Cellular actions of neurosteroids: implications for post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a highly debilitating psychiatric disorder that can arise following exposure to at least one traumatic event. It is characterised by hyperarousal, intrusive recall of traumatic memories (‘flashbacks’) and the overgeneralisation of fear to harmless situations that resemble the original traumatic event(s). The efficacy of current psychological and pharmacological treatments is modest at best.

Neurosteroids are endogenous neuromodulators that potently enhance the activation of GABAA receptors—the most common class of inhibitory receptor in the brain. Neurosteroids are produced in the brain at times of acute stress, and may serve a protective function by enhancing inhibition and limiting the excessive firing of excitatory neurons. For example, neurosteroids might reduce the strength of fear memories, or prevent their overgeneralisation, by decreasing activity in memory-related brain areas such as the hippocampus. A failure of this mechanism, perhaps owing to low baseline neurosteroid levels, might increase the risk of disorders such as PTSD. But despite their importance, most of the evidence for the actions of neurosteroids has been obtained from isolated brain tissue. To address this, the current project would investigate the role of neurosteroids in shaping the changes in activity and connectivity between neurons in vivo that are thought to underlie memory formation. Our aim is to increase understanding of the mechanisms of resilience in the face of aversive events, and to identify compounds that have therapeutic potential.

The project would comprise a programme of laboratory-based neuroscience research to investigate the actions of neurosteroids on in vivo electrophysiological measures of brain activity in mice. A key goal would be to determine the ability of neurosteroids to limit the induction or stabilisation of long-term potentiation (LTP) of hippocampal synaptic strength, a cellular analogue of the processes thought to underlie memory formation. This might normally be undesirable, but not when the strength and generalisation of a traumatic, highly aversive memory overwhelms our ability to discriminate between safe and dangerous situations. Parallel experiments would investigate the actions of neurosteroids on the firing of hippocampal excitatory and inhibitory neurons, and on brain oscillations that may play a role in the formation and stabilisation of memory-related synaptic changes. If administration of neurosteroids can impair the stabilisation of hippocampal synaptic changes, this would pave the way for future behavioural investigations of the role of these compounds in the consolidation and generalisation of aversive memories in mice, and perhaps ultimately a new avenue for more effective therapeutic interventions in PSTD.

Diversity statement

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.