Metabolism modulates network synchrony in the aging brain

Brain aging is associated with hypometabolism and global changes in functional connectivity. Using functional MRI (fMRI), we show that network synchrony, a collective property of brain activity, decreases with age. Applying quantitative methods from statistical physics, we provide a generative (Ising) model for these changes as a function of the average communication strength between brain regions. We find that older brains are closer to a critical point of this communication strength, in which even small changes in metabolism lead to abrupt changes in network synchrony. Finally, by experimentally modulating metabolic activity in younger adults, we show how metabolism alone—independent of other changes associated with aging—can provide a plausible candidate mechanism for marked reorganization of brain network topology.

State-dependent changes in perception and coding in the mouse somatosensory cortex

SUMMARYAn animal’s behavioral state is reflected in the dynamics of cortical population activity and its capacity to process sensory information. To better understand the relationship between behavioral states and information processing, mice are trained to detect varying amplitudes of whisker-deflection under two-photon calcium imaging. Layer 2/3 neurons (n=1436) in the vibrissal primary somatosensory cortex are imaged across different behavioral states, defined based on detection performance (low to high-state) and pupil diameter. The neurometric curve in each behavioral state mirrors the corresponding psychometric performance, with calcium signals predictive of the animal’s choice outcome. High behavioral states are associated with lower network synchrony, extending over shorter cortical distances. The decrease of correlations in variability across neurons in the high state results in enhanced information transmission capacity at the population level. The observed state-dependent changes suggest that the coding regime within the first stage of cortical processing may underlie adaptive routing of relevant information through the sensorimotor system.HighlightsNetwork synchrony and pupil diameter are coupled to changes in behavioral state.High behavioral state results in enhanced information transmission capacity at the population level, with neurometric curve in each behavioral state mirroring the corresponding psychometric performanceBehavioral state and calcium signal in primary somatosensory cortex predict choice outcome.eTOCIn BriefLee et al. investigates the relationship between behavioral states and information processing in the primary somatosensory cortex. They demonstrate increases in behavioral state results in decrease cortical variability, enhanced information transmission capacity and stimulus encoding at the population level.

Metabolism modulates network synchrony in the aging brain

Brain aging is associated with hypometabolism and associated global changes in functional connectivity. Using fMRI, we show that network synchrony, a collective property of brain activity, decreases with age. Applying quantitative methods from statistical physics, we provide a generative (Ising) model for these changes as a function of the average communication strength between brain regions. In particular, we find healthy brains to be poised at a critical point of this communication strength, enabling a balance between segregated (to functional domains) and integrated (between domains) patterns of synchrony. However, one characteristic of criticality is a high sensitivity to small changes. Thus, minute weakening of pairwise communication between regions, as seen in the aging brain, gives rise to qualitatively abrupt changes in synchrony. Finally, by experimentally modulating metabolic activity in younger adults, we show how metabolism alone–independent of other changes associated with aging–can provide a mechanism for global changes in synchrony.

Interneuron transplantation: a prospective surgical therapy for medically refractory epilepsy

Excitatory-inhibitory imbalance is central to epilepsy pathophysiology. Current surgical therapies for epilepsy, such as brain resection, laser ablation, and neurostimulation, target epileptic networks on macroscopic scales, without directly correcting the circuit-level aberrations responsible for seizures. The transplantation of inhibitory cortical interneurons represents a novel neurobiological method for modifying recipient neural circuits in a physiologically corrective manner. Transplanted immature interneurons have been found to disperse in the recipient brain parenchyma, where they develop elaborate structural morphologies, express histochemical markers of mature interneurons, and form functional inhibitory synapses onto recipient neurons. Transplanted interneurons also augment synaptic inhibition and alter recipient neural network synchrony, two physiological processes disrupted in various epilepsies. In rodent models of epilepsy, interneuron transplantation corrects recipient seizure phenotypes and associated behavioral abnormalities. As such, interneuron transplantation may represent a novel neurobiological approach to the surgical treatment of human epilepsy. Here, the authors describe the preclinical basis for applying interneuron transplantation to human epilepsy, discuss its potential clinical applications, and consider the translational hurdles to its development as a surgical therapy.

Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer’s disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca2+ dynamics and network synchrony

SUMMARYWhile many neuronal membrane-anchored proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding. Using mass spectrometry (MS)-based proteomics, we showed that the neuronal sheddome mirrors human cerebrospinal fluid (hCSF). Among shed synaptic proteins in hCSF was the ectodomain of CNTNAP2 (CNTNAP2-ecto), a risk factor for neurodevelopmental disorders (NDD). Using structured-illumination microscopy (SIM), we mapped the spatial organization of neuronal CNTNAP2-ecto shedding. Using affinity chromatography followed by MS, we identified the ATP2B/PMCA Ca2+ extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto coimmunoprecipitates with PMCA2, a known autism risk factor, and enhances its activity, thereby modulating neuronal Ca2+ levels. Finally, we showed that CNTNAP2-ecto regulates neuronal network synchrony in primary cultures and brain slices. These data provide new insights into the biology of synaptic ectodomain shedding and reveal a novel mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony.