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1.
Development ; 150(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36633189

RESUMO

Adult neurogenesis is supported by multipotent neural stem cells (NSCs) with unique properties and growth requirements. Adult NSCs constitute a reversibly quiescent cell population that can be activated by extracellular signals from the microenvironment in which they reside in vivo. Although genomic imprinting plays a role in adult neurogenesis through dose regulation of some relevant signals, the roles of many imprinted genes in the process remain elusive. Insulin-like growth factor 2 (IGF2) is encoded by an imprinted gene that contributes to NSC maintenance in the adult subventricular zone through a biallelic expression in only the vascular compartment. We show here that IGF2 additionally promotes terminal differentiation of NSCs into astrocytes, neurons and oligodendrocytes by inducing the expression of the maternally expressed gene cyclin-dependent kinase inhibitor 1c (Cdkn1c), encoding the cell cycle inhibitor p57. Using intraventricular infusion of recombinant IGF2 in a conditional mutant strain with Cdkn1c-deficient NSCs, we confirm that p57 partially mediates the differentiation effects of IGF2 in NSCs and that this occurs independently of its role in cell-cycle progression, balancing the relationship between astrogliogenesis, neurogenesis and oligodendrogenesis.


Assuntos
Inibidor de Quinase Dependente de Ciclina p57 , Células-Tronco Neurais , Inibidor de Quinase Dependente de Ciclina p57/genética , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Neurônios/metabolismo , Impressão Genômica , Diferenciação Celular/genética
2.
J R Soc Interface ; 20(198): 20220607, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36596460

RESUMO

Alzheimer's disease is the most common cause of dementia and is linked to the spreading of pathological amyloid-ß and tau proteins throughout the brain. Recent studies have highlighted stark differences in how amyloid-ß and tau affect neurons at the cellular scale. On a larger scale, Alzheimer's patients are observed to undergo a period of early-stage neuronal hyperactivation followed by neurodegeneration and frequency slowing of neuronal oscillations. Herein, we model the spreading of both amyloid-ß and tau across a human connectome and investigate how the neuronal dynamics are affected by disease progression. By including the effects of both amyloid-ß and tau pathology, we find that our model explains AD-related frequency slowing, early-stage hyperactivation and late-stage hypoactivation. By testing different hypotheses, we show that hyperactivation and frequency slowing are not due to the topological interactions between different regions but are mostly the result of local neurotoxicity induced by amyloid-ß and tau protein.


Assuntos
Doença de Alzheimer , Conectoma , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Neurônios , Encéfalo/metabolismo
3.
Int J Mol Sci ; 24(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36614191

RESUMO

Glioblastoma is the most common malignant primary brain tumor. Recent studies have demonstrated that excitatory or activity-dependent signaling-both synaptic and non-synaptic-contribute to the progression of glioblastoma. Glutamatergic receptors may be stimulated via neuron-tumor synapses or release of glutamate by the tumor itself. Ion currents generated by these receptors directly alter the structure of membrane adhesion molecules and cytoskeletal proteins to promote migratory behavior. Additionally, the hyperexcitable milieu surrounding glioma increases the rate at which tumor cells proliferate and drive recurrent disease. Inhibition of excitatory signaling has shown to effectively reduce its pro-migratory and -proliferative effects.


Assuntos
Glioblastoma , Fenômenos Fisiológicos do Sistema Nervoso , Humanos , Glioblastoma/metabolismo , Neurônios/metabolismo , Sinapses/metabolismo , Transdução de Sinais , Moléculas de Adesão Celular Neuronais/metabolismo
4.
J Cell Sci ; 136(5)2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36655764

RESUMO

Neuronal function depends on axonal transport by kinesin superfamily proteins (KIFs). KIF1A is the molecular motor that transports synaptic vesicle precursors, synaptic vesicles, dense core vesicles and active zone precursors. KIF1A is regulated by an autoinhibitory mechanism; many studies, as well as the crystal structure of KIF1A paralogs, support a model whereby autoinhibited KIF1A is monomeric in solution, whereas activated KIF1A is dimeric on microtubules. KIF1A-associated neurological disorder (KAND) is a broad-spectrum neuropathy that is caused by mutations in KIF1A. More than 100 point mutations have been identified in KAND. In vitro assays show that most mutations are loss-of-function mutations that disrupt the motor activity of KIF1A, whereas some mutations disrupt its autoinhibition and abnormally hyperactivate KIF1A. Studies on disease model worms suggests that both loss-of-function and gain-of-function mutations cause KAND by affecting the axonal transport and localization of synaptic vesicles. In this Review, we discuss how the analysis of these mutations by molecular genetics, single-molecule assays and force measurements have helped to reveal the physiological significance of KIF1A function and regulation, and what physical parameters of KIF1A are fundamental to axonal transport.


Assuntos
Transporte Axonal , Doenças do Sistema Nervoso , Humanos , Transporte Axonal/genética , Transporte Axonal/fisiologia , Cinesinas/genética , Cinesinas/metabolismo , Microtúbulos/metabolismo , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Neurônios/metabolismo , Vesículas Sinápticas/genética , Vesículas Sinápticas/metabolismo
5.
Proc Natl Acad Sci U S A ; 120(4): e2209329120, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36656857

RESUMO

The suprachiasmatic nucleus (SCN) is composed of functionally distinct subpopulations of GABAergic neurons which form a neural network responsible for synchronizing most physiological and behavioral circadian rhythms in mammals. To date, little is known regarding which aspects of SCN rhythmicity are generated by individual SCN neurons, and which aspects result from neuronal interaction within a network. Here, we utilize in vivo miniaturized microscopy to measure fluorescent GCaMP-reported calcium dynamics in arginine vasopressin (AVP)-expressing neurons in the intact SCN of awake, behaving mice. We report that SCN AVP neurons exhibit periodic, slow calcium waves which we demonstrate, using in vivo electrical recordings, likely reflect burst firing. Further, we observe substantial heterogeneity of function in that AVP neurons exhibit unstable rhythms, and relatively weak rhythmicity at the population level. Network analysis reveals that correlated cellular behavior, or coherence, among neuron pairs also exhibited stochastic rhythms with about 33% of pairs rhythmic at any time. Unlike single-cell variables, coherence exhibited a strong rhythm at the population level with time of maximal coherence among AVP neuronal pairs at CT/ZT 6 and 9, coinciding with the timing of maximal neuronal activity for the SCN as a whole. These results demonstrate robust circadian variation in the coordination between stochastically rhythmic neurons and that interactions between AVP neurons in the SCN may be more influential than single-cell activity in the regulation of circadian rhythms. Furthermore, they demonstrate that cells in this circuit, like those in many other circuits, exhibit profound heterogenicity of function over time and space.


Assuntos
Arginina Vasopressina , Ritmo Circadiano , Núcleo Supraquiasmático , Animais , Camundongos , Arginina , Ritmo Circadiano/fisiologia , Neurônios/metabolismo , Núcleo Supraquiasmático/metabolismo
6.
Molecules ; 28(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36677581

RESUMO

In the course of action potential firing, all axons and neurons release K+ from the intra- cellular compartment into the interstitial space to counteract the depolarizing effect of Na+ influx, which restores the resting membrane potential. This efflux of K+ from axons results in K+ accumulation in the interstitial space, causing depolarization of the K+ reversal potential (EK), which can prevent subsequent action potentials. To ensure optimal neuronal function, the K+ is buffered by astrocytes, an energy-dependent process, which acts as a sink for interstitial K+, absorbing it at regions of high concentration and distributing it through the syncytium for release in distant regions. Pathological processes in which energy production is compromised, such as anoxia, ischemia, epilepsy and spreading depression, can lead to excessive interstitial K+ accumulation, disrupting sensitive trans-membrane ion gradients and attenuating neuronal activity. The changes that occur in interstitial [K+] resulting from both physiological and pathological processes can be monitored accurately in real time using K+-sensitive microelectrodes, an invaluable tool in electrophysiological studies.


