RESUMO
Sexual dimorphisms in the brain underlie behavioral sex differences, but the function of individual sexually dimorphic neuronal populations is poorly understood. Neuronal sexual dimorphisms typically represent quantitative differences in cell number, gene expression, or other features, and it is unknown whether these dimorphisms control sex-typical behavior exclusively in one sex or in both sexes. The progesterone receptor (PR) controls female sexual behavior, and we find many sex differences in number, distribution, or projections of PR-expressing neurons in the adult mouse brain. Using a genetic strategy we developed, we have ablated one such dimorphic PR-expressing neuronal population located in the ventromedial hypothalamus (VMH). Ablation of these neurons in females greatly diminishes sexual receptivity. Strikingly, the corresponding ablation in males reduces mating and aggression. Our findings reveal the functions of a molecularly defined, sexually dimorphic neuronal population in the brain. Moreover, we show that sexually dimorphic neurons can control distinct sex-typical behaviors in both sexes.
Assuntos
Agressão/fisiologia , Hipotálamo/metabolismo , Neurônios/metabolismo , Caracteres Sexuais , Comportamento Sexual , Animais , Feminino , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Comportamento Sexual AnimalRESUMO
BACKGROUND: Pharmacologic manipulations directed at the periaqueductal gray have demonstrated the importance of the µ-opioid receptor in modulating reflexive responses to nociception. The authors hypothesized that a supraspinal pathway centered on neurons in the periaqueductal gray containing the µ-opioid receptor could modulate nociceptive and itch behaviors. METHODS: The study used anatomical, optogenetic, and chemogenetic approaches in male and female mice to manipulate µ-opioid receptor neurons in the periaqueductal gray. Behavioral assays including von Frey, Hargreaves, cold plantar, chloroquine-induced itch, hotplate, formalin-induced injury, capsaicin-induced injury, and open field tests were used. In separate experiments, naloxone was administered in a postsurgical model of latent sensitization. RESULTS: Activation of µ-opioid receptor neurons in the periaqueductal gray increased jumping (least-squares mean difference of -3.30 s; 95% CI, -6.17 to -0.44; P = 0.023; n = 7 or 8 mice per group), reduced itch responses (least-squares mean difference of 70 scratching bouts; 95% CI, 35 to 105; P < 0.001; n = 8 mice), and elicited modestly antinociceptive effects (least-squares mean difference of -0.7 g on mechanical and -10.24 s on thermal testing; 95% CI, -1.3 to -0.2 and 95% CI, -13.77 to -6.70, and P = 0.005 and P < 0.001, respectively; n = 8 mice). Last, the study uncovered the role of the periaqueductal gray in suppressing hyperalgesia after a postsurgical state of latent sensitization (least-squares mean difference comparing saline and naloxone of -12 jumps; 95% CI, -17 to -7; P < 0.001 for controls; and -2 jumps; 95% CI, -7 to 4; P = 0.706 after optogenetic stimulation; n = 7 to 9 mice per group). CONCLUSIONS: µ-Opioid receptor neurons in the periaqueductal gray modulate distinct nocifensive behaviors: their activation reduced responses to mechanical and thermal testing, and attenuated scratching behaviors, but facilitated escape responses. The findings emphasize the role of the periaqueductal gray in the behavioral expression of nociception using reflexive and noxious paradigms.
Assuntos
Nociceptividade , Substância Cinzenta Periaquedutal , Camundongos , Masculino , Feminino , Animais , Substância Cinzenta Periaquedutal/fisiologia , Naloxona/farmacologia , Neurônios/metabolismo , Receptores Opioides , Receptores Opioides mu/fisiologiaRESUMO
The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.
Assuntos
Regulação da Temperatura Corporal/fisiologia , Nociceptividade/fisiologia , Dor/fisiopatologia , Núcleos Parabraquiais/fisiologia , Paladar/fisiologia , Animais , Humanos , Vias Neurais/fisiologia , Vias Neurais/fisiopatologia , Neurônios/fisiologia , Núcleos Parabraquiais/fisiopatologiaRESUMO
Schimmelpenning syndrome is a rare, well-defined constellation of clinical phenotypes associated with the presence of nevus sebaceous and multisystem abnormalities most commonly manifested as cerebral, ocular, and skeletal defects [
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Nevo Sebáceo de Jadassohn/complicações , Adolescente , Astrocitoma/diagnóstico por imagem , Astrocitoma/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Humanos , Masculino , Nevo Sebáceo de Jadassohn/genética , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Convulsões/etiologiaRESUMO
Intraarticular knee injuries and subsequent posttraumatic arthritis (PTOA) are common in athletes. Unfortunately, PTOA may significantly affect performance and overall function, but this condition remains difficult to characterize. In this review, we provide an overview of imaging modalities used to evaluate PTOA among athletes and physically active individuals following knee injury, with the goal to discuss the strengths and limitations of their application in this population. A literature search was performed to identify clinical studies focusing of knee injuries in athletes and athletic persons, specifically using imaging for diagnosis or monitoring disease progression. A total of 81 articles were identified, and 23 were included for review. Studies on plain radiographs (n = 8) and magnetic resonance imaging (MRI) assessed arthritic burden (n = 13), with MRI able to depict the earliest cartilage changes. Few studies (n = 2) leveraged ultrasound. Challenges persist, particularly regarding standardization and reliability across different radiographic grading systems. Additionally, further research is needed to establish the clinical significance of techniques to assess cartilage composition on MRI, including ultrashort echo-time enhanced T2*, T1rho and T2 imaging. Addressing these challenges through standardized protocols and intensified research efforts will enhance the diagnostic utility of imaging modalities in musculoskeletal medicine and enable high-quality prospective studies.
