Developmental Neuropharmacology

Dr Marie Gibbs

BSc (Melbourne) PhD (Monash)
Senior Research Fellow

Tel: +61 3 9905 2714
Fax: +61 3 9905 8192

Memory formation processes, the role of noradrenaline and prenatal compromise:

• Memory formation and role of noradrenaline
  • Modulation of memory by adrenoceptors and other G-protein coupled receptors (GPCRs)
  • Roles of and functional relationship between brain areas involved in memory processing (cortex, basal ganglia, locus coeruleus, amygdala and hippocampus); the involvement of left and right hemispheres and their interactions
  • Roles for astrocytes in memory formation- supply of glutamate to the neurone, glucose uptake and glycogen breakdown
  • GPCR modulation of excitatory and inhibitory neuronal neurotransmitters in memory processing
• Prenatal compromise,
  • The role of adrenoceptors and glucocorticoids in hypoxia- and stress-induced memory impairment
  • strategies for rescue of cognitive damage

Specific Interests

My interest in memory processing and formation covers behavioural, anatomical, cellular and developmental aspects. A sequential model of memory formation with short- , intermediate and long-term components has been developed using a single trial discriminated avoidance task in young chicks (Gibbs and Ng, 1977; Gibbs and Summers, 2002), where postulated cellular events, as well as behavioural events, characterize each of the stages.

Current work is concentrating on the role played by the neurotransmitter noradrenaline in modulation of memory formation; although it is recognized that other neuromodulatory transmitters influence memory. Noradrenaline influences memory processing via arousal, attention and motivational factors such as stress, fear, curiosity and novelty. Without activation of noradrenergic receptors memory does not form. Using the knowledge of noradrenergic interactions in memory in different brain regions and on different cell types we are now able to determine how noradrenaline interacts with excitatory and inhibitory neurotransmission necessary for memory. The scope of the work covers memory at the behavioural, brain (anatomical), cellular (neurons and astrocytes) and molecular levels.

We have recently used the information derived from this memory model to investigate the role of noradrenaline in the effect of prenatal compromise on post-natal memory ability. Disturbances to the central noradrenergic nervous system, are associated with many neurodevelopmental (attention deficit hyperactivity disorder, depression, anorexia, etc) and neurodegenerative diseases that involve cognitive deficits (Alzheimer’s Disease, Parkinson’s disease, etc). Developmental experiments investigate the involvement of prenatal stress and hypoxia on memory ability after birth and the role that noradrenaline and corticosterone play in cognitive impairment.

Current projects

Role of Adrenoceptors in memory formation and consolidation. Noradrenaline potentially acts on 9 different receptors and can thus have many different roles depending on the location of the different adrenoceptors in the brain, their sensitivity and also the timing of their recruitment in the sequence of memory processing.

In collaboration with Roger Summers, studies are being carried out of the role of adrenoceptors in modulating memory formation. There are two important periods in memory processing where noradrenaline plays an essential role. The first occurs at the time of acquisition, where attentional or arousal factors are important and related to noradrenaline release; the second occurs at the time of consolidation, when labile memory is converted into a permanent (long-term) form. The role of noradrenaline in the modulation of memory formation depends on the populations of ARs present in different brain locations and the times at which they are activated in the sequence of memory processing. We have demonstrated modulatory roles for noradrenaline in the avian cortex (mesopallium), the basal ganglia, hippocampus and the locus coeruleus, showing that memory processing in the bird is very much the same as in mammals.

Memory processing at the cellular level Noradrenaline can modulates memory formation by a number of different mechanisms, these include effects on both neurones and astrocytes. In astrocytes, catecholamines can alter the metabolism of glucose and glycogen, and the return of glutamate to neurones. With Leif Hertz, Roger Summers and Dana Hutchinson I am investigating roles for other energy substrates besides glucose and glycogen, such as acetate and lactate in both behavioural and pharmacological experiments, using tissue culture techniques of both astrocytes and neurones. We have demonstrated roles for both ß2- and ß3-adrenoceptors in astrocytes that relate to their function in memory processing. The electrophysiology of adrenoceptor involvement in hippocampal cells is being investigated with Harry Coleman and Helena Parkington in Physiology at Monash.

Lateralization of memory storage processes- both hemispheres are involve but play different roles Left and right hemispheres have different roles in memory processing and the emotional and motivational aspects of a learning situation impact on the formation of memory. The two brain hemispheres play different roles in memory.

Developmental compromise and cognitive ability During pregnancy, exposure of the embryo to hypoxia can lead to subsequent cognitive impairment – the nature of which depends on the gestational age of the embryo at the time. In mid gestation, hypoxia impairs subsequent short-term memory, whereas hypoxia during the last trimester, has no effect on short-term memory, but prevents consolidation from short- to long-term memory. Because of our extensive knowledge of memory processing in the chick, we are able to use the model to describe and identify the nature of damage caused by prenatal hypoxia and stress hormones in the chick. The chick is an ideal model to use if one wishes to explore the cause of the cognitive deficits without the added complication of maternal influences! Both stress hormones, noradrenaline and corticosterone, play an important role in the production of cognitive impairment and our results suggest that it is possible to provide neuroprotection pharmacologically.