Assuntos
Axônios , Neurônios , Microeletrodos , Neurônios/fisiologia , Potenciais da Membrana , Axônios/fisiologia , Potenciais de Ação , Potássio/farmacologia
7.
Neuron ; 111(2): 139-141, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36657394

RESUMO

Oligodendrocyte precursor cells (OPCs) use the vasculature as a scaffold for their migration. In this issue of Neuron, Su et al. determine that astrocytic ensheathment of the vasculature mediates OPC detachment from blood vessels via the secretion of semaphorins, regulating the timing of oligodendrocyte differentiation.


Assuntos
Células Precursoras de Oligodendrócitos , Oligodendroglia , Oligodendroglia/fisiologia , Astrócitos/fisiologia , Neurônios , Neurogênese , Células Precursoras de Oligodendrócitos/fisiologia , Diferenciação Celular/fisiologia
8.
Neuron ; 111(2): 146-149, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36657397

RESUMO

In this issue of Neuron, Babij, Ferrer, and colleagues provide new evidence that ß3 subunit of GABAA receptors is critical for the maturation of functional networks in the neonatal somatosensory cortex.


Assuntos
Neurônios , Receptores de GABA-A , Recém-Nascido , Humanos , Receptores de GABA-A/fisiologia , Ácido gama-Aminobutírico
9.
eNeuro ; 10(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36635250

RESUMO

Avoiding potentially harmful, and consuming safe food is crucial for the survival of living organisms. However, the perceived valence of sensory information can change following conflicting experiences. Pleasurability and aversiveness are two crucial parameters defining the perceived valence of a taste and can be impacted by novelty. Importantly, the ability of a given taste to serve as the conditioned stimulus (CS) in conditioned taste aversion (CTA) is dependent on its valence. Activity in anterior insula (aIC) Layer IV-VI pyramidal neurons projecting to the basolateral amygdala (BLA) is correlated with and necessary for CTA learning and retrieval, as well as the expression of neophobia toward novel tastants, but not learning taste familiarity. Yet, the cellular mechanisms underlying the updating of taste valence representation in this specific pathway are poorly understood. Here, using retrograde viral tracing and whole-cell patch-clamp electrophysiology in trained mice, we demonstrate that the intrinsic properties of deep-lying Layer IV-VI, but not superficial Layer I-III aIC-BLA neurons, are differentially modulated by both novelty and valence, reflecting the subjective predictability of taste valence arising from prior experience. These correlative changes in the profile of intrinsic properties of LIV-VI aIC-BLA neurons were detectable following both simple taste experiences, as well as following memory retrieval, extinction learning, and reinstatement.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Camundongos , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Tonsila do Cerebelo/fisiologia , Paladar/fisiologia , Aprendizagem da Esquiva/fisiologia , Neurônios
10.
Sci Rep ; 13(1): 383, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611081

RESUMO

Acoustic communication signals diversify even on short evolutionary time scales. To understand how the auditory system underlying acoustic communication could evolve, we conducted a systematic comparison of the early stages of the auditory neural circuit involved in song information processing between closely-related fruit-fly species. Male Drosophila melanogaster and D. simulans produce different sound signals during mating rituals, known as courtship songs. Female flies from these species selectively increase their receptivity when they hear songs with conspecific temporal patterns. Here, we firstly confirmed interspecific differences in temporal pattern preferences; D. simulans preferred pulse songs with longer intervals than D. melanogaster. Primary and secondary song-relay neurons, JO neurons and AMMC-B1 neurons, shared similar morphology and neurotransmitters between species. The temporal pattern preferences of AMMC-B1 neurons were also relatively similar between species, with slight but significant differences in their band-pass properties. Although the shift direction of the response property matched that of the behavior, these differences are not large enough to explain behavioral differences in song preferences. This study enhances our understanding of the conservation and diversification of the architecture of the early-stage neural circuit which processes acoustic communication signals.


