Functional magnetic resonance imaging and the neurobiology of vasopressin and oxytocin

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Abstract

Functional magnetic resonance imaging is used to assess the roles of vasopressin (AVP) in aggressive motivation and oxytocin (OXT) in maternal behaviour. In the case of aggression, male rats are triggered to show the autonomic signs of impending attack behaviour by simulating a resident/intruder conflict in the bore of the magnet during the imaging session. Intraventricular injection of AVP alone causes robust changes in brain activity mirroring many areas selective for AVP receptor binding and overlapped with many of the same areas activated during aggression. Pretreatment with an orally active AVP V1a receptor antagonist blocks aggression in bench-top studies and suppressed the pattern of brain activation caused by the intruder or administration of AVP. These findings using imaging corroborate and extended our understanding of the neural circuitry of aggression and the role of AVP neurotransmission in agonistic motivation. In the case of maternal behaviour, primiparous dams are imaged during nursing with and without OXT receptor blockade. Suckling alone activates many cortical and subcortical areas. Intracerebroventricular injection of OXT stimulates brain activity in areas selective to OXT receptor binding and overlap with many of the same areas activated during pup suckling. Pretreatment with OXT receptor antagonist suppresses the pattern of brain activation caused by suckling or administration of OXT. The data suggest that OXT may strengthen mother–infant bond formation partly by acting through brain areas involved in regulating olfactory discrimination, emotions and reward.

Introduction

Vasopressin (AVP) and oxytocin (OXT) comprise a phylogenetically old super family of chemical signals in both vertebrates and invertebrates. The conservation and dispersion of AVP and OXT signalling systems across the animal kingdom attests to their functional significance in evolution. In addition to their function in physiological homoeostasis, these neuropeptides evolved a role in social behaviours related to aggression and affiliation. AVP has a demonstrated role in aggression enhancing agonistic behaviour in amphibians, fish, birds and mammals, including humans. In contrast, OXT is a key hormone enabling milk let-down during breastfeeding and the enhancement of affiliative behaviours associated with caring for young. While both neuropeptides function as neurohormones released from the posterior pituitary gland into the general circulation, their effects on behaviour are achieved by direct neurochemical signalling in the central nervous system. Precisely how and where these neuropeptides act to affect such important behaviours as aggression and affiliation are not entirely clear. With the advent of new non-invasive imaging techniques like functional magnetic resonance imaging (fMRI) it is possible to gain new insights into the neurobiology of these neuropeptides. To this end, fMRI with 3D computational analysis in conscious rats was used to study the role AVP in aggressive motivation and the role of OXT in pup suckling and maternal behaviour.

Functional MRI with ultra-high field animal scanners (≥4.7 T) provide exceptional temporal and spatial resolution making it possible to map in seconds functionally relevant neural networks activated by a variety of environmental and chemical stimuli (Ferris et al., 2001; Tenney et al., 2004; Brevard et al., 2006a, Brevard et al., 2006b). Increased neuronal activity is accompanied by an increase in metabolism concomitant with changes in cerebral blood flow and blood volume to the area of elevated neural activity. Blood oxygen level-dependent (BOLD) fMRI is a technique sensitive to the oxygenation status of haemoglobin (Ogawa et al., 1990). While fMRI has neither the cellular spatial resolution of immunostaining, nor the millisecond temporal resolution of electrophysiology, it does show synchronized changes in neuronal activity across multiple brain areas, providing a unique insight into functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behavioural states. This chapter presents a discussion on the technology and methods for performing imaging studies on awake male rats responding to aggression-provoking stimuli and awake lactating dams responding to pup suckling. These unique experimental models enable two questions: (1) What is the role of centrally released AVP in aggressive motivation? (2) What role does OXT play in suckling-induced brain activation?

Section snippets

Imaging conscious animals

Animals are acquired and cared for in accordance with the guidelines published in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publications No. 85-23, Revised 1985) and adhere to the National Institutes of Health and the American Association for Laboratory Animal Science guidelines. The protocols used in these studies were in compliance with the regulations of the Institutional Animal Care and Use Committee at the University Massachusetts Medical School.

Imaging aggressive motivation and the role of vasopressin neurotransmission

There is a general consensus that AVP functions to facilitate aggressive behaviour across multiple species (Ferris, 2005). Microinjections of AVP into the hypothalamus or amygdala and cerebrointraventricular administration in rodents leads to enhanced aggression while administration of a selective linear V1a antagonist, Manning compound [1-β-mercapto-β,β-cyclopentamethylene propionic acid 2-[0-(methyl) tyrosine] arginine vasopressin, blocks aggressive behaviour (Ferris and Potegal, 1988;

Imaging the “nursing” brain and the role of oxytocin neurotransmission

OXT synthesis mainly occurs in neurons of the paraventricular (PVN) and supraoptic nucleus (SON) of the hypothalamus. It is transported to and released from nerve terminals in the posterior pituitary and various regions of the brain. Suckling stimulates the release of OXT simultaneously into the bloodstream and central nervous system of postpartum rats (Neumann et al., 1993a). Systemically, this neurohormone enhances smooth muscle contractility, which is important for milk ‘let-down’ during

Final summary

These data from two unique experimental paradigms using fMRI, support and extend our previous understanding of AVP's and OXT's effect on brain activity under complex social and emotional conditions. Blocking V1a receptors suppresses aggressive motivation in bench-top studies and during imaging. The imaging data are characterized by a general reduction in BOLD signal particularly in areas identified as the putative neural circuit of aggressive motivation. However, this response is not due to a

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