Professor Sarah Johnson

© 2017 Elsevier Inc. Secondary neurodegeneration (SND) is an insidious and progressive condition involving the death of neurons in regions of the brain that were connected to but undamaged by the initial stroke. Our group have published compelling evidence that exposure to psychological stress can significantly exacerbate the severity SND, a finding that has considerable clinical implications given that stroke-survivors often report experiencing high and unremitting levels of psychological stress. It may be possible to use one or more targeted pharmacological approaches to limit the negative effects of stress on the recovery process but in order to move forward with this approach the most critical stress signals have to be identified. Accordingly, in the current study we have directed our attention to examining the potential effects of corticosterone, delivered orally at stress-like levels. Our interest is to determine how similar the effects of corticosterone are to stress on repair and remodelling that is known to occur after stroke. The study involved 4 groups, sham and stroke, either administered corticosterone or normal drinking water. The functional impact was assessed using the cylinder task for paw asymmetry, grid walk for sensorimotor function, inverted grid for muscle strength and coordination and open field for anxiety-like behaviour. Biochemically and histologically, we considered disturbances in main cellular elements of the neurovascular unit, including microglia, astrocytes, neurons and blood vessels using both immunohistochemistry and western blotting. In short, we identified that corticosterone delivery after stroke results in significant suppression of key microglial and astroglial markers. No changes were observed on the vasculature and in neuronal specific markers. No changes were identified for sensorimotor function or anxiety-like behaviour. We did, however, observe a significant change in motor function as assessed using the inverted grid walk test. Collectively, these results suggest that pharmacologically targeting corticosterone levels in the future may be warranted but that such an approach is unlikely to limit all the negative effects associated with exposure to chronic stress.

© The Author(s) 2018. It has recently been identified that after motor cortex stroke, the ability of microglia processes to respond to local damage cues is lost from the thalamus, a major site of secondary neurodegeneration (SND). In this study, we combine a photothrombotic stroke model in mice, acute slice and fluorescent imaging to analyse the loss of microglia process responsiveness. The peri-infarct territories and thalamic areas of SND were investigated at time-points 3, 7, 14, 28 and 56 days after stroke. We confirmed the highly specific nature of non-responsive microglia processes to sites of SND. Non-responsiveness was at no time observed at the peri-infarct but started in the thalamus seven days post-stroke and persisted for 56 days. Loss of directed process extension is not a reflection of general functional paralysis as phagocytic function continued to increase over time. Additionally, we identified that somal P2Y12 was present on non-responsive microglia in the first two weeks after stroke but not at later time points. Finally, both classical microglia activation and loss of process extension are highly correlated with neuronal damage. Our findings highlight the importance of microglia, specifically microglia dynamic functions, to the progression of SND post-stroke, and their potential relevance as modulators or therapeutic targets during stroke recovery.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Low oxygen post conditioning (LOPC) has shown promising results in terms of neuroprotection after stroke, but the effects on motor function have not been considered. Cortical stroke targeting the motor and sensory cortex was induced by photothrombotic occlusion and after 48¿h allocated to LOPC (11% O2) for 2¿weeks. Motor impairment was assessed using the cylinder and grid walk tests during the exposure period and for two further weeks upon completion of the intervention. Neuroprotection was evaluated by histological and molecular analysis at two time points. Two weeks of LOPC was sufficient to significantly reduce motor deficits and tissue loss after stroke. This functional improvement was associated with increased capillary density, enhanced levels of BDNF, decreased neuronal loss and decreased microglia activation. These improvements, in most instances, were maintained up to 2¿weeks after the end of the treatment. To our knowledge, this is the first study to demonstrate that LOPC induces a persistent improvement in motor function and neuroprotection after stroke, and in doing so provides evidence to support a case for considering taking LOPC forward to early stage clinical research.

