Cerebellar GABA change during visuomotor adaptation relates to adaptation performance and cerebellar network connectivity: A Magnetic Resonance Spectroscopic Imaging study.

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum that underpin human motor adaptation remain unknown. We used a novel Magnetic Resonance Spectroscopic Imaging (MRSI) technique to measure changes in the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the human cerebellum during visuomotor adaptation. Participants used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We were able to spatially resolve adaptation-driven GABA changes at the cerebellar nuclei and in the cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple movement of the right hand increases GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found an increase in GABA in the left cerebellar nuclei and a decrease in GABA in the right cerebellar nuclei during adaptation. Early adaptation-driven GABA change in the right cerebellar nuclei correlated with adaptation performance: Participants showing greater GABA decrease adapted better, suggesting that this early GABA change is behaviourally relevant. Early GABA change also correlated with functional connectivity change in a cerebellar network: Participants showing a greater decrease in GABA also showed greater strength increase in cerebellar network connectivity. These results were specific to GABA, specific to adaptation and specific to the cerebellar network. This study provides the first evidence for plastic changes in cerebellar neurochemistry during a motor adaptation task. Characterising these naturally occurring neurochemical changes may provide a basis for developing therapeutic interventions to facilitate neurochemical changes in the cerebellum that can improve human motor adaptation.

Alcohol, Aggression, and Violence: From Public Health to Neuroscience

Alcohol has been associated with violent crimes and domestic violence across many nations. Various etiological factors were linked to chronic alcohol use and violence including psychiatric comorbidities of perpetrators such as personality disorders, mood disorders, and intermittent explosive disorders. Aggression is the precursor of violence and individuals prone to aggressive behaviors are more likely to commit impulsive violent crimes, especially under the influence of alcohol. Findings from brain studies indicate long-term alcohol consumption induced morphological changes in brain regions involved in self-control, decision-making, and emotional processing. In line with this, the inherent dopaminergic and serotonergic anomalies seen in aggressive individuals increase their susceptibility to commit violent crimes when alcohol present in their system. In relation to this, this article intends to investigate the influence of alcohol on aggression with sociopsychological and neuroscientific perspectives by looking into comorbidity of personality or mood disorders, state of the mind during alcohol consumption, types of beverages, environmental trigger, neurochemical changes, and gender differences that influence individual responses to alcohol intake and susceptibility to intoxicated aggression.

Relating Neurochemical Changes Associated with THC Use to Learning and Memory in Adolescent Rats

<p>Cannabis is the most widely used illicit drug. Adolescents may be especially vulnerable to the effects of cannabis, and alarmingly, adolescence is also a period of heavy cannabis use. However, few studies have investigated the cognitive effects of cannabis use in adolescents specifically. Furthermore, the neurochemical correlates of cognitive impairment associated with cannabis use at any age have received very little experimental attention. This research project sought to address these shortcomings in the literature using THC, the major psychoactive component of cannabis, and a rat model of adolescence. The rate of learning was slower in THC-treated animals, and this was attributable to deficits in the cognitive function of 'chunking', a process by which the information capacity of short-term memory is enlarged. Impairment of chunking by cannabinoids has not been previously reported. Behavioural impairment by THC was associated with impaired hippocampal plasticity, including changes in synaptic activity and architecture, as well as changes in neurogenesis. The attenuation of structural and functional plasticity in the hippocampus in response to training in a learning task was more pronounced than the subtle effects of THC-treatment on the survival and early development of newborn neurons. Importantly, no effects of THC were seen in animals not trained in the maze. Thus, plasticity is more sensitive to the effects of THC during times of learning, and this greater sensitivity likely accounts for the behavioural impairment associated with cannabis use. The data presented in this thesis add significantly to the existing literature by identifying novel behavioural and neurochemical processes by which cannabis use may impair learning and memory. Whether these impairments represent a greater sensitivity of adolescents to THC remains to be determined.</p>

Relating Neurochemical Changes Associated with THC Use to Learning and Memory in Adolescent Rats

<p>Cannabis is the most widely used illicit drug. Adolescents may be especially vulnerable to the effects of cannabis, and alarmingly, adolescence is also a period of heavy cannabis use. However, few studies have investigated the cognitive effects of cannabis use in adolescents specifically. Furthermore, the neurochemical correlates of cognitive impairment associated with cannabis use at any age have received very little experimental attention. This research project sought to address these shortcomings in the literature using THC, the major psychoactive component of cannabis, and a rat model of adolescence. The rate of learning was slower in THC-treated animals, and this was attributable to deficits in the cognitive function of 'chunking', a process by which the information capacity of short-term memory is enlarged. Impairment of chunking by cannabinoids has not been previously reported. Behavioural impairment by THC was associated with impaired hippocampal plasticity, including changes in synaptic activity and architecture, as well as changes in neurogenesis. The attenuation of structural and functional plasticity in the hippocampus in response to training in a learning task was more pronounced than the subtle effects of THC-treatment on the survival and early development of newborn neurons. Importantly, no effects of THC were seen in animals not trained in the maze. Thus, plasticity is more sensitive to the effects of THC during times of learning, and this greater sensitivity likely accounts for the behavioural impairment associated with cannabis use. The data presented in this thesis add significantly to the existing literature by identifying novel behavioural and neurochemical processes by which cannabis use may impair learning and memory. Whether these impairments represent a greater sensitivity of adolescents to THC remains to be determined.</p>

