RESUMEN
Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.
Asunto(s)
Tronco Encefálico , Células Ependimogliales , Conducta Alimentaria , Calor , Hipotálamo , Vías Nerviosas , Neuronas , Animales , Femenino , Masculino , Ratones , Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/citología , Tronco Encefálico/citología , Tronco Encefálico/fisiología , Dopamina/metabolismo , Ingestión de Alimentos/fisiología , Células Ependimogliales/citología , Células Ependimogliales/fisiología , Conducta Alimentaria/fisiología , Ácido Glutámico/metabolismo , Hipotálamo/citología , Hipotálamo/fisiología , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Núcleos Parabraquiales/citología , Núcleos Parabraquiales/metabolismo , Núcleos Parabraquiales/fisiología , Sensación Térmica/fisiología , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/líquido cefalorraquídeo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The perception of and response to danger is critical for an individual's survival and is encoded by subcortical neurocircuits. The amygdaloid complex is the primary neuronal site that initiates bodily reactions upon external threat with local-circuit interneurons scaling output to effector pathways. Here, we categorize central amygdala neurons that express secretagogin (Scgn), a Ca2+-sensor protein, as a subset of protein kinase Cδ (PKCδ)+ interneurons, likely "off cells." Chemogenetic inactivation of Scgn+/PKCδ+ cells augmented conditioned response to perceived danger in vivo. While Ca2+-sensor proteins are typically implicated in shaping neurotransmitter release presynaptically, Scgn instead localized to postsynaptic compartments. Characterizing its role in the postsynapse, we found that Scgn regulates the cell-surface availability of NMDA receptor 2B subunits (GluN2B) with its genetic deletion leading to reduced cell membrane delivery of GluN2B, at least in vitro. Conclusively, we describe a select cell population, which gates danger avoidance behavior with secretagogin being both a selective marker and regulatory protein in their excitatory postsynaptic machinery.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Interneuronas/metabolismo , Proteína Quinasa C-delta/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Secretagoginas/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/fisiología , Animales , Reacción de Prevención , Línea Celular Tumoral , Células Cultivadas , Miedo , Femenino , Humanos , Interneuronas/fisiología , Masculino , Transporte de Proteínas , Ratas , Ratas Wistar , Secretagoginas/genética , Potenciales SinápticosRESUMEN
AIMS: The endocannabinoid system with its type 1 cannabinoid receptor (CB1 R) expressed in postmitotic neuroblasts is a critical chemotropic guidance module with its actions cascading across neurogenic commitment, neuronal polarisation and synaptogenesis in vertebrates. Here, we present the systematic analysis of regional CB1 R expression in the developing human brain from gestational week 14 until birth. In parallel, we diagrammed differences in CB1 R development in Down syndrome foetuses and identified altered CB1 R signalling. METHODS: Foetal brains with normal development or with Down's syndrome were analysed using standard immunohistochemistry, digitalised light microscopy and image analysis (NanoZoomer). CB1 R function was investigated by in vitro neuropharmacology from neonatal Ts65Dn transgenic mice brains carrying an additional copy of ~90 conserved protein-coding gene orthologues of the human chromosome 21. RESULTS: We detected a meshwork of fine-calibre, often varicose processes between the subventricular and intermediate zones of the cortical plate in the late first trimester, when telencephalic fibre tracts develop. The density of CB1 Rs gradually decreased during the second and third trimesters in the neocortex. In contrast, CB1 R density was maintained, or even increased, in the hippocampus. We found the onset of CB1 R expression being delayed by ≥1 month in age-matched foetal brains with Down's syndrome. In vitro, CB1 R excitation induced excess microtubule stabilisation and, consequently, reduced neurite outgrowth. CONCLUSIONS: We suggest that neuroarchitectural impairments in Down's syndrome brains involve the delayed development and errant functions of the endocannabinoid system, with a particular impact on endocannabinoids modulating axonal wiring.
Asunto(s)
Síndrome de Down , Animales , Humanos , Ratones , Encéfalo/metabolismo , Síndrome de Down/metabolismo , Endocannabinoides/metabolismo , Ratones Transgénicos , Receptor Cannabinoide CB1/metabolismo , Receptores de Cannabinoides/metabolismoRESUMEN
Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin-releasing hormone-releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal-regulated kinase 1 and tyrosine hydroxylase with the Ca2+-sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress-induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate-limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long-lasting cortical excitability following acute stress.