© 2016 Elsevier Inc. Exposure to psychological stress is known to seriously disrupt the operation of the substantia nigra (SN) and may in fact initiate the loss of dopaminergic neurons within the SN. In this study, we aimed to investigate how chronic stress modified the SN in adult male mice. Using a paradigm of repeated restraint stress (an average of 20¿h per week for 6¿weeks), we examined changes within the SN using western blotting and immunohistochemistry. We demonstrated that chronic stress was associated with a clear loss of dopaminergic neurons within the SN. The loss of dopaminergic neurons was accompanied by higher levels of oxidative stress damage, indexed by levels of protein carbonylation and strong suppression of both microglial and astrocytic responses. In addition, we demonstrated for the first time, that chronic stress alone enhanced the aggregation of a-synuclein into the insoluble protein fraction. These results indicate that chronic stress triggered loss of dopaminergic neurons by increasing oxidative stress, suppressing glial neuroprotective functions and enhancing the aggregation of the neurotoxic protein, a-synuclein. Collectively, these results reinforce the negative effects of chronic stress on the viability of dopaminergic cells within the SN.

© 2017 IBRO Exposure to chronic stress following stroke has been shown, both clinically and pre-clinically, to impact negatively on the recovery process. While this phenomenon is well established, the specific mechanisms involved have remained largely unexplored. One obvious signaling pathway through which chronic stress may impact on the recovery process is via corticosterone, and its effects on microglial activity and vascular remodeling. In the current study, we were interested in examining how orally delivered corticosterone at a stress-like concentration impacted on microglial activity and vascular remodeling after stroke. We identified that corticosterone administration for two weeks following stroke significantly increased tissue loss and decreased the weight of the spleen and thymus. We also identified that corticosterone administration significantly altered the expression of the key microglial complement receptor, CD11b after stroke. Corticosterone administration did not alter the expression of the vessel basement membrane protein, Collagen IV after stroke. Together, these results suggest that corticosterone is likely to represent only one of the major stress signals responsible for driving the negative impacts of chronic stress on recovery.

© 2017 Wiley Periodicals, Inc. Stroke induces tissue death both at the site of infarction and at secondary sites connected to the primary infarction. This latter process has been referred to as secondary neurodegeneration (SND). Using predominantly fixed tissue analyses, microglia have been implicated in regulating the initial response at both damage sites post-stroke. In this study, we used acute slice based multiphoton imaging, to investigate microglia dynamic process movement in mice 14 days after a photothrombotic stroke. We evaluated the baseline motility and process responses to locally induced laser damage in both the peri-infarct (PI) territory and the ipsilateral thalamus, a major site of post-stroke SND. Our findings show that microglia process extension toward laser damage within the thalamus is lost, yet remains robustly intact within the PI territory. However, microglia at both sites displayed an activated morphology and elevated levels of commonly used activation markers (CD68, CD11b), indicating that the standardly used fixed tissue metrics of microglial ¿activity¿ are not necessarily predictive of microglia function. Analysis of the purinergic P2Y12 receptor, a key regulator of microglia process extension, revealed an increased somal localization on nonresponsive microglia in the thalamus. To our knowledge, this is the first study to identify a non-responsive microglia phenotype specific to areas of SND post-stroke, which cannot be identified by the classical assessment of microglia activation but rather the localization of P2Y12 to the soma.

© 2015 IBRO. Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 µg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24 h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior.

© 2016 IEEE. This paper investigates the design of low-complexity error correction codes for the verification step in continuous variable quantum key distribution (CVQKD) systems. We design new coding schemes based on quasi-cyclic repeat-accumulate codes which demonstrate good performances for CVQKD reconciliation. Given quasi-cyclic repeat-accumulate codes' commercial maturity, low implementation complexity and existing high-speed ASIC implementations, this makes these codes viable candidates for commercial CVQKD systems.

