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Hippocampal network reorganization underlies the formation of a temporal association memory

by Mohsin S. Ahmed, View ORCID ProfileJames B. Priestley, Angel Castro, Fabio Stefanini, Elizabeth M. Balough, Erin Lavoie, Luca Mazzucato, Stefano Fusi, Attila Losonczy in Neuron

The brain has a powerful ability to remember and connect events separated in time. And now, in a new study in mice, scientists have shed light on how the brain can form such enduring links.

Episodic memory requires linking events in time, a function dependent on the hippocampus. In “trace” fear conditioning, animals learn to associate a neutral cue with an aversive stimulus despite their separation in time by a delay period on the order of tens of seconds. But how this temporal association forms remains unclear. Researchers use 2-photon calcium imaging to track neural population dynamics over the complete time-course of learning and show that, in contrast to previous theories, the hippocampus does not generate persistent activity to bridge the time delay. Instead, learning is concomitant with broad changes in the active neural population in CA1. While neural responses were highly stochastic in time, cue identity could be reliably read out from population activity rates over longer timescales after learning. These results question the ubiquity of neural sequences during temporal association learning, and suggest that trace fear conditioning relies on mechanisms that differ from persistent activity accounts of working memory.

“We expected to see repetitive, continuous neural activity that persisted during the fifteen-second gap, an indication of the hippocampus at work linking the auditory tone and the air puff,” said computational neuroscientist Stefano Fusi, PhD, a principal investigator at Columbia’s Zuckerman Institute and the paper’s co-senior author. “But when we began to analyze the data, we saw no such activity.”

Instead, the neural activity recorded during the fifteen-second time gap was sparse. Only a small number of neurons fired, and they did so seemingly at random. This sporadic activity looked distinctly different from the continuous activity that the brain displays during other learning and memory tasks, like memorizing a phone number.

“The activity appears to come in fits and bursts at intermittent and random time periods throughout the task,” said James Priestley, a doctoral candidate co-mentored by Drs. Losonczy and Fusi at Columbia’s Zuckerman Institute and the paper’s co-first author. “To understand activity, we had to shift the way we analyzed data and use tools designed to make sense of random processes.”

A neuronal signature for monogamous reunion

by Jennifer L. Scribner, Eric A. Vance, David S. W. Protter, William M. Sheeran, Elliott Saslow, Ryan T. Cameron, Eric M. Klein, Jessica C. Jimenez, Mazen A. Kheirbek, and Zoe R. Donaldson

A new brain imaging study of prairie voles — which are among only about 5% of mammalian species besides humans who are monogamous — found that when it comes to forming bonds, longing may be as important as being together. The study also sheds light on why it’s so hard to social distance, and could lead to new therapies for conditions like autism and depression.

Monogamous prairie voles form lifelong pair bonds, but the neuronal dynamics that underlie bond formation and maintenance in this species remain largely unknown. Researchers performed imaging of populations of neurons while voles interacted with their pair-bonded partner or a novel vole before and after bond formation. They identified neurons that were active during partner approach and found that this subset of cells was distinct from those that were active during novel approach. Furthermore, the number of partner approach cells increased following bond formation, reflecting the emergence of bonding behaviors and correlating with bond strength. This discovery sheds light on how pair bonds may be encoded within the brain and what changes as bonds mature.

Pair-bond formation depends vitally on neuromodulatory signaling within the nucleus accumbens, but the neuronal dynamics underlying this behavior remain unclear. Using 1-photon in vivo Ca2+ imaging in monogamous prairie voles, they found that pair bonding does not elicit differences in overall nucleus accumbens Ca2+ activity. Instead, they identified distinct ensembles of neurons in this region that are recruited during approach to either a partner or a novel vole. The partner-approach neuronal ensemble increased in size following bond formation, and differences in the size of approach ensembles for partner and novel voles predict bond strength. In contrast, neurons comprising departure ensembles do not change over time and are not correlated with bond strength, indicating that ensemble plasticity is specific to partner approach. Furthermore, the neurons comprising partner and novel-approach ensembles are nonoverlapping while departure ensembles are more overlapping than chance, which may reflect another key feature of approach ensembles. Scientists posit that the features of the partner-approach ensemble and its expansion upon bond formation potentially make it a key neuronal substrate associated with bond formation and maturation.

Joint trajectories of cognition and gait speed in Mexican American and European American older adults: The San Antonio longitudinal study of aging

by Mitzi M. Gonzales Chen‐Pin Wang Myla Quiben Daniel MacCarthy Sudha Seshadri Mini Jacob Helen Hazuda

Measures of cognition and gait speed largely paralleled each other in a San Antonio study of 370 participants that included 9½ years of follow-up. One-fifth of participants were classified into a cognitive and physical vulnerability group. Mexican American participants were almost four times more likely than European Americans to be in the cognitive and physical vulnerability group.

Cognitive decline and gait speed slowing are independent predictors of disability and mortality. While both factors increase in prevalence with advancing age, little is known about their combined patterns of change. The study goal was to identify joint trajectories of cognition and gait speed within an aging bi‐ethnic cohort of Mexican Americans and European Americans.

Participants included 182 Mexican Americans and 188 European Americans, ages 65 to 74, who were followed over a mean of 9.5 years. Cognition was assessed with the mini‐mental state examination and gait speed was examined with a timed 10‐ft walk. Joint trajectory classes of cognition and gait speed were identified with latent growth mixture modeling. Odd‐ratios assessed predictors for trajectory classes.

Three latent trajectory classes were identified: (a) relatively stable cognition and gait (termed stable cognition and gait class, 65.4%); (b) deteriorating cognition and gait (termed cognitive and physical vulnerability class, 22.2%); ( c) stable cognition and deteriorating gait (termed physical vulnerability class, 12.4%). The odds of classification in the cognitive and physical vulnerability class vs stable cognition and gait class was associated with Mexican American ethnicity (OR = 3.771, P = .016), age (OR = 1.186, P = .017), income (OR = 0.828, P = .029), education (OR = 0.703, P < .001), and diabetes (OR = 4.547, P = .010). The odds of classification in the physical vulnerability class was associated with female sex (OR = 6.481, P = .004) and body mass index (OR = 1.118, P = .025).

The trajectories of cognition and gait speed were generally parallel, suggesting the two domains may act synergistically to shape important health outcomes. Socioeconomic disparities and Mexican American ethnicity independently conferred risk for accelerated decline.

“In our community-based sample of Mexican American and European American older adults aged 65 to 74 years old at baseline, the majority of individuals began the study with higher scores in both domains, cognition and gait speed. During follow-up, this group demonstrated resilience to age-related declines and continued to be functionally independent,” said study senior author Helen Hazuda, Ph.D., professor in UT Health San Antonio’s Long School of Medicine and the principal investigator of SALSA.

“In contrast, one-fifth of individuals began the study with lower scores in cognition and gait speed. They experienced deterioration in each domain during the follow-up period,” Dr. Hazuda said.

Design of defect-chemical properties and device performance in memristive systems

by M. Lübben, F. Cüppers, J. Mohr, M. von Witzleben, U. Breuer, R. Waser, C. Neumann, and I. Valov in Science Advances

Researchers have now discovered how to systematically control the functional behavior of these elements. The smallest differences in material composition are found crucial: differences so small that until now experts had failed to notice them.

Future development of the modern nanoelectronics and its flagships internet of things, artificial intelligence, and neuromorphic computing is largely associated with memristive elements, offering a spectrum of inevitable functionalities, atomic level scalability, and low-power operation. However, their development is limited by significant variability and still phenomenologically orientated materials’ design strategy. Researchers highlight the vital importance of materials’ purity, demonstrating that even parts-per-million foreign elements substantially change performance. Appropriate choice of chemistry and amount of doping element selectively enhances the desired functionality. Dopant/impurity-dependent structure and charge/potential distribution in the space-charge layers and cell capacitance determine the device kinetics and functions. The relation between chemical composition/purity and switching/neuromorphic performance is experimentally evidenced, providing directions for a rational design of future memristive devices.

Permittivity values for pure and doped SiO2 as a function of OH− concentration (water content) and dopant concentration.

Cortical excitability controls the strength of mental imagery

by Rebecca Keogh, Johanna Bergmann, Joel Pearson

Highly excitable brain neurons in the visual cortex may reduce a person’s ability to visualise things clearly, neuroscience study finds

Mental imagery provides an essential simulation tool for remembering the past and planning the future, with its strength affecting both cognition and mental health. Research suggests that neural activity spanning prefrontal, parietal, temporal, and visual areas supports the generation of mental images. Exactly how this network controls the strength of visual imagery remains unknown. Here, brain imaging and transcranial magnetic phosphene data show that lower resting activity and excitability levels in early visual cortex (V1-V3) predict stronger sensory imagery. Further, electrically decreasing visual cortex excitability using tDCS increases imagery strength, demonstrating a causative role of visual cortex excitability in controlling visual imagery. Together, these data suggest a neurophysiological mechanism of cortical excitability involved in controlling the strength of mental images.

Brainstem neurons that command mammalian locomotor asymmetries

by Jared M. Cregg, Roberto Leiras, Alexia Montalant, Paulina Wanken, Ian R. Wickersham & Ole Kiehn in Nature Neuroscience

Researchers find that a specific population of brainstem neurons act to control left–right turning of locomotor movements in mammals through distinct axial- and limb-based mechanisms. This turning pathway is the dominant system for natural directional movements.

Descending command neurons instruct spinal networks to execute basic locomotor functions, such as gait and speed. The command functions for gait and speed are symmetric, implying that a separate unknown system directs asymmetric movements, including the ability to move left or right. In the present study, scientists report that Chx10-lineage reticulospinal neurons act to control the direction of locomotor movements in mammals. Chx10 neurons exhibit mainly ipsilateral projection, and their selective unilateral activation causes ipsilateral turning movements in freely moving mice. Unilateral inhibition of Chx10 neurons causes contralateral turning movements. Paired left–right motor recordings identified distinct mechanisms for directional movements mediated via limb and axial spinal circuits. Finally, they identify sensorimotor brain regions that project on to Chx10 reticulospinal neurons, and demonstrate that their unilateral activation can impart left–right directional commands. Together these data identify the descending motor system that commands left–right locomotor asymmetries in mammals.

The claustrum coordinates cortical slow-wave activity

by Kimiya Narikiyo, Rumiko Mizuguchi, Ayako Ajima, Momoko Shiozaki, Hiroki Hamanaka, Joshua P. Johansen, Kensaku Mori & Yoshihiro Yoshihara in Nature Neuroscience

Scientists establish the claustrum-Cre transgenic mouse line and demonstrate that the claustrum orchestrates cortical slow-wave activity by synchronously driving the inhibitory interneurons in widespread cortical areas.

During sleep and awake rest, the neocortex generates large-scale slow-wave (SW) activity. Scientists report that the claustrum coordinates neocortical SW generation. They established a transgenic mouse line that enabled the genetic interrogation of a subpopulation of claustral glutamatergic neurons. These neurons received inputs from and sent outputs to widespread neocortical areas. The claustral neuronal firings mostly correlated with cortical SW activity. In vitro optogenetic stimulation of the claustrum induced excitatory postsynaptic responses in most neocortical neurons, but elicited action potentials primarily in inhibitory interneurons. In vivo optogenetic stimulation induced a synchronized down-state featuring prolonged silencing of neural activity in all layers of many cortical areas, followed by a down-to-up state transition. In contrast, genetic ablation of claustral neurons attenuated SW activity in the frontal cortex. These results demonstrate a crucial role of claustral neurons in synchronizing inhibitory interneurons across wide cortical areas for the spatiotemporal coordination of SW activity.

Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction

by Paul R. Marshall, Qiongyi Zhao, Xiang Li, Wei Wei, Ambika Periyakaruppiah, Esmi L. Zajaczkowski, Laura J. Leighton, Sachithrani U. Madugalle, Dean Basic, Ziqi Wang, Jiayu Yin, Wei-Siang Liau, Ankita Gupte, Carl R. Walkley & Timothy W. Bredy in Nature Neuroscience

Scientists show that regions of the genome adopt a noncanonical Z-DNA state in the prefrontal cortex in response to fear learning and that binding of Adar1 reduces Z-DNA during extinction learning, which is required for memory flexibility.

DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Researchers show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state — effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.

Presynaptic Homeostasis Opposes Disease Progression in Mouse Models of ALS-Like Degeneration: Evidence for Homeostatic Neuroprotection

by Brian O. Orr, Anna G. Hauswirth, Barbara Celona, Len A. Pennacchio, Brian L. Black, Graeme W. Davis

Study reveals a self-corrective mechanism within synapses that is activated by neurodegeneration and slows disease progression in animal models of ALS

  • In Drosophila and mouse, NMJ degeneration induces homeostatic plasticity
  • Deletion of Scnn1a in motoneurons blocks homeostatic plasticity at the mouse NMJ
  • Scnn1a cKO causes precocious disease progression in an ALS-like mutant background
  • A model of “homeostatic neuroprotection” is proposed
Spinal cord neurons (purple) in mice with ALS suffer degeneration and glia infiltration (yellow) twice as fast when a synaptic repair mechanism is removed (right-hand image), compared to when it is intact (left-hand image) Image is credited to Davis Lab / UCSF.

Progressive synapse loss is an inevitable and insidious part of age-related neurodegenerative disease. Typically, synapse loss precedes symptoms of cognitive and motor decline. This suggests the existence of compensatory mechanisms that can temporarily counteract the effects of ongoing neurodegeneration. Here, we demonstrate that presynaptic homeostatic plasticity (PHP) is induced at degenerating neuromuscular junctions, mediated by an evolutionarily conserved activity of presynaptic ENaC channels in both Drosophila and mouse. To assess the consequence of eliminating PHP in a mouse model of ALS-like degeneration, we generated a motoneuron-specific deletion of Scnn1a, encoding the ENaC channel alpha subunit. We show that Scnn1a is essential for PHP without adversely affecting baseline neural function or lifespan. However, Scnn1a knockout in a degeneration-causing mutant background accelerated motoneuron loss and disease progression to twice the rate observed in littermate controls with intact PHP. We propose a model of neuroprotective homeostatic plasticity, extending organismal lifespan and health span.

The Allen Mouse Brain Common Coordinate Framework: A 3D Reference Atlas

by Quanxin Wang, Song-Lin Ding, Yang Li, Hongkui Zeng, Julie A. Harris, Lydia Ng

A manually constructed 3D atlas offers a cellular-level view of the entire mouse brain. This reference brain, called the Allen Mouse Brain Common Coordinate Framework (CCFv3), is derived from serial two-photon tomography images of 1,675 mice.

  • Created a 3D average template brain from 1,675 mice at 10-μm voxel resolution
  • Delineated 43 isocortical areas from multiple surface views using curved coordinates
  • Delineated 329 subcortical areas, 8 ventricle structures, and 81 fiber tracts in 3D
  • The Allen CCF is open access and available with related tools at https://atlas.brain-map.org/

Recent large-scale collaborations are generating major surveys of cell types and connections in the mouse brain, collecting large amounts of data across modalities, spatial scales, and brain areas. Successful integration of these data requires a standard 3D reference atlas. Researchers present the Allen Mouse Brain Common Coordinate Framework (CCFv3) as such a resource. They constructed an average template brain at 10 μm voxel resolution by interpolating high resolution in-plane serial two-photon tomography images with 100 μm z-sampling from 1,675 young adult C57BL/6J mice. Then, using multimodal reference data, they parcellated the entire brain directly in 3D, labeling every voxel with a brain structure spanning 43 isocortical areas and their layers, 329 subcortical gray matter structures, 81 fiber tracts, and 8 ventricular structures. CCFv3 can be used to analyze, visualize, and integrate multimodal and multiscale datasets in 3D and is openly accessible (https://atlas.brain-map.org/).

FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits

by Megan Bowers, Tong Liang, Daniel Gonzalez-Bohorquez, Sara Zocher

A lipid metabolism enzyme controls brain stem cell activity and lifelong brain development. If the enzyme does not work correctly, it causes learning and memory deficits in humans and mice, as researchers have discovered. Regulating stem cell activity via lipid metabolism could lead to new treatments for brain diseases.

-The human FASN R1819W variant affects neurogenesis and cognition in knockin mice

- FASN R1819W impairs human neural stem/progenitor cell (NSPC) proliferation

-FASN-dependent metabolism differentially regulates NSPC activity in mice and humans

Altered neural stem/progenitor cell (NSPC) activity and neurodevelopmental defects are linked to intellectual disability. However, it remains unclear whether altered metabolism, a key regulator of NSPC activity, disrupts human neurogenesis and potentially contributes to cognitive defects. Researchers investigated links between lipid metabolism and cognitive function in mice and human embryonic stem cells (hESCs) expressing mutant fatty acid synthase (FASN; R1819W), a metabolic regulator of rodent NSPC activity recently identified in humans with intellectual disability. Mice homozygous for the FASN R1812W variant have impaired adult hippocampal NSPC activity and cognitive defects because of lipid accumulation in NSPCs and subsequent lipogenic ER stress. Homozygous FASN R1819W hESC-derived NSPCs show reduced rates of proliferation in embryonic 2D cultures and 3D forebrain regionalized organoids, consistent with a developmental phenotype. These data from adult mouse models and in vitro models of human brain development suggest that altered lipid metabolism contributes to intellectual disability.

Three-dimensional architecture of human diabetic peripheral nerves revealed by X-ray phase contrast holographic nanotomography

by Lars B. Dahlin, Kristian R. Rix, Vedrana A. Dahl, Anders B. Dahl, Janus N. Jensen, Peter Cloetens, Alexandra Pacureanu, Simin Mohseni, Niels O. B. Thomsen & Martin Bech in Scientific Reports

Researchers have used synchrotron light to study what happens to the nerves in diabetes. The technique shows the 3D-structure of nerve fibers in very high resolution.

A deeper knowledge of the architecture of the peripheral nerve with three-dimensional (3D) imaging of the nerve tissue at the sub-cellular scale may contribute to unravel the pathophysiology of neuropathy. Researchers demonstrate the feasibility of X-ray phase contrast holographic nanotomography to enable 3D imaging of nerves at high resolution, while covering a relatively large tissue volume. They show various subcomponents of human peripheral nerves in biopsies from patients with type 1 and 2 diabetes and in a healthy subject. Together with well-organized, parallel myelinated nerve fibres we show regenerative clusters with twisted nerve fibres, a sprouted axon from a node of Ranvier and other specific details. A novel 3D construction (with movie created) of a node of Ranvier with end segment of a degenerated axon and sprout of a regenerated one is captured. Many of these architectural elements are not described in the literature. Thus, X-ray phase contrast holographic nanotomography enables identifying specific morphological structures in 3D in peripheral nerve biopsies from a healthy subject and from patients with type 1 and 2 diabetes.

Visualization of regenerative event. (a) 3D rendering showing only the abnormal axon. The regeneration event is visualized in panels (b–g), indicated by lines in panel (a). Arrow: regenerating axon. Arrowhead: original axon.

MISC

Daniel Colón-Ramos Reveals the Mysteries of Worms’ Memories: The Yale neuroscientist seeks to understand the brain’s architecture and function using C. elegans.

Infographic: How the Brain Keeps Track of Time in Memories: Signals from the lateral entorhinal cortex help create “time cells” in the hippocampus, according to some researchers.

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