Orbitostriatal encoding of reward delayed gratification and impulsivity in chronic pain.

Central robust network functional rearrangement is a characteristic of several neurological conditions, including chronic pain. Preclinical and clinical studies have shown the importance of pain-induced dysfunction in both orbitofrontal cortex (OFC) and nucleus accumbens (NAc) brain regions for the emergence of cognitive deficits. Outcome information processing recruits the orbitostriatal circuitry, a pivotal pathway regarding context-dependent reward value encoding. The current literature reveals the existence of structural and functional changes in the orbitostriatal crosstalk in chronic pain conditions, which have emerged as a possible underlying cause for reward and time discrimination impairments observed in individuals affected by such disturbances. However, more comprehensive investigations are needed to elucidate the underlying disturbances that underpin disease development. In this review article, we aim to provide a comprehensive view of the orbitostriatal mechanisms underlying time-reward dependent behaviors, and integrate previous findings on local and network malplasticity under the framework of the chronic pain sphere.

Dynamics of Lateral Habenula-Ventral Tegmental Area Microcircuit on Pain-Related Cognitive Dysfunctions.

Chronic pain is a health problem that affects the ability to work and perform other activities, and it generally worsens over time. Understanding the complex pain interaction with brain circuits could help predict which patients are at risk of developing central dysfunctions. Increasing evidence from preclinical and clinical studies suggests that aberrant activity of the lateral habenula (LHb) is associated with depressive symptoms characterized by excessive negative focus, leading to high-level cognitive dysfunctions. The primary output region of the LHb is the ventral tegmental area (VTA), through a bidirectional connection. Recently, there has been growing interest in the complex interactions between the LHb and VTA, particularly regarding their crucial roles in behavior regulation and their potential involvement in the pathological impact of chronic pain on cognitive functions. In this review, we briefly discuss the structural and functional roles of the LHb-VTA microcircuit and their impact on cognition and mood disorders in order to support future studies addressing brain plasticity during chronic pain conditions.

In vitro embryo production in small ruminants: what is still missing?

In vitro embryo production (IVEP) is an extremely important tool for genetic improvement in livestock and it is the biotechnology that has grown the most recently. However, multiple ovulation followed by embryo transfer is still considered the leading biotechnology for embryo production in small ruminants. This review aimed to identify what is still missing for more efficient diffusion of IVEP in small ruminants, going through the IVEP steps and highlighting the main factors affecting the outcomes. Oocyte quality is essential for the success of IVEP and an aspect to be considered in small ruminants is their reproductive seasonality and strategies to mitigate the effect of season. The logistics for oocyte collection from live females is more complex than in cattle, and tools to simplify this collection system and/or to promote an alternative way of recovering oocytes may be an important point in this scenario. The heterogeneity of oocytes collected from growing follicles in live females or from ovaries collected from abattoirs remains a challenge, and there is a demand to standardize/homogenize the hormonal stimulatory protocols and IVM protocols for each source of oocytes. The use of sexed semen is technically possible, however the low market demand associated with the high costs of the sexing process prevents the routine use of this technique, but its higher availability is an important aspect aiming for greater dissemination of IVEP. New noninvasive approaches for embryo selection are key factors since the selection for transfer or cryopreservation is another difficulty faced among laboratories. Embryo selection is based on morphological traits, although these are not necessarily reliable in predicting pregnancy. Several issues described in this review must be considered by researchers in other to promote the diffusion of IVEP in small ruminants.

Luteinizing hormone secretion, ovulatory capacity, and oocyte quality in peripubertal Gir heifers.

Induction of puberty in cattle breeds that attain puberty in later stages, such as Gir, allows the earlier beginning of reproductive life and it might increase oocyte quality. Here, the ovulatory capacity of prepuberal Gir heifers was studied and its relationship to follicular growth, luteinizing hormone (LH) secretion and oocyte quality was evaluated. Peripubertal Gir heifers were treated with a progesterone-based protocol and according to ovulatory response were separated into groups: not-ovulated (N-OV) and ovulated (OV). Serial blood samples were taken 24 h after estradiol treatment on day 12 to evaluate LH secretion. Cumulus-oocyte complexes (COCs) were collected using ovum pick-up and assessed for brilliant cresyl blue (BCB) staining rate, IVF-grade oocytes rate, and mean oocyte diameter, in comparison with cow oocytes. Gene expression of developmental competence markers (ZAR1, MATER, and IGF2R) was also analyzed. The largest follicle diameters were similar between N-OV and OV groups on the day of estradiol treatment (d12) and the next day and decreased (P = 0.04) in the N-OV group thereafter. LH pulse secretion was different between groups (N-OV = 3.61 ± 0.34 vs OV = 2.83 ± 0.21 ng/ ml; P = 0.04). COC assessment showed that the number of recovered oocytes, BCB+ rate, IVF-grade oocytes and oocyte size was similar (P > 0.05) among groups, resembling adult cow patterns. ZAR1, MATER and IGF2R gene expression in oocytes were also similar (P > 0.05) in N-OV and OV groups. In conclusion, our results demonstrate a lower LH secretion profile in peripubertal Gir heifers prone to ovulate after induction protocol, and that oocyte quality is not affected on a short-term basis by ovulation itself.

Altered Brain Expression of DNA Methylation and Hydroxymethylation Epigenetic Enzymes in a Rat Model of Neuropathic Pain.

The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different CNS regions related to nociception, namely the dorsal root ganglia, the spinal cord, and different brain areas. Decreased global methylation was found in the DRG, the prefrontal cortex, and the amygdala, which was associated with decreased DNMT1/3a expression. In contrast, increased methylation levels and mRNA levels of TET1 and TET3 were linked to augmented pain hypersensitivity and allodynia in inflammatory and neuropathic pain models. Since epigenetic mechanisms may be responsible for the regulation and coordination of various transcriptional modifications described in chronic pain states, with this study, we aimed to evaluate the functional role of TET1-3 and DNMT1/3a genes in neuropathic pain in several brain areas. In a spared nerve injury rat model of neuropathic pain, 21 days after surgery, we found increased TET1 expression in the medial prefrontal cortex and decreased expression in the caudate-putamen and the amygdala; TET2 was upregulated in the medial thalamus; TET3 mRNA levels were reduced in the medial prefrontal cortex and the caudate-putamen; and DNMT1 was downregulated in the caudate-putamen and the medial thalamus. No statistically significant changes in expression were observed with DNMT3a. Our results suggest a complex functional role for these genes in different brain areas in the context of neuropathic pain. The notion of DNA methylation and hydroxymethylation being cell-type specific and not tissue specific, as well as the possibility of chronologically differential gene expression after the establishment of neuropathic or inflammatory pain models, ought to be addressed in future studies.

Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits.

The lateral habenula (LHb) and the ventral tegmental area (VTA), which form interconnected circuits, have important roles in the crucial control of sensory and cognitive motifs. Signaling in the LHb-VTA pathway can be exacerbated during pain conditions by a hyperactivity of LHb glutamatergic neurons to inhibit local VTA DAergic cells. However, it is still unclear whether and how this circuit is endogenously engaged in pain-related cognitive dysfunctions. To answer this question, we modulated this pathway by expressing halorhodopsin in LHb neurons of adult male rats, and then selectively inhibited the axonal projections from these neurons to the VTA during a working memory (WM) task. Behavioral performance was assessed after the onset of an inflammatory pain model. We evaluated the impact of the inflammatory pain in the VTA synapses by performing immunohistochemical characterization of specific markers for GABAergic (GAD65/67) and dopaminergic neurons (dopamine transporter (DAT), dopamine D2 receptor (D2r) and tyrosine hydroxylase (TH)). Our results revealed that inhibition of LHb terminals in the VTA during the WM delay-period elicits a partial recovery of the performance of pain animals (in higher complexity challenges); this performance was not accompanied by a reduction of nociceptive responses. Finally, we found evidence that the pain-affected animals exhibit VTA structural changes, namely with an upregulation of GAD65/67, and a downregulation of DAT and D2r. These results demonstrate a role of LHb neurons and highlight their responsibility in the stability of the local VTA network, which regulates signaling in frontal areas necessary to support WM processes.

