Hugo Leite-Almeida

The impact of age on emotional and cognitive behaviours triggered by experimental neuropathy in rats

ABSTRACT Chronic pain syndromes encompass several clinical entities that frequently affect the individuals’ emotional and cognitive behaviours which, in turn, can also alter pain perception. Additionally, both pain perception and motivational‐affective behaviours change with increasing age. In order to evaluate the influence of age upon the interaction between chronic pain and affective/cognitive behaviours, 3‐, 10‐ and 22‐month‐old rats with 1 month neuropathy (spared nerve injury, SNI model) were compared with age‐matched sham‐operated controls in the open field (OF; locomotor and exploratory behaviours), elevated plus‐maze (EPM; anxiety‐like behaviour), forced swimming (FST; depressive‐like behaviour), working memory water maze (WM; spatial short‐term memory), Morris water maze (MWM; spatial reference memory) and spatial reversal (behavioural flexibility) tests. Locomotor and exploratory activities decreased steadily with age and were further reduced by SNI. Aging was associated with increased anxiety‐like behaviour, which was potentiated by SNI in both 3‐ and 22‐month‐old rats. The performance in the FST was affected by SNI but only in mid‐aged animals. Cognitive performances in the MWM and spatial reversal tests deteriorated with age; however, the SNI lesion was only detrimental in the reversal task to mid‐aged animals. Our data demonstrate that the influence of neuropathic pain on affective and cognitive behaviours is age dependent and varies with the behavioural domain that is tested. Importantly, mid‐aged animals seem to be more susceptible to depression and cognitive deterioration associated to chronic pain than young and old groups.

Striatal dopamine D2 receptors attenuate neuropathic hypersensitivity in the rat

Earlier studies indicate that striatal dopamine D(2) receptors are involved in pain regulation in non-neuropathic conditions. We assessed whether striatal dopamine D(2) receptors contribute to pain regulation also in neuropathic conditions. The spared nerve injury model of neuropathy was induced by unilateral ligation of the tibial and common peroneal nerves in the rat. In awake nerve-injured animals, pain-related withdrawal responses to calibrated monofilaments or noxious heating were attenuated following striatal administration of a dopamine D(2) receptor agonist quinpirole. Pain-related responses were attenuated only in the nerve-injured limb ipsilateral to the injection and in the midline (tail). In unoperated controls, striatal administration of quinpirole at an antihypersensitive dose did not influence withdrawal responses to mechanical stimulation. Attenuation of pain-related responses induced by striatal administration of quinpirole was reversed by intrathecal administration of a dopamine D(2) receptor antagonist (eticlopride) or a non-selective 5-HT receptor antagonist (methysergide), but not by an alpha(2)-adrenoceptor antagonist (atipamezole). In the rostroventromedial medulla of lightly anesthetized neuropathic animals, striatal administration of quinpirole significantly decreased the activity of presumably pronociceptive cells that are activated by noxious stimulation. The innocuous H-reflex in lightly anesthetized control animals was not suppressed by striatal administration of quinpirole at an antihypersensitive dose. The results indicate that striatal dopamine D(2) receptors attenuate neuropathic hypersensitivity. The antihypersensitive effect induced by striatal dopamine D(2) receptors in peripheral neuropathy involves suppression of impulse discharge of presumably pronociceptive neurons in the rostroventromedial medulla, and a descending influence acting on spinal 5-HT and dopamine D(2) receptors.

BRAIN PROJECTIONS FROM THE MEDULLARY DORSAL RETICULAR NUCLEUS: AN ANTEROGRADE AND RETROGRADE TRACING STUDY IN THE RAT

In the last 15 years a role has been ascribed for the medullary dorsal reticular nucleus as a supraspinal pain modulating area. The medullary dorsal reticular nucleus is reciprocally connected with the spinal dorsal horn, is populated mainly by nociceptive neurons and regulates spinal nociceptive processing. Here we analyze the distribution of brain projections from the medullary dorsal reticular nucleus using the iontophoretic administration of the anterograde tracer biotinylated-dextran amine and the retrograde tracer cholera toxin subunit B. Fibers and terminal boutons labeled from the medullary dorsal reticular nucleus were located predominately in the brainstem, although extending also to the forebrain. In the medulla oblongata, anterograde labeling was observed in the orofacial motor nuclei, inferior olive, caudal ventrolateral medulla, rostral ventromedial medulla, nucleus tractus solitarius and most of the reticular formation. Labeling at the pons-cerebellum level was present in the locus coeruleus, A5 and A7 noradrenergic cell groups, parabrachial and deep cerebellar nuclei, whereas in the mesencephalon it was located in the periaqueductal gray matter, deep mesencephalic, oculomotor and anterior pretectal nuclei, and substantia nigra. In the diencephalon, fibers and terminal boutons were found mainly in the parafascicular, ventromedial, and posterior thalamic nuclei and in the arcuate, lateral, posterior, peri- and paraventricular hypothalamic areas. Telencephalic labeling was consistent but less intense and concentrated in the septal nuclei, globus pallidus and amygdala. The well-known role of the medullary dorsal reticular nucleus in nociception and its pattern of brain projections in rats suggests that the nucleus is possibly implicated in the modulation of: (i) the ascending nociceptive transmission involved in the motivational-affective dimension of pain; (ii) the endogenous supraspinal pain control system centered in the periaqueductal gray matter-rostral ventromedial medulla-spinal cord circuitry; (iii) the motor reactions associated with pain.

