Schizophrenia, a complex psychiatric disorder with profound cognitive and behavioral symptoms, affects approximately 1% of the global population. A significant barrier to effective treatment has been the incomplete understanding of how genetic and neural circuit alterations contribute to cognitive deficits, such as disordered thinking and impaired sensory integration. The team at MIT, led by Guoping Feng, focused on elucidating the mechanisms behind impaired belief updating—a cognitive hallmark hypothesized to underlie psychosis—using a sophisticated genetic mouse model.

The study centers on a mutation in the grin2a gene, which encodes a subunit of the NMDA receptor, an essential glutamate receptor integral to synaptic plasticity and neuronal communication. Previous large-scale genomic screenings identified grin2a as one of the top genes harboring mutations with a strong association to schizophrenia. Given the gene’s role in synaptic signaling, the researchers posited that alterations in grin2a could disrupt neural circuits crucial for cognitive flexibility and updating beliefs based on sensory input.

To investigate this, the researchers engineered mice carrying the grin2a mutation and subjected them to behavioral paradigms designed to probe cognitive adaptation to changing reward contingencies. In one key experiment, mice were trained to choose between two levers: one that offered a higher reward but required more effort, and another providing a smaller reward at less cost. Wild-type mice adapted their choices as the task parameters evolved, shifting preference from the high-effort lever to the low-effort one when it became more advantageous. Contrastingly, mutant mice exhibited prolonged indecision and a delayed switch in preference, indicative of impaired belief updating and reduced cognitive flexibility.

Delving deeper into the neural dynamics, the team employed functional ultrasound imaging alongside electrophysiological recordings to pinpoint disruptions within the mediodorsal thalamus, a crucial hub interfacing with the prefrontal cortex to regulate executive functions and decision-making processes. In mice carrying the grin2a mutation, neuronal activity in this thalamic region was diminished and exhibited aberrant patterns correlating with their maladaptive decision behaviors. This supports the theory that dysfunctional thalamocortical circuits impair the integration of new sensory evidence into existing cognitive frameworks.

Taking a step further, the scientists utilized optogenetics to selectively stimulate mediodorsal thalamus neurons in mutant mice, effectively rescuing the deficits in adaptive behavior. By activating these neurons with precisely timed light pulses, the mice began to demonstrate decision-making patterns more akin to their wild-type counterparts. This pioneering intervention highlights the therapeutic potential of targeting discrete neural circuits to ameliorate specific cognitive symptoms of schizophrenia.

The implications of this study extend beyond the grin2a mutation itself. Although only a minority of schizophrenia patients carry mutations in this gene, the identified thalamocortical circuit deficits may represent a convergent pathway through which disparate genetic abnormalities manifest similar cognitive impairments. This circuit-based perspective advocates for a shift in therapeutic strategies from focusing solely on individual genes to modulating neural network function.

Moreover, this research provides a mechanistic explanation for psychosis-related belief disturbances long hypothesized in psychiatric literature. The concept that patients with schizophrenia overweigh prior beliefs at the expense of new sensory information is now traceable to concrete neurogenetic and circuit-level dysfunctions, bridging the gap between high-level cognitive theories and molecular neuroscience.

The study was made possible by a multidisciplinary approach combining behavioral neuroscience, advanced imaging, genetic engineering, and optogenetic technology. This integrative methodology sets a new standard for modeling complex psychiatric disorders and exploring potential interventions in preclinical settings.

Funding support from institutions including the National Institutes of Mental Health and the Stanley Center for Psychiatric Research underscored the importance and collaborative nature of this work. As the researchers continue to dissect the components of this thalamocortical circuit, they aim to identify druggable targets that could restore circuit function and improve cognitive outcomes for patients living with schizophrenia.

Ultimately, this research paves the way for novel treatments that go beyond symptomatic relief toward addressing the neural dysfunctions that underlie the debilitating cognitive and perceptual disturbances of schizophrenia. It marks a significant step forward in psychiatry’s quest to unravel the complex biology of mental illness and develop precision medicine approaches tailored to individual neural circuitry deficits.

Subject of Research: Animals
Article Title: Reduced mediodorsal thalamus activity underlies aberrant belief dynamics in a genetic mouse model of schizophrenia
News Publication Date: 18-Mar-2026
Web References: http://dx.doi.org/10.1038/s41593-026-02237-9
Image Credits: MIT
Keywords: Neuroscience, Psychiatric disorders, Schizophrenia, Brain, Human brain, Genetics, Cognitive impairment, Mediodorsal thalamus, NMDA receptor, grin2a gene, Optogenetics, Thalamocortical circuit

At the crux of this research lies the auditory system’s ability to selectively amplify neural activity associated with specific features of a target voice, such as pitch. When you engage in a conversation against the backdrop of numerous speakers, your auditory cortex does not merely passively filter sounds but actively enhances the neural signals corresponding to the attended voice. This amplification process, previously observed in experimental neuroscience, had yet to be mechanistically incorporated into computational frameworks — until now.

The collaborative study, led by Professor Josh McDermott of MIT’s Department of Brain and Cognitive Sciences and his graduate student Ian Griffith, leveraged a neural network model modified to simulate the multiplicative gain effect of auditory neurons. These gains essentially scale the firing rates of neurons tuned to features found in the attended voice, boosting their signal strength relative to competing stimuli. The researchers hypothesized that such a simple yet powerful motif could be sufficient to replicate the attention-driven auditory processing humans excel at.

Traditional computational models of auditory perception have struggled to replicate the nuanced behavior humans exhibit when selectively listening to one voice among many. While standard algorithms could identify individual sounds in isolation or in quiet environments, they faltered in simulating attentional shifts towards one target in noisy, multi-talker scenarios. McDermott’s team, recognizing this limitation, introduced adjustable gain parameters within the model’s architecture, enabling dynamic enhancement or suppression based on the features of the target audio cue.

Training the model involved sequential exposure to a “cue” — a short audio clip of the target speaker’s voice — followed by a complex auditory mixture containing the target and multiple distractors. By extracting the feature activations produced by the cue, the model assigned multiplicative gains to the corresponding neural units. For instance, if the cue exhibited a low-pitched voice, the neural units responsive to low frequencies were selectively amplified when processing the cocktail party audio. This mechanism effectively elevated the target voice’s prominence within the computational auditory representation.

This amplification alone replicated a remarkable gamut of human-like attention behaviors. The model not only performed the task of identifying words from the target speaker with high accuracy but also mirrored the typical patterns of errors human listeners make. For example, confusion between two voices of similar pitch, such as two male or two female speakers, emerged naturally in both the model and human subjects. Such fidelity suggests the multiplicative gain principle captures fundamental aspects of auditory attention.

Furthermore, the research illuminated the critical role of spatial cues in auditory selective attention. Beyond pitch, where a sound originates spatially contributes significantly to our ability to segregate competing voices. The enhanced computational model incorporated this spatial dimension, demonstrating improved performance when the target and distractor voices originated from distinct horizontal locations. Intriguingly, the model uncovered a novel human perceptual limitation: that separation of sounds along the vertical plane was markedly less effective in aiding selective listening, a phenomenon subsequently corroborated in human experiments.

Importantly, this validated model acts as a powerful tool not only for understanding human cognition but also for accelerating discovery. By simulating attention across a comprehensive array of spatial configurations — a task impractical to perform exhaustively with human subjects due to time and logistics — the model serves as an engine for generating hypotheses and guiding empirical research. This synergy of computational and experimental neuroscience represents a significant methodological advance.

Beyond theoretical implications, the study holds promise for practical applications, particularly in assistive hearing technology. The team envisions adapting their model to simulate auditory perception mediated by cochlear implants. Such devices, while transformative for individuals with hearing impairments, often struggle with selective attention in noisy settings. Insights derived from the multiplicative gain mechanism could guide the design of implant processors that dynamically enhance target voices, significantly improving users’ ability to focus on conversations in social environments.

The broader significance of this work lies in its contribution to a mechanistic understanding of attention, a cornerstone of cognitive neuroscience. By demonstrating that relatively simple multiplicative modulation of neural activity can recapitulate complex perceptual phenomena, the study refines theoretical models and bridges gaps between neurophysiological observations and computational theories. This alignment opens pathways to explore selective attention beyond audition, potentially influencing artificial intelligence systems designed to mimic human perception.

