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International Journal of Molecular... May 2024Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various...
Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (VO) typically presents along with manganese (Mn), especially in welding rods and high-capacity batteries, including electric vehicle batteries; however, the neurotoxic effects of vanadium (V) and Mn co-exposure are largely unknown. In this study, we investigated the neurotoxic impact of MnCl, VO and MnCl-VO co-exposure in an animal model. C57BL/6 mice were intranasally administered either de-ionized water (vehicle), MnCl (252 µg) alone, VO (182 µg) alone, or a mixture of MnCl (252 µg) and VO (182 µg) three times a week for up to one month. Following exposure, we performed behavioral, neurochemical, and histological studies. Our results revealed dramatic decreases in olfactory bulb (OB) weight and levels of tyrosine hydroxylase, dopamine, and 3,4-dihydroxyphenylacetic acid in the treatment groups compared to the control group, with the Mn/V co-treatment group producing the most significant changes. Interestingly, increased levels of α-synuclein expression were observed in the substantia nigra (SN) of treated animals. Additionally, treatment groups exhibited locomotor deficits and olfactory dysfunction, with the co-treatment group producing the most severe deficits. The treatment groups exhibited increased levels of the oxidative stress marker 4-hydroxynonenal in the striatum and SN, as well as the upregulation of the pro-apoptotic protein PKCδ and accumulation of glomerular astroglia in the OB. The co-exposure of animals to Mn/V resulted in higher levels of these metals compared to other treatment groups. Taken together, our results suggest that co-exposure to Mn/V can adversely affect the olfactory and nigral systems. These results highlight the possible role of environmental metal mixtures in the etiology of Parkinsonism.
Topics: Animals; Mice; Manganese; Mice, Inbred C57BL; Vanadium; Manganese Compounds; Male; Olfactory Bulb; Dopamine; Vanadium Compounds; Oxidative Stress; Parkinsonian Disorders; alpha-Synuclein; Chlorides; Tyrosine 3-Monooxygenase; Aldehydes; Substantia Nigra; Disease Models, Animal; 3,4-Dihydroxyphenylacetic Acid
PubMed: 38791326
DOI: 10.3390/ijms25105285 -
International Journal of Molecular... May 2024Tobacco use disorder represents a significant public health challenge due to its association with various diseases. Despite awareness efforts, smoking rates remain high,...
Tobacco use disorder represents a significant public health challenge due to its association with various diseases. Despite awareness efforts, smoking rates remain high, partly due to ineffective cessation methods and the spread of new electronic devices. This study investigated the impact of prolonged nicotine exposure via a heat-not-burn (HnB) device on selected genes and signaling proteins involved in inflammatory processes in the rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions associated with addiction to different drugs, including nicotine. The results showed a reduction in mRNA levels for and , two nuclear receptors and anti-inflammatory transcription factors, along with the dysregulation of gene expression of the epigenetic modulator , in both investigated brain areas. Moreover, decreased mRNA levels and higher AKT phosphorylation were detected in the VTA of HnB-exposed rats with respect to their control counterparts. Finally, significant alterations in ERK 1/2 phosphorylation were observed in both mesolimbic areas, with VTA decrease and NAc increase, respectively. Overall, the results suggest that HnB aerosol exposure disrupts intracellular pathways potentially involved in the development and maintenance of the neuroinflammatory state. Moreover, these data highlight that, similar to conventional cigarettes, HnB devices use affects specific signaling pathways shaping neuroinflammatory process in the VTA and NAc, thus triggering mechanisms that are currently considered as potentially relevant for the development of addictive behavior.
Topics: Animals; Rats; Ventral Tegmental Area; Male; Nucleus Accumbens; Neuroinflammatory Diseases; PPAR gamma; Signal Transduction; PTEN Phosphohydrolase; Smoke; Nicotine; Rats, Wistar; Nicotiana; Tobacco Use Disorder; Phosphorylation
PubMed: 38791298
DOI: 10.3390/ijms25105259 -
Nature Jun 2024Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which...
Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs. Among the opioid receptors, µ-opioid receptors have a key role, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.
