Faculty Bibliography

A subset of children with autism spectrum disorder appear to show an improvement in their behavioural symptoms during the course of a fever, a sign of systemic inflammation^1,2. Here we elucidate the molecular and neural mechanisms that underlie the beneficial effects of inflammation on social behaviour deficits in mice. We compared an environmental model of neurodevelopmental disorders in which mice were exposed to maternal immune activation (MIA) during embryogenesis^3,4 with mouse models that are genetically deficient for contactin-associated protein-like 2 (Cntnap2)⁵, fragile X mental retardation-1 (Fmr1)⁶ or Sh3 and multiple ankyrin repeat domains 3 (Shank3)⁷. We establish that the social behaviour deficits in offspring exposed to MIA can be temporarily rescued by the inflammatory response elicited by the administration of lipopolysaccharide (LPS). This behavioural rescue was accompanied by a reduction in neuronal activity in the primary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity of which was previously implicated in the manifestation of behavioural phenotypes associated with offspring exposed to MIA⁸. By contrast, we did not observe an LPS-induced rescue of social deficits in the monogenic models. We demonstrate that the differences in responsiveness to the LPS treatment between the MIA and the monogenic models emerge from differences in the levels of cytokine production. LPS treatment in monogenic mutant mice did not induce amounts of interleukin-17a (IL-17a) comparable to those induced in MIA offspring; bypassing this difference by directly delivering IL-17a into S1DZ was sufficient to promote sociability in monogenic mutant mice as well as in MIA offspring. Conversely, abrogating the expression of IL-17 receptor subunit a (IL-17Ra) in the neurons of the S1DZ eliminated the ability of LPS to reverse the sociability phenotypes in MIA offspring. Our data support a neuroimmune mechanism that underlies neurodevelopmental disorders in which the production of IL-17a during inflammation can ameliorate the expression of social behaviour deficits by directly affecting neuronal activity in the central nervous system.

Background: Albuminuria is a risk factor for kidney disease progression and CV disease. We examined the relative and absolute effects of CANA by baseline albuminuria among CREDENCE participants.
Method(s): CREDENCE was a double-blind, randomized study of 4401 participants with eGFR 30-<90mL/min/1.73m2 and uACR >300-5000mg/g who demonstrated that CANA significantly reduced renal and CV outcomes, including the primary composite of end-stage kidney disease, doubling serum creatinine, or renal or CV death. We analyzed the effect of CANA on renal, CV, and safety outcomes by baseline uACR.
Result(s): At baseline, 2348 (53.4%), 1547 (35.2%), and 506 (11.5%) participants had uACR <=1000, >1000-<3000, >=3000mg/g. Higher uACR was associated with higher event rates (Figure). CANA reduced renal and CV endpoints, with no statistical variation by uACR (all p heterogeneity >0.17). CANA led to a greater absolute reduction in renal events in those with higher uACR (number needed to treat to prevent 1 episode of the primary composite: 22 and 8 for uACR >1000-<3000 and >=3000mg/g). Rates of renalrelated adverse events were lower with CANA, and the relative reduction was greater with higher uACR (p heterogeneity=0.003). CANA had no significant effect on acute kidney injury, volume depletion, hyperkalemia, urinary tract infections or hypoglycemia, with no differences by uACR (all p heterogeneity >0.12).
Conclusion(s): CANA safely reduces renal and CV events in people with type 2 diabetes and substantial albuminuria, with the greatest absolute renal benefit in those with uACR of 3000-5000mg/g

How does neural activity generate perception? The spatial identities and temporal latencies of activated units correlate with external sensory features, but finding the subspace of activity that is consequential for perception, remains challenging. We trained mice to recognize synthetic odors: optogenetically-driven spatiotemporal patterns of glomerular activity in the olfactory bulb. We then performed precise spatial or temporal perturbations on trained patterns and measured how recognition changes. Changes in recognition reflect the perceptual relevance of the modified feature. We modeled recognition as the matching of glomerular activity to learned templates, and uncovered what forms a perceptually-meaningful pattern template: activation sequences ordered by latencies relative to each other, with surprisingly minimal effect of sniff. Within templates, spatially-identified glomeruli contribute additively, with larger contributions from earlier-activated glomeruli. Template matching with these perceptually-meaningful features can account for animals' responses, with the degree of mismatch predicting changes in recognition. The model accurately generalizes to novel spatio-temporal manipulations of patterns, and produces non-linear responses that resemble the non-linear responses in the data. This is the first report to our knowledge, that not only establishes a causal role for neural activity sequences in perception, but also uncovers the perceptually-relevant coding schemes governing these sequences. Our synthetic approach reveals the fundamental logic of the olfactory code, and provides a general framework for testing links between sensory activity and perception