In sum, the MIT team’s findings decode a fundamental puzzle of human hearing. Through sophisticated modeling of neural gain modulation—essentially simulating how the brain ‘turns up the volume’ on particular sound features—they provide a computational scaffold that explains how our brains mix filtering and amplification to isolate meaningful voices amid noise. Such advances deepen our grasp of brain function and lay the groundwork for innovations that can enhance human communication in an increasingly noisy world.

The study, featuring contributions from Harvard graduate student Ian Griffith and MIT graduate student R. Preston Hess, appears in the latest issue of Nature Human Behaviour. This work was generously supported by the National Institutes of Health, underscoring the importance of funding fundamental research that unravels the mysteries of human cognition with far-reaching implications.

Subject of Research: Neuroscience of selective auditory attention and computational modeling of the cocktail party problem.

Article Title: Optimized feature gains explain and predict successes and failures of human selective listening

News Publication Date: 13-Mar-2026

Web References: https://www.nature.com/articles/s41562-026-02414-7

Image Credits: Steph Stevens

Keywords: Neuroscience, auditory attention, cocktail party problem, neural gain modulation, computational modeling, selective listening, auditory cortex, brain and cognitive sciences, spatial hearing, cochlear implants, neural networks, human auditory perception

The study focuses on the dysfunctional versions of ABCA7 which are present in a minuscule fraction of the population yet have an outsized impact on Alzheimer’s susceptibility. By disrupting lipid homeostasis, specifically within neuronal membranes, these ABCA7 mutations trigger hyperexcitability in brain cells and induce a state of cellular stress. This stress inflicts damage on DNA and other vital intracellular structures, compounding neuronal vulnerability. Strikingly, the research illustrates that many of these deleterious effects can be mitigated when neurons are treated with choline—a key precursor molecule necessary for phosphatidylcholine synthesis, a major component of cell membranes.

According to Djuna von Maydell, the study’s lead author and an MIT graduate student, treatment with choline was able to reverse a substantial number of transcriptional abnormalities in neurons deficient in ABCA7. Additionally, choline therapy suppressed the heightened neuronal excitability and reduced the levels of amyloid beta peptides—proteins that accumulate into plaques and are a hallmark of Alzheimer’s pathology. These findings suggest that enhancing lipid synthesis pathways with choline metabolites could restore neuronal function and slow or prevent disease progression in patients harboring these genetic variants.

Senior author Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, explains that previous work from her lab demonstrated the central role of lipid metabolism disruption in Alzheimer’s disease. In particular, the more common APOE4 gene variant, carried by roughly half of all Alzheimer’s patients, similarly impairs lipid processing and cellular stress responses in the brain. This parallel reinforces the emerging concept that diverse genetic risk factors converge on lipid dyshomeostasis as a final common pathway driving Alzheimer’s onset.

To dissect the impact of ABCA7 variants at a molecular level, the researchers leveraged tissue from the Religious Orders Study/Memory and Aging Project (ROSMAP), a rich longitudinal dataset comprising over a thousand brain samples with accompanying genetic data. Among these, twelve samples carried rare ABCA7 mutations. Single-cell RNA sequencing of neurons isolated from these individuals revealed extensive gene expression changes, particularly in clusters related to lipid metabolism, DNA repair, and oxidative phosphorylation—the mitochondrial process essential for ATP generation.

Mechanistic modeling was performed by introducing ABCA7 variants into human neurons derived from induced pluripotent stem cells (iPSCs). These in vitro models recapitulated many of the gene expression aberrations observed in patient tissue, emphasizing disrupted oxidative phosphorylation pathways. Further functional analyses revealed impaired mitochondrial “safety valves” that ordinarily dissipate excess electrical charge, leading to oxidative stress caused by accumulation of damaging free radicals—a condition strongly linked to neurodegeneration.

One pivotal insight of the study was the discovery that ABCA7 mutations alter the metabolism of phosphatidylcholine, a phospholipid critical for maintaining membrane fluidity and integrity. Dysfunction in phosphatidylcholine metabolism likely induces membrane stiffness and compromises mitochondrial membrane potential, thus impairing energy metabolism and cellular resilience. This lipid imbalance offers a concrete biochemical target poised for therapeutic intervention.

