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A novel rat model of Alzheimer's disease based on lentiviral-mediated expression of mutant APP

Parsi S, Pandamooz S, Heidari S, Naji M, Morfini G, Ahmadiani A, et al.

Neuroscience, 2015 Jan 22;284:99-106.
PMID: 25270904 DOI: 10.1016/j.neuroscience.2014.09.045

Alzheimer's disease (AD) is characterized by progressive and irreversible cognitive and memory impairment. The discovery of familial forms of AD (fAD) in association with specific gene mutations facilitated the generation of numerous rodent models. These models in turn proved valuable for the study of molecular mechanisms underlying AD pathogenesis, and facilitated translational research and preclinical drug development. This study aimed to introduce a new rat model of AD simulating some aspects of the sporadic cases of disease.
Early-life citalopram-induced impairments in sexual behavior and the role of androgen receptor

Soga T, Wong DW, Putteeraj M, Song KP, Parhar IS

Neuroscience, 2012 Dec 6;225:172-84.
PMID: 22960312 DOI: 10.1016/j.neuroscience.2012.08.061

Postnatal treatment with selective serotonin reuptake inhibitors (SSRIs) has been found to affect brain development and the regulation of reproduction in rodent models. The normal masculinization process in the brain requires a transient decrease in serotonin (5-HT) levels in the brain during the second postnatal week. Strict regulation of androgen receptor (AR) and gonadotropin-releasing hormone (GnRH) expression is important to control male reproductive activity. Therefore, this study was designed to examine the effects of a potent SSRI (citalopram) on male sexual behavior and expression levels of AR and GnRH in adult male mice receiving either vehicle or citalopram (10mg/kg) daily during postnatal days 8-21. The citalopram-treated male mice showed altered sexual behavior, specifically a significant reduction in the number of intromissions preceding ejaculation compared with the vehicle-treated mice. The citalopram-treated male mice displayed elevated anxiety-like behavior in an open field test and lower locomotor activity in their home cage during the subjective night. Although there was no change in GnRH and AR mRNA levels in the preoptic area (POA), quantified by real-time polymerase chain reaction, immunostained AR cell numbers in the medial POA were decreased in the citalopram-treated male mice. These results suggest that the early-life inhibition of 5-HT transporters alters the regulation of AR expression in the medial POA, likely causing decreased sexual behavior and altered home cage activity in the subjective night.
Neonatal dexamethasone exposure down-regulates GnRH expression through the GnIH pathway in female mice

Soga T, Dalpatadu SL, Wong DW, Parhar IS

Neuroscience, 2012 Aug 30;218:56-64.
PMID: 22626647 DOI: 10.1016/j.neuroscience.2012.05.023

Synthetic glucocorticoid (dexamethasone; DEX) treatment during the neonatal stage is known to affect reproductive activity. However, it is still unknown whether neonatal stress activates gonadotropin-inhibitory hormone (GnIH) synthesizing cells in the dorsomedial hypothalamus (DMH), which could have pronounced suppressive action on gonadotropin-releasing hormone (GnRH) neurons, leading to delayed pubertal onset. This study was designed to determine the effect of neonatal DEX (1.0mg/kg) exposure on reproductive maturation. Therefore, GnRH, GnIH and GnIH receptors, G-protein coupled receptors (GPR) 147 and GPR74 mRNA levels were measured using quantitative real-time PCR in female mice at postnatal (P) days 21, 30 and in estrus stage mice, aged between P45-50. DEX-treated females of P45-50 had delayed vaginal opening, and irregular estrus cycles and lower GnRH expression in the preoptic area (POA) when compared with age-matched controls. The expression levels of GPR147 and GPR74 mRNA in the POA increased significantly in DEX-treated female mice of P21 and P45-50 compared to controls. In addition, GPR147 and GPR74 mRNA expression was observed in laser captured single GnRH neurons in the POA. Although there was no difference in GnIH mRNA expression in the DMH, immunostained GnIH cell numbers in the DMH increased in DEX-treated females of P45-50 compared to controls. Taken together, the results show that the delayed pubertal onset could be due to the inhibition of GnRH gene expression after neonatal DEX treatment, which may be accounted for in part by the inhibitory signals from the up-regulated GnIH-GnIH receptor pathway to the POA.
Ultra-slow oscillations in cortical networks in vitro

