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Chirality is a fundamental trait of living organisms, encompassing the homochirality of biological molecules and the left-right (LR) asymmetry of visceral organs and the brain. The nervous system in bilaterian organisms displays a lateralized organization characterized by the presence of asymmetrical neuronal circuits and brain functions that are predominantly localized within one hemisphere. Although body asymmetry is relatively well understood, and exhibits robust phenotypic expression and regulation via conserved molecular mechanisms across phyla, current findings indicate that the asymmetry of the nervous system displays greater phenotypic, genetic, and evolutionary variability. In this review we explore the use of nematode, zebrafish, and Drosophila genetic models to investigate neuronal circuit asymmetry. We discuss recent discoveries in the context of body-brain concordance and highlight the distinct characteristics of nervous system asymmetry and its cognitive correlates., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Melatonin (MLT) exerts its physiological effects principally through two high-affinity membrane receptors MT1 and MT2. Understanding the exact mechanism of MLT action necessitates the use of highly selective agonists/antagonists to stimulate/inhibit a given MLT receptor. The respective distribution of MT1 and MT2 within the CNS and elsewhere is controversial, and here we used a "knock-in" strategy replacing MT1 or MT2 coding sequences with a LacZ reporter. The data show striking differences in the distribution of MT1 and MT2 receptors in the mouse brain: whereas the MT1 subtype was expressed in very few structures (notably including the suprachiasmatic nucleus and pars tuberalis), MT2 subtype receptors were identified within numerous brain regions including the olfactory bulb, forebrain, hippocampus, amygdala and superior colliculus. Co-expression of the two subtypes was observed in very few structures, and even within these areas they were rarely present in the same individual cell. In conclusion, the expression and distribution of MT2 receptors are much more widespread than previously thought, and there is virtually no correspondence between MT1 and MT2 cellular expression. The precise phenotyping of cells/neurons containing MT1 or MT2 receptor subtypes opens new perspectives for the characterization of links between MLT brain targets, MLT actions and specific MLT receptor subtypes., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To localise and characterise changes in cognitive networks in Amyotrophic Lateral Sclerosis (ALS) using source analysis of mismatch negativity (MMN) waveforms., Rationale: The MMN waveform has an increased average delay in ALS. MMN has been attributed to change detection and involuntary attention switching. This therefore indicates pathological impairment of the neural network components which generate these functions. Source localisation can mitigate the poor spatial resolution of sensor-level EEG analysis by associating the sensor-level signals to the contributing brain sources. The functional activity in each generating source can therefore be individually measured and investigated as a quantitative biomarker of impairment in ALS or its sub-phenotypes., Methods: MMN responses from 128-channel electroencephalography (EEG) recordings in 58 ALS patients and 39 healthy controls were localised to source by three separate localisation methods, including beamforming, dipole fitting and exact low resolution brain electromagnetic tomography., Results: Compared with controls, ALS patients showed significant increase in power of the left posterior parietal, central and dorsolateral prefrontal cortices (false discovery rate = 0.1). This change correlated with impaired cognitive flexibility (rho = 0.45, 0.45, 0.47, p = .042, .055, .031 respectively). ALS patients also exhibited a decrease in the power of dipoles representing activity in the inferior frontal (left: p = 5.16 × 10 -6 , right: p = 1.07 × 10 -5 ) and left superior temporal gyri (p = 9.30 × 10 -6 ). These patterns were detected across three source localisation methods. Decrease in right inferior frontal gyrus activity was a good discriminator of ALS patients from controls (AUROC = 0.77) and an excellent discriminator of C9ORF72 expansion-positive patients from controls (AUROC = 0.95)., Interpretation: Source localization of evoked potentials can reliably discriminate patterns of functional network impairment in ALS and ALS subgroups during involuntary attention switching. The discriminative ability of the detected cognitive changes in specific brain regions are comparable to those of functional magnetic resonance imaging (fMRI). Source analysis of high-density EEG patterns has excellent potential to provide non-invasive, data-driven quantitative biomarkers of network disruption that could be harnessed as novel neurophysiology-based outcome measures in clinical trials., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

A large multiparametric MRI study has been undertaken to evaluate anatomical patterns of basal ganglia, white matter and cortical grey matter involvement in ALS. Unaffected brain regions are mapped in patients with significant disability. Multiple white matter diffusivity measures, cortical grey matter density alterations, basal ganglia volumes and subcortical grey matter atrophy patterns are evaluated. Results demonstrated a strikingly selective anatomical vulnerability pattern in ALS that preferentially affects specific grey matter structures, commissural white matter tracts and basal ganglia regions, suggestive of networkwise neurodegeneration in ALS. In conclusion, ALS pathology exhibits predilection for selective and inter-connected anatomical sites that can be comprehensively characterized in vivo by multiparametric neuroimaging. The systematic characterization of unaffected brain regions in ALS has implications for the development of classifier analyses and elucidation of disease biology. The involvement and sparing of contiguous brain regions raises important pathophysiological, phylogenetic and ontogenetic questions regarding ALS pathogenesis and disease spread.

Objective: Although a systematic spread of pathologic TDP-43 expression throughout the CNS in amyotrophic lateral sclerosis (ALS) has been proposed, the relationship between cognition and the extent and neuroanatomic distribution of TDP-43 pathology has not received considerable attention., Methods: We investigated the association between cognitive functioning and the extent of TDP-43 pathology in postmortem CNS tissue from 18 patients with ALS stratified into 3 groups based on detailed prospective neuropsychological testing (cognitively not impaired, n = 6; cognitively impaired, n = 6; ALS- frontotemporal dementia [FTD], n = 6) and analyzed these cases for clinicopathologic correlations., Results: Our findings demonstrate a close relationship between cognition and the extent of TDP-43 pathology in non-primary motor areas with a striking difference between ALS-FTD and the 2 other cognitive groups. The specificity of our results was underscored by 2 key findings: first, the absence of an Alzheimer pathology effect, a common confounder in older patients; second, the lack of correlations between the primary motor regions with the highest TDP-43 intensity and cognitive status., Conclusions: Our data suggest a distinct dynamic of TDP-43 progression and distribution in ALS-FTD in contrast to ALS without FTD., (© 2016 American Academy of Neurology.)

Plant grafting is a biologically important phenomenon involving the physical joining of two plants to generate a chimeric organism. It is widely practiced in horticulture and used in science to study the long-distance movement of molecules. Despite its widespread use, the mechanism of graft formation and vascular reconnection is not well understood. Here, we study the dynamics and mechanisms of vascular regeneration in Arabidopsis thaliana during graft formation when the vascular strands are severed and reconnected. We demonstrate a temporal separation between tissue attachment, phloem connection, root growth, and xylem connection. By analyzing cell division patterns and hormone responses at the graft junction, we found that tissues initially show an asymmetry in cell division, cell differentiation, and gene expression and, through contact with the opposing tissue, lose this asymmetry and reform the vascular connection. In addition, we identified genes involved in vascular reconnection at the graft junction and demonstrate that these auxin response genes are required below the graft junction. We propose an inter-tissue communication process that occurs at the graft junction and promotes vascular connection by tissue-specific auxin responses involving ABERRANT LATERAL ROOT FORMATION 4 (ALF4). Our study has implications for phenomena where forming vascular connections are important including graft formation, parasitic plant infection, and wound healing., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The use of spectroscopic Missing Pulse--SSFP (spMP-SSFP) for fast three-dimensional (3D) proton MR spectroscopic imaging (MRSI) at 7 Tesla (T) is demonstrated. Sequence modifications were required regarding the limits of the specific absorption rate as well as hardware limitations with respect to maximum B(1) field strength and B(0) gradient slew rate, as compared to previous studies performed at 3T. The combination of two spatially selective radiofrequency (RF) pulses (with orthogonal slice orientation) and a dual-band chemical shift selective RF pulse for simultaneous water and lipid suppression proved to enable fast 3D MRSI measurements of the brain of healthy volunteers. Using a total measurement time of approximately 8.5 minutes and a nominal and real voxel size of 0.62 cm(3) and 2.6 cm(3), respectively, signals of N-acetyl aspartate, total creatine, choline containing compounds, myo-inositol, and glutamate+glutamine could be detected.