Testing this hypothesis, the team treated ABCA7-mutant neurons with CDP-choline, a bioavailable precursor that feeds directly into phosphatidylcholine biosynthesis. The intervention restored normal production of both saturated and unsaturated phosphatidylcholine variants, recovered mitochondrial membrane potentials, and reduced oxidative stress markers. These results highlight a promising avenue for correcting the metabolic consequences of ABCA7 dysfunction at a cellular level.

Expanding their investigation, researchers generated 3D neuronal organoids from iPSCs harboring ABCA7 mutations. These organoids exhibited elevated amyloid beta accumulation, mirroring early Alzheimer’s pathology. Remarkably, CDP-choline treatment normalized amyloid levels and attenuated neuronal hyperexcitability, suggesting that lipid restoration strategies could mitigate key pathological hallmarks of Alzheimer’s disease in complex cellular systems.

This study builds on prior findings from Tsai’s laboratory, where choline supplementation was effective in reversing APOE4-linked neuronal deficits in mouse models. Currently, clinical trials are underway in collaboration with the University of Texas and MD Anderson Cancer Center to evaluate the impact of choline in humans carrying APOE4 variants. These parallel approaches underscore the potential of choline-related therapeutics in broad-spectrum Alzheimer’s risk reduction.

Choline is naturally abundant in common dietary sources such as eggs, meat, fish, nuts, and legumes, presenting an accessible means to bolster brain lipid metabolism. Tsai suggests that enhancing choline intake, whether through diet or supplementation, could become a widely applicable preventive strategy against Alzheimer’s disease, especially for individuals with genetic susceptibilities related to lipid transporter genes like ABCA7 and APOE4.

Intriguingly, the team also identified a more prevalent ABCA7 variant found in approximately 18% of the general population that was previously considered benign. Their experiments revealed that even this common variant disrupts lipid metabolism pathways akin to the rare mutations studied, implying that ABCA7-related lipid dysregulation may impact a significantly larger segment of people than formerly recognized. Further investigations are needed, but these findings broaden the potential public health relevance of targeting ABCA7 dysfunction.

Overall, this comprehensive study illuminates how perturbations in lipid homeostasis, precipitated by ABCA7 variants, contribute to the cellular dysfunction underlying Alzheimer’s disease. By demonstrating that these effects can be reversed with choline supplementation, the research offers hope for novel preventative and therapeutic approaches. Lipid metabolism thus emerges as a critical nexus in Alzheimer’s pathology, with promising implications for improving brain health through accessible interventions.

Subject of Research:
Article Title: ABCA7 variants impact phosphatidylcholine and mitochondria in neurons
News Publication Date: 10-Sep-2025
Web References: http://dx.doi.org/10.1038/s41586-025-09520-y
Keywords: Alzheimer disease, lipid metabolism, neurological disorders, phosphatidylcholine, mitochondria, ABCA7 gene, oxidative phosphorylation, neurodegeneration, choline supplementation, APOE4, neuronal hyperexcitability, amyloid beta

The findings of the study, published in the prestigious journal, Cell Reports, highlight how augmenting a specific signaling pathway can mitigate the pathology and symptoms associated with fragile X syndrome in mouse models of the condition. The researchers demonstrated that by enhancing the activity of NMDA receptors, they could effectively balance the sometimes chaotic protein synthesis that characterizes fragile X, fostering not just neuronal health but also improving overall synaptic connections crucial for learning and memory.

At the heart of this research is the discovery that NMDA receptors are not merely conduits for ion flow, but hold intricate signaling mechanisms that can be manipulated for therapeutic benefits. Previous studies had shown that calcium ions flowing through these receptors prompt forms of synaptic plasticity, which are essential for the brain’s adaptation to experiences. However, the 2020 study revealed a different mode of receptor signaling—one that does not involve ion flow—highlighting an essential pathway for regulating protein synthesis and thereby influencing neuronal structure, particularly the dendritic spines that play a key role in synaptic connections.

