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1.
J Exp Biol ; 225(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35815434

RESUMO

In birds, like in mammals, the hippocampus critically mediates spatial navigation through the formation of a spatial map. This study investigates the impact of active exploration of an environment on the hippocampus of young domestic chicks. Chicks that were free to actively explore the environment exhibited a significantly higher neural activation (measured by c-Fos expression) compared with those that passively observed the same environment from a restricted area. The difference was limited to the anterior and the dorsolateral parts of the intermediate hippocampus. Furthermore, the nucleus taeniae of the amygdala showed a higher c-Fos expression in the active exploration group than in the passive observation group. In both brain regions, brain activation was correlated with the number of locations that chicks visited during the test. This suggests that the increase of c-Fos expression in the hippocampus is related to increased firing rates of spatially coding neurons. Furthermore, our study indicates a functional linkage of the hippocampus and nucleus taeniae of the amygdala in processing spatial information. Overall, with the present study, we confirm that in birds, like in mammals, hippocampus and amygdala functions are linked and likely related to spatial representations.


Assuntos
Tonsila do Cerebelo , Hipocampo , Tonsila do Cerebelo/metabolismo , Animais , Galinhas/fisiologia , Hipocampo/metabolismo , Mamíferos/metabolismo , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo
2.
Biochem Biophys Res Commun ; 622: 8-14, 2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-35841770

RESUMO

Post-traumatic stress disorder (PTSD) is a pathological fear memory-related disease. The persistence of pathological fearful memories is one of the most characteristic symptoms of PTSD. However, this can be eliminated by intervening in reconsolidation. Inflammation is intimately involved in the pathophysiologic progression of PTSD. Amentoflavone (AF) has anti-inflammatory effects. However, the effect of AF on fear memory reconsolidation remains unclear. In the present series of experiments, the CFC paradigm of rats were constructed. This was followed by AF administration immediately after exposure to the conditioning chamber to observe the maintenance of fear memory. Finally, a Western blot for the amygdala was used to explore the possible molecular biological mechanisms of AF affecting animal behavior. The findings suggest that re-exposure to the conditioning chamber for retrieval of CFC memory followed by immediate intragastric AF administration in rats attenuated the fear response for at least 14 days. In addition, the Western blot results show that the CFC memory intervention effect of AF administration during the reconsolidation phase may be related to the ERK signaling pathway inhibition. In general, the administration of AF in the reconsolidation phase to inhibit neuroinflammation can block the reconsolidation process and disrupt fear memory retention in the long term, at least in part through ERK pathway.


Assuntos
Medo , Sistema de Sinalização das MAP Quinases , Tonsila do Cerebelo/metabolismo , Animais , Biflavonoides , Medo/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Memória , Ratos
3.
Sci Rep ; 12(1): 11581, 2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803999

RESUMO

Short-term behavioral alterations are associated with infection and aid the recovery from sickness. However, concerns have raised that sustained behavioral disturbances after acute neuroinflammation could relate to neurological diseases in the long run. We aimed to explore medium- and long-term behavioral disturbances after acute neuroinflammation in rats, using a model based on the intracerebroventricular administration of the enzyme neuraminidase (NA), which is part of some pathogenic bacteria and viruses. Neurological and behavioral assessments were performed 2 and 10 weeks after the injection of NA, and neuroinflammation was evaluated by gene expression and histology. No alterations were observed regarding basic neurological functions or locomotor capacity in NA-injected rats. However, they showed a reduction in unsupported rearing, and increased grooming and freezing behaviors, which indicate anxiety-like behavior. A principal component analysis including a larger set of parameters further supported such anxiety-like behavior. The anxiety profile was observed 2 weeks after NA-injection, but not after 10 weeks. Concomitantly, the amygdala presented increased number of microglial cells showing a morphologic bias towards an activated state. A similar but subtler tendency was observed in hypothalamic microglia located in the paraventricular nucleus. Also, in the hypothalamus the pattern recognition receptor toll-like receptor 4 (TLR4) was slightly overexpressed 2 weeks after NA injection. These results demonstrate that NA-induced neuroinflammation provokes anxiety-like behavior in the medium term, which disappears with time. Concurrent microgliosis in the amygdala could explain such behavior. Further experiments should aim to explore subtle but long-lasting alterations observed 10 weeks after NA injection, both in amygdala and hypothalamus, as well as mild behavioral changes.


