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Internal states drive survival behaviors, but their neural implementation is poorly understood. Recently, we identified a line attractor in the ventromedial hypothalamus (VMH) that represents a state of aggressiveness. Line attractors can be implemented by recurrent connectivity or neuromodulatory signaling, but evidence for the latter is scant. Here, we demonstrate that neuropeptidergic signaling is necessary for line attractor dynamics in this system by using cell-type-specific CRISPR-Cas9-based gene editing combined with single-cell calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+ neurons that control aggression diminished attack, reduced persistent neural activity, and eliminated line attractor dynamics while only slightly reducing overall neural activity and sex- or behavior-specific tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor in mammals. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.
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The hypothalamus regulates innate social behaviors, including mating and aggression. These behaviors can be evoked by optogenetic stimulation of specific neuronal subpopulations within MPOA and VMHvl, respectively. Here, we perform dynamical systems modeling of population neuronal activity in these nuclei during social behaviors. In VMHvl, unsupervised analysis identified a dominant dimension of neural activity with a large time constant (>50 s), generating an approximate line attractor in neural state space. Progression of the neural trajectory along this attractor was correlated with an escalation of agonistic behavior, suggesting that it may encode a scalable state of aggressiveness. Consistent with this, individual differences in the magnitude of the integration dimension time constant were strongly correlated with differences in aggressiveness. In contrast, approximate line attractors were not observed in MPOA during mating; instead, neurons with fast dynamics were tuned to specific actions. Thus, different hypothalamic nuclei employ distinct neural population codes to represent similar social behaviors.
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Conducta Sexual Animal , Núcleo Hipotalámico Ventromedial , Animales , Conducta Sexual Animal/fisiología , Núcleo Hipotalámico Ventromedial/fisiología , Hipotálamo/fisiología , Agresión/fisiología , Conducta SocialRESUMEN
Jellyfish are radially symmetric organisms without a brain that arose more than 500 million years ago. They achieve organismal behaviors through coordinated interactions between autonomously functioning body parts. Jellyfish neurons have been studied electrophysiologically, but not at the systems level. We introduce Clytia hemisphaerica as a transparent, genetically tractable jellyfish model for systems and evolutionary neuroscience. We generate stable F1 transgenic lines for cell-type-specific conditional ablation and whole-organism GCaMP imaging. Using these tools and computational analyses, we find that an apparently diffuse network of RFamide-expressing umbrellar neurons is functionally subdivided into a series of spatially localized subassemblies whose synchronous activation controls directional food transfer from the tentacles to the mouth. These data reveal an unanticipated degree of structured neural organization in this species. Clytia affords a platform for systems-level studies of neural function, behavior, and evolution within a clade of marine organisms with growing ecological and economic importance.
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Evolución Biológica , Hidrozoos/genética , Modelos Animales , Neurociencias , Animales , Animales Modificados Genéticamente , Conducta Animal , Conducta Alimentaria , Marcación de Gen , Hidrozoos/fisiología , Modelos Biológicos , Red Nerviosa/fisiología , Neuronas/metabolismo , Neuropéptidos/metabolismoRESUMEN
Females exhibit complex, dynamic behaviors during mating with variable sexual receptivity depending on hormonal status1-4. However, how their brains encode the dynamics of mating and receptivity remains largely unknown. The ventromedial hypothalamus, ventro-lateral subdivision contains estrogen receptor type 1-positive neurons that control mating receptivity in female mice5,6. Unsupervised dynamical systems analysis of calcium imaging data from these neurons during mating uncovered a dimension with slow ramping activity, generating a line attractor in neural state space. Neural perturbations in behaving females demonstrated relaxation of population activity back into the attractor. During mating population activity integrated male cues to ramp up along this attractor, peaking just before ejaculation. Activity in the attractor dimension was positively correlated with the degree of receptivity. Longitudinal imaging revealed that attractor dynamics appear and disappear across the estrus cycle and are hormone-dependent. These observations suggest that a hypothalamic line attractor encodes a persistent, escalating state of female sexual arousal or drive during mating. They also demonstrate that attractors can be reversibly modulated by hormonal status, on a timescale of days.
