn NPs的形貌及成分特征，确认复合物制备成功。CCK-8检测结果表明:75 µg/mL MgO-Zn NPs对R28细胞无毒性。体内实验发现:小鼠玻璃体腔内注射MgO-Zn NPs溶液后，其眼表和角膜均未出现明显不良反应，显示其良好的眼部耐受性。TUNEL染色结果显示:视网膜兴奋毒性模型小鼠的RGCs数量较正常小鼠显著减少(P<0.05)，表明模型建立成功;而MgO-Zn NPs干预后显著减少了NMDA诱导的RGCs凋亡(P<0.05)。HE染色表明:MgO-Zn NPs干预后模型小鼠视网膜层结构得到部分恢复(P<0.05)。F-VEP测量结果显示:模型小鼠的P2波潜伏期增长、振幅降低(均P<0.001)，接受MgO-Zn NPs干预的模型小鼠P2波的潜伏期和振幅均得到一定程度的恢复(均P<0.05)。RNA测序结果表明:MgO-Zn NPs改善了NMDA诱导的视网膜转录组异常，差异表达基因主要与磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase，PI3K)-蛋白激酶B(protein kinase B，Akt)通路和哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)信号通路相关。免疫荧光染色结果显示:MgO-Zn NPs干预显著降低了模型小鼠视网膜组织的p-Akt和p-mTOR的表达水平(均P<0.01)。结论: MgO-Zn NPs既可保护视网膜神经元，又可作为眼内药物递送载体，有望作为具有双重功能的青光眼治疗候选药物。.

ID: 42057649
Title: The association among glutamate, GABA, and anterior cingulate connectivity in schizophrenia spectrum disorders: Implications for symptom domains.
Abstract: Schizophrenia-spectrum disorders (SSD) are characterized by structural and functional brain abnormalities, including disrupted functional connectivity within networks such as the salience network. The anterior cingulate cortex (ACC), a core hub of this network, has shown alterations in the major neurotransmitter systems comprising glutamate (Glu) and γ-aminobutyric acid (GABA). While dysfunctional glutamatergic signaling has been proposed as a key mechanism in SSDs, the relationship between anterior cingulate cortex (ACC) functional connectivity, glutamatergic neurotransmission, and clinical symptomatology remains poorly understood. Here, we combined resting-state functional MRI to measure functional brain connectivity with proton magnetic resonance spectroscopy to measure Glu and GABA levels in the dorsal ACC of 26 patients with schizophrenia spectrum disorders and 38 healthy controls. Patients showed reduced connectivity within the salience network compared to controls. Across the whole sample, a dorsal ACC-seed showed glutamate-dependent connectivity to several clusters, including right insula, thalamus, and cerebellum. In patients, the averaged connectivity of these clusters was associated with positive symptom severity. These findings suggest that disrupted glutamatergic modulation of large-scale brain networks may underlie core clinical features in schizophrenia spectrum disorders.

ID: 42349608
Title: How Do Similar Thalamocortical Circuits Produce Psychosis Versus Compulsivity?
Abstract: The thalamus is now recognized as a dynamic regulator of cortical information flow, with the thalamic reticular nucleus (TRN) providing inhibitory control over the routing, gain, and timing of thalamocortical communication. Schizophrenia and obsessive-compulsive disorder (OCD) both involve thalamocortical abnormalities, yet produce distinct clinical phenotypes, psychosis versus compulsivity. This narrative review synthesizes evidence from neuroimaging, electrophysiology, postmortem studies, and animal models to compare thalamocortical gating mechanisms across these disorders. In schizophrenia, converging evidence supports weakened TRN-mediated inhibition as a core gating deficit. Postmortem reductions in GAD67 and parvalbumin within TRN neurons, optogenetic models reproducing sensory gating deficits through TRN parvalbumin (PV) suppression, and a ∼40% reduction in sleep spindle density collectively point to diminished inhibitory regulation of thalamic relay output. At the network level, this maps onto reduced thalamo-prefrontal connectivity with increased thalamo-sensorimotor coupling, consistent with deficient top-down filtering and excessive bottom-up sensory transmission. In OCD, no study has directly examined TRN structure or function. However, cortico-striato-thalamo-cortical (CSTC) models implicate thalamic relay disinhibition through basal ganglia pathways, and emerging evidence of increased spindle frequencies correlating with obsession severity suggests a pattern qualitatively distinct from schizophrenia. These preliminary observations raise the possibility that OCD involves temporally inflexible rather than weakened gating, though this hypothesis remains speculative. Together, these lines of evidence suggest that similar thalamocortical architectures may be disrupted through distinct regulatory mechanisms, insufficient inhibitory control versus loss of temporal flexibility, offering a framework for understanding how overlapping circuits produce divergent psychiatric phenotypes.

