What does the mean mean? A simple test for neuroscience

Trial-averaged metrics, e.g. tuning curves or population response vectors, are a ubiquitous way of characterizing neuronal activity. But how relevant are such trial-averaged responses to neuronal computation itself? Here we present a simple test to estimate whether average responses reflect aspects of neuronal activity that contribute to neuronal processing. The test probes two assumptions implicitly made whenever average metrics are treated as meaningful representations of neuronal activity: Reliability: Neuronal responses repeat consistently enough across trials that they convey a recognizable reflection of the average response to downstream regions. Behavioural relevance: If a single-trial response is more similar to the average template, it is more likely to evoke correct behavioural responses. We apply this test to two data sets: (1) Two-photon recordings in primary somatosensory cortices (S1 and S2) of mice trained to detect optogenetic stimulation in S1; and (2) Electrophysiological recordings from 71 brain areas in mice performing a contrast discrimination task. Under the highly controlled settings of Data set 1, both assumptions were largely fulfilled. In contrast, the less restrictive paradigm of Data set 2 met neither assumption. Simulations predict that the larger diversity of neuronal response preferences, rather than higher cross-trial reliability, drives the better performance of Data set 1. We conclude that when behaviour is less tightly restricted, average responses do not seem particularly relevant to neuronal computation, potentially because information is encoded more dynamically. Most importantly, we encourage researchers to apply this simple test of computational relevance whenever using trial-averaged neuronal metrics, in order to gauge how representative cross-trial averages are in a given context

PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

BACKGROUND: Cells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARgamma) Coactivator 1-alpha (PGC-1alpha), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models. METHODOLOGY/PRINCIPAL FINDINGS: We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1alpha. Compared to control cells, PGC-1alpha and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1alpha direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1alpha activation with the PPARgamma agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord. CONCLUSIONS/SIGNIFICANCE: PGC-1alpha down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARgamma agonists, suggesting a potential therapeutic approach for FRDA.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Novel microsatellite markers for conservation of Australian native Samadera bidwillii

Ashwath, N ORCiD: 0000-0002-4032-4507; Naik, VM ORCiD: 0000-0002-6223-5484Microsatellite markers were developed for Samadera bidwillii, a nationally listed vulnerable shrub or small tree, to enable investigation of its genetic structure and diversity within and among populations from its known distribution throughout coastal areas mainly in fragmented and disturbed lands from Mackay to Gympie, Queensland, Australia. The loci were tested for cross-amplification in related Samadera species. Ten polymorphic microsatellite markers were isolated and characterised from an enriched library of S. bidwillii, which exhibited di- and trinucleotide repeats. The mean number of alleles per locus ranged from 1.3 to 2.5 and mean expected and observed heterozygosities ranged from 0.06 to 0.33 and from 0.03 to 0.26, respectively in five populations. All loci successfully amplified in six other closely associated Samadera species also reported from Australia. Developed loci can be used in genetic diversity, population structure and gene flow studies with an emphasis on the conservation of S. bidwillii and related species

Optogenetic investigation of the LGN koniocellular influence on V1 activity

The lateral geniculate nucleus (LGN) of the primate thalamus is organized into parallel parvo-, magno- and konio-cellular projection streams to primary visual cortex (V1). While magno and parvo cells label positive for Parvalbumin and project to layer-4 of V1, konio neurons project to the superficial layers of V1 and are positive for CamKII and Calbindin [1] [2]. Of the three systems, our understanding of the konio pathway and its contribution to vision is still very limited. Here we used optogenetics in anaesthetized macaque monkeys to investigate the influence of koniocellular LGN neurons on V1. To this end we injected the construct AAV5-CamKIIa-ChR2-eYFP into the LGN of two monkeys. Post-mortem histological and immunohistochemical analysis verified that ChR2 expression was predominantly present in the koniocellular system, which is characterized by its expression of CamKII and a focus on the LGN intercalated layers. In earlier experiments optogenetic stimulation that was applied to neurons in the LGN intercalated layers resulted in activation of the superficial layers in V1, but not layer 4, as determined from current-source-density measurements (CSD) from multi-contact laminar recordings in V1. Preliminary analysis of the cortical LFP also showed a power decrease in the beta frequency range (15-30Hz) for the superficial layers during optogenetic stimulation. In additional control experiments in one monkey, we found that electrical micro-stimulation in a parvocellular layer activated layer 4 of V1 similar to visual flicker stimulation. In contrast, electrical microstimulation in the intercalated LGN layers induced activity in superficial layers of V1 similarly to the optogenetic stimulation. In summary, we show for the first time the effective connectivity of the koniocellular LGN projection to V1 and its influence on the LFP. Methodologically, our results demonstrate that both circuit probing approaches, optogenetics and electrical microstimulation, render results with very similar specificity. Reference 1. Hendry, S.H. and T. Yoshioka, A neurochemically distinct third channel in the macaque dorsal lateral geniculate nucleus. Science, 1994. 264(5158): p. 575-577. 2. Casagrande, V.A., et al., The morphology of the koniocellular axon pathway in the macaque monkey. Cereb Cortex, 2007. 17(10): p. 2334-2345