Assuntos
Drosophila melanogaster , Drosophila , Animais , Masculino , Feminino , Drosophila/fisiologia , Drosophila melanogaster/fisiologia , Corte , Evolução Biológica , Neurônios , Drosophila simulans , Comportamento Sexual Animal/fisiologia , Vocalização Animal/fisiologia
11.
Proc Natl Acad Sci U S A ; 120(3): e2215905120, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36638214

RESUMO

In multicellular organisms, cell-adhesion molecules connect cells into tissues and mediate intercellular signaling between these cells. In vertebrate brains, synaptic cell-adhesion molecules (SAMs) guide the formation, specification, and plasticity of synapses. Some SAMs, when overexpressed in cultured neurons or in heterologous cells co-cultured with neurons, drive formation of synaptic specializations onto the overexpressing cells. However, genetic deletion of the same SAMs from neurons often has no effect on synapse numbers, but frequently severely impairs synaptic transmission, suggesting that most SAMs control the function and plasticity of synapses (i.e., organize synapses) instead of driving their initial establishment (i.e., make synapses). Since few SAMs were identified that mediate initial synapse formation, it is difficult to develop methods that enable experimental control of synaptic connections by targeted expression of these SAMs. To overcome this difficulty, we engineered novel SAMs from bacterial proteins with no eukaryotic homologues that drive synapse formation. We named these engineered adhesion proteins "Barnoligin" and "Starexin" because they were assembled from parts of Barnase and Neuroligin-1 or of Barstar and Neurexin3ß, respectively. Barnoligin and Starexin robustly induce the formation of synaptic specializations in a specific and directional manner in cultured neurons. Synapse formation by Barnoligin and Starexin requires both their extracellular Barnase- and Barstar-derived interaction domains and their Neuroligin- and Neurexin-derived intracellular signaling domains. Our findings support a model of synapse formation whereby trans-synaptic interactions by SAMs drive synapse organization via adhesive interactions that activate signaling cascades.


Assuntos
Moléculas de Adesão Celular Neuronais , Sinapses , Células Cultivadas , Moléculas de Adesão Celular Neuronais/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Neurônios/metabolismo , Técnicas de Cocultura , Hipocampo/metabolismo
12.
Nat Commun ; 14(1): 218, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639365

RESUMO

Familial dysautonomia (FD) is a rare genetic neurologic disorder caused by impaired neuronal development and progressive degeneration of both the peripheral and central nervous systems. FD is monogenic, with >99.4% of patients sharing an identical point mutation in the elongator acetyltransferase complex subunit 1 (ELP1) gene, providing a relatively simple genetic background in which to identify modifiable factors that influence pathology. Gastrointestinal symptoms and metabolic deficits are common among FD patients, which supports the hypothesis that the gut microbiome and metabolome are altered and dysfunctional compared to healthy individuals. Here we show significant differences in gut microbiome composition (16 S rRNA gene sequencing of stool samples) and NMR-based stool and serum metabolomes between a cohort of FD patients (~14% of patients worldwide) and their cohabitating, healthy relatives. We show that key observations in human subjects are recapitulated in a neuron-specific Elp1-deficient mouse model, and that cohousing mutant and littermate control mice ameliorates gut microbiome dysbiosis, improves deficits in gut transit, and reduces disease severity. Our results provide evidence that neurologic deficits in FD alter the structure and function of the gut microbiome, which shifts overall host metabolism to perpetuate further neurodegeneration.