The Simulated Physiological Oocyte Maturation (SPOM) system in domestic animals: A systematic review.

Simulated Physiological Oocyte Maturation (SPOM) mimics in vitro the physiological events of oocyte maturation. The system uses cAMP modulators in two steps (pre IVM and IVM) and has presented promising results that are arousing the curiosity of IVF programs in different animal species, generating several papers, adaptations, and controversies worldwide. This study systematically analyses the data in the literature on the use of SPOM and compares the outcomes to the original paper (Albuz et al. Hum. Rep., 25: 2999-3011 2010), classifying them into success or failure. The PubMed, Scopus, and Google Scholar databases were searched and 22 studies were included, from which data on 26 experiments were extracted and evaluated via descriptive statistical analysis. Only experiments that assessed the blastocyst rate (BR) were considered for the success parameter, i.e. success (increase in BR) or failure (either no difference or a reduction in BR). The experiments applied the SPOM system in the following species: cattle, sheep, goats, mice, mares and cats. Three experiments (3/26) could not be evaluated for success or failure, and of the remaining, 34.7% (8/23) succeeded in improving blastocyst production. More than two-thirds (69.2%, 18/26) of experiments were conducted in cattle; of those, 86.8% (13/15) used TCM-199 as the IVM media, and 22.2% did not use forskolin or IBMX modulators as indicated in the original study. Also, 27.7% (5/18) of the experiments in cattle used the same type and dose of FSH, and 22% (4/18) used the same protein source and concentration as indicated in the original study. All experiments conducted in mice (3) kept the parameters of the original study in terms of forskolin and IBMX doses and BSA and FSH concentrations, however, they removed cilostamide from IVM. Cilostamide was used during IVM in more than half (53.8%) of all experiments, but only in cattle and sheep. Considering oocyte and embryo assessments, six experiments assessed cAMP levels and most (5/6) of these observed an increase: in cattle (2), sheep (2), and mice (1). Ten experiments evaluated the effect of SPOM on nuclear maturation, and in 90% (9/10), the SPOM system was able to arrest meiosis (cattle, sheep and mice). Thirteen experiments evaluated the total cell number (cattle, mice and sheep), and six (6/13) showed an increase. Our findings clearly indicate difficulties in reproducing the SPOM system worldwide, demonstrating that the meiosis arrest is not sufficient to ensure successful SPOM application. They also suggest that the different supplements used in the IVM medium and/or their interaction with modulators for different durations may produce a significant bias that affects experimental success.

Altered prefrontal-striatal theta-band oscillatory dynamics underlie working memory deficits in neuropathic pain rats.

BACKGROUND: Prelimbic medial prefrontal cortex (PL-mPFC) and nucleus accumbens core region (NAcc) play an important role in supporting several executive cognitive mechanisms, such as spatial working memory (WM). Recently, this circuit has been also associated with both sensory and affective components of pain. However, it is still unclear whether this circuit is endogenously engaged in neuropathic pain-related cognitive dysfunctions. METHODS: To answer this question, we induced the expression of halorhodopsin in local PL-mPFC neurons projecting to NAcc, and then selectively inhibited the terminals of these neurons in the NAcc while recording neural activity during the performance of a delayed non-match to sample (DNMS) spatial WM task. Within-subject behavioural performance and PL-mPFC to NAcc circuit neural activity was assessed after the onset of a persistent rodent neuropathic pain model-spared nerve injury (SNI). RESULTS: Our results revealed that the induction of the neuropathy reduced WM performance, and altered the interplay between PL-mPFC and NAcc neurons namely in increasing the functional connectivity from NAcc to PL-mPFC, particularly in the theta-band spontaneous oscillations; in addition, these behavioural and functional perturbations were partially reversed by selective optogenetic inhibition of PL-mPFC neuron terminals into the NAcc during the DNMS task delay-period, without significant antinociceptive effects. CONCLUSIONS: Altogether, these results strongly suggest that the PL-mPFC excitatory output into the NAcc plays an important role in the deregulation of WM under pain conditions. SIGNIFICANCE: Selective optogenetic inhibition of prefrontal-striatal microcircuit reverses pain-related working memory deficits but has no significant impact on pain responses. Neuropathic pain underlies an increase of functional connectivity between the nucleus accumbens core area and the prelimbic medial prefrontal cortex mediated by theta-band activity.