Functional identification of primate lateral geniculate nucleus projections to visual cortex using optogenetics and electrical stimulation

Optogenetics and electrical stimulation are routinely used to assess neuronal connectivity. However cell-specific approaches, especially in primates, are still very limited. Here we compare the capacities of optogenetics and electrical stimulation to isolate the specific pathways from the lateral geniculate nucleus (LGN) to primary visual cortex (V1) in the macaque visual system. The organization of LGN into three anatomically separate and neurochemically distinct cell projection systems with virtually no cross-talk provides unique conditions to test for cell-specific targeting by electrical and optogenetic stimulation techniques. For the optogenetics experiments, we injected AAV5-CamKIIα-ChR2-eYFP into the LGN of four macaque monkeys. Histological analysis revealed primarily the predicted laminar expression pattern of the optogenetic construct in CamKIIα-rich LGN konio layers, but also showed some expression in parvalbumin positive magno- and parvo cells. We also observed a retrograde tracing mechanism of the AAV5 virus particles that labeled V1 layer 6 cortico-thalamic feedback neurons and retinal ganglion cells. That expression of the construct also allowed modulation of spiking activity in LGN was confirmed in prior electrophysiology experiments. Neurons expressing ChR2 could be identified reliably based on their short latency (<5ms) spiking responses to direct blue light (473nm) stimulation. Parallel laminar-resolved recordings of the V1 local field potential showed that selective activation of LGN konio layers with optogenetics caused selective electrical current inflow in the supra-granular layers of V1 in agreement with anatomical predictions about the koniocellular projection. Electrical stimulation of LGN konio layers revealed the same supra-granular V1 activation pattern. In contrast, electrical stimulation of LGN parvo layers activated also V1 granular layers in a way that closely resembled visual stimulus driven responses. These findings indicate comparable capacities of both stimulation methods to isolate and identify spatially segregated thalamo-cortical circuit mechanisms of the primate brain

Neuron

Electrical microstimulation and more recently optogenetics are widely used to map large-scale brain circuits. However, the neuronal specificity achieved with both methods is not well understood. Here we compare cell-targeted optogenetics and electrical microstimulation in the macaque monkey brain to functionally map the koniocellular lateral geniculate nucleus (LGN) projection to primary visual cortex (V1). Selective activation of the LGN konio neurons with CamK-specific optogenetics caused selective electrical current inflow in the supra-granular layers of V1. Electrical microstimulation targeted at LGN konio layers revealed the same supra-granular V1 activation pattern as the one elicited by optogenetics. Taken together, these findings establish a selective koniocellular LGN influence on V1 supra-granular layers, and they indicate comparable capacities of both stimulation methods to isolate thalamo-cortical circuits in the primate brain

Establishing user needs for a stability assessment tool to guide wheelchair prescription

Purpose: The WheelSense project aims to develop a system for assessing the stability and performance of wheelchairs through a user-centred design process. This study sought to capture user needs and define the specification for the system. Method: A mixed methods approach was adopted. An online survey was completed by 98 participants working in wheelchair provision. The results were built upon through 10 semi-structured interviews and one focus group (n = 5) with professionals working in wheelchair provision in three NHS Trusts in the UK. Results: The results provided a picture of the current UK practice in stability testing. Issues with the reliability and usefulness of the existing methods used to assess the stability and performance of wheelchairs were highlighted. Requirements for a new system were ascertained. These included improved accuracy of tipping angles, features to support record keeping, improved client/carer education support and ability to model or predict client-wheelchair system performance in different configurations. Conclusions: The paper concludes that there is a need for improved tools to determine the stability of the client-wheelchair system and support the prescription process, to ensure client safety and optimum equipment performance. A list of requirements has been produced to guide the future development of WheelSense. Implications for Rehabilitation The results of this survey and interview-based study present a picture of wheelchair stability testing practices in the UK, and highlight the need for new, more informative methods for guiding wheelchair prescription. The requirements for the design of a new system, or further development of existing tools to support the stability testing and prescription of wheelchairs have been established