Mok SY, Nadasdy Z, Lim YM, Goh SY

Neuroscience, 2012 Mar 29;206:17-24.
PMID: 22266346 DOI: 10.1016/j.neuroscience.2012.01.009

An ultra-slow oscillation (<0.01 Hz) in the network-wide activity of dissociated cortical networks is described in this article. This slow rhythm is characterized by the recurrence of clusters of large synchronized bursts of activity lasting approximately 1-3 min, separated by an almost equivalent interval of relatively smaller bursts. Such rhythmic activity was detected in cultures starting from the fourth week in vitro. Our analysis revealed that the propagation motifs of constituent bursts were strongly conserved across multiple oscillation cycles, and these motifs were more consistent at the electrode level compared with the neuronal level.
Cloning and functional expression of novel cholesterol transporters ABCG1 and ABCG4 in gonadotropin-releasing hormone neurons of the tilapia

Phang YL, Soga T, Kitahashi T, Parhar IS

Neuroscience, 2012 Feb 17;203:39-49.
PMID: 22198513 DOI: 10.1016/j.neuroscience.2011.12.016

In addition to reproduction, gonadotropin-releasing hormone (GnRH) has been postulated to control cholesterol metabolism via cholesterol transport, which is carried out partly by the members of ATP-binding cassette (ABC) transporters G1 (ABCG1) and G4 (ABCG4). However, there is yet to be evidence demonstrating the relationship between these transporters with reference to GnRH neurons. In the present study, we cloned two ABCG1 messenger RNA (mRNA) variants and one ABCG4 mRNA and examined their expression in the brain including GnRH neurons (GnRH1, GnRH2, and GnRH3) in the cichlid tilapia (Oreochromis niloticus). Comparison of nucleotide sequences of the tilapia ABCG1 and ABCG4 with that of other fish species showed that both of these genes are evolutionarily conserved among fishes. ABCG1 and ABCG4 were shown to have high mRNA expressions in the CNS, pituitary, and gonads. In the brain, real-time polymerase chain reaction (PCR) showed that ABCG4 mRNA was higher than ABCG1a in all brain regions including the olfactory bulb (ABCG1=13.34, ABCG4=6796.35; P<0.001), dorsal telencephalon (ABCG1=8.64, ABCG4=10149.13; P=0.001), optic tectum (ABCG1=22.12, ABCG4=13931.04; P<0.01), cerebellum (ABCG1=8.68, ABCG4=12382.90; P<0.01), and preoptic area-midbrain-hypothalamus (ABCG1=21.36, ABCG4=13255.41; P=0.001). Similarly, although ABCG1 mRNA level is much higher in the pituitary compared with the brain, it was still significantly lower compared with ABCG4 (ABCG1=337.73, ABCG4=1157.87; P=0.01). The differential pattern of expression of ABCG1 and ABCG4 in the brain versus pituitary suggests that the two transporters are regulated by different mechanisms. Furthermore, ABCG1 and ABCG4 mRNA expressions were found in all three types of laser-captured GnRH neurons with highly similar percentage of expressions, suggesting that cholesterol efflux from GnRH neurons may require heterodimerization of both ABCG1 and ABCG4.
A comparison between the effects of three potential scar-reducing agents applied at a site of sciatic nerve repair

Ngeow WC, Atkins S, Morgan CR, Metcalfe AD, Boissonade FM, Loescher AR, et al.

Neuroscience, 2011 May 5;181:271-7.
PMID: 21377512 DOI: 10.1016/j.neuroscience.2011.02.054