Asunto(s)
Neuronas Adrenérgicas/metabolismo , Factor Neurotrófico Ciliar/metabolismo , Hipotálamo/metabolismo , Locus Coeruleus/metabolismo , Estrés Fisiológico , Neuronas Adrenérgicas/patología , Animales , Factor Neurotrófico Ciliar/genética , Hipotálamo/patología , Locus Coeruleus/patología , Ratones , Ratones Noqueados , RatasRESUMEN
Psychostimulant use is an ever-increasing socioeconomic burden, including a dramatic rise during pregnancy. Nevertheless, brain-wide effects of psychostimulant exposure are incompletely understood. Here, we performed Fos-CreERT2-based activity mapping, correlated for pregnant mouse dams and their fetuses with amphetamine, nicotine, and caffeine applied acutely during midgestation. While light-sheet microscopy-assisted intact tissue imaging revealed drug- and age-specific neuronal activation, the indusium griseum (IG) appeared indiscriminately affected. By using GAD67gfp/+ mice we subdivided the IG into a dorsolateral domain populated by γ-aminobutyric acidergic interneurons and a ventromedial segment containing glutamatergic neurons, many showing drug-induced activation and sequentially expressing Pou3f3/Brn1 and secretagogin (Scgn) during differentiation. We then combined Patch-seq and circuit mapping to show that the ventromedial IG is a quasi-continuum of glutamatergic neurons (IG-Vglut1+) reminiscent of dentate granule cells in both rodents and humans, whose dendrites emanate perpendicularly toward while their axons course parallel with the superior longitudinal fissure. IG-Vglut1+ neurons receive VGLUT1+ and VGLUT2+ excitatory afferents that topologically segregate along their somatodendritic axis. In turn, their efferents terminate in the olfactory bulb, thus being integral to a multisynaptic circuit that could feed information antiparallel to the olfactory-cortical pathway. In IG-Vglut1+ neurons, prenatal psychostimulant exposure delayed the onset of Scgn expression. Genetic ablation of Scgn was then found to sensitize adult mice toward methamphetamine-induced epilepsy. Overall, our study identifies brain-wide targets of the most common psychostimulants, among which Scgn+/Vglut1+ neurons of the IG link limbic and olfactory circuits.
Asunto(s)
Mapeo Encefálico , Encéfalo/metabolismo , Regulación de la Expresión Génica , Lóbulo Límbico/metabolismo , Animales , Axones/metabolismo , Encéfalo/diagnóstico por imagen , Dendritas/metabolismo , Femenino , Glutamato Descarboxilasa/genética , Humanos , Interneuronas/metabolismo , Lóbulo Límbico/anatomía & histología , Lóbulo Límbico/efectos de los fármacos , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Bulbo Olfatorio/metabolismo , Factores del Dominio POU/genética , Factores del Dominio POU/metabolismo , Secretagoginas/genética , Secretagoginas/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/genética , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The rostral migratory stream (RMS) is viewed as a glia-enriched conduit of forward-migrating neuroblasts in which chemorepulsive signals control the pace of forward migration. Here we demonstrate the existence of a scaffold of neurons that receive synaptic inputs within the rat, mouse, and human fetal RMS equivalents. These neurons express secretagogin, a Ca2+-sensor protein, to execute an annexin V-dependent externalization of matrix metalloprotease-2 (MMP-2) for reconfiguring the extracellular matrix locally. Mouse genetics combined with pharmacological probing in vivo and in vitro demonstrate that MMP-2 externalization occurs on demand and that its loss slows neuroblast migration. Loss of function is particularly remarkable upon injury to the olfactory bulb. Cumulatively, we identify a signaling cascade that provokes structural remodeling of the RMS through recruitment of MMP-2 by a previously unrecognized neuronal constituent. Given the life-long presence of secretagogin-containing neurons in human, this mechanism might be exploited for therapeutic benefit in rescue strategies.
Asunto(s)
Calcio/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Neuroglía/metabolismo , Neuronas/metabolismo , Bulbo Olfatorio/metabolismo , Secretagoginas/genética , Animales , Anexina A5/genética , Anexina A5/metabolismo , Movimiento Celular , Feto , Regulación de la Expresión Génica , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Microtomía , Neuroglía/ultraestructura , Neuronas/ultraestructura , Bulbo Olfatorio/citología , Cultivo Primario de Células , Ratas , Ratas Wistar , Secretagoginas/metabolismo , Sinapsis/metabolismo , Sinapsis/ultraestructura , Técnicas de Cultivo de TejidosRESUMEN
The microtubule-associated protein tau, in its hyperphosphorylated form, is the major component of paired helical filaments and other aggregates in neurodegenerative disorders commonly referred to as "tauopathies". Recent evidence, however, indicates that mislocalization of hyperphosphorylated tau to subsynaptic sites leads to synaptic impairment and cognitive decline even long before formation of tau aggregates and neurodegeneration occur. A similar, but reversible hyperphosphorylation of tau occurs under physiologically controlled conditions during hibernation. Here, we study the hibernating Golden hamster (Syrian hamster, Mesocricetus auratus). A transient spine reduction was observed in the hippocampus, especially on apical dendrites of hippocampal CA3 pyramidal cells, but not on their basal dendrites. This distribution of structural synaptic regression was correlated to the distribution of phosphorylated tau, which was highly abundant in apical dendrites but hardly detectable in basal dendrites. Surprisingly, hippocampal memory assessed by a labyrinth maze was not affected by hibernation. The present study suggests a role for soluble hyperphosphorylated tau in the process of reversible synaptic regression, which does not lead to memory impairment during hibernation. We hypothesize that tau phosphorylation associated spine regression might mainly affect unstable/dynamic spines while sparing established/stable spines.
Asunto(s)
Espinas Dendríticas/metabolismo , Hibernación/fisiología , Hipocampo/citología , Memoria/fisiología , Neuronas/ultraestructura , Proteínas tau/metabolismo , Animales , Nivel de Alerta/fisiología , Cricetinae , Homólogo 4 de la Proteína Discs Large , Femenino , Hipocampo/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Aprendizaje por Laberinto , Proteínas de la Membrana/metabolismo , Mesocricetus/fisiología , Actividad Motora , Alineación de Secuencia , Sinapsis/fisiología , Factores de Tiempo , Letargo/fisiologíaRESUMEN
Despite the growing body of evidence pointing on the involvement of tissue non-specific alkaline phosphatase (TNAP) in brain function and diseases like epilepsy and Alzheimer's disease, our understanding about the role of TNAP in the regulation of neurotransmission is severely limited. The aim of our study was to integrate the fragmented knowledge into a comprehensive view regarding neuronal functions of TNAP using objective tools. As a model we used the signal transduction molecular network of a pyramidal neuron after complementing with TNAP related data and performed the analysis using graph theoretic tools. The analyses show that TNAP is in the crossroad of numerous pathways and therefore is one of the key players of the neuronal signal transduction network. Through many of its connections, most notably with molecules of the purinergic system, TNAP serves as a controller by funnelling signal flow towards a subset of molecules. TNAP also appears as the source of signal to be spread via interactions with molecules involved among others in neurodegeneration. Cluster analyses identified TNAP as part of the second messenger signalling cascade. However, TNAP also forms connections with other functional groups involved in neuronal signal transduction. The results indicate the distinct ways of involvement of TNAP in multiple neuronal functions and diseases.
