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1.
Elife ; 82019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31625906

RESUMO

Medial and lateral hypothalamic loci are known to suppress and enhance appetite, respectively, but the dynamics and functional significance of their interaction have yet to be explored. Here we report that, in larval zebrafish, primarily serotonergic neurons of the ventromedial caudal hypothalamus (cH) become increasingly active during food deprivation, whereas activity in the lateral hypothalamus (LH) is reduced. Exposure to food sensory and consummatory cues reverses the activity patterns of these two nuclei, consistent with their representation of opposing internal hunger states. Baseline activity is restored as food-deprived animals return to satiety via voracious feeding. The antagonistic relationship and functional importance of cH and LH activity patterns were confirmed by targeted stimulation and ablation of cH neurons. Collectively, the data allow us to propose a model in which these hypothalamic nuclei regulate different phases of hunger and satiety and coordinate energy balance via antagonistic control of distinct behavioral outputs.


Assuntos
Apetite , Hipotálamo/fisiologia , Rede Nervosa/fisiologia , Neurônios Serotoninérgicos/fisiologia , Peixe-Zebra/fisiologia , Animais , Larva/fisiologia
2.
Brain Struct Funct ; 224(8): 2775-2786, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31399877

RESUMO

This study evaluated the hypothalamic neuronal activation during exercise and investigated whether this activation is related to heat storage and exercise duration. Rats were subjected to a treadmill running that was interrupted at three different moments: (1) at the early phase, when minimal heat dissipation occurred due to tail vasoconstriction and the tail skin temperature (Tskin) reached its nadir; (2) at the steady-state phase, when both the Tskin and core body temperature (Tcore) plateaued at a high level (~ 20 min); and (3) at fatigue, when Tcore and Tskin were still elevated. c-Fos expression in the medial and ventromedial preoptic areas (mPOA and vmPOA), median preoptic nucleus (MnPO), paraventricular and supraoptic nucleus (PVN and SON), and septohypothalamic nucleus (SHy) was determined. Exercise increased the expression of c-Fos in all brain areas, but with different activation patterns of activation. c-Fos expression in the SHy and vmPOA was similar in all exercising groups, while in the mPOA, MnPO, and PVN, c-Fos expression gradually increased during exercise. Increased c-Fos in the SON was only evident after 20 min of exercise. Neuronal activation in the mPOA, MnPO, PVN, and SON was positively correlated with both exercise duration and heat storage. Our findings indicate that with the exception of SON, the brain areas analyzed are recruited following small changes in Tcore (~ 0.5 °C), while the SON is recruited only when Tcore reaches higher values (greater than 1.0 °C increase). c-Fos expression in the PVN, mPOA, MnPO, and SON is also influenced by exercise duration, which does not occur in the SHy and vmPOA.


Assuntos
Regulação da Temperatura Corporal , Hipotálamo/fisiologia , Atividade Motora , Neurônios/fisiologia , Animais , Masculino , Proteínas Proto-Oncogênicas c-fos , Ratos Wistar , Corrida , Temperatura Cutânea
3.
Int J Mol Sci ; 20(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426457

RESUMO

Previous studies have shown that the sphingolipid-derived mediator sphingosine-1-phosphate (S1P) reduces food intake by activating G protein-coupled S1P receptor-1 (S1PR1) in the hypothalamus. Here, we examined whether feeding regulates hypothalamic mobilization of S1P and other sphingolipid-derived messengers. We prepared lipid extracts from the hypothalamus of C57Bl6/J male mice subjected to one of four conditions: free feeding, 12 h fasting, and 1 h or 6 h refeeding. Liquid chromatography/tandem mass spectrometry was used to quantify various sphingolipid species, including sphinganine (SA), sphingosine (SO), and their bioactive derivatives SA-1-phosphate (SA1P) and S1P. In parallel experiments, transcription of S1PR1 (encoded in mice by the S1pr1 gene) and of key genes of sphingolipid metabolism (Sptlc2, Lass1, Sphk1, Sphk2) was measured by RT-PCR. Feeding increased levels of S1P (in pmol-mg-1 of wet tissue) and SA1P. This response was accompanied by parallel changes in SA and dihydroceramide (d18:0/18:0), and was partially (SA1P) or completely (S1P) reversed by fasting. No such effects were observed with other sphingolipid species targeted by our analysis. Feeding also increased transcription of Sptlc2, Lass1, Sphk2, and S1pr1. Feeding stimulates mobilization of endogenous S1PR1 agonists S1P and SA1P in mouse hypothalamus, via a mechanism that involves transcriptional up-regulation of de novo sphingolipid biosynthesis. The results support a role for sphingolipid-mediated signaling in the central control of energy balance.


Assuntos
Ingestão de Alimentos , Hipotálamo/metabolismo , Lisofosfolipídeos/metabolismo , Transdução de Sinais , Esfingosina/análogos & derivados , Animais , Regulação da Expressão Gênica , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esfingolipídeos/metabolismo , Esfingosina/metabolismo
4.
J Vet Med Sci ; 81(8): 1121-1128, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31270283

RESUMO

Wild animals tend to avoid novel objects that do not elicit clear avoidance behaviors in domesticated animals. We previously found that the basolateral complex of the amygdala (BLA) and dorsal bed nucleus of the stria terminalis (dBNST) were larger in trapped wild rats compared with laboratory rats. Based on these findings, we hypothesized that the BLA and/or dBNST would be differentially activated when wild and laboratory rats showed different avoidance behaviors towards novel objects. In this study, we placed novel objects at one end of the home cage. We measured the time spent in that half of the cage and expressed the data as a percentage of the time spent in that region with no object placement. We found that this percentage was lower in the wild rats compared with the laboratory rats. These behavioral differences were accompanied by increased Fos expression in the BLA, but not in the dBNST, of the wild rats. These results suggest that wild rats show greater BLA activation compared with laboratory rats in response to novel objects. We also found increased Fos expression in the paraventricular nucleus of the hypothalamus, ventral BNST, and ventromedial hypothalamus, but not in the central amygdala of wild rats. Taken together, our data represent new information regarding differences in behavioral and neural responses towards novel objects in wild vs. laboratory rats.


Assuntos
Animais Selvagens/psicologia , Aprendizagem da Esquiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Ratos/psicologia , Animais , Animais Selvagens/anatomia & histologia , Técnica Indireta de Fluorescência para Anticorpo , Hipotálamo/fisiologia , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos/anatomia & histologia
5.
Nat Neurosci ; 22(9): 1477-1492, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358991

RESUMO

Animals have evolved specialized neural circuits to defend themselves from pain- and injury-causing stimuli. Using a combination of optical, behavioral and genetic approaches in the larval zebrafish, we describe a novel role for hypothalamic oxytocin (OXT) neurons in the processing of noxious stimuli. In vivo imaging revealed that a large and distributed fraction of zebrafish OXT neurons respond strongly to noxious inputs, including the activation of damage-sensing TRPA1 receptors. OXT population activity reflects the sensorimotor transformation of the noxious stimulus, with some neurons encoding sensory information and others correlating more strongly with large-angle swims. Notably, OXT neuron activation is sufficient to generate this defensive behavior via the recruitment of brainstem premotor targets, whereas ablation of OXT neurons or loss of the peptide attenuates behavioral responses to TRPA1 activation. These data highlight a crucial role for OXT neurons in the generation of appropriate defensive responses to noxious input.


Assuntos
Tronco Encefálico/fisiologia , Vias Neurais/fisiologia , Nociceptividade/fisiologia , Nociceptores/fisiologia , Animais , Tronco Encefálico/citologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Vias Neurais/citologia , Nociceptores/citologia , Ocitocina , Peixe-Zebra
6.
Nat Commun ; 10(1): 2505, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175285

RESUMO

Brain signals that govern memory formation remain incompletely identified. The hypothalamus is implicated in memory disorders, but how its rapidly changing activity shapes memorization is unknown. During encounters with objects, hypothalamic melanin-concentrating hormone (MCH) neurons emit brief signals that reflect object novelty. Here we show that targeted optogenetic silencing of these signals, performed selectively during the initial object encounters (i.e. memory acquisition), prevents future recognition of the objects. We identify an upstream inhibitory microcircuit from hypothalamic GAD65 neurons to MCH neurons, which constrains the memory-promoting MCH cell bursts. Finally, we demonstrate that silencing the GAD65 cells during object memory acquisition improves future object recognition through MCH-receptor-dependent pathways. These results provide causal evidence that object-associated signals in genetically distinct but interconnected hypothalamic neurons differentially control whether the brain forms object memories. This gating of memory formation by hypothalamic activity establishes appropriate behavioral responses to novel and familiar objects.


