Neuroendocrine mechanisms underlying female aggression

Childbirth is a potent cause of psychiatric disorders in women; perhaps more than any other lifetime event, it causes significant changes in a woman’s physiology and psychology. Following childbirth some mothers experience mood lability and increases in aggressive behaviour and irritability are common. In males there is compelling evidence that central vasopressin release facilitates aggression. If vasopressin fulfils a similar role in females, and since female rats are only aggressive during lactation, this change in behaviour may reflect the observed vasopressin system upregulation at this time.
Using the rat model, we will test the hypothesis that changes in vasopressin receptor distribution and vasopressin innervation govern aggressive behaviour. We will evoke aggression in lactating rats by exposing them to a conspecific. We will measure central vasopressin release by microdialysis in identified brain areas during aggressive behaviour and quantify aggressive behavior following intracranial microinfusions of selective vaspressin antagonists and agonists. Changes in vasopressin receptor genes (V1a and V1b) expression from pregnancy through lactation will be measured by in situ hybridisation. Following aggressive encounters, the brain regions involved will be identified by immunocytochemical detection of immediate early gene expression, and neurones in these regions will be immunocytochemically labelled for the presence of vasopressin receptor. We will be able to identify vasopressin neurones directly within the rat brain by using transgenic rats that express a novel vasopressin green fluorescent protein fusion gene.

During pregnancy and after birth a woman’s body, including her brain, undergoes major changes in response to fluctuating hormone (chemical signals released into the bloodstream) levels. We tend to assume that motherhood is joyful and rewarding, but in some women these brain changes can cause serious and long lasting effects on her emotional state; in extreme cases the woman may harm her child. It is estimated that in Britain at least 10% of women from all ages and backgrounds suffer from anxiety and depression following the birth of their child. Effective drug treatment of this condition requires a better understanding of the hormones that influence her brain and cause this behaviour.
Female rats are not normally aggressive, however following birth they become fiercely defensive of their pups against intruders. Little is known about what causes this dramatic change in behaviour but we are becoming increasingly aware that hormonal signals within the brain are involved. The hormone vasopressin regulates aggressive behaviour in male rats and we propose to study the role of vasopressin in the brain in relation to aggressive behaviour in female rats after they have given birth.
We will identify nerve cells in the female rat brain that are involved in aggressive behaviour, and investigate whether they contain vasopressin, or the vasopressin receptor that signals its effect on nerve cells. To aid identification of vasopressin within the brain we will use rats that have had their genetic code modified so that the nerve cells that contain vasopressin glow green under fluorescent light. We will measure changes in vasopressin receptor numbers during nursing of the pups, and the vasopressin levels (by the intensity of the green light) in discrete brain regions during provoked aggressive behaviour. Substances that change how vasopressin attaches to its signalling receptor will be inserted in the brain and any changes in aggressive behaviour that this causes will be recorded.

The main achievement of the project has been the demonstration that vasopressin and oxytocin are regulators of maternal aggression in the rat. Moreover we have provided more evidence to suggest that dendritically-released vasopressin from the magnocellular neurones acts as a diffusible hormone-like signal to exert behavioural effects at distant targets. Release of vasopressin at target brain regions was measurable and changes in mRNA expression of the vasopressin receptors (v1a and v1b) suggest that sensitivity to vasopressin changes dynamically through the peripartum period. Moreover, vasopressin antagonist treatment blocks maternal aggression but not maternal behaviour suggesting vasopressin as a key peptide for the regulation of this particular social behaviour.