Combined Chair-Based Exercises Improve Functional Fitness, Mental Well-Being, Salivary Steroid Balance, and Anti-microbial Activity in Pre-frail Older Women.

INTRODUCTION: Regular exercise has long been shown to positively impact the immune system responsiveness and improve mental well-being (MWB). However, the putative links between biomarkers of mental health and immune efficiency in exercising subjects have been scarcely investigated. The aim of this study was to verify the effect of a 14-week combined chair-based exercise program (CEP) on salivary steroid hormones and anti-microbial proteins, functional fitness, and MWB indexes in pre-frail older women. METHODS: The participant women (82.8 4.6 years old; n = 32) were randomly divided into the exercising group (CEP, n = 17) and the non-exercising control group (CG, n = 15). The pre/post assessment included: (1) salivary anti-microbial proteins lysozyme; (Lys) and immunoglobulin-A (IgA); (2) salivary steroid hormones of testosterone (TT) and cortisol (COR); (3) functional fitness (gait speed, hand grip strength, and static balance); (4) MWB questionnaires (happiness, depression state, satisfaction with life, and stress). RESULTS: Significant differences with large Cohen's (d) effect sizes were found on increased salivary TT (p < 0.05; d = 0.60) after exercise intervention. The results revealed a decrease in IgA levels after CEP (p < 0.01, d = 0.30). The increase in subjective happiness levels (p < 0.05, d = 0.30) and decrease of stress perception (p < 0.01, d = 2.60) and depressive state (p < 0.05, d = 0.30) were found after intervention in the CEP group. Robust statistical differences in gait speed (p < 0.05; d = 0.60) and balance tests (p < 0.05; d = 0.80) were also found in the CEP group. In control, COR increased moderately (p < 0.05; d = 0.65) while no changes were found for the other indicators. Correlation analyses showed inter-dependence between pre-post variations of MWB, biochemical indexes, and fitness function (e.g., COR inverse correlation with hand grip strength and balance tests). CONCLUSION: The CEP program was able to improve functional-fitness performance, decrease feelings of stress, and increase happiness. The CEP also induced clinically relevant hormonal and immune responses, which suggests that chair exercises that combine muscular strength, balance, and gait speed training are promising interventions to improve physical and mental health of older pre-frail adults.

Arterial stiffness in type 2 diabetes: determinants and indication of a discriminative value.

OBJECTIVES: To identify the clinical discriminative value and determinants of arterial stiffness in individuals with type 2 diabetes mellitus (T2DM). METHODS: This prospective cohort study included 51 individuals (53.57±9.35 years) diagnosed with T2DM (stage glucose≥126 mg/dL; diagnostic time: 87.4±69.8 months). All participants underwent an initial evaluation of personal habits, medications, and history; arterial stiffness assessment by carotid-femoral pulse wave velocity (cfPWV) using SphygmoCor; and blood laboratory analysis. A statistical analysis was performed using SPSS software, and values of p≤0.05 were considered significant. RESULTS: A cut-off cfPWV value of 7.9 m/s was identified for T2DM [Sensitivity (SE): 90% and Specificity (SP): 80%]. A subgroup analysis revealed higher glycated hemoglobin (Hb1Ac) (p=0.006), obesity (p=0.036), and dyslipidemia (p=0.013) than those with cfPWV ≥7.9 m/s. Multivariate analysis identified higher stage glucose (p=0.04), Hb1Ac (p=0.04), hypertension (p=0.001), and dyslipidemia (p=0.01) as determinant factors of cfPWV; positive and significant correlation between cfPWV and glucose (r=0.62; p=0.0003) and Hb1Ac (r=0.55; p=0.0031). CONCLUSIONS: In T2DM, an indicator of the discriminative value of arterial stiffness was cfPWV of 7.9 m/s. Clinical findings and comorbidities, such as hypertension, glucose, poor glycemic control, and dyslipidemia, were associated with and were determinants of arterial stiffness in T2DM. Reinforcement of monitoring risk factors, such as hypertension, dyslipidemia, and glycemic control, seems to be essential to the process of arterial stiffening. Confirmation of this discriminative value in larger populations is recommended.