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Line attractors are emergent population dynamics hypothesized to encode continuous variables such as head direction and internal states1-4. In mammals, direct evidence of neural implementation of a line attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles2,3. Linear dynamical systems modeling has revealed that neurons in the hypothalamus exhibit approximate line attractor dynamics in male mice during aggressive encounters5. We have previously hypothesized that these dynamics may encode the variable intensity of an aggressive internal motive state. Here, we report that these neurons also showed line attractor dynamics in head-fixed mice observing aggression6. We identified and perturbed line attractor-contributing neurons using 2-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations yielded integration and persistent activity that drove the system along the line attractor, while transient off-manifold perturbations were followed by rapid relaxation back into the attractor. Furthermore, single-cell stimulation and imaging revealed selective functional connectivity among attractor-contributing neurons. Intriguingly, individual differences among mice in line attractor stability were correlated with the degree of functional connectivity among attractor neurons. Mechanistic RNN modelling indicated that dense subnetwork connectivity and slow neurotransmission7 best recapitulate our empirical findings. Our work bridges circuit and manifold levels3, providing causal evidence of continuous attractor dynamics encoding an affective internal state in the mammalian hypothalamus.
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Most animals have compound eyes, with tens to thousands of lenses attached rigidly to the exoskeleton. A natural assumption is that all of these species must resort to moving either their head or their body to actively change their visual input. However, classic anatomy has revealed that flies have muscles poised to move their retinas under the stable lenses of each compound eye1-3. Here we show that Drosophila use their retinal muscles to smoothly track visual motion, which helps to stabilize the retinal image, and also to perform small saccades when viewing a stationary scene. We show that when the retina moves, visual receptive fields shift accordingly, and that even the smallest retinal saccades activate visual neurons. Using a head-fixed behavioural paradigm, we find that Drosophila perform binocular, vergence movements of their retinas-which could enhance depth perception-when crossing gaps, and impairing the physiology of retinal motor neurons alters gap-crossing trajectories during free behaviour. That flies evolved an ability to actuate their retinas suggests that moving the eye independently of the head is broadly paramount for animals. The similarities of smooth and saccadic movements of the Drosophila retina and the vertebrate eye highlight a notable example of convergent evolution.
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Drosophila , Movimientos Oculares , Músculos , Retina , Visión Ocular , Animales , Drosophila/fisiología , Movimientos Oculares/fisiología , Músculos/fisiología , Retina/fisiología , Movimientos Sacádicos/fisiología , Visión Ocular/fisiología , Visión Binocular , Percepción de Profundidad , Neuronas Motoras , Cabeza/fisiología , Drosophila melanogaster/fisiología , Evolución BiológicaRESUMEN
Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.
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Retroalimentación Fisiológica , Microglía/fisiología , Inhibición Neural , Neuronas/fisiología , 5'-Nucleotidasa/metabolismo , Potenciales de Acción , Adenosina/metabolismo , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antígenos CD/metabolismo , Apirasa/metabolismo , Calcio/metabolismo , Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Inhibición Neural/genética , Receptor de Adenosina A1/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Factores de TiempoRESUMEN
The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.
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Acetilcolina , Colinérgicos , Acetilcolina/metabolismo , Prosencéfalo/metabolismo , Neuronas Colinérgicas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , LógicaRESUMEN
Abnormal lipid homeostasis has been observed in the brain of Parkinson's disease (PD) patients and experimental models, although the mechanism underlying this phenomenon is unclear. Notably, previous studies have reported that the PD-linked protein Parkin functionally interacts with important lipid regulators, including Sterol Regulatory Element-Binding Proteins (SREBPs) and cluster of differentiation 36 (CD36). Here, we demonstrate a functional relationship between Parkin and lipoprotein lipase (LPL), a triglyceride lipase that is widely expressed in the brain. Using a human neuroblastoma cell line and a Parkin knockout mouse model, we demonstrate that Parkin expression level positively correlates with neuronal LPL protein level and activity. Importantly, our study identified SREBP2, a major regulator of sterol and fatty acid synthesis, as a potential mediator between Parkin and LPL. Supporting this, SREBP2 genetic ablation abolished Parkin effect on LPL expression. We further demonstrate that Parkin-LPL pathway regulates the formation of intracellular lipid droplets, and that this pathway is upregulated upon exposure to PD-linked oxidative stress induced by rotenone. Finally, we show that inhibition of either LPL or SREBP2 exacerbates rotenone-induced cell death. Taken together, our findings reveal a novel pathway linking Parkin, SREBP2 and LPL in neuronal lipid homeostasis that may be relevant to the pathogenesis of PD.
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Lipoproteína Lipasa , Enfermedad de Parkinson , Proteína 2 de Unión a Elementos Reguladores de Esteroles , Ubiquitina-Proteína Ligasas , Animales , Humanos , Ratones , Homeostasis , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/fisiología , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Ratones Noqueados , Neuronas/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Rotenona/efectos adversos , Transducción de Señal , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
OBJECTIVES: To find out if Rituximab (RTX) is effective in "treatment naive" idiopathic inflammatory myopathies (IIM), and whether there could be differential treatment responses between the "treatment naive" and treatment "refractory" IIM. METHODS: Data obtained from a prospectively maintained database comprising patients with IIM treated with rituximab. Patient details were obtained at baseline, 3-months, 6-months intervals, and subsequent follow up visits. Treatment response was categorised as improved, worsening, or stable based on manual muscle testing (MMT8) scores, patient global and physician global improvement (PtGA and PGA) for skin and joint symptoms improvement and spirometry at 6 months. The time to clinical improvement and remission were noted and survival analysis curves were constructed. RESULTS: 60 patients with IIM (including 18 with anti-SRP myopathy) were included, out of which 33 who received RTX were treatment naïve. The remaining 27 were started on rituximab for refractory myopathy. Mean age was 39 years (SD12.58) in "treatment-naive" group and 43 years (SD 12.12) in "refractory" group. At 6 months of follow up, 48/55 (87%) patients showed response, 31/31 (100%) in "treatment-naive" and 17/24 (70%) in "refractory" cases, p 0.006*. In refractory group, 7 (29%) had stable disease. The mean changes in MMT8 were significantly more in the "treatment-naive" treatment group (13.41(SD 7.31) compared with "refractory" IIM 8.33 (SD 7.92) (p= 0.017*). Majority of patients were able to reduce dose below 5 mg/day before 6 months. No major adverse events were reported over the median follow-up of 24 (IQR 36) months. CONCLUSIONS: Rituximab is effective and safe across the spectrum of IIM. Early use in disease is associated with better outcomes.
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INTRODUCTION/AIMS: In Guillain-Barré syndrome (GBS), the sensitivity and specificity of phrenic compound muscle action potential (CMAP) measurements to predict endotracheal mechanical ventilation are unknown. Hence, we sought to estimate sensitivity and specificity. METHODS: We performed a 10-year retrospective analysis of adult GBS patients from our single-center laboratory database (2009 to 2019). The phrenic nerve amplitudes and latencies before ventilation were recorded along with other clinical and demographic features. Receiver operating curve (ROC) analysis with area under the curve (AUC) was used to determine the sensitivity and specificity with 95% confidence interval (CI) for phrenic amplitudes and latencies in predicting the need for mechanical ventilation. RESULTS: Two hundred five phrenic nerves were analyzed in 105 patients. The mean age was 46.1 ± 16.2 years, with 60% of them being male. Fourteen patients (13.3%) required mechanical ventilation. The average phrenic amplitudes were lower in the ventilated group (P = .003), but average latencies did not differ (P = .133). ROC analysis confirmed that phrenic amplitudes could predict respiratory failure (AUC = 0.76; 95% CI, 0.61 to 0.91; P < .002), but phrenic latencies could not (AUC = 0.60; 95% CI, 0.46 to 0.73; P = .256). The best threshold for amplitude was ≥0.6 mV, with sensitivity, specificity, and positive and negative predictive values of 85.7%, 58.2%, 24.0%, and 96.4%, respectively. DISCUSSION: Our study suggests that phrenic CMAP amplitudes can predict the need for mechanical ventilation in GBS. In contrast, phrenic CMAP latencies are not reliable. The high negative predictive value of phrenic CMAP amplitudes ≥0.6 mV can preclude mechanical ventilation, making these a useful adjunct to clinical decision-making.
