Neuroscience
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Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for the human disease multiple sclerosis (MS), a demyelinating and neurodegenerative pathology of the central nervous system. Both diseases share physiopathological and clinical characteristics, mainly associated with a neuroinflammatory process that leads to a set of motor, sensory, and cognitive symptoms. In MS, gray matter atrophy is related to the emergence of cognitive deficits and contributes to clinical progression. ⋯ In the present work we show the presence of region-specific microglia and astrocyte activation in the FrCx, during the first hours of acute EAE onset. It is accompanied by the production of the pro-inflammatory cytokines IL-6 and TNF-α, in the absence of detectable leukocyte infiltration. These findings expand previous studies showing presynaptic neural dysfunction occurring at the FrCx and might contribute to the understanding of the mechanisms involved in the genesis and prevalence of common MS symptoms.
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Spike and wave discharges (SWDs), generated within cortico-thalamo-cortical networks, are the electroencephalographic biomarker of absence epilepsy. The current work aims to identify mechanisms of SWD initiation, maintenance and termination by the analyses of dynamics and directionality of mutual interactions between the neocortex and various functionally different thalamic nuclei. ⋯ The initiation of SWD is due to a gradual increase in intracortical coupling, followed by a selective increase in first unidirectional and later bidirectional coupling between the cortex and thalamus and also intrathalamically. Once the network is oscillating, coupling decreases in most of the channel pairs, although the cortex keeps its influence on the cRTN. The SWD is dampened by a gradual increase in coupling strength and in the number of channel pairs that influence each other; the latter might represent an endogenous brake of SWDs.
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Increased innervation of forebrain targets by midbrain dopaminergic neurons in the absence of FGF-2.
Fibroblast growth factors (FGFs) regulate development and maintenance, and reduce vulnerability of neurons. FGF-2 is essential for survival of midbrain dopaminergic (DA) neurons and is responsible for their dysplasia and disease-related degeneration. We previously reported that FGF-2 is involved in adequate forebrain (FB) target innervation by these neurons in an organotypic co-culture model. ⋯ Here, we demonstrate that lack of FGF-2 results in an increased volume of the striatal target area in mice. We further add evidence that the low molecular weight (LMW) FGF-2 isoform is responsible for this phenotype, as this isoform is predominantly expressed in the embryonic ventral midbrain (VM) as well as in postnatal striatum (STR) and known to act via canonical transmembrane FGF receptor (FGFR) activation. Additionally, we confirm that the phenotype with an enlarged FB-target area by DA neurons can be mimicked in an ex-vivo explant model by inhibiting the canonical FGFR signaling, which resulted in decreased extracellular signal-regulated kinase (ERK) activation, while AKT activation remained unchanged.
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Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT1Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT1R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1μg/h) plus saline as drinking fluid, and gene expression was assessed by real-time qPCR. ⋯ SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT1R in the PVN similarly attenuated aldosterone-induced saline intake by ∼50% and hypertension by ∼70%. These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT1R signaling in the PVN. This central aldosterone-MR-AT1R neuro-modulatory pathway appears to play a major role in the progressive hypertension.
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Temporal lobe epilepsy in human and animals is attributed to alterations in brain function especially hippocampus formation. Changes in synaptic activity might be causally related to the alterations during epileptogenesis. Transient receptor potential vanilloid 1 (TRPV1) as one of the non-selective ion channels has been shown to be involved in synaptic transmission. ⋯ SE induced an upregulation of TRPV1 mRNA and protein content in the whole hippocampal extract, as well as its distribution in both CA1 and CA3 regions. Activation and inhibition of TRPV1 receptors (via capsaicin 1μM and capsazepine 10μM, respectively) did not influence basal synaptic transmission in CA1 and CA3 regions of control slices, however, capsaicin increased and capsazepine decreased synaptic transmission in both regions in tissues from epileptic animals. Taken together, these findings suggest that a higher expression of TRPV1 in the epileptic condition is accompanied by alterations in basal synaptic transmission.