Catecholamine involvement in lateral hypothalamic self-stimulation : with special reference to the dorsal noradrenergetic system

Six experiments were undertaken to determine the involvement of the nigrostriatal dopamine (DA) pathway and the dorsal noradrenergic (NA) pathway in mediating lateral hypothalamic (LH) self-stimulation. All subjects were implanted with bipolar electrodes in the LH area and were trained to self-stimulate. Once this behavior had stabilized (20-30 days), lesions at various levels of the nigrostriatal DA system and the dorsal NA system were made via intracerebral injections of the catecholamine (CA) neurotoxin, 6-hydroxydopamine (6-OHDA) and/or electrolytic lesions. Testing for self-stimulation was resumed 24 hrs. after the lesions and continued for a period of 5 days. At the conclusion of testing, the animals were sacrificed and prepared for histological examination. -- Destruction of several CA systems by injections of 6-OHDA (8μg/4μl) in the cells of origin (A9) of the nigrostriatal DA system resulted in a strong suppression of LH self-stimulation (p<.025). Injections of 6-OHDA (8μg/4μl) anterior to the cells of origin (A6) of the dorsal NA system had little or no effect on LH self-stimulation (Experiment 2). 6-OHDA (4μg/μl) and electrolytic lesions of the dorsal NA bundle in combination with electrolytic lesions of A6 also failed to substantially affect LH self-stimulation (Experiments 3 & 5). The fourth experiment attempted to further examine the role of the dorsal NA system in LH self-stimulation by injections of procaine ( a local anesthetic), d-amphetamine and glutamate (a neural excitant) directly in A6. All three treatments resulted in considerable suppression of LH self-stimulation (p<.001) but these results were rendered questionable due to possible non-specific effects and methodological considerations. The sixth and final experiment revealed that self-stimulation is rapidly obtained from the region of A6 when a sensitive shaping procedure that maximizes behavioral arousal is employed. -- Together; these results suggest that LH self-stimulation is mediated by the nigrostriatal and mesolimbic DA systems alone or in combination with the dorsal NA system but the dorsal NA system itself does not seem necessary for maintenance of LH self-estimulation. Thus, noradrenergic theories of self-stimulation (e.g. Stein & Wise, 1971) must be reconsidered

Behavioral outcome measures to improve experimental stroke research

Functional recovery after an experimental stroke can be assessed by multiple behavioural tests, however, there is no consensus about which test to use in long-term stroke recovery studies or whether the tests are affected by stroke surgery, post-operative care or behavioural compensation due to repeated testing. This review describes the tests most commonly used to assess motor and sensorimotor function, cognition and mood in stroke animals. Although it is difficult to predict the direction of future research, it may be possible to prevent false-positive results by selecting an appropriate task or a battery of tasks. It is also expected that the upcoming stroke recovery recommendations and the improved dialogue between academy, industry and healthcare professionals will further promote translational success

Is Environmental Enrichment Ready for Clinical Application in Human Post-stroke Rehabilitation?

Environmental enrichment (EE) has been widely used as a means to enhance brain plasticity mechanisms (e.g., increased dendritic branching, synaptogenesis, etc.) and improve behavioral function in both normal and brain-damaged animals. In spite of the demonstrated efficacy of EE for enhancing brain plasticity, it has largely remained a laboratory phenomenon with little translation to the clinical setting. Impediments to the implementation of enrichment as an intervention for human stroke rehabilitation and a lack of clinical translation can be attributed to a number of factors not limited to: (i) concerns that EE is actually the “normal state” for animals, whereas standard housing is a form of impoverishment; (ii) difficulty in standardizing EE conditions across clinical sites; (iii) the exact mechanisms underlying the beneficial actions of enrichment are largely correlative in nature; (iv) a lack of knowledge concerning what aspects of enrichment (e.g., exercise, socialization, cognitive stimulation) represent the critical or active ingredients for enhancing brain plasticity; and (v) the required “dose” of enrichment is unknown, since most laboratory studies employ continuous periods of enrichment, a condition that most clinicians view as impractical. In this review article, we summarize preclinical stroke recovery studies that have successfully utilized EE to promote functional recovery and highlight the potential underlying mechanisms. Subsequently, we discuss how EE is being applied in a clinical setting and address differences in preclinical and clinical EE work to date. It is argued that the best way forward is through the careful alignment of preclinical and clinical rehabilitation research. A combination of both approaches will allow research to fully address gaps in knowledge and facilitate the implementation of EE to the clinical setting

Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke

Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect. SIGNIFICANCE STATEMENT There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients

Agreed definitions and a shared vision for new standards in stroke recovery research: The Stroke Recovery and Rehabilitation Roundtable taskforce.

