Nucleus incertus and relaxin-3 - an emerging modulatory role in arousal , stress and memory

Nucleus incertus and relaxin-3 - an emerging modulatory role in arousal , stress and memory

Nucleus incertus and relaxin-3 - an emerging modulatory role in arousal , stress and memory (#13)

Sherie Ma ¹

Florey Neuroscience Institutes, University Of Melbourne, VIC, Australia

The nucleus incertus (NI) of the pontine periventricular grey consists of GABAergic neurons with long-range ascending projections to forebrain. Efferent and afferent connections implicate the NI in processes of ‘behavioural planning, habenular function, hippocampal/cortical activity in attention/memory, and in oculomotor control’. The NI is a site of corticotropin releasing-factor (CRF) action, and forms a neural circuit positioned to modulate arousal/stress responses and the de/synchronization of hippocampal theta rhythm, an oscillatory activity (4-12 Hz) prominent in the electroencephalograph (EEG) during exploration and memory processes. Theta rhythm underlies goal-oriented behaviour and cognition, and is a neurophysiological signature of REM sleep. The NI is also a primary site for neurons expressing the neuropeptide, relaxin-3, which can modulate septohippocampal activity and theta rhythm and are associated with spatial working memory in the rat. However, NI function in awake, behaving animals remains unclear.

Therefore, we used a pharmacogenetic approach (i.e. designer receptors exclusively activated by designer drugs, DREADDs) to modulate NI activity in freely-moving rats and assessed the behavioural and physiological consequences. An adeno-associated viral vector was used to transduce a modified human muscarinic receptor, hM3Dq, into NI neurons of adult male rats. For behavioural and EEG recordings, hM3Dq was activated by the specific DREADD ligand, clozapine-N-oxide (CNO).

In hM3Dq-expressing rats, NI activation with CNO produced long-lasting theta activity, associated with increased locomotor activity, with significantly greater and persistent horizontal and vertical plane activity, but not increased movement velocity, suggesting effects related to increased arousal and impairment of habituation and rest. Current studies are examining effects of NI activation on tests of spatial and emotional memory, anxiety/aversive behaviour, and associated neural activity, along with comparative studies of NI inactivation with hM4Di.

Current data suggest NI activity regulates behavioural state and I will review our findings on this emerging integrative neural network and its therapeutic potential.

Authors contributing to this presentation.

Ma, S

Dr. Sherie Ma is a senior research scientist at the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia. During her PhD and postdoctoral training, she has worked in USA at the University of California, Irvine, in Spain at Universidad Autonoma Madrid and Universitat de Valencia, and in France at Universite Paris Descartes. Her main scientific skills are in vivo electrophysiology with juxtacellular labeling of single neurons in anesthetized rats, and in freely-moving behaving rats using telemetry, to better understand neural circuitry underlying behaviour. Her research over the last decade, has characterised the neuroanatomy and physiological functions of a novel neuropeptide discovered by Florey scientists in 2002, known as relaxin-3, and the function of the hindbrain nucleus incertus, which is the primary source of relaxin-3 in rodent and primate brain. These and other studies indicate that relaxin-3 plays a role regulating stress responses, cognitive and arousal processes.

Nucleus incertus and relaxin-3 - an emerging modulatory role in arousal , stress and memory (#13)

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