RESUMO
Rodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans.
Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Reação de Fuga , Adulto , Animais , Medo , Feminino , Reação de Congelamento Cataléptica , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto , Especificidade da EspécieRESUMO
Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.
Assuntos
Neuralgia/sangue , Neuralgia/fisiopatologia , Neurônios/fisiologia , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Supraóptico/citologia , Potenciais de Ação/efeitos dos fármacos , Animais , Colecistocinina/farmacologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Inflamação/induzido quimicamente , Inflamação/complicações , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Ocitocina/sangue , Ocitocina/genética , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Medula Espinal/citologia , Transdução Genética , Vasopressinas/genética , Vasopressinas/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
Temperature sensing is a crucial feature of the nervous system, enabling organisms to avoid physical danger and choose optimal environments for survival. TRPM8 (Transient Receptor Potential Melastatin type 8) belongs to a select group of ion channels which are gated by changes in temperature, are expressed in sensory nerves and/or skin cells and may be involved in temperature sensing. This channel is activated by a moderate decrease in temperature, with a threshold of approximately 25 °C in heterologous expression systems, and by a variety of natural and synthetic compounds, including menthol. While the physiological role of TRPM8 as a transducer of gentle cooling is widely accepted, its involvement in acute noxious cold sensing in healthy tissues is still under debate. Although accumulating evidence indicates that TRPM8 is involved in neuropathic cold allodynia, in some animal models of nerve injury peripheral and central activation of TRPM8 is followed by analgesia. A variety of inflammatory mediators, including bradykinin and prostaglandin E(2), modulate TRPM8 by inhibiting the channel and shifting its activation threshold to colder temperatures, most likely counteracting the analgesic action of TRPM8. While important progress has been made in unraveling the biophysical features of TRPM8, including the revelation of its voltage dependence, the precise mechanism involved in temperature sensing by this channel is still not completely understood. This article will review the current status of knowledge regarding the (patho)physiological role(s) of TRPM8, its modulation by inflammatory mediators, the signaling pathways involved in this regulation, and the biophysical properties of the channel.