We have investigated the effect of three potential scar-reducing agents applied at a sciatic nerve repair site in C57-black-6 mice. Under anaesthesia the nerve was transected, repaired using four epineurial sutures, and 100 μl of either triamcinolone acetonide (1 mg/100 μl), an interleukin-10 peptide fragment (125 ng/100 μl or 500 ng/100 μl) or mannose-6-phosphate (M6P, 200 mM or 600 mM) was injected into and around the nerve. After 6 weeks the extent of regeneration was assessed electrophysiologically by determining the ratio of the compound action potential (CAP) modulus evoked by electrical stimulation of the nerve 2 mm distal or proximal to the repair site. The conduction velocity of the fastest components in the CAP was also calculated. The percentage area of collagen staining (PAS) at the repair site was analysed using Picrosirius Red and image analysis. Comparisons were made with a placebo group (100 μl of phosphate buffered saline) and sham-operated controls. The median CAP modulus ratio in the 600 mM M6P group was 0.44, which was significantly higher than in the placebo group (0.24, P=0.012: Kruskal-Wallis test). Conduction velocities were also faster in the 600 mM M6P group (median 30 m s(-1)) than in the placebo group (median 27.8 m s(-1); P=0.0197: Kruskal-Wallis test). None of the other treated groups were significantly different from the placebo, and all had significantly lower CAP ratios than the sham controls (P<0.05). All repair groups had a significantly higher PAS for collagen than sham controls. We conclude that the administration of 600 mM mannose-6-phosphate to a nerve repair site enhances axonal regeneration.
Protective effect of magnesium acetyltaurate against endothelin-induced retinal and optic nerve injury

Arfuzir NN, Lambuk L, Jafri AJ, Agarwal R, Iezhitsa I, Sidek S, et al.

Neuroscience, 2016 06 14;325:153-64.
PMID: 27012609 DOI: 10.1016/j.neuroscience.2016.03.041

Vascular dysregulation has long been recognized as an important pathophysiological factor underlying the development of glaucomatous neuropathy. Endothelin-1 (ET1) has been shown to be a key player due to its potent vasoconstrictive properties that result in retinal ischemia and oxidative stress leading to retinal ganglion cell (RGC) apoptosis and optic nerve (ON) damage. In this study we investigated the protective effects of magnesium acetyltaurate (MgAT) against retinal cell apoptosis and ON damage. MgAT was administered intravitreally prior to, along with or after administration of ET1. Seven days post-injection, animals were euthanized and retinae were subjected to morphometric analysis, TUNEL and caspase-3 staining. ON sections were stained with toluidine blue and were graded for neurodegenerative effects. Oxidative stress was also estimated in isolated retinae. Pre-treatment with MgAT significantly lowered ET1-induced retinal cell apoptosis as measured by retinal morphometry and TUNEL staining. This group of animals also showed significantly lesser caspase-3 activation and significantly reduced retinal oxidative stress compared to the animals that received intravitreal injection of only ET1. Additionally, the axonal degeneration in ON was markedly reduced in MgAT pretreated animals. The animals that received MgAT co- or post-treatment with ET1 also showed improvement in all parameters; however, the effects were not as significant as observed in MgAT pretreated animals. The current study showed that the intravitreal pre-treatment with MgAT reduces caspase-3 activation and prevents retinal cell apoptosis and axon loss in ON induced by ET1. This protective effect of ET1 was associated with reduced retinal oxidative stress.
Fulltext Cloning and serotonergic regulation of RING finger protein38 (rnf38) in the brain of medaka (Oryzias latipes)

Moriya S, Khel NB, Parhar IS

Neuroscience, 2015 May 21;294:109-15.
PMID: 25772790 DOI: 10.1016/j.neuroscience.2015.03.012

Serotonin (5-HT) is a key regulator of mood and sexual behaviors. 5-HT reuptake inhibitors have been used as antidepressants. Really interesting new gene (RING) finger proteins have been associated with 5-HT regulation but their role remains largely unknown. Some RING finger proteins are involved in the serotonergic system, therefore, we speculate that the gene expression of RING finger protein38 (rnf38) is regulated by the serotonergic system. In the present study, we aimed to identify the full length sequence of medaka (Oryzias latipes) rnf38 mRNA and investigate its association with the serotonergic system using an antidepressant, citalopram (CIT). We identified the full length rnf38 cDNA, which consisted of 2726 nucleotides spanning 12 exons and the deduced protein sequence consisting of 518 amino acid residues including a RING finger domain, a KIT motif and a coiled-coil domain. Medaka exposed to 10(-7)M of CIT showed anxiety-like behavior. The expressions of 5-HT-related genes, pet1, solute carrier family 6, member 4A (slc6a4) and tryptophan hydroxylase (tph2) were significantly low (P<0.05) in the hindbrain. On the other hand, rnf38 gene was significantly high (P<0.05) in the telencephalon and the hypothalamus. This shows that 5-HT synthesis and transport in the hindbrain is suppressed by CIT, which induces rnf38 gene expression in the forebrain where 5-HT neurons project. Thus, the expression of rnf38 is negatively regulated by the serotonergic system.
Associations Between Delay Discounting and Connectivity of the Valuation-control System in Healthy Young Adults

