Faculty Bibliography

Formaldehyde, a reactive aldehyde widely present in the environment and associated with occupational exposure, has been linked to cognitive impairment and Alzheimer's disease (AD) in multiple epidemiological and animal studies. However, its contribution to AD-like pathology in human neural models remains poorly understood. We utilized a 3D culture system of human neural progenitor cells (ReNcell VM) differentiated into neurons and glial cells to model chronic formaldehyde exposure. Additionally, we established a 3D human AD model by transducing ReN cells with APP and PSEN1 mutations to assess the effects of formaldehyde in an AD genetic background. Long-term formaldehyde exposure (up to 12 weeks) induced a dose-dependent increase in Aβ40, Aβ42, APP, and phosphorylated tau levels in both wild-type and AD-mutant 3D cultures. These changes mimic hallmark features of AD neuropathology, suggesting that formaldehyde acts as a pathological driver in both sporadic and familial contexts. Our study provides direct evidence that chronic formaldehyde exposure may initiate and accelerate amyloid and tau pathologies in 3D human neural cell models. These findings support growing concerns about formaldehyde as a modifiable risk factor in neurodegeneration.

Lewy body dementia is a heterogeneous disease that is underdiagnosed and poorly understood. Pathologically, Lewy body dementia is characterised by the accumulation of intraneuronal aggregates of misfolded α-synuclein, known as Lewy bodies and Lewy neurites. The genetic architecture of Lewy body dementia is complex, involving both common genetic variants with small risk effects and rare genetic variants with large effects. Alzheimer's disease pathology frequently coexists with Lewy body pathology and influences the clinical presentation. A deeper understanding of the pathophysiological pathways, including mitochondrial dysfunction, lysosomal dysfunction, and neuroinflammation, can enhance disease modelling, and this knowledge will ultimately facilitate the development of therapeutic interventions. The biological relationships that Lewy body dementia shares with other neurodegenerative and psychiatric disorders might also be crucial for the development of therapeutic strategies.

Consciousness Science is entering an age of unprecedented opportunity, thanks to recent empirical and theoretical advances, increasing interest in the topic, and technological advances in neuroscience. The role theories will play in a maturing science of consciousness deserves a closer look.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

Gonadal hormones act throughout the brain and modulate psychiatric symptoms. Yet how hormones influence cognitive processes is unclear. Exogenous 17β-estradiol, the most potent estrogen, modulates dopamine in the nucleus accumbens core, which instantiates reward prediction errors (RPEs), the difference between received and expected reward. Here we show that following endogenous increases in 17β-estradiol, dopamine RPEs and behavioral sensitivity to previous rewards are enhanced, and nucleus accumbens core dopamine reuptake proteins are reduced. Rats adjusted how quickly they initiated trials in a task with varying reward states, balancing effort against expected rewards. Nucleus accumbens core dopamine reflected RPEs that influenced rats' initiation times. Higher 17β-estradiol predicted greater sensitivity to reward states and larger RPEs. Proteomics revealed reduced dopamine transporter expression following 17β-estradiol increases. Finally, knockdown of midbrain estrogen receptors suppressed sensitivity to reward states. Therefore, endogenous 17β-estradiol predicts dopamine reuptake and RPE signaling, and causally dictates the impact of previous rewards on behavior.

Dopamine (DA) is essential for the production of vigorous actions, but how DA modifies the gain of motor commands remains unclear. Here we show that subsecond DA transients in the striatum of mice are neither required nor sufficient for specifying the vigor of ongoing forelimb movements. Our findings have important implications for our understanding of how DA contributes to motor control under physiological conditions and in Parkinson's disease.

BACKGROUND:Despite the high potential of transcranial ultrasound stimulation (TUS) for non-invasive brain therapy and interrogation, real-time monitoring of brain responses to TUS remains a challenge. Traditional methods to monitor direct neural responses are invasive and mostly incompatible with precise TUS delivery while other non-invasive approaches to visualize the induced responses suffer from poor penetration depth, lack of sensitivity, or low temporal resolution. OBJECTIVE:We present an integrated approach for high precision delivery of ultrasound into the mouse brain and simultaneous whole-brain oximetry with functional optoacoustic tomography to characterize the hemodynamic response elicited by TUS. METHODS:A spherically focused ultrasound array was employed to non-invasively deliver holographic TUS and simultaneously detect multispectral optoacoustic signals from the brains of anesthetized mice. Ultrasound pressure and pulse duration were varied, while the number of stimuli (5), stimulation duration (15 s), and ultrasound frequency (3 MHz) were kept constant. The acquired optoacoustic data were tomographically reconstructed and spectrally unmixed to render three-dimensional maps of oxygenated and deoxygenated hemoglobin in real time. RESULTS:TUS-evoked brain-wide hemodynamics were efficiently monitored via spectroscopic optoacoustic imaging with high spatial and temporal resolution. Holographic TUS targeted to the somatosensory cortex elicited distinct hemodynamic responses, which extended beyond the stimulated region, involving subcortical arteries and pial veins. CONCLUSIONS:Our method provides new transformative non-invasive capabilities to study the effects of ultrasound on a living brain thus help unleash the strong potential of TUS in neuroscience and medicine.