RESUMEN
BACKGROUND: The periaqueductal gray (PAG) is at the center of a powerful descending antinociceptive neuronal network, and is a key node in the descending pain regulatory system of pain. However, less is known about the altered perfusion of PAG in chronic migraine (CM). AIM: To measure the perfusion of PAG matter, an important structure in pain modulation, in CM with magnetic resonance (MR) perfusion without contrast administration. METHODS: Three-dimensional pseudocontinuous arterial spin labeling (3D-PCASL) and brain structure imaging were performed in 13 patients with CM and 15 normal subjects. The inverse deformation field generated by brain structure image segmentation was applied to the midbrain PAG template to generate individualized PAG. Then the perfusion value of the PAG area of the midbrain was extracted based on the individual PAG mask. RESULTS: Cerebral blood flow (CBF) value of PAG in CM patients (47.98 ± 8.38 mL/100 mg min) was significantly lower than that of the control group (59.87 ± 14.24 mL/100 mg min). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve was 0.77 (95% confidence interval [CI], 0.60, 0.94), and the cutoff value for the diagnosis of CM was 54.83 mL/100 mg min with a sensitivity 84.60% and a specificity 60%. CONCLUSION: Imaging evidence of the impaired pain conduction pathway in CM may be related with the decreased perfusion in the PAG, which could be considered as an imaging biomarker for the diagnosis and therapy evaluation.
Asunto(s)
Circulación Cerebrovascular , Imagen por Resonancia Magnética , Trastornos Migrañosos , Sustancia Gris Periacueductal , Marcadores de Spin , Humanos , Sustancia Gris Periacueductal/diagnóstico por imagen , Sustancia Gris Periacueductal/fisiopatología , Femenino , Masculino , Adulto , Trastornos Migrañosos/diagnóstico por imagen , Trastornos Migrañosos/fisiopatología , Circulación Cerebrovascular/fisiología , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/normas , Persona de Mediana Edad , Imagenología Tridimensional/métodos , Enfermedad Crónica , BiomarcadoresRESUMEN
The insular cortex is an important hub for sensory and emotional integration. It is one of the areas consistently found activated during pain. While the insular's connections to the limbic system might play a role in the aversive and emotional component of pain, its connections to the descending pain system might be involved in pain intensity coding. Here, we used anterograde tracing with viral expression of mCherry fluorescent protein, to examine the connectivity of insular axons to different brainstem nuclei involved in the descending modulation of pain in detail. We found extensive connections to the main areas of descending pain control, namely, the periaqueductal gray (PAG) and the raphe magnus (RMg). In addition, we also identified an extensive insular connection to the parabrachial nucleus (PBN). Although not as extensive, we found a consistent axonal input from the insula to different noradrenergic nuclei, the locus coeruleus (LC), the subcoereuleus (SubCD) and the A5 nucleus. These connections emphasize a prominent relation of the insula with the descending pain modulatory system, which reveals an important role of the insula in pain processing through descending pathways.
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Tronco Encefálico , Corteza Insular , Dolor , Animales , Dolor/fisiopatología , Masculino , Sustancia Gris Periacueductal , Vías Nerviosas , RatasRESUMEN
BACKGROUND: Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence. METHODS: Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed. RESULTS: There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16). CONCLUSIONS: The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms.
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Núcleos Cerebelosos , Ácido Glutámico , Glutamina , Espectroscopía de Resonancia Magnética , Sustancia Gris Periacueductal , Ácido gamma-Aminobutírico , Humanos , Femenino , Masculino , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Adulto , Ácido gamma-Aminobutírico/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/diagnóstico por imagen , Persona de Mediana Edad , Núcleos Cerebelosos/metabolismo , Núcleos Cerebelosos/diagnóstico por imagen , Trastornos de Cefalalgia/metabolismo , Imagen por Resonancia MagnéticaRESUMEN
Resistance to stress is a key determinant for mammalian functioning. While many studies have revealed neural circuits and substrates responsible for initiating and mediating stress responses, little is known about how the brain resists to stress and prevents overreactions. Here, we identified a previously uncharacterized neuropeptide Y (NPY) neuronal population in the dorsal raphe nucleus and ventrolateral periaqueductal gray region (DRN/vlPAG) with anxiolytic effects in male mice. NPYDRN/vlPAG neurons are rapidly activated by various stressful stimuli. Inhibiting these neurons exacerbated hypophagic and anxiety responses during stress, while activation significantly ameliorates acute stress-induced hypophagia and anxiety levels and transmits positive valence. Furthermore, NPYDRN/vlPAG neurons exert differential but synergic anxiolytic effects via inhibitory projections to the paraventricular thalamic nucleus (PVT) and the lateral hypothalamic area (LH). Together, our findings reveal a feedforward inhibition neural mechanism underlying stress resistance and suggest NPYDRN/vlPAG neurons as a potential therapeutic target for stress-related disorders.
