Dynamic Gain Decomposition Reveals Functional Effects of Dendrites, Ion Channels, and Input Statistics in Population Coding.

Modern, high-density neuronal recordings reveal at ever higher precision how information is represented by neural populations. Still, we lack the tools to understand these processes bottom-up, emerging from the biophysical properties of neurons, synapses, and network structure. The concept of the dynamic gain function, a spectrally resolved approximation of a population's coding capability, has the potential to link cell-level properties to network-level performance. However, the concept is not only useful but also very complex because the dynamic gain's shape is co-determined by axonal and somato-dendritic parameters and the population's operating regime. Previously, this complexity precluded an understanding of any individual parameter's impact. Here, we decomposed the dynamic gain function into three components corresponding to separate signal transformations. This allowed attribution of network-level encoding features to specific cell-level parameters. Applying the method to data from real neurons and biophysically plausible models, we found: (1) The encoding bandwidth of real neurons, approximately 400 Hz, is constrained by the voltage dependence of axonal currents during early action potential initiation. (2) State-of-the-art models only achieve encoding bandwidths around 100 Hz and are limited mainly by subthreshold processes instead. (3) Large dendrites and low-threshold potassium currents modulate the bandwidth by shaping the subthreshold stimulus-to-voltage transformation. Our decomposition provides physiological interpretations when the dynamic gain curve changes, for instance during spectrinopathies and neurodegeneration. By pinpointing shortcomings of current models, it also guides inference of neuron models best suited for large-scale network simulations.

Fibroblast growth factor 9 (FGF9)-mediated neurodegeneration: Implications for progressive multiple sclerosis?

AIMS: Fibroblast growth factor (FGF) signalling is dysregulated in multiple sclerosis (MS) and other neurological and psychiatric conditions, but there is little or no consensus as to how individual FGF family members contribute to disease pathogenesis. Lesion development in MS is associated with increased expression of FGF1, FGF2 and FGF9, all of which modulate remyelination in a variety of experimental settings. However, FGF9 is also selectively upregulated in major depressive disorder (MDD), prompting us to speculate it may also have a direct effect on neuronal function and survival. METHODS: Transcriptional profiling of myelinating cultures treated with FGF1, FGF2 or FGF9 was performed, and the effects of FGF9 on cortical neurons investigated using a combination of transcriptional, electrophysiological and immunofluorescence microscopic techniques. The in vivo effects of FGF9 were explored by stereotactic injection of adeno-associated viral (AAV) vectors encoding either FGF9 or EGFP into the rat motor cortex. RESULTS: Transcriptional profiling of myelinating cultures after FGF9 treatment revealed a distinct neuronal response with a pronounced downregulation of gene networks associated with axonal transport and synaptic function. In cortical neuronal cultures, FGF9 also rapidly downregulated expression of genes associated with synaptic function. This was associated with a complete block in the development of photo-inducible spiking activity, as demonstrated using multi-electrode recordings of channel rhodopsin-transfected rat cortical neurons in vitro and, ultimately, neuronal cell death. Overexpression of FGF9 in vivo resulted in rapid loss of neurons and subsequent development of chronic grey matter lesions with neuroaxonal reduction and ensuing myelin loss. CONCLUSIONS: These observations identify overexpression of FGF9 as a mechanism by which neuroaxonal pathology could develop independently of immune-mediated demyelination in MS. We suggest targeting neuronal FGF9-dependent pathways may provide a novel strategy to slow if not halt neuroaxonal atrophy and loss in MS, MDD and potentially other neurodegenerative diseases.

Climate micro-mobilities as adaptation practice in the Pacific: the case of Samoa.

Recent debates on climate mobilities have largely ignored the dynamics of mobility patterns including short-distance and short-duration circular movements to enhance adaptative capacity and resilience of households and individuals, enabling them to remain in place despite facing increasingly severe climatic risks. This paper explores Pacific Islanders' climate-related mobilities with reference to cases from Samoa. It first conceptualizes Samoan mobility, which is rooted in Samoan culture, norms and worldviews, and then uses this as a framework to examine ways in which people shift and diversify their residential locations for climate-associated reasons. The study employs a comparative case study approach using conversational (the Pacific-originated talanoa-style) interviews with 40 participants in two villages in Samoa-one urban and the other rural. Findings suggest that shifting spatially and temporarily between two residences (a practice called fa'a-'aigalua) occurs not only within the village but across villages. Thereby, villagers reduce the risk of incurring physical harm from climate-related disasters, while minimizing the risk of cultural harm from place detachment. Our study challenges the discourse of 'vulnerable Pacific Islanders' by demonstrating the adaptability of Samoans to changing socio-ecological and climatic circumstances and their ability to develop a variety of climate resilience strategies, including micro-mobilities and circular migration. This article is part of the theme issue 'Climate change adaptation needs a science of culture'.

Recording electrical activity from the brain of behaving octopus.

Octopuses, which are among the most intelligent invertebrates,1,2,3,4 have no skeleton and eight flexible arms whose sensory and motor activities are at once autonomous and coordinated by a complex central nervous system.5,6,7,8 The octopus brain contains a very large number of neurons, organized into numerous distinct lobes, the functions of which have been proposed based largely on the results of lesioning experiments.9,10,11,12,13 In other species, linking brain activity to behavior is done by implanting electrodes and directly correlating electrical activity with observed animal behavior. However, because the octopus lacks any hard structure to which recording equipment can be anchored, and because it uses its eight flexible arms to remove any foreign object attached to the outside of its body, in vivo recording of electrical activity from untethered, behaving octopuses has thus far not been possible. Here, we describe a novel technique for inserting a portable data logger into the octopus and implanting electrodes into the vertical lobe system, such that brain activity can be recorded for up to 12 h from unanesthetized, untethered octopuses and can be synchronized with simultaneous video recordings of behavior. In the brain activity, we identified several distinct patterns that appeared consistently in all animals. While some resemble activity patterns in mammalian neural tissue, others, such as episodes of 2 Hz, large amplitude oscillations, have not been reported. By providing an experimental platform for recording brain activity in behaving octopuses, our study is a critical step toward understanding how the brain controls behavior in these remarkable animals.

"There's so much more to that sinking island!"-Restorying migration from Kiribati and Tuvalu to Aotearoa New Zealand.

BACKGROUND AND AIMS: Many Pacific people are considering cross-border mobility in response to the climate crisis, despite exclusion from international protection frameworks. The 'Migration with dignity' concept facilitates immigration within existing laws but without host government support. Through the metaphor of Pacific navigation, we explore the role of dignity in the lives of I-Kiribati and Tuvaluans in Aotearoa New Zealand. METHODS: Combining talanoa (pacific research method) with I-Kiribati and Tuvaluan community members, alongside critical community psychology and thematic analysis, we depict climate mobility as a wa or vaka moana (ocean-going canoes) journey. ANALYSIS: Participants are expert navigators, navigating immigration obstacles to (re)grow their roots in Aotearoa New Zealand before charting a course for future generations to thrive. They draw strength from culture and community to overcome the adversity of precarious living and visa non-recognition. CONCLUSION: Reconceptualising climate mobility through a Pacific lens imagines both dignity and cultural preservation as possible, despite the indignities and limitations of socio-political systems and protections for climate migrants.

Ultrafast population coding and axo-somatic compartmentalization.

Populations of cortical neurons respond to common input within a millisecond. Morphological features and active ion channel properties were suggested to contribute to this astonishing processing speed. Here we report an exhaustive study of ultrafast population coding for varying axon initial segment (AIS) location, soma size, and axonal current properties. In particular, we studied their impact on two experimentally observed features 1) precise action potential timing, manifested in a wide-bandwidth dynamic gain, and 2) high-frequency boost under slowly fluctuating correlated input. While the density of axonal channels and their distance from the soma had a very small impact on bandwidth, it could be moderately improved by increasing soma size. When the voltage sensitivity of axonal currents was increased we observed ultrafast coding and high-frequency boost. We conclude that these computationally relevant features are strongly dependent on axonal ion channels' voltage sensitivity, but not their number or exact location. We point out that ion channel properties, unlike dendrite size, can undergo rapid physiological modification, suggesting that the temporal accuracy of neuronal population encoding could be dynamically regulated. Our results are in line with recent experimental findings in AIS pathologies and establish a framework to study structure-function relations in AIS molecular design.

Theta activity paradoxically boosts gamma and ripple frequency sensitivity in prefrontal interneurons.

Fast oscillations in cortical circuits critically depend on GABAergic interneurons. Which interneuron types and populations can drive different cortical rhythms, however, remains unresolved and may depend on brain state. Here, we measured the sensitivity of different GABAergic interneurons in prefrontal cortex under conditions mimicking distinct brain states. While fast-spiking neurons always exhibited a wide bandwidth of around 400 Hz, the response properties of spike-frequency adapting interneurons switched with the background input's statistics. Slowly fluctuating background activity, as typical for sleep or quiet wakefulness, dramatically boosted the neurons' sensitivity to gamma and ripple frequencies. We developed a time-resolved dynamic gain analysis and revealed rapid sensitivity modulations that enable neurons to periodically boost gamma oscillations and ripples during specific phases of ongoing low-frequency oscillations. This mechanism predicts these prefrontal interneurons to be exquisitely sensitive to high-frequency ripples, especially during brain states characterized by slow rhythms, and to contribute substantially to theta-gamma cross-frequency coupling.

Risk of a disaster: Risk knowledge, interpretation and resilience.

Knowledge and interpretation of local risks are essential in disaster mitigation. Auckland's exposure to multiple hazards is a source of national concern. Considering the multiplicity of natural hazards in Auckland, investigations on how communities can enhance their resilience to possible disasters have become imperative. Convincing individuals to embark on activities that would reduce their vulnerability to natural hazards is difficult, especially in communities that have not recently experienced the impact of natural hazards. This research investigated risk knowledge and interpretation in the South African community in Auckland. Data for this study were collected from both primary and secondary sources. A questionnaire was distributed amongst the South African population, and follow-up interviews with participants constituted the primary sources of data collection. Other sources were materials in the public domain. Regarding data analysis, an independent-sample t-test and Spearman's correlation analysis were used to analyse the quantitative research data. A general inductive approach for qualitative data was used to analyse the research interviews. The research confirmed the subjectivity in risk perception and also revealed a high-risk perception, especially for earthquake, flood and tsunami. Whilst this study agreed that there is a relationship between risk perception and preparedness, such relationship is often contextual. The research concludes that risk perception could contribute to disaster resilience if communities appreciate the impact of a natural hazard irrespective of disaster experience or otherwise.

Macromolecular and electrical coupling between inner hair cells in the rodent cochlea.

Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, in mice 30% of the IHCs are electrochemically coupled in 'mini-syncytia'. This coupling permits transfer of fluorescently-labeled metabolites and macromolecular tracers. The membrane capacitance, Ca2+-current, and resting current increase with the number of dye-coupled IHCs. Dual voltage-clamp experiments substantiate low resistance electrical coupling. Pharmacology and tracer permeability rule out coupling by gap junctions and purinoceptors. 3D electron microscopy indicates instead that IHCs are coupled by membrane fusion sites. Consequently, depolarization of one IHC triggers presynaptic Ca2+-influx at active zones in the entire mini-syncytium. Based on our findings and modeling, we propose that IHC-mini-syncytia enhance sensitivity and reliability of cochlear sound encoding.

Climate change impacts and disaster resilience among micro businesses in the tourism and hospitality sector: The case of Kratie, Cambodia.

Cambodia is considered extremely vulnerable to climate change due to high poverty, limited infrastructure, and weak adaptive capacity. Kratie province, in particular, has suffered from climate-induced disasters, including floods, droughts, storms, lightning, and heatwaves. To date, climate change interventions in the province have primarily focused on impacts on agriculture. However, enhancing the climate resilience of micro businesses in the tourism and hospitality sector is also crucial since the provincial economy increasingly depends on the interlinkage between agriculture, tourism and related enterprises. This article examines how climate change has impacted micro businesses in Kratie Town, and how they responded to the impacts. This study is based on semi-structured interviews with micro entrepreneurs randomly selected in the town. Results show that businesses have been predominantly affected by floods and storms. Business exposures and locations, types of business, production and supply chains, and client bases determined different impacts of and responses to these climate-related hazards. Businesses adopted primarily temporary and reactive responses rather than long-term systematic measures. Strengthening adaptive infrastructure, both physical and informational, will improve businesses' capability to prepare for and cope with these disasters.

Dynamic Gain Analysis Reveals Encoding Deficiencies in Cortical Neurons That Recover from Hypoxia-Induced Spreading Depolarizations.

Cortical regions that are damaged by insults, such as ischemia, hypoxia, and trauma, frequently generate spreading depolarization (SD). At the neuronal level, SDs entail complete breakdown of ionic gradients, persisting for seconds to minutes. It is unclear whether these transient events have a more lasting influence on neuronal function. Here, we describe electrophysiological changes in cortical neurons after recovery from hypoxia-induced SD. When examined with standard measures of neuronal excitability several hours after recovery from SD, layer 5 pyramidal neurons in brain slices from mice of either sex appear surprisingly normal. However, we here introduce an additional parameter, dynamic gain, which characterizes the bandwidth of action potential encoding by a neuron, and thereby reflects its potential efficiency in a multineuronal circuit. We find that the ability of neurons that recover from SD to track high-frequency inputs is markedly curtailed; exposure to hypoxia did not have this effect when SD was prevented pharmacologically. Staining for Ankyrin G revealed at least a fourfold decrease in the number of intact axon initial segments in post-SD slices. Since this effect, along with the effect on encoding, was blocked by an inhibitor of the Ca2+-dependent enzyme, calpain, we conclude that both effects were mediated by the SD-induced rise in intracellular Ca2+ Although effects of calpain activation were detected in the axon initial segment, changes in soma-dendritic compartments may also be involved. Whatever the precise molecular mechanism, our findings indicate that in the context of cortical circuit function, effectiveness of neurons that survive SD may be limited.SIGNIFICANCE STATEMENT Spreading depolarization, which commonly accompanies cortical injury, entails transient massive breakdown of neuronal ionic gradients. The function of cortical neurons that recover from hypoxia-induced spreading depolarization is not obviously abnormal when tested for usual measures of neuronal excitability. However, we now demonstrate that they have a reduced bandwidth, reflecting a significant impairment of their ability to precisely encode high-frequency components of their synaptic input in output spike trains. Thus, neurons that recover from spreading depolarizations are less able to function normally as elements in the multineuronal cortical circuitry. These changes are correlated with activation of the calcium-dependent enzyme, calpain.

An axon initial segment is required for temporal precision in action potential encoding by neuronal populations.

Central neurons initiate action potentials (APs) in the axon initial segment (AIS), a compartment characterized by a high concentration of voltage-dependent ion channels and specialized cytoskeletal anchoring proteins arranged in a regular nanoscale pattern. Although the AIS was a key evolutionary innovation in neurons, the functional benefits it confers are not clear. Using a mutation of the AIS cytoskeletal protein ßIV-spectrin, we here establish an in vitro model of neurons with a perturbed AIS architecture that retains nanoscale order but loses the ability to maintain a high NaV density. Combining experiments and simulations, we show that a high NaV density in the AIS is not required for axonal AP initiation; it is, however, crucial for a high bandwidth of information encoding and AP timing precision. Our results provide the first experimental demonstration of axonal AP initiation without high axonal channel density and suggest that increasing the bandwidth of the neuronal code and, hence, the computational efficiency of network function, was a major benefit of the evolution of the AIS.

Ultrafast optogenetic stimulation of the auditory pathway by targeting-optimized Chronos.

