Papers by Maria Jose Galazo
Frontiers in psychiatry, Apr 15, 2024
Episodic memories are thought to be stabilized through the coordination of cortico-hippocampal ac... more Episodic memories are thought to be stabilized through the coordination of cortico-hippocampal activity during sleep. However, the timing and mechanism of this coordination remain unknown. To investigate this, we studied the relationship between hippocampal reactivation and slow-wave sleep UP and Down states of the retrosplenial cortex (RTC) and prefrontal cortex (PFC). We found that hippocampal reactivation are strongly correlated with specific cortical states. Reactivation occurred during sustained cortical UP states or during the transition from UP to Down state. Interestingly, sustained UP states from the PFC were more coordinated with memory reactivation in the hippocampus, whereas hippocampal reactivation was biased to occur during the cortical UP to Down state transition of the RTC. Reactivation usually occurred within 150-200 ms of a cortical UP-state onset, indicating that a build-up of excitation during cortical UP state activity influences the probability of memory reactivation in CA1. Conversely, CA1 reactivation occurred 30-50 ms before the onset of a cortical Down state, suggesting that memory reactivation affects Down state initiation in RTC and PFC, but the effect in RTC was more robust. Our findings provide evidence that supports and highlights the complexity of bidirectional communication between cortical regions and the hippocampus during sleep.
Journal of comparative neurology, Jun 10, 2003
Reelin is a large secretable protein which, when developmentally defective, causes the reeler bra... more Reelin is a large secretable protein which, when developmentally defective, causes the reeler brain malformation in mice and a recessive form of lissencephaly with cerebellar hypoplasia in humans. In addition, Reelin is heavily expressed throughout the adult brain, although its function/s there are still poorly understood. To gain insight into which adult neuronal circuits may be under the influence of Reelin, we systematically mapped Reelinimmunoreactive neuronal somata, axons, and neuropil in the brain and brainstem of ferrets. Results show that Reelin immunoreactivity is found in widespread but specific sets of neuronal bodies, axonal tracts, and gray matter neuropil regions. Depending on the region, the immunoreactive neuronal somata correspond to interneurons, projection neurons, or both. Some well-defined axonal projection systems are immunoreactive, whereas most other white matter tracts are unlabeled. The labeled pathways include, among others, the lateral olfactory tract, the entorhinohippocampal (perforant) pathway, the retroflex bundle, and the stria terminalis. Labeled axons in these tracts contain large numbers of discrete, very small, immunoreactive particles, suggestive of secretory vesicles under the light microscope. The neuropil in the terminal arborization fields of these axons is also heavily immunoreactive. Taken together, our observations are consistent with the notion that some neurons may anterogradely transport Reelin along their axons in large membrane-bound secretory vesicles (Derer et al. [2001] J. Comp. Neurol. 440:136-143) and secrete it into their terminal arborization fields, which may be quite distant from the somata synthesizing the protein. These findings have implications for identifying where Reelin acts in adult brain circuits.
Cerebral Cortex, May 20, 2007
Nature Communications, Oct 7, 2019
Interhemispheric axons of the corpus callosum (CC) facilitate the higher order functions of the c... more Interhemispheric axons of the corpus callosum (CC) facilitate the higher order functions of the cerebral cortex. According to current views, callosal and non-callosal fates are determined early after a neuron's birth, and certain populations, such as cortical layer (L) 4 excitatory neurons of the primary somatosensory (S1) barrel, project only ipsilaterally. Using a novel axonal-retrotracing strategy and GFP-targeted visualization of Rorb + neurons, we instead demonstrate that L4 neurons develop transient interhemispheric axons. Locally restricted L4 connectivity emerges when exuberant contralateral axons are refined in an areaand layer-specific manner during postnatal development. Surgical and genetic interventions of sensory circuits demonstrate that refinement rates depend on distinct inputs from sensory-specific thalamic nuclei. Reductions in input-dependent refinement result in mature functional interhemispheric hyperconnectivity, demonstrating the plasticity and bona fide callosal potential of L4 neurons. Thus, L4 neurons discard alternative interhemispheric circuits as instructed by thalamic input. This may ensure optimal wiring.
Cell Reports, Feb 1, 2017
Highlights d MN cultures from SMA or ALS patients or controls contain cells with different SMN le... more Highlights d MN cultures from SMA or ALS patients or controls contain cells with different SMN levels d In these cultures, high SMN MNs survive better than MNs harboring low SMN levels d An Nedd8-activating enzyme inhibitor increases SMN and survival of ALS and SMA MNs d The effect of drugs that correct SMN2 splicing is limited to SMA and not ALS
Frontiers in Cell and Developmental Biology, Sep 7, 2021
Mutations in RAC1 allele are implicated in multiple brain tumors, indicating a rigorous control o... more Mutations in RAC1 allele are implicated in multiple brain tumors, indicating a rigorous control of Rac1 activity is required for neural tissue normal development and homeostasis. To understand how elevated Rac1 activity affects neural crest cells (NCCs) development, we have generated Rac1 CA ;Wnt1-Cre2 mice, in which a constitutively active Rac1 G12V mutant is expressed specifically in NCCs derivatives. Our results revealed that augmented Rac1 activity leads to enlarged midbrain and altered cell density, accompanied by increased NCCs proliferation rate and misrouted cell migration. Interestingly, our experimental data also showed that elevated Rac1 activity in NCCs disrupts regionalization of dopaminergic neuron progenitors in the ventral midbrain and impairs their differentiation. These findings shed light on the mechanisms of RAC1 mutation correlated brain tumor at the cellular and molecular level.
European Journal of Neuroscience, Jan 18, 2006
Reelin, a large extracellular matrix glycoprotein, is secreted by several neuron populations in t... more Reelin, a large extracellular matrix glycoprotein, is secreted by several neuron populations in the developing and adult rodent brain. Secreted Reelin triggers a complex signaling pathway by binding lipoprotein and integrin membrane receptors in target cells. Reelin signaling regulates migration and dendritic growth in developing neurons, while it can modulate synaptic plasticity in adult neurons. To identify which adult neural circuits can be modulated by Reelin-mediated signaling, we systematically mapped the distribution of Reelin in adult rat brain using sensitive immunolabeling techniques. Results show that the distribution of intracellular and secreted Reelin is both very widespread and specific. Some interneuron and projection neuron populations in the cerebral cortex contain Reelin. Numerous striatal neurons are weakly immunoreactive for Reelin and these cells are preferentially located in striosomes. Some thalamic nuclei contain Reelin-immunoreactive cells. Double-immunolabeling for GABA and Reelin reveals that the Reelin-immunoreactive cells in the visual thalamus are the intrinsic thalamic interneurons. High local concentrations of extracellular Reelin selectively outline several dendrite spine-rich neuropils. Together with previous mRNA data, our observations suggest abundant axoplasmic transport and secretion in pathways such as the retino-collicular tract, the entorhino-hippocampal ('perforant') path, the lateral olfactory tract or the parallel fiber system of the cerebellum. A preferential secretion of Reelin in these neuropils is consistent with reports of rapid, activity-induced structural changes in adult brain circuits.
Elsevier eBooks, 2016
Thalamocortical (TC) input is a key determinant of the content and dynamics of information flow i... more Thalamocortical (TC) input is a key determinant of the content and dynamics of information flow in the cerebral cortex. This input reaches the cortex via a diverse array of TC pathways, whose intricate and overlapping wiring architectures are not yet well understood. The traditional division between specific and nonspecific TC pathways needs revision in view of evidence for the prevalence of “multispecific” TC axons that branch to innervate restricted domains in several cortical areas, often with different laminar patterns. Multispecific TC wiring might both allow parallel processing of the same input across spatially distributed assemblies of cortical and thalamic cells and favor coherence in their membrane potential fluctuations. Besides, the observation that the multispecific TC axons develop by interstitial branching suggests a flexible mechanism for generating diversity in such assemblies during evolution.
Neuron, Feb 1, 2016
Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function ... more Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function and connectivity. Activity-dependent mechanisms also contribute to wiring and circuit assembly, but whether and how they relate to TF-directed neuronal differentiation is poorly investigated. Here we demonstrate that the TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of Kv1 voltage-dependent potassium channels and the resulting postnatal switch to a Kv1-dependent firing mode. Loss of Cux1 function led to a decrease in the expression of Kv1 transcripts, aberrant firing responses, and selective loss of CC contralateral innervation. Firing and innervation were rescued by re-expression of Kv1 or postnatal reactivation of Cux1. Knocking down Kv1 mimicked Cux1-mediated CC axonal loss. These findings reveal that activitydependent processes are central bona fide components of neuronal TF-differentiation programs and establish the importance of intrinsic firing modes in circuit assembly within the neocortex.
Anales de la Real Academia Nacional de Medicina, 2009
Thalamocortical (TC) pathways are still mainly understood as the gateway for ascending sensory-mo... more Thalamocortical (TC) pathways are still mainly understood as the gateway for ascending sensory-motor information into the cortex. However, it is now clear that a great many TC cells are involved in interactions between cortical areas via the thalamus. We review recent data, including our own, which demonstrate the generalized presence in rodent thalamus of two major TC cell types characterized, among other features, by their axon development, arborization and laminar targeting in the cortex. Such duality may allow inputs from thalamus to access cortical circuits via "bottom-up"-wired axon arbors or via "top-down"-wired axon arbors.
Neuron, Jul 1, 2016
Corticothalamic projection neurons (CThPN) are a diverse set of neurons, critical for function of... more Corticothalamic projection neurons (CThPN) are a diverse set of neurons, critical for function of the neocortex. CThPN development and diversity needs to be precisely regulated, but little is known about molecular controls over their differentiation and functional specialization, critically limiting understanding of cortical development and complexity. We report the identification of a set of genes that both define CThPN, and likely control their differentiation, diversity, and function. We selected the CThPN-specific transcriptional co-regulator Fog2 for functional analysis. We identify that Fog2 controls CThPN molecular differentiation, axonal targeting, and diversity, in part by regulating the expression level of Ctip2 by CThPN, via combinatorial interactions with other molecular controls. Loss of Fog2 specifically disrupts differentiation of subsets of CThPN specialized in motor function, indicating that Fog2 coordinates subtype and functionalarea differentiation. These results confirm that we identified key controls over CThPN development, and identify Fog2 as a critical control over CThPN diversity.
Cerebral Cortex, Dec 1, 2002
Reelin is a large secretable protein which is widely expressed by specific neuronal populations. ... more Reelin is a large secretable protein which is widely expressed by specific neuronal populations. In the embryonic brain, Reelin plays a signaling role critical for the correct positioning of migrating neuroblasts. Reelin is also expressed in the adult mammalian brain, including humans; however, its function/s there remain poorly understood. To gain insight into which neuronal populations and specific circuits may be influenced by Reelin in the adult, we have conducted a light and electron microscope analysis of Reelinimmunoreactive neuron types in the cerebral cortex and subcortical regions of adult macaque monkeys. Results show that the great majority of brain neurons, including interneurons and projection neurons, are immunoreactive for Reelin although some neuronal populations do not contain Reelin. The immunoreactive protein is located intracellularly, mainly in neuronal somata. Reelin is also present in gray matter neuropil as well as in some long axonal pathways and their terminal arborizations, suggesting that it can be axonally transported over long distances. The staining patterns in the labeled neurons are remarkably diverse. Our observations reveal a wider distribution of Reelin in the adult macaque brain than in any other species investigated to date. The data show that Reelin is in a position to influence most brain circuits in the adult primate brain.