© 2015 IEEE. A source coding problem over a noiseless broadcast channel where the source is preinformed about the contents of the cache of all receivers, is an index coding problem. Furthermore, if each message is requested by one receiver, then we call this an index coding problem with a unicast message setting. This problem can be represented by a directed graph. In this paper, we first define a structure (we call generalized interlinked cycle (GIC)) in directed graphs. A GIC consists of cycles which are interlinked in some manner (i.e., not disjoint), and it turns out that the GIC is a generalization of cliques and cycles. We then propose a simple scalar linear encoding scheme with linear time encoding complexity. This scheme exploits GICs in the digraph. We prove that our scheme is optimal for a class of digraphs with message packets of any length. Moreover, we show that our scheme can outperform existing techniques, e.g., partial clique cover, local chromatic number, composite-coding, and interlinked cycle cover.

© 2015 IEEE. Intrinsic Optical Signal imaging is a technique which allows the visualisation and mapping of activity related changes within the brain with excellent spatial and temporal resolution. We analysed a variety of signal and image processing techniques applied to real mouse imaging data. The results were compared in an attempt to overcome the unique issues faced when performing the technique on mice and improve the understanding of post processing options available.

© 2015 IEEE. We study the index coding problem in the unicast message setting, i.e., where each message is requested by one unique receiver. This problem can be modeled by a directed graph. We propose a new scheme called interlinked cycle cover, which exploits interlinked cycles in the directed graph, for designing index codes. This new scheme generalizes the existing clique cover and cycle cover schemes. We prove that for a class of infinitely many digraphs with messages of any length, interlinked cycle cover provides an optimal index code. Furthermore, the index code is linear with linear time encoding complexity.

© 2015 IEEE. This paper investigates the capacity regions of two-receiver broadcast channels where each receiver (i) has both common and private-message requests, and (ii) knows part of the private message requested by the other receiver as side information. We first propose a transmission scheme and derive an inner bound for the two-receiver memoryless broadcast channel. We next prove that this inner bound is tight for the deterministic channel and the more capable channel, thereby establishing their capacity regions.We show that this inner bound is also tight for all classes of two-receiver broadcast channels whose capacity regions were known prior to this work. Our proposed scheme is consequently a unified capacity-achieving scheme for these classes of broadcast channels.

This paper considers the finite-field multi-way relay channel with pairwise message sharing, where multiple users exchange messages through a single relay and where the users may share parts of their source messages (meaning that some message parts are known/common to more than one user). In this paper, we design an optimal functional-decode-forward coding scheme that takes the shared messages into account. More specifically, we design an optimal function for the relay to decode (from the users on the uplink) and forward (back to the users on the downlink). We then show that this proposed function-decode-forward coding scheme can achieve the capacity region of the finite-field multi-way relay channel with pairwise message sharing. This paper generalizes our previous result for the case of three users to any number of users. © 2014 IEEE.

This paper investigates the capacity region of three-receiver AWGN broadcast channels where the receivers (i) have private-message requests and (ii) know the messages requested by some other receivers as side information. We classify these channels based on their side information into eight groups, and construct different transmission schemes for the groups. For six groups, we characterize the capacity region, and show that it improves both the best known inner and outer bounds. For the remaining two groups, we improve the best known inner bound by using side information during channel decoding at the receivers. © 2014 IEEE.

In this paper low-density parity-check (LDPC) codes are considered for burst erasure channels. Multiple burst erasure correcting LDPC codes are constructed using superposition and the burst erasure correcting performances of the resulting codes are derived as a property of the stopping set size of the base matrices and the choice of permutation matrices for the superposition.

We investigate the effect of channel gain quantization on the information capacity of unknown time varying flat fading channels. The phase and/or amplitude of the flat fading channel gain is modelled as a finite state Markov (FSM) process and the information capacity of the FSM channel is calculated numerically as a measure for choosing the number of channel quantization levels, as well as quantization thresholds. The results indicate that for binary signalling, the capacity is saturated beyond 8 to 16 levels of phase and 8 to 16 levels of amplitude quantization.