Topics: Animals; Female; Male; Mice; Analgesics, Opioid; Central Amygdaloid Nucleus; Dopamine; Dopaminergic Neurons; Fentanyl; Mice, Inbred C57BL; Nucleus Accumbens; Opioid-Related Disorders; Optogenetics; Receptors, Opioid, mu; Reinforcement, Psychology; Substance Withdrawal Syndrome; Ventral Tegmental Area
PubMed: 38778097
DOI: 10.1038/s41586-024-07440-x -
Brain Research Bulletin Jul 2024The medial prefrontal cortex (mPFC) forms output pathways through projection neurons, inversely receiving adjacent and long-range inputs from other brain regions....
INTRODUCTION
The medial prefrontal cortex (mPFC) forms output pathways through projection neurons, inversely receiving adjacent and long-range inputs from other brain regions. However, how afferent neurons of mPFC are affected by chronic stress needs to be clarified. In this study, the effects of chronic restraint stress (CRS) on the distribution density of mPFC dendrites/dendritic spines and the projections from the cortex and subcortical brain regions to the mPFC were investigated.
METHODS
In the present study, C57BL/6 J transgenic (Thy1-YFP-H) mice were subjected to CRS to establish an animal model of depression. The infralimbic (IL) of mPFC was selected as the injection site of retrograde AAV using stereotactic technique. The effects of CRS on dendrites/dendritic spines and afferent neurons of the mPFC IL were investigaed by quantitatively assessing the distribution density of green fluorescent (YFP) positive dendrites/dendritic spines and red fluorescent (retrograde AAV recombinant protein) positive neurons, respectively.
RESULTS
The results revealed that retrograde tracing virus labeled neurons were widely distributed in ipsilateral and contralateral cingulate cortex (Cg1), second cingulate cortex (Cg2), prelimbic cortex (PrL), infralimbic cortex, medial orbital cortex (MO), and dorsal peduncular cortex (DP). The effects of CRS on the distribution density of mPFC red fluorescence positive neurons exhibited regional differences, ranging from rostral to caudal or from top to bottom. Simultaneously, CRS resulted a decrease in the distribution density of basal, proximal and distal dendrites, as well as an increase in the loss of dendritic spines of the distal dendrites in the IL of mPFC. Furthermore, varying degrees of red retrograde tracing virus fluorescence signals were observed in other cortices, amygdala, hippocampus, septum/basal forebrain, hypothalamus, thalamus, mesencephalon, and brainstem in both ipsilateral and contralateral brain. CRS significantly reduced the distribution density of red fluorescence positive neurons in other cortices, hippocampus, septum/basal forebrain, hypothalamus, and thalamus. Conversely, CRS significantly increased the distribution density of red fluorescence positive neurons in amygdala.
CONCLUSION
Our results suggest a possible mechanism that CRS leads to disturbances in synaptic plasticity by affecting multiple inputs to the mPFC, which is characterized by a decrease in the distribution density of dendrites/dendritic spines in the IL of mPFC and a reduction in input neurons of multiple cortices to the IL of mPFC as well as an increase in input neurons of amygdala to the IL of mPFC, ultimately causing depression-like behaviors.
Topics: Animals; Prefrontal Cortex; Mice, Inbred C57BL; Stress, Psychological; Mice, Transgenic; Mice; Restraint, Physical; Depression; Male; Dendritic Spines; Disease Models, Animal; Afferent Pathways; Dendrites; Neurons, Afferent; Brain
PubMed: 38777132
DOI: 10.1016/j.brainresbull.2024.110981 -
Nature Communications May 2024In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes,...
In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.
Topics: Animals; Long-Term Potentiation; Ventral Tegmental Area; Male; Dopamine; Mice; Optogenetics; Dopaminergic Neurons; Hippocampus; Learning; Mice, Transgenic; CA1 Region, Hippocampal; Synapses; Mice, Inbred C57BL; Memory
PubMed: 38773091
DOI: 10.1038/s41467-024-47481-4 -
Proceedings of the National Academy of... May 2024The striato-nigral (Str-SN) circuit is composed of medium spiny neuronal projections that are mainly sent from the striatum to the midbrain substantial nigra (SN), which...