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Síndrome de Guillain-Barré , Adulto , Humanos , Masculino , Persona de Mediana Edad , Femenino , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/terapia , Respiración Artificial , Nervio Frénico , Estudios Retrospectivos , ElectrofisiologíaRESUMEN
INTRODUCTION: Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal hematopoietic disorder, where there is deficiency of glycosylphosphatidylinositol (GPI) anchored proteins in the cell membrane, leading to increased complement sensitivity of red blood cells, intravascular hemolysis and vascular inflammation. Arterial and venous strokes in patients with PNH are a rarity posing significant diagnostic and therapeutic challenges. We report our experience with management of PNH patients with cerebrovascular emergencies. METHODS: We report 2 patients with PNH, one who was previously diagnosed with PNH and had arterial stroke, the other had an index presentation of cerebral venous sinus thrombosis (CVT) and was subsequently diagnosed with PNH. We also present the systematic review of literature reporting similar cases, highlighting the challenges in management. RESULTS: Both patients presented to our centre with cerebrovascular emergency. The first patient was a diagnosed with PNH, and presented with left hemispheric infarction caused by thrombosis of middle cerebral artery. He was thrombolysed and underwent mechanical thrombectomy, which was unsuccessful in view of repeated re - thrombosis of the vessel. The patient survived with significant disability. The second patient had severe cerebral venous sinus thrombosis with large right hemispheric hemorrhagic venous infarction. She underwent emergency decompressive hemicraniectomy complicated by massive blood loss and disseminated intravascular coagulation. She subsequently had recurrent life threatening intracranial bleed secondary to platelet transfusions, thrombocytopenia, and use of contrast agents. She progressed to develop Budd Chiari syndrome and was initiated on Eculuzimab. She became transfusion independent, however remained in minimally conscious state and succumbed to sepsis. CONCLUSIONS: Management of arterial and venous strokes is complex in patients with PNH. Invasive procedures and platelet transfusions are to be avoided in acute thrombosis, till robust evidence is available establishing the safety of the same in patients with PNH. Eculuzimab is a promising option, but far from reach for patients in developing countries.
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Limited literature is available on stimulus induced after discharges (SIAD) in patients with peripheral nerve hyperexcitability (PNH). The aim of the study was to examine the diagnostic utility of SIAD in the diagnosis and monitoring of primary PNH disorders. In this retrospective study, we studied 26 patients who were admitted with a diagnosis of primary PNH to the department of Neurology from January 2013 to April 2019. Their clinical profile, immunological characteristics were extracted from the database and nerve conduction studies were relooked for the presence of SIAD. 76% of patients in the primary PNH cohort had SIAD with 90% of them being voltage-gated potassium channel complex antibody positive; predominantly against contactin-associated protein-2 antigen and rest being paraneoplastic. There was also resolution of SIAD following treatment indicating reversible hyperexcitability. SIAD is a sensitive marker for Primary PNH syndrome with monitoring and diagnostic implications.
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Potenciales de Acción/fisiología , Electrodiagnóstico/normas , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/fisiopatología , Conducción Nerviosa/fisiología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Nervio Tibial/fisiología , Adulto , Electrodiagnóstico/métodos , Electromiografía , Femenino , Estudios de Seguimiento , Humanos , Síndrome de Isaacs/diagnóstico , Síndrome de Isaacs/fisiopatología , Masculino , Persona de Mediana Edad , Miocimia/diagnóstico , Miocimia/fisiopatología , Estudios RetrospectivosRESUMEN
OBJECTIVES: To study the clinical profile and outcomes of patients with paraproteinemic neuropathy (PPN) and to explore the utility of nerve conduction studies (NCSs) to differentiate between the demyelinating subtypes. METHODS: We did a retrospective analysis of patients diagnosed with PPN between January 2010 and December 2019 in an inpatient setting. The study population consisted of patients above 16 years of age presenting with clinical features suggestive of chronic peripheral neuropathy and on evaluation was found to have PPN. RESULTS: A total of 74 patients were identified. The patients were predominantly in the 6th decade, and the majority were males. The subtypes of PPN were monoclonal gammopathy of undetermined significance (MGUS) (45.9%), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) (24.3%), solitary plasmacytoma (17.6%), multiple myeloma (8.1%), and AL amyloidosis (4.1%). There are specific features on NCS which can help in identifying POEMS syndrome and IgM MGUS. The majority of patients with PPN tend to stabilize or improve with treatment; however, many have a severe residual disability. New terminology and classification of these entities as 'monoclonal gammopathies of neurological significance' can aid in early diagnosis and the development of effective treatment, to prevent residual disability. CONCLUSION: PPN has a heterogeneous spectrum of clinical, biochemical, and electrophysiological features. NCS can help distinguish POEMS syndrome and IgM MGUS from other demyelinating subtypes.
