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Abstract:
Midbrain dopaminergic neurons (MbDNs) in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) modulate cognition, reward behavior and voluntary movement, respectively. Recent findings indicate that VTA and SNpc MbDNs form subpopulations that are divergent in their electrophysiological features, functions and vulnerability to neurodegeneration in Parkinson’s disease. This diversity can be correlated with the anatomical organization of these two populations and their afferent and efferent connections. However, it is largely unexplored how MbDN diversity is established during development. Previous studies have demonstrated that the identity of MbDN subtypes can be directly linked to their temporal and spatial origin in the embryonic midbrain (Blaess et al., 2011; Hayes et al., 2011). Different subsets of MbDNs are derived from a ventral progenitor pool in the developing midbrain that is subdivided into a medial and a lateral domain. The relationship between developmental origin and the identity of MbDNs in the adult brain is likely reflected by the regulated activity of genes inducing cell fate during embryogenesis. Thus, the timing of Sonic hedgehog (Shh) signaling might play a role in the determination of the fate of MbDN subpopulations, since MbDN precursors respond differently to Shh. To address whether Shh signaling regulates the specification of MbDN subtypes, conditional gene inactivation approach was used in this study. Removal of Shh signaling at particular time point during MbDN induction results in the selective loss of a specific subset of MbDN precursors in the embryo. Using viral tracing and immunohistochemical analysis, this study demonstrates that this population of MbDN precursors gives rise to mesocortical projection neurons in the VTA. Furthermore, optogenetics and physiological analysis reveals that mesocortical MbDNs inhibit prefrontal cortical pyramidal neurons via an inhibitory cortical microcircuit. Other MbDN-derived projections are largely unaffected. Thus, temporally precise Shh signaling in the midbrain is required for establishing a specific mesocortical microcircuit. This is the first study establishing a causal link between early developmental induction mechanisms and the functional properties of MbDNs in the adult brain. Furthermore, constitutive activation of Shh signaling results in a massive increase in the number of MbDNs and the ventralization of the dorsal midbrain. Interestingly, analysis of MbDNp domain shows that only medial MbDN precursor domain was significantly increased. Due to the perinatal lethality of the mutant mice, investigation of MbDN specification in the adult brains was not possible. In addition, this study demonstrates that the development of the red nucleus (RN) neuron subpopulations is determined by the duration of Shh signaling as well. While inactivation of Shh signaling does not affect the generation of the parvocellular RN neurons, the neurons of magnocellular RN are severely reduced and disorganized.