Three-dimensional (3D) (1)H MR spectroscopic imaging (SI) allows metabolic changes in human tissue to be identified. In clinical practice, fast acquisition techniques are required to achieve an adequate spatial resolution within acceptable total measurement times. In this study a novel fast pulse sequence for 3D (1)H SI based on the condition of steady-state free precession (SSFP), termed "spectroscopic missing-pulse SSFP" (spMP-SSFP), is proposed. It combines 3D spatial preselection with the acquisition of full spin echoes (SEs), and thus makes subsequent phase correction of spectra redundant. The sequence was applied to a phantom and healthy human brains in vivo at 3 Tesla. Metabolic images are acquired with a spatial resolution of 1.8 cm(3) within a total measurement time of about 6 min. With a lower signal-to-noise ratio (SNR) per unit measurement time compared to previous spectroscopic SSFP implementations, 3D spatial preselection can now be realized with spMP-SSFP. Since the method does not require separate techniques for water and lipid suppression, and employs a simple data-processing approach, spMP-SSFP is a robust, fast SI method that requires only minimal user interaction.

The combined administration of phentermine and fenfluramine (PHEN/FEN) has been used as a treatment for obesity. Recent evidence suggests that this drug mixture may also be an effective medication for substance abuse disorders, including cocaine dependence. It is well-established that repeated high-dose fenfluramine causes serotonin (5-HT) terminal degeneration in laboratory animals, and no studies have addressed possible interactions between phentermine and fenfluramine. The purpose of the present work was to examine the effect of phentermine coadministration on fenfluramine-induced depletion of 5-HT in mouse forebrain. In addition, because of the potential for cocaine abuse in drug addicts taking PHEN/FEN as a medication, we examined the effects of PHEN/FEN on forebrain 5-HT levels in the presence or absence of cocaine. Fenfluramine (0, 3, 10, 30 mg/kg, s.c. twice daily for 4 days) caused a dose-dependent reduction in forebrain 5-HT without affecting dopamine or norepinephrine. Phentermine coadministration (7 mg/kg, s.c. twice daily for 4 days) did not significantly alter the 5-HT-depleting effect of fenfluramine. Likewise, cocaine (10 mg/kg, i.p.), administered 60 min prior to or 60 min after PHEN/FEN, had no effect on the PHEN/FEN-induced decrease in central 5-HT. The present results indicate that doses of phentermine far above those typically administered to humans do not potentiate the 5-HT-depleting effect of repeated high-dose fenfluramine. Moreover, exposure to cocaine does not significantly alter the long-term neurochemical actions of the PHEN/FEN mixture.

Fenfluramine is an anorectic agent in clinical use that is believed to act by enhancing 5-hydroxytryptamine (5-HT) neurotransmission. Tolerance to the anorectic properties of fenfluramine develops rapidly and long-lasting depletions of brain 5-HT have been reported to occur after repeated administration. It is possible that tolerance to fenfluramine may be related to the 5-HT depletions. Rats (n = 96), previously allowed to drink sweetened condensed milk during daily 15-min sessions, were treated with fenfluramine (6.25 mg/kg/12 hr x 4 days) or saline. Two or 8 weeks later rats were administered fenfluramine acutely (0, 1.25, 6.25 or 12.5 mg/kg; n = 6/group), tested for milk intake and sacrificed 2 hr later. Brains were removed and regions assayed for dopamine, 5-HT and metabolites. Acute administration of fenfluramine produced a dose-dependent decrease in milk intake and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in cortex, hypothalamus and hippocampus. Tolerance to the effects of acute fenfluramine on milk intake was observed in rats at 2 weeks (ED50 = 3.24 vs. 6.37 mg/kg; saline vs. fenfluramine pretreatment, respectively) and, to a lesser extent, at 8 weeks (ED50 = 2.99 vs. 4.04 mg/kg; saline vs. fenfluramine pretreatment) after the 4-day regimen of fenfluramine. Levels of 5-HT and 5-HIAA in somatosensory cortex, hypothalamus, striatum and hippocampus were depleted significantly 2 weeks after the last daily fenfluramine injection. The acute 5-HT depleting effect of fenfluramine was markedly attenuated in these regions 2 weeks after the 4-day regimen of fenfluramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Numerous recent studies indicate that when amphetamines are administered continuously or in high doses, they exert long-lasting toxic effects on dopamine (DA) neurons in the central nervous system (CNS). Specifically, it has been shown that amphetamines can decrease the content of brain DA, reduce the number of synaptosomal DA uptake sites and selectively depress the in vitro activity of neostriatal tyrosine hydroxylase (TH). To date, however, anatomical evidence of DA neuronal destruction following amphetamines has not been reported. In this study, chemical methods were used in conjunction with the Fink-Heimer method which allows for the selective silver impregnation of degenerating nerve fibers, in order to determine whether methylamphetamine, a potent psychomotor stimulant often abused by man, causes actual DA neural degeneration. It has been found that methylamphetamine induces terminal degeneration along with correlative DA neurochemical deficits in the neostriatum and nucleus accumbens; furthermore, that in cresyl violet-stained sections of the substantia nigra (SN), pars compacta, and ventral tegmental area (VTA), there is no evidence of cell body loss in rats in which 50-60% of neostriatal DA terminals have been destroyed.

