Electrophysiological characterisation of neurons located in the bed nucleus of the stria terminalis (BNST) in aging, sex and a model of frontotemporal dementia

Abstract

Chronic stress and anxiety disorders are placing an increasing economic burden on western society. The anterolateral BNST (BNSTALG) plays a key role in mediating a number of stress related responses. There are three neuronal populations within the BNSTALG: Type I, Type II and Type III neurons. This thesis examined the electrophysiological properties of neurons located in the BNSTALG in different genders, healthy aging, a mouse model of frontotemporal dementia (CHMP2B) and during the different stages of the oestrous cycle. Overall I found that the oestrous cycle had very little effect on the electrophysiological properties of these cells; the only trend observed was in the maximum rate of rise of Type II neurons: diestrus was slower than metestrus and proestrus. There were a number of intrinsic electrophysiological properties which were affected by gender; Type II cells showed a decreased excitability in the female cohort driven by changes in passive membrane properties. Specifically the observed change in input resistance may be mediated by changes in allopregnanolone, which is 8-10 fold higher in females; changes in allopregnanolone levels leads to changes in GABAA subunit expression which may mediate changes in tonic inhibition and input resistance. In aged female mice, Type I neurons had a more hyperpolarised resting membrane potential and wider action potentials, while Type II neurons from the aged cohort displayed an increase in excitability most likely due to a more depolarised threshold. Activity in Type II neurons are thought to mediate an ‘anxiety off’ switch therefore these increases in excitability may indicate an anxiolytic role of these more excitable populations. Finally I examined the BNSTALG neurons in the CHMP2B model of frontotemporal dementia. Type II neurons had a more hyperpolarised threshold and faster latency. Overall these studies show that the stress regulatory brain region is susceptible to changes with gender, aging and in dementia models.