Loganathan K, Lv J, Cropley V, Ho ETW, Zalesky A

Neuroscience, 2021 01 01;452:295-310.
PMID: 33242540 DOI: 10.1016/j.neuroscience.2020.11.026

The process of valuation assists in determining if an object or course of action is rewarding. Delay discounting is the observed decay of a rewards' subjective value over time. Encoding the subjective value of rewards across a spectrum has been attributed to brain regions belonging to the valuation and executive control systems. The valuation system (VS) encodes reward value over short and long delays, influencing reinforcement learning and reward representation. The executive control system (ECS) becomes more active as choice difficulty increases, integrating contextual and mnemonic information with salience signals in the modulation of decision-making. Here, we aimed to identify resting-state functional connectivity-based patterns of the VS and ECS correlated with value-setting and delay discounting (outside-scanner paradigm) in a large (n = 992) cohort of healthy young adults from the Human Connectome Project (HCP). Results suggest the VS may be involved in value-setting of small, immediate rewards while the ECS may be involved in value-setting and delay discounting for large and small rewards over a range of delays. We observed magnitude sensitive connections involving the posterior cingulate cortex, time-sensitive connections with the ventromedial and lateral prefrontal cortex while connections involving the posterior parietal cortex appeared both magnitude- and time-sensitive. The ventromedial prefrontal cortex and posterior parietal cortex could act as "comparator" regions, weighing the value of small rewards against large rewards across various delay duration to aid in decision-making.
Direction of commissural axon projections in different regions of the spinal cord during chicken embryonic development

Li H, Yang C, Yusoff NM, Yahaya BH, Lin J

Neuroscience, 2017 09 01;358:269-276.
PMID: 28687312 DOI: 10.1016/j.neuroscience.2017.06.053

Few researchers have investigated the direction of commissural axon projections on the contralateral side of the vertebrate embryonic spinal cord, especially for comparison between its different regions. In this study, pCAGGS-GFP plasmid expression was limited to different regions of the chicken embryonic spinal cord (cervical, anterior limb, anterior thorax, posterior thorax and posterior limb) at E3 using in ovo electroporation with modified electrodes and optimal electroporation conditions. Then open-book technique was performed at E6 to analyze the direction of axon projections in different spinal cord regions. The results show that in the five investigated regions, most axons projected rostrally after crossing the floor plate while a minority projected caudally. And there was a significant difference between the rostral and caudal projection quantities (P<0.01). The ratio of rostral and caudal projections was significantly different between the five investigated regions (P<0.05), except between the cervical region and the anterior limb (P>0.05). The projections were most likely to be rostral for the posterior limb followed by the posterior thorax, cervical region, anterior limb and anterior thorax. Our data for the direction of the commissural axon projections will be helpful in the future analyses of axon projection mechanisms and spinal cord-brain circuit formation.
Functional brain imaging of walking while talking - An fNIRS study

Metzger FG, Ehlis AC, Haeussinger FB, Schneeweiss P, Hudak J, Fallgatter AJ, et al.

Neuroscience, 2017 02 20;343:85-93.
PMID: 27915210 DOI: 10.1016/j.neuroscience.2016.11.032

