Transcranial Low-Intensity Focused Ultrasound Stimulation of the Visual Thalamus Produces Long-Term Depression of Thalamocortical Synapses in the Adult Visual Cortex.

Transcranial focused ultrasound stimulation (tFUS) is a noninvasive neuromodulation technique, which can penetrate deeper and modulate neural activity with a greater spatial resolution (on the order of millimeters) than currently available noninvasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). While there are several studies demonstrating the ability of tFUS to modulate neuronal activity, it is unclear whether it can be used for producing long-term plasticity as needed to modify circuit function, especially in adult brain circuits with limited plasticity such as the thalamocortical synapses. Here we demonstrate that transcranial low-intensity focused ultrasound (LIFU) stimulation of the visual thalamus (dorsal lateral geniculate nucleus, dLGN), a deep brain structure, leads to NMDA receptor (NMDAR)-dependent long-term depression of its synaptic transmission onto layer 4 neurons in the primary visual cortex (V1) of adult mice of both sexes. This change is not accompanied by large increases in neuronal activity, as visualized using the cFos Targeted Recombination in Active Populations (cFosTRAP2) mouse line, or activation of microglia, which was assessed with IBA-1 staining. Using a model (SONIC) based on the neuronal intramembrane cavitation excitation (NICE) theory of ultrasound neuromodulation, we find that the predicted activity pattern of dLGN neurons upon sonication is state-dependent with a range of activity that falls within the parameter space conducive for inducing long-term synaptic depression. Our results suggest that noninvasive transcranial LIFU stimulation has a potential for recovering long-term plasticity of thalamocortical synapses in the postcritical period adult brain.

Thinning of Poly(methyl methacrylate) and Poly(vinyl chloride) Thin Films Induced by High-Energy Ions of Different Stopping Powers.

Ion bombardment is an important tool of materials processing, but usually leads to erosion of the surface and significant thickness reductions when thin layers are used. The growing use of polymer thin films in a variety of applications, from coatings and membranes to biomedical and electronic devices, calls for a deeper understanding of the thinning process induced by energetic ions espe-cially for very thin films. Here, thinning and surface morphology changes induced by high-energy ion bombardment in PMMA and PVC thin films were investigated, focusing on the role of the initial thickness of the films and the stopping power of the ions. We used thin films with initial thicknesses varying from 13 to 800 nm, and light and heavy ions as projectiles in the energy range of 2-2000 MeV, where the electronic stopping dominates. Thickness reductions as a function of fluence were monitored and thinning cross sections were extracted from curves. A supralinear scaling between the thinning cross sections and the electronic stopping power of the beams was observed, with a much enhanced thinning efficiency for the swift heavy ions. The scaling with the stopping power dE/dx is almost independent of the initial thickness of the films. At intermediate and large fluences, changes in the physicochemical properties of the irradiated polymers may modulate and decelerate the thinning process of the remaining film. The importance of this secondary process depends on the stopping power and the balance between erosion and the chemical transformations induced by the beam. We also observe a trend for the thinning efficiency to become larger in very thin films. Depending on the type of beam and polymer, this effect is more or less pronounced. PMMA films irradiated with 2 MeV H+ show the most systematic correlation between initial thickness and thinning cross sections, while in PVC films the initial thickness plays a minor role for all investigated beams.

Norepinephrine potentiates and serotonin depresses visual cortical responses by transforming eligibility traces.

Reinforcement allows organisms to learn which stimuli predict subsequent biological relevance. Hebbian mechanisms of synaptic plasticity are insufficient to account for reinforced learning because neuromodulators signaling biological relevance are delayed with respect to the neural activity associated with the stimulus. A theoretical solution is the concept of eligibility traces (eTraces), silent synaptic processes elicited by activity which upon arrival of a neuromodulator are converted into a lasting change in synaptic strength. Previously we demonstrated in visual cortical slices the Hebbian induction of eTraces and their conversion into LTP and LTD by the retroactive action of norepinephrine and serotonin Here we show in vivo in mouse V1 that the induction of eTraces and their conversion to LTP/D by norepinephrine and serotonin respectively potentiates and depresses visual responses. We also show that the integrity of this process is crucial for ocular dominance plasticity, a canonical model of experience-dependent plasticity.

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity.

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, "all-or-none," elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.

Afterhyperpolarization amplitude in CA1 pyramidal cells of aged Long-Evans rats characterized for individual differences.

Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield. Studies in the inbred Fisher 344 rat strain document an age-related increase in the slow afterhyperpolarization (AHP) that normally occurs after a burst of action potentials, and serves to reduce subsequent firing. We evaluated the status of the AHP in the outbred Long-Evans rat, a well-established model for studying individual differences in neurocognitive aging. In contrast to the findings reported in the Fisher 344 rats, in the Long-Evan rats we detected a selective reduction in AHP in cognitively impaired aged individuals. We discuss plausible scenarios to account for these differences and also discuss possible implications of these differences.

