2021 news

18 May 2021

Balance between Protection and Pathogenic Response to Aerosol Challenge with Mycobacterium tuberculosis (Mtb) in Mice Vaccinated with TriFu64, a Fusion Consisting of Three Mtb Antigens

Sadaf Sulman, Benjamin O. Savidge, Kawther Alqaseer, Mrinal K. Das, Neda Nezam Abadi, John E. Pearl, Obolbek Turapov, Galina V. Mukamolova, M. Waheed Akhtar and Andrea May Cooper

Tuberculosis vaccines capable of reducing disease worldwide have proven difficult to develop. BCG is effective in limiting childhood disease, but adult TB is still a major public health issue. Development of new vaccines requires identification of antigens that are both spatially and temporally available throughout infection, and immune responses to which reduce bacterial burden without increasing pathologic outcomes. Subunit vaccines containing antigen require adjuvants to drive appropriate long-lived responses. We generated a triple-antigen fusion containing the virulence-associated EsxN (Rv1793), the PPE42 (Rv2608), and the latency associated Rv2628 to investigate the balance between bacterial reduction and weight loss in an animal model of aerosol infection. We found that in both a low pattern recognition receptor (PRR) engaging adjuvant and a high PRR-engaging adjuvant (MPL/TDM/DDA) the triple-antigen fusion could reduce the bacterial burden, but also induced weight loss in the mice upon aerosol infection. The weight loss was associated with an imbalance between TNFα and IL-17 transcription in the lung upon challenge. These data indicate the need to assess both protective and pathogenic responses when investigating subunit vaccine activity.

12 January 2021

Phosphodiesterase type 1 inhibition alters medial prefrontal cortical activity during goal-driven behaviour and partially reverses neurophysiological deficits in the rat phencyclidine model of schizophrenia

Jessica Hayes, Bettina Laursen, Elin Eneberg, Jan Kehler, Lars Kyhn Rasmussen, Morten Langgard, Jesper F. Bastlund, Todor V. Gerdjikov

In this study the research group explored whether phosphodiesterase 1b inhibition reverses neural deficits in the phencyclidine model of schizophrenia in rodents. They recorded neuronal activity in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) of rats carrying out a sustained attention task. Consistent with their previous work, they found that phencyclidine pre-treatment reduces neuronal firing in NAc and mPFC and impairs cross-talk between the two regions. Further, they found that phosphodiesterase 1b inhibition reverses the deficit in mPFC-NAc synchrony and deficits in neuronal firing to discrete motivational cues. On the other hand, phosphodiesterase 1b inhibition also reduced goal-directed behaviours and baseline neuronal activity in mPFC. They concluded that phosphodiesterase 1b inhibition may potentially be beneficial in disorders linked to dysfunction in the mPFC-NAc network. 

11 January 2021

Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption

Kate Z. Peters, Andrew M.J. Young, James E. McCutcheon

Why do we sometimes get distracted by things around us and what is happening in the brain when this happens? Distractions are a way of pausing what we are doing to check whether something important is occurring in our environment. In an animal like a rat this might mean being alert to potential threats (e.g. predators) even while in the middle of a meal. In these experiments we explored whether neurons in a brain region called the ventral tegmental area (VTA) were involved in distraction. The VTA is essential for reward (i.e. responding to good things like food) and learning and we wanted to know if it also responds to distractions. In the Leicester Division of Biomedical Sciences facility we used the cutting edge technique fibre photometry to measure the activity of brain cells in this area. Rats were presented with distracting events (flashing lights, tones etc.) whilst they were already drinking a sweet solution. We found that these distractors caused the rats to pause drinking, and that the VTA responded differently depending on if the rat was distracted or not distracted. These results show that this important brain area, the VTA, is involved in monitoring the world for interesting or novel events. This may be important in disorders that affect attention such as schizophrenia and post-traumatic stress disorder.