Since functional imaging of whole body movements is not feasible with functional magnetic resonance imaging (fMRI), the present study presents in vivo functional near-infrared spectroscopy (fNIRS) as a suitable technique to measure body movement effects on fronto-temporo-parietal cortical activation in single- and dual-task paradigms. Previous fNIRS applications in studies addressing whole body movements were typically limited to the assessment of prefrontal brain areas. The current study investigated brain activation in the frontal, temporal and parietal cortex of both hemispheres using functional near-infrared spectroscopy (fNIRS) with two large 4×4 probe-sets with 24 channels each during single and dual gait tasks. 12 young healthy adults were measured using fNIRS walking on a treadmill: the participants performed two single-task (ST) paradigms (walking at different speeds, i.e. 3 and 5km/h) and a dual task (DT) paradigm where a verbal fluency task (VFT) had to be executed while walking at 3km/h. The results show an increase of activation in Broca's area during the more advanced conditions (ST 5km/h vs. ST 3km/h, DT vs. ST 3km/h, DT vs. 5km/h), while the corresponding area on the right hemisphere was also activated. DT paradigms including a cognitive task in conjunction with whole body movements elicit wide-spread cortical activation patterns across fronto-temporo-parietal areas. An elaborate assessment of these activation patterns requires more extensive fNIRS assessments than the traditional prefrontal investigations, e.g. as performed with portable fNIRS devices.
Advancing Neuroscience Research in Africa: Invertebrate Species to the Rescue

Balogun WG, Cobham AE, Amin A, Seeni A

Neuroscience, 2018 03 15;374:323-325.
PMID: 29427653 DOI: 10.1016/j.neuroscience.2018.01.062

Neuroscience research and training in many African countries are difficult due to funding and infrastructure deficit. This has resulted in few neuroscientists within Africa. However, invertebrates such as Drosophila and Caenorhabditis elegans could provide the perfect answer to these difficulties. These organisms are cheap, easy to handle and offer a comparable advantage over vertebrates in neuroscience research modeling because they have a simple nervous system and exhibit well-defined behaviors. Studies using invertebrates have helped to understand neurosciences and the complexes associated with it. If Africa wants to catch up with the rest of the world in neuroscience research, it needs to employ this innovative cost-effective approach in its research. To improve invertebrate neuroscience within the Africa continent, the authors advocated the establishment of invertebrate research centers either at regional or national level across Africa. Finally, there is also a need to provide public funding to consolidate the gains that have been made by not-for-profit international organizations over the years.
Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy

Tan KL, Lee HC, Cheah PS, Ling KH

Neuroscience, 2023 Feb 10;511:1-12.
PMID: 36496187 DOI: 10.1016/j.neuroscience.2022.12.003

Mitochondrial dysfunctions have been described in Down syndrome (DS) caused by either partial or full trisomy of chromosome 21 (HSA21). Mitochondria play a crucial role in various vital functions in eukaryotic cells, especially in energy production, calcium homeostasis and programmed cell death. The function of mitochondria is primarily regulated by genes encoded in the mitochondrion and nucleus. Many genes on HSA21 are involved in oxidative phosphorylation (OXPHOS) and regulation of mitochondrial functions. This review highlights the HSA21 dosage-sensitive nuclear-encoded mitochondrial genes associated with overexpression-related phenotypes seen in DS. This includes impaired mitochondrial dynamics, structural defects and dysregulated bioenergetic profiles such as OXPHOS deficiency and reduced ATP production. Various therapeutic approaches for modulating energy deficits in DS, effects and molecular mechanism of gene therapy and drugs that exert protective effects through modulation of mitochondrial function and attenuation of oxidative stress in DS cells were discussed. It is prudent that improving DS pathophysiological conditions or quality of life may be feasible by targeting something as simple as cellular mitochondrial biogenesis and function.
Fulltext Higher-order Brain Areas Associated with Real-time Functional MRI Neurofeedback Training of the Somato-motor Cortex

Auer T, Dewiputri WI, Frahm J, Schweizer R

Neuroscience, 2018 May 15;378:22-33.
PMID: 27133575 DOI: 10.1016/j.neuroscience.2016.04.034

