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1.
Endocrine ; 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39292367

RESUMO

BACKGROUND/OBJECTIVE: Primary hyperparathyroidism (PHPT) may be asymptomatic or present with renal calculi, secondary osteoporosis, fractures and neuropsychiatric manifestations. Posterior reversible encephalopathy syndrome (PRES) and parkinsonism are atypical manifestations that may be rarely associated with PHPT. We report two patients who presented with the conditions mentioned above. CASE REPORT: The first patient involved a 38-year-old woman who presented with diminution of vision, seizures, altered behavior and hypertension over eight months. An MRI of the brain done had shown vasogenic edema involving the parieto-occipital regions, suggestive of PRES. A metabolic screen revealed PTH-dependent hypercalcemia that was localized to the left inferior parathyroid gland. Following focused parathyroidectomy, there was improvement in sensorium, vision and normalization of blood pressure. The second patient was of a 74-year-old man who presented with progressive extrapyramidal symptoms of gait abnormalities and rigidity since the past eight months. He was initiated on Selegeline and Levodopa for the same purpose, and subsequently reported minimal improvement in symptoms. Investigations revealed PHPT associated with a right inferior parathyroid adenoma. Within two weeks following surgery, there was an improvement in rigidity and gait and he was able to ambulate without support. DISCUSSION: PRES has been reported to occur in the context of preeclampsia, hypertension, infection, sepsis and autoimmune conditions. PRES associated with hypercalcemia is rarely reported. While extra-pyramidally related manifestations are described in hypoparathyroidism, PHPT related parkinsonism is not commonly encountered. Identifying the underlying aetiology and initiation of corrective measures may lead to amelioration of patient symptomatology. CONCLUSION: The occurrence of PRES and parkinsonism is rare in primary hyperparathyroidism; the two patients described above highlight the importance of screening for hypercalcemia in the setting of neurological manifestations.

2.
Cell ; 187(21): 5998-6015.e18, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39191257

RESUMO

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.


Assuntos
Neurônios , Neuropeptídeos , Transdução de Sinais , Animais , Neuropeptídeos/metabolismo , Neuropeptídeos/genética , Camundongos , Masculino , Feminino , Neurônios/metabolismo , Sistemas CRISPR-Cas/genética , Ocitocina/metabolismo , Hipotálamo/metabolismo , Edição de Genes , Receptores de Vasopressinas/metabolismo , Receptores de Vasopressinas/genética , Camundongos Endogâmicos C57BL , Receptor alfa de Estrogênio/metabolismo
3.
Nature ; 634(8035): 901-909, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39142338

RESUMO

Females exhibit complex, dynamic behaviours 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, ventrolateral subdivision contains oestrogen receptor type 1-positive neurons that control mating receptivity in female mice5,6. Here, unsupervised dynamical system 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 oestrus 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.


Assuntos
Hipotálamo , Neurônios , Comportamento Sexual Animal , Animais , Feminino , Masculino , Camundongos , Comportamento Sexual Animal/fisiologia , Neurônios/fisiologia , Neurônios/metabolismo , Hipotálamo/fisiologia , Hipotálamo/metabolismo , Ciclo Estral/fisiologia , Ejaculação/fisiologia , Excitação Sexual , Cálcio/metabolismo , Sinais (Psicologia) , Receptor alfa de Estrogênio/metabolismo
4.
Nature ; 634(8035): 910-918, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39142337

RESUMO

Continuous attractors are an emergent property of neural population dynamics that have been hypothesized to encode continuous variables such as head direction and eye position1-4. In mammals, direct evidence of neural implementation of a continuous attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles2,3. Dynamical systems modelling 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 and persistence of an aggressive internal state. Here we report that these neurons also showed line-attractor dynamics in head-fixed mice observing aggression6. This allowed us to identify and manipulate line-attractor-contributing neurons using two-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations yielded integration of optogenetic stimulation pulses 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. Notably, individual differences among mice in line-attractor stability were correlated with the degree of functional connectivity among attractor-contributing neurons. Mechanistic recurrent neural network 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.


Assuntos
Afeto , Modelos Neurológicos , Rede Nervosa , Neurônios , Animais , Masculino , Camundongos , Afeto/fisiologia , Agressão/psicologia , Cálcio/metabolismo , Hipotálamo/citologia , Hipotálamo/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Neurônios/metabolismo , Optogenética , Análise de Célula Única , Transmissão Sináptica , Feminino
5.
bioRxiv ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39211163

RESUMO

Hypothalamic VMHdm SF1 neurons are activated by predator cues and are necessary and sufficient for instinctive defensive responses. However, such data do not distinguish which features of a predator encounter are encoded by VMHdm SF1 neural activity. To address this issue, we imaged VMHdm SF1 neurons at single-cell resolution in freely behaving mice exposed to a natural predator in varying contexts. Our results reveal that VMHdm SF1 neurons do not represent different defensive behaviors, but rather encode predator identity and multiple predator-evoked internal states, including threat-evoked fear/anxiety; neophobia or arousal; predator imminence; and safety. Notably, threat and safety are encoded bi-directionally by anti-correlated subpopulations. Finally, individual differences in predator defensiveness are correlated with differences in VMHdm SF1 response dynamics. Thus, different threat-related internal state variables are encoded by distinct neuronal subpopulations within a genetically defined, anatomically restricted hypothalamic cell class. Highlights: Distinct subsets of VMHdm SF1 neurons encode multiple predator-evoked internal states. Anti-correlated subsets encode safety vs. threat in a bi-directional mannerA population code for predator imminence is identified using a novel assay VMHdm SF1 dynamics correlate with individual variation in predator defensiveness.

6.
bioRxiv ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38826298

RESUMO

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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-38814804

RESUMO

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.

8.
J Clin Neuromuscul Dis ; 25(3): 122-131, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38441928

RESUMO

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.


Assuntos
Paralisia Bulbar Progressiva , Doenças Neuromusculares , Insuficiência Respiratória , Humanos , Feminino , Pessoa de Meia-Idade , Centros de Atenção Terciária , Estudos Retrospectivos , Doenças Neuromusculares/complicações , Doenças Neuromusculares/diagnóstico , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia
9.
bioRxiv ; 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37961374

RESUMO

Internal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial hypothalamus (VMH) that represents an internal state of aggressiveness. Line attractors can be implemented by recurrent connectivity and/or neuromodulatory signaling, but evidence for the latter is scant. Here we show that neuropeptidergic signaling is necessary for line attractor dynamics in this system, using a novel approach that integrates cell type-specific, anatomically restricted CRISPR/Cas9-based gene editing with microendoscopic calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1 + neurons that control aggression suppressed attack, reduced persistent neural activity and eliminated line attractor dynamics, while only modestly impacting neural activity and sex- or behavior-tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.

10.
BMJ Case Rep ; 16(10)2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37802588

RESUMO

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.


Assuntos
Insuficiência Cardíaca Sistólica , Doenças Musculares , Humanos , Masculino , Hipertrofia , Debilidade Muscular , Doenças Musculares/diagnóstico , Adulto
11.
J Stroke Cerebrovasc Dis ; 32(11): 107305, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37677898

RESUMO

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.

12.
Proc Natl Acad Sci U S A ; 120(28): e2218830120, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37399414

RESUMO

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.


Assuntos
Acetilcolina , Colinérgicos , Acetilcolina/metabolismo , Prosencéfalo/metabolismo , Neurônios Colinérgicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Lógica
13.
BMJ Neurol Open ; 5(1): e000414, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37396795

RESUMO

Background: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is characterised by the combination of opsoclonus and arrhythmic action myoclonus with axial ataxia and dysarthria. In adults, a majority are paraneoplastic secondary to solid organ tumours and could harbour antibodies against intracellular epitopes; however, certain proportions have detectable antibodies to various neuronal cell surface antigens. Anti-N-methyl-D-aspartate (NMDAR) antibodies and ovarian teratomas have been implicated in OMAS. Methods: Report of two cases and review of literature. Results: Two middle-aged women presented with subacute-onset, rapidly progressive OMAS and behavioural changes consistent with psychosis. The first patient had detectable antibodies to NMDAR in the cerebrospinal fluid (CSF) alone. Evaluation for ovarian teratoma was negative. The second patient had no detectable antibodies in serum or CSF; however, she had an underlying ovarian teratoma. Patient A was treated with pulse steroids, therapeutic plasma exchange (TPE) followed by bortezomib (BOR) and dexamethasone, while patient B was treated with steroids, TPE followed by surgical resection of ovarian teratoma. Both patients had favourable outcomes and were asymptomatic at the 6 monthly follow-up. Conclusions: With coexistent neuropsychiatric manifestations, OMAS can be considered a distinct entity of autoimmune encephalitis, pathogenesis being immune activation against known/unknown neuronal cell surface antigens. The observation of absence of anti-NMDAR antibody in patients with teratoma-associated OMAS and vice versa is intriguing. Further research on the potential role of ovarian teratoma in evoking neuronal autoimmunity and its targets is required. The management challenge in both cases including the potential use of BOR has been highlighted.