Pull-push neuromodulation of cortical plasticity enables rapid bi-directional shifts in ocular dominance.

Neuromodulatory systems are essential for remodeling glutamatergic connectivity during experience-dependent cortical plasticity. This permissive/enabling function of neuromodulators has been associated with their capacity to facilitate the induction of Hebbian forms of long-term potentiation (LTP) and depression (LTD) by affecting cellular and network excitability. In vitro studies indicate that neuromodulators also affect the expression of Hebbian plasticity in a pull-push manner: receptors coupled to the G-protein Gs promote the expression of LTP at the expense of LTD, and Gq-coupled receptors promote LTD at the expense of LTP. Here we show that pull-push mechanisms can be recruited in vivo by pairing brief monocular stimulation with pharmacological or chemogenetical activation of Gs- or Gq-coupled receptors to respectively enhance or reduce neuronal responses in primary visual cortex. These changes were stable, inducible in adults after the termination of the critical period for ocular dominance plasticity, and can rescue deficits induced by prolonged monocular deprivation.

Daily Oscillation of the Excitation-Inhibition Balance in Visual Cortical Circuits.

A balance between synaptic excitation and inhibition (E/I balance) maintained within a narrow window is widely regarded to be crucial for cortical processing. In line with this idea, the E/I balance is reportedly comparable across neighboring neurons, behavioral states, and developmental stages and altered in many neurological disorders. Motivated by these ideas, we examined whether synaptic inhibition changes over the 24-h day to compensate for the well-documented sleep-dependent changes in synaptic excitation. We found that, in pyramidal cells of visual and prefrontal cortices and hippocampal CA1, synaptic inhibition also changes over the 24-h light/dark cycle but, surprisingly, in the opposite direction of synaptic excitation. Inhibition is upregulated in the visual cortex during the light phase in a sleep-dependent manner. In the visual cortex, these changes in the E/I balance occurred in feedback, but not feedforward, circuits. These observations open new and interesting questions on the function and regulation of the E/I balance.

Anatomical Specializations Related to Foraging in the Visual System of a Nocturnal Insectivorous Bird, the Band-Winged Nightjar (Aves: Caprimulgiformes).

Nocturnal animals that rely on their visual system for foraging, mating, and navigation usually exhibit specific traits associated with living in scotopic conditions. Most nocturnal birds have several visual specializations, such as enlarged eyes and an increased orbital convergence. However, the actual role of binocular vision in nocturnal foraging is still debated. Nightjars (Aves: Caprimulgidae) are predators that actively pursue and capture flying insects in crepuscular and nocturnal environments, mainly using a conspicuous "sit-and-wait" tactic on which pursuit begins with an insect flying over the bird that sits on the ground. In this study, we describe the visual system of the band-winged nightjar (Systellura longirostris), with emphasis on anatomical features previously described as relevant for nocturnal birds. Orbit convergence, determined by 3D scanning of the skull, was 73.28°. The visual field, determined by ophthalmoscopic reflex, exhibits an area of maximum binocular overlap of 42°, and it is dorsally oriented. The eyes showed a nocturnal-like normalized corneal aperture/axial length index. Retinal ganglion cells (RGCs) were relatively scant, and distributed in an unusual oblique-band pattern, with higher concentrations in the ventrotemporal quadrant. Together, these results indicate that the band-winged nightjar exhibits a retinal specialization associated with the binocular area of their dorsal visual field, a relevant area for pursuit triggering and prey attacks. The RGC distribution observed is unusual among birds, but similar to that of some visually dependent insectivorous bats, suggesting that those features might be convergent in relation to feeding strategies.

Ionic current correlations are ubiquitous across phyla.

Ionic currents, whether measured as conductance amplitude or as ion channel transcript numbers, can vary many-fold within a population of identified neurons. In invertebrate neuronal types multiple currents can be seen to vary while at the same time their magnitudes are correlated. These conductance amplitude correlations are thought to reflect a tight homeostasis of cellular excitability that enhances the robustness and stability of neuronal activity over long stretches of time. Although such ionic conductance correlations are well documented in invertebrates, they have not been reported in vertebrates. Here we demonstrate with two examples, identified mouse hippocampal granule cells (GCs) and cholinergic basal forebrain neurons, that the correlation of ionic conductance amplitudes between different ionic currents also exists in vertebrates, and we argue that it is a ubiquitous phenomenon expressed by many species across phyla. We further demonstrate that in dentate gyrus GCs these conductance correlations are likely regulated in a circadian manner. This is reminiscent of the known conductance regulation by neuromodulators in crustaceans. However, in GCs we observe a more nuanced regulation, where for some conductance pairs the correlations are completely eliminated while for others the correlation is quantitatively modified but not obliterated.

Light Affects Mood and Learning through Distinct Retina-Brain Pathways.

Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone.

