RESUMEN
BACKGROUND: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. OBJECTIVE: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). METHODS: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. RESULTS: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. CONCLUSION: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.
Asunto(s)
Potenciales Evocados Visuales , Radiocirugia , Animales , Encéfalo , Radiación Ionizante , Radiocirugia/métodos , Porcinos , Porcinos EnanosRESUMEN
Human trace amine-associated receptor subtype 1 (hTAAR1) is a G protein-coupled receptor that has therapeutic potential for multiple diseases, including schizophrenia, drug addiction, and Parkinson's disease (PD). Although several potent agonists have been identified and have shown positive results in various clinical trials for schizophrenia, the discovery of potent hTAAR1 antagonists remains elusive. Herein, we report the results of structure-activity relationship studies that have led to the discovery of a potent hTAAR1 antagonist (RTI-7470-44, 34). RTI-7470-44 exhibited an IC50 of 8.4 nM in an in vitro cAMP functional assay, a Ki of 0.3 nM in a radioligand binding assay, and showed species selectivity for hTAAR1 over the rat and mouse orthologues. RTI-7470-44 displayed good blood-brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. Finally, RTI-7470-44 increased the spontaneous firing rate of mouse VTA dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. Collectively, this work provides a promising hTAAR1 antagonist probe that can be used to study TAAR1 pharmacology and the potential therapeutic role in hypodopaminergic diseases such as PD.
Asunto(s)
Neuronas Dopaminérgicas , Receptores Acoplados a Proteínas G , Animales , Neuronas Dopaminérgicas/metabolismo , Humanos , Ratones , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
Tinnitus, sound perception in the absence of physical stimuli, occurs in 15% of the population and is the top-reported disability for soldiers after combat. Noise overexposure is a major factor associated with tinnitus but does not always lead to tinnitus. Furthermore, people with normal audiograms can get tinnitus. In animal models, equivalent cochlear damage occurs in animals with and without behavioral evidence of tinnitus. But cochlear-nerve-recipient neurons in the brainstem demonstrate distinct, synchronized spontaneous firing patterns only in animals that develop tinnitus, driving activity in central brain regions and ultimately giving rise to phantom perception. Examining tinnitus-specific changes in single-cell populations enables us to begin to distinguish neural changes due to tinnitus from those that are due to hearing loss.
Asunto(s)
Ruido/efectos adversos , Acúfeno/fisiopatología , Animales , Cóclea/inervación , Cóclea/fisiopatología , Pérdida Auditiva Provocada por Ruido/fisiopatología , Humanos , Acúfeno/etiologíaRESUMEN
Following noise overexposure and tinnitus-induction, fusiform cells of the dorsal cochlear nucleus (DCN) show increased spontaneous firing rates (SFR), increased spontaneous synchrony and altered stimulus-timing-dependent plasticity (StDP), which correlate with behavioral measures of tinnitus. Sodium salicylate, the active ingredient in aspirin, which is commonly used to induce tinnitus, increases SFR and activates NMDA receptors in the ascending auditory pathway. NMDA receptor activation is required for StDP in many brain regions, including the DCN. Blocking NMDA receptors can alter StDP timing rules and decrease synchrony in DCN fusiform cells. Thus, systemic activation of NMDA receptors with sodium salicylate should elicit pathological changes to StDP, thereby increasing SFR and synchrony and induce tinnitus. Herein, we examined the action of salicylate in tinnitus generation in guinea pigs in vivo by measuring tinnitus using two behavioral measures and recording single-unit responses from DCN fusiform cells pre- and post-salicylate administration in the same animals. First, we show that animals administered salicylate show evidence of tinnitus using both behavioral paradigms, cross-validating the tests. Second, fusiform cells in animals with tinnitus showed increased SFR, synchrony and altered StDP timing rules, like animals with noise-induced tinnitus. These findings suggest that alterations to fusiform-cell plasticity are an essential component of tinnitus, regardless of induction technique.
Asunto(s)
Plasticidad de la Célula/fisiología , Núcleo Coclear/fisiopatología , Plasticidad Neuronal/fisiología , Acúfeno/fisiopatología , Animales , Vías Auditivas/efectos de los fármacos , Vías Auditivas/fisiología , Plasticidad de la Célula/efectos de los fármacos , Potenciales Evocados Auditivos/efectos de los fármacos , Potenciales Evocados Auditivos/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Cobayas , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ruido , Salicilato de Sodio/farmacologíaRESUMEN
It is known that hearing loss induces plastic changes in the brain, causing loudness recruitment and hyperacusis, increased spontaneous firing rates and neural synchrony, reorganizations of the cortical tonotopic maps, and tinnitus. Much less in known about the central effects of exposure to sounds that cause a temporary hearing loss, affect the ribbon synapses in the inner hair cells, and cause a loss of high-threshold auditory nerve fibers. In contrast there is a wealth of information about central effects of long-duration sound exposures at levels ≤80 dB SPL that do not even cause a temporary hearing loss. The central effects for these moderate level exposures described in this review include changes in central gain, increased spontaneous firing rates and neural synchrony, and reorganization of the cortical tonotopic map. A putative mechanism is outlined, and the effect of the acoustic environment during the recovery process is illustrated. Parallels are drawn with hearing problems in humans with long-duration exposures to occupational noise but with clinical normal hearing.
Asunto(s)
Corteza Auditiva/fisiopatología , Percepción Auditiva , Cóclea/fisiopatología , Trastornos de la Audición/etiología , Audición , Ruido/efectos adversos , Estimulación Acústica , Animales , Vías Auditivas/fisiopatología , Umbral Auditivo , Potenciales Evocados Auditivos , Trastornos de la Audición/fisiopatología , Trastornos de la Audición/psicología , Humanos , Medición de Riesgo , Factores de TiempoRESUMEN
Spontaneous neural activity in the auditory nerve fibers and in auditory cortex in healthy animals is discussed with respect to the question: Is spontaneous activity noise or information carrier? The studies reviewed suggest strongly that spontaneous activity is a carrier of information. Subsequently, I review the numerous findings in the impaired auditory system, particularly with reference to noise trauma and tinnitus. Here the common assumption is that tinnitus reflects increased noise in the auditory system that among others affects temporal processing and interferes with the gap-startle reflex, which is frequently used as a behavioral assay for tinnitus. It is, however, more likely that the increased spontaneous activity in tinnitus, firing rate as well as neural synchrony, carries information that shapes the activity of downstream structures, including non-auditory ones, and leading to the tinnitus percept. The main drivers of that process are bursting and synchronous firing, which facilitates transfer of activity across synapses, and allows formation of auditory objects, such as tinnitus.