Assuntos
Glutamato Descarboxilase/metabolismo , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/fisiologia , Melaninas/metabolismo , Memória/fisiologia , Neurônios/metabolismo , Hormônios Hipofisários/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , /fisiologia , Animais , Hipotálamo/citologia , Hipotálamo/metabolismo , Memória/efeitos dos fármacos , Camundongos , Inibição Neural/fisiologia , Vias Neurais , Optogenética , Piperidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , /efeitos dos fármacos
7.
Neuron ; 103(1): 133-146.e8, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31104950

RESUMO

Oxytocin (OT) release by axonal terminals onto the central nucleus of the amygdala exerts anxiolysis. To investigate which subpopulation of OT neurons contributes to this effect, we developed a novel method: virus-delivered genetic activity-induced tagging of cell ensembles (vGATE). With the vGATE method, we identified and permanently tagged a small subpopulation of OT cells, which, by optogenetic stimulation, strongly attenuated contextual fear-induced freezing, and pharmacogenetic silencing of tagged OT neurons impaired context-specific fear extinction, demonstrating that the tagged OT neurons are sufficient and necessary, respectively, to control contextual fear. Intriguingly, OT cell terminals of fear-experienced rats displayed enhanced glutamate release in the amygdala. Furthermore, rats exposed to another round of fear conditioning displayed 5-fold more activated magnocellular OT neurons in a novel environment than a familiar one, possibly for a generalized fear response. Thus, our results provide first evidence that hypothalamic OT neurons represent a fear memory engram.


Assuntos
Medo/fisiologia , Hipotálamo/fisiologia , Memória/fisiologia , Ocitocina/fisiologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Meio Ambiente , Extinção Psicológica/fisiologia , Medo/psicologia , Feminino , Reação de Congelamento Cataléptica , Inativação Gênica , Ácido Glutâmico/metabolismo , Hipotálamo/citologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Optogenética , Ocitocina/genética , Ratos , Ratos Wistar
9.
Elife ; 82019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946012

RESUMO

The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedbacks are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest that activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.


Assuntos
Hipotálamo/fisiologia , Neurônios/fisiologia , Reprodução , Comportamento Sexual Animal , Animais , Estradiol/metabolismo , Receptor alfa de Estrogênio/deficiência , Feminino , Técnicas de Inativação de Genes , Kisspeptinas/análise , Camundongos Knockout , Neurônios/química
10.
Science ; 364(6437): 253, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30948440

RESUMO

Physiological needs produce motivational drives, such as thirst and hunger, that regulate behaviors essential to survival. Hypothalamic neurons sense these needs and must coordinate relevant brainwide neuronal activity to produce the appropriate behavior. We studied dynamics from ~24,000 neurons in 34 brain regions during thirst-motivated choice behavior in 21 mice as they consumed water and became sated. Water-predicting sensory cues elicited activity that rapidly spread throughout the brain of thirsty animals. These dynamics were gated by a brainwide mode of population activity that encoded motivational state. After satiation, focal optogenetic activation of hypothalamic thirst-sensing neurons returned global activity to the pre-satiation state. Thus, motivational states specify initial conditions that determine how a brainwide dynamical system transforms sensory input into behavioral output.


Assuntos
Comportamento de Escolha/fisiologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Vias Neurais/fisiologia , Sede/fisiologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Optogenética , Células Receptoras Sensoriais/fisiologia , Análise de Célula Única
11.
J Endocrinol ; 241(3): 201-219, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30959480

RESUMO

Chronic stress is a known suppressor of female reproductive function. However, attempts to isolate single causal links between stress and reproductive dysfunction have not yet been successful due to their multi-faceted aetiologies. The gut-derived hormone ghrelin regulates stress and reproductive function and may therefore be pivotal in the neuroendocrine integration of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. Here, we hypothesised that chronic stress disrupts ovarian follicle maturation and that this effect is mediated by a stress-induced increase in acyl ghrelin and activation of the growth hormone secretatogue receptor (GHSR). We gave C57BL/6J female mice 30 min daily chronic predator stress for 4 weeks, or no stress, and gave them daily GHSR antagonist (d-Lys3-GHRP-6) or saline. Exposure to chronic predator stress reduced circulating corticosterone, elevated acyl ghrelin levels and led to significantly depleted primordial follicle numbers. GHSR antagonism stress-dependently altered the expression of genes regulating ovarian responsiveness to gonadotropins and was able to attenuate the stress-induced depletion of primordial follicles. These findings suggest that chronic stress-induced elevations of acyl ghrelin may be detrimental for ovarian follicle maturation.


