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1.
Proc Natl Acad Sci U S A ; 120(33): e2301644120, 2023 08 15.
Article in English | MEDLINE | ID: mdl-37549297

ABSTRACT

Sensory inputs are conveyed to distinct primary areas of the neocortex through specific thalamocortical axons (TCA). While TCA have the ability to reorient postnatally to rescue embryonic mistargeting and target proper modality-specific areas, how this remarkable adaptive process is regulated remains largely unknown. Here, using a mutant mouse model with a shifted TCA trajectory during embryogenesis, we demonstrated that TCA rewiring occurs during a short postnatal time window, preceded by a prenatal apoptosis of thalamic neurons-two processes that together lead to the formation of properly innervated albeit reduced primary sensory areas. We furthermore showed that preterm birth, through serotonin modulation, impairs early postnatal TCA plasticity, as well as the subsequent delineation of cortical area boundary. Our study defines a birth and serotonin-sensitive period that enables concerted adaptations of TCA to primary cortical areas with major implications for our understanding of brain wiring in physiological and preterm conditions.


Subject(s)
Neocortex , Premature Birth , Infant, Newborn , Mice , Animals , Humans , Pregnancy , Female , Neurons/physiology , Serotonin , Cerebral Cortex/physiology , Infant, Premature , Axons/physiology , Thalamus/physiology
2.
PLoS Biol ; 17(9): e3000419, 2019 09.
Article in English | MEDLINE | ID: mdl-31483783

ABSTRACT

Parvalbumin (PV)-positive interneurons modulate cortical activity through highly specialized connectivity patterns onto excitatory pyramidal neurons (PNs) and other inhibitory cells. PV cells are autoconnected through powerful autapses, but the contribution of this form of fast disinhibition to cortical function is unknown. We found that autaptic transmission represents the most powerful inhibitory input of PV cells in neocortical layer V. Autaptic strength was greater than synaptic strength onto PNs as a result of a larger quantal size, whereas autaptic and heterosynaptic PV-PV synapses differed in the number of release sites. Overall, single-axon autaptic transmission contributed to approximately 40% of the global inhibition (mostly perisomatic) that PV interneurons received. The strength of autaptic transmission modulated the coupling of PV-cell firing with optogenetically induced γ-oscillations, preventing high-frequency bursts of spikes. Autaptic self-inhibition represents an exceptionally large and fast disinhibitory mechanism, favoring synchronization of PV-cell firing during cognitive-relevant cortical network activity.


Subject(s)
Interneurons/physiology , Neocortex/physiology , Synapses , Synaptic Transmission , Animals , Female , Male , Mice, Inbred C57BL
3.
Nat Commun ; 9(1): 4725, 2018 11 09.
Article in English | MEDLINE | ID: mdl-30413696

ABSTRACT

The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such cellular mosaic ensures the balanced activity of the two pathways, its developmental origin and pattern remains largely unknown. Here, we show that both SPN populations are specified embryonically and intermix progressively through multidirectional iSPN migration. Using conditional mutant mice, we found that inactivation of the dSPN-specific transcription factor Ebf1 impairs selective dSPN properties, including axon pathfinding, while molecular and functional features of iSPN were preserved. Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, highlighting that intermixing is a parallel process to compartment formation. Our study reveals while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.


Subject(s)
Neostriatum/physiology , Neurons/physiology , Animals , Cell Differentiation , Cell Movement , Embryo, Mammalian/physiology , Gene Deletion , Mice, Inbred C57BL , Neostriatum/embryology , Neurons/cytology , Trans-Activators/deficiency , Trans-Activators/metabolism
4.
J Comp Neurol ; 526(3): 397-411, 2018 Feb 15.
Article in English | MEDLINE | ID: mdl-28921616

ABSTRACT

In mammals, thalamic axons are guided internally toward their neocortical target by corridor (Co) neurons that act as axonal guideposts. The existence of Co-like neurons in non-mammalian species, in which thalamic axons do not grow internally, raised the possibility that Co cells might have an ancestral role. Here, we investigated the contribution of corridor (Co) cells to mature brain circuits using a combination of genetic fate-mapping and assays in mice. We unexpectedly found that Co neurons contribute to striatal-like projection neurons in the central extended amygdala. In particular, Co-like neurons participate in specific nuclei of the bed nucleus of the stria terminalis, which plays essential roles in anxiety circuits. Our study shows that Co neurons possess an evolutionary conserved role in anxiety circuits independently from an acquired guidepost function. It furthermore highlights that neurons can have multiple sequential functions during brain wiring and supports a general role of tangential migration in the building of subpallial circuits.