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Neuronas , Neuropéptido Y , Estrés Psicológico , Animales , Masculino , Neuropéptido Y/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Ratones , Estrés Psicológico/fisiopatología , Ratones Endogámicos C57BL , Ansiedad/fisiopatología , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/fisiología , Sustancia Gris Periacueductal/fisiología , Tronco Encefálico/fisiología , Área Hipotalámica Lateral/fisiología , Estrés FisiológicoRESUMEN
Pavlovian fear conditioning research suggests that the interaction between the dorsal periaqueductal gray (dPAG) and basolateral amygdala (BLA) acts as a prediction error mechanism in the formation of associative fear memories. However, their roles in responding to naturalistic predatory threats, characterized by less explicit cues and the absence of reiterative trial-and-error learning events, remain unexplored. In this study, we conducted single-unit recordings in rats during an 'approach food-avoid predator' task, focusing on the responsiveness of dPAG and BLA neurons to a rapidly approaching robot predator. Optogenetic stimulation of the dPAG triggered fleeing behaviors and increased BLA activity in naive rats. Notably, BLA neurons activated by dPAG stimulation displayed immediate responses to the robot, demonstrating heightened synchronous activity compared to BLA neurons that did not respond to dPAG stimulation. Additionally, the use of anterograde and retrograde tracer injections into the dPAG and BLA, respectively, coupled with c-Fos activation in response to predatory threats, indicates that the midline thalamus may play an intermediary role in innate antipredatory-defensive functioning.
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Optogenética , Sustancia Gris Periacueductal , Animales , Sustancia Gris Periacueductal/fisiología , Ratas , Masculino , Neuronas/fisiología , Amígdala del Cerebelo/fisiología , Conducta Predatoria/fisiología , Miedo/fisiología , Complejo Nuclear Basolateral/fisiologíaRESUMEN
Comorbid chronic neuropathic pain and anxiety is a common disease that represents a major clinical challenge. The underlying mechanisms of chronic neuropathic pain and anxiety are not entirely understood, which limits the exploration of effective treatment methods. Glutamatergic neurons in the ventrolateral periaqueductal gray (vlPAG) have been implicated in regulating pain, but the potential roles of the vlPAG in neuropathic pain-induced anxiety have not been investigated. Herein, whole-cell recording and immunofluorescence showed that the excitability of CamkIIα neurons in the vlPAG (vlPAGCamkIIα+ neurons) was decreased in mice with spared nerve injury (SNI), while electroacupuncture (EA) activated these neurons. We also showed that chemogenetic inhibition of vlPAGCamkIIα+ neurons resulted in allodynia and anxiety-like behaviors in naive mice. Furthermore, chemogenetic activation of vlPAGCamkIIα+ neurons reduced anxiety-like behaviors and allodynia in mice with SNI, and EA had a similar effect in alleviating these symptoms. Nevertheless, EA combined with chemogenetic activation failed to further relieve allodynia and anxiety-like behaviors. Artificial inhibition of vlPAGCamkIIα+ neurons abolished the analgesic and anxiolytic effects of EA. Overall, our study reveals a novel mechanism of neuropathic pain-induced anxiety and shows that EA may relieve comorbid chronic neuropathic pain and anxiety by activating vlPAGCamkIIα+ neurons.