The first Stroke Recovery and Rehabilitation Roundtable established a game changing set of new standards for stroke recovery research. Common language and definitions were required to develop an agreed framework spanning the four working groups: translation of basic science, biomarkers of stroke recovery, measurement in clinical trials and intervention development and reporting. This paper outlines the working definitions established by our group and an agreed vision for accelerating progress in stroke recovery research

Analysis of the eukaryotic topoisomerase II DNA gate: a single-molecule FRET and structural perspective

Type II DNA topoisomerases (topos) are essential and ubiquitous enzymes that perform important intracellular roles in chromosome condensation and segregation, and in regulating DNA supercoiling. Eukaryotic topo II, a type II topoisomerase, is a homodimeric enzyme that solves topological entanglement problems by using the energy from ATP hydrolysis to pass one segment of DNA through another by way of a reversible, enzyme-bridged double-stranded break. This DNA break is linked to the protein by a phosphodiester bond between the active site tyrosine of each subunit and backbone phosphate of DNA. The opening and closing of the DNA gate, a critical step for strand passage during the catalytic cycle, is coupled to this enzymatic cleavage/religation of the backbone. This reversible DNA cleavage reaction is the target of a number of anticancer drugs, which can elicit DNA damage by affecting the cleavage/religation equilibrium. Because of its clinical importance, many studies have sought to determine the manner in which topo II interacts with DNA. Here we highlight recent single-molecule fluorescence resonance energy transfer and crystallographic studies that have provided new insight into the dynamics and structure of the topo II DNA gate

Local Luminous Infrared Galaxies. II. AGN Activity from Spitzer/IRS spectra

We quantify the active galactic nucleus (AGN) contribution to the mid-infrared (mid-IR) and the total infrared (IR, 8-1000micron) emission in a complete volume-limited sample of 53 local luminous infrared galaxies (LIRGs). We decompose the Spitzer Infrared Spectrograph (IRS) low-resolution 5-38micron spectra of the LIRGs into AGN and starburst components using clumpy torus models and star-forming galaxy templates, respectively. We find that 50% (25/50) of local LIRGs have an AGN component detected with this method. There is good agreement between these AGN detections through mid-IR spectral decomposition and other AGN indicators, such as the optical spectral class, mid-IR spectral features and X-ray properties. Taking all the AGN indicators together, the AGN detection rate in the individual nuclei of LIRGs is ~62%. The derived AGN bolometric luminosities are in the range L_bol(AGN)=0.4 -50x10^{43} erg/s. The AGN bolometric contribution to the IR luminosities of the galaxies is generally small, with 70% of LIRGs having L_bol(AGN)/L_IR<0.05. Only ~8% of local LIRGs have a significant AGN bolometric contribution L_bol(AGN)/L_IR > 0.25. From the comparison of our results with literature results of ultraluminous infrared galaxies, we confirm that in the local universe the AGN bolometric contribution to the IR luminosity increases with the IR luminosity of the galaxy/system. If we add up the AGN bolometric luminosities we find that AGNs only account for 5%^{+8%}_{-3%} of the total IR luminosity produced by local LIRGs (with and without AGN detections). This proves that the bulk of the IR luminosity of local LIRGs is due to star formation activity. Taking the newly determined IR luminosity density of LIRGs in the local universe, we then estimate an AGN IR luminosity density of Omega_IR(AGN) = 3x10^5 L_sun Mpc^{-3}$ in LIRGs.Comment: 20 pages, accepted for publication in Ap

The infrared supernova rate in starburst galaxies

We report the results of our ongoing search for extincted supernovae (SNe) at near-infrared wavelengths. We have monitored at 2.2 micron a sample of 46 Luminous Infrared Galaxies and detected 4 SNe. The number of detections is still small but sufficient to provide the first estimate of supernova rate at near-infrared wavelengths. We measure a SN rate ofv 7.6+/-3.8 SNu which is an order of magnitude larger than observed in quiescent galaxies. On the other hand, the observed near-infrared rate is still a factor 3-10 smaller than that estimated from the far-infrared luminosity of the galaxies. Among various possibilities, the most likely scenario is that dust extinction is so high (Av>30) to obscure most SNe even in the near-IR. The role of type Ia SNe is also discussed within this context. We derive the type Ia SN rate as a function of the stellar mass of the galaxy and find a sharp increase toward galaxies with higher activity of star formation. This suggests that a significant fraction of type Ia SNe are associated with young stellar populations. Finally, as a by-product, we give the average K-band light curve of core-collapse SNe based on all the existing data, and review the relation between SN rate and far-infrared luminosity.Comment: A&A, in press, 13 page

A roadmap for research in post-stroke fatigue:Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable

Rationale: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. Methods: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. Results: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. Conclusions: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue