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Genetic control of neurogenesis in the ventral telencephalon
The switch from self-renewing division to neurogenic division is a crucial step to obtain the right amount of neurons, and premature exhaustion of the progenitor pool is linked to severe developmental disorders such as microcephaly (Chen et al., 2009; Sakai et al., 2012; Pilaz et al., 2016). It is well established that the timing of cell fate specification and differentiation in the nervous system is regulated by a process of lateral inhibition mediated via Notch signaling. Notch is a cell-surface receptor that is activated by its ligand Delta. Ligand-induced activation induces proteolytic cleavage of Notch and translocation of its intracellular domain to the cell nucleus, where it represses expression of transcription factors that promote neural differentiation. One of this genes is achaete-scute homolog 1 (Ascl1, previously known as Mash1). This gene encodes basic helix-loop-helix (bHLH) transcription factor that plays a role in the fate commitment and generation of different neuronal population, including olfactory and autonomic neurons. In the vTel, Ascl1 is expressed in the LGE and MGE and mutant mouse analyses have shown that it regulates the rate at which early progenitors differentiate into late progenitors, and therefore control the number of neurons generated (Long et al., 2009; Yun et al., 2002). Ascl1 has an epistatic relationship with its downstream effectors, homeobox genes Dlx1 and Dlx2; while the former seems more important for correct specification of dorsal striatal neurons, the latter have more relevance for nucleus accumbens (Long et al., 2009). Interestingly, homeobox genes Gsx1 and Gsx2 have been shown to control the balance between proliferation and differentiation in the LGE by interacting with both Ascl1 and Dlx genes (Pei et al., 2011; Wang et al., 2009 and 2013). Members of the Dlx family of homeodomain transcription factors are related to drosophila distal-less (Dll) gene. Within the ventral telencephalon, Dlx1, Dlx2, Dlx5 and Dlx6 are expressed in partially overlapping patterns in parts of the septum, the LGE, MGE and POA. They are expressed at different moments of differentiation, with Dlx2 being the earliest and Dlx1 expressed before Dlx5, which in turn precedes Dlx6. Dlx1 and 2 are expressed in proliferating progenitors and downregulate Notch signaling to promote differentiation of neurons, while Dlx5 and Dlx6 are expressed by postmitotic neurons in the SVZ and mantle area and seem to be implicated in migration and differentiation (Wang et al., 2011). In particular, Dlx genes control the migration of cortical interneurons by repressing dendrite and axon formation (Cobos et al., 2007; Wang et al., 2010). Therefore, transcriptional cascades control different aspects of neurogenesis, from regionalization of progenitor domains to the generation and specification of newborn neurons.
Radial and tangential migration in the ventral telencephalon
Once neurons are generated and specified by transcriptional cascades in distinct vTel domains, they undergo a phase of migration, which can be radial or tangential. The morphogenesis of the vTel relies on a highly complex choreography of cell movements, which is essential for the formation of nuclei as well as their cellular diversity.
Radial migration of projection neurons
The process of radial migration has been intensively studied in the mammalian cerebral cortex. In this structure, glutamatergic projection neurons have two different modes of migration: multipolar migration with random directional movement and locomotion, which is a unidirectional movement guided by radial glia fibers (Ohtaka-Maruyama and Okado, 2015). During development, newborn neurons switch from multipolar migration to locomotion to reach their final position in the cortex. Radial glia, whose processes contact both the apical surface and the basal surface, provide a scaffold to the migrating neuron. Therefore, the radial organization of the cortex is based on a point-to-point relation between the VZ and the overlaying structure formed by postmitotic neurons (Marín and Rubenstein, 2003).
Although the process of cell migration in the basal ganglia has received way less attention, several viral tracing and fate-mapping studies using in utero electroporation have explored the contribution of radial migration in its morphogenesis. It has been established that cells migrate radially from the LGE to generate projections neurons of the striatum (Wichterle et al., 2001; Hamasaki et al., 2003), and from the MGE to produce projections neurons of the GP (Xu et al., 2008; Nóbrega-Pereira et al., 2010).
Tangential migration of interneurons
Tangential migration is by definition migration which is not radial. It englobes very different processes that can either by built on cell/cell interaction, such as in chain migration, or involve the movements of isolated cells. Over the past 20 years, it has been well established (Gelman et al., 2012; Marin et al., 2000; Marín and Rubenstein, 2001, 2003) that tangential migration plays a central role in the generation and diversity of interneurons in the entire telencephalon. Indeed, the POA, MGE and LGE/CGE have been shown to generate all the interneurons of the neocortex and hippocampus that undergo a long journey to reach their targets (Ciceri et al., 2013; Corbin and Butt, 2011; Corbin et al., 2001; Marin et al., 2000; Torigoe et al., 2016). Such long-range tangential process has been also shown to occur in the production of olfactory bulb interneurons by the dLGE and their progressive migration along the rostral migratory stream (RMS). On a much shorter scale, all the interneurons of the striatum have been shown to originate in the MGE or POA (Evans et al., 2012; Gonzales and Smith, 2015; Marin et al., 2000). Indeed, the POA produces cholinergic striatal interneurons and the MGE, GABAergic interneurons (Gonzales and Smith, 2015; Marin et al., 2000; Nery et al., 2002; Villar-Cerviño et al., 2015). Thus the striatum is a complex mosaic of LGE-radially derived projection neurons and tangentially migrating interneurons produced in the MGE and POA. In addition, a series of additional streams of interneurons are essential to populate distinct domains of the amygdala (Bupesh et al., 2011; Hirata et al., 2009; Waclaw et al., 2010).
At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Their migration is regulated by extrinsic guidance cues, distributed along migratory streams, intrinsic genetic programs that grant specification and set the timing of migration, adhesion molecules and cytoskeletal elements that transduce molecular signaling into coherent movement (Peyre et al., 2015).
Tangential migration of projection neurons
While tangentially migrating projection neurons (such as Cajal-Retzius cells, subplate neurons and cortical plate transient neurons) have important roles in the formation of the cerebral cortex, these populations are usually considered as transient and not part of adult brain structures (Barber and Pierani, 2015). For this reason, and despite the different nuclear versus laminar organization of resulting structures, it has long been assumed that formation of the main basal ganglia nuclei, the striatum and the GP, followed a sequence akin to the cerebral cortex; that is, radial migration of projection neurons and contribution via tangential migration of interneurons of different origins (Hamasaki et al., 2003). However, several studies revealed that tangential migration of projection neurons can be observed in the vTel. For instance, tangential migration from the MGE largely contributes to formation of the GP, in addition to the well-established radial one (Nobrega-Pereira et al., 2010).
Table of contents :
I. General introduction
II. The self
A. How to define and study the self
B. The neuroscience of the self
1.Self-recognition across modalities: towards a unified representation of the self?
2. From personality traits to self-reflection
3. Building the self in time: autobiographical memory
C. The default-network, self-processing and spontaneous thoughts
1. Characterization of the default-network
2. The overlap between self-related processing and the default-network 26
3. Neural correlates of spontaneous thoughts
a) The relevance of spontaneous thoughts
b) Intrinsic and extrinsic modes of attention
c) How has the self-relatedness of thoughts been probed and what is
its relationship with DN activity?
D. The “I” and the “Me”: from philosophy to cognitive neuroscience
1. The “I” and the “Me”: what is it?
a) Defining the “I” and the “Me”
b) The idea of a narrative self
c) The “I” and the immunity principle
2. Re-interpretation of the neuroscientific findings
3. The “I” and the “Me” in cognitive neuroscience
III. The self and the living body
A. The embodied self
B. How malleable is bodily self-consciousness?
1. Body ownership and self-location
2. First-person perspective
3. Agency
C. A distinction between experience and introspection relative to the body
D. Interactions between bodily processes and higher order self
E. From the somatosensory/motor body to the visceral body
IV. The visceral body
A. Theoretical considerations about the visceral body and the self
1. A bodily-centered reference frame for the self
2. About visceral signals
B. Pathways from the viscera to the brain
C. Resting state cortical activity and physiological signals
D. Heart and brain
1. Stimuli processing and the timing of the cardiac cycle
2. Heartbeat-evoked responses
a) Origin of the cardiac signal that reaches the brain
b) Characterization of the HER waveform
c) HER amplitude modulation by different cognitive factors
3. Cardiac interoception
a) Cardiac interoception measures
b) Neural correlates
c) Relationship between cardiac interoception and cognition
d) What cardiac interoception does and does not tell us
E. A major role of the insula?
F. Visceral signals and bodily awareness
V. Article I: Neural responses to heartbeats in the default-network encode the self in spontaneous thoughts
A. Technical remarks on heartbeat-evoked responses
1. Confounding artefacts: cardiac-field and pulse artefacts
2. Correction and control of artefacts
B. Abstract in French
C. Article
VI. Article II: Is the cardiac monitoring function related to the self in both the default-network and right anterior insula?
A. Abstract in French
B. Article
VII.Article III: Imagining the self is associated with neural responses to heartbeats in medial motor regions and the ventromedial prefrontal
A. Abstract in French
B. Article
VIII. General discussion
A. Main results and discussion on the consistency between tasks
1. HERs encode the self in spontaneous thoughts
2. HERs distinguish self- and other-imagination
B. What do these results tell us about the self?
1. The “I” and the “Me”: two distinct and graded dimensions of the self in spontaneous thoughts
2. What is contrasted when we compare Self and Other?
C. Consistency of the results between tasks
D. What do these results tell us about spontaneous vs oriented thoughts?
E. Proposal of a mechanism for the implementation of the self
1. What is this signal?
2. Three hypotheses to explain the link between HERs and the self