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Ansiedad , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Electroacupuntura , Neuralgia , Neuronas , Sustancia Gris Periacueductal , Animales , Neuralgia/terapia , Electroacupuntura/métodos , Neuronas/fisiología , Neuronas/metabolismo , Masculino , Ansiedad/terapia , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Ratones , Ratones Endogámicos C57BL , Hiperalgesia/terapia , Dolor Crónico/terapia , Ácido Glutámico/metabolismo , Modelos Animales de Enfermedad , Conducta Animal/fisiologíaRESUMEN
Despite significant advances in the study of fear and fear memory formation, little is known about fear learning and expression in females. This omission has been proven surprising, as normal and pathological behaviors are highly influenced by ovarian hormones, particularly estradiol and progesterone. In the current study, we investigated the joint influence of serotonin (5-HT) neurotransmission and estrous cycle phases (low or high levels of estradiol and progesterone) on the expression of conditioned fear in a group of female rats that were previously divided according to their response to stressful stimuli into low or high anxiety-like subjects. The baseline amplitude of the unconditioned acoustic startle responses was high in high-anxiety female rats, with no effect on the estrous cycle observed. Data collected during the proestrus-estrus phase revealed that low-anxiety rats had startle amplitudes similar to those of high-anxiety rats. It is supposed that high-anxiety female rats benefit from increased estradiol and progesterone levels to achieve comparable potentiated startle amplitudes. In contrast, female rats experienced a significant decrease in hormone levels during the Diestrus phase. This decrease is believed to play a role in preventing them from displaying a heightened startle response when faced with strongly aversive stimuli. Data collected after 5-HT and 8-OH-DPAT were administered into the basolateral nuclei and dorsal periaqueductal gray suggest that 5-HT neurotransmission works with progesterone and estrogen to reduce startle potentiation, most likely by activating the serotonin-1A receptor subtype.
Asunto(s)
Complejo Nuclear Basolateral , Estradiol , Miedo , Sustancia Gris Periacueductal , Progesterona , Receptor de Serotonina 5-HT1A , Reflejo de Sobresalto , Animales , Femenino , Ratas , Ansiedad/metabolismo , Ansiedad/fisiopatología , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/efectos de los fármacos , Condicionamiento Clásico/fisiología , Condicionamiento Clásico/efectos de los fármacos , Estradiol/farmacología , Estradiol/metabolismo , Ciclo Estral/fisiología , Miedo/fisiología , Miedo/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacos , Progesterona/farmacología , Progesterona/metabolismo , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Reflejo de Sobresalto/fisiología , Reflejo de Sobresalto/efectos de los fármacos , Serotonina/metabolismoRESUMEN
Social play is pervasive in juvenile mammals, yet it is poorly understood in terms of its underlying brain mechanisms. Specifically, we do not know why young animals are most playful and why most adults cease to social play. Here, we analyze the synaptic mechanisms underlying social play. We found that blocking the rat periaqueductal gray (PAG) interfered with social play. Furthermore, an age-related decrease of neural firing in the PAG is associated with a decrease in synaptic release of glycine. Most importantly, modulation of glycine concentration-apparently acting on the glycinergic binding site of the N-methyl-D-aspartate (NMDA) receptor-not only strongly modulates social play but can also reverse the age-related decline in social play. In conclusion, we demonstrate that social play critically depends on the neurotransmitter glycine within the PAG.
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Glicina , Sustancia Gris Periacueductal , Conducta Social , Animales , Glicina/metabolismo , Ratas , Sustancia Gris Periacueductal/fisiología , Sustancia Gris Periacueductal/metabolismo , Masculino , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The dorsal periaqueductal gray (dPAG) contains a tonically GABAergic network controlling defensive responses. Determining how this intrinsic dPAG inhibitory circuit functions might provide critical insights into how anti-predatory responses are organized.