This current investigation builds on these prior discoveries, utilizing the insights on NMDA receptors to dissect their contributions to synaptic functions in a sophisticated manner. The pivotal component of this research was the molecular subunit known as GluN2B. The team identified that altering this specific receptor subunit altered the dynamics of protein synthesis and synaptic structure. By examining the genetic contributions of GluN2A and GluN2B, they determined that while both are essential for triggering synaptic plasticity, it is the GluN2B subunit that uniquely governs the physical structure of dendritic spines. This is a significant revelation, as it pinpoints a potential target for therapeutics aimed at reversing the symptoms of fragile X syndrome.

Researchers employed advanced genetic manipulation techniques to selectively inactivate the two different subunits of NMDA receptors in their model organisms. Their findings were illuminating; the absence of the GluN2B subunit alone caused alterations in spine morphology, indicating its unique role in determining synaptic structure. This contrasts sharply with GluN2A, which, when knocked out, did not affect spine size. This dissection of the NMDA receptor components offered a deeper understanding of how disruptions in these proteins can lead to conditions such as fragile X syndrome.

To further investigate the signaling pathways governed by the GluN2B subunit, the researchers turned their attention to its carboxy-terminal domain (CTD). The CTD is integral to how the receptor communicates within the cell, influencing downstream effects like spine morphology. Experimental manipulation revealed that modifications to the CTD of GluN2B can completely obliterate its influence on spine structure, thereby emphasizing its role in mediating important cellular functions.

In a remarkable extension of findings, modifying the CTD of GluN2B led to an increase in bulk protein synthesis similar to what is observed in fragile X syndrome. Conversely, by augmenting non-ionic signaling through this subunit, the researchers succeeded in suppressing excessive protein synthesis, aligning results more with symptoms seen in tuberous sclerosis—another neurodevelopmental disorder. This duality of effects opens new therapeutic avenues, suggesting that pharmacological targeting of the GluN2B pathway could potentially address not just fragile X, but related disorders, by modifying cellular signaling profiles.

The crucial breakthrough in this line of inquiry came when the team implemented an experimental drug, Glyx-13, which specifically targets the GluN2B subunit of NMDA receptors. Their results were promising; treatment with Glyx-13 not only normalized aberrant protein synthesis in fragile X model mice but also appeared to restore typical synaptic plasticity, enhancing neuronal excitability. Moreover, the study drew correlations between the drug’s effects and its potential to mitigate specific symptoms associated with fragile X, such as seizures, which are commonly observed in affected individuals.

The implications of this research propagate through emerging discussions on the neuropathology of autism and related disorders, as scientists and clinicians alike begin to reevaluate the role of NMDA receptors in neurological health. By honing in on the molecular intricacies of NMDA receptor signaling, there is hope that future therapeutics could be designed not just for fragile X, but for a wide spectrum of neurodevelopmental challenges, fundamentally transforming how they are approached in medical settings.

Senior author Mark Bear expressed his excitement at how the findings have crystallized existing knowledge into actionable insights. The significant connection between the molecular mechanisms of NMDA receptors and their role in fragile X syndrome signifies a potential shift in treatment paradigms for patients affected by this disorder. With current therapies largely symptomatic, these discoveries provide inspiration for future research avenues that prioritize the underlying biological mechanisms of neurodevelopmental conditions.

Ultimately, this study not only lays the groundwork for novel therapeutic strategies targeting NMDA receptors but also underscores the importance of ongoing basic research in unraveling the complexities of brain function. Through such work, scientists at MIT and beyond are paving the way toward a brighter future for those living with fragile X syndrome and similar disorders, promising innovative approaches that could potentially enhance quality of life and cognitive function.

The collaborative efforts of Bear’s team, alongside contributions from various researchers and institutions, illustrate the power of interdisciplinary scientific inquiry, and the potential for advancing our understanding of brain disorders. With support from the FRAXA Foundation, the National Institutes of Health, and other organizations, the study exemplifies how funding and collaboration can catalyze groundbreaking discoveries in health and medicine.

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Keywords: Autism, NMDA receptors, Hippocampal neurons, Neuronal synapses, Dendritic spines, Neurological disorders, Neuroscience.