ID: 42377275
Title: The clinical and molecular landscape of thalamic glioma.
Abstract: Thalamic gliomas (TGs) remain a formidable clinical challenge for accurate diagnosis and effective therapy. This study aims to refine molecular diagnosis and surgical management of TGs by integrating clinicopathological and multi-omics data. We analyzed 106 TGs, comprising 65 diffuse midline glioma (DMG) and 41 non-DMG, using genomic profiling, single-cell RNA sequencing, and orthogonal assays. Surgical outcomes were evaluated using rigorous causal inference frameworks, including propensity score matching and difference-in-differences analyses. Genomic profiling revealed striking mutual exclusivity between H3F3A mutations and CDKN2A/B (9p21) loss. Single-cell and orthogonal assays validated that 9p21 loss emerged as a highly specific adjunctive marker favoring non-DMG over DMG. Causal inference analyses consistently demonstrated that microsurgical third ventriculostomy (mTV) confers profound protection against postoperative hydrocephalus (risk reduction > 60%). Multivariate analysis identified the transfrontal approach as an independent predictor of postoperative motor deficits. Survival analysis showed that the median overall survival of this cohort following surgical resection was 21.0 months. Extent of resection and tumor mutational burden emerged as the principal independent determinants of prognosis, whereas postoperative KPS showed survival stratification in univariable/subgroup analyses but was not independently significant in multivariable model. In this 106-patient cohort study, we delineated the somatic mutational landscape of thalamic glioma and showed that 9p21 loss is mutually exclusive with H3F3A mutations, providing a highly specific adjunctive marker for thalamic glioma. We further demonstrated that maximal surgical resection confers a survival benefit and intraoperative mTV serves as a standardized treatment workflow to optimize care for thalamic glioma. Thalamic gliomas are rare brain tumors that grow in a deep and delicate part of the brain, making both diagnosis and surgery especially difficult. In this study, we analyzed 106 surgically treated thalamic gliomas to better understand their molecular features and the factors that influence patient outcomes. We found that two genetic changes, H3F3A mutation and CDKN2A/B loss, were rarely seen together, which may help doctors distinguish different tumor types. We also found that a surgical procedure called microsurgical third ventriculostomy was associated with a markedly lower risk of postoperative hydrocephalus, a serious buildup of fluid in the brain. In addition, patients who underwent more extensive tumor removal tended to live longer. These findings suggest that combining careful molecular testing with maximal safe resection and proactive cerebrospinal fluid management may improve care for patients with thalamic glioma.

ID: 42382108
Title: CEST MRI reveals nicotine-induced alterations in glutamate-associated molecular connectivity in the mouse brain.
Abstract: Understanding how neurotransmitter systems organize into large-scale networks is essential for elucidating the mechanisms through which drugs, diseases, and behavioral states alter brain function. Existing imaging modalities such as functional MRI (fMRI) and positron emission tomography (PET) provide measures of hemodynamic and metabolic connectivity, but cannot noninvasively map neurotransmitter-associated networks with high spatial resolution. Herein, we introduce a chemical exchange saturation transfer (CEST) MRI-based framework for mapping glutamate-associated molecular connectivity and apply it to characterize nicotine-induced network reorganization in the mouse brain. Male C57BL/6 mice underwent dynamic glutamate-weighted CEST (gluCEST) MRI before and after seven days of nicotine exposure. Regional glutamate-weighted CEST time series were extracted from 51 brain regions, and connectivity was evaluated using within-subject temporal correlation and inter-subject covariance analyses. Graph theory analyses identified four baseline glutamate-associated modules involving frontal-sensorimotor, cortico-hippocampal, intra-hippocampal, and cortico-striatal circuits. Nicotine exposure attenuated these baseline networks in analyses performed without global signal regression (GSR) and with conditional GSR, whereas full GSR reduced the apparent magnitude of these effects. Nicotine also reduced nodal strength in the CA1 and insular cortex. In contrast, nicotine selectively strengthened a thalamo-striato-motor circuit involving the motor cortex, mediodorsal and ventral thalamic nuclei, and caudoputamen. This pattern remained evident even under full GSR. Subject-level covariance analysis confirmed widespread nicotine-induced attenuation of glutamate-associated connectivity and revealed a distinct sensory-limbic module involving the lateral geniculate nucleus, amygdala, and piriform cortex that was selectively disrupted following nicotine exposure. These results demonstrate the feasibility of dynamic gluCEST MRI for mapping glutamate-associated molecular connectivity in vivo and detecting pharmacologically induced network remodeling. This approach provides a noninvasive platform for investigating glutamatergic dysregulation in addiction, neuropsychiatric disorders, and therapeutic response.