14.
bioRxiv ; 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37292695

RESUMO

Cyclic changes in hormonal state are well-known to regulate mating behavior during the female reproductive cycle, but whether and how these changes affect the dynamics of neural activity in the female brain is largely unknown. The ventromedial hypothalamus, ventro-lateral subdivision (VMHvl) contains a subpopulation of VMHvl Esr1+,Npy2r- neurons that controls female sexual receptivity. Longitudinal single cell calcium imaging of these neurons across the estrus cycle revealed that overlapping but distinct subpopulations were active during proestrus (mating-accepting) vs. non-proestrus (rejecting) phases. Dynamical systems analysis of imaging data from proestrus females uncovered a dimension with slow ramping activity, which generated approximate line attractor-like dynamics in neural state space. During mating, the neural population vector progressed along this attractor as male mounting and intromission proceeded. Attractor-like dynamics disappeared in non-proestrus states and reappeared following re-entry into proestrus. They were also absent in ovariectomized females but were restored by hormone priming. These observations reveal that hypothalamic line attractor-like dynamics are associated with female sexual receptivity and can be reversibly regulated by sex hormones, demonstrating that attractor dynamics can be flexibly modulated by physiological state. They also suggest a potential mechanism for the neural encoding of female sexual arousal.

15.
Muscle Nerve ; 68(2): 191-197, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37300403

RESUMO

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.


Assuntos
Síndrome de Guillain-Barré , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/terapia , Respiração Artificial , Nervo Frênico , Estudos Retrospectivos , Eletrofisiologia
16.
Cell ; 186(1): 178-193.e15, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36608653

RESUMO

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.


Assuntos
Comportamento Sexual Animal , Núcleo Hipotalâmico Ventromedial , Animais , Comportamento Sexual Animal/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Hipotálamo/fisiologia , Agressão/fisiologia , Comportamento Social
17.
Hum Mol Genet ; 32(9): 1466-1482, 2023 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-36519761

RESUMO

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.


Assuntos
Lipase Lipoproteica , Doença de Parkinson , Proteína de Ligação a Elemento Regulador de Esterol 2 , Ubiquitina-Proteína Ligases , Animais , Humanos , Camundongos , Homeostase , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos Knockout , Neurônios/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Rotenona/efeitos adversos , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
19.
Nature ; 612(7938): 116-122, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36289333

RESUMO

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.


Assuntos
Drosophila , Movimentos Oculares , Músculos , Retina , Visão Ocular , Animais , Drosophila/fisiologia , Movimentos Oculares/fisiologia , Músculos/fisiologia , Retina/fisiologia , Movimentos Sacádicos/fisiologia , Visão Ocular/fisiologia , Visão Binocular , Percepção de Profundidade , Neurônios Motores , Cabeça/fisiologia , Drosophila melanogaster/fisiologia , Evolução Biológica
20.
Indian J Psychiatry ; 64(6): 588-594, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36714666

RESUMO

Context: Myths and stigma about suicide and mental health among doctors are widely prevalent in India. Didactic methods of teaching alone may not be adequate to bridge the knowledge gap. Methods: Fifty-seven MBBS students participated voluntarily by accepting an invitation. They were examined pre-intervention with the Suicide Opinion Questionnaire (SOQ) for their attitudes and beliefs about suicide. Students then underwent a custom-made extracurricular Suicide Sensitization and Prevention workshop. It consisted of a 120-min session that included a didactic session on the bio-psycho-social model of suicide and two role-plays demonstrating Suicide Prevention Early Intervention Communication (SPEIC). Students were examined again after seven days with SOQ, and with the SPEIC checklist. Results: Fifty students completed the study protocol. There was a 9.5% increase in SOQ scores post-intervention indicating a change toward positive attitudes/beliefs about suicide. The emotional perturbation subscale showed the highest degree of improvement, whereas the acceptability subscale showed the least improvement. Students were able to recall 40% and 60% from the Do-Checklist and the Do Not Checklist from the SPEIC after seven days from the workshop. There was no difference in SOQ performances pre- and post-intervention in students who knew someone with psychiatric illness, or with a history of an attempt or death by suicide. Conclusion: Using role-plays and interactive teaching methods can be effective in teaching psychiatry and mental health issues to medical students. The results indicate not only better understanding of subject matter but also recall after a week from the intervention.

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