Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation.

Optimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing patient-derived point mutation in Grin2a (Grin2aY700X+/-), a gene that confers high-risk for schizophrenia and recently identified by large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found that Grin2aY700X+/- mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional in Grin2aY700X+/- mice, and in vivo task recordings showed that MD neurons encoded dynamic values and behavioral states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2aY700X+/- mice, and enhancing MD activity rescued task deficits in Grin2aY700X+/- mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics.

Infralimbic parvalbumin neural activity facilitates cued threat avoidance.

The infralimbic cortex (IL) is essential for flexible behavioral responses to threatening environmental events. Reactive behaviors such as freezing or flight are adaptive in some contexts, but in others a strategic avoidance behavior may be more advantageous. IL has been implicated in avoidance, but the contribution of distinct IL neural subtypes with differing molecular identities and wiring patterns is poorly understood. Here, we study IL parvalbumin (PV) interneurons in mice as they engage in active avoidance behavior, a behavior in which mice must suppress freezing in order to move to safety. We find that activity in inhibitory PV neurons increases during movement to avoid the shock in this behavioral paradigm, and that PV activity during movement emerges after mice have experienced a single shock, prior to learning avoidance. PV neural activity does not change during movement toward cued rewards or during general locomotion in the open field, behavioral paradigms where freezing does not need to be suppressed to enable movement. Optogenetic suppression of PV neurons increases the duration of freezing and delays the onset of avoidance behavior, but does not affect movement toward rewards or general locomotion. These data provide evidence that IL PV neurons support strategic avoidance behavior by suppressing freezing.

Navigational Transmaxillary Endoscopic Approach for Inferomedial Tumors.

Orbital tumors encompass a heterogeneous range of histopathology and usually variable in location. Traditionally, transconjunctival medial orbitotomy is used to access the medial orbital wall. However, it creates potential risk of soft tissue sequelae such as scarring, lid contracture, or entropion/ectropion. For the lesions close to the orbital apex, increased risk of optical nerve injury should be cautious during orbitotomy procedure. Transnasal endoscopic approach to the orbital walls has been applied since 1999. Although it provides good surgical visualization and prevents the soft tissue and neural complications, the narrow nasal corridor increases the surgical complexity. Extensive sphenoethmoidectomy is usually required to gaining access. Furthermore, the resultant medical orbital defect is difficult to repair. The maxillary sinus is the largest paranasal sinuses which is located beneath the orbital floor. It provides an ample working space for instrumentation. Meanwhile, repair of the orbital floor defect is feasible and with high degree of accuracy under navigation control. In this report, we propose a novel computer-assisted endoscopic protocol to excise the medial orbital tumors with immediate repair of the wall defect.

Pandemic Teaching: Using the Allen Cell Types Database for Final Semester Projects in an Undergraduate Neurophysiology Lab Course.

We designed a final semester research project that allowed students to apply the electrophysiological concepts they learned in a lab course to propose and answer experimental questions without access to laboratory equipment. We created the activity based on lesson plans from Ashley Juavinett and the Allen Institute for Brain Science (AIBS) Allen SDK online examples. An interactive graphic interface was added for students to explore and easily quantify subtle neuronal voltage changes. Before starting the final project, students had experience with conventional extracellular and intracellular recording techniques to record and analyze extracellular action potential firing patterns and intracellular resting, action, and synaptic potentials. They demonstrated their understanding of neural signal transmission in required lab reports using data they gathered before the pandemic shutdown. After students left campus, they continued to analyze data and write lab reports focused on neuronal excitability in snail and fly neurons with data supplied by the instructors. For their final project, students were challenged to answer questions addressing neuronal excitability at both the single neuron and neuronal population level by analyzing and interpreting the open-access, patch clamp recording data from the Allen Cell Types Database using code we provided (Python/Jupyter Notebook). This virtual final semester project allowed students to ask real-world medical and scientific questions from "start to end". Through this project, students developed skills to navigate an extensive online database and gained experience with coding-based data analysis. They chose neuronal populations from human and mouse brains to compare passive properties and neuronal excitability between and within brain areas and across different species and disease states. Additionally, students learned to do simple manipulations of Python code, work remotely in teams, and polish their written scientific presentation skills. This activity could complement other remote learning options such as neuronal simulations. Few online sources offer such a wealth of neuroscience data that students can use for class assignments, and even for research and keystone projects. The activity extends the traditional material often taught in upper-level neuroscience courses, with or without a laboratory section, providing a deeper understanding of the range of excitability properties that neurons express.