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OBJECTIVE: Congenital aqueductal stenosis (CAS) is a common etiology of hydrocephalus that occurs in a subset of infants and may be linked to an increased incidence of ophthalmological abnormalities and delayed developmental milestones. Although hydrocephalus is common and widely studied, sparse literature exists on patients with isolated (no identifiable genetic link) CAS along with analysis of ophthalmological manifestations. In this study, the authors sought to describe the ophthalmological abnormalities and delayed developmental milestones of patients with isolated CAS. METHODS: Data of patients with CAS were prospectively entered and monitored in a surgical database maintained by the Department of Neurological Surgery at Children's Hospital of Pittsburgh from January 2005 to October 2016. Patients with a family history of congenital hydrocephalus, positive testing for genetic forms of aqueductal stenosis, other congenital abnormalities suggesting an underlying genetic syndrome, and stenosis/obstruction due to secondary causes were excluded from this study. Prenatal and perinatal history, CSF diversion history, and a variety of outcomes, including ophthalmological deficits and developmental milestones, were collected and analyzed. RESULTS: A total of 41 patients with isolated CAS were identified, with a mean follow-up duration of 6 years. Among that cohort, 26 patients (63.4%) developed neuroophthalmological complications, which were further stratified. Fourteen patients (34.1%) developed strabismus and 11 (26.8%) developed astigmatism, and 1 patient (2.4%) with papilledema was recorded. Among patients with ophthalmological abnormalities, 76.9% had delayed developmental milestones (p = 0.045). CONCLUSIONS: Patients with CAS were found to have increased risk of ophthalmological abnormalities requiring correction, along with an increased risk of delayed developmental milestones. Importantly, there was a significant correlation between the development of ophthalmological abnormalities and delayed developmental milestones that was independent of CSF diversion history. Larger patient cohort studies are required to explore whether earlier development of hydrocephalus, as is the case in CAS, causes elevated rates of neurological and ophthalmological complications, and if earlier CSF diversion correlates with improved outcomes.
RESUMO
The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.
Assuntos
Aprendizagem da Esquiva/fisiologia , Reação de Fuga/fisiologia , Nociceptividade/fisiologia , Núcleos Parabraquiais/fisiologia , Animais , Núcleo Central da Amígdala/fisiologia , Camundongos , Vias Neurais/fisiologia , Neurônios Eferentes/fisiologia , Optogenética , Dor , Substância Cinzenta Periaquedutal/fisiologia , Núcleos Septais/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologiaRESUMO
Neuropathic itch is a pathological condition that is due to damage within the nervous system. This type of itch can be severe and unrelenting, which has a very negative impact on quality of life. Neuropathic itch is more common than generally appreciated because most types of neuropathic pain have a neuropathic itch counterpart. Unfortunately, much like neuropathic pain, there is a lack of effective treatments for neuropathic itch. Here, we consider the neural basis of itch and then describe how injuries within these neural circuits can lead to neuropathic itch in both animal models and human disease states.
Assuntos
Neuralgia/complicações , Prurido/etiologia , Animais , HumanosRESUMO
BACKGROUND: There is extensive debate on the role of fixed pressure shunts in the adult population. Most studies assessing fixed pressure valves do not consider the potential for changes in technique and management of shunts. We sought to examine the natural history of fixed pressure. METHODS: We conducted a retrospective chart review of 169 patients undergoing shunt placement by the senior author Daniel Wecht (DW). The etiology of shunt placement, shunt failure rates, and outcome data was assessed for each patient. RESULTS: Overall, 126 patients underwent initial shunt placement. Thirty-three (26.2%) patients required at least one shunt revision during follow-up. The most common cause of first time revision was mechanical shunt malfunction (13, 39.4%), followed by infection (7, 21.2%), and shunt migration (6, 18.2%). Three patients (9.1%) required revision due to misplaced catheters. Underdrainage or overdrainage of shunts each resulted in revisions for 2 (6.1%) patients. The mean follow-up length was 28.1 ± 6.1 months. CONCLUSION: Fixed pressure shunts failed primarily because of shunt malfunction and occurred most commonly in patients developing hydrocephalus as a result of hemorrhage or normal pressure hydrocephalus (NPH). The overall failure rate between these two groups was proportionally equivalent. Both overdrainage or underdrainage were found to be rare indications for revision.
RESUMO
Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is believed to underlie temporal summation of nociceptive input. However, whether spinoparabrachial neurons, which likely contribute to the affective component of pain, undergo wind-up was unknown. Here, we addressed this question and investigated the underlying neural circuit. We show that one-fifth of lamina I spinoparabrachial neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain's unpleasantness.
Assuntos
Interneurônios/fisiologia , Neurônios/fisiologia , Dor/fisiopatologia , Corno Dorsal da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Camundongos , Técnicas de Patch-ClampRESUMO
Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment.
Assuntos
Neurônios Aferentes/efeitos dos fármacos , Dor/tratamento farmacológico , Receptores Opioides kappa/antagonistas & inibidores , Transdução de Sinais/fisiologia , Animais , Axônios/fisiologia , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Manejo da Dor , Receptores Opioides kappa/metabolismoRESUMO
How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male's territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression.
Assuntos
Agressão/fisiologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Neurônios/fisiologia , Comportamento Social , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Adenoviridae/genética , Animais , Antipsicóticos/farmacologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Feminino , Técnicas In Vitro , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Fatores Sexuais , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismoRESUMO
Compelling evidence links amyloid beta (Aß) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aß are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aß receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal Aß activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of Aß-NgR signaling, mediating Aß's inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT.