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Segregating glutamate receptor trafficking function from the changes in synaptic spine morphology, this study finds that actin depolymerizing factor (ADF)- and cofilin-mediated actin dynamics control AMPAR trafficking during chemically induced long-term potentiation independent of actin's structural role. Dendritic spines undergo actin-based growth and shrinkage during synaptic plasticity, in which the actin depolymerizing factor (ADF)/cofilin family of actin-associated proteins are important. Elevated ADF/cofilin activities often lead to reduced spine size and immature spine morphology but can also enhance synaptic potentiation in some cases. Thus, ADF/cofilin may have distinct effects on postsynaptic structure and function. We found that ADF/cofilin-mediated actin dynamics regulated AMPA receptor (AMPAR) trafficking during synaptic potentiation, which was distinct from actin's structural role in spine morphology. Specifically, elevated ADF/cofilin activity markedly enhanced surface addition of AMPARs after chemically induced long-term potentiation (LTP), whereas inhibition of ADF/cofilin abolished AMPAR addition. We found that chemically induced LTP elicited a temporal sequence of ADF/cofilin dephosphorylation and phosphorylation that underlies AMPAR trafficking and spine enlargement. These findings suggest that temporally regulated ADF/cofilin activities function in postsynaptic modifications of receptor number and spine size during synaptic plasticity.

We exposed a headform instrumented with 10 pressure sensors mounted flush with the surface to a shock wave with three nominal intensities: 70, 140 and 210 kPa. The headform was mounted on a Hybrid III neck, in a rigid configuration to eliminate motion and associated pressure variations. We evaluated the effect of the test location by placing the headform inside, at the end and outside of the shock tube. The shock wave intensity gradually decreases the further it travels in the shock tube and the end effect degrades shock wave characteristics, which makes comparison of the results obtained at three locations a difficult task. To resolve these issues, we developed a simple strategy of data reduction: the respective pressure parameters recorded by headform sensors were divided by their equivalents associated with the incident shock wave. As a result, we obtained a comprehensive set of non-dimensional parameters. These non-dimensional parameters (or amplification factors) allow for direct comparison of pressure waveform characteristic parameters generated by a range of incident shock waves differing in intensity and for the headform located in different locations. Using this approach, we found a correlation function which allows prediction of the peak pressure on the headform that depends only on the peak pressure of the incident shock wave (for specific sensor location on the headform), and itis independent on the headform location. We also found a similar relationship for the rise time. However, for the duration and impulse, comparable correlation functions do not exist. These findings using a headform with simplified geometry are baseline values and address a need for the development of standardized parameters for the evaluation of personal protective equipment (PPE) under shock wave loading.

Mild head trauma, including concussion, can lead to chronic brain dysfunction and degeneration but the underlying mechanisms remain poorly understood. Here, we developed a novel head impact system to investigate the long-term effects of mild head trauma on brain structure and function, as well as the underlying mechanisms in Drosophila melanogaster . We find that Drosophila subjected to repetitive head impacts develop long-term deficits, including impaired startle-induced climbing, progressive brain degeneration, and shortened lifespan, all of which are substantially exacerbated in female flies. Interestingly, head impacts elicit an elevation in neuronal activity and its acute suppression abrogates the detrimental effects in female flies. Together, our findings validate Drosophila as a suitable model system for investigating the long-term effects of mild head trauma, suggest an increased vulnerability to brain injury in female flies, and indicate that early altered neuronal excitability may be a key mechanism linking mild brain trauma to chronic degeneration.

Environmental insults, including mild head trauma, significantly increase the risk of neurodegeneration. However, it remains challenging to establish a causative connection between early-life exposure to mild head trauma and late-life emergence of neurodegenerative deficits, nor do we know how sex and age compound the outcome. Using a Drosophila model, we demonstrate that exposure to mild head trauma causes neurodegenerative conditions that emerge late in life and disproportionately affect females. Increasing age-at-injury further exacerbates this effect in a sexually dimorphic manner. We further identify sex peptide signaling as a key factor in female susceptibility to post-injury brain deficits. RNA sequencing highlights a reduction in innate immune defense transcripts specifically in mated females during late life. Our findings establish a causal relationship between early head trauma and late-life neurodegeneration, emphasizing sex differences in injury response and the impact of age-at-injury. Finally, our findings reveal that reproductive signaling adversely impacts female response to mild head insults and elevates vulnerability to late-life neurodegeneration.