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Sustancia Gris Periacueductal , Conducta Predatoria , Animales , Conducta Predatoria/fisiología , Sustancia Gris Periacueductal/fisiología , Reacción de Fuga/fisiologíaRESUMEN
Although anesthesia provides favorable conditions for surgical procedures, recent studies have revealed that the brain remains active in processing noxious signals even during anesthesia. However, whether and how these responses affect the anesthesia effect remains unclear. The ventrolateral periaqueductal gray (vlPAG), a crucial hub for pain regulation, also plays an essential role in controlling general anesthesia. Hence, it was hypothesized that the vlPAG may be involved in the regulation of general anesthesia by noxious stimuli. Here, we found that acute noxious stimuli, including capsaicin-induced inflammatory pain, acetic acid-induced visceral pain, and incision-induced surgical pain, significantly delayed recovery from sevoflurane anesthesia in male mice, whereas this effect was absent in the spared nerve injury-induced chronic pain. Pretreatment with peripheral analgesics could prevent the delayed recovery induced by acute nociception. Furthermore, we found that acute noxious stimuli, induced by the injection of capsaicin under sevoflurane anesthesia, increased c-Fos expression and activity in the GABAergic neurons of the ventrolateral periaqueductal gray. Specific reactivation of capsaicin-activated vlPAGGABA neurons mimicked the effect of capsaicin and its chemogenetic inhibition prevented the delayed recovery from anesthesia induced by capsaicin. Finally, we revealed that the vlPAGGABA neurons regulated the recovery from anesthesia through the inhibition of ventral tegmental area dopaminergic neuronal activity, thus decreasing dopamine (DA) release and activation of DA D1-like receptors in the brain. These findings reveal a novel, cell- and circuit-based mechanism for regulating anesthesia recovery by nociception, and it is important to provide new insights for guiding the management of the anesthesia recovery period.
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Anestésicos por Inhalación , Ratones Endogámicos C57BL , Nocicepción , Sustancia Gris Periacueductal , Sevoflurano , Sevoflurano/farmacología , Animales , Masculino , Ratones , Anestésicos por Inhalación/farmacología , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Mesencéfalo/efectos de los fármacos , Estado de Conciencia/efectos de los fármacos , Estado de Conciencia/fisiología , Periodo de Recuperación de la Anestesia , Capsaicina/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiologíaRESUMEN
The ventrolateral periaqueductal gray (vlPAG) serves as a central hub for descending pain modulation. It receives upstream projections from the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), and projects downstream to the locus coeruleus (LC) and the rostroventral medulla (RVM). While much research has focused on upstream circuits and the LC-RVM connection, less is known about the PAG-LC circuit and its involvement in neuropathic pain. Here we examined the intrinsic electrophysiological properties of vlPAG-LC projecting neurons in Sham and spared nerve injury (SNI) operated mice. Injection of the retrotracer Cholera Toxin Subunit B (CTB-488) into the LC allowed the identification of LC-projecting neurons in the vlPAG. Electrophysiological recordings from CTB-488 positive cells revealed that both GABAergic and glutamatergic cells that project to the LC exhibited reduced intrinsic excitability after peripheral nerve injury. By contrast, CTB-488 negative cells did not exhibit alterations in firing properties after SNI surgery. An SNI-induced reduction of LC projecting cells was confirmed with c-fos labeling. Hence, SNI induces plasticity changes in the vlPAG that are consistent with a reduction in the descending modulation of pain signals.
