RESUMEN
BACKGROUND: HIV is a neurotropic virus, and it can bring about neurodegeneration and may even result in cognitive impairments. The precise mechanism of HIV-associated white matter (WM) injury is unknown. The effects of multiple clinical contributors on WM impairments and the relationship between the WM alterations and cognitive performance merit further investigation. METHODS: Diffusion tensor imaging (DTI) was performed in 20 antiretroviral-naïve HIV-positive asymptomatic neurocognitive impairment (ANI) adults and 20 healthy volunteers. Whole-brain analysis of DTI metrics between groups was conducted by employing tract-based spatial statistics (TBSS), including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). DTI parameters were correlated with clinical variables (age, CD4+ cell count, CD4+/CD8+ ratio, plasma viral load and duration of HIV infection) and multiple cognitive tests by using multilinear regression analyses. RESULTS: DTI quantified diffusion alterations in the corpus callosum and corona radiata (MD increased significantly, P < 0.05) and chronic axonal injury in the corpus callosum, corona radiata, internal capsule, external capsule, posterior thalamic radiation, sagittal stratum, and superior longitudinal fasciculus (AD increased significantly, P < 0.05). The impairments in the corona radiata had significant correlations with the current CD4+/CD8+ ratios. Increased MD or AD values in multiple white matter structures showed significant associations with many cognitive domain tests. CONCLUSIONS: WM impairments are present in neurologically asymptomatic HIV+ adults, periventricular WM (corpus callosum and corona radiata) are preferential occult injuries, which is associated with axonal chronic damage rather than demyelination. Axonopathy may exist before myelin injury. DTI-TBSS is helpful to explore the WM microstructure abnormalities and provide a new perspective for the investigation of the pathomechanism of HIV-associated WM injury.
Asunto(s)
Axones/fisiología , Disfunción Cognitiva , Infecciones por VIH , Adulto , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Infecciones por VIH/fisiopatología , HumanosRESUMEN
The formation of mate recognition memory in mice is associated with neural changes at the reciprocal dendrodendritic synapses between glutamatergic mitral cell (MC) projection neurons and GABAergic granule cell (GC) interneurons in the accessory olfactory bulb (AOB). Although noradrenaline (NA) plays a critical role in the formation of the memory, the mechanism by which it exerts this effect remains unclear. Here we used extracellular field potential and whole-cell patch-clamp recordings to assess the actions of bath-applied NA (10 µM) on the glutamatergic transmission and its plasticity at the MC-to-GC synapse in the AOB. Stimulation (400 stimuli) of MC axons at 10 Hz but not at 100 Hz effectively induced N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation (LTP), which exhibited reversibility. NA paired with subthreshold 10-Hz stimulation (200 stimuli) facilitated the induction of NMDA receptor-dependent LTP via the activation of α2-adrenergic receptors (ARs). We next examined how NA, acting at α2-ARs, facilitates LTP induction. In terms of acute actions, NA suppressed GC excitatory postsynaptic current (EPSC) responses to single pulse stimulation of MC axons by reducing glutamate release from MCs via G-protein coupled inhibition of calcium channels. Consequently, NA reduced recurrent inhibition of MCs, resulting in the enhancement of evoked EPSCs and spike fidelity in GCs during the 10-Hz stimulation used to induce LTP. These results suggest that NA, acting at α2-ARs, facilitates the induction of NMDA receptor-dependent LTP at the MC-to-GC synapse by shifting its threshold through disinhibition of MCs.
Asunto(s)
Potenciación a Largo Plazo , Neuronas/fisiología , Bulbo Olfatorio/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Sinapsis/fisiología , Potenciales de Acción , Animales , Potenciales Postsinápticos Excitadores , Ácido Glutámico/metabolismo , Interneuronas/fisiología , Ratones Endogámicos BALB C , Receptores de N-Metil-D-Aspartato/fisiología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The repertoire of approximately 1200 odorant receptors (ORs) is mapped onto the array of approximately 1800 glomeruli in the mouse olfactory bulb (OB). The spatial organization of this array is influenced by the ORs. Here we show that glomerular mapping to broad domains in the dorsal OB is determined by two types of olfactory sensory neurons (OSNs), which reside in the dorsal olfactory epithelium. The OSN types express either class I or class II OR genes. Axons from the two OSN types segregate already within the olfactory nerve and form distinct domains of glomeruli in the OB. These class-specific anatomical domains correlate with known functional odorant response domains. However, axonal segregation and domain formation are not determined by the class of the expressed OR protein. Thus, the two OSN types are determinants of axonal wiring, operate at a higher level than ORs, and contribute to the functional organization of the glomerular array.