Calcium signals have profound and varied effects on growth cone motility and growth. Gomez and Zheng review recent evidence on intracellular calcium signalling pathways, providing fresh insight into how this 'simple' ion can have diverse effects on growth cone behaviours. Key Points For more than 25 years intracellular Ca 2+ signalling in growth cones has been recognized to be an important mediator of axon outgrowth and guidance. However, contradictory findings have led to considerable confusion and controversy regarding to the precise functions of Ca 2+ in the regulation of growth cone motility. Recent identification of new molecules that function upstream and downstream of Ca 2+ has provided new insights into how this ion can exert such diverse effects on growth cone behaviour. Direct experimental manipulation of growth cone Ca 2+ concentration shows that Ca 2+ signals serve an instructional role in axon guidance. However, the functionally relevant characteristics of local Ca 2+ signals are not clear. There is evidence to suggest that the baseline Ca 2+ concentration, transient elevations in local Ca 2+ , and the source of Ca 2+ signals may all influence growth cone motility. Growth cones have tight homeostatic control of intracellular Ca 2+ concentrations [Ca 2+ ] i . Changes in [Ca 2+ ] i occur in response to environmental factors that alter Ca 2+ influx and release from intracellular stores. Growth cones express many different Ca 2+ -influx and -release channels. The effects of Ca 2+ influx and release on growth cone motility probably result from both the combinatorial signals generated (cytosolic) and the specific pathways activated (local). Cytosolic Ca 2+ signals with distinct spatiotemporal characteristics can activate specific downstream targets to generate opposing growth cone responses. Some of these targets include kinases and phosphatases that have different affinities for Ca 2+ , so might serve as decoders of Ca 2+ changes of different magnitude. One such pair is Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and calcineurin, which functions as a bimodal switch to decode local Ca 2+ signals of differing magnitude into attraction and repulsion, respectively. Similarly, tyrosine kinase/phosphatase pairs might decode Ca 2+ signals, as Src kinase is inhibited by the Ca 2+ -dependent protease calpain in response to large Ca 2+ transients. Cytosolic Ca 2+ signals also act through several downstream targets that directly modulate cytoskeletal effectors to influence growth cone motility. For example, cytosolic Ca 2+ signals can regulate proteins that activate or inactivate Rho family GTPases. As the Rho GTPases have profound and diverse effects on growth cone motility, crosstalk with this system would allow Ca 2+ to influence many aspects of axon pathfinding. Ca 2+ signals also interact with other second messengers systems such as cyclic AMP, which is an important modulator of growth cone responses to guidance cues. Future work should seek to better understand the intricate signalling networks that are initiated or modulated by Ca 2+ signals. Moreover, determining how these complex signals cooperate to regulate growth cone motility and guidance downstream of guidance cues is necessary for a complete understanding of axon pathfinding. A more complete understanding of the molecular basis of axon pathfinding could provide the necessary basis for developing strategies to enhance axon regeneration and stem cell-based therapies for neurological disorders. Ca 2+ signals have profound and varied effects on growth cone motility and guidance. Modulation of Ca 2+ influx and release from stores by guidance cues shapes Ca 2+ signals, which determine the activation of downstream targets. Although the precise molecular mechanisms that underlie distinct Ca 2+ -mediated effects on growth cone behaviours remain unclear, recent studies have identified important players in both the regulation and targets of Ca 2+ signals in growth cones.

Significance A physics-based animal-to-human scaling law for the effects of a blast wave on brain tissue is proposed. This scaling law, or transfer function, enables the translation of animal-based assessments of injury to the human, thus effectively enabling the derivation of human injury criteria based on animal tests. This is critical both in the diagnosis of traumatic brain injury as well as in the design of blast-protective helmets. Despite recent efforts to understand blast effects on the human brain, there are still no widely accepted injury criteria for humans. Recent animal studies have resulted in important advances in the understanding of brain injury due to intense dynamic loads. However, the applicability of animal brain injury results to humans remains uncertain. Here, we use advanced computational models to derive a scaling law relating blast wave intensity to the mechanical response of brain tissue across species. Detailed simulations of blast effects on the brain are conducted for different mammals using image-based biofidelic models. The intensity of the stress waves computed for different external blast conditions is compared across species. It is found that mass scaling, which successfully estimates blast tolerance of the thorax, fails to capture the brain mechanical response to blast across mammals. Instead, we show that an appropriate scaling variable must account for the mass of protective tissues relative to the brain, as well as their acoustic impedance. Peak stresses transmitted to the brain tissue by the blast are then shown to be a power function of the scaling parameter for a range of blast conditions relevant to TBI. In particular, it is found that human brain vulnerability to blast is higher than for any other mammalian species, which is in distinct contrast to previously proposed scaling laws based on body or brain mass. An application of the scaling law to recent experiments on rabbits furnishes the first physics-based injury estimate for blast-induced TBI in humans.

Repetitive physical insults to the head, including those that elicit mild traumatic brain injury (mTBI), are a known risk factor for a variety of neurodegenerative conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). Although most individuals who sustain mTBI typically achieve a seemingly full recovery within a few weeks, a subset experience delayed-onset symptoms later in life. As most mTBI research has focused on the acute phase of injury, there is an incomplete understanding of mechanisms related to the late-life emergence of neurodegeneration after early exposure to mild head trauma. The recent adoption of Drosophila -based brain injury models provides several unique advantages over existing preclinical animal models, including a tractable framework amenable to high-throughput assays and short relative lifespan conducive to lifelong mechanistic investigation. The use of flies also provides an opportunity to investigate important risk factors associated with neurodegenerative conditions, specifically age and sex. In this review, we survey current literature that examines age and sex as contributing factors to head trauma-mediated neurodegeneration in humans and preclinical models, including mammalian and Drosophila models. We discuss similarities and disparities between human and fly in aging, sex differences, and pathophysiology. Finally, we highlight Drosophila as an effective tool for investigating mechanisms underlying head trauma-induced neurodegeneration and for identifying therapeutic targets for treatment and recovery.

Dendritic spines are small actin-rich protrusions essential for the formation of functional circuits in the mammalian brain. During development, spines begin as dynamic filopodia-like protrusions that are then replaced by relatively stable spines containing an expanded head. Remodeling of the actin cytoskeleton plays a key role in the formation and modification of spine morphology, however many of the underlying regulatory mechanisms remain unclear. Capping protein (CP) is a major actin regulating protein that caps the barbed ends of actin filaments, and promotes the formation of dense branched actin networks. Knockdown of CP impairs the formation of mature spines, leading to an increase in the number of filopodia-like protrusions and defects in synaptic transmission. Here, we show that CP promotes the stabilization of dendritic protrusions, leading to the formation of stable mature spines. However, the localization and function of CP in dendritic spines requires interactions with proteins containing a capping protein interaction (CPI) motif. We found that the CPI motif-containing protein Twinfilin-1 (Twf1) also localizes to spines where it plays a role in CP spine enrichment. The knockdown of Twf1 leads to an increase in the density of filopodia-like protrusions and a decrease in the stability of dendritic protrusions, similar to CP knockdown. Finally, we show that CP directly interacts with Shank and regulates its spine accumulation. These results suggest that spatiotemporal regulation of CP in spines not only controls the actin dynamics underlying the formation of stable postsynaptic spine structures, but also plays an important role in the assembly of the postsynaptic apparatus underlying synaptic function.

Guidance of developing axons involves turning of the motile tip, the growth cone, in response to a variety of extracellular cues 1 , 2 . Little is known about the intracellular mechanism by which the directional signal is transduced. Ca 2+ is a key second messenger in growth cone extension 3 , 4 and has been implicated in growth-cone turning 5 , 6 . Here I report that a direct, spatially restricted elevation of intracellular Ca 2+ concentration ([Ca 2+ ] i ) on one side of the growth cone by focal laser-induced photolysis (FLIP) of caged Ca 2+ consistently induced turning of the growth cone to the side with elevated [Ca 2+ ] i (attraction). Furthermore, when the resting [Ca 2+ ] i at the growth cone was decreased by the removal of extracellular Ca 2+ , the same focal elevation of [Ca 2+ ] i by FLIP induced repulsion. These results provide direct evidence that a localized Ca 2+ signal in the growth cone can provide the intracellular directional cue for extension and is sufficient to initiate both attraction and repulsion. By integrating local and global Ca 2+ signals, a growth cone could thus generate different turning responses under different environmental conditions during guidance.

Modeling Kevlar yarn response as a function of twist requires creating a model at the filament level that incorporates capturing the mechanical interaction of numerous fibers. The inherent complexity of building a multiscale interwoven fibrous structure manually is prohibitive for such an endeavor; therefore, computer-aided simulations are preferred. In this study, a random walk methodology was employed to generate a fibrous structure along the axis of a yarn. Since the directionality of the fibers is randomly oriented along the axis, the fibers can wind around each other and tangle or terminate on demand. The resultant geometry can represent the tortuous path that yarn filaments experience. Yarn twist can be introduced through imposing a rotation matrix to the geometry or conducting an initial analysis that applies the preload. The analysis method employed in this paper captures the correct prestress of the twisted yarns at zero, three, and ten twists per inch. The analysis then loaded the yarn until filament fracture occurred. The predicted ultimate load was within 5% for all three twists per inch analyzed. The zero twists per inch linear response matched test results to within 5%.