Faculty Bibliography

Motor neurons have highly diverse anatomical, functional and molecular features, and differ significantly in their susceptibility in disease. Extraocular motor neurons, residing in the oculomotor, trochlear and abducens cranial nuclei (nIII, nIV and nVI), control eye movements. Recent work has begun to clarify the developmental mechanisms by which functional diversity among extraocular motor neurons arises. However, we know little about the role and consequences of extraocular motor neuron diversity in eye movement control. Here, we highlight recent work investigating the anatomical, functional and molecular features of extraocular motor neurons. Further, we frame hypotheses where studying ocular motor circuits in the larval zebrafish is poised to illuminate the consequences of motor neuron diversity for behavior.

Deep-learning-based MR image reconstruction in settings where large fully sampled dataset collection is infeasible requires methods that effectively use both under-sampled and fully sampled datasets. This paper evaluates a weakly supervised, multi-coil, physics-guided approach to MR image reconstruction, leveraging both dataset types, to improve both the quality and robustness of reconstruction. A physics-guided end-to-end variational network (VarNet) is pretrained in a self-supervised manner using a 4

Cardiomyopathies represent a diverse group of heart diseases that can be broadly classified into ischemic and nonischemic etiologies, each requiring distinct diagnostic approaches. Noninvasive imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), play a pivotal role in the diagnosis, risk stratification, and prognosis of these conditions. This paper reviews the characteristic CT and MRI findings associated with ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM), focusing on their ability to provide detailed anatomical, functional, and tissue characterization. In ICM, CT and MRI reveal myocardial scarring, infarct size, and coronary artery disease, while MRI further distinguishes tissue viability through late gadolinium enhancement (LGE). Conversely, nonischemic cardiomyopathies demonstrate a wide array of findings, with MRI's LGE pattern analysis being particularly critical for identifying specific subtypes, such as restrictive, hypertrophic, or dilated cardiomyopathies. By comparing the strengths and limitations of these modalities, this paper highlights their complementary roles in improving diagnostic accuracy, risk stratification, prognosis, and therapeutic decision making in both ischemic and nonischemic cardiomyopathies.

OBJECTIVE:Genome-wide association studies implicate metabo-psychiatric origins for anorexia nervosa (AN). There are two case reports totaling six adult females who experienced complete remission of AN following a treatment comprised of ketogenic diet (targeting metabolism) with ketamine infusions (targeting psychiatric origins), but no study has determined the efficacy of ketogenic diet, alone. We addressed this gap in knowledge, with exploration of potential molecular mechanisms, using an animal model. METHOD/METHODS:Adult C57BL6 female mice underwent 2 or 3 cycles of activity-based anorexia (ABA1, ABA2, ABA3), an animal model of AN relapse, in which AN-like maladaptive behaviors of hyperactivity and voluntary food restriction are elicited when wheel access is combined with food restriction. ABA was categorized as severe, based on weight loss ≥ 20%, food restriction-evoked increase in wheel counts > 10,000/6 h, and crouching/grimace, and compared across two groups: (1) KG, fed ketogenic food continuously (N = 25); and (2) CON, fed standard diet (N = 28). RESULTS:86% of CON versus none of the KG were crouching with grimace during ABA1. 93% of CON versus 11% of KG lost weight severely during ABA2 (p < 0.001, 8% difference of group mean weights). Severe hyperactivity was prevalent among CON (86%) and rare for KG (4%) during ABA2 (p < 0.001 on all food-restricted days). ABA up-regulated BDNF (brain-derived neurotrophic factor) in the hippocampus of both groups but ketone body, β-hydroxybutyrate, in urine was increased only among KG. DISCUSSION/CONCLUSIONS:Ketogenic diet may reduce severity of AN relapse through reduction of compulsive exercise, via mechanisms that are in addition to BDNF up-regulation and involve β-hydroxybutyrate.

Measuring whole-brain distributed functional activity is an important unmet need in neuroscience, requiring high temporal resolution and cellular specificity across large volumes. Functional optoacoustic neuro-tomography (FONT) with genetically encoded calcium ion indicators is a promising approach towards this goal. However, it has not yet been applied in the near-infrared (NIR) range that provides deep penetration and low vascular background optimal for in vivo neuroimaging. Here, we study the noninvasive multimodal fluorescence and optoacoustic imaging performance of state-of-the-art NIR calcium ion indicator NIR-GECO2G in the mouse brain. We observe robust in vivo signals with widefield fluorescence, and for the first time, with FONT. We also show that in both modalities, the NIR-GECO2G signal improves more than twofold in the biliverdin-enriched Blvra

Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer's disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved.

Apical and basal dendrites of pyramidal neurons receive anatomically and functionally distinct inputs, implying compartment-level functional diversity during behavior. To test this, we imaged in vivo calcium signals from soma, apical dendrites, and basal dendrites in mouse hippocampal CA3 pyramidal neurons during head-fixed navigation. To capture compartment-specific population dynamics, we developed computational tools to automatically segment dendrites and extract accurate fluorescence traces from densely labeled neurons. We validated the method on sparsely labeled preparations and synthetic data, predicting an optimal labeling density for high experimental throughput and analytical accuracy. Our method detected rapid, local dendritic activity. Dendrites showed robust spatial tuning, similar to soma but with higher activity rates. Across days, apical dendrites remained more stable and outperformed in decoding of the animal's position. Thus, population-level apical and basal dendritic differences may reflect distinct compartment-specific input-output functions and computations in CA3. These tools will facilitate future studies mapping sub-cellular activity and their relation to behavior.

Vertebrates stabilize gaze using a neural circuit that transforms sensed instability into compensatory counterrotation of the eyes. Sensory feedback tunes this vestibulo-ocular reflex throughout life. We studied the functional development of vestibulo-ocular reflex circuit components in the larval zebrafish, with and without sensation. Blind fish stabilize gaze normally, and neural responses to body tilts mature before behavior. In contrast, synapses between motor neurons and the eye muscles mature with a time course similar to behavioral maturation. Larvae without vestibular sensory experience, but with mature neuromuscular junctions, had a strong vestibulo-ocular reflex. Development of the neuromuscular junction, and not sensory experience, therefore determines the rate of maturation of an ancient behavior.

Cerebellar transcranial alternating current stimulation (ctACS) has the potential to be an appealing, non-invasive treatment option for psychiatric and neurological disorders. However, realization of this potential has been limited by gaps in our knowledge of how ctACS affects cerebellar output on single cell and population levels. Previously, we showed that AC stimulation applied to the cerebellar surface produced a strong, frequency-dependent modulation of Purkinje cell (PC) and cerebellar nuclear (CN) cell activity. Here, to approximate more closely the ctACS conditions, we investigated how AC stimulation applied to the external skull surface overlying crus 1 altered PC and CN activity in anesthetized adult female Sprague-Dawley rats. PC and CN activity showed a frequency-dependent modulation in response to ctACS at frequencies ranging from 0.5 to 80 Hz. A unimodal response was seen for most PCs across all frequencies, whereas most CN cells transitioned to bimodal patterns as stimulus frequency increased. The frequency-dependence of the phases of the local minima of the CN cell modulation were consistent with CN cells being driven synaptically by PC activity. Furthermore, comparison of responses with ipsilateral and contralateral placement of the stimulus electrode with respect to the recording site showed that the strength and pattern of the entrainment depended on the stimulus electrode location, suggesting that ctACS electrode placement could be used to target specific cerebellar output channels. In sum, the results show that transcranial stimulation of the cerebellar cortex can modulate cerebellar output, which has potential implications for its use in treating neurological and psychiatric disorders.