Assuntos
Grelina/fisiologia , Folículo Ovariano/fisiologia , Comportamento Predatório , Estresse Fisiológico , Animais , Apoptose , Peso Corporal , Corticosterona/sangue , Estro , Feminino , Grelina/sangue , Sistema Hipotálamo-Hipofisário , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipófise/fisiologia , Sistema Hipófise-Suprarrenal , Ratos , Ratos Wistar , Receptores de Grelina/antagonistas & inibidores , Estresse Psicológico
12.
Neuron ; 102(1): 60-74, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30946827

RESUMO

Threat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits underlying the "engram" of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.


Assuntos
Encéfalo/fisiopatologia , Medo/fisiologia , Memória/fisiologia , Trauma Psicológico/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/fisiopatologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Núcleo Central da Amígdala/fisiologia , Núcleo Central da Amígdala/fisiopatologia , Hormônio Liberador da Corticotropina/metabolismo , Medo/psicologia , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Hipotálamo/fisiopatologia , Interneurônios/metabolismo , Interneurônios/fisiologia , Trauma Psicológico/metabolismo , Trauma Psicológico/psicologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Tálamo/metabolismo , Tálamo/fisiologia , Tálamo/fisiopatologia
14.
Gen Physiol Biophys ; 38(2): 187-190, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30821254

RESUMO

The aim of this study was to investigate the effect of chronic predator scent stress (PSS) on monoamine levels in rat thalamus and hypothalamus. Rats were exposed to the PSS (sand containing cat urine) for ten minutes daily for ten days. Control animals were exposed to the sand containing clean water. Fifteen days later, rats' behavior and thalamic and hypothalamic levels of monoamines were analyzed. PSS rats had elevated anxiety, increased thalamic serotonin and decreased hypothalamic dopamine concentrations. This decrease in hypothalamic dopamine may explain, at least in part, lowered corticosterone levels observed in PSS animals in our previous studies.


Assuntos
Dopamina , Hipotálamo , Odorantes , Serotonina , Tálamo , Animais , Corticosterona , Hipotálamo/fisiologia , Comportamento Predatório , Ratos , Serotonina/metabolismo , Estresse Psicológico , Tálamo/fisiologia
15.
Gene ; 699: 1-7, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30853631

RESUMO

Gonadotropin-releasing hormone (GnRH) plays an important role in regulating the activities of other components downstream of the hypothalamic-pituitary-gonadal (HPG) axis and maintaining the normal reproductive cycle of animals. However, the molecular mechanisms by which GnRH synthesis and secretion are regulated in sheep remains unclear. In this study, a series of eight recombinant vectors with deletion fragments were constructed and cotransfected with pGL3-Basic and pRL-SV40 into sheep hypothalamic neuronal cells. After treatment with 1 nM kisspeptin, the core promoter of the sheep GnRH gene was identified to be in the region of -1912 bp to -1461 bp by dual-luciferase reporter assay. Bioinformatics analysis showed that there was a binding site for the transcription factor Otx-2 in the core promoter region (-1786 to -1770 bp) that was highly conserved among different species. The expression patterns of Kiss-1, Otx-2 and GnRH in the sheep hypothalamus were the same, and the expression of Kiss-1, Otx-2 and GnRH was significantly higher in the breeding season than in nonbreeding season (P < 0.01). In addition, when hypothalamic neurons were cultured in vitro with kisspeptin, kisspeptin induced the expression of GnRH and Otx-2. In conclusion, these results provide evidence that the core promoter region (-1786 to -1770 bp) of the GnRH gene is involved in the regulation of hypothalamic activity by kisspeptin and that binding of the transcription factor Otx-2 mediates this activation.


Assuntos
Expressão Gênica/genética , Hormônio Liberador de Gonadotropina/genética , Kisspeptinas/genética , Regiões Promotoras Genéticas/genética , Ovinos/genética , Animais , Sítios de Ligação/genética , Cruzamento/métodos , Hipotálamo/fisiologia , Neurônios/fisiologia , Fatores de Transcrição Otx/genética , Reprodução/genética
16.
J Steroid Biochem Mol Biol ; 189: 187-194, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30853652