Asunto(s)
Fosfatasa Alcalina/metabolismo , Redes Reguladoras de Genes , Neuronas/metabolismo , Mapas de Interacción de Proteínas , Transducción de Señal/fisiología , Fosfatasa Alcalina/fisiología , Animales , Análisis por Conglomerados , Bases de Datos de Compuestos Químicos , Redes Reguladoras de Genes/fisiología , Humanos , Neuronas/enzimología , Mapas de Interacción de Proteínas/fisiología , Transmisión Sináptica/genéticaRESUMEN
Several studies have shown that L-aspartate (Asp) is present in synaptic vesicles and released exocytotically from presynaptic terminals, possibly by Ca(2+)-dependent corelease of Asp and L-glutamate (Glu). It has been demonstrated that both excitatory amino acids (EAAs) are released from the rat striatum as part of corticostriatal neurotransmission. The single or colocalized occurrence of Asp and Glu in specific synaptic boutons of the chicken medial striatum/nucl. accumbens has been demonstrated by our group using ultrastructural immunocytochemistry. However, evidence for the presence of EAAs in any specific striatal pathway was only circumstantial. Here, we report on the distribution of Asp and Glu in specific synaptic terminals of the amygdalostriatal pathway, both in rat and chicken brains, combining anterograde tracing with postembedding immunogold labeling of Asp or Glu. Immunoreactivity for Asp and Glu was observed in amygdalofugal terminals with asymmetrical synaptic junctions (morphologically representing excitatory synapses) in both species. The postsynaptic targets were either dendritic spines or small dendrites, whereas axosomatic or axo-axonic connections were not observed. Ultrastructurally, the synaptic terminals immunoreactive for Asp were indistinguishable from those immunoreactive for Glu. The findigs are consistent with an Asp-Glu corelease mechanism, with a distinct synaptic contingent, evolutionarily conserved in the amygdalostriatal pathway.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Ácido Aspártico/metabolismo , Axones/metabolismo , Ácido Glutámico/metabolismo , Vías Nerviosas/fisiología , Núcleo Accumbens/metabolismo , Amígdala del Cerebelo/ultraestructura , Animales , Axones/ultraestructura , Pollos , Femenino , Inmunohistoquímica , Masculino , Microscopía Electrónica , Vías Nerviosas/ultraestructura , Núcleo Accumbens/ultraestructura , Ratas , Ratas Wistar , Sinapsis/metabolismoRESUMEN
Mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene can result in skeletal and dental hypomineralization and severe neurological symptoms. TNAP is expressed in the synaptic cleft and the node of Ranvier in normal adults. Using TNAP knockout (KO) mice (Akp2(-/-)), we studied synaptogenesis and myelination with light- and electron microscopy during the early postnatal days. Ablation of TNAP function resulted in a significant decrease of the white matter of the spinal cord accompanied by ultrastructural evidence of cellular degradation around the paranodal regions and a decreased ratio and diameter of the myelinated axons. In the cerebral cortex, myelinated axons, while present in wild-type, were absent in the Akp2( -/- ) mice and these animals also displayed a significantly increased proportion of immature cortical synapses. The results suggest that TNAP deficiency could contribute to neurological symptoms related to myelin abnormalities and synaptic dysfunction, among which epilepsy, consistently present in the Akp2(-/-) mice and observed in severe cases of hypophosphatasia.
Asunto(s)
Fosfatasa Alcalina/metabolismo , Corteza Cerebral/enzimología , Corteza Cerebral/crecimiento & desarrollo , Médula Espinal/enzimología , Médula Espinal/crecimiento & desarrollo , Sinapsis/enzimología , Fosfatasa Alcalina/análisis , Fosfatasa Alcalina/genética , Animales , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Técnicas de Inactivación de Genes , Ratones , Ratones Noqueados , Vaina de Mielina/metabolismo , Médula Espinal/citología , Médula Espinal/metabolismo , Sinapsis/metabolismoRESUMEN
Alzheimer's disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being "en passant", can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.
RESUMEN
Composition of the brain extracellular matrix changes in time as maturation proceeds. Chondroitin sulfate proteoglycan 5 (CSPG-5), also known as neuroglycan C, has been previously associated to differentiation since it shapes neurite growth and synapse forming. Here, we show that this proteoglycan persists in the postnatal rat brain, and its expression is higher in cortical regions with plastic properties, including hippocampus and the medial prefrontal cortex at the end of the second postnatal week. Progressively accumulating after birth, CSPG-5 typically concentrates around glutamatergic and GABAergic terminals in twelve-week old rat hippocampus. CSPG-5-containing perisynaptic matrix rings often appear at the peripheral margin of perineuronal nets. Electron microscopy and analysis of synaptosomal fraction showed that CSPG-5 accumulates around, and is associated to synapses, respectively. In vitro analyses suggest that neurons, but less so astrocytes, express CSPG-5 in rat primary neocortical cultures, and CSPG-5 produced by transfected neuroblastoma cells appear at endings and contact points of neurites. In human subjects, CSPG-5 expression shifts in brain areas of the default mode network of suicide victims, which may reflect an impact in the pathogenesis of psychiatric diseases or support diagnostic power.
