Faculty Bibliography

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.

PURPOSE OF REVIEW/OBJECTIVE:Initiation of hemodialysis treatment with a thrice-weekly prescription is currently the standard of care irrespective of patients' residual kidney function (RKF), comorbidities, and preferences. RECENT FINDINGS/RESULTS:Each year ∼12 000 Veterans with advanced kidney disease progress to end-stage kidney disease (ESKD) requiring dialysis and comprise greater than 10% of the US incident ESKD population. Dialysis is costly and is associated with impaired health-related quality of life (HRQOL) and high mortality risk, especially in the first year of treatment. Evidence suggests an incremental dialysis transition using twice-weekly hemodialysis provides various benefits, including more dialysis-free time, longer RKF preservation, less vascular access damage, and lower patient burden. Pragmatic studies are needed to inform the efficacy and safety of incremental hemodialysis as a personalized dialysis regimen, and could inform its consideration as a conservation strategy during times of supply shortages. Broadly implementing twice-weekly hemodialysis could also potentially allow more Veterans to receive care within VA-based dialysis units. The VA IncHVets Trial is a pragmatic, multicenter, randomized controlled trial comparing the efficacy and safety of twice-weekly incremental vs. thrice-weekly hemodialysis among Veterans transitioning to ESKD. SUMMARY/CONCLUSIONS:Further research is needed to determine whether incremental hemodialysis is well tolerated, effective, and facilitates a more favorable transition to dialysis.

Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary DG cell type, granule cells (GCs). Numerous MC synapses are on GC proximal dendrites in the inner molecular layer (IML). However, field recordings of the GC excitatory postsynaptic potential (fEPSPs) have not been used to study this pathway selectively. Here we describe methods to selectively activate MC axons in the IML using mice with Cre recombinase expressed in MCs. Slices were made after injecting adeno-associated virus (AAV) encoding channelrhodopsin (ChR2) in the DG. In these slices, we show that fEPSPs could be recorded reliably in the IML in response to optogenetic stimulation of MC axons. Furthermore, fEPSPs were widespread across the septotemporal axis. However, fEPSPs were relatively weak because they were small in amplitude and did not elicit a significant population spike in GCs. They also showed little paired pulse facilitation. We confirmed the extracellular findings with patch clamp recordings of GCs despite different recording chambers and other differences in methods. Together the results provide a simple method for studying MC activation of GCs and add to the evidence that this input is normally weak but widespread across the GC population.

Mutations of the Cullin-3 (Cul3) E3 ubiquitin ligase are associated with autism and schizophrenia, neurological disorders characterized by sleep disturbances and altered synaptic function. Cul3 engages dozens of adaptor proteins to recruit hundreds of substrates for ubiquitination, but the adaptors that impact sleep and synapses remain ill-defined. Here we implicate Insomniac (Inc), a conserved protein required for normal sleep and synaptic homeostasis in Drosophila, as a Cul3 adaptor. Inc binds Cul3 in vivo, and mutations within the N-terminal BTB domain of Inc that weaken Inc-Cul3 associations impair Inc activity, suggesting that Inc function requires binding to the Cul3 complex. Deletion of the conserved C-terminus of Inc does not alter Cul3 binding but abolishes Inc activity in the context of sleep and synaptic homeostasis, indicating that the Inc C-terminus has the properties of a substrate recruitment domain. Mutation of a conserved, disease-associated arginine in the Inc C-terminus also abolishes Inc function, suggesting that this residue is vital for recruiting Inc targets. Inc levels are negatively regulated by Cul3 in neurons, consistent with Inc degradation by autocatalytic ubiquitination, a hallmark of Cullin adaptors. These findings link Inc and Cul3 in vivo and support the notion that Inc-Cul3 complexes are essential for normal sleep and synaptic function. Furthermore, these results indicate that dysregulation of conserved substrates of Inc-Cul3 complexes may contribute to altered sleep and synaptic function in autism and schizophrenia associated with Cul3 mutations.

Making adaptive decisions in complex environments requires appropriately identifying sources of error^1,2. The frontal cortex is critical for adaptive decisions, but its neurons show mixed selectivity to task features³ and their uncertainty estimates⁴, raising the question of how errors are attributed to their most likely causes. Here, by recording neural responses from tree shrews (Tupaia belangeri) performing a hierarchical decision task with rule reversals, we find that the mediodorsal thalamus independently represents cueing and rule uncertainty. This enables the relevant thalamic population to drive prefrontal reconfiguration following a reversal by appropriately attributing errors to an environmental change. Mechanistic dissection of behavioural switching revealed a transthalamic pathway for cingulate cortical error monitoring^5,6 to reconfigure prefrontal executive control⁷. Overall, our work highlights a potential role for the thalamus in demixing cortical signals while providing a low-dimensional pathway for cortico-cortical communication.

Acute rheumatic fever (ARF) is an immune-mediated nonsuppurative complication of group A streptococcal (GAS) pharyngitis. Approximately 470,000 new cases of ARF occur annually, with a more significant disease burden in developing countries with higher rates of untreated or inadequately treated GAS infections. Globally, over 275,000 deaths yearly are attributed to rheumatic heart disease (RHD). The most significant contributors to the spread of GAS pharyngitis are household overcrowding, poor sanitation, and inadequate access to healthcare. The pathophysiology of ARF is characterized by an aberrant immune response to GAS infection triggered by molecular mimicry between GAS antigens and self-antigens. This immune response typically manifests 2 to 4 weeks after the initial GAS infection and may lead to the development of carditis, valvulitis, Sydenham chorea, subcutaneous nodules, erythema marginatum, and polyarthritis that is usually migratory. The severity and distribution of these manifestations vary significantly between individuals making the diagnosis of ARF challenging. Early recognition of ARF using the modified Jones criteria is essential in treating acute infection and preventing complications. A major long-term consequence is RHD, which carries significant morbidity and mortality.