Hypothalamic neurochemical changes in long-term recovered bilateral subdiaphragmatic vagotomized rats

BackgroundVagus nerve is one of the crucial routes in communication between immune and central nervous systems. Impaired vagal nerve function may intensify peripheral inflammatory processes. This effect subsides along with prolonged recovery after permanent nerve injury. One of the results of such compensation is a normalized plasma concentration of stress hormone corticosterone – a marker of hypothalamic-pituitary-adrenal (HPA) axis activity. In the present work we strive to explain this corticosterone normalization by studying the mechanisms responsible for compensation-related neurochemical alterations in the hypothalamus. Methods Using microarrays and HPLC we measured genome-wide gene expression and major amino acid neurotransmitters content in hypothalamus of bilaterally vagotomized rats, one month after surgery.ResultsOur results show that, in the long-term, vagotomy affects hypothalamic amino acids concentration but not mRNA expression of tested genes.ConclusionsWe propose an alternative pathway of immune to CNS communication after vagotomy, leading to activation of HPA axis, by influencing central amino acids and subsequent monoaminergic neurotransmission.

In vivo MR spectroscopy reflects synapse density in a Huntington′s disease mouse model

Background: Striatal medium spiny neurons are highly susceptible in Huntington′s disease (HD), resulting in early synaptic perturbations that lead to neuronal dysfunction and death. Non-invasive imaging techniques, such as proton magnetic resonance spectroscopy (1H-MRS), have been used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the molecular connection between brain neurochemical alterations and synaptic dysregulation is unknown, limiting our ability to monitor potential treatments that may affect synapse function. Objective: Assess the intersection of synapse density and 1H-MRS during disease progression in an HD mouse model. Methods: We conducted in vivo longitudinal 1H-MRS in the striatum followed by ex-vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD: thalamo-striatal (T-S) and cortico-striatal (C-S) pathways. We used the heterozygous knock-in zQ175 HD mouse model as well as zQ175 mice lacking one allele of CK2α′(zQ175(Tg/0):CK2α′(+/-)), a kinase previously shown to regulate synapse function in HD. Results: Longitudinal analyses of excitatory synapse density showed early and sustained reduction in T-S synapses in zQ175 mice, preceding C-S synapse depletion, which was rescued in zQ175:CK2α′(+/-). Linear regression analyses showed C-S synapse number correlated with 1H-MRS-measured levels of GABA while T-S synapse number positively correlated with alterations in the levels of alanine, phosphoethanolamine, lactate, and taurine relative to total creatine. Conclusion: We propose these neurochemicals could be used as surrogate biomarkers to monitor circuit-specific synaptic dysfunction using 1H-MRS in the zQ175 mouse model and perhaps in HD pre-clinical studies.

Meta-Analysis of Neurochemical Changes Estimated via Magnetic Resonance Spectroscopy in Mild Cognitive Impairment and Alzheimer's Disease

The changes of neurochemicals in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients has been observed via magnetic resonance spectroscopy in several studies. However, whether it exists the consistent pattern of changes of neurochemicals in the encephalic region during the progression of MCI to AD were still not clear. The study performed meta-analysis to investigate the patterns of neurochemical changes in the encephalic region in the progress of AD. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases, and finally included 63 studies comprising 1,086 MCI patients, 1,256 AD patients, and 1,907 healthy controls. It showed that during the progression from MCI to AD, N-acetyl aspartate (NAA) decreased continuously in the posterior cingulate (PC) (SMD: −0.42 [95% CI: −0.62 to −0.21], z = −3.89, P &lt; 0.05), NAA/Cr (creatine) was consistently reduced in PC (SMD: −0.58 [95% CI: −0.86 to −0.30], z = −4.06, P &lt; 0.05) and hippocampus (SMD: −0.65 [95% CI: −1.11 to −0.12], z = −2.44, P &lt; 0.05), while myo-inositol (mI) (SMD: 0.44 [95% CI: 0.26–0.61], z = 4.97, P &lt; 0.05) and mI/Cr (SMD: 0.43 [95% CI: 0.17–0.68], z = 3.30, P &lt; 0.05) were raised in PC. Furthermore, these results were further verified by a sustained decrease in the NAA/mI of PC (SMD: −0.94 [95% CI: −1.24 to −0.65], z = −6.26, P &lt; 0.05). Therefore, the levels of NAA and mI were associated with the cognitive decline and might be used as potentially biomarkers to predict the possible progression from MCI to AD.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42020200308.

Ochratoxin A induces behavioral and neurochemical changes in adult zebrafish

Ochratoxin A (OTA) is a mycotoxin produced by species of filamentous fungi widely found as a contaminant in food and with high toxic potential. Studies have shown that this toxin cause kidney and liver damage, however, data on the effects of exposure to OTA on the central nervous system are still scarce. Zebrafish (Danio rerio) is a teleost often used in translational research due to its physiological, genetic, and behavioral homology with mammals, in addition to being useful as an environmental bioindicator. Thus, this study aimed to investigate the effects of exposure to OTA on behavioral and neurochemical parameters in adult zebrafish. The animals were treated with different doses of OTA (1.38, 2.77, and 5.53 mg/kg) and submitted to behavioral evaluations in the open tank and social interaction tests. Subsequently, they were euthanized, and the brains were used to assess markers associated with oxidative status. In the open tank test OTA induced changes in distance, absolute turn angle, mean speed, and time-freezing. However, no significant effects were observed in the social interaction test. Moreover, OTA also induced alterations in neurochemical parameters with changes in non-protein thiols (NPSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR). This study showed that OTA can affect neurobiological aspects in zebrafish even at low doses.

2D vs 3D morphological analysis of dorsal root ganglia in health and painful neuropathy

Dorsal root ganglia (DRGs) are clusters of sensory neurons that transmit the sensory information from the periphery to the central nervous system, and satellite glial cells (SGCs), their supporting trophic cells. Sensory neurons are pseudounipolar neurons with a heterogeneous neurochemistry reflecting their functional features. DRGs, not protected by the blood brain barrier, are vulnerable to stress and damage of different origin (i.e., toxic, mechanical, metabolic, genetic) that can involve sensory neurons, SGCs or, considering their intimate intercommunication, both cell populations. DRG damage, primary or secondary to nerve damage, produces a sensory peripheral neuropathy, characterized by neurophysiological abnormalities, numbness, paraesthesia and dysesthesia, tingling and burning sensations and neuropathic pain. DRG stress can be morphologically detected by light and electron microscope analysis with alterations in cell size (swelling/atrophy) and in different sub-cellular compartments (i.e., mitochondria, endoplasmic reticulum, and nucleus) of neurons and/or SGCs. In addition, neurochemical changes can be used to portray abnormalities of neurons and SGC. Conventional immunostaining, i.e., immunohistochemical detection of specific molecules in tissue slices can be employed to detect, localize and quantify particular markers of damage in neurons (i.e., nuclear expression ATF3) or SGCs (i.e., increased expression of GFAP), markers of apoptosis (i.e., caspases), markers of mitochondrial suffering and oxidative stress (i.e., 8-OHdG), markers of tissue inflammation (i.e., CD68 for macrophage infiltration), etc. However classical (2D) methods of immunostaining disrupt the overall organization of the DRG, thus resulting in the loss of some crucial information. Whole-mount (3D) methods have been recently developed to investigate DRG morphology and neurochemistry without tissue slicing, giving the opportunity to study the intimate relationship between SGCs and sensory neurons in health and disease. Here, we aim to compare classical (2D) vs whole-mount (3D) approaches to highlight “pros” and “cons” of the two methodologies when analysing neuropathy-induced alterations in DRGs.

510 - EFFECT OF SLEEP DEPRIVATION ON SOCIAL RESILIENCE THROUGH ΔFOSB ACTIVATION

Introduction:Stress can have a variety of detrimental effects on humans. From depression and anxiety to schizophrenia, stress plays a factor in the development of these diseases through neurochemical changes in the brain and elevated levels of hormones. Among the geriatric population, decreased sleep levels are known to be a frequent issue; insomnia rates among the senior population are much higher in frequency compared to any other age group. Sleep deprivation also leads to major consequences in the brain and sleep disruption is linked to neuropsychological illness; however, the specific mechanisms involved in these effects are not understood. This study focuses on the resilient effects of ΔFosB, a protein known to mediate resilience to stress and the direct effect of sleep deprivation on ΔFosB expression in areas known to mediate resilience to social stress. We hypothesize that ΔFosB may be part of the mechanism through which sleep alters resilience to social stress.Methods:Mice were sleep-deprived for an eight-hour period for five days. After sleep deprivation they were subject to social defeat and underwent avoidance testing. The brains of these mice were removed, and immunohistochemistry analysis was conducted to determine ∆FosB expression in various sections of the brain.Results:The preliminary findings of this study indicates that sleep is altered in resilient animals and that sleep deprivation may lead to increased resilience to social defeat. The most significant decrease in ∆FosB expression was found in the prelimbic cortex, a change associated with resilience, and which was observed after chronic sleep deprivation. Contrarily, there was also an increase of ∆FosB expression in the nucleus accumbens.Conclusion:These findings indicate that changes in ∆FosB activation in the brain is a significant factor for promoting resilient behavior in situations of social stress. In particular, a decrease in ∆FosB activation in the PLC plays a role in explaining how sleep deprivation contributes to decreased social resilience in situations of social stress.