Asunto(s)
Corteza Cerebelosa/metabolismo , Proteoglicanos Tipo Condroitín Sulfato/fisiología , Proteínas de la Membrana/fisiología , Neuritas/metabolismo , Proteoglicanos/fisiología , Sinapsis/metabolismo , Animales , Línea Celular , Humanos , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND AND PURPOSE: N,N-dimethyltryptamine (DMT) is an endogenous ligand of the Sigma 1 receptor (Sig-1R) with documented in vitro cytoprotective properties against hypoxia. Our aim was to demonstrate the in vivo neuroprotective effect of DMT following ischemia-reperfusion injury in the rat brain. METHODS: Transient middle cerebral occlusion (MCAO) was induced for 60 min in male Wistar rats using the filament occlusion model under general anaesthesia. Before the removal of the filament the treatment group (n = 10) received an intra-peritoneal (IP) bolus of 1 mg/kg-body weight (bw) DMT dissolved in 1 ml 7% ethanol/saline vehicle, followed by a maintenance dose of 2 mg/Kg-bw/h delivered over 24 h via osmotic minipumps. Controls (n = 10) received a vehicle bolus only. A third group (n = 10) received a Sig-1R antagonist (BD1063, 1 mg/kg-bw bolus +2 mg/kg-bw/h maintenance) in parallel with the DMT. Lesion volume was measured by MRI 24 h following the MCAO. Shortly after imaging the animals were terminated, and the native brains and sera were removed. Four rats were perfusion fixed. Functional recovery was studied in two separate group of pre-trained animals (n = 8-8) using the staircase method for 30 days. The expression levels of proteins involved in apoptosis, neuroplasticity and inflammatory regulation were assessed by real-time qPCR and ELISA. RESULTS: DMT treated rats were characterized by lower ischemic lesion volume (p = .0373), and better functional recovery (p = .0084) compared to the controls. Sig-1R was expressed both in neurons and in microglia in the peri-infarct cortex, and the DMT induced change in the lesion volume was hindered by BD1063. Lower APAF1 expression (mRNA and protein) and higher BNDF levels were documented on DTM, while decreased TNF-α, IL1-ß, IL-6 and increased IL-10 expressions indicated the compound's anti-inflammatory potential. CONCLUSION: Our results indicate a Sig-1R dependent reduction of the ischemic brain injury following exogenous DMT administration in rats, presumably through a combined anti-apoptotic, pro-neurotrophic and anti-inflammatory treatment effect.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , N,N-Dimetiltriptamina/farmacología , Fármacos Neuroprotectores/farmacología , Recuperación de la Función/efectos de los fármacos , Animales , Encéfalo/patología , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Masculino , N,N-Dimetiltriptamina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Piperazinas/farmacología , Ratas , Ratas Wistar , Resultado del TratamientoRESUMEN
Calcium-binding proteins are widely used to distinguish neuronal subsets in the brain. This study focuses on secretagogin, an EF-hand calcium sensor, to identify distinct neuronal populations in the brainstem of several vertebrate species. By using neural tube whole mounts of mouse embryos, we show that secretagogin is already expressed during the early ontogeny of brainstem noradrenaline cells. In adults, secretagogin-expressing neurons typically populate relay centres of special senses and vegetative regulatory centres of the medulla oblongata, pons and midbrain. Notably, secretagogin expression overlapped with the brainstem column of noradrenergic cell bodies, including the locus coeruleus (A6) and the A1, A5 and A7 fields. Secretagogin expression in avian, mouse, rat and human samples showed quasi-equivalent patterns, suggesting conservation throughout vertebrate phylogeny. We found reduced secretagogin expression in locus coeruleus from subjects with Alzheimer's disease, and this reduction paralleled the loss of tyrosine hydroxylase, the enzyme rate limiting noradrenaline synthesis. Residual secretagogin immunoreactivity was confined to small submembrane domains associated with initial aberrant tau phosphorylation. In conclusion, we provide evidence that secretagogin is a useful marker to distinguish neuronal subsets in the brainstem, conserved throughout several species, and its altered expression may reflect cellular dysfunction of locus coeruleus neurons in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Tronco Encefálico/metabolismo , Norepinefrina/metabolismo , Secretagoginas/metabolismo , Animales , Masculino , Mesencéfalo/metabolismo , Neuronas/metabolismo , Ratas Wistar , Tirosina 3-Monooxigenasa/metabolismo , Vertebrados/metabolismoRESUMEN
