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Injury to the facial nerve can occur after different etiologies and range from simple transection of the branches to varying degrees of segmental loss. Management depends on the extent of injury and options include primary repair for simple transections and using autografts, allografts, or conduits for larger gaps. Tissue engineering plays an important role to create artificial materials that are able to mimic the nerve itself without extra morbidity in the patients. The use of neurotrophic factors or stem cells inside the conduits or around the repair site is being increasingly studied to enhance neural recovery to a greater extent. Preclinical studies remain the hallmark for development of these novel approaches and translation into clinical practice. This review will focus on preclinical models of repair after facial nerve injury to help researchers establish an appropriate model to quantify recovery and analyze functional outcomes. Different bioengineered materials, including conduits and nerve grafts, will be discussed based on the experimental animals that were used and the defects introduced. Future directions to extend the applications of processed nerve allografts, bioengineered conduits, and cues inside the conduits to induce neural recovery after facial nerve injury will be highlighted. IMPACT STATEMENT: Recovery after facial nerve injury is a complex process, which involves different management options such as primary repair or the use of nerve grafts or conduits. Various tissue-engineered approaches are increasingly studied on preclinical models with limited, but promising, translation to the clinical setting. Herein, preclinical models focusing on different recovery methods after facial nerve injury are comprehensively reviewed based on the experimental animals used. The review provides key insights into current developments and future directions on this highly relevant topic to help researchers further expand the field of tissue engineering and facial nerve recovery.

Hypercoagulability is common in SARS-CoV-2 and has been associated with arterial thrombosis leading to acute limb ischemia (ALI). Our objective was to determine the outcomes of concurrent COVID-19 infection and ALI, particularly during the Delta variant surge and the impact of vaccination status.A retrospective review was performed of patients treated at a single healthcare system between March 2020 and December 2021 for ALI and recent (14 days) COVID-19 infection or who developed ALI during hospitalization for the same disease. Patients were grouped by year as well as by pre and post Delta variant emergence in 2021 based on WHO timeline (January-May vs. June-December). Baseline demographics, imaging, interventions, and outcomes were evaluated. A control cohort of all ALI patients requiring surgical intervention for a two-year period prior to the pandemic was used for comparison. Primary outcomes were in-hospital mortality and amputation-free survival. Kaplan-Meier survival and Cox proportional hazards analysis were performed.40 acutely ischemic limbs were identified in 36 patients with COVID-19, the majority during the Delta surge (52.8%) and after the wide availability of vaccines. The rate of COVID-19 associated ALI, though low overall, nearly doubled during the Delta surge (0.37% vs. 0.20%, p-value=.09). Baseline demographics and comorbidities are summarized in Table 1. Intervention (open or endovascular revascularization vs. primary amputation) was performed on 31 limbs in 28 individuals with the remaining 8 treated with systemic anti-coagulation. Post-operative mortality was 48% and overall mortality was 50%. Major amputation following revascularization was significantly higher with COVID ALI (25% vs. 3%, p=0.006) compared to the pre-pandemic group. 30-day amputation-free survival was significantly lower (log-rank p0.001). COVID infection (aHR=6.2, p0.001) and age (HR=1.1, p=0.006) were associated with 30-day amputation in multivariate analysis. Severity of COVID infection, defined as vasopressor usage, was not associated with post-revascularization amputation. There was a higher incidence of re-thrombosis in the latter half of 2021 with the Delta surge as reintervention for recurrent ischemia of the same limb was more common than our previous experience (21% vs. 0%, p=0.55). COVID-19 associated limb ischemia occurred almost exclusively in non-vaccinated patients (92%).ALI observed with Delta appears more resistant to standard therapy. Unvaccinated status correlated highly with ALI occurrence in the setting of COVID-19 infection. Information of limb loss as a COVID complication among non-vaccinated may help to increase compliance.

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.

Distinct components of working memory are coordinated by different classes of inhibitory interneurons in the PFC, but the role of cholecystokinin (CCK)-positive interneurons remains enigmatic. In humans, this major population of interneurons shows histological abnormalities in schizophrenia, an illness in which deficient working memory is a core defining symptom and the best predictor of long-term functional outcome. Yet, CCK interneurons as a molecularly distinct class have proved intractable to examination by typical molecular methods due to widespread expression of CCK in the pyramidal neuron population. Using an intersectional approach in mice of both sexes, we have succeeded in labeling, interrogating, and manipulating CCK interneurons in the mPFC. Here, we describe the anatomical distribution, electrophysiological properties, and postsynaptic connectivity of CCK interneurons, and evaluate their role in cognition. We found that CCK interneurons comprise a larger proportion of the mPFC interneurons compared with parvalbumin interneurons, targeting a wide range of neuronal subtypes with a distinct connectivity pattern. Phase-specific optogenetic inhibition revealed that CCK, but not parvalbumin, interneurons play a critical role in the retrieval of working memory. These findings shine new light on the relationship between cortical CCK interneurons and cognition and offer a new set of tools to investigate interneuron dysfunction and cognitive impairments associated with schizophrenia.SIGNIFICANCE STATEMENTCholecystokinin-expressing interneurons outnumber other interneuron populations in key brain areas involved in cognition and memory, including the mPFC. However, they have proved intractable to examination as experimental techniques have lacked the necessary selectivity. To the best of our knowledge, the present study is the first to report detailed properties of cortical cholecystokinin interneurons, revealing their anatomical organization, electrophysiological properties, postsynaptic connectivity, and behavioral function in working memory.

NMDA receptors (NMDAR) are important in the formation of activitydependent connections in the brain. In sensory pathways, NMDAR disruption during discrete developmental periods has enduring effects on wiring and function. Yet, it is not clear whether NMDAR-limited critical periods exist for higher-order circuits governing mood and cognition. This question is urgent for neurodevelopmental disorders, like schizophrenia, that have NMDAR hypofunction and treatment-resistant cognitive symptoms. As proof of concept, we developed a novel mouse model where developmental NMDAR deficits can be ameliorated by inducible Cre recombinase. Rescue of NMDARs in either adolescence or adulthood yields surprisingly strong improvements in higher-order behavior. Similar levels of behavioral plasticity are observed regardless of intervention age, with degree of plasticity dependent on the specific behavioral circuit. These results reveal higher-order brain function as amenable to treatment in adulthood and identify NMDAR as a key target for cognitive dysfunction.

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signaling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 is restored to wildtype by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive behaviors, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.