(+/-)-3,4-Methylenedioxyamphetamine (MDA), an amphetamine analog with hallucinogenic activity, produced selective long-lasting reductions in the level of serotonin, the number of serotonin uptake sites, and the concentration of 5-hydroxyindoleacetic acid in rat brain. Morphological studies suggested that these neurochemical deficits were due to serotonin nerve terminal degeneration. These results show that MDA has toxic activity for serotonin neurons in rats and raise the question of whether exposure to MDA and related hallucinogenic amphetamines can produce serotonin neurotoxicity in the human brain.

Repeated high doses (25 and 100 mg/kg) of methylamphetamine produce long-term depletions of both dopamine (DA) and serotonin (5-HT) in the rat brain. In the DA system, depletions are most pronounced in the neostriatum and substantia nigra, with decreased levels in these two regions being significantly correlated. Within the 5-HT system, levels are most reduced in the amygdala, frontal cortex and neostriatum. When both the DA and 5-HT depleting actions of methylamphetamine are considered, the hypothalamus stands out as one of the more resistant brain regions. The regional pattern of reduced 5-HT levels following methylamphetamine is similar to that seen after p-chloroamphetamine. After both methylamphetamine and p-chloroamphetamine, a loss of 5-HT synaptosomal uptake sites occurs. Serotonergic systems are more sensitive than DA systems to the apparent neurotoxic actions of methylamphetamine.

(+/-)-3,4-Methylenedioxymethylamphetamine (MDMA) was administered s.c. to rats (10, 20 or 40 mg/kg b. wt.) and guinea pigs (20 mg/kg) twice a day for 4 days, 2 weeks before decapitation. Norepinephrine, dopamine and serotonin (5-HT) levels were assayed in the hippocampus, hypothalamus, striatum and neocortex. In rats, MDMA produced dose-dependent reductions in 5-HT in all brain regions examined. The highest dose also reduced norepinephrine and/or dopamine in some regions. The 20-mg/kg dose of MDMA depleted 5-HT in all regions of the guinea pig brain assayed. In both species, repeated administration of 20 mg/kg of MDMA reduced the Vmax but not the Km of 5-HT uptake 2 weeks after administration. A single 40-mg/kg injection of MDMA depleted 5-HT 2 and 8 weeks after administration to rats in all regions of the brain examined except the hypothalamus. Administration of 80 mg/kg of MDMA twice a day for 2 days to rats depleted striatal 5-HT and dopamine. Brain sections from rats injected with MDMA according to this dosage regimen were stained by the Fink-Heimer method. Degenerating axon terminals and cell bodies were observed in the striatum and somatosensory cortex, respectively. These findings suggest that MDMA is toxic to serotonergic and, to a lesser extent, catecholaminergic neurons. Some neurons that do not contain these transmitters (neocortical neurons) are also affected.