Neuroscience
-
The bacterial exoenzyme C3 transferase (C3) irreversibly inhibits RhoA GTPase leading to stimulation of axonal outgrowth in injured neurons. C3 has been used successfully in models of neurotrauma and shows promise as an option to support cell survival and axonal growth of dopaminergic (DA) neurons in Parkinson's disease (PD) cell therapy. Whether the continuous expression of C3 in DA neurons is well-tolerated is unknown. ⋯ To evaluate the impact of C3 expression on striatal terminals of the nigrostriatal pathway, we compared the rotational behavior of wildtype mice injected unilaterally with either C3 or 6-hydroxydopamine (6-OHDA). Mice injected with C3 exhibited similar ipsiversive rotations to the site of injection in comparison to control mice injected with EYFP and significantly fewer ipsiversive rotations compared to 6-OHDA lesioned mice. Non-significant difference between C3 and EYFP controls in behavioral and histological analyses demonstrate that transduced DA neurons express C3 continuously without apparent adverse effects, supporting the use of C3 in efficacy studies targeting DA neurons.
-
During prolonged dehydration, body fluid homeostasis is challenged by extracellular fluid (ECF) hyperosmolality, which induce important functional changes in the hypothalamus, in parallel with other effector responses, such as the activation of the local renin-angiotensin system (RAS). Therefore, in the present study we investigated the role of sodium-driven ECF hyperosmolality on glial fibrillary acid protein (GFAP) immunoreactivity and protein expression, membrane capacitance, mRNA expression of RAS components and glutamate balance in cultured hypothalamic astrocytes. Our data show that hypothalamic astrocytes respond to increased hyperosmolality with a similar decrease in GFAP expression and membrane capacitance, indicative of reduced cellular area. ⋯ Incubation with hypertonic solution also decreases the immunoreactivity to the membrane glutamate/aspartate transporter (GLAST) as well as tritiated-aspartate uptake by astrocytes. This latter effect is completely restored to basal levels when astrocytes previously exposed to hypertonicity are incubated under isotonic conditions. Together with a direct effect on two important local signaling systems (glutamate and RAS), these synaptic rearrangements driven by astrocytes may accomplish for a coordinated increase in the excitatory drive onto the hypothalamic neurosecretory system, ultimately culminating with increased AVP release in response to hyperosmolality.
-
The present study examined if repeated bouts of micro- and hypergravity during parabolic flight (PF) alter structural integrity of the neurovascular unit (NVU) subsequent to free radical-mediated changes in regional cerebral perfusion. Six participants (5♂, 1♀) aged 29 ± 11 years were examined before, during and after a 3 h PF and compared to six sex and age-matched (27 ± 6 years) normogravity controls. Blood flow was measured in the anterior (middle cerebral artery, MCA; internal carotid artery, ICA) and posterior (vertebral artery, VA) circulation (duplex ultrasound) in-flight over the course of 15 parabolas. ⋯ Increased oxidative-nitrosative stress defined by a free radical-mediated reduction in NO and elevations in glio-vascular GFAP and S100ß were observed after PF (P < 0.05), the latter proportional to the increase in VA flow (r = 0.908, P < 0.05). In contrast, biomarkers of neuronal-axonal damage (neuron-specific enolase, neurofilament light-chain, ubiquitin carboxy-terminal hydrolase L1 and tau) did not change (P > 0.05). Collectively, these findings suggest that the cumulative effects of repeated gravitational transitions may promote minor blood-brain barrier disruption, potentially related to the combined effects of haemodynamic (posterior cerebral hyperperfusion) and molecular (systemic oxidative-nitrosative) stress.
-
The allocation of attention to specific target stimuli is key to pursue a task successfully and attain a goal in an environment that is full of distractions and competing stimuli. Area 8A in the caudal dorsolateral prefrontal cortex is considered a central area for the top-down control of attention and lesion studies in both human and non-human primates have demonstrated that this area is critical for the successful selection of targets according to internal rules. ⋯ Both parts of area 8A share connections with the parietal multimodal higher order spatial processing region. The present functional neuroimaging study demonstrates that (a) frontal area 8A is critical for the rule-based attentional selection between alternative stimuli that face the individual and (b) that there is a functional dissociation between dorsal area 8A involved in the attentional selection of auditory stimuli and ventral area 8A in the selection of visual stimuli.
-
The neural network undergoes remodeling in response to neural activity and interventions, such as antidepressants. Cell adhesion molecules that link pre- and post-synaptic membranes are responsible not only for the establishment of the neural circuitry, but also for the modulation of the strength of each synaptic connection. Among the various classes of synaptic cell adhesion molecules, a non-clustered protocadherin, Arcadlin/Paraxial protocadherin/Protocadherin-8 (Acad), is unique in that it is induced quickly in response to neural activity. ⋯ This treatment reduced spine density in the dentate gyrus and CA1. Chronic fluoxetine treatment did not suppress spine density in Acad-/- mice, suggesting that fluoxetine-induced decrease in spine density is largely due to Arcadlin. The present findings confirm the spine-repulsing activity of Arcadlin and its involvement in the remodeling of hippocampal neurons in response to antidepressants.