Anatomical record (Hoboken, N.J. : 2007), Jan 16, 2018
The olfactory nerve constitutes the first cranial pair. Compared with other cranial nerves, it de... more The olfactory nerve constitutes the first cranial pair. Compared with other cranial nerves, it depicts some atypical features. First, the olfactory nerve does not form a unique bundle. The olfactory axons join other axons and form several small bundles or fascicles: the fila olfactoria. These fascicles leave the nasal cavity, pass through the lamina cribrosa of the ethmoid bone and enter the brain. The whole of these fascicles is what is known as the olfactory nerve. Second, the olfactory sensory neurons, whose axons integrate the olfactory nerve, connect the nasal cavity and the brain without any relay. Third, the olfactory nerve is composed by unmyelinated axons. Fourth, the olfactory nerve contains neither Schwann cells nor oligodendrocytes wrapping its axons. But it contains olfactory ensheathing glia, which is a type of glia unique to this nerve. Fifth, the olfactory axons participate in the circuitry of certain spherical structures of neuropil that are unique in the brain: the...
Down syndrome (DS) is the most common chromosomal aneuploidy. Although trisomy on chromosome 21 c... more Down syndrome (DS) is the most common chromosomal aneuploidy. Although trisomy on chromosome 21 can display variable phenotypes, there is a common feature among all DS individuals: the presence of intellectual disability. This condition is partially attributed to abnormalities found in the hippocampus of individuals with DS and in the murine model for DS, Ts65Dn. To check if all hippocampal areas were equally affected in 4-5 month adult Ts65Dn mice, we analysed the morphology of dentate gyrus granule cells and cornu ammonis pyramidal neurons using Sholl method on Golgi-Cox impregnated neurons. Structural plasticity has been analysed using immunohistochemistry for plasticity molecules followed by densitometric analysis (Brain Derived Neurotrophic Factor (BDNF), Polysialylated form of the Neural Cell Adhesion Molecule (PSA-NCAM) and the Growth Associated Protein 43 (GAP43)). We observed an impairment in the dendritic arborisation of granule cells, but not in the pyramidal neurons in t...
N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of... more N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP) in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing...
Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiolog... more Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist) after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting t...
Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocamp... more Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its role is unknown. Here, we demonstrate, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal role for MIF in cell proliferation was demonstrated using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supportin...
After the division of neuronal precursors, many of the newly generated cells become immature neur... more After the division of neuronal precursors, many of the newly generated cells become immature neurons, which migrate to their final destination in the nervous system, extend neurites and make appropriate connections. For most neurons these events occur in a narrow time window and, once in their definitive location, they immediately start the final stages of their differentiation program, remaining immature only for a short time. The main objective of this review is to present and discuss recent data on a peculiar population of cells in the adult brain, which retain an immature neuronal phenotype for an unusually prolonged time. We review and discuss recent evidence on the temporal and spatial origin of these cells, their distribution in rodents and other mammals, their structure and neurochemical phenotype, and their putative fate and function. The review is mainly focused on the population of immature neurons located in the layer II of certain cortical regions, but we will also desc...
The connectivity of the neurons of the olfactory bulb is highly idiosyncratic and constitutes an ... more The connectivity of the neurons of the olfactory bulb is highly idiosyncratic and constitutes an exception to the general plan of how neurons, and especially cortical neurons, construct circuits. The majority of synaptic contacts in the circuits of the cortex are axo-dendritic. In these contacts, the axon is the presynaptic element, which transmits the signal, and the dendrite is the postsynaptic element, which receives the signal. However, the majority of synaptic contacts in the circuits of the olfactory bulb are dendro-dendritic. In fact, most of the neurons of the olfactory bulb lack an axon. Moreover, a high percentage of the dendro-dendritic synapses are reciprocal. This means that the roles of presynaptic and postsynaptic element are not clearly defined, in clear contrast with the universality of unidirectional synaptic transmission in the cortex and elsewhere in the central nervous system. In this review, we analyze and discuss some peculiarities of the circuits of the olfactory bulb.
Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration... more Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.
Anatomical record (Hoboken, N.J. : 2007), Jan 16, 2018
The olfactory nerve constitutes the first cranial pair. Compared with other cranial nerves, it de... more The olfactory nerve constitutes the first cranial pair. Compared with other cranial nerves, it depicts some atypical features. First, the olfactory nerve does not form a unique bundle. The olfactory axons join other axons and form several small bundles or fascicles: the fila olfactoria. These fascicles leave the nasal cavity, pass through the lamina cribrosa of the ethmoid bone and enter the brain. The whole of these fascicles is what is known as the olfactory nerve. Second, the olfactory sensory neurons, whose axons integrate the olfactory nerve, connect the nasal cavity and the brain without any relay. Third, the olfactory nerve is composed by unmyelinated axons. Fourth, the olfactory nerve contains neither Schwann cells nor oligodendrocytes wrapping its axons. But it contains olfactory ensheathing glia, which is a type of glia unique to this nerve. Fifth, the olfactory axons participate in the circuitry of certain spherical structures of neuropil that are unique in the brain: the...
Down syndrome (DS) is the most common chromosomal aneuploidy. Although trisomy on chromosome 21 c... more Down syndrome (DS) is the most common chromosomal aneuploidy. Although trisomy on chromosome 21 can display variable phenotypes, there is a common feature among all DS individuals: the presence of intellectual disability. This condition is partially attributed to abnormalities found in the hippocampus of individuals with DS and in the murine model for DS, Ts65Dn. To check if all hippocampal areas were equally affected in 4-5 month adult Ts65Dn mice, we analysed the morphology of dentate gyrus granule cells and cornu ammonis pyramidal neurons using Sholl method on Golgi-Cox impregnated neurons. Structural plasticity has been analysed using immunohistochemistry for plasticity molecules followed by densitometric analysis (Brain Derived Neurotrophic Factor (BDNF), Polysialylated form of the Neural Cell Adhesion Molecule (PSA-NCAM) and the Growth Associated Protein 43 (GAP43)). We observed an impairment in the dendritic arborisation of granule cells, but not in the pyramidal neurons in t...
N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of... more N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP) in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing...
Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiolog... more Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist) after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting t...
Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocamp... more Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its role is unknown. Here, we demonstrate, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal role for MIF in cell proliferation was demonstrated using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supportin...
After the division of neuronal precursors, many of the newly generated cells become immature neur... more After the division of neuronal precursors, many of the newly generated cells become immature neurons, which migrate to their final destination in the nervous system, extend neurites and make appropriate connections. For most neurons these events occur in a narrow time window and, once in their definitive location, they immediately start the final stages of their differentiation program, remaining immature only for a short time. The main objective of this review is to present and discuss recent data on a peculiar population of cells in the adult brain, which retain an immature neuronal phenotype for an unusually prolonged time. We review and discuss recent evidence on the temporal and spatial origin of these cells, their distribution in rodents and other mammals, their structure and neurochemical phenotype, and their putative fate and function. The review is mainly focused on the population of immature neurons located in the layer II of certain cortical regions, but we will also desc...
The connectivity of the neurons of the olfactory bulb is highly idiosyncratic and constitutes an ... more The connectivity of the neurons of the olfactory bulb is highly idiosyncratic and constitutes an exception to the general plan of how neurons, and especially cortical neurons, construct circuits. The majority of synaptic contacts in the circuits of the cortex are axo-dendritic. In these contacts, the axon is the presynaptic element, which transmits the signal, and the dendrite is the postsynaptic element, which receives the signal. However, the majority of synaptic contacts in the circuits of the olfactory bulb are dendro-dendritic. In fact, most of the neurons of the olfactory bulb lack an axon. Moreover, a high percentage of the dendro-dendritic synapses are reciprocal. This means that the roles of presynaptic and postsynaptic element are not clearly defined, in clear contrast with the universality of unidirectional synaptic transmission in the cortex and elsewhere in the central nervous system. In this review, we analyze and discuss some peculiarities of the circuits of the olfactory bulb.
Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration... more Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.
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Papers by Emilio Varea