Optical imaging of cleavage stage bovine embryos using hyperspectral and confocal approaches reveals metabolic differences between on-time and fast-developing embryos.

The assessment of embryo quality aims to enhance subsequent pregnancy and live birth outcomes. Metabolic analysis of embryos has immense potential in this regard. As a step towards this goal, here we assess the metabolism of bovine embryos using label-free optical imaging. We compared embryos defined as either on-time or fast-developing, as fast dividing embryos are more likely to develop to the blastocyst stage. Specifically, bovine embryos at 48 (Day 2) and 96 (Day 4) hours post fertilization were fixed and separated based on morphological assessment: on-time (Day 2: 2 cell; Day 4: 5-7 cell) or fast-developing (Day 2: 3-7 cell; Day 4: 8-16 cell). Embryos with different developmental rates on Day 2 and Day 4 were correlated with metabolic activity and DNA damage. Confocal microscopy was used to assess metabolic activity by quantification of cellular autofluorescence specific for the endogenous fluorophores NAD(P)H and FAD with a subsequent calculation of the optical redox ratio. Separately, hyperspectral microscopy was employed to assess a broader range of endogenous fluorophores. DNA damage was determined using γH2AX immunohistochemistry. Hyperspectral imaging showed significantly lower abundance of endogenous fluorophores in fast-developing compared to on-time embryos on Day 2, indicating a lower metabolic activity. On Day 4 of development there was no difference in the abundance of FAD between on-time and fast-developing embryos. There was, however, significantly higher levels of NAD(P)H in fast-developing embryos leading to a significantly lower optical redox ratio when compared to on-time embryos. Collectively, these results demonstrate that fast-developing embryos present a 'quiet' metabolic pattern on Day 2 and Day 4 of development, compared to on-time embryos. There was no difference in the level of DNA damage between on-time and fast-developing embryos on either day of development. To our knowledge, this is the first collective use of confocal and hyperspectral imaging in cleavage-stage bovine embryos in the absence of fluorescent tags.

Arterial stiffness in type 2 diabetes: determinants and indication of a discriminative value

OBJECTIVES: To identify the clinical discriminative value and determinants of arterial stiffness in individuals with type 2 diabetes mellitus (T2DM). METHODS: This prospective cohort study included 51 individuals (53.57±9.35 years) diagnosed with T2DM (stage glucose≥126 mg/dL; diagnostic time: 87.4±69.8 months). All participants underwent an initial evaluation of personal habits, medications, and history; arterial stiffness assessment by carotid-femoral pulse wave velocity (cfPWV) using SphygmoCor; and blood laboratory analysis. A statistical analysis was performed using SPSS software, and values of p≤0.05 were considered significant. RESULTS: A cut-off cfPWV value of 7.9 m/s was identified for T2DM [Sensitivity (SE): 90% and Specificity (SP): 80%]. A subgroup analysis revealed higher glycated hemoglobin (Hb1Ac) (p=0.006), obesity (p=0.036), and dyslipidemia (p=0.013) than those with cfPWV ≥7.9 m/s. Multivariate analysis identified higher stage glucose (p=0.04), Hb1Ac (p=0.04), hypertension (p=0.001), and dyslipidemia (p=0.01) as determinant factors of cfPWV; positive and significant correlation between cfPWV and glucose (r=0.62; p=0.0003) and Hb1Ac (r=0.55; p=0.0031). CONCLUSIONS: In T2DM, an indicator of the discriminative value of arterial stiffness was cfPWV of 7.9 m/s. Clinical findings and comorbidities, such as hypertension, glucose, poor glycemic control, and dyslipidemia, were associated with and were determinants of arterial stiffness in T2DM. Reinforcement of monitoring risk factors, such as hypertension, dyslipidemia, and glycemic control, seems to be essential to the process of arterial stiffening. Confirmation of this discriminative value in larger populations is recommended.