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Locus Coeruleus , Ratones Endogámicos C57BL , Neuronas , Sustancia Gris Periacueductal , Animales , Sustancia Gris Periacueductal/fisiopatología , Sustancia Gris Periacueductal/fisiología , Locus Coeruleus/fisiopatología , Locus Coeruleus/patología , Locus Coeruleus/fisiología , Neuronas/fisiología , Masculino , Ratones , Potenciales de Acción/fisiología , Vías Nerviosas/fisiopatología , Neuralgia/fisiopatología , Neuralgia/patología , Traumatismos de los Nervios Periféricos/fisiopatología , Traumatismos de los Nervios Periféricos/patología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Stimulation of the dorsal half of the rat periaqueductal gray (DPAG) with 60-Hz pulses of increasing intensity, 30-µA pulses of increasing frequency, or increasing doses of an excitatory amino acid elicits sequential defensive responses of exophthalmia, immobility, trotting, galloping, and jumping. These responses may be controlled by voltage-gated calcium channel-specific firing patterns. Indeed, a previous study showed that microinjection of the DPAG with 15 nmol of verapamil, a putative blocker of L-type calcium channels, attenuated all defensive responses to electrical stimulation at the same site as the injection. Accordingly, here we investigated the effects of microinjection of lower doses (0.7 and 7 nmol) of both verapamil and mibefradil, a preferential blocker of T-type calcium channels, on DPAG-evoked defensive behaviors of the male rat. Behaviors were recorded either 24 h before or 10 min, 24 h, and 48 h after microinjection. Effects were analyzed by both threshold logistic analysis and repeated measures analysis of variance for treatment by session interactions. Data showed that the electrodes were all located within the dorsolateral PAG. Compared to the effects of saline, verapamil significantly attenuated exophthalmia, immobility, and trotting. Mibefradil significantly attenuated exophthalmia and marginally attenuated immobility while facilitating trotting. While galloping was not attenuated by either antagonist, jumping was unexpectedly attenuated by 0.7 nmol verapamil only. These results suggest that T-type calcium channels are involved in the low-threshold freezing responses of exophthalmia and immobility, whereas L-type calcium channels are involved in the trotting response that precedes the full-fledged escape responses of galloping and jumping.
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Bloqueadores de los Canales de Calcio , Canales de Calcio Tipo L , Canales de Calcio Tipo T , Estimulación Eléctrica , Mibefradil , Sustancia Gris Periacueductal , Verapamilo , Animales , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/fisiología , Masculino , Canales de Calcio Tipo T/fisiología , Canales de Calcio Tipo T/efectos de los fármacos , Canales de Calcio Tipo T/metabolismo , Canales de Calcio Tipo L/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Mibefradil/farmacología , Verapamilo/farmacología , Ratas , Ratas Wistar , Microinyecciones , Relación Dosis-Respuesta a DrogaRESUMEN
OBJECTIVE: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine. BACKGROUND: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain. METHODS: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed. RESULTS: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification. CONCLUSIONS: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed.
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Modelos Animales de Enfermedad , Trastornos Migrañosos , Nitroglicerina , Animales , Nitroglicerina/farmacología , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Masculino , Femenino , Ratones , Hiperalgesia/fisiopatología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones Endogámicos C57BL , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/fisiopatología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Proteínas de Unión al Calcio/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Emociones/fisiología , Emociones/efectos de los fármacos , Proteínas de Microfilamentos/metabolismo , Vasodilatadores/farmacología , Enfermedad Crónica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Núcleo Caudal del Trigémino/efectos de los fármacos , Núcleo Caudal del Trigémino/metabolismoRESUMEN
Comparative research suggests that the hypothalamus is critical in switching between survival behaviors, yet it is unclear if this is the case in humans. Here, we investigate the role of the human hypothalamus in survival switching by introducing a paradigm where volunteers switch between hunting and escape in response to encounters with a virtual predator or prey. Given the small size and low tissue contrast of the hypothalamus, we used deep learning-based segmentation to identify the individual-specific hypothalamus and its subnuclei as well as an imaging sequence optimized for hypothalamic signal acquisition. Across 2 experiments, we employed computational models with identical structures to explain internal movement generation processes associated with hunting and escaping. Despite the shared structure, the models exhibited significantly different parameter values where escaping or hunting were accurately decodable just by computing the parameters of internal movement generation processes. In experiment 2, multi-voxel pattern analyses (MVPA) showed that the hypothalamus, hippocampus, and periaqueductal gray encode switching of survival behaviors while not encoding simple motor switching outside of the survival context. Furthermore, multi-voxel connectivity analyses revealed a network including the hypothalamus as encoding survival switching and how the hypothalamus is connected to other regions in this network. Finally, model-based fMRI analyses showed that a strong hypothalamic multi-voxel pattern of switching is predictive of optimal behavioral coordination after switching, especially when this signal was synchronized with the multi-voxel pattern of switching in the amygdala. Our study is the first to identify the role of the human hypothalamus in switching between survival behaviors and action organization after switching.