Asunto(s)
Axones/metabolismo , Neurópilo/metabolismo , Bulbo Olfatorio/metabolismo , Nervio Olfatorio/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Receptores Odorantes/genética , Animales , Axones/ultraestructura , Biomarcadores/análisis , Tipificación del Cuerpo/genética , Mapeo Encefálico , Codón/genética , Regulación del Desarrollo de la Expresión Génica/genética , Conos de Crecimiento/metabolismo , Conos de Crecimiento/ultraestructura , Ratones , Ratones Transgénicos , Neurópilo/ultraestructura , Bulbo Olfatorio/ultraestructura , Nervio Olfatorio/citología , Vías Olfatorias/fisiología , Neuronas Receptoras Olfatorias/citología , Receptores Odorantes/clasificación , Olfato/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
In comparison with many mammals, there is limited knowledge of the role of pheromones in conspecific communication in the gray short-tailed opossum. Here we report that mitral/tufted (M/T) cells of the accessory olfactory bulb (AOB) of male opossums responded to female urine but not to male urine with two distinct patterns: excitation followed by inhibition or inhibition. Either pattern could be mimicked by application of guanosine 5'-O-3-thiotriphosphate and blocked by guanosine 5'-O-2-thiodiphosphate, indicating that the response of neurons in this pathway is through a G-protein-coupled receptor mechanism. In addition, the inhibitor of phospholipase C (PLC), U73122, significantly blocked urine-induced responses. Male and female urine were ineffective as stimuli for M/T cells in the AOB of female opossums. These results indicate that urine of diestrous females contains a pheromone that directly stimulates vomeronasal neurons through activation of PLC by G-protein-coupled receptor mechanisms and that the response to urine is sexually dimorphic.
Asunto(s)
Bulbo Olfatorio/fisiología , Zarigüeyas/fisiología , Orina , Órgano Vomeronasal/fisiología , Animales , Inhibidores Enzimáticos/farmacología , Estrenos/farmacología , Femenino , Masculino , Microelectrodos , Pirrolidinonas/farmacología , Fosfolipasas de Tipo C/antagonistas & inhibidoresRESUMEN
The vomeronasal organ (VNO) is important for activating accessory olfactory pathways that are involved in sexually dimorphic mating behavior. The VNO of male garter snakes is critically important for detection of, and response to, female sex pheromones. In the present study, under voltage-clamp conditions, male snake VNO neurons were stimulated with female sexual attractiveness pheromone. Thirty-nine of 139 neurons exhibited inward current responses (reversal potential: -10.6 +/- 2.8 mV). The amplitude of the inward current was dose dependent, and the relationship could be fitted by the Hill equation. Under current-clamp conditions, application of pheromone produced membrane depolarizing responses and increases in firing frequency. These results suggest that the female pheromone directly affects male snake VNO neurons and results in opening of ion channels, thereby converting the pheromone signal to an electrical signal. The response to female pheromone is sexually dimorphic, that is, the pheromone does not evoke responses in VNO neurons of female snakes. An associated finding of the present study is that the female sex pheromone, which is insoluble in aqueous solutions, became soluble in the presence of Harderian gland homogenate.
Asunto(s)
Membrana Celular/efectos de los fármacos , Colubridae , Neuronas Receptoras Olfatorias/efectos de los fármacos , Feromonas/farmacología , Órgano Vomeronasal/efectos de los fármacos , Animales , Electrofisiología , Femenino , Masculino , Técnicas de Placa-ClampRESUMEN
After training with an odour paired with foot shock on postnatal day 11, rat pups show an aversion to the odour in testing on postnatal day 12. The mechanisms underlying this aversive olfactory learning involve disinhibition of mitral/tufted cells in the olfactory bulb by the somatosensory stimulation-induced activation of centrifugal noradrenergic fibres originating in the locus coeruleus. The activity of mitral/tufted cells is regulated through gamma-aminobutyric acidA (GABA(A)) receptors in the external plexiform layer and GABA(B) receptors in the glomerular layer. We have previously presented that aversive olfactory learning in young rats is modulated through GABA(A) receptors in the olfactory bulb. In the present study we examined the consequence of manipulating GABA(B) receptors in the olfactory bulb during training. Baclofen, a GABA(B) receptor agonist when infused into the olfactory bulb during the pairing of an odour with foot shock, prevented aversive olfactory learning in a dose-dependent manner. Infusion of saclofen, a GABA(B) receptor antagonist, during training with a citral odour in the absence of foot shock produced aversive responses not only to the odour, but also to strange odours (benzaldehyde and vanillin) not previously presented. Such olfactory aversions were observed even if saclofen was infused without odour exposure. These results suggest that olfactory learning in young rats is modulated through GABA(B) receptors in the olfactory bulb.