Subject(s)
Afferent Pathways/physiology , Axon Guidance/genetics , Cell Movement/physiology , Gene Expression Regulation, Developmental/physiology , Pontine Tegmentum , Thalamus , Animals , Animals, Newborn , Cholera Toxin/metabolism , Deoxyuridine/analogs & derivatives , Deoxyuridine/metabolism , Embryo, Mammalian , Female , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , LIM-Homeodomain Proteins/genetics , LIM-Homeodomain Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pontine Tegmentum/cytology , Pontine Tegmentum/embryology , Pontine Tegmentum/growth & development , Pregnancy , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Thalamus/cytology , Thalamus/embryology , Thalamus/growth & development , Thyroid Nuclear Factor 1/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
5.
Curr Biol ; 23(9): 810-6, 2013 May 06.
Article in English | MEDLINE | ID: mdl-23623550

ABSTRACT

Sensory maps, such as the representation of mouse facial whiskers, are conveyed throughout the nervous system by topographic axonal projections that preserve neighboring relationships between adjacent neurons. In particular, the map transfer to the neocortex is ensured by thalamocortical axons (TCAs), whose terminals are topographically organized in response to intrinsic cortical signals. However, TCAs already show a topographic order early in development, as they navigate toward their target. Here, we show that this preordering of TCAs is required for the transfer of the whisker map to the neocortex. Using Ebf1 conditional inactivation that specifically perturbs the development of an intermediate target, the basal ganglia, we scrambled TCA topography en route to the neocortex without affecting the thalamus or neocortex. Notably, embryonic somatosensory TCAs were shifted toward the visual cortex and showed a substantial intermixing along their trajectory. Somatosensory TCAs rewired postnatally to reach the somatosensory cortex but failed to form a topographic anatomical or functional map. Our study reveals that sensory map transfer relies not only on positional information in the projecting and target structures but also on preordering of axons along their trajectory, thereby opening novel perspectives on brain wiring.


Subject(s)
Neocortex/embryology , Somatosensory Cortex/embryology , Thalamus/embryology , Vibrissae/embryology , Animals , Axons/metabolism , Brain Mapping , Mice , Neocortex/cytology , Neocortex/metabolism , Somatosensory Cortex/cytology , Somatosensory Cortex/metabolism , Thalamus/cytology , Thalamus/metabolism , Trans-Activators/metabolism , Vibrissae/cytology , Vibrissae/metabolism
6.
Neuron ; 77(3): 472-84, 2013 Feb 06.
Article in English | MEDLINE | ID: mdl-23395374

ABSTRACT

Major outputs of the neocortex are conveyed by corticothalamic axons (CTAs), which form reciprocal connections with thalamocortical axons, and corticosubcerebral axons (CSAs) headed to more caudal parts of the nervous system. Previous findings establish that transcriptional programs define cortical neuron identity and suggest that CTAs and thalamic axons may guide each other, but the mechanisms governing CTA versus CSA pathfinding remain elusive. Here, we show that thalamocortical axons are required to guide pioneer CTAs away from a default CSA-like trajectory. This process relies on a hold in the progression of cortical axons, or waiting period, during which thalamic projections navigate toward cortical axons. At the molecular level, Sema3E/PlexinD1 signaling in pioneer cortical neurons mediates a "waiting signal" required to orchestrate the mandatory meeting with reciprocal thalamic axons. Our study reveals that temporal control of axonal progression contributes to spatial pathfinding of cortical projections and opens perspectives on brain wiring.


Subject(s)
Cerebral Cortex/physiology , Neural Pathways/physiology , Thalamus/physiology , Age Factors , Animals , Axons/physiology , Body Patterning/genetics , Calbindin 2 , Cerebral Cortex/cytology , Contactin 2/metabolism , Cytoskeletal Proteins , DNA-Binding Proteins/metabolism , Embryo, Mammalian , Gene Expression Regulation, Developmental/genetics , Glycoproteins/genetics , Homeodomain Proteins/genetics , Intracellular Signaling Peptides and Proteins , Leukocyte L1 Antigen Complex/metabolism , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nuclear Proteins/metabolism , POU Domain Factors/genetics , Repressor Proteins/metabolism , S100 Calcium Binding Protein G/metabolism , Semaphorins , T-Box Domain Proteins , Thalamus/cytology , Thyroid Nuclear Factor 1 , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Wnt3A Protein/genetics , tau Proteins/genetics
7.
Curr Biol ; 21(20): 1748-55, 2011 Oct 25.
Article in English | MEDLINE | ID: mdl-22000108

ABSTRACT

How guidance cues are integrated during the formation of complex axonal tracts remains largely unknown. Thalamocortical axons (TCAs), which convey sensory and motor information to the neocortex, have a rostrocaudal topographic organization initially established within the ventral telencephalon [1-3]. Here, we show that this topography is set in a small hub, the corridor, which contains matching rostrocaudal gradients of Slit1 and Netrin 1. Using in vitro and in vivo experiments, we show that Slit1 is a rostral repellent that positions intermediate axons. For rostral axons, although Slit1 is also repulsive and Netrin 1 has no chemotactic activity, the two factors combined generate attraction. These results show that Slit1 has a dual context-dependent role in TCA pathfinding and furthermore reveal that a combination of cues produces an emergent activity that neither of them has alone. Our study thus provides a novel framework to explain how a limited set of guidance cues can generate a vast diversity of axonal responses necessary for proper wiring of the nervous system.


Subject(s)
Axons/physiology , Growth Cones/physiology , Nerve Growth Factors/metabolism , Nerve Tissue Proteins/metabolism , Thalamus/embryology , Thalamus/physiology , Tumor Suppressor Proteins/metabolism , Animals , COS Cells , Cerebral Cortex/embryology , Cerebral Cortex/metabolism , Chlorocebus aethiops , Ephrin-A5/genetics , Ephrin-A5/metabolism , Gene Expression Regulation, Developmental , Mice , Mice, Transgenic , Nerve Growth Factors/genetics , Nerve Tissue Proteins/genetics , Netrin-1 , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Semaphorin-3A/genetics , Semaphorin-3A/metabolism , Tumor Suppressor Proteins/genetics , beta-Galactosidase/genetics , beta-Galactosidase/metabolism , Roundabout Proteins
8.
Neuron ; 69(6): 1085-98, 2011 Mar 24.
Article in English | MEDLINE | ID: mdl-21435555

ABSTRACT

How brain connectivity has evolved to integrate the mammalian-specific neocortex remains largely unknown. Here, we address how dorsal thalamic axons, which constitute the main input to the neocortex, are directed internally to their evolutionary novel target in mammals, though they follow an external path to other targets in reptiles and birds. Using comparative studies and functional experiments in chick, we show that local species-specific differences in the migration of previously identified "corridor" guidepost neurons control the opening of a mammalian thalamocortical route. Using in vivo and ex vivo experiments in mice, we further demonstrate that the midline repellent Slit2 orients migration of corridor neurons and thereby switches thalamic axons from an external to a mammalian-specific internal path. Our study reveals that subtle differences in the migration of conserved intermediate target neurons trigger large-scale changes in thalamic connectivity, and opens perspectives on Slit functions and the evolution of brain wiring.


Subject(s)
Cell Movement/physiology , Cerebral Cortex/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Thalamus/metabolism , Analysis of Variance , Animals , Axons/metabolism , Cerebral Cortex/embryology , Chick Embryo , Humans , Immunohistochemistry , In Situ Hybridization , Mice , Mice, Transgenic , Nerve Net/embryology , Nerve Net/metabolism , Neural Pathways/embryology , Neural Pathways/metabolism , Species Specificity , Thalamus/embryology , Turtles
9.
Front Neurosci ; 2(1): 47-55, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18982106

ABSTRACT

The different gene members of the Egr family of transcriptional regulators have often been considered to have related functions in brain, based on their co-expression in many cell-types and structures, the relatively high homology of the translated proteins and their ability to bind to the same consensus DNA binding sequence. Recent research, however, suggest this might not be the case. In this review, we focus on the current understanding of the functional roles of the different Egr family members in learning and memory. We briefly outline evidence from mutant mice that Egr1 is required specifically for the consolidation of long-term memory, while Egr3 is primarily essential for short-term memory. We also review our own recent findings from newly generated forebrain-specific conditional Egr2 mutant mice, which revealed that Egr2, as opposed to Egr1 and Egr3, is dispensable for several forms of learning and memory and on the contrary can act as an inhibitory constraint for certain cognitive functions. The studies reviewed here highlight the fact that Egr family members may have different, and in certain circumstances antagonistic functions in the adult brain.

10.
Article in English | MEDLINE | ID: mdl-18958188

ABSTRACT

It is well established that Egr1/zif268, a member of the Egr family of transcription factors, is critical for the consolidation of several forms of memories. Recently, the Egr3 family member has also been implicated in learning and memory. Because Egr family members encode closely related zinc-finger transcription factors sharing a highly homologous DNA binding domain that recognises the same DNA sequence, they may have related functions in brain. Another Egr family member expressed in brain, Egr2/Krox20 is known to be crucial for normal hindbrain development and has been implicated in several inherited peripheral neuropathies; however, due to Egr2-null mice perinatal lethality, its potential role in cognitive functions in the adult has not been yet explored. Here, we generated Egr2 conditional mutant mice allowing postnatal, forebrain-specific Cre-mediated Egr2 excision and tested homozygous, heterozygous and control littermates on a battery of behavioural tasks to evaluate motor capacity, exploratory behaviour, emotional reactivity and learning and memory performance in spatial and non-spatial tasks. Egr2-deficient mice had no sign of locomotor, exploratory or anxiety disturbances. Surprisingly, they also had no impairment in spatial learning and memory, taste aversion memory or fear memory using a trace conditioning paradigm. On the contrary, Egr2-deficient mice had improved performance in motor learning on a rotarod, and in object recognition memory. These results clearly do not extend the phenotypic consequences resulting from either Egr1 or Egr3 loss-of-function to Egr2. In contrast, they indicate that Egr family members may have different, and in certain circumstances antagonistic functions in the adult brain.

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