The significance of tumor budding in oral cancer survival and its relevance to the eighth edition of the American Joint Committee on Cancer staging system.

BACKGROUND: To explore the clinicopathological significance of tumor budding (TB) on oral squamous cell carcinoma (OSCC) prognosis. METHODS: Data of 200 patients with OSCC were retrieved from the cancer registration database in Taipei Veterans General Hospital. Clinicopathological characteristics and survival relevant to TB were analyzed. RESULTS: The data showed that TB was predominant in the tongue and floor of the mouth in younger patients with OSCC and correlated with several pathological factors, such as perineural invasion and lymphovascular invasion. Patients with TB have significantly lower recurrence-free survival (P ≤ .0001). TB was significantly associated with lymph node metastasis in patients with early cancer stage (P = .042). Multivariate analysis demonstrated extranodal extension and TB as independent predictors of lymph node recurrence (adjusted hazard ratio = 9.90 and 3.89, respectively). CONCLUSION: TB is a significant predictor of tumor aggression with locoregional failure even in the revised 8th American Joint Committee on Cancer staging system.

Intense threat switches dorsal raphe serotonin neurons to a paradoxical operational mode.

Survival depends on the selection of behaviors adaptive for the current environment. For example, a mouse should run from a rapidly looming hawk but should freeze if the hawk is coasting across the sky. Although serotonin has been implicated in adaptive behavior, environmental regulation of its functional role remains poorly understood. In mice, we found that stimulation of dorsal raphe serotonin neurons suppressed movement in low- and moderate-threat environments but induced escape behavior in high-threat environments, and that movement-related dorsal raphe serotonin neural dynamics inverted in high-threat environments. Stimulation of dorsal raphe Î³-aminobutyric acid (GABA) neurons promoted movement in negative but not positive environments, and movement-related GABA neural dynamics inverted between positive and negative environments. Thus, dorsal raphe circuits switch between distinct operational modes to promote environment-specific adaptive behaviors.

Making Sense of Optogenetics.

This review, one of a series of articles, tries to make sense of optogenetics, a recently developed technology that can be used to control the activity of genetically-defined neurons with light. Cells are first genetically engineered to express a light-sensitive opsin, which is typically an ion channel, pump, or G protein-coupled receptor. When engineered cells are then illuminated with light of the correct frequency, opsin-bound retinal undergoes a conformational change that leads to channel opening or pump activation, cell depolarization or hyperpolarization, and neural activation or silencing. Since the advent of optogenetics, many different opsin variants have been discovered or engineered, and it is now possible to stimulate or inhibit neuronal activity or intracellular signaling pathways on fast or slow timescales with a variety of different wavelengths of light. Optogenetics has been successfully employed to enhance our understanding of the neural circuit dysfunction underlying mood disorders, addiction, and Parkinson's disease, and has enabled us to achieve a better understanding of the neural circuits mediating normal behavior. It has revolutionized the field of neuroscience, and has enabled a new generation of experiments that probe the causal roles of specific neural circuit components.

The discrimination of type I and type II collagen and the label-free imaging of engineered cartilage tissue.

Using excitation polarization-resolved second harmonic generation (SHG) microscopy, we measured SHG intensity as a function of the excitation polarization angle for type I and type II collagens. We determined the second order susceptibility (χ((2))) tensor ratios of type I and II collagens at each pixel, and displayed the results as images. We found that the χ((2)) tensor ratios can be used to distinguish the two types of collagen. In particular, we obtained χ(zzz)/χ(zxx) = 1.40 ± 0.04 and χ(xzx)/χ(zxx) = 0.53 ± 0.10 for type I collagen from rat tail tendon, and χ(zzz)/χ(zxx) = 1.14 ± 0.09 and χ(xzx)/χ(zxx) = 0.29 ± 0.11 for type II collagen from rat trachea cartilage. We also applied this methodology on the label-free imaging of engineered cartilage tissue which produces type I and II collagen simultaneously. By displaying the χ((2)) tensor ratios in the image format, the variation in the χ((2)) tensor ratios can be used as a contrast mechanism for distinguishing type I and II collagens.