In the present study, we used an innovative music-rest interleaved fMRI paradigm to investigate the neural correlates of tinnitus distress. Tinnitus is a poorly-understood hearing disorder where individuals perceive sounds, in the absence of an external source. Although the great majority of individuals habituate to chronic tinnitus and report few symptoms, a minority report debilitating distress and annoyance. Prior research suggests that a diverse set of brain regions, including the attention, the salience, and the limbic networks, play key roles in mediating both the perception of tinnitus and its impact on the individual; however, evidence of the degree and extent of their involvement has been inconsistent. Here, we minimally modified the conventional resting state fMRI by interleaving it with segments of jazz music. We found that the functional connectivity between a set of brain regions-including cerebellum, precuneus, superior/middle frontal gyrus, and primary visual cortex-and seeds in the dorsal attention network, the salience network, and the amygdala, were effective in fractionating the tinnitus patients into two subgroups, characterized by the severity of tinnitus-related distress.  https://www.selleckchem.com/products/loxo-195.html  Further, our findings revealed cross-modal modulation of the attention and salience networks by the visual modality during the music segments. On average, the more bothersome the reported tinnitus, the stronger was the exhibited inter-network functional connectivity. This study substantiates the essential role of the attention, salience, and limbic networks in tinnitus habituation, and suggests modulation of the attention and salience networks across the auditory and visual modalities as a possible compensatory mechanism for bothersome tinnitus.Alzheimer's disease (AD) is the leading form of dementia but lacks curative treatments. Current understanding of AD aetiology attributes the development of the disease to the misfolding of two proteins; amyloid-β (Aβ) and hyperphosphorylated tau, with their pathological accumulation leading to concomitant oxidative stress, neuroinflammation, and neuronal death. These processes are regulated at multiple levels to maintain homeostasis and avert disease. However, many of the relevant regulatory proteins appear to be downregulated in the AD-afflicted brain. Enhancement/restoration of these 'protective' proteins, therefore, represents an attractive therapeutic avenue. Gene therapy is a desirable means of achieving this because it is not associated with the side-effects linked to systemic protein administration, and sustained protein expression virtually eliminates compliance issues. The current article represents a focused and succinct review of the better established 'protective' protein targets for gene therapy enhancement/restoration rather than being designed as an exhaustive review incorporating less validated protein subjects. In addition, we will discuss how the risks associated with uncontrolled or irreversible gene expression might be mitigated through combining neuronal-specific promoters, inducible expression systems and localised injections. Whilst many of the gene therapy targets reviewed herein are yet to enter clinical trials, preclinical testing has thus far demonstrated encouraging potential for the gene therapy-based treatment of AD.Endoplasmic reticulum (ER) triggers the regional specific astroglial responses to status epilepticus (SE, a prolonged seizure activity). However, the epiphenomena/downstream effecters for ER stress and the mechanism of ER stress signaling in astroglial apoptosis have not been fully understood. In the present study, tunicamycin-induced ER stress resulted in reactive astrogliosis-like events showing astroglial hypertrophy with the elevated extracellular signal-activated protein kinase 1/2 (ERK1/2) and cyclin-dependent kinase 5 (CDK5) phosphorylations in the CA1 region of the rat hippocampus. However, tunicamycin increased CDK5, but not ERK1/2, phosphorylation in the molecular layer of the dentate gyrus. Roscovitine (a CDK5 inhibitor) suppressed the effect of tunicamycin in the molecular layer of the dentate gyrus and the CA1 region, while U0126 (an ERK1/2 inhibitor) reversed it in the CA1 region. Salubrinal (an ER stress inhibitor) abrogated activations of ERK1/2 and CDK5, and attenuated reactive astrogliosis in the CA1 region and astroglial apoptosis in the molecular layer of the dentate gyrus following status epilepticus (SE, a prolonged seizure activity). These findings indicate that ER stress may induce reactive astrogliosis via ERK1/2-mediated CDK5 activation in the CA1 region. In the molecular layer of the dentate gyrus, however, ER stress may participate in astroglial apoptosis through ERK1/2-independent CDK5 activation following SE.Intrinsic properties of neurons are one major determinant for how neurons respond to their synaptic inputs and shape their outputs in neural circuits. Here, we studied the intrinsic properties of neurons in the chicken posterior portion of the dorsal nucleus of the lateral lemniscus (LLDp), the first interaural level difference (ILD) encoder of the avian auditory pathway. Using whole-cell recordings in brain slices, we revealed that the LLDp is composed of a heterogeneous neuron population based on their firing patterns. LLDp neurons were broadly classified as either phasic or tonic firing neurons, with further classification applied to tonic firing neurons, such as regular (most dominant, n = 82 out of 125 cells, 65.6%), pauser, or adaptive firing. Neurons with different firing patterns were distributed about evenly across the dorsoventral as well as mediolateral axis of LLDp. Phasic firing neurons were of faster membrane time constant, and lower excitability than tonic firing neurons. The action potentials (APs) elicited at the current thresholds displayed significant differences in first spike latency, AP peak amplitude, half-width, and maximal rising and falling rates. Interestingly, for APs elicited at suprathreshold currents (400 pA above thresholds), some of the differences diminished while a few others emerged. Remarkably, most parameters of the APs at thresholds were significantly different from those of APs at suprathresholds. Combined with our previous study (Curry and Lu, 2016), the results lend support to the two-cell type model for ILD coding in the avian system.