Biology subjects

Ribeiro, J. A.

Publications and source records attributed to Ribeiro, J. A..

6 recordsLinked to original sources

bioRxiv2024

Postweaning development influences endogenous VPAC1 modulation of LTP induced by theta-burst stimulation: a link to maturation of the hippocampal GABAergic system?

Long-term potentiation (LTP) induced by theta-burst stimulation (TBS) undergoes postweaning developmental changes partially linked to GABAergic circuit maturation. Endogenous VIP acting on VPAC1 receptors strongly influences LTP induced by theta-burst stimulation (TBS), an effect dependent on GABAergic transmission. Although VPAC1 receptor levels are developmentally regulated during embryogenesis, its variation along postweaning development is unknow, as is VPAC1 modulation of LTP or its relation to hippocampal GABAergic circuit maturation. As such, we investigated how VPAC1 modulation of LTP adjusts from weaning to adulthood along with GABAergic circuit maturation. As described, LTP induced by TBS (5x4) (5 bursts, 4 pulses delivered at 100Hz) was increasingly greater from weaning to adulthood. The influence of the VPAC1 receptor antagonist PG 97-269 (100nM) on TBS-induced LTP was much larger in juvenile (3-week-old) than in young-adult (6-7-week-old) or adult (12-week-old) rats. This effect was not associated to a developmental decrease in synaptic VPAC1 receptor levels. However, an increase in pre and post synaptic GABAergic synaptic markers, suggests an increase in the number of GABAergic synaptic contacts that is more prominent than the one observed in glutamatergic connections during this period. Conversely, endogenous VPAC2 receptor activation did not significantly influence of TBS-induced LTP. VPAC2 receptor levels enhance pronouncedly during postweaning development, but not at synaptic sites. Given the involvement of VIP interneurons in several aspects of hippocampal-dependent learning, neurodevelopmental disorders, and epilepsy, this could provide important insights into the role of VIP modulation of hippocampal synaptic plasticity during normal and altered brain development potentially contributing to epileptogenesis.

neuroscience↗

bioRxiv2024

Obesity differentially effects the somatosensory cortex and striatum of TgF344-AD rats

1Lifestyle choices leading to obesity, hypertension and diabetes in mid-life contribute directly to the risk of late-life Alzheimers disease (AD). However, in late-life or in late-stage AD conditions, obesity reduces the risk of AD and disease progression. To examine the mechanisms underlying this paradox, TgF344-AD rats were fed a varied high-carbohydrate, high-fat (HCHF) diet to induce obesity from nine months of age representing early stages of AD to twelve months of age in which rats exhibit the full spectrum of AD symptomology. We hypothesized regions primarily composed of gray matter, such as the somatosensory cortex (SSC), would be differentially affected compared to regions primarily composed of white matter, such as the striatum. We found increased myelin and oligodendrocytes in the somatosensory cortex of rats fed the HCHF diet with an absence of neuronal loss. We observed decreased inflammation in the somatosensory cortex despite increased AD pathology. Compared to the somatosensory cortex, the striatum had fewer changes. Overall, our results suggest that the interaction between diet and AD progression affects myelination in a brain region specific manner such that regions with a lower density of white matter are preferentially effected. Our results offer a possible mechanistic explanation for the obesity paradox.

neuroscience↗

bioRxiv2024

Obesity Facilitates Sex-Specific Improvement In Cognition And Neuronal Function In A Rat Model Of Alzheimer's Disease

Obesity reduces or increases the risk of developing Alzheimers disease (AD) depending on whether it is assessed in mid-life or late-life. There is currently no consensus on the relationship between obesity and AD or the mechanism or their interaction. Here, we aim to differentiate the cause-and-effect relationship between obesity and AD in a controlled rat model of AD. We induced obesity in 9-month-old TgF344-AD rats, that is pathology-load wise similar to early symptomatic phase of human AD. To more accurately model human obesity, we fed both TgF344-AD and non-transgenic littermates a varied high-carbohydrate-high-fat diet consisting of human food for 3 months. Obesity increased overall glucose metabolism and slowed cognitive decline in TgF344-AD rats, specifically executive function, without affecting non-transgenic rats. Pathological analyses of prefrontal cortex and hippocampus showed that obesity in TgF344-AD rats produced varied effects, with increased density of myelin and oligodendrocytes, lowered density and activation of microglia that we propose contributes to the cognitive improvement. However, obesity also decreased neuronal density, and promoted deposition of amyloid-beta plaques and tau inclusions. After 6 months on the high-carbohydrate-high-fat diet, detrimental effects on density of neurons, amyloid-beta plaques, and tau inclusions persisted while the beneficial effects on myelin, microglia, and cognitive functions remained albeit with a lower effect size. By examining the effect of sex, we found that both beneficial and detrimental effects of obesity were stronger in female TgF344-AD rats indicating that obesity during early symptomatic phase of AD is protective in females.