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Hipotálamo , Imagen por Resonancia Magnética , Humanos , Hipotálamo/fisiología , Imagen por Resonancia Magnética/métodos , Masculino , Adulto , Femenino , Adulto Joven , Hipocampo/fisiología , Reacción de Fuga/fisiología , Aprendizaje Profundo , Mapeo Encefálico/métodos , Sustancia Gris Periacueductal/fisiologíaRESUMEN
To assess the possible interactions between the dorsolateral periaqueductal gray matter (dlPAG) and the different domains of the nucleus ambiguus (nA), we have examined the pattern of double-staining c-Fos/FoxP2 protein immunoreactivity (c-Fos-ir/FoxP2-ir) and tyrosine hydroxylase (TH) throughout the rostrocaudal extent of nA in spontaneously breathing anaesthetised male Sprague-Dawley rats during dlPAG electrical stimulation. Activation of the dlPAG elicited a selective increase in c-Fos-ir with an ipsilateral predominance in the somatas of the loose (p < 0.05) and compact formation (p < 0.01) within the nA and confirmed the expression of FoxP2 bilaterally in all the domains within the nA. A second group of experiments was made to examine the importance of the dlPAG in modulating the laryngeal response evoked after electrical or chemical (glutamate) dlPAG stimulations. Both electrical and chemical stimulations evoked a significant decrease in laryngeal resistance (subglottal pressure) (p < 0.001) accompanied with an increase in respiratory rate together with a pressor and tachycardic response. The results of our study contribute to new data on the role of the mesencephalic neuronal circuits in the control mechanisms of subglottic pressure and laryngeal activity.
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Estimulación Eléctrica , Laringe , Sustancia Gris Periacueductal , Proteínas Proto-Oncogénicas c-fos , Ratas Sprague-Dawley , Animales , Masculino , Ratas , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/fisiología , Estimulación Eléctrica/métodos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Laringe/fisiología , Laringe/metabolismo , Factores de Transcripción Forkhead/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Presión , Bulbo Raquídeo/metabolismo , Bulbo Raquídeo/fisiología , Ácido Glutámico/metabolismoRESUMEN
Escape behavior is a set of locomotor actions that move an animal away from threat. While these actions can be stereotyped, it is advantageous for survival that they are flexible.1,2,3 For example, escape probability depends on predation risk and competing motivations,4,5,6,7,8,9,10,11 and flight to safety requires continuous adjustments of trajectory and must terminate at the appropriate place and time.12,13,14,15,16 This degree of flexibility suggests that modulatory components, like inhibitory networks, act on the neural circuits controlling instinctive escape.17,18,19,20,21,22 In mice, the decision to escape from imminent threats is implemented by a feedforward circuit in the midbrain, where excitatory vesicular glutamate transporter 2-positive (VGluT2+) neurons in the dorsal periaqueductal gray (dPAG) compute escape initiation and escape vigor.23,24,25 Here we tested the hypothesis that local GABAergic neurons within the dPAG control escape behavior by setting the excitability of the dPAG escape network. Using in vitro patch-clamp and in vivo neural activity recordings, we found that vesicular GABA transporter-positive (VGAT+) dPAG neurons fire action potentials tonically in the absence of synaptic inputs and are a major source of inhibition to VGluT2+ dPAG neurons. Activity in VGAT+ dPAG cells transiently decreases at escape onset and increases during escape, peaking at escape termination. Optogenetically increasing or decreasing VGAT+ dPAG activity changes the probability of escape when the stimulation is delivered at threat onset and the duration of escape when delivered after escape initiation. We conclude that the activity of tonically firing VGAT+ dPAG neurons sets a threshold for escape initiation and controls the execution of the flight action.
