Salient cues can prompt the rapid interruption of planned actions. It has been proposed that fast, reactive behavioral inhibition involves specific basal ganglia pathways, and we tested this by comparing activity in multiple rat basal ganglia structures during performance of a stop-signal task. Subthalamic nucleus (STN) neurons showed low-latency responses to Stop cues, irrespective of whether actions were successfully canceled or not. By contrast, neurons downstream in the substantia nigra pars reticulata (SNr) responded to Stop cues only in trials with successful cancellation. Recordings and simulations together indicate that this sensorimotor gating arises from the relative timing of two distinct inputs to neurons in the SNr dorsolateral “core” subregion: cue-related excitation from STN and movement-related inhibition from striatum. Our results support race models of action cancellation, with successful stopping requiring Stop cue information to be transmitted from STN to SNr before increased striatal input creates a point of no return.

The suppression of inappropriate actions is critical for flexible behavior. Cortical-basal ganglia networks provide key gating mechanisms for action suppression, yet the specific roles of neuronal subpopulations are poorly understood. Here, we examine Arkypallidal (“Arky”) and Prototypical (“Proto”) globus pallidus neurons during a Stop task, which requires abrupt cancellation of an imminent action. We first establish that Arky neurons can be identified by their firing properties across the natural sleep/wake cycle. We then show that Stop responses are earlier and stronger in the Arky, compared to the Proto, subpopulation. In contrast to other basal ganglia neurons, pallidal Stop responses are selective to Stop, rather than Go, cues. Furthermore, the timing of these Stop responses matches the suppression of developing striatal Go-related activity. Our results support a two-step model of action suppression: actions-in-preparation are first paused via a subthalamic-nigral pathway, then cancelled via Arky GABAergic projections to striatum.

The enzyme ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is one of the most abundant proteins in the mammalian nervous system. In humans, UCH-L1 is also found in the ubiquitinated inclusion bodies that characterize neurodegenerative diseases in the brain, suggesting its involvement in neurodegeneration. The physiologic role of UCH-L1 in neurons, however, remains to be further elucidated. For example, previous studies have provided evidence both for and against the role of UCH-L1 in synaptic function in the brain. Here, we have characterized a line of knockout mice deficient in the UCH-L1 gene. We found that, in the absence of UCH-L1, synaptic transmission at the neuromuscular junctions (NMJs) is markedly impaired. Both spontaneous and evoked synaptic activity are reduced; paired pulse-facilitation is impaired, and synaptic transmission fails to respond to high-frequency, repetitive stimulation at the NMJs of UCH-L1 knockout mice. Morphologic analyses of the NMJs further revealed profound structural defects-loss of synaptic vesicles and accumulation of tubulovesicular structures at the presynaptic nerve terminals, and denervation of the muscles in UCH-L1 knockout mice. These findings demonstrate that UCH-L1 is required for the maintenance of the structure and function of the NMJ and that the loss of normal UCH-L1 activity may result in neurodegeneration in the peripheral nervous system. electrophysiology | knockout mice | neurodegeneration | synaptic transmission

Developing skeletal myofibers in vertebrates are intrinsically “pre-patterned” for motor nerve innervation. However, the intrinsic factors that regulate muscle pre-patterning remain unknown. Here we show that a functional skeletal muscle dihydropyridine receptor (DHPR, the L-type Ca2+ channel in muscle) is required for muscle pre-patterning during the development of the neuromuscular junction (NMJ). Targeted deletion of the β1 subunit of DHPR (Cacnb1) in mice leads to muscle pre-patterning defects, aberrant innervation and precocious maturation of the NMJ. Reintroducing the Cacnb1 gene into Cacnb1−/− muscles reverses the pre-patterning defects and restores normal development of the NMJ. The mechanism by which DHPRs govern muscle pre-patterning is independent of their role in excitation-contraction coupling (E-C coupling), but requires Ca2+ influx through the L-type Ca2+ channel. Our findings demonstrate that the skeletal muscle DHPR retrogradely regulates the patterning and formation of the NMJ.

The aqueous MeOH extract of the leaves and root of Xanthocercis zambesiaca (Leguminosae) and eight structurally related nitrogen-containing sugars, fagomine (1), 4-O-beta-D-glucopyranosylfagomine (2), 3-O-beta-D-glucopyranosylfagomine (3), 3-epifagomine (4), 2,5-dideoxy-2,5-imino-D-mannitol (5), castanospermine (6), alpha-homonojirimycin (7), and 1-deoxynojirimycin (8) were evaluated for antihyperglycemic effects in streptozotocin (STZ)-diabetic mice. The insulin-releasing effects of 1 were also investigated. The blood glucose level fell after i.p. injection of the extract (50 mg/kg). Compounds 1, 2, 5, and 6 reduced the blood glucose level after i.p. injection of 150 mumol/kg. Compound 1 increased plasma insulin level in STZ-diabetic mice and potentiated the 8.3-mM glucose-induced insulin release from the rat isolated-perfused pancreas. The 1-induced potentiation of insulin release may partly contribute to antihyperglycemic action.

No abstract

Many chronic neuroscience studies require neural probes that can reliably record with a large number of electrodes in a densely configured array. Previous works have shown that adverse tissue reaction can be significantly reduced as probe shanks are scaled down toward subcellular dimensions. In addition, flexible probes can mitigate shear stress-induced tissue damage due to micromotion. However, both size reduction and flexibility compromise probe's ability to penetrate the pia mater, especially when many electrodes are distributed across multiple probe shanks. In this paper, we present a method to lithographically pattern a biodegradable silk coating that provides temporary mechanical stiffness for the surgical insertion of flexible probes without any conventional design constraints on the probe size, shape, or material. After insertion, the silk is completely dissolved in the tissue, only leaving the flexible minimum-geometry probes inside the brain. We validated the design by successfully inserting silk-backed 64-channel parylene probes into the motor cortex of Long-Evans rats (n = 6) and recorded in vivo neural activity for six weeks.[2014-0249]

Alzheimer's disease (AD) is pathologically characterized by deposition of β-amyloid (Aβ) peptides, which closely correlates with the balance of nerve growth factor (NGF)-related TrkA/p75NTR signaling. (−)-Epigallocatechin-3-gallate (EGCG) is used for prevention and treatment of many neurodegenerative diseases, including AD. However, whether the neuroprotective effects of EGCG treatment were via modulating the balance of TrkA/p75NTR signaling was still unknown. In this study, we found that EGCG treatment (2 mg · kg –1 · day –1) dramatically ameliorated the cognitive impairments, reduced the overexpressions of Aβ(1–40) and amyloid precursor protein (APP), and inhibited the neuronal apoptosis in the APP/PS1 mice. Interestingly, the EGCG treatment enhanced the relative expression level of NGF by increasing the NGF/proNGF ratio in the APP/PS1 mice. Moreover, after EGCG treatment, TrkA signaling was activated by increasing the phosphorylation of TrkA following the increased phosphorylation of c-Raf, ERK1/2, and cAMP response element-binding protein (CREB), simultaneously the p75NTR signaling was significantly inhibited by decreasing the p75ICD expression, JNK2 phosphorylation, and cleaved-caspase 3 expression, so that the Aβ deposits and neuronal apoptosis in the hippocampus were inhibited.