neuroscience↗

bioRxiv2022

Mismatch novelty exploration training impairs VPAC1 receptor mediated modulation of hippocampal synaptic plasticity by endogenous VIP

Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity. Inhibition of VIP interneurons by prefrontal cortex GABAergic projections promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97-269 (100nM) enhanced both LTP and depotentiation in naive animals but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated to maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs. Significance statementThis work sheds light into the contribution of hippocampal neuropeptide VIP and VIP containing GABAergic neurons on the reformulation of hippocampal circuit communication leading to altered synaptic plasticity responses upon training in repeated exposure to object mismatch novelty as compared with routine training paradigms with and without objects. Although still far from the clinic, the results suggest that VIP receptor ligands may be useful to co-adjuvate cognitive stimuli therapies based on these aspects of novelty, aiming at the cognitive rescue of aged individuals or epilepsy patients, that show impaired capacity in novelty induced adaptations of cognitive function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/521348v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@191228forg.highwire.dtl.DTLVardef@173f3b5org.highwire.dtl.DTLVardef@1850869org.highwire.dtl.DTLVardef@eb5991_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Cellular and molecular mechanisms involved in LTP induced by mild theta-burst stimulation in hippocampal slices from young male rats: from weaning to adulthood.

Long-term potentiation (LTP) is a highly studied cellular process yet determining the transduction and GABAergic pathways that are the essential vs. modulatory for LTP elicited by theta-burst stimulation (TBS) in the hippocampal CA1 area is still elusive, due to the use of different TBS intensities, patterns, or different rodent/cellular models. We now characterized the developmental maturation and the transduction and GABAergic pathways required for mild TBS-induced LTP in hippocampal CA1 area in male rats. LTP induced by TBS (5x4) (5 bursts of 4 pulses delivered at 100Hz) lasted for up to 3h and was increasingly larger from weaning to adulthood. Stronger TBS patterns - TBS (15x4) or three TBS (15x4) separated by 6 min induced nearly maximal LTP not being the best choice to study the value of LTP-enhancing drugs. LTP induced by TBS (5x4) in young adults was fully dependent on NMDA receptor and CaMKII activity but independent of PKA or PKC activity. Furthermore, it was partially dependent on GABAB receptor activation and was potentiated by GABAA receptor blockade and less by GAT-1 transporter blockade. AMPA GluA1 phosphorylation on Ser831 (CaMKII target) but not GluA1 Ser845 (PKA target) was essential for LTP expression. The phosphorylation of the Kv4.2 channel was observed at Ser438 (CaMKII target) but not at Thr602 or Thr607 (ERK/MAPK pathway target). This suggests that cellular kinases like PKA, PKC or kinases of the ERK/MAPK family although important modulators of TBS (5x4)-induced LTP may not be essential for its expression in the CA1 area of the hippocampus. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/440440v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@cf78caorg.highwire.dtl.DTLVardef@1031737org.highwire.dtl.DTLVardef@1e91d6corg.highwire.dtl.DTLVardef@18abe3b_HPS_FORMAT_FIGEXP M_FIG C_FIG LTP induced by theta-burst stimulation (TBS) in young adult male rat hippocampal CA1 area is increasingly more robust with the number of bursts and number of spaced TBS trains. LTP induced by TBS shows developmental maturation increasing potentiation from weaning to adulthood. Expression of LTP induced by mild TBS (5x4) in young adults requires NMDA receptor and CaMKII activity and AMPA Ser831 phosphorylation, but not PKA or PKC activity, and is likely curtailed by Kv4.2 Ser438 phosphorylation.

neuroscience↗

bioRxiv2020

Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis

Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, none have been developed to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that differs from other DHFR antifolates, thus opening perspectives for the development of novel and relevant MtDHFR inhibitors.

biochemistry↗