ID: 42396332
Title: Brain-gut axis imaging, motion correction with [ 11 C]-carfentanil total-body PET.
Abstract: Mu-opioid receptors (MORs) are expressed throughout the body including in the brain and gastrointestinal (GI) tract. Total-body PET imaging of the brain and GI tract offers a promising approach for cross-sectional in vivo evaluation of the MOR brain-GI axis. However, intestinal motility and bladder filling introduce motion throughout the GI tract over the scan window. Here we establish analysis methodology to account for motion for dynamic imaging of the brain-GI axis, to further characterize peripheral MORs throughout the body and provide a framework for semi-automatic total-body PET modeling. 4 subjects underwent 90-min dynamic [ 11 C]-carfentanil (cfn) total-body PET acquisitions at baseline, after intravenous naloxone (central antagonist) administration, and after orally administered loperamide (peripheral agonist and P-glycoprotein substrate). Thalamic MOR availability was measured using the Logan reference tissue model. Using CT-based segmentation, the GI tract was subdivided into anatomical segments, in addition to other peripheral organs (e.g., liver, psoas muscle). Frame-by-frame semi-automatic motion correction was performed with three distinct reference frames (11-14 min post-injection, p.i., 35-40 min p.i., and 85-90 min p.i.). The performance of these three were compared to manual correction. Compartment modeling and Logan graphical analysis were performed to estimate relevant kinetic parameters (K1, VT, VTLogan). Across the 4 subjects and regions, kinetic parameter estimates were highly correlated (r>0.7) for K1, VT and VT Logan when comparing semi-automatic (reference frame at 35-40 min p.i.) and manual correction. With semi-automatic motion correction, graphical-based estimation of VTLogan in the gastrointestinal tract was significantly decreased with loperamide relative to baseline (p<0.05). As expected, naloxone decreased brain thalamic MOR availability but loperamide did not. With semi-automatic motion correction and [ 11 C]-cfn total-body PET, pharmacologic perturbations of MOR brain-GI axis can be quantitatively characterized, reducing the burden of image analysis for these studies.

ID: 42396598
Title: Evolutionary implications of NOTCH2NLC mutations: brain structural changes in neuronal intranuclear inclusion disease revealed by comprehensive morphometry.
Abstract: This study investigated brain structural changes associated with NOTCH2NLC gene mutations in neuronal intranuclear inclusion disease (NIID) patients, focusing on the evolutionary implications of this human-specific gene in brain development. We analysed 41 NIID patients and 21 healthy controls using voxel-based morphometry and surface-based morphometry to assess differences in grey matter volume and cortical complexity. Spatial relationships between brain atrophy and white matter hyperintensity volume as well as cerebrospinal fluid fraction were examined. Additionally, we conducted exploratory Spearman correlation analyses to evaluate associations between regional grey matter volume and clinical variables, including GGC repeat length, disease duration, age at onset and cognitive scores. NIID patients exhibited extensive reductions in grey matter volume and cortical thinning in multiple brain regions, with pronounced effects in the prefrontal cortex and cerebellum. The parietal lobe, insula and posterior cingulate gyrus showed decreased gyrification index and fractal dimension, while certain regions of the temporal and frontal lobes showed increased gyrification index and fractal dimension. Furthermore, in the NIID group, white matter hyperintensity volume and cerebrospinal fluid fraction were negatively correlated with grey matter volume in the olfactory cortex, orbital gyrus, anterior cingulate gyrus, insula, amygdala and temporal pole. Exploratory analyses suggested that longer GGC repeats were associated with greater atrophy in the striatum, middle cingulate cortex, sensorimotor cortex and cerebellum; earlier age at onset with thalamic (mediodorsal/pulvinar), occipital and cerebellar atrophy; and poorer cognitive scores with atrophy in the anterior cingulate cortex, superior occipital gyrus and superior temporal pole. This study uncovers widespread and complex cerebral structural changes in NIID patients, predominantly affecting the prefrontal cortex, cerebellum, insula and limbic system structures. These findings provide new insights into the neuroanatomical basis of NIID and support the hypothesis that human-specific genetic innovations driving cortical expansion may concurrently confer selective vulnerability to neurodegeneration.

ID: 42398899
Title: High-Fidelity Transcranial Ultrasound Multi-focal Stimulation via Physics-Aware Hologram Technique.
Abstract: Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation modality that offers deep brain access with high spatial precision. However, its broader application is limited by the difficulty of reliably generating complex transcranial acoustic fields, particularly for multi-target stimulation through the skull. These limitations can lead to focal distortion, off-target exposure, and reduced reliability of neuromodulation outcomes. Here, we introduce a physics-aware hologram technique for precise transcranial ultrasound neuromodulation. Unlike conventional approaches that rely on simplified phase-based approximations, the proposed method generates fabrication-ready holographic implementations while preserving consistency between numerical field synthesis and physical acoustic realization. This enables accurate formation of single-, dual-, and tri-focal stimulation patterns under transcranial conditions and improves localized targeting for multi-region neuromodulation. We validated the proposed technique through in silico simulations, ex vivo acoustic measurements through skulls, and in vivo experiments. Compared with state-of-the-art methods, the proposed approach achieved improved focal reconstruction, enhanced energy confinement at intended targets, and reduced off-target acoustic leakage. To further assess functional relevance, we applied this approach in a neuropathic pain mouse model using simultaneous bilateral stimulation of the thalamic nuclei. The stimulation induced measurable changes in neuronal activity, reflected by reduced c-Fos expression, together with preliminary improvements in pain-related behavioral responses. These findings support the capability of the proposed technique to enable spatially localized and reproducible neuromodulation in vivo. Collectively, this work provides a practical proof-of-concept strategy for achieving high-precision, multi-target transcranial neuromodulation and supports further investigation of TOAH for neuroscience research and future therapeutic applications.

ID: 42402909
Title: Replicable subcortical alterations linked to neurological soft signs in schizophrenia spectrum disorders.
Abstract: Neurological soft signs (NSS) are frequent in schizophrenia spectrum disorders (SSD) and have been linked to structural alterations in basal ganglia-thalamic (BGT) regions. We hypothesized that SSD patients would show BGT volume differences compared to healthy controls (HC) and that NSS severity would relate to BGT volume and surface morphology in a replicable pattern. Structural 3T T1-weighted MRI scans were obtained from 327 SSD patients and 134 matched HC in Mannheim (Germany) and Bern (Switzerland). NSS were assessed using the Heidelberg Scale and the Neurological Evaluation Scale (NES). BGT volumes were segmented using FSL-FIRST and compared across groups using general linear models adjusted for age, sex, intracranial volume, and daily antipsychotic medication. Associations with NSS scores were tested using regression analyses. High-NSS compared to low-NSS SSD patients showed reduced left accumbens volume in both cohorts, with a significant main effect in the Mannheim cohort (β = -43.73, p = .002 uncorrected, p = .019 corrected) and a partial replication in the Bern cohort (β = -53.06, uncorrected p = .03, p > .05, corrected). In contrast, IF-related effects on left accumbens and bilateral thalamic volumes were cohort specific. Daily antipsychotic medication and illness duration did not mediate or moderate these associations. This bicentric MRI study provides converging evidence that NSS severity in SSD is associated with BGT alterations, particularly reduced left nucleus accumbens volume. However, thalamic and surface-level findings were cohort specific, indicating partial rather than uniform reproducibility. Associations were not explained by daily dosage of antipsychotic medication or illness duration.

ID: 42409151
Title: Takeda G protein-coupled receptor 5 orchestrates anxiolysis by enhancing anterior paraventricular thalamic nucleus glutamatergic neuronal activity to engage distinct downstream circuits.
Abstract: The pathogenesis of anxiety disorders remains elusive, underscoring the urgent need for novel therapeutic targets. This study investigated the role of Takeda G protein-coupled receptor 5 (TGR5) in anxiety and its underlying molecular and neural circuit mechanisms. Open field, elevated plus maze and novelty-suppressed feeding tests were used to assess anxiety-like behaviors. Immunofluorescent, Western blot and RNAscope in situ hybridization were used to characterize TGR5 expression. Adeno-associated virus vectors carrying Cre-dependent double-floxed inverted open-reading frame (DIO) sequence were injected into the anterior paraventricular thalamic nucleus (aPVT) of vGlut2-Cre mice for TGR5 bidirectional modulation. Fiber photometry and chemogenetic manipulations were used to assess neuronal activity along with behaviors. In vitro electrophysiology recordings were used to assess neuronal excitability and ICav3.1. Channelrhodopsin-2-assisted circuit mapping was used to explain neural circuits and synaptic mechanisms. Chronic restraint stress (CRS) selectively downregulated TGR5 expression in aPVT glutamatergic neurons. TGR5 overexpression in aPVT glutamatergic neurons alleviated anxiety-like behaviors in CRS mice, while knockdown combined with subthreshold stress exacerbated anxiety phenotypes. Mechanistically, TGR5 activation enhanced aPVT glutamatergic neuronal excitability via the cAMP/PKA/Cav3.1 pathway. TGR5 activation enhanced presynaptic glutamate release probability in the monosynaptic projection from aPVT to medial prefrontal cortex and restored the excitation-inhibition balance in the bed nucleus of the stria terminalis through direct efferent and indirect local circuit modulation under CRS, thereby contributing to emotional homeostasis. Our findings establish TGR5 as a pivotal regulator of anxiety, providing a crucial experimental foundation for novel therapeutics and a deeper understanding of anxiety disorders.