RESUMO

We have previously shown that expression of the androgen receptor (AR) in neurons within the brain positively regulates hind-limb muscle mass and physical activity in male mice. To further investigate the region of the brain responsible for mediating these effects of testosterone and to determine whether they are only important for muscle mass accrual during development or whether they are also important for the maintenance of muscle mass in the adult, we deleted the AR specifically in the hypothalamus of adult male mice (Hyp-ARKOs). Hyp-ARKO mice were generated by bilateral stereotaxic microinjection of an adeno-associated virus (AAV) expressing GFP and iCre recombinase under the control of the e-synapsin promoter into the hypothalamus of 10-week-old exon 3-AR floxed male mice. AR mRNA was deleted by 45% in the hypothalamus of Hyp-ARKOs at 5 weeks post-AAV-eSyn-iCre injection. This led to an increase in the mass of the androgen-dependent organs, seminal vesicles and kidneys, by 30% (P < 0.01) and 10% (P < 0.05) respectively, and an increase in serum luteinizing hormone (LH) by 2 fold (P < 0.05). Whilst the mean value for serum testosterone was higher in the Hyp-ARKOs, this did not reach statistical significance. Despite a phenotype consistent with increased androgen bioactivity in Hyp-ARKOs, which would be expected to increase muscle mass, the mass of the hind-limb muscles, gastrocnemius (Gast) (P = 0.001), extensor digitorum longus (EDL) (P < 0.001) and soleus (Sol) (P < 0.01) were paradoxically decreased by 12-19% compared to controls. Voluntary physical activity was reduced by 65% (P < 0.05) in Hyp-ARKO male mice and was associated with a reduction in gene expression of Drd1a and Maob (P ≤ 0.05) in the hypothalamus, suggesting involvement of the brain dopaminergic system. These data provide compelling evidence that androgen signalling via the AR in the hypothalamus acts to positively regulate the maintenance of hind-limb muscle mass and voluntary activity in adult male mice, independent of AR signalling in peripheral tissues.


Assuntos
Hipotálamo/fisiologia , Músculo Esquelético/fisiologia , Receptores Androgênicos/metabolismo , Animais , Membro Posterior/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal
17.
Keio J Med ; 68(1): 27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30905886

RESUMO

Although sleep is a ubiquitous behavior in animal species with well-developed central nervous systems, many aspects in the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has triggered an intensive research examining the exact role of the orexinergic and other neural pathways in the regulation of sleep/wakefulness. The orexin receptor antagonist suvorexant, which specifically block the endogenous waking system, has been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for "sleepiness" (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMG) measurements. We have so far screened >8,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutation in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Since these dominant mutations cause strong phenotypic traits, we expect that the mutated genes will provide new insights into the elusive pathway regulating sleep/wakefulness. Indeed, through a systematic cross-comparison of the Sleepy mutants and sleep-deprived mice, we have recently found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.


Assuntos
Cataplexia/genética , Narcolepsia/genética , Proteínas do Tecido Nervoso/genética , Distúrbios do Início e da Manutenção do Sono/genética , Sono/fisiologia , Vigília/fisiologia , Animais , Azepinas/farmacologia , Cataplexia/tratamento farmacológico , Cataplexia/fisiopatologia , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Hipotálamo/fisiopatologia , Camundongos , Camundongos Transgênicos , Mutação , Narcolepsia/tratamento farmacológico , Narcolepsia/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Polissonografia , Medicamentos Indutores do Sono/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Triazóis/farmacologia
18.
Neuron ; 102(1): 120-127.e4, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30765165

RESUMO

Throughout life, individuals learn to predict a punishment via its association with sensory stimuli. This process ultimately prompts goal-directed actions to prevent the danger, a behavior defined as avoidance. Neurons in the lateral habenula (LHb) respond to aversive events as well as to environmental cues predicting them, supporting LHb contribution to cue-punishment association. However, whether synaptic adaptations at discrete habenular circuits underlie such associative learning to instruct avoidance remains elusive. Here, we find that, in mice, contingent association of an auditory cue (tone) with a punishment (foot shock) progressively causes cue-driven LHb neuronal excitation during avoidance learning. This process is concomitant with the strengthening of LHb AMPA receptor-mediated neurotransmission. Such a phenomenon occludes long-term potentiation and occurs specifically at hypothalamus-to-habenula synapses. Silencing hypothalamic-to-habenulainputs or optically inactivating postsynaptic AMPA receptors within the LHb disrupts avoidance learning. Altogether, synaptic strengthening at a discrete habenular circuit transforms neutral stimuli into salient punishment-predictive cues to guide avoidance.


Assuntos
Aprendizagem da Esquiva/fisiologia , Sinais (Psicologia) , Habenula/fisiologia , Hipotálamo/fisiologia , Potenciação de Longa Duração/fisiologia , Punição , Sinapses/fisiologia , Animais , Aprendizagem por Associação/fisiologia , Masculino , Camundongos , Técnicas de Patch-Clamp , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/fisiologia
19.
Neuroscience ; 404: 541-556, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738854

RESUMO

Aging is associated with sleep-wake disruption, dampening of circadian amplitudes, and a reduced homeostatic sleep response. Aging is also associated with a decline in hypothalamic cell proliferation. We hypothesized that the aging-related decline in cell-proliferation contributes to the dysfunction of preoptic-hypothalamic sleep-wake and circadian systems and consequent sleep-wake disruption. We determined if cytosine-ß-D-arabinofuranoside (AraC), an antimitotic agent known to suppress hypothalamic cell proliferation and neurogenesis, causes sleep-wake instability in young mice. The sleep-wake profiles were compared during baseline, during 4 weeks of artificial cerebrospinal fluid (aCSF) + 5-bromo-2'-deoxyuridine (BrdU) or AraC+BrdU infusion into the lateral ventricle, and 8 weeks after treatments. The sleep-wake architecture after AraC treatment was further compared with sleep-wake profiles in aged mice. Compared to aCSF+BrdU, 4 weeks of AraC+BrdU infusion significantly decreased (-96%) the number of BrdU+ cells around the third ventricular wall and adjacent preoptic-hypothalamic area and produced a) sleep disruption during the light phase with decreases in non-rapid eye movement (nonREM) (-9%) and REM sleep (-21%) amounts, and increased numbers of shorter (<2 min; 142 versus 98 episodes/12 h) and decreased numbers of longer (>5 min; 19 versus 26 episodes/12 h) nonREM sleep episodes; and b) wake disruption during the dark phase, with increased numbers of shorter (138 versus 91 episodes/12 h) and decreased numbers of longer active waking (17 versus 24 episodes/12 h) episodes. AraC-treated mice also exhibited lower delta activity within nonREM recovery sleep. The sleep-wake architecture of AraC-treated mice was similar to that observed in aged mice. These findings are consistent with a hypothesis that a decrease in hypothalamic cell proliferation/neurogenesis is detrimental to sleep-wake and circadian systems and may underlie sleep-wake disturbance in aging.


Assuntos
Envelhecimento/fisiologia , Proliferação de Células/fisiologia , Hipotálamo/fisiologia , Neurogênese/fisiologia , Sono/fisiologia , Vigília/fisiologia , Fatores Etários , Envelhecimento/efeitos dos fármacos , Animais , Antimitóticos/administração & dosagem , Antimitóticos/toxicidade , Proliferação de Células/efeitos dos fármacos , Ritmo Delta/efeitos dos fármacos , Ritmo Delta/fisiologia , Hipotálamo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos
20.
Andrologia ; 51(5): e13258, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30809834

RESUMO

Seminal oxidative stress (OS) is a major cause of male factor infertility and can be measured as oxidation-reduction potential (ORP). Studies showed significant negative relationships of ORP with sperm count, motility or DNA integrity. Since these parameters are also positively or negatively associated with reproductive hormones follicle-stimulating hormone (FSH), luteinising hormone (LH), testosterone, testicular volume and the occurrence of varicocele, it is important to understand the mechanistic relationship between ORP and hormonal and/or testicular parameters. Therefore, we studied the relationship between ORP levels, standard hormone profiles and testicular volume in infertile men with and without varicocele. Results show a highly significant negative relationship of ORP with testicular volume and significantly positive correlations with FSH and LH. Yet, when adding varicocele as covariate, the relationship with FSH/LH became nonsignificant. Contrary, the presence of varicocele had only a contributing influence on the association of ORP with the testis volume. No association was found with estradiol. We propose that since OS causes degeneration of Sertoli cell with testicular shrinkage, such negative effect would result in a negative feedback on the hypothalamus with less inhibin secretion. This may result in increased secretion of LH and FSH. Thus, systemic and/or local OS may be responsible for smaller testis volumes.


Assuntos
Infertilidade Masculina/diagnóstico , Estresse Oxidativo/fisiologia , Testículo/patologia , Varicocele/patologia , Adulto , Idoso , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/metabolismo , Humanos , Hipotálamo/fisiologia , Infertilidade Masculina/sangue , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Inibinas/metabolismo , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Oxirredução , Estudos Retrospectivos , Sêmen , Contagem de Espermatozoides , Testosterona/sangue , Testosterona/metabolismo , Varicocele/complicações , Adulto Jovem
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