The striato-nigral (Str-SN) circuit is composed of medium spiny neuronal projections that are mainly sent from the striatum to the midbrain substantial nigra (SN), which is essential for regulating motor behaviors. Dysfunction of the Str-SN circuitry may cause a series of motor disabilities that are associated with neurodegenerative disorders, such as Huntington's disease (HD). Although the etiology of HD is known as abnormally expanded CAG repeats of the huntingtin gene, treatment of HD remains tremendously challenging. One possible reason is the lack of effective HD model that resembles Str-SN circuitry deficits for pharmacological studies. Here, we first differentiated striatum-like organoids from human pluripotent stem cells (hPSCs), containing functional medium spiny neurons (MSNs). We then generated 3D Str-SN assembloids by assembling striatum-like organoids with midbrain SN-like organoids. With AAV-hSYN-GFP-mediated viral tracing, extensive MSN projections from the striatum to the SN are established, which formed synaptic connection with GABAergic neurons in SN organoids and showed the optically evoked inhibitory postsynaptic currents and electronic field potentials by labeling the striatum-like organoids with optogenetic virus. Furthermore, these Str-SN assembloids exhibited enhanced calcium activity compared to that of individual striatal organoids. Importantly, we further demonstrated the reciprocal projection defects in HD iPSC-derived assembloids, which could be ameliorated by treatment of brain-derived neurotrophic factor. Taken together, these findings suggest that Str-SN assembloids could be used for identifying MSN projection defects and could be applied as potential drug test platforms for HD.
Topics: Humans; Huntington Disease; Organoids; Substantia Nigra; Corpus Striatum; Neurons; Cell Differentiation; GABAergic Neurons; Pluripotent Stem Cells; Optogenetics
PubMed: 38771878
DOI: 10.1073/pnas.2316176121 -
Proceedings of the National Academy of... May 2024Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine...
Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine projections. We predicted that an exploitation-bias that emerges in older adulthood would be associated with lower microstructural integrity of the locus coeruleus. Leveraging in vivo histological methods from quantitative MRI-magnetic transfer saturation-we provide evidence that older age is associated with lower locus coeruleus integrity. Critically, we demonstrate that an exploitation bias in older adulthood, assessed with a foraging task, is sensitive and specific to lower locus coeruleus integrity. Because the locus coeruleus is uniquely vulnerable to Alzheimer's disease pathology, our findings suggest that aging, and a presymptomatic trajectory of Alzheimer's related decline, may fundamentally alter decision-making abilities in later life.
Topics: Locus Coeruleus; Humans; Decision Making; Aged; Male; Female; Aging; Magnetic Resonance Imaging; Alzheimer Disease; Middle Aged; Aged, 80 and over; Reward
PubMed: 38771873
DOI: 10.1073/pnas.2322617121 -
Brain Stimulation 2024
Topics: Humans; Trigeminal Nerve; Locus Coeruleus; Pupil; Male; Adult; Female; Electric Stimulation; Healthy Volunteers; Young Adult
PubMed: 38763412
DOI: 10.1016/j.brs.2024.05.008 -
Nature Communications May 2024The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively....
The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine release in reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.
Topics: Ventral Tegmental Area; Animals; Glutamic Acid; Basal Forebrain; Male; Reward; GABAergic Neurons; Avoidance Learning; Mice; Dopamine; Nucleus Accumbens; Neurons; gamma-Aminobutyric Acid; Dopaminergic Neurons; Mice, Inbred C57BL; Behavior, Animal
PubMed: 38762463
DOI: 10.1038/s41467-024-48340-y -
Stem Cell Reports Jun 2024The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson's disease. Shortcuts to...
The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson's disease. Shortcuts to obtaining DA cells through direct reprogramming often include forced expression of the transcription factor LMX1A. Although reprogramming with LMX1A can generate tyrosine hydroxylase (TH)-positive cells, their regional identity remains elusive. Using an in vitro model of early human neural tube patterning, we report that forced LMX1A expression induced a ventral-to-dorsal fate shift along the entire neuroaxis with the emergence of roof plate fates despite the presence of ventralizing molecules. The LMX1A-expressing progenitors gave rise to grafts containing roof plate-derived choroid plexus cysts as well as ectopically induced TH-positive neurons of a forebrain identity. Early activation of LMX1A prior to floor plate specification was necessary for the dorsalizing effect. Our work suggests using caution in employing LMX1A for the induction of DA fate, as this factor may generate roof plate rather than midbrain fates.
Topics: Humans; Dopaminergic Neurons; LIM-Homeodomain Proteins; Mesencephalon; Transcription Factors; Human Embryonic Stem Cells; Cell Differentiation; Body Patterning; Tyrosine 3-Monooxygenase; Animals; Gene Expression Regulation, Developmental
PubMed: 38759646
DOI: 10.1016/j.stemcr.2024.04.010