The piriform cortex is the first area of integration for all peripheral odor information and it is believed to generate a unique and wholistic representation of behavioral relevance, sensory object. However, what properties of the cortical neural population activity define odor objects remains unknown. To address this question, we recorded cortical spiking responses to synthetic odors made of fully parameterized optogenetic activity patterns in the olfactory bulb, enabling independent and precise control of the incoming neural responses unattainable with natural odorants. Then, we measured changes in the neural response to a range of controlled spatial and temporal perturbations of the pattern for which we previously established their behavioral relevance. We developed an experimental approach to systematically probe cortical neural activity and found features of the population code which represent behaviorally relevant information

The affective state is the combination of emotion and mood, with mood reflecting a running average of sequential emotional events together with an underlying internal affective state. There is now extensive evidence that odors can overtly or subliminally modulate mood and emotion. Relying primarily on neurobiological literature, here we review what is known about how odors can affect emotions/moods and how emotions/moods may affect odor perception. We take the approach that form can provide insight into function by reviewing major brain regions and neural circuits underlying emotion and mood, and then reviewing the olfactory pathway in the context of that emotion/mood network. We highlight the extensive neuroanatomical opportunities for odor-emotion/mood convergence, as well as functional data demonstrating reciprocal interactions between these processes. Finally, we explore how the odor- emotion/mood interplay is, or could be, used in medical and/or commercial applications.

Spike-and-wave discharges (SWDs) of absence epilepsy are considered as pathologic alterations of sleep spindles; however, their network-level relationship has never been convincingly revealed. In order to observe the development and generalization of the thalamocortical SWDs and the concomitant alterations of sleep related oscillations, we performed local field potential (LFP) and single unit recordings in rats for three months during their maturation. We found that while SWDs and spindles look similar in young, they become different with maturation and shift to appear in different brain states. Thus, despite being generated by the same network, they are likely two distinct manifestations of the thalamocortical activity. We show that while spindles are already mainly global oscillations, SWDs appear mainly only focally in young. They become capable to generalize later with maturation, when the out-of-focus brain regions develop a decreased inhibitory/excitatory balance. These results suggest that a hyperexcitable focus is not sufficient alone to drive generalized absence seizures. Importantly, we also found the gradual age dependent disappearance of sleep spindles coinciding with the simultaneous gradual emergence of spike and waves, which both could be reversed by the proper dosing of ethosuximide (ETX). Based on these observations we conclude that the absence seizure development might be a multi-step process, which might involve the functional impairment of cortical interneurons and network-level changes that negatively affect sleep quality.

Purpose/UNASSIGNED:To revisit the "loopole," an unusual coil topology whose unbalanced current distribution captures both loop and electric dipole properties, which can be advantageous in ultra-high-field MRI. Methods/UNASSIGNED:Loopole coils were built by deliberately breaking the capacitor symmetry of traditional loop coils. The corresponding current distribution, transmit efficiency, and signal-to-noise ratio (SNR) were evaluated in simulation and experiments in comparison to those of loops and electric dipoles at 7 T (297 MHz). Results/UNASSIGNED:, the loopole demonstrated significant performance boost in either the transmit efficiency or SNR at the center of a dielectric sample when compared to a traditional loop. Modest improvements were observed when compared to an electric dipole. Conclusion/UNASSIGNED:The loopole can achieve high performance by supporting both divergence-free and curl-free current patterns, which are both significant contributors to the ultimate intrinsic performance at ultra-high field. While electric dipoles exhibit similar hybrid properties, loopoles maintain the engineering advantages of loops, such as geometric decoupling and reduced resonance frequency dependence on sample loading.