Role of other neurotransmitters in memory. Other neurotransmitters are also important for memory and we are examining the role of other neurotransmitters, aside from noradrenaline, such as serotonin, dopamine, the inhibitory neurotransmitter, GABA, the excitatory neurotransmitter glutamate, adenosine, ATP and nitric oxide, in different memory areas, as well as the interaction of noradrenaline with the function of these transmitters.

Selected highly cited landmark publications :

Mark, R.F. and Watts (Gibbs), M.E. Drug inhibition of memory formation in chickens. I. Long-term memory. Proc. Royal Society of London. B. 178, 439-454, 1971

Watts (Gibbs), M. E. and Mark, R. F. Drug inhibition of memory formation in chickens. II. Short-term memory. Proc. Royal Society of London. B. 178, 455-464, 1971

Gibbs, M.E. and Ng, K.T. Psychobiology of memory: towards a model of memory formation. Biobehavioral Reviews 1, 113-136, 1977

Gibbs, M.E. and Summers, R.J. Role of adrenoceptor subtypes in memory consolidation. Progress in Neurobiology, 67, 2002, 345-391

Selected recent publications :

Gibbs,M.E. and Summers, R.J. Separate roles for 2- and 3- adrenoceptors in memory consolidation. Neuroscience 95, 2000, 913-922

Gibbs, M.E. and Summers, R.J. Neural transmitters and memory formation: I Principle transmitters. Adrenergic Receptors. In: Memories are Made of These: From Messengers to Molecules. Eds G. Riedel and B. Platt. Published on line Eureka.com, Landes Biosciences. 2003 Kluwer Academic/Plenum Publishers 2004

Gibbs, M.E. and Summers, R.J. Effects of glucose and 2-deoxyglucose on memory formation in the chick: interaction with 3-adrenoceptor agonists. Neuroscience, 114, 2002, 69-79.

Rickard, N.R. and Gibbs, M.E. Hemispheric dissociation of the involvement of NOS isoforms in memory for discriminated avoidance in the chick. Learning and Memory, 10, 314-318,2003

Gibbs, M.E., Andrew, R.J. and Ng, K.T. Hemispheric lateralization of memory stages for discriminated avoidance learning in the chick. Behavioural Brain Research, 139, 2003, 157-165.

Hertz, L., Chen, Y., Gibbs, M.E., Zang, P. and Peng, L. Astrocytic adrenoceptors: A major drug target in neurological and psychiatric disorders? Current Drug Targets-CNS and Neurological Disorders. Current Drug Targets: CNS neurological disorders 3:239-268,2004

Camm, E.J., Lambert, G., R. Harding and Gibbs, M.E. The involvement of catecholamines in hypoxia-induced memory impairment. Neuroscience, 128, 2004, 545-553.

Rodricks, C.L., Rose, I., Miller, S. and Gibbs, M.E The effect of prenatal hypoxia and malnutrition on memory consolidation in the chick. Developmental Brain Research, 148, 113-119,2004

Gibbs, M.E. and Summers, R.J. Contrasting roles for ß1, ß2 and ß3-adrenoceptors in memory formation in the chick. Neuroscience, 131, 31-42, 2005.

Gibbs, M.E. and Johnston, G.A.R. Opposing roles for GABA A and GABA C receptors in short-term memory formation in young chicks. Neuroscience 131, 2005, 567–576.

Gibbs, M.E., O’Dowd, B. S., Hertz, E. and Hertz, L. Astrocytic energy metabolism consolidates memory in young chicks. Neuroscience, 141, 9-13, 2006

Gibbs, M.E, Anderson, D.G. and Hertz, L. Inhibition of Glycogenolysis in Astrocytes Interrupts Memory Consolidation in Young Chickens. GLIA , 54 214-222, 2006

Collaborations

Professor Roger Summers, Dr Bronwyn Evans, Dr Dana Hutchinson (Pharmacology) Monash University

Dr Harry Coleman, Dr Suzie Miller; Professor Richard Harding; Professor Graham Jenkin, Ms Candice Rodricks (Physiology, Monash University);

Professor Leif Hertz (University of Saskatchewan, China Medical University, Shenyang, PR China))

Professor Richard Andrew (University of Sussex)

Professor Graham Johnston (University of Sydney)

Dr Gavin Lambert (Human Neurotransmitter Laboratory, Baker Heart Research Institute)

Dr Emily Camm, A/Prof Sandra Rees (Anatomy and Cell Biology, University of Melbourne)

Professor Kim Ng, Dr Nikki Rickard (Psychology, Monash University).