Asunto(s)
Reacción de Fuga , Neuronas GABAérgicas , Sustancia Gris Periacueductal , Animales , Sustancia Gris Periacueductal/fisiología , Sustancia Gris Periacueductal/metabolismo , Ratones , Reacción de Fuga/fisiología , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismo , Masculino , Ratones Endogámicos C57BL , FemeninoRESUMEN
BACKGROUND: The periaqueductal gray (PAG) plays a well-established pivotal role in the descending pain modulatory circuit. The objective of this study was to investigate morphological changes in the astroglia in models that are commonly used in pain and itch studies. METHODS: Five different mouse models of pain, as well as two models of chronic itch, were established using complete Freund's adjuvant (CFA), spared nerve injury (SNI), bone cancer pain (BCP), cisplatin (CIS), and paclitaxel (PTX) for pain, and diphenylcyclopropenone (DCP) and acetone and diethyl ether followed by water (AEW) for chronic itch. von Frey tests and video recordings were employed to assess pain and itching behaviors. The immunofluorescence of S100ß, pSTAT3, and glial fibrillary acidic protein (GFAP) was examined. Two- and three-dimensional studies were used to evaluate changes in astrocyte morphology. RESULTS: Significant scratching was caused by DCP and AEW, whereas the administration of CFA, SNI, BCP, CIS, and PTX produced clear mechanical allodynia. The expression of GFAP in the lPAG/vlPAG was upregulated in CFA, SNI, BCP, CIS, PTX, and DCP mice but decreased in AEW mice. According to Sholl analysis, CFA, SNI, PTX, and BCP mice showed substantially higher astrocyte intersections in the vlPAG, whereas CFA, SNI, BCP, CIS, and DCP mice presented longer peak lengths. In three-dimensional analysis, CFA, SNI, PTX, and DCP mice showed increased astrocyte surface areas, while CIS and AEW mice showed both reduced surface areas and/or volumes of astrocytes. CONCLUSION: The findings showed that different pain and itching conditions have different astrocyte morphologies, and these variations in morphological changes help to explain the pathophysiology of these conditions.
Asunto(s)
Astrocitos , Modelos Animales de Enfermedad , Dolor , Sustancia Gris Periacueductal , Prurito , Animales , Astrocitos/patología , Astrocitos/metabolismo , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/patología , Prurito/patología , Prurito/fisiopatología , Masculino , Dolor/patología , Dolor/fisiopatología , Dolor/metabolismo , Ratones , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones Endogámicos C57BL , Hiperalgesia/patología , Hiperalgesia/fisiopatologíaRESUMEN
Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.
Asunto(s)
Acetaminofén , Analgésicos , Ácidos Araquidónicos , Sustancia Gris Periacueductal , Transcriptoma , Animales , Masculino , Ratones , Acetaminofén/efectos adversos , Amidohidrolasas/metabolismo , Amidohidrolasas/genética , Analgésicos/farmacología , Ácidos Araquidónicos/farmacología , Benzoquinonas/farmacología , Glicéridos , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacosRESUMEN
The neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in male mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naïve mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to height threats through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG.
Asunto(s)
Miedo , Cuerpos Geniculados , Ratones Endogámicos C57BL , Colículos Superiores , Vías Visuales , Animales , Masculino , Miedo/fisiología , Ratones , Cuerpos Geniculados/fisiología , Colículos Superiores/fisiología , Vías Visuales/fisiología , Sustancia Gris Periacueductal/fisiología , Neuronas/fisiología , Corteza Visual Primaria/fisiología , Percepción Visual/fisiología , Conducta Animal/fisiologíaRESUMEN
The olfactory tubercle (TUB), also called the tubular striatum, receives direct input from the olfactory bulb and, along with the nucleus accumbens, is one of the two principal components of the ventral striatum. As a key component of the reward system, the ventral striatum is involved in feeding behavior, but the vast majority of research on this structure has focused on the nucleus accumbens, leaving the TUB's role in feeding behavior understudied. Given the importance of olfaction in food seeking and consumption, olfactory input to the striatum should be an important contributor to motivated feeding behavior. Yet the TUB is vastly understudied in humans, with very little understanding of its structural organization and connectivity. In this study, we analyzed macrostructural variations between the TUB and the whole brain and explored the relationship between TUB structural pathways and feeding behavior, using body mass index (BMI) as a proxy in females and males. We identified a unique structural covariance between the TUB and the periaqueductal gray (PAG), which has recently been implicated in the suppression of feeding. We further show that the integrity of the white matter tract between the two regions is negatively correlated with BMI. Our findings highlight a potential role for the TUB-PAG pathway in the regulation of feeding behavior in humans.