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Gammopatía Monoclonal de Relevancia Indeterminada , Paraproteinemias , Enfermedades del Sistema Nervioso Periférico , Plasmacitoma , Humanos , Masculino , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Paraproteinemias/complicaciones , Paraproteinemias/diagnóstico , Estudios RetrospectivosRESUMEN
Hyperthermophiles, a subset of prokaryotes that thrive in adverse temperatures, potentially utilize the protein molecular biosystem for maintaining thermostability in a wide range of temperatures. Recent studies revealed that these organisms have smaller proportions of intrinsically disordered proteins. In this study, we performed sequence and structural analysis to investigate the maintenance of protein conformation and their stability at different temperatures. The sequence analysis reveals the higher proportion of charged amino acids are responsible for preventing the helix formation and, hence, become disordered regions. For structural analysis, we chose shikimate dehydrogenase from four species, namely Listeria monocytogenes, Escherichia coli, Thermus thermophilus, and Methanopyrus kandleri, and evaluated the protein adaptation at 283 K, 300 K, and 395 K temperatures. From this investigation, we found more residues of shikimate dehydrogenase prefer an order-to-disorder transition at 395 K only for hyperthermophilic species. The solvent-accessible surface area (SASA) and hydrogen-bond analysis revealed that the tertiary conformation and the number of hydrogen bonds for hyperthermophilic shikimate dehydrogenase are highly preserved at 395 K, compared to 300 K. Our simulation results conjointly provide shikimate dehydrogenase of hyperthermophile which resists high temperatures through stronger protein tertiary conformations.
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Oxidorreductasas de Alcohol/química , Bacterias/enzimología , Proteínas Intrínsecamente Desordenadas/química , Simulación de Dinámica Molecular , Temperatura , Secuencia de Aminoácidos , Conformación ProteicaRESUMEN
Regulatory T cells (Tregs) continuously suppress autoreactive immune responses within tissues to prevent autoimmunity, yet the recirculatory behavior of Tregs between and within tissues enabling the maintenance of peripheral tolerance remains incompletely defined. Here, we quantified homing efficiency to and the dwell time of Tregs within secondary lymphoid organs (SLOs) and used intravital two-photon microscopy to measure Treg surveillance behavior of dendritic cells. Tregs homed substantially less efficiently to SLOs compared with conventional CD4+ T cells (Tconvs), despite similar expression of homing receptors. Tregs remained on average 2-3 times longer within the LN than Tconvs before exiting, and retained Tregs differed from recirculating Tregs in phenotype, motility and interaction duration with dendritic cells. Taken together, these data revealed fundamental differences in Treg versus conventional T cell in vivo recirculation and migration behaviors, identified a Treg population with prolonged LN dwell time, and provided quantitative insight into their spatiotemporal behavior within LNs.
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Linfocitos T CD4-Positivos/inmunología , Movimiento Celular , Ganglios Linfáticos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Dendríticas/inmunología , Ratones Endogámicos C57BL , Factores de TiempoRESUMEN
Charles Bonnet syndrome (CBS) is a rare condition that encompasses three clinical features: complex visual hallucinations, ocular pathology causing visual deterioration, and preserved cognitive status. Common associated ocular pathologies include age-related macular degeneration, glaucoma, and cataracts. Several theories have been proposed to try to explain the visual hallucinations. However, the pathophysiology remains poorly understood, and treatment is largely based on anecdotal data. The lack of awareness of CBS among medical professionals often leads to inappropriate diagnosis and medication. In a country like India, where awareness of mental health is not widespread, cultural myths and stigma prevent patients from seeking professional help. Here we describe two cases of CBS and revisit different ocular morbidities that have been reported to occur in conjunction with CBS. Psychiatrists and ophthalmologists alike must be sensitive to this clinical condition to ensure prompt diagnosis and treatment.
