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1. Theta-gamma coupling emerges from spatially heterogeneous cholinergic neuromodulation

   https://doi.org/10.1371/journal.pcbi.1009235  

   Yang, Yihao ; Gritton, Howard ; Sarter, Martin ; Aton, Sara J. ; Booth, Victoria ; Zochowski, Michal ( July 2021 , PLOS Computational Biology)

   Rubin, Jonathan (Ed.)

   Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K + current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information. 

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2. A proof of concept ‘phase zero’ study of neurodevelopment using brain organoid models with Vis/near-infrared spectroscopy and electrophysiology

   https://doi.org/10.1038/s41598-020-77929-8  

   Dutta, Anirban ; Karanth, Sneha Sudhakar ; Bhattacharya, Mahasweta ; Liput, Michal ; Augustyniak, Justyna ; Cheung, Mancheung ; Stachowiak, Ewa K. ; Stachowiak, Michal K. ( December 2020 , Scientific Reports)

   null (Ed.)

   Abstract Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain development, including local synaptic E–I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a 'Phase Zero' clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology with studying E–I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity (chi-square (2, N = 10) = 20, p = 4.5400e−05), and spectral exponent between 30–50 Hz (chi-square (2, N = 16) = 13.88, p = 0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl- l -carnitine (LCLA), was found on the CCO activity (chi-square (3, N = 10) = 25.44, p = 1.2492e−05), spectral exponent between 1 and 20 Hz (chi-square (3, N = 16) = 43.5, p = 1.9273e−09) and 30–50 Hz (chi-square (3, N = 16) = 23.47, p = 3.2148e−05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present the feasibility of a multimodal approach, combining electrophysiology and broadband Vis–NIR spectroscopy, to monitor neurodevelopment in brain organoid models that can complement traditional drug design approaches to test clinically meaningful hypotheses. 

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3. Homeostatic regulation of extracellular signal-regulated kinase 1/2 activity and axonal Kv7.3 expression by prolonged blockade of hippocampal neuronal activity

   https://doi.org/10.3389/fncel.2022.838419  

   Baculis, Brian C. ; Kesavan, Harish ; Weiss, Amanda C. ; Kim, Edward H. ; Tracy, Gregory C. ; Ouyang, Wenhao ; Tsai, Nien-Pei ; Chung, Hee Jung ( July 2022 , Frontiers in Cellular Neuroscience)

   Homeostatic plasticity encompasses the mechanisms by which neurons stabilize their synaptic strength and excitability in response to prolonged and destabilizing changes in their network activity. Prolonged activity blockade leads to homeostatic scaling of action potential (AP) firing rate in hippocampal neurons in part by decreased activity of N-Methyl-D-Aspartate receptors and subsequent transcriptional down-regulation of potassium channel genes includingKCNQ3which encodes K_v7.3. Neuronal K_v7 channels are mostly heterotetramers of K_v7.2 and K_v7.3 subunits and are highly enriched at the axon initial segment (AIS) where their current potently inhibits repetitive and burst firing of APs. However, whether a decrease in K_v7.3 expression occurs at the AIS during homeostatic scaling of intrinsic excitability and what signaling pathway reducesKCNQ3transcript upon prolonged activity blockade remain unknown. Here, we report that prolonged activity blockade in cultured hippocampal neurons reduces the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) followed by a decrease in the activation of brain-derived neurotrophic factor (BDNF) receptor, Tropomyosin receptor kinase B (TrkB). Furthermore, both prolonged activity blockade and prolonged pharmacological inhibition of ERK1/2 decreaseKCNQ3andBDNFtranscripts as well as the density of K_v7.3 and ankyrin-G at the AIS. Collectively, our findings suggest that a reduction in the ERK1/2 activity and subsequent transcriptional down-regulation may serve as a potential signaling pathway that links prolonged activity blockade to homeostatic control of BDNF-TrkB signaling and K_v7.3 density at the AIS during homeostatic scaling of AP firing rate.

    

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4. Neural efficiency and spatial task difficulty: A road forward to mapping students’ neural engagement in spatial cognition

   Snowden, Ariel W. ; Warren, Christopher M. ; Goodridge, Wade ; Fang, Ning ( January 2021 , Engineering design graphics journal)

   The current study examined the neural correlates of spatial rotation in eight engineering undergraduates. Mastering engineering graphics requires students to mentally visualize in 3D and mentally rotate parts when developing 2D drawings. Students’ spatial rotation skills play a significant role in learning and mastering engineering graphics. Traditionally, the assessment of students’ spatial skills involves no measurements of neural activity during student performance of spatial rotation tasks. We used electroencephalography (EEG) to record neural activity while students performed the Revised Purdue Spatial Visualization Test: Visualization of Rotations (Revised PSVT:R). The two main objectives were to 1) determine whether high versus low performers on the Revised PSVT:R show differences in EEG oscillations and 2) identify EEG oscillatory frequency bands sensitive to item difficulty on the Revised PSVT:R.  Overall performance on the Revised PSVT:R determined whether participants were considered high or low performers: students scoring 90% or higher were considered high performers (5 students), whereas students scoring under 90% were considered low performers (3 students). Time-frequency analysis of the EEG data quantified power in several oscillatory frequency bands (alpha, beta, theta, gamma, delta) for comparison between low and high performers, as well as between difficulty levels of the spatial rotation problems.   Although we did not find any significant effects of performance type (high, low) on EEG power, we observed a trend in reduced absolute delta and gamma power for hard problems relative to easier problems. Decreases in delta power have been reported elsewhere for difficult relative to easy arithmetic calculations, and attributed to greater external attention (e.g., attention to the stimuli/numbers), and consequently, reduced internal attention (e.g., mentally performing the calculation). In the current task, a total of three spatial objects are presented. An example rotation stimulus is presented, showing a spatial object before and after rotation. A target stimulus, or spatial object before rotation is then displayed. Students must choose one of five stimuli (multiple choice options) that indicates the correct representation of the object after rotation. Reduced delta power in the current task implies that students showed greater attention to the example and target stimuli for the hard problem, relative to the moderate and easy problems. Therefore, preliminary findings suggest that students are less efficient at encoding the target stimuli (external attention) prior to mental rotation (internal attention) when task difficulty increases.  Our findings indicate that delta power may be used to identify spatial rotation items that are especially challenging for students. We may then determine the efficacy of spatial rotation interventions among engineering education students, using delta power as an index for increases in internal attention (e.g., increased delta power). Further, in future work, we will also use eye-tracking to assess whether our intervention decreases eye fixation (e.g., time spent viewing) toward the target stimulus on the Revised PSVT:R. By simultaneously using EEG and eye-tracking, we may identify changes in internal attention and encoding of the target stimuli that are predictive of improvements in spatial rotation skills among engineering education students.  

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5. Lymphatic injury alters the contractility and mechanosensitivity of collecting lymphatics to intermittent pneumatic compression

   https://doi.org/10.1113/JP281206  

   Mukherjee, Anish ; Nepiyushchikh, Zhanna ; Michalaki, Eleftheria ; Dixon, J. Brandon ( April 2021 , The Journal of Physiology)

   We present the firstin vivoevidence that lymphatic contraction can entrain with an external oscillatory mechanical stimulus.

   Lymphatic injury can alter collecting lymphatic contractility, but not much is known about how its mechanosensitivity to external pressure is affected, which is crucial given the current pressure application methods for treating lymphoedema.

   We show that oscillatory pressure waves (OPW), akin to intermittent pneumatic compression (IPC) therapy, optimally entrain lymphatic contractility and modulate function depending on the frequency and propagation speed of the OPW.

   We show that the OPW‐induced entrainment and contractile function in the intact collecting lymphatics are enhanced 28 days after a contralateral lymphatic ligation surgery.

   The results show that IPC efficacy can be improved through proper selection of OPW parameters, and that collecting lymphatics adapt their function and mechanosensitivity after a contralateral injury, switching their behaviour to a pump‐like configuration that may be more suited to the altered microenvironment.

   Intermittent pneumatic compression (IPC) is commonly used to control the swelling due to lymphoedema, possibly modulating the collecting lymphatic function. Lymphoedema causes lymphatic contractile dysfunction, but the consequent alterations in the mechanosensitivity of lymphatics to IPC is not known. In the present work, the spatiotemporally varying oscillatory pressure waves (OPW) generated during IPC were simulated to study the modulation of lymphatic function by OPW under physiological and pathological conditions. OPW with three temporal frequencies and three propagation speeds were applied to rat tail collecting lymphatics. The entrainment of the lymphatics to OPW was significantly higher at a frequency of 0.05 Hz compared with 0.1 Hz and 0.2 Hz (P = 0.0054 andP = 0.014, respectively), but did not depend on the OPW propagation speed. Lymphatic function was significantly higher at a frequency of 0.05 Hz and propagation speed of 2.55 mm/s (P = 0.015). Exogenous nitric oxide was not found to alter OPW‐induced entrainment. A contralateral lymphatic ligation surgery was performed to simulate partial lymphatic injury in rat tails. The intact vessels showed a significant increase in entrainment to OPW, 28 days after ligation (compared with sham) (P = 0.016), with a similar increase in lymphatic transport function (P = 0.0029). The results suggest an enhanced mechanosensitivity of the lymphatics, along with a transition to a pump‐like behaviour, in response to a lymphatic injury. These results enhance our fundamental understanding of how lymphatic mechanosensitivity assists the coordination of lymphatic contractility and how this might be leveraged in IPC therapy.

    

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