Underlying mechanisms of oxygen uptake kinetics in chronic post-stroke individuals: A correlational, cross-sectional pilot study.

Post-stroke individuals presented deleterious changes in skeletal muscle and in the cardiovascular system, which are related to reduced oxygen uptake ([Formula: see text]) and take longer to produce energy from oxygen-dependent sources at the onset of exercise (mean response time, MTRON) and during post-exercise recovery (MRTOFF). However, to the best of our knowledge, no previous study has investigated the potential mechanisms related to [Formula: see text] kinetics response (MRTON and MRTOFF) in post-stroke populations. The main objective of this study was to determine whether the MTRON and MRTOFF are related to: 1) body composition; 2) arterial compliance; 3) endothelial function; and 4) hematological and inflammatory profiles in chronic post-stroke individuals. Data on oxygen uptake ([Formula: see text]) were collected using a portable metabolic system (Oxycon Mobile®) during the six-minute walk test (6MWT). The time to achieve 63% of [Formula: see text] during a steady state (MTRON) and recovery (MRTOFF) were analyzed by the monoexponential model and corrected by a work rate (wMRTON and wMRTOFF) during 6MWT. Correlation analyses were made using Spearman's rank correlation coefficient (rs) and the bias-corrected and accelerated bootstrap method was used to estimate the 95% confidence intervals. Twenty-four post-stroke participants who were physically inactive took part in the study. The wMRTOFF was correlated with the following: skeletal muscle mass (rs = -0.46), skeletal muscle mass index (rs = -0.45), augmentation index (rs = 0.44), augmentation index normalized to a heart rate of 75 bpm (rs = 0.64), reflection magnitude (rs = 0.43), erythrocyte (rs = -0.61), hemoglobin (rs = -0.54), hematocrit (rs = -0.52) and high-sensitivity C-reactive protein (rs = 0.58), all p < 0.05. A greater amount of oxygen uptake during post-walking recovery is partially related to lower skeletal muscle mass, greater arterial stiffness, reduced number of erythrocytes and higher systemic inflammation in post-stroke individuals.

The SPOM-adapted IVM system improves in vitro production of bovine embryos.

This study aimed to test the effects of an IVM SPOM adaptation (SPOM-adapted IVM) on the production, total number of cells (TNC), apoptosis, and cryotolerance (post-warming survival and cytoskeleton actin integrity) of bovine IVP embryos. Two experiments were conducted with two experimental groups based on IVM treatment: A control group (TCM 199 without FCS) and an SPOM-adapted group (TCM 199 with forskolin and IBMX in pre-IVM and IVM with cilostamide). The first experiment evaluated embryo in vitro production, TNC, and apoptosis rate on D9 of development. In the second experiment, embryos were vitrified/warmed at D7 (control fresh and vitrified; SPOM-adapted fresh and vitrified) and assessed regarding post-warming survival rates and cytoskeleton actin integrity. Statistical analysis was performed using GraphPad INSTAT software at a significance level of 5%. An increase (p < 0.05) in blastocyst production was observed in the SPOM-adapted group comparing to the control group. There was no difference (p > 0.05) in the TNC or apoptosis rate between the groups. Regarding cryopreservation, no differences were found (p > 0.05) in actin integrity or post-warming survival rates between the vitrified groups. In both vitrified groups, we observed a significantly lower uninjured pattern of actin integrity compared to the fresh groups (p < 0.05). We conclude that the SPOM-adapted IVM system is beneficial for blastocyst production and does not affect the quality and cryotolerance of the produced embryos.

Energy Cost During the 6-Minute Walk Test and Its Relationship to Real-World Walking After Stroke: A Correlational, Cross-Sectional Pilot Study.