Assuntos
Disautonomia Familiar , Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Disautonomia Familiar/genética , Disbiose/metabolismo , Neurônios/metabolismo , Sistema Nervoso Central/metabolismo
13.
Nat Commun ; 14(1): 196, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639374

RESUMO

Adaptive behaviors arise from an integration of current sensory context and internal representations of past experiences. The central amygdala (CeA) is positioned as a key integrator of cognitive and affective signals, yet it remains unknown whether individual populations simultaneously carry current- and future-state representations. We find that a primary nociceptive population within the CeA of mice, defined by CGRP-receptor (Calcrl) expression, receives topographic sensory information, with spatially defined representations of internal and external stimuli. While Calcrl+ neurons in both the rostral and caudal CeA respond to noxious stimuli, rostral neurons promote locomotor responses to externally sourced threats, while caudal CeA Calcrl+ neurons are activated by internal threats and promote passive coping behaviors and associative valence coding. During associative fear learning, rostral CeA Calcrl+ neurons stably encode noxious stimulus occurrence, while caudal CeA Calcrl+ neurons acquire predictive responses. This arrangement supports valence-aligned representations of current and future threats for the generation of adaptive behaviors.


Assuntos
Núcleo Central da Amígdala , Nociceptividade , Camundongos , Animais , Neurônios/metabolismo , Condicionamento Clássico , Medo/fisiologia
14.
Commun Biol ; 6(1): 74, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658362

RESUMO

Neurons in the lateral hypothalamus expressing the neuropeptide Hypocretin, also known as orexin, are known critical modulators of arousal stability. However, their role in the different components of the arousal construct such as attention and decision making is poorly understood. Here we study Hypocretin neuronal circuit dynamics during stop action impulsivity in a Go/NoGo task in mice. We show that Hypocretin neuronal activity correlates with anticipation of reward. We then assessed the causal role of Hypocretin neuronal activity using optogenetics in a Go/NoGo task. We show that stimulation of Hypocretin neurons during the cue period dramatically increases the number of premature responses. These effects are mimicked by amphetamine, reduced by atomoxetine, a norepinephrine uptake inhibitor, and blocked by a Hypocretin receptor 1 selective antagonist. We conclude that Hypocretin neurons have a key role in the integration of salient stimuli during wakefulness to produce appropriate and timely responses to rewarding and aversive cues.


Assuntos
Hipotálamo , Optogenética , Camundongos , Animais , Orexinas , Peptídeos e Proteínas de Sinalização Intracelular , Neurônios/fisiologia , Comportamento Impulsivo
15.
BMC Neurosci ; 24(1): 5, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658491

RESUMO

BACKGROUND: Autism spectrum condition or 'autism' is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in the cerebral cortex is hypothesised to be critical for the aetiology of autism making improved understanding of how risk factors impact on the development of these cells an important area of research. In the current study we aim to combine bioinformatics analysis of human foetal cerebral cortex gene expression data with anatomical and electrophysiological analysis of a 16p11.2+/- rat model to investigate how genetic risk factors impact on inhibitory neuron development. METHODS: We performed bioinformatics analysis of single cell transcriptomes from gestational week (GW) 8-26 human foetal prefrontal cortex and anatomical and electrophysiological analysis of 16p11.2+/- rat cerebral cortex and hippocampus at post-natal day (P) 21. RESULTS: We identified a subset of human interneurons (INs) first appearing at GW23 with enriched expression of a large fraction of risk factor transcripts including those expressed from the 16p11.2 locus. This suggests the hypothesis that these foetal INs are vulnerable to mutations causing autism. We investigated this in a rat model of the 16p11.2 microdeletion. We found no change in the numbers or position of either excitatory or inhibitory neurons in the somatosensory cortex or CA1 of 16p11.2+/- rats but found that CA1 Sst INs were hyperexcitable with an enlarged axon initial segment, which was not the case for CA1 pyramidal cells. LIMITATIONS: The human foetal gene expression data was acquired from cerebral cortex between gestational week (GW) 8 to 26. We cannot draw inferences about potential vulnerabilities to genetic autism risk factors for cells not present in the developing cerebral cortex at these stages. The analysis 16p11.2+/- rat phenotypes reported in the current study was restricted to 3-week old (P21) animals around the time of weaning and to a single interneuron cell-type while in human 16p11.2 microdeletion carriers symptoms likely involve multiple cell types and manifest in the first few years of life and on into adulthood. CONCLUSIONS: We have identified developing interneurons in human foetal cerebral cortex as potentially vulnerable to monogenic autism risk factors and the 16p11.2 microdeletion and report interneuron phenotypes in post-natal 16p11.2+/- rats.


Assuntos
Transtorno Autístico , Interneurônios , Humanos , Ratos , Animais , Transtorno Autístico/genética , Neurônios , Córtex Cerebral , Fatores de Risco
16.
Mol Brain ; 16(1): 10, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658598

RESUMO

Social animals become stressed upon social isolation, proactively engaging in affiliative contacts among conspecifics after resocialization. We have previously reported that calcitonin receptor (Calcr) expressing neurons in the central part of the medial preoptic area (cMPOA) mediate contact-seeking behaviors in female mice. Calcr neurons in the posterodorsal part of the medial amygdala (MeApd) are also activated by resocialization, however their role in social affiliation is still unclear. Here we first investigated the functional characteristics of MeApd Calcr + cells; these neurons are GABAergic and show female-biased Calcr expression. Next, using an adeno-associated virus vector expressing a short hairpin RNA targeting Calcr we aimed to identify its molecular role in the MeApd. Inhibiting Calcr expression in the MeApd increased social contacts during resocialization without affecting locomotor activity, suggesting that the endogenous Calcr signaling in the MeApd suppresses social contacts. These results demonstrate the distinct roles of Calcr in the cMPOA and MeApd for regulating social affiliation.


Assuntos
Complexo Nuclear Corticomedial , Receptores da Calcitonina , Feminino , Animais , Camundongos , Receptores da Calcitonina/metabolismo , Tonsila do Cerebelo/metabolismo , Neurônios/metabolismo , Área Pré-Óptica/metabolismo
17.
Cell Death Dis ; 14(1): 52, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681682

RESUMO

Patients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase complex, develop cerebellar atrophy and gait phenotypes. However, the underlying mechanisms remain unexplored. Here, we identify a crucial role of Wdr4 in cerebellar development. Wdr4 deficiency in granule neuron progenitors (GNPs) not only reduces foliation and the sizes of external and internal granular layers but also compromises Purkinje neuron organization and the size of the molecular layer, leading to locomotion defects. Mechanistically, Wdr4 supports the proliferation of GNPs by preventing their cell cycle exit. This effect is mediated by Wdr4-induced ubiquitination and degradation of Arhgap17, thereby activating Rac1 to facilitate cell cycle progression. Disease-associated Wdr4 variants, however, cannot provide GNP cell cycle maintenance. Our study identifies Wdr4 as a previously unappreciated participant in cerebellar development and locomotion, providing potential insights into treatment strategies for diseases with WDR4 mutations, such as primordial dwarfism and Galloway-Mowat syndrome.


Assuntos
Microcefalia , Neurogênese , Humanos , Neurogênese/fisiologia , Neurônios/metabolismo , Células de Purkinje/metabolismo , Microcefalia/genética , Locomoção , Cerebelo , Proteínas de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo
18.
Transl Psychiatry ; 13(1): 20, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36683039

