Browsing by Author "Fuenzalida, Marco"

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    Corticotropin-releasing factor system in the lateral septum: Implications in the pathophysiology of obesity
    (2022-09-20) Olivares-Barraza, Rossy; Marcos, José Luis; Martínez-Pinto, Jonathan; Fuenzalida, Marco; Bravo, Javier A.; Gysling, Katia; Sotomayor-Zárate, Ramón
    Obesity is a pandemic associated with lifestyles changes. These include excess intake of obesogenic foods and decreased physical activity. Brain areas, like the lateral hypothalamus (LH), ventral tegmental area (VTA), and nucleus accumbens (NAcc) have been linked in both homeostatic and hedonic control of feeding in experimental models of diet-induced obesity. Interestingly, these control systems are regulated by the lateral septum (LS), a relay of γ-aminobutyric (GABA) acid neurons (GABAergic neurons) that inhibit the LH and GABAergic interneurons of the VTA. Furthermore, the LS has a diverse receptor population for neurotransmitters and neuropeptides such as dopamine, glutamate, GABA and corticotropin-releasing factor (CRF), among others. Particularly, CRF a key player in the stress response, has been related to the development of overweight and obesity. Moreover, evidence shows that LS neurons neurophysiologically regulate reward and stress, although there is little evidence of LS taking part in homeostatic and hedonic feeding. In this review, we discuss the evidence that supports the role of LS and CRF on feeding, and how alterations in this system contribute to weight gain obesity.
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    Corticotropin-releasing factor system in the lateral septum: Implications in the pathophysiology of obesity
    (2022-09-20) Olivares-Barraza, Rossy; Marcos, José Luis; Martínez-Pinto, Jonathan; Fuenzalida, Marco; Bravo, Javier A.; Gysling, Katia; Sotomayor-Zárate, Ramón
    Obesity is a pandemic associated with lifestyles changes. These include excess intake of obesogenic foods and decreased physical activity. Brain areas, like the lateral hypothalamus (LH), ventral tegmental area (VTA), and nucleus accumbens (NAcc) have been linked in both homeostatic and hedonic control of feeding in experimental models of diet-induced obesity. Interestingly, these control systems are regulated by the lateral septum (LS), a relay of γ-aminobutyric (GABA) acid neurons (GABAergic neurons) that inhibit the LH and GABAergic interneurons of the VTA. Furthermore, the LS has a diverse receptor population for neurotransmitters and neuropeptides such as dopamine, glutamate, GABA and corticotropin-releasing factor (CRF), among others. Particularly, CRF a key player in the stress response, has been related to the development of overweight and obesity. Moreover, evidence shows that LS neurons neurophysiologically regulate reward and stress, although there is little evidence of LS taking part in homeostatic and hedonic feeding. In this review, we discuss the evidence that supports the role of LS and CRF on feeding, and how alterations in this system contribute to weight gain obesity.
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    Enhanced Astrocyte Activity and Excitatory Synaptic Function in the Hippocampus of Pentylenetetrazole Kindling Model of Epilepsy
    (2023-09-25) Díaz, Franco; Aguilar, Freddy; Wellmann, Mario; Martorell, Andrés; González-Arancibia, Camila; Chacana-Véliz, Lorena; Negrón-Oyarzo, Ignacio; Chávez, Andrés E.; Fuenzalida, Marco; Nualart, Francisco; Sotomayor-Zárate, Ramón; Bonansco, Christian
    Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca2+ activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca2+-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte–neuron interactions are pivotal mechanisms in epileptogenesis.
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    Ketamine-Treatment During Late Adolescence Impairs Inhibitory Synaptic Transmission in the Prefrontal Cortex and Working Memory in Adult Rats
    (2019-08) Pérez, Miguel Ángel; Morales, Camila; Santander, Odra; García, Francisca; Gómez, Isabel; Peñaloza-Sancho, Valentín; Fuentealba, Pablo; Dagnino-Subiabre, Alexies; Moya, Pablo R.; Fuenzalida, Marco
    Schizophrenia (SZ) is associated with changes in the structure and function of several brain areas. Several findings suggest that these impairments are related to a dysfunction in g-aminobutyric acid (GABA) neurotransmission in brain areas such as the medial prefrontal cortex (mPFC), the hippocampus (HPC) and the primary auditory cortex (A1); however, it is still unclear how the GABAergic system is disrupted in these brain areas. Here, we examined the effect of ketamine (Ket) administration during late adolescence in rats on inhibition in the mPFC-, ventral HPC (vHPC), and A1. We observe that Ket treatment reduced the expression of the calcium-binding protein parvalbumin (PV) and the GABA-producing enzyme glutamic acid decarboxylase 67 (GAD67) as well as decreased inhibitory synaptic efficacy in the mPFC. In addition, Kettreated rats performed worse in executive tasks that depend on the integrity and proper functioning of the mPFC. Conversely, we do not find such changes in vHPC or A1. Together, our results provide strong experimental support for the hypothesis that during adolescence, the function of the mPFC is more susceptible than that of HPC or A1 to NMDAR hypofunction, showing apparent structure specificity. Thus, the impairment of inhibitory circuitry in mPFC could be a convergent primary site of SZ-like behavior during the adulthood.
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    The Long-Term Pannexin 1 Ablation Produces Structural and Functional Modifications in Hippocampal Neurons
    (2022-11-17) Flores-Muñoz, Carolina; García-Rojas, Francisca; Pérez, Miguel A.; Santander, Odra; Mery, Elena; Ordenes, Stefany; Illanes-González, Javiera; López-Espíndola, Daniela; González-Jamett, Arlek M.; Fuenzalida, Marco; Martínez, Agustín D.; Ardiles, Álvaro O.
    Enhanced activity and overexpression of Pannexin 1 (Panx1) channels contribute to neuronal pathologies such as epilepsy and Alzheimer’s disease (AD). The Panx1 channel ablation alters the hippocampus’s glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, Panx1-knockout (Panx1-KO) mice still retain the ability to learn, suggesting that compensatory mechanisms stabilize their neuronal activity. Here, we show that the absence of Panx1 in the adult brain promotes a series of structural and functional modifications in the Panx1-KO hippocampal synapses, preserving spontaneous activity. Compared to the wild-type (WT) condition, the adult hippocampal neurons of Panx1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and an increased proportion of multiple synaptic contacts. These modifications seem to rely on the actin–cytoskeleton dynamics as an increase in the actin polymerization and an imbalance between the Rac1 and the RhoA GTPase activities were observed in Panx1-KO brain tissues. Our findings highlight a novel interaction between Panx1 channels, actin, and Rho GTPases, which appear to be relevant for synapse stability.
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    The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability
    (2019) Pérez, Viviana; Bermedo-Garcia, Francisca; Zelada, Diego; Court, Felipe A.; Pérez, Miguel Ángel; Fuenzalida, Marco; Ábrigo, Johanna; Cabello-Verrugio, Claudio; Moya-Alvarado, Guillermo; Tapia, Juan Carlos; Valenzuela, Vicente; Hetz, Claudio; Bronfman, Francisca C.; Henríquez, Juan Pablo
    The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.