BACKGROUND: After experiencing stroke, individuals expend more energy walking than people who are healthy. However, among individuals who have experienced stroke, the correlation between the energy cost of walking, as measured by validated tests (such as the 6-minute walk test), and participation in walking, as measured by more sensitive tools (such as an ambulatory activity monitor), remains unknown. OBJECTIVE: The main objective of this study was to determine whether the energy cost of walking is correlated with participation in walking. DESIGN: This study was a correlational, cross-sectional pilot study. METHODS: Data from 23 participants who had experienced chronic stroke were analyzed. On the first day, data on oxygen uptake were collected using a portable metabolic system while participants walked during the 6-minute walk test. Then, the ambulatory activity monitor was placed on the participants' nonparetic ankle and removed 9 days later. The energy cost of walking was calculated by dividing the mean oxygen uptake recorded during the steady state by the walking speed. RESULTS: The energy cost of walking was correlated with the following: the number of steps (Spearman rank correlation coefficient [rs] = -0.59); the percentage of time spent in inactivity (rs = 0.48), low cadence (rs = 0.67), medium cadence (rs = -0.56), high cadence (rs = -0.65), and the percentages of steps taken at low cadence (rs = 0.65) and high cadence (rs = -0.64). LIMITATIONS: Individuals who were physically inactive, convenience sampling, and a small sample size were used in this study. CONCLUSIONS: Higher energy costs of walking were associated with fewer steps per day and lower cadence in real-world walking in individuals who had experienced stroke.

Bidirectional optogenetic modulation of prefrontal-hippocampal connectivity in pain-related working memory deficits.

Dysfunction of the prefrontal-hippocampal circuit has been identified as a leading cause to pain-related working-memory (WM) deficits. However, the underlying mechanisms remain poorly determined. To address this issue, we implanted multichannel arrays of electrodes in the prelimbic cortex (PL-mPFC), and in the dorsal hippocampal CA1 field (dCA1) to record the neural activity during the performance of a delayed non-match to sample (DNMS) task. The prefrontal-hippocampal connectivity was selectively modulated by bidirectional optogenetic inhibition or stimulation of local PL-mPFC glutamatergic calcium/calmodulin-dependent protein kinase-II alpha (CaMKIIα) expressing neurons during the DNMS task delay-period. The within-subject behavioral performance was assessed using a persistent neuropathic pain model - spared nerve injury (SNI). Our results showed that the induction of the neuropathic pain condition affects the interplay between PL-mPFC and dCA1 regions in a frequency-dependent manner, and that occurs particularly across theta oscillations while rats performed the task. In SNI-treated rats, this disruption was reversed by the selective optogenetic inhibition of PL-mPFC CaMKIIα-expressing neurons during the last portion of the delay-period, but without any significant effect on pain responses. Finally, we found that prefrontal-hippocampal theta connectivity is strictly associated with higher performance levels. Together, our findings suggest that PL-mPFC CaMKIIα-expressing neurons could be modulated by painful conditions and their activity may be critical for prefrontal-hippocampal connectivity during WM processing.

Selective optogenetic inhibition of medial prefrontal glutamatergic neurons reverses working memory deficits induced by neuropathic pain.

Stability of local medial prefrontal cortex (mPFC) network activity is believed to be critical for sustaining cognitive processes such as working memory (WM) and decision making. Dysfunction of the mPFC has been identified as a leading cause to WM deficits in several chronic pain conditions; however, the underlying mechanisms remain largely undetermined. Here, to address this issue, we implanted multichannel arrays of electrodes in the prelimbic region of the mPFC and recorded the neuronal activity during a food-reinforced delayed nonmatch to sample (DNMS) task of spatial WM. In addition, we used an optogenetic technique to selectively suppress the activity of excitatory pyramidal neurons that are considered the neuronal substrate for memory retention during the delay period of the behavioral task. Within-subject behavioral performance and pattern of neuronal activity were assessed after the onset of persistent pain using the spared nerve injury model of peripheral neuropathy. Our results show that the nerve lesion caused a disruption in WM and prelimbic spike activity and that this disruption was reversed by the selective inhibition of prelimbic glutamatergic pyramidal neurons during the delay period of the WM task. In spared nerve injury animals, photoinhibition of excitatory neurons improved the performance level and restored neural activity to a similar profile observed in the control animals. In addition, we found that selective inhibition of excitatory neurons does not produce antinociceptive effects. Together, our findings suggest that disruption of balance in local prelimbic networks may be crucial for the neurological and cognitive deficits observed during painful syndromes.

Animal models of congenital hypoalgesia: Untapped potential for assessing pain-related plasticity.

Over the last 20 years a large number of transgenic mouse models have been produced showing different degrees of congenital hypoalgesia; some of these models mimic known human conditions while others seemingly have no human counterpart. However, very little significant contributions to our understanding of pain neurobiology were obtained from this multitude of animal models; in most cases the study of these animals was limited to the characterization of its pain perception without addressing the long term consequences of their hypoalgesic condition. In this review we discuss the untapped potential that these animal models of congenital hypoalgesia hold for future studies addressing brain plasticity during permanent conditions of reduced pain perception, and that may result in important insights on the interplay between pain, emotion, and cognition. Revisiting hypoalgesia using modern techniques of functional neurophysiology in awake animals may complement the recent literature of functional clinical and preclinical studies that improve our understanding of the central malplasticity caused by pain.

Elderly people with limited mobility: their families and the implications of their dependency

Introduction and objectives: The family has suffered several changes throughout the times, leading to many elderly people living alone or with other elderly. In a family the situation of the elderly that depended on others can compromise the family's relationships, which leads to little availability to motivate them to mobilization. The objective of the study was to understand the way the family functions in view of to the dependence of the elderly with limited mobility in a community context. Methodology: Descriptive study, exploratory of a quantitive character. The data was gathered through a questionnaire, including the Lawton & Brody (1969) scales, the lifestyle profile (Nahas, 2013) and the familiar APGAR (Smilkstein, 1978). Non-probabilistic sample, composed by 1298 elderly with limited mobility, from 26 civil parishes from the municipality of Vila Nova de Famalicão. Results and discussion: Most of the people polled considered that his own family was a functional one (64.8%) and 49.6% were moderately dependent. By analysing the physical activity lifestyle profile and the familiar functionality one could con-clude that 65.2% had a positive profile, presenting typical behaviours of an active lifestyle. We think that the fact that 73.1% are inserted in functional families had something to do with it. We have verified a perfect association (p = 0.000) between dependency, lifestyle physical activity and familiar functionality - APGAR. Conclusions: The results show that the family determines the lifestyle physical acti-vity and the elderly's dependency. A functional family influences a positive physical activity profile, even in the elderly with limited mobility

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Role of cAMP modulator supplementations during oocyte in vitro maturation in domestic animals.

Cyclic adenosine monophosphate (cAMP) is an important molecule in signal transduction within the cell, functioning as a second cell messenger of gonadotrophin stimulation. The concentration of cAMP in cumulus-oocyte complexes (COCs) is known to be controlled through modulation of its synthesis by adenylyl cyclase (AC) and by degradation through the cyclic nucleotide phosphodiesterase (PDE) enzymes. One of the main obstacles for in vitro embryo production is the optimization of reproduction processes that occur in oocyte maturation. The function of cAMP is important in maintaining meiotic arrest in mammalian oocytes. When the oocyte is physically removed from the antral follicle for in vitro maturation (IVM), intra-oocyte cAMP concentrations decrease and spontaneous meiotic resumption begins, due to the depletion of inhibitory factors from the follicle. In many studies, relatively greater cAMP concentrations before IVM has been reported to improve oocyte competence, leading to subsequent benefits in embryonic development in different species. There, therefore, has been an increase in oocyte cAMP concentrations with several treatments and different approaches, such as invasive AC, stimulators of AC activity, PDE inhibitors, and cAMP analogs. The aim of this review is to comprehensively evaluate and provide data related to (i) the use of cAMP modulators during IVM and the effects on completion of meiosis and cytoplasmic reorganization, which are required for development of oocytes with the capacity to contribute to fertilization and subsequent embryonic development; and (ii) the main cAMP modulators and the effects when used in oocyte IVM.