Download THE CENTRAL CONTROL OF GROWTH HORMONE RELEASE

THE CENTRAL CONTROL OF GROWTH HORMONE RELEASE –
Electrophysiology and Functional Role of Neuroendocrine Somatostatin Neurons
Supervisor name: Christian Broberger
Department: Dept. of Neuroscience
Background: Growth hormone (GH), and its down-stream mediator, insulin-like growth
factor-I (IGF-I), exert powerful age-dependent effects on metabolism1. In childhood and
adolescence, the GH axis orchestrates normal growth by actions on bone and muscle. In
adulthood, GH has potent lipolytic actions1 and altered GH secretion disrupts glucose
homeostasis2. The secretion of GH into the bloodstream occurs in discrete pulses, a pattern that
is necessary for the hormone’s full actions on target organs3. The mechanisms underlying GH
pulsatility remain obscure, however. - The GH-producing cells in the pituitary are under
competing influences from two populations of neuroendocrine neurons in the hypothalamus:
growth hormone-releasing hormone (GHRH) neurons, which stimulate GH release, and
somatostatin (Som) neurons, which inhibit GH release4. Recent evidence suggests that
intermittent relief of Som secretion, rather than pulsatile GHRH release underlies the plasma
profile of GH5, but the neuronal interactions that produce normal GH secretion remain elusive.
Thus, it is not known e.g. how Som neurons contribute to pulse generation; how Som neurons –
and thus the control of GH release – are integrated within the broader CNS network that
controls feeding and energy balance; and if neuroendocrine network interactions change in an
age- and sex-dependent manner.
Hypothesis: Som cells possess electrophysiological characteristics that allow them to
participate in the GH pulse generator. Modulation of these properties determines the functional
state of the somatotrophic axis and, as a consequence, of whole-body metabolism.
Objectives: In the proposed project the postdoctoral candidate will
1) characterize the membrane properties and network behaviour of hypothalamic Som neurons;
2) identify how Som electrophysiology is modulated by feedback signals, glycaemic state and
hormones (e.g. leptin), and signals from other metabolism-regulating CNS populations;
3) determine how experimental manipulation of Som neurons affects hormone status in the
somatotrophic axis and metabolism.
Work Plan incl. Methodology: These issues will be explored using transgenic mice where
fluorescent reporter proteins and ion channels genetically engineered for control by light
(optogenetically) or by exogenous ligands (DREADD methodology) are selectively expressed
by Cre expression in Som neurons following stereotactic viral delivery, using AAV vectors.
The electrical properties and network behaviour, as well as its modulation by hormones,
neurotransmitters, glucose and lipids, will be determined by in vitro patch clamp recordings
and Ca2+ imaging (using transgenic expression of the indicator, GCaMP3). In vivo
manipulation of Som electrophysiology will be investigated for effects on temporal patterns of
hormonal status and a comprehensive repertoire of growth and metabolic parameters, e.g.
feeding, glucose tolerance and fat metabolism. The experiments will initially be performed in
prepubertal males, but once the basic properties of the system in this model have been
determined, Som neurons and their actions will be recorded in male and female mice during
early development, adolescence and in adulthood.
Significance: The GH/IGF-I system is a drug target in disorders ranging from gigantism,
acromegaly and idiopathic short stature to age-related GH deficiency6, and regulates lipid
metabolism1. Moreover, GH therapy increases the risk for developing type 2 diabetes even in
children7, highlighting its powerful counterregulatory actions on glucose homeostasis. The
proposed project will provide conceptually new information for the understanding of these and
other conditions that may be exploited for therapeutic strategies, as well as crucial insight into
the fundamental endocrine question of how pulsatile hormone release is generated.
The laboratory: In the past few years, we have identified an oscillating population of
neuroendocrine dopamine neurons whose behaviour may be part of the pulse generator for
pituitary prolactin secretion8, 9, 10. Our group, within a department characterized by state-of-theart neuroscience and an international atmosphere, uses electrophysiology, neuroanatomy and
behavioural protocols to dissect neural networks in the hypothalamus that underlie basic
survival functions such as metabolism, reproduction and aggression.
Postdoc profile: We particularly welcome candidates with training in electrophysiological
recording techniques, but all candidates with experience from working with experimental
animal models are encouraged to apply.
References:
1. Chia DJ, 2014. Minireview: mechanisms of growth hormone-mediated gene regulation. Mol
Endocrinol; 28(7):1012-25.
2. Holt RI, Simpson HL, Sönksen PH, 2003. The role of the growth hormone-insulin-like
growth factor axis in glucose homeostasis. Diabet Med; 20(1):3-15
3. Norstedt G, Palmiter R, 1984. Secretory rhythm of growth hormone regulates sexual
differentiation of mouse liver. Cell; 36(4):805-12.
4. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R, 1973.
Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth
hormone. Science; 179(4068):77-9.
5. Veldhuis JD, Bowers CY, 2011. Regulated recovery of pulsatile growth hormone secretion
from negative feedback: a preclinical investigation. Am J Physiol Regul Integr Comp Physiol;
301(4):R1143-52.
6. Ayuk J, Sheppard MC, 2006. Growth hormone and its disorders. Postgrad Med J.;
82(963):24-30.
7. Cutfield WS, Wilton R, Bennmarker H, Albertsson-Wikland K, Chatelain R, Ranke MB, et
al, 2000. Incidence of diabetes mellitus and impaired glucose tolerance in children and
adolescents receiving growth-hormone treatment. Lancet; 355:610-613.
8. Lyons DJ, Horjales E, Broberger C, 2010. A slow oscillation in tuberoinfundibular dopamine
(TIDA) neurons: Switch to tonic firing via thyrotropin-releasing hormone (TRH). Neuron;
65(2): 217-29.
9. Briffaud V, Williams P, Courty J, Broberger C, 2015. Excitation of Tuberoinfundibular
Dopamine (TIDA) Neurons by Oxytocin: Cross-talk in the Control of Lactation. J Neurosci,
35(10):4229-37.
10. Stagkourakis S, Kim H, Lyons DJ, Broberger C, 2016. Dopamine Autoreceptor Regulation
of a Hypothalamic Dopaminergic Network. Cell Reports, in press.
Contact details:
Christian Broberger, M.D., Ph.D.
E-mail: [email protected]
Office phone: +46-(0)8 5248 7038
Cell phone: +46-(0)70 22 69 327