Assuntos
Microglia , Neuraminidase , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade , Microglia/metabolismo , Neuraminidase/metabolismo , Doenças Neuroinflamatórias , Ratos
4.
Stress ; 25(1): 267-275, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35855548

RESUMO

Several studies suggest a link between acute changes in inflammatory parameters due to an endotoxin or (psychological) stressor and the brain's stress response. The extent to which basal circulating levels of inflammatory markers are associated with the brain's stress response has been hardly investigated so far. In the present study, baseline plasma levels of the cytokine interleukin (IL)-6 were obtained and linked to neural markers of psychosocial stress using a modified version of the Montreal Imaging Stress Task in a sample of N = 65 healthy subjects (N = 39 female). Of three a-priori defined regions of interest - the amygdala, anterior insula, and anterior cingulate cortex - baseline IL-6 was significantly and negatively associated with stress-related neural activation in the right amygdala and left anterior insula. Our results suggest that baseline cytokines might be related to differences in the neural stress response and that this relationship could be inverse to that previously reported for induced acute changes in inflammation markers.


Assuntos
Tonsila do Cerebelo , Interleucina-6 , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Citocinas , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Interleucina-6/sangue , Imageamento por Ressonância Magnética/métodos , Estresse Psicológico/sangue
5.
Neuron ; 110(15): 2438-2454.e8, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35700736

RESUMO

GluN3A is an atypical glycine-binding subunit of NMDA receptors (NMDARs) whose actions in the brain are mostly unknown. Here, we show that the expression of GluN3A subunits controls the excitability of mouse adult cortical and amygdalar circuits via an unusual signaling mechanism involving the formation of excitatory glycine GluN1/GluN3A receptors (eGlyRs) and their tonic activation by extracellular glycine. eGlyRs are mostly extrasynaptic and reside in specific neuronal populations, including the principal cells of the basolateral amygdala (BLA) and SST-positive interneurons (SST-INs) of the neocortex. In the BLA, tonic eGlyR currents are sensitive to fear-conditioning protocols, are subject to neuromodulation by the dopaminergic system, and control the stability of fear memories. In the neocortex, eGlyRs control the in vivo spiking of SST-INs and the behavior-dependent modulation of cortical activity. GluN3A-containing eGlyRs thus represent a novel and widespread signaling modality in the adult brain, with attributes that strikingly depart from those of conventional NMDARs.


Assuntos
Tonsila do Cerebelo , Neocórtex , Receptores de Glicina , Receptores de N-Metil-D-Aspartato , Tonsila do Cerebelo/metabolismo , Animais , Córtex Cerebral/metabolismo , Glicina/metabolismo , Interneurônios/metabolismo , Camundongos , Neocórtex/metabolismo , Neurônios/metabolismo , Receptores de Glicina/genética , Receptores de Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo
6.
Front Endocrinol (Lausanne) ; 13: 893029, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35655799