Optogenetic tools, providing non-invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light-off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature. In order to enhance neural expression, we improved its trafficking to the plasma membrane (Chronos-ES/TS). Following efficient transduction of SGNs using early postnatal injection of the adeno-associated virus AAV-PHPB into the mouse cochlea, fiber-based optical stimulation elicited optical auditory brainstem responses (oABR) with minimal latencies of 1 ms, thresholds of 5 µJ and 100 µs per pulse, and sizable amplitudes even at 1,000 Hz of stimulation. Recordings from single SGNs demonstrated good temporal precision of light-evoked spiking. In conclusion, efficient virus-mediated expression of targeting-optimized Chronos-ES/TS achieves ultrafast optogenetic control of neurons.

The synaptic ribbon is critical for sound encoding at high rates and with temporal precision.

We studied the role of the synaptic ribbon for sound encoding at the synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in mice lacking RIBEYE (RBEKO/KO). Electron and immunofluorescence microscopy revealed a lack of synaptic ribbons and an assembly of several small active zones (AZs) at each synaptic contact. Spontaneous and sound-evoked firing rates of SGNs and their compound action potential were reduced, indicating impaired transmission at ribbonless IHC-SGN synapses. The temporal precision of sound encoding was impaired and the recovery of SGN-firing from adaptation indicated slowed synaptic vesicle (SV) replenishment. Activation of Ca2+-channels was shifted to more depolarized potentials and exocytosis was reduced for weak depolarizations. Presynaptic Ca2+-signals showed a broader spread, compatible with the altered Ca2+-channel clustering observed by super-resolution immunofluorescence microscopy. We postulate that RIBEYE disruption is partially compensated by multi-AZ organization. The remaining synaptic deficit indicates ribbon function in SV-replenishment and Ca2+-channel regulation.

TMS of primary motor cortex with a biphasic pulse activates two independent sets of excitable neurones.

BACKGROUND: Biphasic pulses produced by most commercially available TMS machines have a cosine waveform, which makes it difficult to study the interaction between the two phases of stimulation. OBJECTIVE: We used a controllable pulse TMS (cTMS) device delivering quasi-rectangular pulse outputs to investigate whether monophasic are more effective than biphasic pulses. METHODS: Temporally symmetric ("biphasic") or highly asymmetric ("monophasic") charge-balanced biphasic stimuli were used to target the hand area of motor cortex in the anterior-posterior (AP) or posterior-anterior (PA) initial current direction. RESULTS: We observed the lowest motor thresholds and shortest motor evoked potential (MEP) latencies with initial PA pulses, and highest thresholds and longest latencies with AP pulses. Increasing pulse symmetry tended to increase threshold with a PA direction whereas it lowered thresholds and shortened latencies with an AP direction. Furthermore, it steepened the MEP input-output curve with both directions. CONCLUSIONS: "Biphasic" TMS pulses can be viewed as two monophasic pulses of opposite directions, each stimulating a different set of interneurons with different thresholds (PA < AP). At threshold, the reverse phase of an initially PA pulse increases threshold compared with "monophasic" stimulation. At higher intensities, the reverse phase begins to activate AP-sensitive neurones and increase the effectiveness of stimulation above that of a "monophasic" PA pulse. "Biphasic" stimulation with initially AP pulses is dominated at threshold by activation produced by the lower threshold reverse (PA) phase. SIGNIFICANCE: The effects of biphasic stimulation are best understood as the summed output of two independent sets of directionally selective neural populations.

Gender bias in scholarly peer review.

Peer review is the cornerstone of scholarly publishing and it is essential that peer reviewers are appointed on the basis of their expertise alone. However, it is difficult to check for any bias in the peer-review process because the identity of peer reviewers generally remains confidential. Here, using public information about the identities of 9000 editors and 43000 reviewers from the Frontiers series of journals, we show that women are underrepresented in the peer-review process, that editors of both genders operate with substantial same-gender preference (homophily), and that the mechanisms of this homophily are gender-dependent. We also show that homophily will persist even if numerical parity between genders is reached, highlighting the need for increased efforts to combat subtler forms of gender bias in scholarly publishing.

Low Somatic Sodium Conductance Enhances Action Potential Precision in Time-Coding Auditory Neurons.

Auditory nerve fibers encode sounds in the precise timing of action potentials (APs), which is used for such computations as sound localization. Timing information is relayed through several cell types in the auditory brainstem that share an unusual property: their APs are not overshooting, suggesting that the cells have very low somatic sodium conductance (gNa). However, it is not clear how gNa influences temporal precision. We addressed this by comparing bushy cells (BCs) in the mouse cochlear nucleus with T-stellate cells (SCs), which do have normal overshooting APs. BCs play a central role in both relaying and refining precise timing information from the auditory nerve, whereas SCs discard precise timing information and encode the envelope of sound amplitude. Nucleated-patch recording at near-physiological temperature indicated that the Na current density was 62% lower in BCs, and the voltage dependence of gNa inactivation was 13 mV hyperpolarized compared with SCs. We endowed BCs with SC-like gNa using two-electrode dynamic clamp and found that synaptic activity at physiologically relevant rates elicited APs with significantly lower probability, through increased activation of delayed rectifier channels. In addition, for two near-simultaneous synaptic inputs, the window of coincidence detection widened significantly with increasing gNa, indicating that refinement of temporal information by BCs is degraded by gNa Thus, reduced somatic gNa appears to be an adaption for enhancing fidelity and precision in time-coding neurons. SIGNIFICANCE STATEMENT: Proper hearing depends on analyzing temporal aspects of sounds with high precision. Auditory neurons that specialize in precise temporal information have a suite of unusual intrinsic properties, including nonovershooting action potentials and few sodium channels in the soma. However, it was not clear how low sodium channel availability in the soma influenced the temporal precision of action potentials initiated in the axon initial segment. We studied this using dynamic clamp to mimic sodium channels in the soma, which yielded normal, overshooting action potentials. Increasing somatic sodium conductance had major negative consequences: synaptic activity evoked action potentials with lower fidelity, and the precision of coincidence detection was degraded. Thus, low somatic sodium channel availability appears to enhance fidelity and temporal precision.

5 kHz Transcranial Alternating Current Stimulation: Lack of Cortical Excitability Changes When Grouped in a Theta Burst Pattern.

Background: Suprathreshold transcranial single pulse electrical stimulation (tES) is painful and not applicable in a repetitive mode to induce plastic after-effects. Objective: In order to circumvent this pain problem, we applied here a 5 kHz transcranial alternating current stimulation (tACS) theta burst protocol with a field intensity of up to 10 mA to the primary motor cortex (M1). Furthermore, we were interested in finding out whether electrical theta burst stimulation (eTBS) is able to induce lasting after-effects on cortical plasticity. Methods: Three different eTBS protocols were applied at 5 mA in a sham controlled, double blinded cross-over design on the M1 region of seventeen healthy subjects during the first part of the study. The second study part consists of three different eTBS protocols ranging from 5 mA to 10 mA and 1 ms to 5 ms sinusoidal bursts, applied to the M1 region of 14 healthy subjects. Results: We were able to apply all eTBS protocols in a safe manner, with only six subjects reporting mild side effects related to the stimulation. However, no eTBS protocol induced lasting effects on muscle- evoked potential (MEP) amplitudes when compared to sham stimulation. Significant inhibition of MEP amplitude was only seen in the lower intensity protocols as compared to baseline. Conclusion: eTBS is a safe method to apply high frequency tACS with up to 10 mA intensity. Future studies need to explore the parameter space to a larger extent in order to assure efficacy.

Disruption of adaptor protein 2µ (AP-2µ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing.

Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2µ (AP-2µ) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2µ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates, and vesicle depletion of the membrane-distal synaptic ribbon in AP-2µ-deficient IHCs, indicating a further role of AP-2µ in clathrin-dependent vesicle reformation on a timescale of many seconds. Finally, we show that AP-2 sorts its IHC-cargo otoferlin. We propose that binding of AP-2 to otoferlin facilitates replenishment of release sites, for example, via speeding AZ clearance of exocytosed material, in addition to a role of AP-2 in synaptic vesicle reformation.