Retrograde tracing with choleratoxin B, injected into the nucleus accumbens (Ac) and bed nucleus of stria terminalis, lateral part (BSTL), yielded labeled perikarya in a ring-shaped area of arcopallium, including dorsal and hilar subdivisions, with a wedge-shaped node of dense accumulation in the amygdalopiriform area (APir). Also, the position of source neurons for this arcopallio-subpallial pathway was verified by anterograde tracing. Three subregions of arcopallium (amygdalopiriform, dorsal, hilar) were injected with dextran (10 kDa), and fibers and terminal fields were detected in Ac, BSTL and extended amygdala (EA). Most abundant projections to Ac arose from APir. The study enabled precise description of the main output fiber streams: the dorsal stream follows the dorsal border of arcopallium and, continuing in the ventral amygdalofugal tract, it traverses the EA and the BSTL before reaching the Ac. The ventral stream of fibers enters the EA along the ventral subpallial border and terminates in the basal nucleus and ventral pallidum. The course of the pathway was reconstructed in 3D. Retrogradely labeled arcopallial neurons were devoid of DARPP-32. DARPP-32 was present in the Ac but not the BSTL. No colocalization between the calcium binding proteins calbindin, parvalbumin and calretinin, and retrogradely labeled neurons was detected, despite a considerable territorial overlap. This finding further supports the excitatory nature of the arcopallial-accumbens pathway. Conjoint and convergent amygdalar input to EA, including BSTL, as well as to Ac subregions likely transmits fear and aggression related signals to both viscerolimbic (EA) and learned reward- and motivation-related (Ac) ventrobasal forebrain regions.
Asunto(s)
Amígdala del Cerebelo/citología , Núcleo Accumbens/citología , Amígdala del Cerebelo/metabolismo , Animales , Proteínas Aviares/metabolismo , Prosencéfalo Basal/citología , Prosencéfalo Basal/metabolismo , Calbindina 2/metabolismo , Calbindinas/metabolismo , Pollos , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Imagenología Tridimensional , Vías Nerviosas/citología , Vías Nerviosas/metabolismo , Técnicas de Trazados de Vías Neuroanatómicas , Núcleo Accumbens/metabolismo , Parvalbúminas/metabolismo , Prosencéfalo/citología , Prosencéfalo/metabolismo , Núcleos Septales/citología , Núcleos Septales/metabolismoRESUMEN
Adaptation to motherhood includes maternal behaviour and lactation during the postpartum period. The major organizing centres of maternal behaviour and lactation are located in the hypothalamic medial preoptic area (MPOA) and the arcuate nucleus, respectively. Insulin-like growth factor I (IGF-I) is an effector of the growth hormone axis; however, its function in the brain is largely unexplored. We identified increased maternal IGF binding protein-3 (IGFBP-3) expression in preoptic rat microarray data and confirmed it by RT-PCR. In situ hybridization histochemistry showed markedly elevated IGFBP-3 expression in the MPOA and the arcuate nucleus in rat dams. Prolonged intracerebroventricular injection of IGF-I or antagonism of brain IGFBP-3 with an inhibitor (NBI-31772) using osmotic minipumps increased pup retrieval time, suggesting reduced maternal motivation. Suckling-induced prolactin release and pup weight gain were also suppressed by IGF-I, suggesting reduced lactation. In addition, IGF-I-induced tyrosine hydroxylase expression and its specific phosphorylation in tuberoinfundibular dopaminergic neurons suppress prolactin secretion. Thus, IGF-I may inhibit both behavioural and lactational alterations in mothers. Neurons in the MPOA and arcuate nuclei express IGFBP-3 during the postpartum period to neutralize IGF-I effects. IGFBP-3 can prevent the blockade of maternal behaviour and lactation exerted by IGF-I, suggesting a novel modulatory mechanism underlying the behavioural and hormonal effects during central maternal adaptations.
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Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lactancia , Conducta Materna/fisiología , Animales , Animales Recién Nacidos , Femenino , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Ratas , Ratas WistarRESUMEN
Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.