RESUMO

Post-traumatic stress disorder impedes pubertal development and disrupts pulsatile LH secretion in humans and rodents. The posterodorsal sub-nucleus of the medial amygdala (MePD) is an upstream modulator of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator, pubertal timing, as well as emotional processing and anxiety. Psychosocial stress exposure alters neuronal activity within the MePD increasing the expression of Urocortin3 (Ucn3) and its receptor corticotropin-releasing factor type-2 receptor (CRFR2) while enhancing the inhibitory output from the MePD to key hypothalamic reproductive centres. We test the hypothesis that psychosocial stress, processed by the MePD, is relayed to the hypothalamic GnRH pulse generator to delay puberty in female mice. We exposed C57Bl6/J female mice to the predator odor, 2,4,5-Trimethylthiazole (TMT), during pubertal transition and examined the effect on pubertal timing, pre-pubertal LH pulses and anxiety-like behaviour. Subsequently, we virally infected Ucn3-cre-tdTomato female mice with stimulatory DREADDs targeting MePD Ucn3 neurons and determined the effect on pubertal timing and pre-pubertal LH pulse frequency. Exposure to TMT during pubertal development delayed puberty, suppressed pre-pubertal LH pulsatility and enhanced anxiety-like behaviour, while activation of MePD Ucn3 neurons reduced LH pulse frequency and delayed puberty. Early psychosocial stress exposure decreases GnRH pulse generator frequency delaying puberty while inducing anxiety-behaviour in female mice, an effect potentially involving Ucn3 neurons in the MePD.


Assuntos
Hormônio Luteinizante , Urocortinas , Tonsila do Cerebelo/metabolismo , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Luteinizante/metabolismo , Camundongos , Maturidade Sexual , Urocortinas/metabolismo , Urocortinas/farmacologia
7.
eNeuro ; 9(3)2022.
Artigo em Inglês | MEDLINE | ID: mdl-35580986

RESUMO

The dorsal raphe (DR) nucleus contains many tyrosine hydroxylase (TH)-positive neurons which are regarded as dopaminergic (DA) neurons. These DA neurons in the DR and periaqueductal gray (PAG) region (DADR-PAG neurons) are a subgroup of the A10 cluster, which is known to be heterogeneous. This DA population projects to the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) and has been reported to modulate various affective behaviors. To characterize, the histochemical features of DADR-PAG neurons projecting to the CeA and BNST in mice, the current study combined retrograde labeling with Fluoro-Gold (FG) and histological techniques, focusing on TH, dopamine transporter (DAT), vasoactive intestinal peptide (VIP), and vesicular glutamate transporter 2 (VGlut2). To identify putative DA neurons, DAT-Cre::Ai14 mice were used. It was observed that DATDR-PAG neurons consisted of the following two subpopulations: TH+/VIP- and TH-/VIP+ neurons. The DAT+/TH-/VIP+ subpopulation would be non-DA noncanonical DAT neurons. Anterograde labeling of DATDR-PAG neurons with AAV in DAT-Cre mice revealed that the fibers exclusively innervated the lateral part of the CeA and the oval nucleus of the BNST. Retrograde labeling with FG injections into the CeA or BNST revealed that the two subpopulations similarly innervated these regions. Furthermore, using VGlut2-Cre::Ai14 mice, it was turned out that the TH-/VIP+ subpopulations innervating both CeA and BNST were VGlut2-positive neurons. These two subpopulations of DATDR-PAG neurons, TH+/VIP- and TH-/VIP+, might differentially interfere with the extended amygdala, thereby modulating affective behaviors.


Assuntos
Núcleo Dorsal da Rafe , Substância Cinzenta Periaquedutal , Tonsila do Cerebelo/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina , Neurônios Dopaminérgicos/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Camundongos , Substância Cinzenta Periaquedutal/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Peptídeo Intestinal Vasoativo
8.
Neurotoxicol Teratol ; 92: 107094, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35513163