RESUMO

Natural rewards, such as food, and sex are appetitive stimuli available for animals in their natural environment. Similarly, addictive rewards such as drugs of abuse possess strong, positive valence, but their action relies on their pharmacological properties. Nevertheless, it is believed that both of these kinds of rewards activate similar brain circuitry. The present study aimed to discover which parts of the brain process the experience of natural and addictive rewards. To holistically address this question, we used a single-cell whole-brain imaging approach to find patterns of activation for acute and prolonged sucrose and cocaine exposure. We analyzed almost 400 brain structures and created a brain-wide map of specific, c-Fos-positive neurons engaged by these rewards. Acute but not prolonged sucrose exposure triggered a massive c-Fos expression throughout the brain. Cocaine exposure on the other hand potentiated c-Fos expression with prolonged use, engaging more structures than sucrose treatment. The functional connectivity analysis unraveled an increase in brain modularity after the initial exposure to both types of rewards. This modularity was increased after repeated cocaine, but not sucrose, intake. To check whether discrepancies between the processing of both types of rewards can be found on a cellular level, we further studied the nucleus accumbens, one of the most strongly activated brain structures by both sucrose and cocaine experience. We found a high overlap between natural and addictive rewards on the level of c-Fos expression. Electrophysiological measurements of cellular correlates of synaptic plasticity revealed that natural and addictive rewards alike induce the accumulation of silent synapses. These results strengthen the hypothesis that in the nucleus accumbens drugs of abuse cause maladaptive neuronal plasticity in the circuitry that typically processes natural rewards.


Assuntos
Cocaína , Animais , Cocaína/farmacologia , Açúcares/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Neurônios/metabolismo , Sacarose/metabolismo , Sacarose/farmacologia
19.
Curr Protoc ; 3(1): e654, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36688682

RESUMO

Glial cells are the support cells of the nervous system. Glial cells typically have elaborate morphologies that facilitate close contacts with neighboring neurons, synapses, and the vasculature. In the retina, Müller glia (MG) are the principal glial cell type that supports neuronal function by providing a myriad of supportive functions via intricate cell morphologies and precise contacts. Thus, complex glial morphology is critical for glial function, but remains challenging to resolve at a sub-cellular level or reproducibly quantify in complex tissues. To address this issue, we developed GliaMorph as a Fiji-based macro toolkit that allows 3D glial cell morphology analysis in the developing and mature retina. As GliaMorph is implemented in a modular fashion, here we present guides to (a) setup of GliaMorph, (b) data understanding in 3D, including z-axis intensity decay and signal-to-noise ratio, (c) pre-processing data to enhance image quality, (d) performing and examining image segmentation, and (e) 3D quantification of MG features, including apicobasal texture analysis. To allow easier application, GliaMorph tools are supported with graphical user interfaces where appropriate, and example data are publicly available to facilitate adoption. Further, GliaMorph can be modified to meet users' morphological analysis needs for other glial or neuronal shapes. Finally, this article provides users with an in-depth understanding of data requirements and the workflow of GliaMorph. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Download and installation of GliaMorph components including example data Basic Protocol 2: Understanding data properties and quality 3D-essential for subsequent analysis and capturing data property issues early Basic Protocol 3: Pre-processing AiryScan microscopy data for analysis Alternate Protocol: Pre-processing confocal microscopy data for analysis Basic Protocol 4: Segmentation of glial cells Basic Protocol 5: 3D quantification of glial cell morphology.


Assuntos
Neuroglia , Retina , Fiji , Neuroglia/fisiologia , Neurônios
20.
FASEB J ; 37(2): e22778, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36688823

RESUMO

In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-ß-peptide (Aß) and phosphorylated tau (p-tau), as well as neurodegeneration; however, the regulatory mechanisms remain unclear. We constructed APP- and tau-transgenic AD mice with deletion of IKKß specifically in neurons, and observed that IKKß deficiency reduced cerebral Aß and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKß decreased apoptosis and maintained synaptic proteins (e.g., PSD-95 and Munc18-1) in the brain and improved cognitive function only in APP-transgenic mice, but not in tau-transgenic mice. Additionally, IKKß deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKß deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau, in the brain of tau-transgenic mice. Interestingly, deficiency of IKKß in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKKß deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Aß production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKß deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Aß and p-tau, before IKKß/NF-κB can be targeted for AD therapies.


Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Quinase I-kappa B , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , Modelos Animais de Doenças
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