Pristerà, Alessandro, Blomeley, Craig, Lopes, Emanuel, Threlfell, Sarah, Merlinia, Elisa, Burdakov, Denis, Cragg, Stephanie, Guillemot, Francois, and Ang, Siew-Lan
Midbrain dopamine neurons, which can be regulated by neuropeptides and hormones, play a fundamental role in controlling cognitive processes, reward mechanisms, and motor functions. The hormonal actions of insulin-like growth factor 1 (IGF-1) produced by the liver have been well described, but the role of neuronally derived IGF-1 remains largely unexplored. We discovered that dopamine neurons secrete IGF-1 from the cell bodies following depolarization, and that IGF-1 controls release of dopamine in the ventral midbrain. In addition, conditional deletion of dopamine neuron-derived IGF-1 in adult mice leads to decrease of dopamine content in the striatum and deficits in dopamine neuron firing and causes reduced spontaneous locomotion and impairments in explorative and learning behaviors. These data identify that dopamine neuron-derived IGF-1 acts as a regulator of dopamine neurons and regulates dopamine-mediated behaviors. Midbrain dopamine (mDA) neurons play a fundamental role in a multitude of cognitive processes, including reward processing, learning, decision making, and motivation to engage in goal-orientated behaviors (like eating and drinking) (1, 2). mDA neurons are organized into nuclei in the ventral midbrain, with the two major ones being the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). VTA and SNc neurons send long projection axons to the ventral striatum, prefrontal cortex, and dorsal striatum. Dysregulation of DA transmission in humans is associated with cognitive impairments such as schizophrenia, anxiety, and depression (3). In addition, mDA neurons control motor function; their degeneration in the SNc underlies movement problems in Parkinson’s disease (4). A detailed knowledge of the biology and functioning of mDA neurons is therefore important to understand both physiological and pathological states. Insulin-like growth factor 1 (IGF-1) is a pleiotropic 70 amino-acid residues long hormone that is mainly secreted from the liver, under the influence of the growth hormone (5). Its biological actions are dependent on the developmental stage, its concentration, time course of action, and target cell type. IGF-1 has been shown to promote differentiation and maturation of neurons, and IGF-1 whole-body KO and IGF-1 receptor (IGF-1R) brain-specific conditional KO mice have reduced brain size (6, 7). In the adult mouse brain, IGF-1 modulates neuronal plasticity and positively promotes neurogenesis (8). In humans, IGF-1 deficiency causes dwarfism (5) and mutations in the Igf1 gene cause growth failure in utero, microcephaly, and mental retardation postnatally (9). In addition to its production by the liver, IGF-1 can also be synthesized in the CNS by neurons. While the role of peripheral IGF-1 secreted mainly from the liver has been extensively studied, the role of neuronally derived IGF-1 is only beginning to be uncovered. Neuronal IGF-1 has been shown to affect neuronal function by modulating excitability and synaptic connections. For example, Cao et al. (10) demonstrated that IGF-1 is secreted from dendrites and cell bodies of mitral neurons in the olfactory bulb following depolarization. Further investigation showed that IGF-1 modulates synaptic plasticity of mitral cells during social learning in an autocrine fashion (11). IGF-1 has also been recently reported to be highly up-regulated in vasoactive intestinal peptide (VIP)-expressing interneurons of the cortex following sensory experience. VIP neuron-derived IGF-1 acutely promotes inhibition onto VIP neurons in a cell-autonomous manner (12). Interestingly, Igf1 transcripts have been found in mDA neurons, preferentially in the SNc, both by microarray (in adult) (13) and single-cell RT-qPCR (at postnatal day 4) (14), yet whether and which mDA neurons express IGF-1 protein was not explored. Studies have shown that the activity of mDA neurons is regulated by neuropeptides secreted from afferent neurons (15) and hormones from the periphery (16, 17). The sensitivity of mDA neurons to IGF-1 signaling has been supported by the demonstration that ectopic application of IGF-1 promotes survival of mDA neurons following a toxic insult in vitro (13) and in vivo (18). Despite the notion that mDA neurons themselves may be a source of IGF-1 in the adult brain and that neuronally derived IGF-1 can act as a neuromodulator, no studies to date have explored the role of mDA neuron-derived IGF-1. Considering the involvement of DA signaling in shaping cognitive and motor function, both in physiological and pathological scenarios, we believe that a detailed understanding of DA neuron modulation is of great importance. In this study, we show that mDA neurons synthesize and secrete IGF-1 from the cell body following depolarization. We also demonstrate that IGF-1 controls striatal DA levels, local DA release in the midbrain, and DA neuron firing. Moreover, elimination of DA neuron-derived IGF-1 in mice is sufficient to cause hypoactivity, reduced exploratory behavior, and impaired motor learning skills., Proceedings of the National Academy of Sciences of the United States of America, ISSN:0027-8424, ISSN:1091-6490