RESUMO

Excessive fat and sugar intake represents a risk towards the development of different pathologies, such as obesity, diabetes, sociability and memory deficits. Although the adolescence stage is a susceptible period for these and other risks, effects of energy-dense nutrients in such an age period have not been fully investigated. In the present study, neurobehavioral alterations following a 4-week exposure to either normal diet (ND) or high-fat diet (HFD) plus normal water (NW) or liquid sugar (LS) were evaluated in young hamsters. HFD + LS and ND + LS significantly reduced food intake and water consumption, which was, in the latter group, almost completely substituted by LS. All obesogenic diets accounted for increased abdominal fat and liver weight with respect to body weight (p < 0.05-0.001). Additionally, glucose levels notably increased (p < 0.0001) together with insulin and triglycerides in HFD + LS (p < 0.001) and ND + LS (p < 0.01) while cholesterol displayed only a moderate increase (p < 0.05) in HFD + NW and HFD + LS. Animals fed with HFD and/or LS exhibited impaired social memory plus increased winning percentages (0.05 < p < 0.01) during the tube test. Interestingly, these same treatments led to a down-regulation of phosphorylated cAMP Response-Element Binding Protein (pCREB) in HFD + NW (p < 0.0001) for all areas, but rather was upregulated (p < 0.05) in ND + LS of the amygdala. Overall, in view of a brief exposure to palatable foods interfering with normal metabolic and social memory activities, the downregulation of pCREB constitutes a key indicator of neurobehavioral deficits during obesogenic diets. Compensatory mechanisms may be also occurring in the amygdala that strongly regulates emotional states via connections with other limbic areas.


Assuntos
Encéfalo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Dieta Hiperlipídica , Comportamento Social , Gordura Abdominal , Tonsila do Cerebelo/metabolismo , Animais , Glicemia , Encéfalo/metabolismo , Cricetinae , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Emoções , Transtornos da Memória/induzido quimicamente , Fatores de Tempo
9.
Chem Senses ; 472022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35522083

RESUMO

Somatostatin neurons in the central nucleus of the amygdala (CeA/Sst) can be parsed into subpopulations that project either to the nucleus of the solitary tract (NST) or parabrachial nucleus (PBN). We have shown recently that inhibition of CeA/Sst-to-NST neurons increased the ingestion of a normally aversive taste stimulus, quinine HCl (QHCl). Because the CeA innervates other forebrain areas such as the lateral hypothalamus (LH) that also sends axonal projections to the NST, the effects on QHCl intake could be, in part, the result of CeA modulation of LH-to-NST neurons. To address these issues, the present study investigated whether CeA/Sst-to-NST neurons are distinct from CeA/Sst-to-LH neurons. For comparison purposes, additional experiments assessed divergent innervation of the LH by CeA/Sst-to-PBN neurons. In Sst-cre mice, two different retrograde transported flox viruses were injected into the NST and the ipsilateral LH or PBN and ipsilateral LH. The results showed that 90% or more of retrograde-labeled CeA/Sst neurons project either to the LH, NST, or PBN. Separate populations of CeA/Sst neurons projecting to these different regions suggest a highly heterogeneous population in terms of synaptic target and likely function.


Assuntos
Tonsila do Cerebelo , Hipotálamo , Tonsila do Cerebelo/metabolismo , Animais , Tronco Encefálico/metabolismo , Hipotálamo/metabolismo , Camundongos , Neurônios/metabolismo , Quinina/farmacologia , Somatostatina/metabolismo , Paladar/fisiologia
10.
Neuroscience ; 493: 69-80, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35490969

RESUMO

The medial nucleus of the amygdala (MeA) is known to regulate social behavior. This brain area is functionally positioned in a crossroads between sensory information processing and behavioral modulation. On the one hand, it receives direct chemosensory input from the accessory olfactory bulb. On the other hand, it orchestrates various behavioral outputs via brain-wide projections under the regulation of multiple neuromodulatory systems. Previously, we showed that adult male Sprague Dawley (SD) rats and C57BL/6J mice, the most widely used rodent models in neuroscience research, differ in their dynamics of motivation to interact with a novel same-sex conspecific and that this difference correlates with the level of c-Fos expression in the MeA. Here we used chronically implanted electrodes to compare rhythmic local field potential signals recorded from these animals during free and restricted social interactions. We found a significant induction of rhythmicity in the theta (4-12 Hz) and gamma (30-80 Hz) bands during both free and restricted social interaction in both rats and mice. However, the induction of gamma rhythmicity, thought to reflect activity of local neuronal networks, was significantly higher in rats than mice. Nevertheless, in contrast to rats, mice exhibited induction of rhythmicity, in both the theta and gamma bands, in synchrony with investigation of social, but not object stimuli. These results suggest that during interaction with a novel same-sex conspecific, the MeA of C57BL/6J mice is mostly involved in sensory information processing while in SD rats it is mainly active in modulating the social motivation state of the animal.