Neurofeedback (NFB) allows subjects to learn self-regulation of neuronal brain activation based on information about the ongoing activation. The implementation of real-time functional magnetic resonance imaging (rt-fMRI) for NFB training now facilitates the investigation into underlying processes. Our study involved 16 control and 16 training right-handed subjects, the latter performing an extensive rt-fMRI NFB training using motor imagery. A previous analysis focused on the targeted primary somato-motor cortex (SMC). The present study extends the analysis to the supplementary motor area (SMA), the next higher brain area within the hierarchy of the motor system. We also examined transfer-related functional connectivity using a whole-volume psycho-physiological interaction (PPI) analysis to reveal brain areas associated with learning. The ROI analysis of the pre- and post-training fMRI data for motor imagery without NFB (transfer) resulted in a significant training-specific increase in the SMA. It could also be shown that the contralateral SMA exhibited a larger increase than the ipsilateral SMA in the training and the transfer runs, and that the right-hand training elicited a larger increase in the transfer runs than the left-hand training. The PPI analysis revealed a training-specific increase in transfer-related functional connectivity between the left SMA and frontal areas as well as the anterior midcingulate cortex (aMCC) for right- and left-hand trainings. Moreover, the transfer success was related with training-specific increase in functional connectivity between the left SMA and the target area SMC. Our study demonstrates that NFB training increases functional connectivity with non-targeted brain areas. These are associated with the training strategy (i.e., SMA) as well as with learning the NFB skill (i.e., aMCC and frontal areas). This detailed description of both the system to be trained and the areas involved in learning can provide valuable information for further optimization of NFB trainings.
The Association Between Depth of the Olfactory Sulcus, Age, Gender and Olfactory Function: An MRI-based Investigation in More Than 1000 Participants

Li Z, Abdul Manan H, Heitmann H, Witte V, Wirkner K, Riedel-Heller S, et al.

Neuroscience, 2023 May 21;519:31-37.
PMID: 36934780 DOI: 10.1016/j.neuroscience.2023.03.017

OBJECTIVE: The present study aimed to investigate the relationship between olfactory sulcus (OS) depth and olfactory function considering age and gender and to provide normative data on OS depth in a population with normal olfactory function.
MATERIALS AND METHODS: OS depth was obtained using T1 magnetic resonance imaging scans. Participants (mean age ± sd = 57 ± 16 years, ranging from 20 to 80 years) were screened for olfactory function using the Sniffin' Sticks Screening 12 test. They were divided into an olfactory dysfunction group (n = 604) and a normosmia group (n = 493). Participants also completed questionnaires measuring depression, anxiety and quality of life.
RESULTS: The right OS was deeper than the left side in all age groups. On the left side, women had deeper OS compared with men, exhibiting a higher degree of symmetry in left and right OS depth in women. Variance of olfactory function was largely determined by age, OS depth explained only minor portions of this variance. Normative data for minimum OS depth was 7.55 mm on the left and 8.78 mm on the right for participants aged between 18 and 35 years (n = 144), 6.47 mm on the left and 6.99 mm on the right for those aged 36-55 years (n = 120), and 5.28 mm on the left and 6.19 mm on the right for participants older than 55 years (n = 222).
CONCLUSION: Considering the limited resolution of the presently used T1 weighted MR scans and the nature of the olfactory screening test, OS depth explained only minor portions of the variance of olfactory function, which was largely determined by age. Age-related normative data of OS depth are presented as a reference for future work.
Nanostructured Photonics Probes: A Transformative Approach in Neurotherapeutics and Brain Circuitry

Ahmed Taha B, Addie AJ, Saeed AQ, Haider AJ, Chaudhary V, Arsad N

Neuroscience, 2024 Dec 06;562:106-124.
PMID: 39490518 DOI: 10.1016/j.neuroscience.2024.10.046

Neuroprobes that use nanostructured photonic interfaces are capable of multimodal sensing, stimulation, and imaging with unprecedented spatio-temporal resolution. In addition to electrical recording, optogenetic modulation, high-resolution optical imaging, and molecular sensing, these advanced probes combine nanophotonic waveguides, optical transducers, nanostructured electrodes, and biochemical sensors. The potential of this technology lies in unraveling the mysteries of neural coding principles, mapping functional connectivity in complex brain circuits, and developing new therapeutic interventions for neurological disorders. Nevertheless, achieving the full potential of nanostructured photonic neural probes requires overcoming challenges such as ensuring long-term biocompatibility, integrating nanoscale components at high density, and developing robust data-analysis pipelines. In this review, we summarize and discuss the role of photonics in neural probes, trends in electrode diameter for neural interface technologies, nanophotonic technologies using nanostructured materials, advances in nanofabrication photonics interface engineering, and challenges and opportunities. Finally, interdisciplinary efforts are required to unlock the transformative potential of next-generation neuroscience therapies.

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