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Aminas/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Alucinaciones/diagnóstico , Alucinaciones/tratamiento farmacológico , Lorazepam/uso terapéutico , Degeneración Macular/complicaciones , Ácido gamma-Aminobutírico/uso terapéutico , Anciano , Aminas/administración & dosificación , Concienciación , Ácidos Ciclohexanocarboxílicos/administración & dosificación , Femenino , Gabapentina , Alucinaciones/psicología , Humanos , Lorazepam/administración & dosificación , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/psicología , Imagen por Resonancia Magnética , Masculino , Síndrome , Resultado del Tratamiento , Trastornos de la Visión/tratamiento farmacológico , Trastornos de la Visión/etiología , Trastornos de la Visión/psicología , Ácido gamma-Aminobutírico/administración & dosificaciónRESUMEN
Line attractors are emergent population dynamics hypothesized to encode continuous variables such as head direction and internal states. In mammals, direct evidence of neural implementation of a line attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles. Estrogen receptor type 1 (Esr1)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) show line attractor dynamics in male mice during fighting. We hypothesized that these dynamics may encode continuous variation in the intensity of an internal aggressive state. Here, we report that these neurons also show line attractor dynamics in head-fixed mice observing aggression. We exploit this finding to identify and perturb line attractor-contributing neurons using 2-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations demonstrate that integration and persistent activity are intrinsic properties of these neurons which drive the system along the line attractor, while transient off-manifold perturbations reveal rapid relaxation back into the attractor. Furthermore, stimulation and imaging reveal selective functional connectivity among attractor-contributing neurons. Intriguingly, individual differences among mice in line attractor stability were correlated with the degree of functional connectivity among contributing neurons. Mechanistic modelling indicates that dense subnetwork connectivity and slow neurotransmission are required to explain our empirical findings. Our work bridges circuit and manifold paradigms, shedding light on the intrinsic and operational dynamics of a behaviorally relevant mammalian line attractor.
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OBJECTIVES: Neuromuscular disorders could have respiratory involvement early or late into illness. Rarely, patients may present with a hypercapnic respiratory failure (with minimal motor signs) unmasking an underlying disease. There are hardly any studies which have addressed the spectrum and challenges involved in management of this subset, especially in the real-world scenario. METHODS: A retrospective study comprising consecutive patients hospitalized with hypercapnic respiratory failure as the sole/dominant manifestation. The clinical-electrophysiological spectrum, phrenic conductions, diaphragm thickness, and outcomes were analyzed. RESULTS: Twenty-seven patients were included, the mean age was 47.29 (SD 15.22) years, and the median duration of respiratory symptoms was 2 months (interquartile range [IQR] 1-4). Orthopnea was present in 23 patients (85.2%) and encephalopathy in 8 patients (29.6%). Phrenic nerve latencies and amplitudes were abnormal in 83.3% and 95.6%, respectively. Abnormal diaphragm thickness was noted in 78.5%. Based on a comprehensive electrophysiological strategy and paraclinical tests, an etiology was established in all. Reversible etiologies were identified in 17 patients (62.9%). These included myasthenia gravis (anti-AChR and MuSK), inflammatory myopathy, riboflavin transporter deficiency neuronopathy, Pompe disease, bilateral phrenic neuritis, and thyrotoxicosis. Respiratory onset motor neuron disease was diagnosed in 8 patients (29.6%). Despite diaphragmatic involvement, a functional respiratory recovery was noted at discharge (45%) and last follow-up (60%). Predictors for good outcomes included female sex, normal nerve conductions, and recent-onset respiratory symptoms. DISCUSSION: A good functional recovery was noted in most of the patients including respiratory onset motor neuron disease. A systematic algorithmic approach helps in proper triaging, early diagnosis, and treatment. Clinical and electrodiagnostic challenges and observations from a tertiary care referral center are discussed.
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Parálisis Bulbar Progresiva , Enfermedades Neuromusculares , Insuficiencia Respiratoria , Humanos , Femenino , Persona de Mediana Edad , Centros de Atención Terciaria , Estudios Retrospectivos , Enfermedades Neuromusculares/complicaciones , Enfermedades Neuromusculares/diagnóstico , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/etiologíaRESUMEN
A man in his 20s presented with a 6-year history of calf muscle hypertrophy, proximal muscle weakness and muscle cramps. Along with this, he also had patchy hair loss, facial puffiness and slurring of speech. On examination, he had mild symmetrical proximal muscle weakness, a delayed relaxation phase of his deep tendon reflexes and a rare neurological sign of myoedema. His laboratory investigations revealed elevated thyroid-stimulating hormone levels with high creatine kinase levels, and an echocardiogram showed left ventricular systolic dysfunction. He was diagnosed with Hoffman syndrome, a rare pseudohypertrophic myopathy associated with severe and prolonged hypothyroidism. He had an excellent response to thyroid hormone replacement.