Assuntos
Tonsila do Cerebelo , Interação Social , Tonsila do Cerebelo/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Periodicidade , Ratos , Ratos Sprague-Dawley
11.
J Neurosci ; 42(21): 4250-4266, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35504727

RESUMO

The Protocadherin-10 (PCDH10) gene is associated with autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). The PCDH10 protein is a homophilic cell adhesion molecule that belongs to the δ2-protocadherin family. PCDH10 is highly expressed in the developing brain, especially in the basolateral nucleus of the amygdala (BLA). However, the role of PCDH10 in vivo has been debatable: one paper reported that a Pcdh10 mutant mouse line showed changes in axonal projections; however, another Pcdh10 mutant mouse line was reported to have failed to detect axonal phenotypes. Therefore, the actual roles of PCDH10 in the brain remain to be elucidated. We established a new Pcdh10 KO mouse line using the CRISPR/Cas9 system, without inserting gene cassettes to avoid nonspecific effects, examined the roles of PCDH10 in the brain, and studied the behavioral consequences of Pcdh10 inactivation. Here, we show that Pcdh10 KO mice do not show defects in axonal development. Instead, we find that Pcdh10 KO mice exhibit impaired development of excitatory synapses in the dorsal BLA. We further demonstrate that male Pcdh10 KO mice exhibit reduced anxiety-related behaviors, impaired fear conditioning, decreased stress-coping responses, and mildly impaired social recognition and communication. These results indicate that PCDH10 plays a critical role in excitatory synapse development, but not axon development, in the dorsal BLA and that PCDH10 regulates anxiety-related, fear-related, and stress-related behaviors. Our results reveal the roles of PCDH10 in the brain and its relationship to relevant psychiatric disorders such as ASD, OCD, and MD.SIGNIFICANCE STATEMENT Protocadherin-10 (PCDH10) encodes a cell adhesion molecule and is implicated in autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). PCDH10 is highly expressed in the basolateral nucleus of the amygdala (BLA). However, the phenotypes of previously published Pcdh10 mutant mice are debatable, and some are possibly because of the nonspecific effects of the LacZ/Neo cassette inserted in the mice. We have generated a new Pcdh10 mutant mouse line without the LacZ/Neo cassette. Using our new mouse line, we reveal the roles of PCDH10 for excitatory synapse development in the BLA. The mutant mice exhibit anxiety-related, fear-related, and stress-related behaviors, which are relevant to ASD, OCD, and MD, suggesting a possible treatment strategy for such psychiatric disorders.


Assuntos
Transtorno do Espectro Autista , Transtorno Obsessivo-Compulsivo , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/genética , Ansiedade/psicologia , Transtorno do Espectro Autista/metabolismo , Medo/fisiologia , Humanos , Masculino , Camundongos , Protocaderinas , Sinapses/metabolismo
12.
Behav Brain Res ; 430: 113928, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35597476

RESUMO

Strong evidence has implicated ubiquitin signaling in the process of fear memory formation. While less abundant than ubiquitination, evidence suggests that protein SUMOylation may also be involved in fear memory formation in neurons. However, the importance of amygdala protein SUMOylation in fear memory formation has never been directly examined. Furthermore, while recent evidence indicates that males and females differ significantly in the requirement for ubiquitin signaling during fear memory formation, whether sex differences also exist in the importance of protein SUMOylation to this process remains unknown. Here we found that males and females differ in the requirement for protein SUMOylation in the amygdala during fear memory formation. Western blot analysis revealed that while females had higher resting levels of SUMOylation, both sexes showed global increases following fear conditioning. However, SUMOylation-specific proteomic analysis revealed that only females have increased targeting of individual proteins by SUMOylation following fear conditioning, some of which were heat shock proteins. This suggests that protein SUMOylation is more robustly engaged in the amygdala of females following fear conditioning. In vivo siRNA mediated knockdown of Ube2i, the coding gene for the essential E2 ligase for SUMOylation conjugation, in the amygdala impaired fear memory in males without any effect in females. Importantly, higher siRNA concentrations than what was needed to impair memory in males reduced Ube2i levels in the amygdala of females but resulted in an increase in SUMOylation levels, suggesting a compensatory effect in females that was not observed in males. Collectively, these data reveal a novel, sex-specific role for protein SUMOylation in the amygdala during fear memory formation and expand our understanding of how ubiquitin-like signaling regulates memory formation.


Assuntos
Proteômica , Sumoilação , Tonsila do Cerebelo/metabolismo , Medo/fisiologia , Feminino , Humanos , Masculino , RNA Interferente Pequeno/metabolismo , Ubiquitinas/metabolismo
13.
Psychopharmacology (Berl) ; 239(7): 2041-2061, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35359158

RESUMO

Clinical studies suggest that women are more likely than men to relapse to alcohol drinking in response to stress; however, the mechanisms underlying this sex difference are not well understood. A number of preclinical behavioral models have been used to study stress-induced alcohol intake. Here, we review paradigms used to study effects of stress on alcohol intake in rodents, focusing on findings relevant to sex differences. To date, studies of sex differences in stress-induced alcohol drinking have been somewhat limited; however, there is evidence that amygdala-centered circuits contribute to effects of stress on alcohol seeking. In addition, we present an overview of inflammatory pathways leading to microglial activation that may contribute to alcohol-dependent behaviors. We propose that sex differences in neuronal function and inflammatory signaling in circuits centered on the amygdala are involved in sex-dependent effects on stress-induced alcohol seeking and suggest that this is an important area for future studies.


Assuntos
Alcoolismo , Caracteres Sexuais , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/metabolismo , Tonsila do Cerebelo/metabolismo , Etanol/farmacologia , Feminino , Humanos , Masculino
14.
Neuropharmacology ; 212: 109074, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35487273

RESUMO

Alcohol use disorder is a complex psychiatric disorder that can be modeled in rodents using a number of drinking paradigms. Drinking-in-the-dark (DID) is widely used to model the binge/intoxication stage of addiction, and chronic intermittent ethanol vapor procedures (CIE) are used to induce dependence and model withdrawal/negative affect induced escalation of drinking. We discuss experiments showing the ventral striatum (vStr) and extended amygdala (EA) are engaged in response to ethanol in rodents through c-Fos/Fos immunoreactivity studies. We also discuss experiments in rodents that span a wide variety of techniques where the function of vStr and EA structures are changed following DID or CIE, and the role of neurotransmitter and neuropeptide systems studies in these ethanol-related outcomes. We note where signaling systems converge across regions and paradigms and where there are still gaps in the literature. Dynorphin/κ-opioid receptor (KOR) signaling, as well as corticotropin releasing factor (CRF)/CRF receptor signaling were found to be important regulators of drinking behaviors across brain regions and drinking paradigms. Future research will require that females and a variety of rodent strains are used in preclinical experiments in order to strengthen the generalizability of findings and improve the likelihood of success for testing potential therapeutics in human laboratory studies.


Assuntos
Consumo de Bebidas Alcoólicas , Estriado Ventral , Tonsila do Cerebelo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Etanol , Humanos , Receptores de Hormônio Liberador da Corticotropina , Estriado Ventral/metabolismo
15.
Acta Neuropathol ; 143(5): 531-545, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35366087

RESUMO

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-ß, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer's disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the "amygdala region" rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution.


Assuntos
Doença de Alzheimer , Neuropatologia , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fatores de Risco
16.
Psychopharmacology (Berl) ; 239(8): 2559-2571, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35467104

RESUMO

RATIONALE: The development of substance use disorders involves long-lasting adaptations in specific brain areas that result in an elevated risk of relapse. Some of these adaptations are regulated by the mTOR network, a signalling system that integrates extracellular and intracellular stimuli and modulates several processes related to plasticity. While the role of the mTOR network in cocaine- and alcohol-related disorders is well established, little is known about its participation in opiate use disorders. OBJECTIVES: To use a heroin self-administration and a withdrawal protocol that induce incubation of heroin-seeking in male rats and study the associated effects on the expression of several genes related to the mTOR system and, in the specific case of Rictor, its respective translated protein and phosphorylation. RESULTS: We found that heroin self-administration elicited an increase in the expression of the genes Igf1r, Igf2r, Akt2 and Gsk3a in the basolateral complex of the amygdala, which was not as evident at 30 days of withdrawal. We also found an increase in the expression of Rictor (a protein of the mTOR complex 2) after heroin self-administration compared to the saline group, which was occluded at the 30-day withdrawal period. The activation levels of Rictor, measured by the phosphorylation rate, were also reduced after heroin self-administration, an effect that seemed more apparent in the protracted withdrawal group. CONCLUSIONS: These results suggest that heroin self-administration under extended access conditions modifies the expression profile of activators and components of the mTOR complexes and show a putative irresponsive mTOR complex 2 after withdrawal from heroin use.


Assuntos
Heroína , Síndrome de Abstinência a Substâncias , Tonsila do Cerebelo/metabolismo , Animais , Heroína/farmacologia , Masculino , Ratos , Ratos Endogâmicos Lew , Autoadministração , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
17.
Int J Mol Sci ; 23(5)2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35269678

RESUMO

Approach and avoidance (A/A) tendencies are stable behavioral traits in responding to rewarding and fearful stimuli. They represent the superordinate division of emotion, and individual differences in such traits are associated with disease susceptibility. The neural circuitry underlying A/A traits is retained to be the cortico-limbic pathway including the amygdala, the central hub for the emotional processing. Furthermore, A/A-specific individual differences are associated with the activity of the endocannabinoid system (ECS) and especially of CB1 receptors whose density and functionality in amygdala differ according to A/A traits. ECS markedly interacts with the immune system (IS). However, how the interplay between ECS and IS is associated with A/A individual differences is still ill-defined. To fill this gap, here we analyzed the interaction between the gene expression of ECS and immune system (IS) in relation to individual differences. To unveil the deep architecture of ECS-IS interaction, we performed cell-specific transcriptomics analysis. Differential gene expression profiling, functional enrichment, and protein-protein interaction network analyses were performed in amygdala pyramidal neurons of mice showing different A/A behavioral tendencies. Several altered pro-inflammatory pathways were identified as associated with individual differences in A/A traits, indicating the chronic activation of the adaptive immune response sustained by the interplay between endocannabinoids and the IS. Furthermore, results showed that the interaction between the two systems modulates synaptic plasticity and neuronal metabolism in individual difference-specific manner. Deepening our knowledge about ECS/IS interaction may provide useful targets for treatment and prevention of psychopathology associated with A/A traits.