Cerebral Cortex, Feb 2, 2009
Input to apical dendritic tufts is now deemed crucial for associative learning, attention, and si... more Input to apical dendritic tufts is now deemed crucial for associative learning, attention, and similar ''feedback'' interactions in the cerebral cortex. Excitatory input to apical tufts in neocortical layer 1 has been traditionally assumed to be predominantly cortical, as thalamic pathways directed to this layer were regarded relatively scant and diffuse. However, the sensitive tracing methods used in the present study show that, throughout the rat neocortex, large numbers (mean~4500/mm 2) of thalamocortical neurons converge in layer 1 and that this convergence gives rise to a very high local density of thalamic terminals. Moreover, we show that the layer 1-projecting neurons are present in large numbers in most, but not all, motor, association, limbic, and sensory nuclei of the rodent thalamus. Some layer 1-projecting axons branch to innervate large swaths of the cerebral hemisphere, whereas others arborize within only a single cortical area. Present data imply that realistic modeling of cortical circuitry should factor in a dense axonal canopy carrying highly convergent thalamocortical input to pyramidal cell apical tufts. In addition, they are consistent with the notion that layer 1-projecting axons may be a robust anatomical substrate for extensive ''feedback'' interactions between cortical areas via the thalamus.
Nature Reviews Neuroscience, Oct 9, 2013
The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal s... more The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation. In recent years, several key controls over the specification and differentiation of neocortical projection neurons have been identified. This work provides substantial insight into the "molecular logic" underlying cortical development, increasingly supporting a model in which individual progenitor-stage and postmitotic regulators are embedded within highly-interconnected networks that gate sequential developmental decisions. Here, we provide an integrative account of the molecular controls that direct the progressive development and delineation of subtype and area identity of neocortical projection neurons. Two major classes of neurons, interneurons and projection neurons, populate the neocortex 1. Interneurons connect locally within the neocortex, are largely inhibitory, and are generated by progenitors in the subpallial (ventral) proliferative zone of the telencephalon before migrating to the neocortex 2-4. In contrast, projection neurons send axons to distant brain targets, are excitatory, and are generated by progenitors in the pallial (dorsal) proliferative zone 5,6. Interneuron diversity and development have been reviewed elsewhere 7-9 ; in this article, we focus exclusively on projection neurons. Individual phenotypic characteristics, such as dendritic morphology, electrophysiological properties, or projection patterns, have been used in the past to systematically classify projection neurons 6,10-12. Although these classification schemes have facilitated investigation of projection neuron development and function, a more comprehensive understanding of neuronal diversity will require integration of these and other phenotypic data, including transcriptomic and epigenomic profiles 13. Here, we group neurons primarily by the target of their axons (Box 1), both because hodology is centrally related to function, and because establishment of appropriate projections requires successful stepwise execution of elaborate developmental programs. Projection neurons progressively acquire subtype and area identities, and their developmental trajectories can be followed along three distinct axes: time, subtype differentiation, and area differentiation. Most work to date has addressed each of these axes separately, providing descriptive analyses of individual molecular controls acting either in
Zinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofa... more Zinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specificZmiz1knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling ofZmiz1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migrationin vitro. We also presented evidence that Zmiz1 regulates Prox1 expressionin vitroandin vivoby modulating chromatin accessibility at Prox1 regulatory regions. Fur...
In the cerebral cortex, cortical projection neurons comprise classes of neurons project to distan... more In the cerebral cortex, cortical projection neurons comprise classes of neurons project to distant regions of the central nervous system. These neurons develop from the same progenitor pool, but they acquire strikingly different inputs and outputs to underpin strikingly different functions. The question of how corticospinal projection neurons - involved in motor function and implicated in paralysis - and callosal projection neurons - involved in cognitive function and implicated in autism - develop represents a fundamental and clinically important question in neurodevelopment. A network of transcription factors, including the selector gene Fezf2, is central to specifying cortical projection neuron fates. Gene regulation up- and down-stream of these transcription factors, however, is not well understood, particularly as it relates to the development of the major inputs to cortical projection neurons. Here we show that the miR-193b~365 microRNA cluster downstream of Fezf2 cooperativel...
bioRxiv (Cold Spring Harbor Laboratory), May 23, 2022
Highlights • Tle4 promotes CThPN identity and blocks SCPN identity in early-born cortical neurons... more Highlights • Tle4 promotes CThPN identity and blocks SCPN identity in early-born cortical neurons • Tle4 is necessary to maintain CThPN identity during circuit maturation • TLE4-FEZF2 complex epigenetically regulates Fezf2 expression in developing CThPN • TLE4-FEZF2 regulates corticofugal subtypes distinction and maturation of CThPN was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
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Papers by Maria Jose Galazo