GABAergic inhibtion within the hippocampo-prefrontal circuit: importance for cognition and behaviour.

Lead Research Organisation: University of Nottingham
Department Name: Sch of Psychology

Abstract

Healthy brain activity is shaped by a balance of excitatory and inhibitory neurotransmission (Isaacson & Scanziani, 2011, Neuron). More recently, imbalances in neural activity, due to reductions in inhibitory GABA transmission (so-called 'disinhibition'), in brain regions mediating cognitive function, including hippocampus (important for everyday memory) and prefrontal cortex (important for cognitive control and attention), have been linked to cognitive disorders, including age-related cognitive decline (Huang & Mucke, 2012, Cell), schizophrenia and autism (Marin, 2012, Nature Rev Neurosci). However, the role of balanced cortico-hippocampal activity and inhibitory GABA transmission in distinct cognitive functions, as well as suitable approaches to sustain/restore balanced activity to support cognition remain to be clarified.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M008770/1 01/10/2015 31/10/2024
1804204 Studentship BB/M008770/1 01/10/2016 11/11/2020
 
Description The aim of this project is to understand the potential cognitive effects of reduced GABA transmission (disinhibition) in the hippocampus. Such effects are present in several cognitive disorders. This award has allowed us to undertake research to understand how hyperactivity in the hippocampus can effect cognitive processes controlled by multiple brain regions. To date we have found that reduced GABA transmission in the hippocampus can cause significant changes in activity in brain areas which control a multitude of functions, including the pre-frontal cortex, septum and hypothalamus. Therefore providing a potential mechanism for behavioural changes which have been observed during periods of hippocampal disinhibition.
Exploitation Route Our findings show reduced GABA transmission in the hippocampus leads to activation changes in other clinically relevant brain regions. These findings open further research opportunities to understand how these regions interact and what effect that has on observable behaviour. In addition this work also provides an opportunity to test how pharmaceutical interventions might alter the effects of hippocampal disinhibition on network activity.
Sectors Pharmaceuticals and Medical Biotechnology
 
Description LIN-Magdeburg SPECT Imaging 
Organisation Leibniz Association
Department Leibniz Institute for Neurobiology
Country Germany 
Sector Academic/University 
PI Contribution We as a research team designed the experimental procedure and provided the theoretical basis for the work carried out. The theoretical basis for the experiments was based on previous work done by the group, whereby changes in hippocampal activity had significant effects on pre-frontal cortex controlled tasks. We as a team performed in vivo cannula implantation's which provided the route of administration to induce GABA disinhibition in the ventral hippocampus. We also ran the SPECT scans under the guidance of members of the SPECT lab at the institute.
Collaborator Contribution Our collaborators at the Leibniz Institute for Neurobiology (LIN) provided significant expertise and technology in order to facilitate the research carried out. Specifically they enabled us to use a SPECT imaging system optimised at the institute (Kolodziej et al, 2014). The research was all undertaken at the LIN using the imaging facilities at the institute. All experiments undertaken at the LIN were also funded by research money provided by the LIN. All animals used in the study were sourced by the LIN and intra-cerebral cannula implants were performed at the institute. SPECT imaging was undertaken using the facilities at the institute, using the protocol previously specified in previous experiments. Dr Jurgen Goldschmidt and Dr Anja Oelschlegel provided expertise and guidance on the setup and implementation of the SPECT imaging procedures. All data processing and analysis was done at the institute using the procedures optimised for the software at the LIN. Post-experimental ex vivo analysis of cannula placements was also performed at the institute.
Impact Hippocampal disinhibition caused significant activation changes in multiple brain regions. We observed increased rCBF around the infusion site in the ventral hippocampus, whereas rCBF in the dorsal hippocampus was markedly decreased, possibly reflecting reduced ventral hippocampal feedforward inhibition. Importantly, ventral hippocampal disinhibition caused marked extra-hippocampal changes in neocortical and subcortical sites. This included marked activation of medial prefrontal cortex and lateral septum, and less pronounced changes in other sites, including ventral striatum activation, and deactivation of amygdala and piriform cortex. This work is to be presented in the form of a poster at the BNA festival of neuroscience 2019.
Start Year 2018