Assuntos
Endocanabinoides , Transcriptoma , Tonsila do Cerebelo/metabolismo , Animais , Endocanabinoides/metabolismo , Camundongos , Plasticidade Neuronal , Neurônios/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo
18.
Front Neural Circuits ; 16: 831074, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250495

RESUMO

Taking advantage of two Otp-specific reporter lines of transgenic mice (Otp-eGFP and Otp-Cre; Rpl22-HA), we identify and describe different Otp cell populations across various pallial regions, including the pallial amygdala, the piriform cortex, the mesocortex, the neocortex, and the hippocampal complex. Some of these populations can be followed throughout development, suggesting migration from external sources (for example, those of the pallial amygdala and at least some of the cingulate cortex). Other cells become visible during postnatal development (some of those in the neocortex and hippocampal formation) or in adulthood (those of the parahippocampal lobe), and seem to be produced locally. We discuss the possible role of Otp in these different populations during different moments of ontogenesis. We also analyze the connectivity patterns of some of these cells and discuss their functional implications. For example, our data suggest that Otp cells of the pallial amygdala might be engaged in networks with other Otp cells of the medial amygdala with the same embryonic origin, and may regulate specific aspects of social behavior. Regarding Otp cells in the parahippocampal lobe, they seem to be projection neurons and may regulate hippocampal function during spatial navigation and memory formation. The two reporter transgenic mice employed here provide very powerful tools for high precision studies on these different Otp cells of the pallium, but careful attention should be paid to the age and to differences between lines.


Assuntos
Tonsila do Cerebelo , Córtex Cerebral , Tonsila do Cerebelo/metabolismo , Animais , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Proteínas de Homeodomínio/metabolismo , Interneurônios/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo
19.
Nat Neurosci ; 25(3): 381-389, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35260864

RESUMO

Recent genetic studies have identified variants associated with bipolar disorder (BD), but it remains unclear how brain gene expression is altered in BD and how genetic risk for BD may contribute to these alterations. Here, we obtained transcriptomes from subgenual anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with BD and neurotypical controls, including 511 total samples from 295 unique donors. We examined differential gene expression between cases and controls and the transcriptional effects of BD-associated genetic variants. We found two coexpressed modules that were associated with transcriptional changes in BD: one enriched for immune and inflammatory genes and the other with genes related to the postsynaptic membrane. Over 50% of BD genome-wide significant loci contained significant expression quantitative trait loci (QTL) (eQTL), and these data converged on several individual genes, including SCN2A and GRIN2A. Thus, these data implicate specific genes and pathways that may contribute to the pathology of BP.


Assuntos
Transtorno Bipolar , Giro do Cíngulo , Tonsila do Cerebelo/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Giro do Cíngulo/metabolismo , Humanos , Transcriptoma
20.
Bioengineered ; 13(4): 8101-8114, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35313782

RESUMO

Neuropeptide Y (NPY) is a highly conserved endogenous peptide in the central and peripheral nervous systems, which has been implicated in nociceptive signaling in neuropathic pain. However, downstream mechanistic actions remain uncharacterized. In this study, we sought to investigate the mechanism of NPY and its receptor NPY2R in the amygdala in rats with neuropathic pain-like behaviors induced by chronic constriction injury (CCI) of the sciatic nerve. The expression of NPY and NPY2R was found to be aberrantly up-regulated in neuropathic pain-related microarray dataset. Further, NPY was found to act on NPY2R in the basolateral amygdala (BLA). As reflected by the decrease in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) as well as the increase of NPY expression in the amygdala of rats with neuropathic pain-like behaviors, NPY was closely related to the effect of amygdala nerve activity in neuropathic pain. Subsequently, mechanistic investigations indicated that NPY2R activated the MAPK signaling pathway in the amygdala. NPY2R-induced decrease of MWT and TWL were also restored in the presence of MAPK signaling pathway antagonist. Moreover, it was revealed that NPY2R overexpression promoted the viability while inhibiting the apoptosis of microglia. Taken together, NPY in the amygdala interacts with NPY2R to activate the MAPK signaling pathway, thereby promoting the occurrence of neuropathic pain.


Assuntos
Neuralgia , Neuropeptídeo Y , Tonsila do Cerebelo/metabolismo , Animais , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Neuropeptídeo Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo
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