Differential effects of left/right neuropathy on rats' anxiety and cognitive behavior

Summary It has long been a matter of dispute whether some pain‐related phenomena occur with a lateralization bias. We demonstrate that in a model of chronic neuropathic pain, left‐sided pain is detrimental to emotional behaviour, whereas right‐sided pain affects cognitive function, particularly in prefrontal cortex–dependent tasks. ABSTRACT Chronic pain is frequently accompanied by a deterioration of emotional behavior and cognitive function. A small number of studies in humans concluded that pain‐associated negative affect is more pronounced when pain is localized in the left side of the body. It has been suggested that such side bias results from cortical function lateralization. It is not known, however, if other pain‐associated behavioral changes are differentially affected by left‐ and right‐sided pain. To test this hypothesis, the performance of rats with a unilateral spared nerve injury neuropathy installed in the left (SNI‐L) or in the right (SNI‐R) side was compared in anxiety (elevated‐plus maze) and cognitive (spatial working and reference memory, attentional set‐shifting task, and delay‐to‐signal impulsivity task) behavioral paradigms. Results show that SNI‐L animals presented an increased anxiety‐like profile while maintaining preserved cognitive function. On the contrary, SNI‐R animals presented cognitive deficits in all tasks except in the reference memory, but displayed a normal anxiety‐like profile. Our results show that left‐ and right‐sided neuropathic pain differentially affects emotional behavior, which is in accordance with previous observations in human subjects, both in experimentally induced pain and in chronic pain conditions. Additionally, our results demonstrate that the cognitive function deterioration associated with unilateral neuropathic chronic pain conditions is also differentially affected.

Development and characterization of a PHB-HV-based 3D scaffold for a tissue engineering and cell-therapy combinatorial approach for spinal cord injury regeneration.

Spinal cord injury (SCI) leads to devastating neurological deficits. Several tissue engineering (TE)-based approaches have been investigated for repairing this condition. Poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB-HV) is found to be particularly attractive for TE applications due to its properties, such as biodegradability, biocompatibility, thermoplasticity and piezoelectricity. Hence, this report addresses the development and characterization of PHB-HV-based 3D scaffolds, produced by freeze-drying, aimed to SCI treatment. The obtained scaffolds reveal an anisotropic morphology with a fully interconnected network of pores. In vitro studies demonstrate a lack of cytotoxic effect of PHB-HV scaffolds. Direct contact assays also reveal their ability to support the culture of CNS-derived cells and mesenchymal-like stem cells from different sources. Finally, histocompatibility studies show that PHB-HV scaffolds are well tolerated by the host tissue, and do not negatively impact the left hindlimb locomotor function recovery. Therefore results herein presented suggest that PHB-HV scaffolds may be suitable for SCI treatment.

Absence of Tau triggers age-dependent sciatic nerve morphofunctional deficits and motor impairment

Dementia is the cardinal feature of Alzheimers disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well‐established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor‐related tests, we herein provide evidence of an age‐dependent motor impairment in Tau−/− animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor‐related information. Specifically, we show that the sciatic nerve of old (17–22‐months) Tau−/− mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age‐matched wild‐type (Tau+/+) littermates and younger (4–6 months) Tau−/− and Tau+/+ mice. In addition, the sciatic nerves of Tau−/− mice exhibit a progressive hypomyelination (assessed by g‐ratio) specifically affecting large‐diameter, motor‐related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.

Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy

BackgroundRecently we showed that unilateral peripheral neuropathic lesions impacted differentially on rat’s emotional/cognitive behavior depending on its left/right location; importantly, this observation recapitulates clinical reports. The prefrontal cortex (PFC), a brain region morphofunctionally affected in chronic pain conditions, is involved in the modulation of both emotion and executive function and displays functional lateralization. To test whether the PFC is involved in the lateralization bias associated with left/right pain, c-fos expression in medial and orbital areas was analyzed in rats with an unilateral spared nerve injury neuropathy installed in the left or in the right side after performing an attentional set-shifting, a strongly PFC-dependent task.ResultsSNI-R animals required more trials to successfully terminate the reversal steps of the attentional set-shifting task. A generalized increase of c-fos density in medial and orbital PFC (mPFC/OFC), irrespectively of the hemisphere, was observed in both SNI-L and SNI-R. However, individual laterality indexes revealed that contrary to controls and SNI-L, SNI-R animals presented a leftward shift in c-fos density in the ventral OFC (VO). None of these effects were observed in the neighboring primary motor area.ConclusionsOur results demonstrate that chronic neuropathic pain is associated with a bilateral mPFC and OFC hyperactivation. We hypothesize that the impaired performance of SNI-R animals is associated with a left/right activity inversion in the VO, whose functional integrity is critical for reversal learning.

Variable delay-to-signal: a fast paradigm for assessment of aspects of impulsivity in rats

Testing impulsive behavior in rodents is challenging and labor-intensive. We developed a new behavioral paradigm—the Variable Delay-to-Signal (VDS) test—that provides rapid and simultaneous assessment of response and decision impulsivity in rodents. Presentation of a light at variable delays signals the permission for action (nose poke) contingent with a reward. 2 blocks of 25 trials at 3 s delay flank a block of 70 trials in which light is presented with randomly selected 6 or 12 s delays. Exposure to such large delays boosts the rate of premature responses when the delay drops to 3 s in the final block, an effect that is blunted by an acute methamphetamine challenge and that correlates with the delay-discounting (DD) paradigm (choice impulsivity). Finally, as expected, treatment with the NMDA antagonist MK-801 caused a generalized response increase in all VDS blocks. The pharmacological validation, particularly with methamphetamine which has a well established dual effect on response and decision impulsivity, and the correlations between the impulsive behavior in the DD and VDS paradigms, suggests that the later is able to provide, in a single session, a multi-dimensional assessment of impulsive behavior.

Structural laterality is associated with cognitive and mood outcomes: An assessment of 105 healthy aged volunteers

Abstract The human brain presents multiple asymmetries that dynamically change throughout life. These phenomena have been associated with cognitive impairments and psychiatric disorders although possible associations with specific patterns of cognitive aging are yet to be determined. We have therefore mapped and quantified morphological asymmetries in a heterogeneous and aged population (65.2±8.0 years old, 52 male and 53 female) to explore potential associations between the asymmetries in specific brain regions and cognitive performance. The sample was characterized in a battery of neuropsychological tests and in terms of brain structural asymmetries using a ROI‐based approach. A substantial number of brain areas presented some degree of asymmetry. Such biases survived a stringent statistical correction and were largely confirmed in a voxel‐based analysis. In specific brain areas, like the thalamus and insula, asymmetry was correlated with cognition and mood descriptors as the Stroop words/colors test or depressive mood scale, respectively. Curiously in the latter, the association was independent of its left/right direction. Altogether, results reveal that asymmetry is widespread in the aged brain and that area‐specific biases (degree and direction) associate with the functional profile of the individual. Graphical abstract Figure. No caption available. HighlightsThe aged brain presents ubiquitous structural asymmetries.Age, education and cognitive performance group do not influence asymmetries.Sex affects laterality only in the fusiform gyrus.In specific brain areas (a)symmetry associates with cognitive and mood outcomes.Cognition is better explained by laterality than by absolute left or right volumes.

Impact of Chronic Stress Protocols in Learning and Memory in Rodents: Systematic Review and Meta-Analysis.

The idea that maladaptive stress impairs cognitive function has been a cornerstone of decades in basic and clinical research. However, disparate findings have reinforced the need to aggregate results from multiple sources in order to confirm the validity of such statement. In this work, a systematic review and meta-analyses were performed to aggregate results from rodent studies investigating the impact of chronic stress on learning and memory. Results obtained from the included studies revealed a significant effect of stress on global cognitive performance. In addition, stressed rodents presented worse consolidation of learned memories, although no significantly differences between groups at the acquisition phase were found. Despite the methodological heterogeneity across studies, these effects were independent of the type of stress, animals’ strains or age. However, our findings suggest that stress yields a more detrimental effect on spatial navigation tests’ performance. Surprisingly, the vast majority of the selected studies in this field did not report appropriate statistics and were excluded from the quantitative analysis. We have therefore purposed a set of guidelines termed PROBE (Preferred Reporting Orientations for Behavioral Experiments) to promote an adequate reporting of behavioral experiments.