Biology subjects

Mangia, S.

Publications and source records attributed to Mangia, S..

5 recordsLinked to original sources

bioRxiv2026

Computational modeling of neurotransmitter cycling predicts human brain glutamate and GABA dynamics in response to administration of exogenous ketones

Administration of ketones is used as a therapeutic option in multiple conditions, including epilepsy, mental health disorders, and brain aging. A proposed mechanism of action involves the modulation of glutamate and GABA, the brains primary excitatory and inhibitory neurotransmitters, which jointly regulate the excitatory-inhibitory balance. However, the precise mechanism by which ketones influence these neurotransmitters remains unclear. In this study, we hypothesize that ketones modulate glutamate and GABA through the pseudomalate-spartate shuttle (PMAS). To test this, we developed a computational model of neurotransmitter cycling centered on the PMAS, simulating the temporal dynamics and steady-state concentrations of glutamate and GABA as functions of ketone metabolism. We then compared the model outputs with MRS data from ketone administration experiments and found agreement with the model predictions, providing quantitative support for the model. Building on this agreement, we performed metabolic control analysis, which identified partial displacement of glucose metabolism through the PMAS as the dominant mechanism underlying the observed reductions in glutamate and GABA and revealed key enzymes that selectively modulate each neurotransmitter. Overall, the model provides researchers and clinicians with a framework for hypothesis testing and treatment optimization, while also serving as a foundation for future model expansions.

neuroscience↗

bioRxiv2025

Simultaneous zero echo time fMRI of rat brain and spinal cord

PurposeFunctional assessments of the central nervous system (CNS) are essential for many areas of research. Functional MRI (fMRI) typically targets either the brain or the spinal cord, but usually not both, due to the obstacles associated with simultaneous image acquisitions from distant fields of view (FOVs) with conventional MRI. In this work, we establish a novel MRI approach that enables artefact-free, quiet, simultaneous fMRI of both brain and spinal cord, avoiding the need for dynamic shimming procedures. MethodsWe utilized zero echo time (TE) Multi-Band-SWeep Imaging with Fourier Transformation (MB-SWIFT) technique at 9.4T in a simultaneous dual-FOV configuration and two separate radio frequency (RF) transmit-receive surface coils. The first coil covered the rat brain, while the second was positioned approximately at the T13-L1 level of the rat"s spinal cord with copper shielding to minimize the coupling between the RF coils. Eight Sprague-Dawley rats were used for hindlimb stimulation fMRI studies. ResultsRobust and specific activations were detected in both the brain and spinal cord during hind paw stimulation at individual and group levels. The results established the feasibility of the novel approach for simultaneous functional assessment of the lumbar spinal cord and brain in rats. ConclusionThis study demonstrated the feasibility of a novel dual-FOV fMRI approach based on zero-TE MB-SWIFT and set the stage for translation to humans. The methodology enables comprehensive functional CNS evaluations of great value in different conditions such as pain, spinal cord injury, neurodegenerative diseases, and aging.

neuroscience↗

bioRxiv2024

Whisker stimulation with different frequencies reveals non-uniform modulation of functional magnetic resonance imaging signal across sensory systems in awake rats

Primary sensory systems are classically considered to be separate units, however there is current evidence that there are notable interactions between them. We examined the cross-sensory interplay by applying a quiet and motion-tolerant zero echo time functional magnetic resonance imaging (fMRI) technique to elucidate the evoked brain-wide responses to whisker pad stimulation in awake and anesthetized rats. Specifically, characterized the brain-wide responses in core and non-core regions to whisker pad stimulation by the varying stimulation-frequency, and determined whether isoflurane-medetomidine anesthesia, traditionally used in preclinical imaging, confounded investigations related to sensory integration. We demonstrated that unilateral whisker pad stimulation not only elicited robust activity along the whisker-mediated tactile system, but also in auditory, visual, high-order, and cerebellar regions, indicative of brain-wide cross-sensory and associative activity. By inspecting the response profiles to different stimulation frequencies and temporal signal characteristics, we observed that the non-core regions responded to stimulation in a very different way compared to the primary sensory system, likely reflecting different encoding modes between the primary sensory, cross-sensory, and integrative processing. Lastly, while the activity evoked in low-order sensory structures could be reliably detected under anesthesia, the activity in high-order processing and the complex differences between primary, cross-sensory, and associative systems were visible only in the awake state. We conclude that our study reveals novel aspects of the cross-sensory interplay of whisker-mediated tactile system, and importantly, that these would be difficult to observe in anesthetized rats.

neuroscience↗

bioRxiv2021

Perception affects the brain's metabolic response to sensory stimulation

Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical profile (neurometabolic response). Here we show that perceived and unperceived isoluminant chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level dependent functional MRI (BOLD-fMRI) in primary visual cortex (V1) have markedly different neurometabolic responses as measured by functional MRS. In particular, a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of malate-aspartate shuttle, occurred in V1 only when the flickering is perceived, without any relation with behavioral or physiological variables. Wheras the BOLD-fMRI signal in V1, a proxy for input to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary visual areas was larger during perceived than unperceived flickering indicating increased output from V1. These results indicate that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS provides unique information about local input/output balance that is not measured by BOLD-fMRI. Significance statementVisual perception has a measurable metabolic effect in the primary visual cortex (V1). Here we show that the upregulation of energy metabolism induced by isoluminant chromatic flickering depends on subjective visual perception. Within V1, perceived and unperceived stimuli that are contrast-matched to elicit similar blood-oxygenation level-dependent fMRI response are associated with clearly distinct neurochemical profiles. Specifically, regional accumulations of lactate (an index of aerobic glycolysis) and glutamate (an index of malate-aspartate shuttle) only develop during perceived stimuli, together with a larger activation of secondary visual areas. Our results imply a dissociation between metabolic and functional response, and indicate that that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1.

neuroscience↗

bioRxiv2021

Whole-brain studies of spontaneous behavior in head-fixed rats enabled by zero echo time MB-SWIFT fMRI

Understanding the link between the brain activity and behavior is a key challenge in modern neuroscience. Behavioral neuroscience, however, lacks tools to record whole-brain activity in complex behavioral settings. Here we demonstrate that a novel Multi-Band SWeep Imaging with Fourier Transformation (MB-SWIFT) functional magnetic resonance imaging (fMRI) approach enables whole-brain studies in spontaneously behaving head-fixed rats. First, we show anatomically relevant functional parcellation. Second, we show sensory, motor, exploration, and stress-related brain activity in relevant networks during corresponding spontaneous behavior. Third, we show odor-induced activation of olfactory system with high correlation between the fMRI and behavioral responses. We conclude that the applied methodology enables novel behavioral study designs in rodents focusing on tasks, cognition, emotions, physical exercise, and social interaction. Importantly, novel zero echo time and large bandwidth approaches, such as MB-SWIFT, can be applied for human behavioral studies, allowing more freedom as body movement is dramatically less restricting factor.

neuroscience↗