To date, most in vitro toxicity testing has focused on acute effects of compounds at high concentrations. This testing strategy does not reflect real-life exposures, which might contribute to long-term disease outcome. We used a 3D-human dopaminergic in vitro LUHMES cell line model to determine whether effects of short-term rotenone exposure (100 nM, 24 h) are permanent or reversible. A decrease in complex I activity, ATP, mitochondrial diameter, and neurite outgrowth were observed acutely. After compound removal, complex I activity was still inhibited; however, ATP levels were increased, cells were electrically active and aggregates restored neurite outgrowth integrity and mitochondrial morphology. We identified significant transcriptomic changes after 24 h which were not present 7 days after wash-out. Our results suggest that testing short-term exposures in vitro may capture many acute effects which cells can overcome, missing adaptive processes, and long-term mechanisms. In addition, to study cellular resilience, cells were re-exposed to rotenone after wash-out and recovery period. Pre-exposed cells maintained higher metabolic activity than controls and presented a different expression pattern in genes previously shown to be altered by rotenone. NEF2L2, ATF4, and EAAC1 were downregulated upon single hit on day 14, but unchanged in pre-exposed aggregates. DAT and CASP3 were only altered after re-exposure to rotenone, while TYMS and MLF1IP were downregulated in both single-exposed and pre-exposed aggregates. In summary, our study shows that a human cell-based 3D model can be used to assess cellular adaptation, resilience, and long-term mechanisms relevant to neurodegenerative research.

Redox response of actinide materials to highly ionizing radiation.

Energetic radiation can cause dramatic changes in the physical and chemical properties of actinide materials, degrading their performance in fission-based energy systems. As advanced nuclear fuels and wasteforms are developed, fundamental understanding of the processes controlling radiation damage accumulation is necessary. Here we report oxidation state reduction of actinide and analogue elements caused by high-energy, heavy ion irradiation and demonstrate coupling of this redox behaviour with structural modifications. ThO2, in which thorium is stable only in a tetravalent state, exhibits damage accumulation processes distinct from those of multivalent cation compounds CeO2 (Ce(3+) and Ce(4+)) and UO3 (U(4+), U(5+) and U(6+)). The radiation tolerance of these materials depends on the efficiency of this redox reaction, such that damage can be inhibited by altering grain size and cation valence variability. Thus, the redox behaviour of actinide materials is important for the design of nuclear fuels and the prediction of their performance.

Does nocturnality drive binocular vision? Octodontine rodents as a case study.

Binocular vision is a visual property that allows fine discrimination of in-depth distance (stereopsis), as well as enhanced light and contrast sensitivity. In mammals enhanced binocular vision is structurally associated with a large degree of frontal binocular overlap, the presence of a corresponding retinal specialization containing a fovea or an area centralis, and well-developed ipsilateral retinal projections to the lateral thalamus (GLd). We compared these visual traits in two visually active species of the genus Octodon that exhibit contrasting visual habits: the diurnal Octodon degus, and the nocturnal Octodon lunatus. The O. lunatus visual field has a prominent 100° frontal binocular overlap, much larger than the 50° of overlap found in O. degus. Cells in the retinal ganglion cell layer were 40% fewer in O. lunatus (180,000) than in O. degus (300,000). O. lunatus has a poorly developed visual streak, but a well developed area centralis, located centrally near the optic disk (peak density of 4,352 cells/mm(2)). O. degus has a highly developed visual streak, and an area centralis located more temporally (peak density of 6,384 cells/mm(2)). The volumes of the contralateral GLd and superior colliculus (SC) are 15% larger in O. degus compared to O. lunatus. However, the ipsilateral projections to GLd and SC are 500% larger in O. lunatus than in O. degus. Other retinorecipient structures related to ocular movements and circadian activity showed no statistical differences between species. Our findings strongly suggest that nocturnal visual behavior leads to an enhancement of the structures associated with binocular vision, at least in the case of these rodents. Expansion of the binocular visual field in nocturnal species may have a beneficial effect in light and contrast sensitivity, but not necessarily in stereopsis. We discuss whether these conclusions can be extended to other mammalian and non-mammalian amniotes.

An apparatus for in situ spectroscopy of radiation damage of polymers by bombardment with high-energy heavy ions.

A new target station providing Fourier transform infrared (FT-IR) spectroscopy and residual gas analysis (RGA) for in situ observation of ion-induced changes in polymers has been installed at the GSI Helmholtz Centre for Heavy Ion Research. The installations as well as first in situ measurements at room temperature are presented here. A foil of polyimide Kapton HN(®) was irradiated with 1.1 GeV Au ions. During irradiation several in situ FT-IR spectra were recorded. Simultaneously outgassing degradation products were detected with the RGA. In the IR spectra nearly all bands decrease due to the degradation of the molecular structure. In the region from 3000 to 2700 cm(-1) vibration bands of saturated hydrocarbons not reported in literature so far became visible. The outgassing experiments show a mixture of C(2)H(4), CO, and N(2) as the main outgassing components of polyimide. The ability to combine both analytical methods and the opportunity to measure a whole fluence series within a single experiment show the efficiency of the new setup.